Meningitis & Septicaemia in Children & Adults 2013 Tuesday 5 & Wednesday 6 November 2013 Royal Society of Medicine, London, UK Organised by Meningitis Research Foundation 12 CPD Credits (event 84188)
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Contents Meningitis Research Foundation Conference Meningitis & Septicaemia in Children & Adults 2013 Welcome
Day one morning sessions – abstracts
Day one afternoon sessions – abstracts
Novartis satellite breakfast session
Day two morning sessions – abstracts
Day two afternoon sessions – abstracts
Chair & Speaker Biographies
Sponsors & Exhibitors
Introducing Meningitis Research Foundation Meningitis Research Foundation marks 25 years at the forefront of meningitis and septicaemia campaigning in 2014. A registered charity, we have offices and staff in the UK, Ireland, Scotland and Malawi and links to medical and scientific professionals across the world. We have a vision of a world free from meningitis and septicaemia and have invested over £17m in vital research and studies to speed up diagnosis, improve treatment and ultimately to prevent the diseases. We also spend around £1m a year supporting families and individuals already affected by the diseases and on supplying free symptom information and professionally endorsed treatment algorithms and guides to members of the public and health professionals.
Our Freefone helpline is available 365 days a year, taking hundreds of calls each month, while our website www.meningitis.org - provides detailed information and support for all. We depend on you - our friends and colleagues - to keep us on track; fighting the right causes, backing the best research projects and providing timely information for a wide range of audiences. If you, your friends, family and colleagues are inspired to help, please do get in touch. We value your support.
Front cover: Patron Paralympic Gold medallist Jonnie Peacock with Junior Ambassador Sofia Crockatt; a Health Surveillance Assistant triaging at Zingwangwa primary health clinic, in Blantyre; MRF member visit to University of Leicester research project. Back cover: Members at Pushing the Boundaries: Life beyond childhood limb loss at Alder Hey, Liverpool; Amputee Robbie Jones at No.10 with our MenB petition; Raising awareness in Malawi with a young member of Balaka Radio Listening Club.
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Meningitis & Septicaemia in Children & Adults 2013
Welcome I am delighted to welcome you to Meningitis Research Foundation’s 2013 conference – Meningitis and Septicaemia in Children and Adults – our ninth international conference. This year’s event takes place against an unprecedented backdrop. A new vaccine against serogroup B meningococcal disease was licensed earlier in the year by the European Commission. Since then it has been under consideration by the JCVI for inclusion, or otherwise, into the UK’s national immunisation programme. We are still not clear about its future. This is understandably a cause of great concern to our 15,500 members and supporters, many of whom are living with either bereavement from, or the sequelae of, MenB. The session in the conference on MenB will shed light on the complex issues involved. I would like to thank our eminent Steering Committee for putting together such a highquality programme. Over the two days we will be examining clinical management from the perspective of various disciplines, and looking at current successes in vaccination and possibilities for the future. I hope these two days will provide an opportunity for sharing state-ofthe-art knowledge on topics of global interest, and for forging new collaborations. It is my great pleasure to welcome our expert speakers from the UK and overseas. In addition to the invited programme of talks we have had an excellent response to our call for posters, with over 50 submissions this year, and I encourage all of you to visit these posters, which represent a real showcase for talent. For the first time this year, there will be a session in which the best of them are presented to you. At the charity we are working hard towards our vision of a world free from meningitis and septicaemia through research and education, as well as offering support to people affected. We have an active international focus, and the conference includes a session about our current Action Meningitis project in Malawi.
Meningitis Research Foundation was set up nearly 25 years ago by a group of parents whose children had been affected by meningitis and septicaemia. Since then we have awarded 140 research grants at a cost of over £17m, mostly funded by public donation. Much of this funding continues to come from families and communities affected by these diseases, and I would like to pay tribute to them for turning their personal tragedies into a powerful force for change. This year the opening session of the conference includes a presentation by one of our members, Karen Crockatt, whose daughter Sofia lost a leg in 2007. I am grateful to our sponsors who have supported the event. They are represented here and I hope you will take the opportunity to visit their stands and talk to them. On the charity’s own stand you will find a variety of resources for health professionals together with public education materials. I would also like to thank the session chairs for their help, and my colleagues for their hard work in organising the event. Finally I thank you, the delegates, for working to prevent and treat these deadly diseases as effectively as possible. I hope you find Meningitis Research Foundation’s 2013 conference both informative and enjoyable.
Christopher Head Chief Executive
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Useful Information If you have any queries during the Conference, please contact a member of the Meningitis Research Foundation (MRF) team. You can identify them by their yellow badges. The Conference occupies three main areas in the Royal Society of Medicine (RSM): the Max Rayne Atrium (Atrium), The Cavendish Room (Cavendish) and the Guy Whittle Auditorium (Auditorium).
Bulletin board Messages can be left throughout the conference on a special bulletin board at the MRF stand in the Atrium.
Business services Basic services are supplied by the RSM including free faxes and paid-for photocopying. Please inquire at the RSM reception on the ground floor. There is also a laptop and printer available at MRF reception.
Cloakroom The cloakroom is located on the ground floor, next to the main RSM reception. Coats and bags can be stored free of charge. There are also lockers which take £1 coins – refunded when emptied.
Conference evaluations You will find a conference evaluation form in your delegate bag. Please fill in and leave at the MRF reception desk before you leave.
CPD certification The Royal College of Physicians has approved 12 CPD credits (84188) – six per day. You should have enlisted for your CPD certificate at registration. Please make sure your details have been submitted so we can make your certificate available for collection from the MRF registration desk when you leave.
Disabled access There is removable seating in the Auditorium for wheelchairs and a personal hearing system with an RSM receiver and earpiece. Disabled toilets are located on the ground floor, next to the Atrium.
Fire & evacuation procedure If the fire alarm sounds, it will be followed by a PA announcement about the cause. Should an investigation result in an emergency evacuation, a further PA announcement will be made. Proceed quickly and calmly to the nearest fire exit. Escape routes and emergency exits are clearly indicated by the Fire Exit signs. The assembly point is in Cavendish Square. RSM Fire Wardens will give any instructions needed and these must be followed. Do not stop to collect personal possessions and do not use the lifts. Those needing assistance will be helped by MRF staff.
First Aid The RSM has numerous qualified first aiders. If an accident occurs, please alert MRF staff and contact RSM reception on the ground floor.
Internet access Complimentary Wi-Fi access is available throughout the RSM. The access password is available from MRF reception and MRF’s stand in the Atrium.
Lunch & refreshments Both lunches and all refreshments are served in the Atrium and Cavendish room.
Mobile phones, landlines & pagers Please switch off all mobile phones and pagers when you are in the Auditorium. Mobile phones can be used outside the Auditorium and you can re-charge them in the cloakroom. The RSM will not take messages for delegates via its switchboard but there is a public, coin operated telephone in the cloakroom on the ground floor should you need a landline.
Parking There is no parking at the RSM and limited meter parking in the neighbouring streets but there are numerous car parks in the area, including one directly under Cavendish Square.
Our sponsors and exhibitors have stands in the Atrium and Cavendish, together with an MRF stand. You can visit during registration, coffee breaks and lunch on both days and during the Wine Reception on day one.
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Photography MRF staff and a professional photographer will be taking photographs discreetly at some points during the conference. These photographs may be used in multimedia formats to promote future MRF activity. If you do not want to be photographed or have your image used in this manner, please make yourself known to MRF staff.
Conference 2013 Steering Committee Prof Ray Borrow, Public Health England, Vaccine Evaluation Unit, Manchester Prof Ian Feavers, National Institute for Biological Standards and Control
Prof Adam Finn, University of Bristol
Over 50 posters have been submitted and these are displayed in Cavendish. You can visit them during registration, coffee breaks and lunch on both days and during the Wine Reception on day one.
Prof Brian Greenwood, London School of Hygiene and Tropical Medicine
Questions during the conference
Prof Paul Heath, St George’s University of London
Questions will be taken at the discretion of each Chair. Please wait until questions are invited and raise your hand. When you are called please give your name and where you are from. Each delegate seat has a microphone handset. To use the microphone handset hold it as you would a mobile phone. Press the blue button continuously while you are speaking. Remember to release the button when you have finished speaking or the speaker’s microphone won’t work.
Prof Nigel Klein, Great Ormond Street Children’s Hospital and Institute of Child Health, University College London
Dr Mary Ramsay, Public Health England, London
The RSM is a no smoking building. It is not permitted in any part of the building or on the pavements outside.
Prof Christoph Tang, University of Oxford
Linda Glennie, Meningitis Research Foundation
Prof George Griffin, St George’s University of London
Prof David Lalloo, Liverpool School of Tropical Medicine Dr Simon Nadel, St Mary’s Hospital, Imperial College London Prof Andrew Pollard, University of Oxford
Dr Caroline Trotter, University of Cambridge
These are located downstairs, through the Atrium, by the Auditorium. Disabled facilities are available on the ground floor, next to the Atrium.
Voting Should any of the presentations require delegate participation, a voting button is built into the microphone handset in the Auditorium seating.
Wine Reception Everyone is invited to this reception which follows the final presentation on day one. It’s being held in the Atrium and the Cavendish room.
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Programme – Tuesday 5 November 2013 8:00 REGISTRATION & COFFEE 9:10 Welcome Chris Head, CEO,
12:30 Towards global genomic disease surveillance; the Meningitis Research Foundation (MRF) Meningococcus Genome Library and beyond
Meningitis Research Foundation
Burden of illness Chair: Dr Mary Ramsay, Public Health England, London 9:20 Current epidemiology of meningococcal disease in the UK and Europe, including issues for surveillance relating to a MenB vaccine
Dr Shamez Ladhani,
parent’s experience of meningococcal A disease Karen Crockatt, Member and Ambassador of Meningitis Research Foundation
10:05 New studies of QALY loss in patients and carers; family impact of meningitis and septicaemia Dr Hareth Al-Janabi, Health economic evaluation for public health 10:30 decisions involving severe diseases which primarily affect young children – problems and possible solutions Prof Philippe Beutels,
Chair: Prof Paul Heath, St George’s University of London
Dr Ifeanyichukwu Okike, St George’s University of London
14:30 Novartis Group B Streptococcus vaccine programme Dr Karen Slobod, Novartis Global Development, USA
15:00 COFFEE, EXHIBITION & POSTERS
Chair: Prof Brian Greenwood, London School of Hygiene and Tropical Medicine
15:30 Confronting cryptococcal meningitis in Africa St George’s University London
11:00 COFFEE, EXHIBITION & POSTERS
Advances from research: implications for prevention & treatment Chair: Prof Nigel Klein,
15:55 The impact of MenAfriVac on serogroup A invasive meningococcal disease and carriage in Chad Dr Doumagoum Moto Daugla, Centre de Support en Santé Internationale, Chad
Great Ormond Street Children’s Hospital and Institute of Child Health, University College London
11:30 Factor H binding protein and vaccine approaches Prof Christoph Tang, University of
Group B streptococcal infection & neonatal meningitis
Prof Tom Harrison,
University of Antwerp, Belgium
13:00 LUNCH, EXHIBITION & POSTERS
Tackling meningitis in Africa
University of Birmingham
14:00 Neonatal meningitis in the UK
Public Health England, London
Prof Martin Maiden, University of
he emerging picture of host genetic 12:00 T control of susceptibility and outcome in meningococcal disease - evidence from multiple GWAS Prof Michael Levin, St Mary’s Hospital, Imperial College London
16:20 Elimination of meningitis A epidemics in Africa; MenAfriVac future plans
Dr Marie-Pierre Préziosi, Meningitis Vaccine Project (WHO/PATH), Switzerland
16:45 Implementing an mHealth triage intervention for health care workers at primary health centres in urban Blantyre, Malawi – a pilot study
Dr Nicola Desmond, Malawi-Liverpool-Wellcome Clinical Research Programme, Malawi
WINE RECEPTION 17:10 - 18:30
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Programme – Wednesday 6 November 2013 8:00
REGISTRATION & BREAKFAST for day two and satellite session delegates
Novartis satellite breakfast session Chair: Emeritus Prof Richard Moxon, University of Oxford
8:20 Confidence in numbers: the evidence base for assessing the public health impact of vaccines against invasive meningococcal diseases. Dr Jamie Findlow, Public Health England, Manchester; Measuring disease burden and estimating vaccine impact, Dr Simon Nadel, St Mary’s Hospital, London; Challenges to quantifying the severity of meningococcal disease
Poster Presentations Chair Prof David Lalloo, Liverpool School of
13:20 E17 Dr Iain Kennedy, Public Health England, London; V48 Dr John Perez, Pfizer Vaccine Research, Collegeville, PA, USA; E16 Dorothea Hill, University of Oxford; P2 Dr Edmund Loh, University of Oxford, V43 Prof Robert Read, University of Southampton
Award for best poster
Prevention of meningitis & septicaemia
Current issues in clinical management
Chair: Prof Andrew Pollard, University of Oxford 14:00 Current issues with meningococcal vaccine programmes in the Netherlands and the UK
Chair: Prof Robert Heyderman, Malawi-Liverpool-
Dr Mary Ramsay, Public Health England, London
Wellcome Trust Clinical Research Programme
9:20 D ebate on aggressive vs restricted fluid resuscitation in childhood sepsis Prof Michael Levin & Dr David Inwald, St Mary’s Hospital, Imperial College London
10.00 Round up of new developments in clinical management of meningitis or sepsis in paediatric and adult settings
Dr Simon Nadel, St Mary’s Hospital, London
Management of sepsis and meningitis in 10:25 developing countries Dr Louisa Pollock,
Dr Fiona van der Netherlands (RIVM)
Klis, Public Health Institute of
14:30 C arriage studies – what do they add? Human bacterial challenge experiments as an alternative Dr Caroline Trotter, University of Cambridge; Prof Stephen Gordon, Liverpool School of Tropical Medicine
15:05 COFFEE, EXHIBITION & POSTERS
Future prospects for prevention of meningococcal disease Chair: Prof Ian Feavers, National Institute for Biological
Wellcome Trust Tropical Centre, Liverpool
10:50 COFFEE, EXHIBITION & POSTERS
Preventing pneumococcal disease Chair: Prof Ray Borrow, Public Health England Vaccine Evaluation Unit, Manchester
Standards and Control, Potters Bar
15:30 Non-routine use of meningococcal vaccines in outbreaks and for individuals with clinical risk factors
Dr Matthew Snape, University of
11:20 Current epidemiology and summary of vaccines in development; the need for higher-valent and alternative vaccines
16:00 Meningococcal vaccines – have we been asking the wrong questions?
Prof David Goldblatt,
16:30 Immunisation against serogroup B meningococcal disease – hopes and fears Panel discussion moderated by Prof Paul Heath. Panellists: Prof Adam Finn, Dr Simon Nadel, Prof Robert Read, Dr Matthew Snape and Dr Caroline Trotter
Institute of Child Health, London
11:50 Pneumococcal conjugate vaccine implementation in Africa with a focus on Kenya Prof Anthony Scott, London School of and Tropical Medicine
12:20 LUNCH, EXHIBITION & POSTERS
Prof Adam Finn, University of
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Captions: Dr Ed Guccione explaining the MRF research project at the University of Sheffield; Supporter Cathy Fox trekked to Everest.
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Morning – Tuesday 5 November 2013 9:10 Welcome hris Head, CEO, C Meningitis Research Foundation
Burden of illness Chair: Dr Mary Ramsay, Public Health England, London 9:20 Current epidemiology of meningococcal disease in the UK and Europe, including issues for surveillance relating to a MenB vaccine Dr Shamez Ladhani, Public Health England, London Neisseria meningitidis is a major cause of morbidity and mortality worldwide. In the United Kingdom, routine immunisation against meningococcal capsular group C (MenC) since 1999 has meant that most invasive meningococcal infections are now caused by meningococcal capsular group B (MenB). Since the early 2000s, however, the incidence of invasive MenB disease has continued to decline across all age groups – a trend that has been observed across many countries in Europe and elsewhere. In England and Wales, Public Health England (PHE) conducts enhanced national surveillance for invasive meningococcal disease (IMD) through its national meningococcal reference unit (MRU). The provision of a free national PCR testing service by the MRU ensures high case ascertainment across all age groups. From 2006/07 to 2012/13, the number of IMD cases declined from 1132 to 799, while the proportion of MenB cases declined from 88% to 78%. The decline in IMD was observed across all age groups and was most marked in children younger than five years, who remain at highest risk. Overall, however, N. meningitidis remains the single most important cause of childhood bacterial meningitis in England and Wales. In adults, recent increases in capsular group Y (MenY) disease appear to have stabilised. On the other hand, MenW cases increased year-on-year, from 18 cases in 2008 to 46 in 2012. In addition to routine surveillance, PHE routinely assesses the completeness of case ascertainment using a number of different methodologies. In order to better estimate the total burden of meningococcal disease in England, PHE is currently collaborating with the meningitis charities to link multiple national data sources, including the MRU surveillance, electronic reporting of laboratory-confirmed cases, hospitalisation records and death registrations. Preliminary results indicate that, in addition to the ~800 laboratory-confirmed IMD cases annually, a further ~600 hospitalised individuals had a clinical diagnosis of IMD.
Around half of these individuals, however, had been tested PCR-negative for N. meningitidis by the MRU. In summary, despite the declining trends in IMD incidence, N. meningitidis remains a major cause of serious bacterial infections in children and adults. Most cases are due to MenB and young children remain at highest risk. 9:45
parent’s experience of meningococcal A disease Karen Crockatt, Member and Ambassador of Meningitis Research Foundation
In February 2007, at the age of 2, Karen’s daughter Sofia contracted meningococcal meningitis and septicaemia and as a result lost her left leg below the knee and sustained severe damage to her right leg. She is now the first ever MRF Junior Ambassador and recently ran the Mini Great North Run and raised £10,000 for MRF. 10:05 N ew studies of QALY loss in patients and carers; family impact of meningitis and septicaemia
Dr Hareth Al-Janabi, University of
Background: Meningitis frequently results in disabling after-effects for the survivor. We investigated whether these after-effects also had an adverse impact on the health of survivors’ family members. Health (QALY) losses for family members, as well as patients, are relevant in economic evaluations (as used by NICE and other bodies). We therefore examined the implications of the findings for economic analyses of prevention strategies for meningitis. Methods: We conducted a cross-sectional survey with 1600 family members of survivors in the UK. Family members were recruited through Meningitis Research Foundation in May 2012. We generated ‘exposure’ and ‘control’ groups based on whether the family member was close to a survivor who developed after-effects. We measured the impact of after-effects on family members’ health (EQ-5D-5L) scores and analysed the association between family member and survivor health status using multivariable regression modelling. We also examined whether survivor health status affected the health status of multiple family members. Findings: Health scores were significantly lower for family members ‘exposed’ to after-effects, relative to those family members who were not. This finding persisted when examining only those family members close to a survivor of MenB.
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Morning – Tuesday 5 November 2013 Family members exposed to at least one aftereffect from meningitis had 2.3 times higher odds of reporting anxiety and depression. The after-effects of meningitis had an impact on multiple family members, but the impact diminished with social distance from the survivor. Total health losses to the family were projected to be an additional 48% of the health losses to the survivor. Interpretation: Meningitis results in significant health losses for the family as well as the patient. In economic and clinical evaluations focused on population health improvement, the potential health gains to both patients and family members should be considered. 10:30 Health economic evaluation for public health decisions involving severe diseases which primarily affect young children – problems and possible solutions Prof Philippe Beutels, University of Antwerp, Belgium
The standard guiding principle for priority setting in health care is based largely, though not exclusively, on the incremental cost per Quality Adjusted Life Year (QALY) gained of new interventions. This rationale is grounded in the utilitarian theory of justice, which focuses on optimal efficiency irrespective of distributional issues. That is, the focus is on maximising health gains under a budget constraint in the population as a whole, without an a priori concern for the characteristics of the intervention or the individuals enjoying the health gains. When using the QALY as a summary measure of “a healthy life year” in priority setting, some implicit assumptions are made, including: (1) a small QALY decrement for many people (eg, gastroenteritis, acute otitis media) can be as undesirable as a large QALY decrement in few people (eg, meningitis, encephalitis); (2) 1 QALY gained in a child is equal to 1 QALY gained in an elderly person; (3) 1 QALY gained by cure is equal to 1 QALY gained by prevention; (4) a QALY decrement incurred through unhealthy life style choices is equal to the same QALY decrement incurred by chance.
Yet when the general population’s preferences are elicited, they show deviations from these implicit assumptions. For instance, in recent surveys done in Belgium, people believe priority should be given to (1) prevention over cure for severe diseases; (2) prevention over cure for young children; (3) preventing or curing diseases in children, rather than in elderly persons; (4) preventing severe disease in 100 people over preventing non-severe disease in 100,000 people; (5) preventing or curing diseases acquired by chance, rather than those acquired through unhealthy life style choices. The above observations and potential ways of dealing with knowledge about these preferences, only partially embedded in the current approach to prioritisation, will be discussed focusing on infectious disease prevention. Decisions on preventing severe disease in children should take account of additional equity considerations. Further research is needed to document these considerations in different contexts. 11:00 COFFEE, EXHIBITION & POSTERS
Advances from research: implications for prevention & treatment Chair: Prof Nigel Klein, Great Ormond Street Children’s Hospital and Institute of Child Health, University College London
11:30 Factor H binding protein and vaccine approaches Prof Christoph Tang, University of
To cause disease, pathogenic bacteria must avoid detection and elimination by the immune system. Understanding the mechanisms of immune evasion by bacteria is not only informative about the molecular basis of virulence, but can also direct vaccine design and provide clues about why some individuals that become infected develop disease while others remain perfectly well. The meningococcus has evolved several mechanisms that promote resistance against killing by the complement system, an evolutionarily conserved aspect of host immunity. For example, the bacterium expresses a protein at its surface that can recruit a human molecule, named factor H, that switches off the complement system. The implications of this and other mechanisms of complement evasion on the pathogenesis and prevention of meningococcal disease will be discussed.
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Morning – Tuesday 5 November 2013 12:00 The emerging picture of host genetic control of susceptibility and outcome in meningococcal disease - evidence from multiple GWAS Prof Michael Levin, St Mary’s Hospital, Imperial College London Genetic factors are well established as important determinants of both susceptibility and outcome of infectious diseases. With support from MRF an initial genome wide study of meningococcal disease was undertaken, which identified susceptibility genes in the factor H region. With support of both MRF and the EU funded EUCLIDS study, two further genome wide association studies have been undertaken using meningococcal disease patients in Austria, Holland and Spain as well as the UK. The talk will describe ongoing analysis of the three genome wide studies, and their combined metaanalysis to identify the genetic basis of different clinical phenotypes and outcome of meningococcal disease. The importance of genes in regulating important clinical phenotypes such as coagulopathy, acidosis, neutrophil response and need for ventilation will be discussed as well ongoing studies of genes controlling susceptibility.
into the PubMLST.org/Neisseria and Neisseria.org websites, facilitating community access and efficient comparison with other data. Meningococcal isolates are cultured and high-quality chromosomal DNA samples prepared at the PHE-MRU. The samples are sent to the Wellcome Trust Sanger Institute, where the sequence data are generated. The data are automatically downloaded in Oxford, assembled into contiguous sequences and uploaded into the BIGSdb software platform which automatically annotates the genomes at more than 1600 loci and makes the data available via the web. This pipeline has been shown to produce very high quality data efficiently and to date a total of 923 isolates have been completed, with 514 from the epidemiological year 2010-2011 and 409 from 20112012, with the data for 2012-2013 available soon. This provides unparalleled information on the diversity of meningococcal disease isolates in the run-up to possible vaccine implementation. 13:00 LUNCH, EXHIBITION & POSTERS See page 22 for all biographies.
Towards global genomic disease 12:30 surveillance; the Meningitis Research Foundation (MRF) Meningococcus Genome Library and beyond Prof Martin Maiden, University of Oxford The MRF Meningococcus Genome Library is a charity-led initiative to provide high-quality genomic epidemiological data for meningococcal disease in England, Wales and Northern Ireland. Funding has been provided to establish the complete genome sequence data for all meningococcal disease isolates submitted to the Public Health England Meningococcal Reference Unit (PHE-MRU) for the epidemiological years 2010-2011, 2011-2012 and 2012-2013. The goal is to provide open-access data for research and surveillance as an exemplar project. It builds on existing collaborations among the MRF, PHE-MRU (Professor Ray Borrow), the Wellcome Trust Sanger Institute (Professor Julian Parkhill), and the University of Oxford (Professor Martin Maiden). An automated pipeline for genome sequence determination has been established, which generates compiled, annotated sequences which are integrated
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Afternoon – Tuesday 5 November 2013 Group B streptococcal infection & neonatal meningitis Chair: Prof Paul Heath, St George’s University of London
14:00 Neonatal meningitis in the UK Dr Ifeanyichukwu Okike, St George’s University of London
Previous United Kingdom (UK) studies of meningitis in infants were conducted in the 1980s and 1990s. Both showed decline in associated mortality with no change in the neurodevelopment outcome for survivors (50% of infants having some form of disability at 5 years of age). Initiatives such as vaccines against some of the causes (Hib: 1992, MenC: 1999 and PCV: 2006) were introduced in order to reduce the burden of disease in children including neonates. Additionally, the RCOG introduced a guideline for the prevention of early onset group B streptococcal (GBS) infection in 2003. NICE guidelines (feverish illness, 2007 and bacterial meningitis 2010) aimed to improve outcome in children. We undertook a prospective, enhanced populationbased active surveillance study in infants <90 days of age in the UK and Ireland using the British Paediatric Surveillance Unit, routine national microbiological surveillance and by parental reporting of cases via meningitis support charities during July 2010 - July 2011. The overall incidence for UK and Ireland was 0.38/1000 live births (95% CI: 0.35-0.42) and the median age of presentation was 17 days (IQR 4-41 days). The incidence of neonatal (≤ 28 days) bacterial meningitis was 0.21/1000 (0.18-0.24) in England and Wales. The majority [205/324 (63%)] of cases were admitted from home. In neonates 50% of cases were admitted from home. Non-specific clinical features dominated while fever was absent in 153 (47%) of cases at presentation. GBS (150, 50%) was the leading cause followed by Escherichia coli (40, 13%), Streptococcus pneumoniae (28, 9%) Neisseria meningitidis (23, 8%) and Listeria monocytogenes (11, 4%). 90 (27%) of the cases had a poor outcome (died/suffered complications) at the time
of completion of the study questionnaires. Bacterial meningitis in infants <90 days of age remains a significant cause of mortality and morbidity in the UK and Ireland. Despite all the current prevention strategies, the incidence has not changed since the 1980s with GBS remaining the leading pathogen. Our results also show that with the existing initiatives outcome remains unchanged when compared to 16 years ago. It is therefore time to formulate new strategies through better prevention, especially with an effective GBS and other vaccines. One of our ongoing projects is on initiatives with potential for better outcomes through early identification and improved management of cases. Funding for the neoMen project is by Meningitis Research Foundation (MRF). Novartis Group B Streptococcus vaccine 14:30 programme Shabir A. Madhi1, Geert Leroux-Roels2, Anthonet Koen1, Lisa Jose1, Clare Cutland1, Cathy Maes2, Ajoke Ter Meulen3, Frederick Wittke3, Leah Martell3, Karen Slobod3 1
DST/NRF Vaccine Preventable Diseases, University of Witwatersrand, Johannesburg, South Africa; 2Center for Vaccinology, Ghent University and Hospital, Ghent, Belgium;
Novartis Vaccines & Diagnostics, Cambridge MA, USA
Background: GBS is a leading cause of neonatal sepsis and meningitis. No licensed vaccine exists. Two studies were conducted examining safety and immunogenicity of the Novartis investigational trivalent (serotypes Ia, Ib and III) GBS CRM197glycoconjugate vaccine, first in non-pregnant and then in pregnant women. Methods: Dosage (5 or 20 µg of each glycoconjugate), formulation (unadjuvanted or with Al(OH)3) and schedule (1 or 2 injections) were evaluated in non-pregnant Belgian women. Results informed a subsequent study in 320 pregnant South African women examining 5, 2.5 or 0.5 µg dosages (vs placebo) for safety and immunogenicity at baseline and at delivery.
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Afternoon – Tuesday 5 November 2013 Results: Vaccines were well tolerated with no vaccine-related SAE. All dosages and formulations were immunogenic (ELISA). GMC (µg/ml; combining data across groups) obtained on day 61 among nonpregnant women revealed no added benefit from 20 vs 5 µg dosage (11.6 vs 14.4 µg/ml); 2 vs 1 injection (11.8 vs 14.1 µg/ml) or adjuvant vs no adjuvant (10.4 vs 16.0 µg /ml). Accordingly, pregnant women received 1 injection of unadjuvanted vaccine at dosages ≤ 5 µg. Responses to 0.5 µg trended lower than those to 2.5 or 5 µg for all serotypes. Among pregnant women with undetectable Ia-specific Ab at baseline, highest Ab responses occurred after 5 µg (6.5 µg /ml) vs 2.5 µg (3.2 µg /ml) or 0.5 µg (2.43 µg / ml; serotype Ia) dosages. Conclusions: Data support use of a single injection of 5 µg (each glycoconjugate) of unadjuvanted trivalent vaccine to larger scale studies in pregnant women. 15:00 COFFEE, EXHIBITION & POSTERS See page 22 for all biographies.
Tackling meningitis in Africa Chair: Prof Brian Greenwood, London School of Hygiene and Tropical Medicine
15:30 Confronting cryptococcal meningitis in Africa; New diagnostic, prevention and treatment strategies to reduce disease burden Prof Tom Harrison, St George’s University London
Cryptococcosis remains a very common opportunistic infection in HIV-infected patients, and is now the leading cause of adult meningitis in many parts of sub-Saharan Africa. Despite expansion of antiretroviral programmes, cases have not decreased in most African centres. Furthermore, treatment is unsatisfactory: in Africa, mortality has ranged from 24% at 10 weeks in a trial setting in South Africa, to >50% in cohorts treated with fluconazole. A recent CDC analysis estimated the 3 month associated mortality in Africa to be 70%. The combination of high incidence and difficulties with treatment mean cryptococcal meningitis is a very common cause of death in AIDS patients, accounting for up to 20% of all AIDS-related deaths in some cohorts. While tuberculosis is much more common, treatment is available and effective; the high case fatality rate for cryptococcal meningitis drives a high death toll. The CDC analysis estimated that cryptococcal disease is associated with at least 100,000 deaths per year in Sub-Saharan Africa alone. Drivers of the high case fatality rate include the inadequacy of current antifungal regimens and late presentation. A new point-of-care immunodiagnostic test has the potential to enable earlier, primary care-based, diagnosis for all symptomatic cases. In addition, the test can facilitate screening and preemptive treatment as a cost-effective preventative strategy in patients with late-stage HIV infection in areas of high incidence. While drug discovery aimed specifically at Cryptococcus species is very limited, improving access to, and optimising our use of, current antifungal drugs, including in resource-limited settings, together with systematic management of the common complication of raised CSF pressure, and improved diagnosis, has the potential to significantly reduce the global disease burden.
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Afternoon – Tuesday 5 November 2013 15:55 The impact of MenAfriVac on serogroup A invasive meningococcal disease and carriage in Chad Dr Doumagoum Moto Daugla, Centre de Support en Santé Internationale, Chad
Background: A serogroup A meningococcal polysaccharide/tetanus toxoid conjugate vaccine (PsA-TT)(MenAfriVac®) was licensed in India in 2009 and pre-qualified by WHO in 2010 on the basis of its safety and immunogenicity. This vaccine is now being deployed across the African meningitis belt. We have studied the impact of PsA-TT on meningococcal meningitis and carriage in Chad during a serogroup A meningococcal meningitis epidemic. Methods: Data on the incidence of meningitis before and after vaccination were obtained from national records. In 2012, surveillance was enhanced in the regions where vaccination with PsA-TT had been undertaken the previous year and in three districts where reactive vaccination in response to an outbreak was undertaken. Meningococcal carriage was studied in an age stratified sample of residents of a rural area approximately six months before and after vaccination. Meningococci obtained from cerebrospinal fluid or pharyngeal swabs were characterised by conventional microbiological and by molecular methods. Results: Approximately 1.8 million subjects aged 1-29 years received a single dose of PsA-TT during the course of a vaccination campaign undertaken in three regions of Chad in and around the capital N’Djamena during a ten-day period in December 2011. The incidence of meningitis during the 2012 meningitis season in these three regions was 2.5 per 105 (57/2.3 x 106) whereas in regions where mass vaccination had not been undertaken it was 43.6 per 105 (3809/8.7 x 106), a 94% difference in incidence (p<0.001). No case of serogroup A meningococcal meningitis was detected in the three vaccinated regions despite reinforced surveillance. Thirty-two serogroup A carriers were identified in 4278 age stratified subjects (0.75%) living in a rural area near to the capital four to six months prior to vaccination whilst only 1 serogroup A meningococcus was isolated in 5001 subjects resident in the same community approximately 6 months following vaccination (adjusted OR =0.019: 95% CI 0.002, 0.14)(p<0.001).
Interpretation: PSA-TT was highly effective at preventing serogroup A invasive meningococcal disease and carriage in Chad. How long this protection will persist needs to be determined. 16:20 Elimination of meningitis A epidemics in Africa; MenAfriVac future plans Dr Marie-Pierre Préziosi, on behalf of the Meningitis Vaccine Project (MVP) and partners: MVP is a partnership between PATH and the World Health Organization (WHO)
Recurrent meningococcal epidemics have been a major plague for over a century in the African meningitis belt where outbreaks occur annually with large epidemics striking at intervals ranging between 8 and 12 years. The Meningitis Vaccine Project (MVP) is a partnership between the World Health Organization and PATH, funded by the Bill & Melinda Gates Foundation. It was established in 2001 with the mission to eliminate epidemic meningitis as a public health problem in sub-Saharan Africa through the development, testing, licensure, introduction, and widespread use of affordable meningococcal conjugate vaccines. Following international standards, an affordable MenA conjugate vaccine, MenAfriVac (Serum Institute of India, Ltd), was successfully developed and licensed through an innovative public private partnership. The vaccine was launched at public health scale in December 2010 and has already been introduced into ten African countries through single dose mass campaigns (Benin, Burkina Faso, Cameroon, Chad, Ghana, Mali, Niger, Nigeria, Senegal and Sudan) reaching to date over 112 million persons aged 1- to 29-years, with early results suggesting a major impact on MenA transmission and disease. The last three epidemic seasons (2011, 2012 and 2013) were characterised by a dramatic fall in cases of group A meningococcal disease in vaccinated countries. The high vaccine coverage achieved augurs well for further rollout of the vaccine in Nigeria and in the additional sixteen countries that constitute the African meningitis belt (Burundi, Central Africa, Côte d’Ivoire, Democratic Republic of Congo, Eritrea, Ethiopia, Guinea, Guinea Bissau, Kenya, Mauritania, Rwanda, South Sudan, The Gambia, Tanzania, Togo and Uganda). Continuing surveillance for cases of meningitis and monitoring of vaccination coverage and safety will be crucial to confirm the effects of the vaccine as it is being introduced across the entire belt.
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Afternoon – Tuesday 5 November 2013 Protecting new birth cohorts through routine vaccination after completion of the mass campaigns, is crucial to sustaining the full impact of MenAfriVac and achieving the overall public health goal. Research from recent and ongoing studies suggest that this could be best achieved through follow-up campaigns and immunisation starting in late infancy. The presentation will cover the MVP project latest operations and research, including successes to date in implementing the Men A vaccine, key research results and future priorities. A pilot study to assess the feasibility of 16:45 implementing ETAT triage components to facilitate recognition of severe illness in children through mobile technologies at Primary Health Centres in urban Blantyre, Malawi Thomasena O’Byrne1, Deborah Nyirenda3, Rachel Perrin2, Sara Marshall2, Marije Geldof7, Sarah BarZeev5, Norman Lufesi6, Eltas Nyirenda6, Queen Dube3,4, Naor Bar-Zeev3, Linda Glennie2, Elizabeth Molyneux4, Robert Heyderman3,5, Nicola Desmond3,5 1
Action Meningitis, Meningitis Research Foundation, Malawi; Meningitis Research Foundation, UK; 3Malawi Liverpool Wellcome Trust Clinical Research Programme, Malawi; 4College of Medicine, Malawi; 5Liverpool School of Tropical Medicine, UK; 6Ministry of Health, Malawi 7D-Tree International, Malawi 2
Hospital based studies suggest that late presentation is a driving factor for mortality from severe febrile illness in resource-poor contexts. Recent research into health seeking pathways for acute bacterial meningitis at primary health level identified factors linked to service provision and misdiagnoses as contributing to late presentation for appropriate care in tertiary hospitals. These factors include unsystematic and informal triage, high numbers of patients and erratic consultation systems. The aim of this study was to explore the feasibility of implementing a triage system based on the Emergency Triage, Assessment and Treatment (ETAT) protocol recommended by the World Health Organisation (WHO) for resource-poor settings, within 5 Primary Health Centres (PHCs) in Blantyre district referring to Queen Elizabeth Central Hospital (QECH), facilitated through the use of mHealth technologies. We used a mixed methods approach to evaluate whether this implementation will provide a systematic and timely approach to recognising severe illness at PHCs. We conducted a six-month intervention with baseline and post-intervention evaluation
components, incorporating a comprehensive training programme for low cadre health workers, Patient Journey Modelling, self completed questionnaires, focus group discussions and semi-structured interviews. Patients were monitored through the system and on reaching QECH to follow up referrals, accuracy of triage outcomes and timeliness of the system. 41,358 paediatric cases were seen overall in five clinics over the six-month intervention period with 101 Emergency, 14,284 Priority and 26,973 nonpriority or Queue cases. High levels of agreement (kappa = 0.71) were reached following training between low cadre health worker triage outcomes and clinically trained health staff. Overall 644 (1.6%) cases were referred: 100 of these had been defined as Emergency representing 15.5% of total referrals. A significant number were Priority case referrals (74% of all referrals) whilst 62 cases who had been clinically triaged as non-Priority or Queue, were referred. Of all 644 referrals made, only 240 (37.3%) actually reached QECH, showing a large dropout between primary level referral and arrival at tertiary care. Worryingly 67% of all Emergency referrals never arrived at QECH, but mean time from referral for those Emergency cases that reached QECH was 3.5 hours. The intervention was well received by primary health workers and patients and pre and post evaluation showed a substantial improvement on patient flows and experiences within the clinic. Our pilot intervention study has shown that establishing an mHealth phone-based triage system is feasible and acceptable at primary health level and that it has the potential to significantly improve patient pathways. We are currently working with the Ministry of Health to develop a full intervention on the impact of the phone-based algorithm and to address other priority gaps in community responses to severe paediatric illness in Malawi. 17:10 EVENING WINE RECEPTION Everyone is invited to this reception which is being held in the Atrium and the Cavendish room. See page 22 for all biographies.
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Morning – Wednesday 6 November 2013 8:00 REGISTRATION & BREAKFAST for day two and satellite session delegates
Novartis satellite breakfast session
8:20 Confidence in numbers: the evidence base for assessing the public health impact of vaccines against invasive meningococcal diseases
Emeritus Prof Richard Moxon, Professor of Paediatrics, University of Oxford
The Novartis Vaccines sponsored breakfast symposium will explore the challenges in assessing the evidence behind vaccination against invasive meningococcal diseases.
Richard Moxon MA, F.Med.Sci, FRS is Emeritus Professor of Paediatrics and a Professorial Fellow of Jesus College at the University of Oxford. His paediatric and research training was in the UK (1966-1969) and the USA (1970-1974).
he session will be chaired by Prof T Richard Moxon, Emeritus Professor of Paediatrics at the University of Oxford, who will introduce the speakers and emphasise some of the scientific challenges underpinning the introduction of new vaccines.
He was Assistant and then Associate Professor of Paediatrics at Johns Hopkins University in Baltimore (1974-1984), becoming the Eudowood Director of Pediatric Infectious Diseases in 1981 before he was elected as Action Research Professor and Chairman of Paediatrics at Oxford University (1984-2008) and Head of the Molecular Infectious Diseases Group in the Weatherall Institute of Molecular Medicine (1988-2008).
Dr Jamie Findlow, Deputy Head of the Vaccine Evaluation Unit for Public Health England, will review the evidence used to guide assumptions of disease incidence, carriage impact, herd protection and strain coverage prior to large scale implementation.
He is a Fellow of the UK Royal College of Paediatrics and Child Health and of the UK Academy of Medical Sciences and was elected a Fellow of the Royal Society in 2007. His major research interests have been on the pathogenesis and prevention of sepsis and meningitis caused by the bacteria Haemophilus influenzae and Neisseria meningitidis.
Dr Simon Nadel, Consultant in Paediatric Intensive Care at St. Mary’s Hospital London, will then discuss the challenges of quantifying meningococcal disease mortality and morbidity.
Dr Findlow is the Deputy Head of the Public Health England (PHE) Vaccine Evaluation Unit (VEU) located at the Manchester Royal Inﬁrmary.
A discussion will then be led by Professor Moxon, inviting the audience to put questions to the panel.
Dr Jamie Findlow, Deputy Head of Vaccine Evaluation Unit, Public Health England, Manchester
He joined the VEU as a Clinical Scientist in 2000 and was responsible for the completion of serology from clinical trials of Neisseria meningitidis polysaccharide and conjugate vaccines. He subsequently undertook a PhD entitled “Serological correlates for and immunogenicity of candidate serogroup B N. meningitidis vaccines.” Following his PhD, he has been involved in development and evaluation of immunoassays including those for N. meningitidis, Haemophilus inﬂuenzae type b, diphtheria, tetanus and Streptococcus pneumoniae. Dr Simon Nadel, Consultant in Paediatric Intensive Care, St Marys Hospital, London See biography on page 29
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Morning – Wednesday 6 November 2013 Current issues in clinical management Chair: Prof Robert Heyderman, Malawi-Liverpool-Wellcome Trust
9:20 Debate on aggressive vs restricted fluid resuscitation in childhood sepsis Prof Michael Levin & Dr David Inwald, St Mary’s Hospital, Imperial College London
Early management of paediatric sepsis consists of supportive therapy, antibiotics and source control. Currently there are no adjunctive therapies which have been proven in clinical trials. Supportive therapy consists of ABC management including fluid bolus therapy and early initiation of intensive care for children with fluid resistant shock, including intubation, mechanical ventilation, inotropes and organ support. The debate will focus on the ongoing controversy about fluid management in critically ill children, looking at the evidence for and against generous fluid bolus therapy in severe infection. 10.00 Round up of new developments in clinical management of meningitis or sepsis in paediatric and adult settings Dr Simon Nadel, St Mary’s Hospital, London Simon Nadel will summarise recent developments in the management of sepsis and meningitis, focussing on emergency care and management of complications. This will include a summary of advances in fluid management, organ failure and neuroprotection. Prospects for further development will also be discussed. 10:25 Management of sepsis and meningitis in developing countries Dr Louisa Pollock, Wellcome Trust Tropical Centre, Liverpool
What are the essential requirements to effectively manage sepsis? Inotropes and mechanical ventilation? Broad-spectrum antibiotics and saline? Or maybe nurses and electricity? Low income countries face the highest burden of sepsis and meningitis, with the most limited resources. Access to care is challenging, and standard of care is often poor. As a result casefatality rates and risk of sequelae may be at least twice as high as in high-income countries.
Global initiatives to develop and implement evidencebased guidelines for the management of sepsis and meningitis have delivered improved outcomes in highincome countries, but are such guidelines feasible in resource-limited settings? If partial implementation is necessary, which elements will result in the greatest impact, for the least cost? The evidence base for the management of sepsis and meningitis is limited, particularly in children. Initial research is often undertaken in high-income countries, but differences in aetiology, co-morbidities and health systems may mean that results may not be generalisable to low and middle income countries with the highest burden of disease. Well conducted clinical trials based in countries where the potential for positive impact is greatest are essential. The FEAST trial, investigating fluid management in shock in African children, is an excellent example, although its unexpected results may have generated more questions than answers. This presentation will begin with an overview of the clinical context of sepsis and meningitis in developing countries, including the challenges to providing effective care. Current efforts to develop and implement evidence-based guidelines appropriate to resource-limited settings will be summarised, and the impact of recent research discussed. Finally, ongoing research gaps will be highlighted. 10:50 COFFEE, EXHIBITION & POSTERS
Preventing pneumococcal disease Chair: Prof Ray Borrow, Public Health England Vaccine Evaluation Unit, Manchester
11:20 Current epidemiology and summary of vaccines in development; the need for higher-valent and alternative vaccines Prof David Goldblatt, Institute of Child Health, University College London
The first pneumococcal conjugate vaccine was licensed by the FDA in 2000 and immediately introduced in the infant immunisation programme in the USA. The vaccine, a mixture of seven capsular polysaccharides each individually conjugated to a protein carrier molecule, proved highly successful in reducing the incidence of infection due to the serotypes in the vaccine in immunised children. The vaccine was also shown to prevent the acquisition of pneumococci in the nasopharynx (NP), thus preventing the spread of pneumococci and reducing the incidence of disease in the unvaccinated and suebsequently became widely used around the world.
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Morning – Wednesday 6 November 2013 The consequence of reduced NP carriage of the 7 serotypes in the vaccine resulted in replacement carriage by serotypes not in the vaccine and a proportion of these emerged as causes of infection. In 2009/10 two new extended valency conjugates were licensed, containing 10 and 13 serotypes respectively. These vaccines have proven to be efficacious although with only 3 years of follow up since their widespread introduction more time is required to understand their potential for mediating an indirect effect and the possibility of further replacement disease. Looking at emerging serotypes post PCV13 introduction does provide an insight into the possible design of future conjugates. There is burgeoning interest in new approaches to providing non-serotype specific immunity. Protein containing vaccines might be one way of achieving this, either using relevant pneumococcal proteins as carrier molecules, or indeed standalone pneumococcal protein vaccines, although the route to licensure for the latter is complicated. Pneumococcal conjugate vaccine 11:50 implementation in Africa with a focus on Kenya Prof Anthony Scott, London School of Hygiene and Tropical Medicine
Pneumococcal disease is a frequent cause of pneumonia, meningitis and sepsis in Africa. According to a WHO, pneumococcal disease is estimated to have caused 447,000 deaths among African children aged < 5 years in the year 2000. In a trial in The Gambia, 9-valent Pneumococcal Conjugate Vaccine had an efficacy of 37% against radiologically-confirmed pneumonia and 16% against all-cause mortality in children aged 6-29 months. A trial in South Africa confirmed the utility of the vaccine in countries with high HIV prevalence. Pneumococcal conjugate vaccines were introduced into the routine national immunisation programme (NIP) in the USA and the UK in 2000 and 2006, respectively. The first introduction of PCV into an African NIP took place in 2009 (Rwanda) and since 2011 the vaccine has been introduced widely with support from the GAVI Alliance. To date, 39 African countries have been approved for GAVI support for PCV introduction.
arm of the WHO Vaccine Preventable Diseases surveillance is collating information on bacterial meningitis from 49 sentinel surveillance sites and of bacteraemic pneumonia from a handful of sites. Because of logistic and technical reasons the frequency of isolation of S. pneumoniae in the baseline surveillance is relatively low. The GAVI Alliance has funded specific studies of vaccine impact in South Africa (case-control study) and in Kenya (before-after study). Other before-after studies are taking place in The Gambia, Malawi, Togo, Mozambique and Zambia. To date there are no published results from any of these studies. However, the surveillance for Invasive Pneumococcal Disease taking place at the KEMRIWellcome Trust Research Programme in Kilifi, Kenya, is published monthly and the impact of the vaccine is already evident in the frequency of cases observed (http://www.kemri-wellcome.org/index.php/en/studies_ inner/75). The 10-valent PCV was introduced in January 2011, including a catch-up campaign for children aged <5 years. The baseline frequency of IPD of vaccine serotypes was 15-40 cases per year. Following vaccine introduction VT IPD cases have been progressively reduced and in 2013 there have been no cases at all so far. Introduction of PCV7 in the USA and the UK was associated with considerable herd protection and with a variable degree of ‘serotype replacement disease’. Nasopharyngeal carriage of vaccine serotypes was virtually eliminated from the vaccinated population. The magnitude of these effects in Africa will be critical to cost-effectiveness analyses of the vaccine and to the sustainability of the vaccine programme. The talk will present recently published or emerging data on the impact of PCV in Africa on transmission, carriage and indirect vaccine protection. 12:20 LUNCH, EXHIBITION & POSTERS See page 22 for all biographies.
Across Africa surveillance mechanisms and tailored studies to evaluate the impact of the vaccine are relatively sparse. The Invasive Bacterial Diseases
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Afternoon – Wednesday 6 November 2013 Presentations of top five poster abstracts Chair: Prof David Lalloo, Liverpool School of Tropical Medicine
13:20 E17 Dr Iain Kennedy, Public Health England; V48 Dr John Perez, Pfizer Vaccine Research, Collegeville, PA, USA; E16 Dorothea Hill, University of Oxford; P2 Dr Edmund Loh, University of Oxford; V43 Prof Robert Read, University of Southampton
Award for best poster
Prevention of meningitis & septicaemia Chair: Prof Andrew Pollard, University of Oxford 14:00 Current issues with meningococcal vaccine programmes in the UK Dr Mary Ramsay, Public Health England, London Introduction: MenC conjugate vaccination was introduced into the UK infant schedule in 1999, accompanied by a catch-up programme to 18 years, later extended to those under 25 years. Coverage in school aged cohorts and pre-school children was high and led to an immediate and dramatic fall in MenC cases which has been now been sustained for over 10 years. In 2004, following evidence of declining individual protection from MenC given at 2, 3, 4 months, the 2 month dose was removed from the infant schedule and booster dose of vaccine (combined with Hib) was added for toddlers. Methods and results: Surveillance of meningococcal disease relies on confirmed cases ascertained by Public Health England. MenC cases are followed individually to determine vaccination status and risk factors for infection. Recent trends in MenC cases are consistent with excellent control of disease. Fewer than 30 cases are reported annually, many occurring in adults and older children who have not been vaccinated – often because they were born and raised overseas. Travel is also commonly reported. MenC vaccine failures are unusual but have been reported even after a full primary course (or two or three doses) plus booster. Although results are consistent with high short term protection, there is evidence of declining protection with age. The excellent control is therefore probably attributable to indirect protection from the impact of the catch-up programme on carriage. Numbers of cases due to serogroups other than B remain uncommon although recent increases in MenY and MenW have been observed. Sero-prevalence studies are performed
using serum bactericidal assays on residual sera collected from microbiology laboratories across the country. The most recent study suggested that those children vaccinated in the catch-up programme in 1999-2000 are still relatively well protected. Antibody levels in those vaccinated in infancy, however, appear to decline with age and very limited benefit appears to have accrued from the toddler booster. A range of clinical studies have been conducted to look at antibody responses to various schedules in infancy. These suggest that immune responses to different MenC conjugate vaccines vary and the degree of boosting achieved by the toddler dose is affected by the conjugate received in infancy. Studies of boosting in teenagers have recently commenced. Discussion: Post-marketing surveillance of MenC, suggests that most children vaccinated in infancy, with or without a toddler booster, will be unprotected by teenage years. In 2013 the UK schedule was modified to be based on a single dose of MenC (at 3 months) followed by a toddler MenC/Hib booster. A teenager booster is due to commence in Year 10 (1415 years) the 2013/14 academic year, with a catch-up programme for university students commencing in 2014-2015. 14:15 Current issues with meningococcal vaccine programmes in the Netherlands: Timing of adolescent booster after single primary MenCC immunisation at young age - the TIM-study, an intervention study among Dutch teenagers Susanne P. Stoof1,2, Fiona R.M. van der Klis1, Debbie M. van Rooijen1, Elisabeth A.M. Sanders2, Guy A.M. Berbers1 1
National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands; 2Department of Immunology and Infectious Diseases, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, The Netherlands
Background: The main purpose of vaccination is achieving long-term individual (and herd) immunity. For many infectious diseases, this requires a booster vaccination in addition to primary vaccination. As has been shown previously, immunity against Meningococcal serogroup C disease (MenC) wanes after several years in infants and toddlers, indicating that also for MenC a booster vaccination might be necessary. Young children between 0-5 years of age are most vulnerable to invasive MenC disease. Vaccination at a young age is therefore most appropriate but does not lead to long term protection. Since teenagers aged between 12-18 years are also at risk for developing invasive MenC disease, a booster MenC vaccination during or prior
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Afternoon – Wednesday 6 November 2013 to adolescence can be considered. Determining the appropriate age for this booster vaccination is a challenge as a booster vaccination during late adolescence probably leads to more prolonged individual (and herd) protection, but leaves the young adolescents at risk. In an attempt to determine the optimal age for a booster (second) vaccination, a study is currently conducted in The Netherlands (TIM study). In the Dutch immunisation program, MenC is administered at the age of 14 months as a single dose vaccination. Aim: To establish an appropriate age for an adolescent MenCC booster vaccination. Methods: Three age-groups were recruited with healthy 10 year olds (n=91), 12 year olds (n=91) and 15 year olds (n=86). All participants were primed with MenC-PS tetanus toxoid conjugated vaccine (NeisVac C™) 9 years earlier, and received the same MenCC vaccination at the beginning of the study. Blood samples were collected prior to (T0) and 1 month (T1) and 1 year (T2) after vaccination. MenCPS specific IgG levels, avidity and IgG subclasses were measured using a fluorescent-bead-based multiplex immunoassay (MIA). Functional antibody levels were measured using the serum bactericidal antibody assay (SBA). Results: 268 participants were enrolled, 259 (96.6%) completed all study visits. Nine years after primary MenCC vaccination, 45% of the 15 year olds still had protective antibody levels against MenC compared to 34% of the 12 year olds and 19% of the 10 year olds. All participants developed extremely high serum MenC-PS specific IgG levels and SBA titre 1 month after the study MenCC vaccination. At T2, 100% of all age groups still had protective antibody levels against MenC, but the 15 year-olds remained the highest serum MenC-PS specific IgG levels and SBA titre and showed the lowest level of decrease in antibody levels. Conclusion: Nine years after their primary MenCC vaccination, all participants developed considerably high antibody levels in response to the study vaccination and all participants were still well protected one year later. One year after the study vaccination, the oldest age group remained the highest (protective) antibody levels and showed the lowest level of antibody decrease.
This suggests that persistence of individual - and indirectly herd-immunity increases with the age at which an adolescent booster is administered. 14:30 C arriage studies – what do they add? Human bacterial challenge experiments as an alternative Dr Caroline Trotter, University of Cambridge & Prof Stephen Gordon, Liverpool School of Tropical Medicine
Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae are the major causes of bacterial meningitis worldwide and share a home in the human nasopharynx. Studying nasopharyngeal carriage is essential as this state is the natural reservoir, the source of transmission and the prerequisite of invasive disease including meningitis. A full understanding of carriage will not only inform the epidemiology of infection but also help in prediction and measurement of control measures’ impact. Many studies of carriage have been conducted, particularly in the context of vaccination. Caroline Trotter will briefly review some major findings, strengths and weaknesses of these carriage studies and pose the question whether alternative approaches are required. Stephen Gordon will address the role of controlled human infection studies, focusing on experimental human pneumococcal carriage, and ask if the study of healthy volunteers will be sufficiently informative as to be ethically justified in the search for new vaccines to prevent meningitis. 15:05 COFFEE, EXHIBITION & POSTERS
Future prospects for prevention of meningococcal disease Chair: Prof Ian Feavers, National Institute for Biological Standards and Control, Potters Bar
15:30 Non-routine use of meningococcal vaccines in outbreaks and for individuals with clinical risk factors Dr Matthew Snape, University of Oxford In view of their increased risk for meningococcal disease, specific immunisation guidelines have been developed for individuals who are immunodeficient, are on immunomodulatory treatment or have occupational exposure to Neisseria meningitidis. These recommend the use of additional dose(s) of plain polysaccharide and/ or protein-polysaccharide
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Afternoon â€“ Wednesday 6 November 2013 conjugate serogroup A, C, W and Y vaccines. Where applicable these are to be administered prior to commencing immunosuppressive therapy. Recent developments in this area include the extension of approved age ranges for the protein-polysaccharide MenACWY vaccines and the increasing use of eculizumab, a recombinant humanized monoclonal IgG that specifically inhibits the complement cascade, thus rendering recipients at increased risk of meningococcal disease. Furthermore, the recent interim statement from the Joint Committee on Vaccines and Immunisation (JCVI) has recommended the use of the licensed serogroup B meningococcal vaccine in the same high risk groups as defined for the quadrivalent MenACWY vaccines. This presentation will review the evidence base underpinning existing guidelines, and what further research is required. The use of the above vaccines in outbreak settings will also be discussed. 16:00 M eningococcal vaccines - have we been asking the wrong questions? Prof Adam Finn, University of Bristol Over the last decade many of the precepts which drove the development, licensure and implementation of conjugate vaccines, including those used to prevent meningococcal vaccines, have not turned out to represent the primary mechanism of their effectiveness. Accumulating evidence suggests that these vaccines efficiently block acquisition of nasopharyngeal carriage in recently immunised individuals. This effect may be mediated by high levels of anticapsular IgG exhibited on mucosal surfaces and its consequences for downstream transmission may surpass, by some distance, the importance of direct protective effects of immunisation which have driven the design and implementation of vaccine programmes to date. The very different composition of new meningococcal vaccines, which do not contain capsular antigens, adds to the uncertainties around their effectiveness which beset all vaccines designed to prevent very unusual, severe infections, since it cannot be assumed they will have the same or similar mucosal effects. Finding out has not, to date, been a major priority. The last ten years have also seen the general acceptance and implementation of cost-effectiveness evaluation as the driver for introduction of novel health service interventions. As the concept that healthcare costs have to be contained and resources
rationally disbursed takes root, this approach raises questions about how best to attribute value to the benefits of approaches that are very diverse. Efforts to assess whether the funding decisions reached by this process match the priorities favoured by the public and healthcare professionals charged with their delivery are only just getting underway. That evaluation of the questions whether any particular infectious disease merits prevention through universal immunisation and at what cost should follow rather than precede the development of vaccines to do so is an anomalous consequence of the timing of the evolution of this process and this chronology should probably change in the future. In the meantime, we have to confront the present and how primary prevention of meningococcal disease can progress. Since everyone wants this to happen, the question is not really whether, but when and how to move forward. Occasional stumbles need not develop into headlong falls. 16:30 Immunisation against serogroup B meningococcal disease â€“ hopes and fears Panel discussion moderated by Prof Paul Heath Panellists Prof Adam Finn, Dr Simon Nadel, Prof Robert Read, Dr Matthew Snape, Dr Caroline Trotter 17:10 CLOSE See page 22 for all biographies.
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Chair & Speaker Biographies
Captions: Supporter Fiona Bonn completes the London to Paris cycle ride; An MRF research visit with Bella the Brain and Prof Tom Solomon at the University of Liverpool.
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Chair & Speaker Biographies Dr Hareth Al-Janabi, University of Birmingham Dr Hareth Al-Janabi is a Medical Research Council-funded early career fellow at the University of Birmingham. He conducts research on economic issues in healthcare, mainly focusing on the costs and benefits of healthcare treatments. He is currently developing techniques to capture the normally ignored - impacts of disease and treatments on patients’ families. Before working in academia, Hareth was an economist at the Department of Health and a policy adviser at the Treasury. Prof Philippe Beutels, University of Antwerp, Belgium Philippe Beutels holds degrees in Commercial Engineering and Medical Sciences. He has published about 150 contributions in peer-reviewed journals and books and delivered over 100 lectures at scientific symposia, mainly on topics related to health economics, mathematical modelling and epidemiology of infectious diseases. He’s currently Associate Professor at the University of Antwerp, Belgium, where he heads the Centre for Health Economics Research & Modelling Infectious Diseases (CHERMID). He’s also Senior Visiting Fellow at the University of New South Wales, Australia. Prof Ray Borrow, Public Health England, Manchester Professor Ray Borrow is Head of the Vaccine Evaluation Unit at Public Health England (formerly Health Protection Agency), Manchester, UK, where he is responsible for the evaluation of serological responses to various bacterial and viral vaccines with a special interest in meningococcal and pneumococcal vaccines. He gained his PhD in 1994, his MRCPath in 2003 and he became a Professor of Vaccine Preventable Diseases in the Faculty of Medical and Human Sciences at the University of Manchester in 2009 and Visiting Professor at the School of Healthcare Sciences, Manchester Metropolitan University in 2011. His scientific findings have resulted in over 240 peer reviewed published papers. Until recently he served as a member of the DH Joint Committee on Vaccination and Immunisation (JCVI) and continues to date as an expert advisor. He is an ad hoc advisor to WHO on both meningococcal and pneumococcal vaccines. He chairs the scientific advisory panel for Meningitis Research Foundation.
Karen Crockatt, Member and Ambassador of Meningitis Research Foundation Karen Crockatt works as a Head of Procurement for Ramsay Healthcare. She trained as a nurse many years ago specialising in Theatre and has held various operational management roles within the NHS and private healthcare sectors, including Directorate Management, commissioning roles and Group Procurement. She is an MRF trained befriender and recently appointed Ambassador for the North West. She is also a Trustee for www.littlelegs.org.uk, the charity for children with congenital limb deficiencies or amputations of part of their legs or feet. Her husband Nick is a European and Middle East Regional Director with a large medical devices company and is also an MRF Ambassador. They have 2 children, Domenico aged 24, who has just graduated from university, and Sofia aged 9. Dr Doumagoum Moto Daugla, Centre de Support en Santé Internationale, Chad Dr Doumagoum Moto Daugla, Director, Centre de Support en Sante Internationale (CSSI) in N’Djamena, Chad is the principal investigator of the Chad arm of the African Meningococcal Carriage Consortium (MenAfriCar). Dr Daugla studied medicine and specialised in paediatrics at the State University of Leningrad, Russia. He has also undertaken further specialised training in the areas of epidemiology, public health, and management of public health projects. Dr Daugla is a senior public health expert and as such has extensive experience in organising, planning and evaluating services as well as excellent knowledge of the national health policy health system in Chad. In addition to having worked as a paediatrician and holding many positions in various hospitals in Chad, Dr Daugla has also held senior positions within the National Union of Diocesan Associations and the Swiss Tropical Institute. Dr Daugla is experienced in conducting epidemiological investigations and evaluations of programmes and health projects. In 2000 he led six cross-sectional surveys of the prevalence of HIV/AIDS in Chad. From 2001 to 2002 he was the principal investigator in two studies on human resources of the Ministry of Public Health on behalf
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Chair & Speaker Biographies of the MOH, WHO N’Djamena and WHO Geneva. In 2004, he was the national consultant on “The study of the socio-economic impacts of HIV/AIDS on the health sector in Chad” on behalf of UNDP. From 2002 to 2010 he was Vice-President of the National Expert Committee on Poliomyelitis in Chad. Dr Daugla has been the Director of CSSI since 2006 and is the local supervisor to several researchers at different levels (Masters and PhD candidates). Dr Nicola Desmond, Malawi-Liverpool-Wellcome Clinical Research Programme, Malawi Nicola is a Wellcome Trust Ethics and Society Fellow and Lecturer at Liverpool School of Tropical Medicine. She is a medical anthropologist with over 12 years experience in subSaharan Africa currently based at MLW in Blantyre, Malawi where she leads the social science programme. This programme uses high quality mixed methods approaches and qualitative research with a focus on four research areas: social impacts of medical technologies, health seeking behaviour, engagement with health services for prevention and treatment and the bioethics of health research. She is leading work on addressing patient pathways through mHealth technologies at primary health levels in collaboration with Meningitis Research Foundation. Prof Ian Feavers, National Institute for Biological Standards and Control (NIBSC) Ian Feavers, PhD, is Head of the Division of Bacteriology at the NIBSC, UK. He studied for his PhD at the University of Newcastle upon Tyne, eventually moving to NIBSC after periods of postdoctoral research at the University of Sheffield and the Friedrich Miescher Institut in Basel. During the late 1990s, when new conjugate vaccines were being introduced, he headed the laboratory responsible for the control and standardisation of meningococcal and pneumococcal vaccines. Ian continues to oversee an active research programme on the molecular genetics and immunology of meningococcal and pneumococcal antigens. Because of his broad experience of bacterial vaccines and molecular biology, he has been closely involved with a number of meningococcal vaccine developments.
He regularly contributes to WHO and EU guidelines, serves as one of NIBSC’s representatives on the Vaccine Working Party of the EMA, and is a member of the JCVI subgroup on meningococcal vaccines. Ian teaches on a number of vaccine related courses in the University of London and is a Visiting Professor at Imperial College. Prof Adam Finn, University of Bristol Adam Finn is Professor of Paediatrics and a member of the Schools of Clinical Sciences and of Cellular and Molecular Medicine at the University of Bristol and an honorary Consultant in Paediatric Infectious Diseases and Immunology at Bristol Royal Hospital for Children. He is director of the South West Medicines for Children Research Network and heads the Bristol Children’s Vaccine Centre. He trained in Infectious Diseases at the Children’s Hospital of Philadelphia and in Immunology at the Institute of Child Health in London where he obtained his PhD. He worked in Sheffield between 1992 and 2001 where he was involved in several trials of meningococcal group C and other vaccines. His current main research interest is the biology of respiratory infections and how vaccines affect transmission of infections. Prof David Goldblatt, Institute of Child Health, University College London David Goldblatt is Professor of Vaccinology and Immunology and Head of the Immunobiology Unit at the Institute of Child Health, University College London (UCL). He is a Consultant Paediatric Immunologist at the Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH) where he is also Director of Clinical Research and Development and Director of the National Institute for Health Research GOSH/ UCL Biomedical Research Centre. He obtained his medical degree from the University of Cape Town, South Africa, his Paediatric qualifications from the Royal College of Physicians (London) and a PhD in Immunology from the University of London, United Kingdom. He has a long-standing interest in the immune response to vaccines and infectious diseases. He has an active research programme studying bacterial conjugate vaccines in the young and the elderly, the ontogeny of the immune response to
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Meningitis & Septicaemia in Children & Adults 2013
Chair & Speaker Biographies bacterial carriage and infection and evaluation of functional immunity to S. pneumoniae proteins. He has been a regular advisor to the World Health Organisation (WHO) on bacterial conjugate vaccines and is Director of the WHO Reference Laboratory for Pneumococcal Serology based at the UCL Institute of Child Health in London. He has served on numerous committees including United Kingdom Department of Health Joint Committee on Vaccines and Immunisation and MRC and Wellcome Trust funding panels. Prof Stephen Gordon, Liverpool School of Tropical Medicine Professor Gordon joined the Liverpool School of Tropical Medicine in 2005, with a remit to establish laboratory and clinical research on susceptibility to pulmonary infections in the School. Prior to his appointment, he had completed two Wellcome Trust Research Fellowships in Blantyre, Malawi and a Clinical Lectureship in the University of Sheffield. Stephenâ€™s research in Sheffield and Malawi focused on susceptibility to respiratory infection and in particular, on the effect of HIV infection on susceptibility to pneumococcal disease. The work demonstrated that pulmonary mucosal defence is regulated differently than systemic defence against infection, and can be perturbed by environmental exposures including indoor air pollution. The Respiratory Infection laboratory now focuses on mechanisms for antigen presentation to the mucosal surface leading to effective mucosal defence against bacterial infections. They also study the effect of biomass fuel smoke on defence against infection. Recent work includes a study of inhaled pneumococcal polysaccharide vaccine, assessment of the pulmonary response to pneumococcal conjugate vaccine and the current study of experimental pneumococcal carriage as a pulmonary antigen challenge.Â Work on biomass fuel smoke indicates that acute and chronic exposures result in very different immune responses, probably leading to altered defence against infection and COPD by different mechanisms. Stephen holds an Honorary Consultant Contract in General Medicine in the Royal Liverpool University Hospital and University Hospital Aintree. He combines Respiratory and General Medicine with research and teaching in the School.
Prof Brian Greenwood, London School of Hygiene and Tropical Medicine Brian Greenwood qualified in medicine at the University of Cambridge, UK in 1962. Following house-officer appointments in London, he spent 3 years in Western Nigeria as a medical registrar and research fellow at University College Hospital, Ibadan. After receiving training in clinical immunology in the UK, he returned to Nigeria in 1970, this time to help in establishing a new medical school at Ahmadu Bello University, Zaria where he developed his research interests in malaria and meningococcal disease whilst continuing to teach and practice clinical medicine. In 1980, he moved to the UK Medical Research Council Laboratories in The Gambia which he directed for the next 15 years. In The Gambia, he helped to establish a multi-disciplinary research programme which focused on some of the most important infectious diseases prevalent in The Gambia and neighbouring countries such as malaria, pneumonia, measles, meningitis, hepatitis and HIV. Work undertaken during this period included demonstration of the efficacy of insecticide treated bednets in preventing death from malaria in African children and demonstration of the impact of Haemophilus influenzae type b and pneumococcal conjugate vaccines when deployed in sub-Saharan Africa. In 1996, he was appointed to the staff of the London School of Hygiene and Tropical Medicine where he is now Manson Professor of Clinical Tropical Medicine. From 2001-2009 he directed the Gates Malaria Partnership which supported a programme of research and capacity development in many countries in Africa directed at improving treatment and prevention of malaria. In 2008, he became director of a new capacity development initiative supported by the Wellcome Trust and the Bill and Melinda Gates Foundation, the Malaria Capacity Development Consortium (MCDC), which operates a post-graduate malaria training programme in five countries in sub-Saharan Africa, and he also directs a consortium (MenAfriCar) established with support from the Wellcome Trust and the Bill and Melinda Gates Foundation to study meningococcal carriage in Africa.
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Chair & Speaker Biographies Prof Tom Harrison, St George’s University London Tom Harrison is Professor of Infectious Diseases and Medicine, and Joint Head of the Research Centre for Infection and Immunity, at St George’s University of London, and Honorary Consultant at St George’s NHS HealthCare Trust. He trained in Infectious Diseases in London and in Boston USA. His initial research training was in the laboratory of Professor Stuart Levitz in Boston, where he worked on immune responses to Cryptococcus neoformans. Clinical research training was through the programmes in Clinical Effectiveness and International Health at Harvard Medical School, and though clinical trial work, developed first in Thailand in collaboration with the Wellcome Trust Bangkok Unit, and subsequently in Cape Town, Mbarara, Uganda, and Lilongwe, Malawi. He has served on the cryptococcal guidelines panels of the Infectious Diseases Society of America, The Southern African HIV Clinicians Society, and the WHO. Prof Paul Heath, St George’s University of London Paul Heath is a Professor / Honorary Consultant in Paediatric Infectious Diseases at St George’s, University of London and Vaccine Institute in London. His training in paediatrics and infectious diseases was at the Royal Children’s Hospital, Melbourne, the John Radcliffe Hospital, Oxford and St George’s Hospital, London. His particular research interests are in the epidemiology of vaccine preventable diseases, in clinical vaccine trials, particularly in at-risk groups, and in perinatal infections. He coordinates a national neonatal infection surveillance network (neonIN) and recently, a national study on neonatal meningitis. He sits on national committees concerned with meningitis, Group B streptococcus prevention, pneumococcal and Hib infections, neonatal infections and on immunisation policies in children. He is a Fellow of the Royal Australasian College of Physicians, a Fellow of the Royal College of Paediatrics and Child Health, a member of the research committee of the European Society of Paediatric Infectious Diseases and a member of the steering committee of the international Brighton Collaboration on vaccine safety.
Prof Robert Heyderman, Malawi-Liverpool-Wellcome Trust Programme Rob Heyderman is a clinician scientist who trained in London and Zimbabwe. He directs the MalawiLiverpool-Wellcome Trust Clinical Research Programme (MLW) which has an internationally recognised translational research portfolio, linking an excellent laboratory base to strong hospital and community-based research teams (http://www.mlw.medcol.mw). The research activities of the MLW Programme are focused under four interlinked research themes Malaria; TB & HIV; Non-Communicable Diseases (NCDs); and Microbes, Immunity & Vaccines. His own research focuses on i) the endothelial biology & coagulopathy of severe infection, ii) immunity to mucosal pathogens and prevention through vaccination, iii) regulation of host inflammation, and iv) the diagnosis and management of meningitis and sepsis. Dorothea Hill, University of Oxford Dorothea Hill is a Ph.D. student in the molecular epidemiology of Neisseria meningitidis at the University of Oxford. During her BA in biological sciences at St. Catherine’s college, Oxford, she became interested in the evolutionary aspects of pathogen transmission, and joined Martin Maiden’s group as a research assistant following graduation in 2010. Here she worked on the MenAfriCar project, diagnosing the serogroups of meningococcal isolates from the African meningitis belt prior to the introduction of a serogroup A vaccine, MenAfriVac. In 2011, Dorothea moved away from the laboratory to pursue computational approaches for the study of meningococcal epidemiology for her Ph.D. project, which is centred on the establishment of the Meningitis Research Foundation Meningococcus Genome Library, in collaboration with Public Health England and the Sanger Institute. Her main research interest is population genomics, in particular investigating meningococcal transmission patterns and host range with phylogenetic and clustering methods, using second and third generation genome sequencing technology.
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Chair & Speaker Biographies Dr David Inwald, St Mary’s Hospital, Imperial College London David qualified from Cambridge University and trained in adult and paediatric medicine before completing his training in paediatric intensive care medicine at Great Ormond Street Children’s Hospital. He is a Consultant in Paediatric Critical Care Medicine at St Mary’s Hospital, London and an Honorary Senior Lecturer in Paediatrics at Imperial College. He has research interests in sepsis and patient safety. Dr Iain Kennedy, Public Health England, London Iain is a Specialty Registrar in Public Health Medicine, working at the Public Health England Centre for Infectious Disease Surveillance and Control, London. He gained his medical degree and a BSc in public health, from the University of Glasgow. He completed his initial training in hospitals in Glasgow, before moving to London to take up a two year fellowship on the Chief Medical Officer’s Clinical Advisors scheme (what is now the National Medical Director’s Clinical Fellows scheme). During this time he worked with organisations across the NHS, independent sector and WHO on aspects of health promotion, patient safety and care pathway development. Now in his fourth and final year of public health training, Iain intends to practice in health protection, and has interests in vaccine preventable disease, global health, and medical education and training. He is a Member of the Faculty of Public Health.
Prof Nigel Klein, Great Ormond Street Children’s Hospital and Institute of Child Health, University College London Professor Nigel Klein is Professor and Consultant in Paediatric Infectious Diseases and Immunology at Great Ormond Street Children’s Hospital, London, and the Institute of Child Health, University College London. He trained at UCL, obtaining degrees in Anatomy and in Medicine. He is currently Head of the Infectious Diseases and Microbiology Unit at ICH. He has been working in the fields of meningitis and sepsis for many years, in both a clinical and academic capacity. Dr Shamez Ladhani, Public Health England, London Dr Shamez Ladhani completed his medical training at the United Medical and Dental Schools of Guy’s and St Thomas’s Hospitals, London, and subsequently specialised in paediatrics. In 2000, he travelled to Kenya to work as a paediatric registrar in a district hospital and then went on to complete a PhD in genetic epidemiology of vaccine preventable infections. During 2007-2009, he completed the two-year national grid training programme in paediatric infectious diseases at St George’s Hospital in South London. Currently, he works as a paediatric infectious disease consultant at St George’s Hospital, clinical lecturer at St George’s University of London and clinical epidemiologist at Public Health England. He is the clinical lead for enhanced national surveillance of a number of vaccine-preventable infections, including Haemophilus influenzae, S. pneumoniae and N. meningitidis. He is also involved with conducting clinical trials on behalf of the Department of Health to inform national immunisation policy.
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Chair & Speaker Biographies Prof David Lalloo, Liverpool School of Tropical Medicine David Lalloo is Professor of Tropical Medicine and Dean of Clinical Sciences and International Public Health at the Liverpool School of Tropical Medicine, Director of the Wellcome Trust Liverpool Tropical Centre and an Honorary Consultant at the Royal Liverpool University Hospital. He trained in Infectious Diseases and Tropical Medicine in London, Papua New Guinea and Oxford. His major research interests are in clinical trials in the tropics, particularly in malaria and HIV related infections and he currently works in a number of countries including Uganda, Malawi, South Africa, Sri Lanka and Vietnam. He is chair of the PHE Advisory Committee on Malaria, a member of the Steering Committee of the UK National Travel Health Network and Centre (NaTHNaC) and is the lead author of the UK malaria treatment guidelines. Prof Michael Levin, St Mary’s Hospital, Imperial College London Michael Levin is Professor of Paediatrics and International Child Health, and Director of the Wellcome Centre for Tropical Clinical Medicine at Imperial College London. He trained in medicine in South Africa and in paediatrics in the UK before specialising in infectious diseases. His research has focused on life threatening infections of childhood. He currently heads an international EU-funded consortium studying novel diagnostic methods for tuberculosis in Africa working with colleagues in Malawi and South Africa. He recently led an ESPID funded consortium studying the genetic basis of meningococcal disease, and is a co-investigator on the MRC funded Phase III trial of fluids as supportive treatment for critical illness in African children (“FEAST”), the results of which are recently published in the New England Journal of Medicine. He is the co-ordinator of a recently funded European Commission FP7 award studying the genetic basis of meningococcal and other life threatening bacterial infections of childhood, working with a consortium of colleagues from Europe, Africa and Singapore.
Edmund Loh, University of Oxford Dr Edmund Loh is a Swedish Research Council postdoctoral researcher, currently working in The Sir William Dunn School of Pathology at University of Oxford. Edmund obtained both his MSc in Biomedicine and PhD in Molecular Biology at Umeå University in Sweden. His main research interest is investigating how bacteria sense their environment and regulate their virulence genes accordingly in an RNA-dependent manner. For the past ten years, Edmund has been researching how RNA molecules (non-coding RNAs) mediate gene regulation in human bacterial pathogens. These RNA molecules are found in bacteria to higher organisms such as humans. Differential expression or mutations in these ncRNAs result in a variety of serious diseases such as cancer, autism and Alzheimer’s. In disease-causing bacteria, dysregulation in ncRNA expression could lead to severe diseases and ultimately death of the host. One of Edmund’s major discoveries was the identification and characterisation of the first transacting riboswitch in Listeria monocytogenes that is capable of functioning both in cis and in trans (Loh et al., Cell 2009). This work established a novel paradigm as it described a new level of RNAmediated gene regulation into the ever-growing and complex world of RNA. Edmund was also involved in setting up the first comprehensive coordinated transcriptional genome map of Listeria monocytogenes grown in different conditions (ToledoArana et al., Nature 2009). He has recently published a paper entitled “Temperature triggers immune evasion by Neisseria meningitidis” (Loh et al., Nature 2013). In this latest work, Edmund and colleagues demonstrated that mechanisms of meningococcal immune evasion and resistance against complement increase in response to an increase in ambient temperature within the human host. Thermoregulation of immune defence could offer an adaptive advantage to the meningococcus during co-infection with other pathogens, and promote the emergence of virulence in an otherwise commensal bacterium.
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Chair & Speaker Biographies Prof Martin Maiden, University of Oxford After an initial training in microbiology, during which he developed an enduring interest in infectious disease and public health, Martin Maiden’s graduate studies used molecular, genetic, and biochemical techniques to study sugar transport in Escherichia coli. He became interested in multi-disciplinary and evolutionary approaches to investigating biological problems and, after a twoyear MRC Training Fellowship, began his independent research career at the National Institute for Biological Standards and Control, where he was a group leader for nine years, including a sabbatical year at the Max-Planck-Institut für Molekulare Genetik, Berlin. In this period he worked mainly on the biology Neisseria meningitidis and its implications for vaccination. In 1997 he moved to a Wellcome Trust Senior Fellowship in Oxford and was appointed Professor of Molecular Epidemiology and a Fellow of Hertford College in 2004. He became a Fellow of the Royal College of Pathologists in 2010 and a Fellow of the Society of Biology in 2012. Dr Simon Nadel, St Mary’s Hospital, London Simon Nadel has been a Consultant in Paediatric Intensive Care since 1994. Prior to this he trained in paediatric infectious diseases. He has been involved in coordinating and running therapeutic trials in children with meningococcal and other septic shock, and has taken part in research studies into the pathophysiology, treatment and outcome of meningococcal disease in children. He has been involved in writing clinical guidelines for the management of children with septicaemia and meningitis. Dr Ifeanyichukwu Okike, St George’s University of London
Dr Okike obtained his medical degree from Uludag University in Bursa, Turkey and did his Internship in Turkey and University Hospital Leuven, Belgium before starting his training in Paediatrics in the UK. The neoMen study and other population based studies will also help put meningitis in the first three months of life into context at a population level. These projects form part of Okike’s PhD with St George’s, University of London and also part of his Specialist Registrar training in Paediatrics. Dr John Perez, Pfizer Vaccine Research, Collegeville, PA, USA Dr John L. Perez is Program and Clinical Lead for Pfizer’s Meningococcal Serogroup B vaccine rLP2086 and is responsible for global clinical development of the vaccine. Dr Perez attended medical school at College of Physicians & Surgeons of Columbia University where he stayed on to complete his training in internal medicine within the Department of Medicine at Columbia University Medical Center. Before that he completed graduate education in Psychology at New York University. Subspeciality training was completed in Infectious Diseases at the Johns Hopkins University School of Medicine while attending the Bloomberg School of Public Health for Clinical Investigation. He was Director of Immunology in 2003 for industry for the clinical development of anti-inflammatory biologics used for the treatment of autoimmune diseases. He joined Pfizer in 2009 to complete the development of the investigational meningococcal serogroup B vaccine. His research interests include infectious complications of biologic therapies and strategies to prevent them, the aging immune system especially in those affected by HIV, and prophylactic and therapeutic vaccine development.
Ifeanyichukwu Okike is a Clinical Research Fellow at St George’s, University of London. He is responsible for coordinating the MRFfunded bacterial meningitis in infants < 90 days of age: burden of disease and assessment of healthcare delivery study (neoMen). Both studies have been collaboration with the British Paediatric Surveillance Unit (BPSU) and Public Health England (PHE).
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Chair & Speaker Biographies Prof Andrew Pollard, University of Oxford Andrew J Pollard, FRCPCH PhD, is Professor of Paediatric Infection and Immunity at the University of Oxford, Director of the Oxford Vaccine Group, James Martin Senior Fellow, Jenner Institute Investigator, Fellow of the Infectious Disease Society of America, Fellow of St Cross College and Honorary Consultant Paediatrician at the Children’s Hospital, Oxford, UK. He obtained his medical degree at St Bartholomew’s Hospital Medical School, University of London in 1989 and trained in Paediatrics at Birmingham Children’s Hospital, UK, specialising in Paediatric Infectious Diseases at St Mary’s Hospital, London, UK and at British Columbia Children’s Hospital, Vancouver, Canada. He obtained his PhD at St Mary’s Hospital, London, UK in 1999 studying immunity to Neisseria meningitidis in children and proceeded to work on anti-bacterial innate immune responses in children in Canada before returning to his current position at the University of Oxford, UK in 2001. He chaired the UK’s NICE meningitis guidelines development group, and the NICE topic expert group developing quality standards for management of meningitis and meningococcal septicaemia. He sits on the Department of Health committee that considers use of meningococcal vaccines and from October 2013 chairs the Joint Committee on Vaccination and Immunisation. He runs a paediatric research group in the UK with 70 staff. Current research activities include clinical trials of new and improved vaccines for children, surveillance of invasive bacterial diseases in children in Nepal, studies of cellular and humoral immune responses to glycoconjugate and typhoid vaccines, and development of a serogroup B meningococcal vaccine. His publications include over 200 manuscripts and books on various topics in paediatrics, infectious diseases, and high altitude medicine.
Dr Louisa Pollock, Wellcome Trust Tropical Centre, Liverpool Louisa Pollock is a general paediatrician with a special interest in infectious diseases and global child health. While working as a paediatric registrar in Malawi in 2006-2007, she gained perspective on the challenges of providing emergency care in resource-limited settings. She became actively involved in ETAT (Emergency Triage, Assessment and Treatment), a WHO training programme which aims to improve paediatric emergency care. In 2008 she led a national ETAT “training of trainers” programme in Malawi with funding from the Scottish Government. On completion of her higher specialist training she worked as a clinical research fellow with Professor Beate Kampmann’s team at Imperial College London and MRC - The Gambia. She assisted with research studies in infant immunology and tuberculosis and helped establish a new training programme in child TB and adapt ETAT to a Gambian setting. In 2013 Louisa was awarded a Wellcome Trust Clinical PhD Fellowship, based at the Wellcome Trust Tropical Centre, Liverpool. Her overall research aim is to address high-burden, high-mortality paediatric problems in resource-limited settings. She is particularly motivated by the inequity of the paediatric research gap - the lack of child-specific data, particularly in diagnostics and in clinical trials, which deprives children worldwide of evidence-based healthcare. She continues to support ETAT training in Malawi as a trustee of the charity Children’s Medical Care Malawi, and is a consultant mentor for the RCPCH ETAT programme in Uganda. Dr Marie-Pierre Préziosi, Meningitis Vaccine Project (WHO/PATH), Switzerland Marie-Pierre Preziosi was appointed in March 2012 as the new director of the Meningitis Vaccine Project (MVP), a partnership between the World Health Organization (WHO) and PATH, established in 2001 through a grant from the Bill & Melinda Gates Foundation, with the mission to eliminate epidemic meningitis as a public health problem in sub-Saharan Africa through the development, testing, introduction, and widespread use of conjugate meningococcal vaccines.
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Chair & Speaker Biographies A project member since 2003, Dr Preziosi most recently served as the director of clinical development, as part of her role as WHO Medical Officer. In this role, she has led the strategy and implementation of the MVP clinical development work, has helped foster strong relationships between the MVP partner organisations, in particular WHO and PATH, and has contributed technical guidance to meningococcal vaccine introduction activities and research to define evidence-based policy for optimal vaccine use. Prior to joining MVP, she was a visiting assistant professor at the Rollins School of Public Health at Emory University in Atlanta, where she conducted research on pertussis vaccination. As an epidemiologist at the Institute for Research and Development, she spent several years in Senegal conducting pertussis vaccine trials. Her interest in vaccines started with Hib vaccine studies at Pasteur Mérieux. Marie-Pierre Preziosi earned her medical degree from Claude Bernard University in Lyon and her PhD in epidemiology from Victor Segalen University in Bordeaux (France). She trained in tropical medicine at the Prince Léopold Institute of Tropical Medicine in Antwerp (Belgium) and in field epidemiology at the Centers for Disease Control and Prevention in Atlanta (USA). Dr Mary Ramsay, Public Health England, London Dr Mary Ramsay obtained her medical degree at University College in London. Before joining the Health Protection Agency she held an academic post at St Mary’s Hospital Medical School in London. She became a Consultant Epidemiologist in 1994 with responsibility for the national surveillance of vaccine preventable diseases, blood-borne hepatitis and transfusion transmissible infections. Since 2009 she has been Head of Immunisation at the Health Protection Agency, and now in Public Health England. She regularly produces information to the Joint Committee on Vaccination and Immunisation to inform policy on vaccination and for a range of groups on the prevention. She is joint Chief Editor of Immunisation Against Infectious Diseases - the recognised national source of advice on vaccination, last published in 2006 and with subsequent updated chapters. She has also been involved in several national guidance documents on public health policy in her disease areas.
In addition she provides expert clinical and public health advice in the field of vaccination and blood borne virus prevention. Her work has directly contributed to several major decisions on national vaccination policy, that, in turn has provided benefits for public health. She often acts as a temporary advisor to WHO on vaccine preventable diseases and advises the European Centre for Disease Control on surveillance and epidemiology of vaccine preventable diseases. Since April this year, her department in Public Health England has now taken on responsibility for implementation and planning of immunisation programmes, requiring her to provide clinical expert leadership to the Screening and Immunisation Teams based in NHS England. Dr Ramsay’s research interests involve establishing the potential role for new vaccines. Prof Robert Read, University of Southampton Professor Robert Read undertook clinical and research training in Leeds, Bristol, London, Nottingham and San Francisco. He was appointed as an academic infectious disease physician at the University of Sheffield in 1995 and served as Professor of Infectious Diseases there from 2002-2012, prior to moving to Southampton in September 2012. Professor Read has research interests in the pathogenesis and prevention of rapidly lethal infectious diseases, especially meningococcal and pneumococcal disease, and influenza. He is the chairman of the Infectious Diseases and Microbiology Speciality Group for the NIHR clinical research network, and chairs the postdoctoral awards panel for the NIHR Personal Training Fellowships scheme. He is the current chairman of the Annual Meeting Program Committee of the Infectious Disease Society of America. He is Editor in Chief of the Journal of Infection and Current Opinion in Infectious Diseases, and is author and co-author of 200 publications mainly in the field of infectious diseases. He was appointed as a member of the UK’s Joint Committee on Vaccination and Immunisation (JCVI) in September 2013.
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Chair & Speaker Biographies Prof Anthony Scott, London School of Hygiene and Tropical Medicine Anthony Scott trained in clinical infectious diseases and epidemiology before moving to the KEMRIWellcome Trust Research Programme in Kilifi, Kenya in 1993. He has spent most of the last 20 years in Kenya, studying pneumococcal disease and pneumonia in children and adults, and vaccines to prevent them. Currently a Wellcome Trust Senior Research Fellow in Clinical Science, Anthony works in clinical paediatrics in Kilifi. He joined the London School of Hygiene and Tropical Medicine in January 2013 after 15 years based at Oxford University and teaches on the short course on the Epidemiological Evaluation of Vaccine, the Intensive Course on Epidemiology and Medical Statistics and the Diploma course in Tropical Medicine & Hygiene. In addition to research Anthony has developed a surveillance network for invasive bacterial diseases in East Africa and co-directs the Kilifi Health and Demographic Surveillance System. He works frequently with WHO and GAVI on vaccine preventable diseases and with the Ministry of Health in Kenya on the evaluation of pneumococcal vaccine. Anthony Scott’s main research interests are in child health and vaccines in East Africa. He runs the Pneumococcal Conjugate Vaccine Impact Study, an effectiveness evaluation of vaccine introduction in Kenya, and a series of associated studies of transmission and modelling of pneumococcal disease, evaluation of vaccine safety, and pathogen population structure. Anthony also works closely with the International Vaccine Access Center at John Hopkins School of Public Health on a project called PERCH (Pneumonia Etiology Research for Child Health) which is a 7-site case-control study of the aetiology of pneumonia in children. Anthony is interested in the epidemiology of invasive bacterial infections in children and the way that they shape childhood mortality, and in international vaccine policy and the economic and epidemiological evaluations required to support that policy.
Dr Karen Slobod, Novartis Global Development, USA Dr Karen Slobod received her medical degree from McGill University in Montreal, completed a residency in paediatrics and then a fellowship in infectious diseases and immunology at St Jude Children’s Research Hospital in Memphis, TN. She joined the faculty of the Department of Infectious Diseases at St Jude and pursued basic and clinical research in vaccine development. She joined Novartis Vaccines & Diagnostics in 2007 and is currently the head of the Maternal Immunization Global Program Team, responsible for the development of the group B streptococcus maternal vaccine. She is based in Cambridge, Massachusetts, USA. Dr Matthew Snape, University of Oxford Dr Matthew Snape is a consultant in General Paediatrics and Vaccinology at the Oxford University Hospitals NHS trust and an Honorary Senior Clinical Lecturer at the University of Oxford. After completing basic training in paediatrics at the Royal Children’s Hospital, Melbourne, he spent 18 months working in the paediatric intensive care unit at St Mary’s Hospital, London. While caring for children suffering overwhelming infections he developed an interest in the prevention of these illnesses by immunisation. This led him to the Oxford Vaccine Group, University of Oxford, where he has been the principal investigator on paediatric studies of meningococcal, pneumococcal, influenza and Hepatitis B vaccines. Dr Snape is partially funded by the Oxford Partnership Comprehensive Biomedical Research Centre.
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Chair & Speaker Biographies Prof Christoph Tang, University of Oxford Professor Christoph Tang is currently Professor of Cellular Pathology at the Sir William Dunn School of Pathology at the University of Oxford, having recently moved from the Centre for Molecular Microbiology and Infection at Imperial College London. His group studies the pathogenesis and prevention of disease caused by Neisseria meningitidis and Shigella flexneri, particularly during interactions with the host innate immune system. He was previously an MRC Clinician Scientist at the University of Oxford, and completed his PhD at the Royal Postgraduate Medical School on the identification of virulence factors in the fungal pathogen, Aspergillus fumigatus. Christoph originally trained in medicine at the University of Liverpool and spent two years working in The Gambia, West Africa. Dr Caroline Trotter, University of Cambridge Dr Caroline Trotter is an infectious disease epidemiologist at the University of Cambridge. Her research focuses on assessing the potential and actual impact of vaccination against different forms of bacterial meningitis on a population level. She uses a range of research methods including mathematical modelling, costeffectiveness analyses, carriage studies, analyses of large databases and seroprevalence studies. She is currently working with the African Meningococcal Carriage Consortium, MenAfriCar (www.menafricar. org).
Dr Fiona van der Klis, Public Health Institute of the Netherlands (RIVM) Fiona van der Klis, PhD, is Head of the Department Immunesurveillance within the Centre Infectious Disease Control of the Public Health Institute of the Netherlands (RIVM). Fiona obtained her PhD in endocrinology and immunology before accepting a research position in the Dutch Antilles. In 2000, she joined the RIVM and has since then increased her knowledge on infectious diseases. Here she leads a group of scientists working in the field of vaccine preventable diseases. The department has extensive experience in monitoring seroprevalence (all components of the national immunisation program), measuring immune responses to natural infection or vaccination and determining the duration of immunity. For this, state of the art techniques are implemented at the laboratory that can measure the quantity and quality of the immune responses after vaccination. The department is one of the leading laboratories in the multiplexed serology field and conducts clinical trials to optimise the national immunisation program. Fiona is involved in several (inter)national projects covering multiple pathogens and themes e.g. MenC immunity (second immunisation study), HPV immunity (monitoring effect of introduction of vaccine, high risk groups like MSM), measles antibodies and elimination goal (WHO, SSI), vaccine responses in immune compromised adolescents and vaccine responsiveness in the ageing population. Fiona is the project leader of a large populationbased study monitoring the protection against the vaccine preventable diseases. This study is an important part of the evaluation of the Dutch National Immunisation program. In addition, she is also project leader of the harmonisation of the immunisation programme of the Dutch Caribbean Islands.
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Poster Presentations Pathogenesis P1-8
Epidemiology & Surveillance E9-22
Clinical Diagnosis, Treatment & Sequelae C23-29
Public Health Management PH30
The posters are displayed in Cavendish. Please visit during breaks, lunchtime and the wine reception. Presenters will be on hand to discuss their work. The five oral presentations and awarding of the poster prize will take place after lunch on Wednesday 6 November.
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Pathogenesis P1 Transcriptional response of pathogenic Neisseria meningitidis with non-phagocytic cells Hajah Mohd Afsar, Tom Mendum, Jane Newcombe, Kikki Bodman-Smith and Johnjoe McFadden Faculty of Health and Medical Sciences, University of Surrey, Guildford UK
Email: email@example.com Neisseria meningitidis is a Gram-negative bacterial pathogen that remains a leading cause of systemic meningococcal infection ranging from bacteraemia, meningitis, and fulminant meningococcal septicaemia world-wide. The ability to adhere to and invade a range of human origin cells is an absolute necessity for N. meningitidis to colonise and disseminate inside its host and so to cause the rapid and damaging invasive form of the disease. From previous studies it has been established that two-component regulatory systems such as PhoP/PhoQ are involved in processes which are crucial for bacterial pathogenesis. We focused on investigation of the specific role played by the N. meningitidis PhoP regulator in the interaction of meningococci with human epithelial cells. In this study, to facilitate confocal microscope studies, bacteria were made fluorescent by transforming them with a Green Fluorescent Protein plasmid. A549 epithelial cells, a respiratory human cell line were challenged with the fluorescent N. meningitidis strain wild-type (L91543) and N. meningitidis strain phoP mutant (L91543/NMB0595 knockout mutant). Thus an epithelial colonisation model was developed to compare the binding and uptake ability of the phoP mutant with the parental wild-type via adhesion and invasion assays. The influence of colonisation on the host cell cytoskeleton during bacterial adhesion and invasion was also examined by confocal microscopy. Finally we analysed the transcriptome of N. meningitidis wild-type and the phoP mutant with and without epithelial cell interaction via a comparative genome hybridisation approach using microarray technology. Our findings demonstrated that the N. meningitidis phoP mutant shows a defect in adherence to and invasion into epithelial cells and this is independent of numbers or replications in cultures. The active nature of the invasion was confirmed by inhibition by cytocholasin D and less damaging of the cell membrane by the phoP mutant was observed by confocal microscopy. Our data suggested that PhoP regulator of the two-component system is involved in the colonisation process of the N. meningitidis.
This fits with our hypothesis that some of the genes controlled or influenced by the PhoP regulator are involved in the N. meningitidis virulence. We have identified some important virulence genes including nspA, tbpA, tbpB and clpB that were differentially significantly regulated in the phoP mutant as revealed by the transcriptomic microarray data. These findings may lead to further identification and characterisation of the novel targets for drug design and future therapeutics.
P2 - Oral Presentation, day two Temperature triggers immune evasion by Neisseria meningitidis Edmund Loh1,2, Elisabeth Kugelberg2, Alexander Tracy1, Qian Zhang2, Bridget Gollan2, Helen Ewles2, Ronald Chalmers3, Vladimir Pelicic2, Christoph M. Tang1,2 1
Sir William Dunn School of Pathology, University of Oxford, Sir Parks Road, Oxford OX1 3RE, UK; 2Centre for Molecular Microbiology and Infection, Imperial College London, London SW7 2AZ, UK; 3School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2NR, UK
Email: firstname.lastname@example.org Neisseria meningitidis has several strategies to evade complement mediated killing, and these contribute to its ability to cause septicaemic disease and meningitis. However, the meningococcus is primarily an obligate commensal of the human nasopharynx, and it is unclear why the bacterium has evolved exquisite mechanisms to avoid host immunity. Here, we demonstrate that mechanisms of meningococcal immune evasion and resistance against complement increase in response to an increase in ambient temperature. We have identified three independent RNA thermosensors located in the 5Â´-untranslated regions of genes necessary for capsule biosynthesis, the expression of factor H binding protein, and sialylation of lipopolysaccharide, which are essential for meningococcal resistance against immune killing. Therefore increased temperature (which occurs during inflammation) acts as a â€˜danger signalâ€™ for the meningococcus, enhancing its defence against human immune killing. Infection with viral pathogens, such as influenza, leads to inflammation in the nasopharynx with an increased temperature and recruitment of immune effectors. Thermoregulation of immune defence could offer an adaptive advantage to the meningococcus during co-infection with other pathogens, and promote the emergence of virulence in an otherwise commensal bacterium.
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Pathogenesis P3 Functional tspB genes are essential for meningococcal survival in human serum Maike G. Müller, Patrick G. Wall, Gregory R. Moe Center for Immunobiology and Vaccine Development, Children’s Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609
Email: email@example.com Keywords: T and B cell stimulating protein B (TspB), prophage, serum survival, IgG-binding protein, DNAbinding protein Background: In developed countries meningococcal disease is relatively rare. However, nasopharyngeal carriage of meningococci without disease is relatively common, ranging from 5% to >80% depending on the population studied. A study of carriage versus disease-causing strains during an epidemic in the Czech Republic showed that prophage DNA was associated with disease-causing strains (Bille et al. 2006, J Exp Med). However, the reasons for the association of prophage DNA with pathogenicity were not determined. Recently, we showed that prophage gene ORF6, whose product, T and B cell stimulating protein B (TspB), is an IgG-binding protein specific for the Fc domain of human IgG2 (Müller et al. 2013, J Immunol). In addition, we found that bacteria grown in the presence of human serum form aggregates enveloped in a matrix of TspB, IgG and DNA that has characteristics of biofilm. Objective: The aim of this study was to determine whether tspB expression had an effect on meningococcal survival in human serum. In addition, we investigated whether functional activities of TspB that give rise to the aggregate/biofilm phenotype can be attributed to specific subdomains of the protein. Methods: Mutants of group B strain H44/76 in which combinations of multiple tspB genes were knocked out were tested for their ability to survive in different concentrations of normal human serum (NHS) or IgGdepleted NHS (dNHS). The effect on serum survival was compared to mutants in which other survival factors such as capsular polysaccharide and factor H binding protein had been knocked out. To investigate the functional activities of TspB, we produced and purified recombinant proteins corresponding to highly conserved subdomains, then characterised their Ig- and DNA-binding activities by ELISA and agarose gel shift assay, respectively.
Results: Knocking out 3 of 3 tspB genes in H44/76 was equivalent to knocking out production of capsular polysaccharide, which was essential for survival. At least two functional copies of tspB were required for survival in >5% NHS or dNHS. In contrast, knocking out fHbp affected survival only at higher concentrations of NHS (>20%) and had no effect on survival in dNHS. Binding activities of TspB to IgG2 Fc and non-specific DNA were localised within separate structural domains. Conclusions: The IgG- and DNA-binding activities of TspB facilitate formation of a biofilm that appears to protect the bacteria from activities leading to bacteriolysis in human serum. The results suggest one possible reason why strains carrying prophage DNA are more likely to be associated with disease.
P4 Inhibition of matrix metalloproteinases attenuates brain damage in experimental meningococcal meningitis Susanna Ricci1,5, Michael Wenzel2, Denis Grandgirard3,5, Tiziana Braccini1, Marco Rinaldo Oggioni4,5, Uwe Koedel2,5, Stephen Leib3,5. 1
LAboratory of Molecular Microbiology and Biotechnology (LA.M.M.B.), Department of Medical Biotechnologies, University of Siena, Italy; 2Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians University, 81377 Munich, Germany; 3Institute for Infectious Diseases, University of Bern, 3010 Bern, Switzerland; 4 Department of Genetics, University of Leicester, Leicester LE1 7RH, UK; 5The ESCMID Study Group for Infectious Diseases of the Brain (ESGIB)
Email: firstname.lastname@example.org Keywords: Neisseria meningitidis, experimental meningococcal meningitis, brain damage, matrix metalloproteinases Background: Neisseria meningitidis is the major causative agent of acute bacterial meningitis in infants, children and young adults. Mortality due to meningococcal meningitis (MM) varies from 4 to 8%, and approximately 5-20% MM survivors suffer from neurological sequelae due to brain damage in the course of meningitis. There are several mediators of brain damage, including matrix metalloproteinases (MMPs). Objectives: Assess the efficacy of a broad metalloproteinase inhibitor, batimastat (BB-94), in a novel model of MM-induced brain damage in the mouse.
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Pathogenesis Methods: The brain damage model is based on i.cist. infection of 6-7 week old BALB/c mice with a serogroup C N. meningitidis strain. Mice were treated with BB-94 at the time of infection and 24h post-infection. Control and treated animals were humanely sacrificed 48h after i.cist. challenge. Enzymatic activity of MMPs in cerebella of infected mice, intracerebral haemorrhages, integrity of the blood-brain barrier (BBB), and apoptosis in the hippocampus were analysed. Results: Mice that received BB-94 presented significantly lower zymographic activity of MMP-9 compared to controls (P<0.001). Treated mice also showed reduced intracerebral bleeding (P<0.05) and diminished BBB breakdown (P<0.05) in comparison with untreated animals. In contrast, no differences in apoptosis were observed between the groups. Finally, zymography data significantly correlated with both BBB disruption (P<0.05) and intracerebral haemorrhages (P<0.001). Conclusions: The MM-induced brain damage model established in the mouse is an effective tool to analyse several crucial readouts in the disease. By using this mouse system, we have shown that: (i) MMPs significantly contribute to experimental MM, and (ii) inhibition of MMPs reduce intracranial complications in mice suffering from MM, thereby representing a potential adjuvant molecule in MM post-infection sequelae.
to environmental cues, however, the precise mechanisms of such regulation are as yet unclear. Previous studies have revealed that the transcription of pilE, which encodes the major pilin subunit, is influenced by the RNA chaperone Hfq, suggesting that noncoding RNAs may be involved in pilE regulation. We have identified a putative promoter for expression of a cis-encoded RNA in the antisense strand of pilE. This putative promoter is conserved across N. meningitidis isolates from different strains and clonal complexes, suggesting that it may play an important role in mediating pilE expression or pilin function. By performing mutational analysis of this promoter along with Northern blotting and strand-specific RT-PCR, we have shown that the promoter is functional in an ectopic E. coli system. We have successfully introduced the promoter mutation into a wild type strain of N. meningitidis and are currently investigating the possible function of the pilE antisense and its mechanism of action in this important human pathogen.
P5 Characterisation of pilE antisense RNA in Neisseria meningitidis Felicia Tan, Edmund Loh, Christoph M. Tang and Rachel M. Exley Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK
Email: email@example.com Keywords: Neisseria meningitidis, gene regulation, type four pili, pilin, small RNA Expression of Type four pili (Tfp) is important for virulence in Neisseria meningitidis. Pili mediate adhesion to host surfaces, twitching motility, DNA uptake, and are subject to phase and antigenic variation. Pili are important for the survival of the meningococcus during colonisation and disease. Moreover, the extensive antigenic variation of Tfp has been proposed to enable the bacterium to avoid immune surveillance. Pilin expression and antigenic variation may be modulated in response
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Pathogenesis P6 The role of multiple copies of the capsulation b locus of Haemophilus influenzae serotype b (Hib) in resisting antibody-dependent, complement mediated bacteriolysis using a functional serum bactericidal assay Kelly Townsend1, Helen Findlow1, Xilian Bai1, Shamez Ladhani2, Mary Slack3, Ray Borrow1 1
Vaccine Evaluation Unit, Public Health England, Manchester Royal Infirmary, Manchester; 2Immunisation, Hepatitis and Blood Safety Department, Public Health England, London; 3Respiratory and Systemic Infection Laboratory, Public Health England, London
Keywords: cap b copy, Hib, SBA assay, Hib vaccine failure, Hib polysaccharide Background: The Haemophilus influenzae serotype b (Hib) polysaccharide capsule, which is encoded by the capsulation (cap) b locus, is a major virulence factor and plays an important role in evading the host immune system by resisting complement-mediated lysis and opsonisation. Up to five copies have been detected in clinical isolates from individuals with invasive disease. Such strains with multiple copies of the cap b locus have been shown to produce significantly more capsular polysaccharide than strains with fewer copies of the cap b locus. In addition, an isogenic strain containing four copies of the cap b gene was shown to be significantly more resistant to complement-mediated, antibodydependent bacteriolysis as well as complementmediated opsonisation by macrophages when compared to a two-copy strain. A recent study reported that children who had been fully vaccinated against Hib were three times more likely to have been infected by a Hib isolate with more than two copies of the cap b gene than unvaccinated paediatric controls. The objective of this study was to use a newly-developed Hib serum bactericidal assay (SBA) to assess the functional relevance of multiple cap b loci in clinical isolates from patients with invasive Hib disease. Methods: A total of 164 serum samples collected from children who developed invasive Hib disease despite having being vaccinated against Hib (vaccine failures) were tested using the Hib SBA against five Hib strains containing 1, 2, 3, 4 or 5 copies of the cap b locus. Geometric mean titres (GMTs) and proportion of children achieving a Hib SBA titre of ≥8 were calculated for samples assayed against each strain at T0 and T60 time points.
Results: Of the 164 serum samples, 127 had sufficient serum for testing against all Hib strains. Geometric mean SBA titres for strains expressing 1, 2, 3, 4 and 5 copies of the cap b locus at time T60 were 46 (95% CI, 29-73), 24 (95% CI, 15-38), 43 (95% CI, 27-69), 55 (95% CI, 33-90), and 20 (95% CI, 13-31), respectively. Overall, there was no association between the number of cap b copies and either Hib SBA GMT or the proportion of children achieving a Hib SBA titre of ≥8. Conclusions: The lack of association between cap b copy numbers and Hib SBA titres suggests that, although increased capsule production may be advantageous in evading complement killing, antibodies against other Hib surface proteins may play an important role inducing bactericidal activity.
P7 Antibody-mediated complement C3b binding to Group B Streptococcus in paired mother and baby serum samples in a refugee population at the ThaiMyanmar border Stephen Thomas1, Jenny Herbert1, Charlotte Brookes1, Claudia Turner2,3,4, Paul Turner2,3,4, Paul T. Heath5, Andrew Gorringe1, Stephen Taylor1 Public Health England, Porton Down, Salisbury; 2Shoklo Malaria Research Unit, Mae Sot; 3Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand; 4Centre for Tropical Medicine, University of Oxford, Oxford; 5Paediatric Infectious Diseases Research Group, Clinical Sciences, St George’s, University of London, UK 1
Keywords: GBS, complement, immunity, vaccine, flow-cytometry Streptococcus agalactiae (group B Streptococcus; GBS) is currently the leading cause of neonatal sepsis and meningitis. Previous studies have shown that opsonophagocytosis determined in a bacterial killing assay may correlate with protection provided by serotype-specific polysaccharide conjugate vaccines. This opsonophagocytosis assay requires a large serum volume and only small number of samples can be evaluated at one time. Thus we have developed a flow cytometry assay to quantify antibody-mediated complement C3b deposition onto GBS bacteria representing the five most prevalent GBS. We have used this assay to determine antibodymediated C3b binding to GBS serotypes 1a, 1b, II, III and V using 1068 sera taken from mothers and
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Pathogenesis cord pairs obtained at the time of birth at the ThaiMyanmar border (Turner et al., 2012, BMC Infect Dis). The initial aim of the study was to determine the level of functional antibody in neonates required to prevent disease. However, there were no cases of GBS disease during the sampling period. The distribution of antibody-mediated C3b binding determined in the sample cohort corresponded with the carriage data, with the highest levels of C3C deposition observed to the most prevalent serotype in this region (serotype II) followed by serotypes 1a, III, V and 1b. Neonates born to mothers carrying serotype II GBS at the time of birth showed higher antibodymediated C3b deposition against serotype II GBS than neonates born to mothers with no carriage. Thus these neonates at risk were likely to be protected from disease by maternal antibody. The trend of higher antibody-mediated C3b deposition in neonates born to carriage positive mothers was also observed for serotype 1a, and likely was not observed for the other three serotypes tested due to small numbers of carriage positive mothers in the study. A maternal GBS carriage rate of 12% was observed in this population, yet detectable antibody-mediated C3b deposition was detected to at least one serotype in 91% of mothers, suggesting carriage may be underestimated in this region or that carriage occurs transiently.
P8 The choroid plexus epithelia as an alternative bacterial entry point into the brain in E. coli K1associated neonatal meningitis Andrea Zelmer & Theresa H. Ward Infection and Immunology Department, London School of Hygiene and Tropical Medicine, London, UK
colonise the intestine and cross the intestinal barrier into the blood stream, before entering the central nervous system (CNS). It has been widely suggested that bacteria cross the blood-brain-barrier by invading and traversing the cells of the cerebral microvascular endothelium. Some studies showed that the epithelial lining of the choroid plexus, the part of the brain where the cerebrospinal fluid is produced, may be an alternative port of entry into the CNS; however this notion is poorly studied, and the potential mechanisms are incompletely understood. In this study we aim to investigate the possibility of E. coli K1 invasion and traversal of the choroid plexus epithelium by utilising an in vitro model of the choroid plexus epithelial barrier. To test our hypothesis, a choroid plexus derived epithelial cell line, Z310, was infected with pathogenic E. coli K1 and nonpathogenic E. coli K12 as a control. A gentamicin exclusion assay followed by a colony forming units assay was performed to assess invasion efficiency of E. coli K1 compared to the nonpathogenic E. coli K12 strain. Intra- or extracellular location of the bacteria was confirmed by confocal microscopy. We found that Z310 cells were efficiently invaded by E. coli K1 but not by E. coli K12. Further, K1 bacteria exhibited cytotoxic effects on Z310 cells and infection led to damage of cellular monolayers. These results strengthen the notion that E. coli K1 can use the choroid plexus epithelium as an alternative port of entry into the CNS during neonatal bacterial meningitis. The mechanisms of entry are unclear, and we are currently investigating the molecular host-pathogen interactions. This work could potentially identify new host targets required for bacterial CNS invasion, leading to the design of new treatments for neonatal bacterial meningitis in the future.
Email: firstname.lastname@example.org Keywords: neonatal bacterial meningitis, E. coli K1, choroid plexus, blood-brain-barrier Neonatal bacterial meningitis (NBM) is a devastating disease, which often leaves affected newborns with serious neurological sequelae. The Gram-negative bacterium E. coli is a major cause of NBM, and accounts for approximately 20% of cases of NBM in the UK and Ireland. The K1 polysaccharide capsule is a major virulence factor, and 80-85% of E. coli isolates from NBM cases carry the K1 capsular antigen on their surface. Upon infection, the bacteria
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Epidemiology & Surveillance E9 Epidemiology and molecular typing of Neisseria meningitidis capsular group W in England and Wales, 2000-2013 Kazim Beebeejaun1, Helen Campbell1, Ray Borrow2, Mary Ramsay1, Steve Gray3, Ed Kaczmarski2, Jay Lucidarme1, Shamez Ladhani1 Public Health England Immunisation Department; 2Public Health England Vaccine Evaluation Unit, Public Health Laboratory, Manchester; 3Public Health England Meningococcal Reference Unit
Email: email@example.com Keywords: N. meningitidis, Epidemiology, W-135, MenW Introduction: Invasive meningococcal disease caused by capsular group W (MenW) incidence has been increasing in England and Wales since 2008. The study describes the epidemiology and molecular characteristics of invasive MenW disease in England and Wales during 2000-2013. Methods: Public Health England (PHE) routinely conducts enhanced surveillance of invasive meningococcal disease through a combination of clinical reporting and laboratory confirmation and characterisation of clinical isolates submitted to the national Meningococcal Reference Unit (MRU). Results: Following the control of national outbreaks related to Hajj pilgrimages in the early 2000s, the number of laboratory-confirmed, invasive MenW cases declined to its lowest in 2008 (19 cases). After 2008, however, MenW cases increased year-on-year to 46 in 2012. In 2013, 20 cases were identified in the first 3 calendar months, which is more than in the whole of 2008. In contrast, the total number of laboratory-confirmed, invasive meningococcal cases has declined from 1256 in 2008 to 746 in 2012. MenW was responsible for 7% of all invasive meningococcal cases in 2012, compared with 1.5% in 2008. Molecular analysis of MenW isolates revealed the increase to be associated with serotype 2a, a predictor of ST/cc11. Cases of MenW:2a increased from 0 cases in 2008 to 25 cases in 2012. In the first 3 months of 2013, MenW:2a was responsible for 14 of the 20 (70%) reported cases. All but one of the 79 non-2a cases during 2008-2013 were caused by non-typeable MenW (MenW:nt), which did not increase during the surveillance period. The age distribution of MenW:2a cases was similar to MenW:nt, with most cases occurring in children and in older adults aged â‰Ľ65 years.
Case fatality was also comparable (5/60 [8.3%] vs. 9/79 [11.4%] cases; P=0.55). Conclusions: An increase in invasive MenW cases has been observed in England and Wales since 2008. This increase was associated with serotype 2a, a predictor of cc11, which was previously associated with MenC disease carrying a worse than average prognosis. Although the disease profile of MenW:2a is currently comparable with MenW:nt this increase warrants careful monitoring in the coming years.
E10 The epidemiology of community-acquired bacteraemia in Liverpool Edward Bevan & Neil French Institute of Infection & Global Health, University of Liverpool and Royal Liverpool & Broadgreen University Hospital Trust
Email: firstname.lastname@example.org; edwardbevan@ me.com Keywords: community-acquired bacteraemia, deprivation, co-morbidity Background: Bacteraemia represents the most significant culmination of any bacterial infection and carries extremely high morbidity and mortality. Few contemporary studies describe the epidemiology of community acquired bacteraemia in the UK1. Objectives: lD escribe the incidence and causes of community acquired bacteraemia in adults in Liverpool: January 2010 to July 2012. lL ink these data with population data, to provide estimates of bacteraemia incidence by age group, district of residence, social deprivation and relationship to patient co-morbidity. Methods: This is a retrospective study, linking hospital data with local population data. Community acquired bacteraemia is defined as a positive blood culture collected within 48 hours of admission to hospital. All positive blood cultures in the study period were linked with hospital admissions data to separate communityacquired from nosocomial bacteraemias. Isolates considered to be contaminants were excluded according to CDC criteria2. This dataset was linked with local population data from national census records3, to produce incidence rate estimates by age group, postcode district and deprivation index, and relationship to patient comorbidity.
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Epidemiology & Surveillance Results: There were 748 episodes of communityacquired bacteraemia during the study period. The overall annual incidence rate of community-acquired bacteraemia was 81.5 per 100,000 (95% CI 75.787.3). The most common organisms were: E. coli (32%), S. aureus (12%), S. pneumoniae (8%), K. pneumoniae (7%), and anaerobic organisms (4%). S. pyogenes accounted for 3%. The annual incidence of community-acquired bacteraemia in adults was found to increase with increasing age. In the >75 age group the incidence rate was: 196.6 per 100,000 (95% CI 173.8-219.4). The incidence rates of bacteraemia by postcode district within the catchment area of the Royal Liverpool University Hospital were also determined. Deprivation scores were determined for each postcode district. We found that the rate of community-acquired bacteraemia was directly proportional to deprivation score (R2=0.47). Many patients who developed bacteraemia had underlying co-morbidities: for S. pneumoniae, 19% had chronic pulmonary disease, 13% had ischemic heart disease and 3% had type 2 diabetes mellitus. Conclusions: This study outlines the epidemiology of community-acquired bacteraemia in Liverpool. Unsurprisingly, we found a strong relationship between patient age and incidence of communityacquired bacteraemia. There was also a positive correlation between deprivation and incidence of community-acquired bacteraemia, and a large proportion of patients with bacteraemia had underlying co-morbidities. Understanding the epidemiology of serious community acquired bacterial infection will allow the rational implementation of novel public health interventions. References 1. Hounsom L, Grayson K, Melzer M. Mortality and associated risk factors in consecutive patients admitted to a UK NHS trust with community acquired bacteraemia. Postgrad Med J 2011; ;87:757762 2. CDC, Laboratory-Confirmed Bloodstream Infection Criteria, Central Line-Associated Bloodstream Infection (CLABSI) Event, January 2013. 3. http://www.ons.gov.uk/ons/guide-method/census/2011/index.html
E11 Antibiotic susceptibility profile of Neisseria meningitidis and Haemophilus influenzae invasive isolates in Croatia Suzana Bukovski1,2 1
University Hospital for Infectious Diseases “Dr Fran Mihaljevi”, Zagreb, Croatia; 2Faculty of Medicine Osijek, University Josip Juraj Strossmayer in Osijek, Croatia
Keywords: Neisseria meningitidis, Haemophilus influenzae, antibiotic, susceptibility, profile Introduction: In Croatia invasive disease (ID), meningitis and/or sepsis, in children is mainly caused by Neisseria meningitidis also in recent years cases in older adults take attention too. On contrary incidence of invasive disease caused by Haemophilus influenzae (IHD) decreased after introduction of conjugate Hib vaccine in 2002. Nevertheless in last five years 10 cases of IHD are recorded and 6 of them in adults caused by H. influenzae non b type. The basis of ID treatment together with supportive care is prompt antibiotic treatment. Therefore antibiotic profile of invasive Neisseria meningitidis and Haemophilus influenzae is of utmost importance. Material and methods: Data of antibiotic susceptibility testing of invasive isolates of Neisseria meningitidis from 2005 to March 2013 and invasive isolates of Haemophilus influenzae from 2008 to 2012 were analysed. For Neisseria meningitidis minimal inhibitory concentration (MIC) using gradient diffusion test (E-test Bio Merieux) on Mueller-Hinton blood agar was done while for Haemophilus influenzae disk diffusion test was done and data were interpreted as susceptible (S), intermediate (I) and resistant (R). Only for 2 isolates MIC for ampicillin and ceftriaxone were done. Results were interpreted according to Clinical Laboratory Standard Institute (CLSI till 2011) and European Committee on Antimicrobial Susceptibility Testing (EUCAST from 2011) recommendations. Results: Antibiotic sensitivity was available for 92 N. meningitidis isolates. All isolates were tested to penicillin (MIC 0,004 µg/mL - 0, 50 µg/mL). Penicillin MIC50 was 0,023 µg/mL while MIC90 was 0,094 µg/ mL. Ceftriaxone was tested for 91 isolates having MICs 0,002 µg/mL- 0,094 µg/mL and MIC90 0,002 µg/mL.
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Epidemiology & Surveillance Sixty two isolates were tested to ciprofloxacin having very low MICs 0,002 µg/mL – 0,006 µg/mL and MIC90 0,003 µg/mL. All isolates were tested to rifampicin (MIC 0,002 µg/mL - 0,064 µg/mL) with MIC90 0,016 µg/mL. All 10 H. influenzae isolates were susceptible to amoxiclav, ceftriaxone and co-trimoxazole and 9/10 were susceptible to amoxicillin. Ampicillin MIC of two isolates were 0,094 and 0,19 µg/mL and for ceftriaxone 0,002 and 0,004 µg/mL. According to EUCAST interpretation cefuroxim for per oral administration has to be interpreted only as (I) or (R) so 3 isolates were interpreted as (I) and 2 (R). Conclusion: Antibiotic sensitivity profile of N. meningitidis is changing through time and increasing penicillin MIC having MIC90 0,094 µg/ mL were recorded. Taking into consideration that more than 50% of IMD were confirmed only by PCR introduction of penA detection routinely should be accelerated. Low ceftriaxone MIC90 and low MICs of ciprofloxacin and rifampicin provide further safe therapeutic and prophylactic use. Between Croatian invasive H. influenzae betalactamase negative ampicillin resistant (BLNAR) or beta-lactamase positive amoxiclav resistant (BLPACR) isolates emerging in the world were not found. Cefuroxim resistant isolates interpreted according to EUCAST has to be taking in consideration for otitis media treatment.
E12 Development of an African adapted PCR algorithm to characterise Neisseria meningitidis from carriers, including uncommon capsular groups Diallo K1, Coulibaly MD1, Rebbetts, LS2, Harrison OB2, Lucidarme J3, Gamougam K4, Tekletsion YK5, Bugri A6, Toure A1, Issaka B7, Dieng M8, Trotter C9, Stuart, JM10, Collard JM7, Sow SO1, Wang X11, Borrow R3, Greenwood B10, Maiden MCJ2, Manigart O10. 1
Centre pour le Développement des Vaccins (CVD), Bamako, Mali; 2University of Oxford (Department of Zoology), Oxford, UK; 3Public Health England, (PHE – Vaccine Evaluation Unit), Manchester, UK; 4Centre de Support en Santé Internationale (CSSI), Ndjamena, Chad; 5Armauer Hansen Research Institute (AHRI), Addis Ababa, Ethiopia; 6Navrongo Health Research Centre (NHRC), Navrongo, Ghana; 7Centre de Recherche Médicale et Sanitaire (CERMES), Niamey, Niger; 8Institut de Recherche pour le Développement (IRD), Dakar, Senegal;
University of Cambridge (Disease Dynamics Unit -Department of Veterinary Medicine), UK; 10London School of Hygiene and Tropical Medicine (LSHTM), London, UK; 11Centre for Disease Control, (CDC – Division of Bacterial diseases), Atlanta, USA
Email: Olivier.email@example.com Keywords: Neisseria meningitidis, Molecular characterisation, African Meningitis Belt, carriage, uncommon capsular groups Introduction: Improvement of detection of Neisseria meningitidis (Nm) is crucial for reliable laboratory diagnosis of meningococcal carriage and better understanding of its epidemiology in the meningitis belt. The African Meningococcal Carriage Consortium (MenAfriCar) has established a simple gel-based PCR for detection and characterisation of NmA, NmW, NmX and NmY, but little is known on the epidemiology of the less common capsular groups (H, E, Z, cnl). We have developed a PCR algorithm that allows simple, rapid and systematic characterisation of all Nm capsular groups using two PCR techniques: gel-based, cheaper but labour intensive, and real-time (RT), more expensive but faster. Samples and methods: Pre-existing primers for gel-based PCR and RT-PCR were blasted against consensus sequences obtained from the Oxford database (ODB). Primers for gel-based PCR (sodC, H, Z) and RT-PCR (porA, cnl, H, E, Z) were created or modified using Primer Express software. A total of 184 isolates from seven African countries were chosen from the first MenAfriCar cross-sectional study in parallel with a panel of 16 positive controls to optimise the PCR algorithm. All samples were characterised at the Department of Zoology, University of Oxford. Positive controls and 38 samples from Mali were utilised in monoplex and multiplex for PCR optimisation. Other isolates were characterised using optimised gel-based and RT-PCR multiplex only. Sensitivity, Specificity, Positive Predictive value (PPV) and Negative Predictive value (NPV) were determined for each primers/probe PCR using Oxford’s results as the Gold Standard. Results: Some existing primers and probes were modified following identification of mismatches between published and consensus sequences available in ODB.
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Epidemiology & Surveillance Our newly designed algorithm allows simultaneous identification of Nm and determination of expression of capsule genes through a first porA, sodC, cnl multiplex PCR; if the isolate is sodC, porA positive and cnl negative, three sequential multiplex PCR from most common capsular groups were initially used: A, W, X, followed by B, C, Y and finally H, E and Z. Sensitivity of our pairs of primers, considered separately, in the multiplex assays range from 75% (porA) to 100%; specificity from 91% (porA) to 100% for gel-based assays; PPV ranges from 60% to 100% and NPV from 64% (porA) to 100%. For RTPCR assays, sensitivity ranges between 50-100%, specificity 74-100%, PPV 50-100% and NPV 89100%. All uncommon capsular groups were detected. Conclusions: Our results demonstrate that a systematic approach for characterisation of 10 different Nm capsular groups using four multiplexes can be used. This tool will allow better understanding of the epidemiology of rare carriage strains in the African meningitis belt. This study was funded by Meningitis Research Foundation.
E13 Genetic characterisation of invasive Neisseria meningitidis isolates in Belarus Glazkova S, Lebedzeu F, Yanovitch O, Nosova E, Titov L Laboratory for Clinical and Experimental Microbiology, The Republican Research and Practical Center for Epidemiology and Microbiology (RRPCEM), Minsk, Belarus
Email: firstname.lastname@example.org Keywords: MLST, Neisseria meningitidis, sequence type Background and aims: Incidence of meningococcal meningitidis during 2006-2012 ranged between 1.2-2.8 per 100.000 population in Belarus. Mainly three serogroups of meningococci circulate in the republic: A, B and C, the leading serogroup is B. Children have a leading role in the age structure of disease: over 70% of total cases of invasive infection came to an age group 0-14 years. The aim of the present study was to describe invasive N. meningitidis strains circulating in Belarus using multilocus sequence typing (MLST).
Material and methods: Thirty-three N. meningitidis strains, isolated from patients having meningococcal meningitidis in 2006-2012 in different regions of Belarus were analysed. DNA from N. meningitidis strains was isolated using «DNA-Sorb-B» kit (AmpliSens, Russia). All isolates were confirmed as N. meningitidis according to growing characteristics and using PCR «50R Neisseria spp., Haemophilus spp., Streptococcus spp. Eph» kit (AmpliSens, Russia). Genogrouping was performed using PCR «N. meningitidis A, B, C» kit (Amplisens, Russia). MLST was performed according to the recommendations of the Neisseria Multi Locus Sequence Typing website (http://pubmlst.org/ neisseria/). Results: From 33 N. meningitidis the isolates were determined as genogroup A (n= 2; 6%), B (n= 21; 64%), C (n= 6; 18%), and four isolates were not possible to genogroup (12%). A total number of 30 sequence types (STs) were determined, 21 of which were not previously reported (70%). Several new alleles of housekeeping genes were obtained: abcZ allele 451, aroE alleles 602 and 603, fumC allele 541 and gdh alleles 560 and 621. Neisseria meningitidis sequence types 18, 3346 and 9300 were represented in two isolates; the remaining STs were only represented by one isolate (27 different STs). Among all STs observed 15 belonged to next clonal complexes: ST 11/ ET 37 complex, ST-18 complex (13.3%), ST 32 complex/ET-5 complex, ST 41/44 complex Lineage 3 (20%), ST 53, ST 103 (13.3%), ST 174. The high number of unique STs (n=21) may reflect that meningococcal population circulating in Belarus was genetically highly heterogeneous. Conclusion: According to the data obtained the meningococcal population circulating in Belarus was highly diverse: showing circulation both unique and widely spread hypervirulent clonal complexes. However, due to the few isolates examined from Belarus the data need to be interpreted with some caution. The results of the study show the need for N. meningitidis epidemiological surveillance and global monitoring of the migration of pathogenic variants through the country.
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Epidemiology & Surveillance E14 The epidemiology of invasive meningococcal disease in Belarus, 2011 and 2012 Glazkova S1, Shymanovich V 2, Titov L1 1
Laboratory for Clinical and Experimental Microbiology, The Republican Research and Practical Center for Epidemiology and Microbiology (RRPCEM), Minsk, Belarus; 2Department of Immunoprophilaxy, The Republic Center for Hygiene, Epidemiology and Public Health (RCHEPH), Minsk, Belarus
Email: email@example.com Keywords: Epidemiology, IMD, Neisseria meningitidis Background and aims: Clinicians in different regions of Belarus should report about each case of invasive meningococcal disease (IMD) following EU-wide reporting standards where possible. Questionnaires are then gathered for a general report issued by RCHEPH. All viable meningococcal strains, isolated from patients with IMD were delivered to RRPCEM for further investigation. Despite IMD is a reportable condition in the republic, no N. meningitidis national AMR surveillance is performed in Belarus, as well as no vaccination against meningococcal meningitidis is used. The objective of the analysis was to describe the epidemiology and surveillance of IMD in Belarus in 2011 and 2012. Material and methods: Neisseria meningitidis microbiological identification and serogrouping was performed using classical cultural methods, biochemical test API NH (BioMerieux, France), and PCR «NHS kit» (Amplisens, Russia). Serogroups of meningococci were determined using «Slidex meningite-Kit-5» (BioMerieux, France) and PCR «N. meningitidis A, B, C» kit (Amplisens, Russia). Results: Invasive meningococcal disease incidence in Belarus decreased from 1.3/100.000 inhabitants in 2011 to 1.2/100.000 in 2012, a total number of 125 and 116 cases of IMD were reported in Belarus in 2011 and 2012, respectively. More than 70% of patients with IMD were under 2 years of age showing the highest incidence rates over 22.5/100.000 in both years. Annual estimate of IMD cases showed seasonal prevalence of autumn-spring period: the majority of cases (up to 70%) were registered in September - October and March. Case fatality ranged from 9.5% - 11%, children under the age of 14 were the main risk group (up to 80%).
Serogroup B is dominating in meningococcal population in Belarus and caused up to 41.9% of IMD (in 2012). IMD cases caused by meningococci of serogroup A and serogroup C were reported in 10.9% and in 12.9%, respectively, in both years. The level of nongroupable and/or polyagglutinable meningococci isolated in patients remained on a high level – up to 37% (in 2011). Meningococci of minor serogroups were isolated rarely: X and W135 - 1.6% in 2011, W135 and E29 - 3.2% in 2012. Conclusion: In 2012 the number of IMD cases decreased in Belarus in comparison with previous year, showing however high morbidity and mortality rates and wide distribution of nongroupable meningococci among Neisseria meningitidis population. Enhanced information of the molecular epidemiology as well as presence of decreased susceptibility or resistance to antimicrobials used for treatment and chemoprophylaxis of meningococcal infection is crucial in Belarus.
E15 Epidemiology and surveillance of meningococcal disease in England and Wales Gray SJ1, Campbell H2, Lord A1, Carr AD1, Newbold LS1, J Lucidarme1, Mallard RH1, Guiver M1, Ladhani S2, Borrow R1, Ramsay M2 and Kaczmarski EB1. 1
Public Health England (PHE) Meningococcal Reference Unit (MRU), Public Health Laboratory Manchester, Manchester Royal Infirmary, Manchester M13 9WL, UK; 2Immunisation Department, PHE, Colindale, London, UK
Email: Steve.firstname.lastname@example.org Keywords: meningococcal disease, epidemiology, surveillance, laboratory Background and Aims: Public Health England (PHE) performs surveillance of invasive meningococcal disease for England and Wales to ascertain case numbers, characterise strains and inform vaccine policy. Materials and Methods: Clinicians notify suspected cases of meningococcal meningitis/septicaemia to the Office for National Statistics. Hospital microbiology laboratories in England and Wales routinely submit invasive meningococcal isolates to PHE for phenotypic characterisation and, since October 2007, porA sequencing. MICs of penicillin, cefotaxime, rifampicin and ciprofloxacin are determined. PHE also routinely receives clinical samples for non-culture detection and capsular group confirmation by PCR. Characterisation of non-culture positives by porA sequencing commenced in January 2012.
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Epidemiology & Surveillance Results and Conclusions: Laboratory confirmed cases rose from 1,448 (1995) to peak at 2,804 (1999) falling to 784 in 2012. The major reduction in cases has been due to the decrease in serogroup C infections, ranging 10 - 39 cases per year from 2005; the consequence of direct and indirect protection afforded by the UK serogroup C conjugate vaccine programme since November 1999. There has also been a sustained decrease in serogroup B cases from 1,710 cases (2001) to 621 (2012), in the absence of any intervention/s. In 2012, serogroup B accounted for 79% of all confirmed cases whereas only 4% (28 cases) were confirmed as serogroup C and 6% W. Serogroup Y accounted for 10% (80) cases in 2012 a reduction from the peak of 93 cases in 2011. During 2012, 379 cases (48%) of invasive meningococcal disease were confirmed by PCR alone. Similar proportions of group B porA strain variants were confirmed for both non-culture positives and isolates. Phenotypic and genotypic shifts have been observed since 1999: specifically the relative contributions of serogroup B associated clonal complexes ST-41/44 (stable), ST-269 (increasing), ST-32 (reducing), ST-213 (low rise and fall) and the reduction of the previously predominant serogroup C ST-11 CCs to meningococcal epidemiology. Although low numbers, an increase in disease due to serogroup W:2a strains (a predictor of CC11) is being monitored: from 2 cases (2009) to 25 cases (2012), nationwide and across all age ranges.
E16 - Oral Presentation, day two The MRF Genome Library: Epidemiology of meningococcal disease-causing lineages in England and Wales from 2010/11 to 2011/12 Hill D. M.C.1, Lucidarme J2, Jolley K. A.1, Tang C3, Kaczmarski E2, Parkhill J4, Green J5, Maiden M.C.J.1, Borrow R2 1
Department of Zoology, University of Oxford, Oxford, OX1 3PS; Vaccine Evaluation Unit, Public Health England, Manchester, M13 9WZ, UK; 3The Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, UK; 4Pathogen Genomics, The Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK; 5 Bioinformatics Group, Public Health England Bioinformatics Unit, Colindale, London, NW9 5EQ, UK 2
Keywords: Meningococcal disease, England and Wales, Public access, Molecular epidemiology, Whole-genome sequencing The Meningitis Research Foundation Meningococcus Genome Library is an open-access database containing the genomes of all invasive meningococcal disease isolates from England, Wales, and Northern Ireland from the 2010/11 and 2011/12 epidemiological years. The 2012/13 genomes will be in the database early in 2014. This project is a collaboration between MRF, Public Health England (PHE), the University of Oxford, and the Sanger Institute, to provide a dataset for all fields of meningococcal research. Its primary objective is to facilitate the design of novel interventions against invasive meningococcal disease (IMD). DNA prepared at the PHE Meningococcal Reference Unit (MRU) is sent to the Sanger Institute for wholegenome sequencing. In Oxford, genomes are assembled and uploaded to the PubMLST database for annotation; genomes can be accessed at all stages of annotation via meningitis.org/research/ genome. PubMLST integrated BIGSdb software analysis tools such as Genome Comparator were used for the extraction of nucleotide and allelic data from loci of interest for population analyses using eBurst and SplitsTree4. There were 899 culture-confirmed cases of IMD in England and Wales in 2010/11 and 2011/12. The most prevalent clonal complex (CC) was ST-41/44CC, comprising 26% of the total. A significant proportion of cases were caused by ST-269CC (19%), ST-23CC (13%), ST-213CC (8%), ST-11CC (7%), and ST-32CC (5%), with a further sixteen CCs causing disease rarely. Since serogroup Y is over-represented in cases confirmed by culture compared to all laboratoryconfirmed cases, ST-23CC may be responsible for a larger proportion of overall IMD than reporting suggests. Current incidence of meningococcal disease in England and Wales is low relative to previous decades (<2 cases/100,000). Cases of ST-269CC IMD have declined in recent years; this CC is diverse however, and rMLST analysis revealed the existence of a further 29 cases from this lineage that are not designated to a CC due to the limited resolution of MLST. The addition of ST-275 as a joint central genotype within ST-269CC is proposed to accurately capture the prevalence of this meningococcal lineage.
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Epidemiology & Surveillance Unlike other lineages, ST-11CC and ST-23CC cases increased between 2010/11 and 2011/12, by 5% and 3% respectively. The proportion of ST-11CC increased in all age groups, with most serogroup W and serogroup C ‘ET-15’ increases in the over 25s. As expected from the association of ST-23CC with older patients, the increase in IMD caused by this CC occurred in the over 25s. Currently, this comprehensive dataset allows high-resolution surveillance and identification of emerging strains.
E17 - Oral Presentation, day two Quality of life changes in children diagnosed with group B meningococcal disease in months following illness Iain Kennedy & Shamez Ladhani Department of Immunisation, Hepatitis and Blood Safety, Centre for Disease Surveillance and Control, Public Health England, London, UK
Email: email@example.com Keywords: meningitis B, children, quality of life Background: N. meningitidis group B is currently the most frequent causative organism for meningococcal disease in the UK. The first ever vaccine against Men B was licensed in early 2013. The Joint Committee on Vaccination and Immunisation’s draft recommendation is that the vaccine is not introduced to the routine schedule, but may be useful in other settings. Previous work has examined the long-term quality of life (QoL) impacts of Men B disease. The key objective of this project was to identify the short term impacts of Men B disease in children in the months following diagnosis. Methods: Patients aged 15 or under in England who had confirmed N. meningitidis group B with sample dates between 1st November 2012 and 31st May 2013 and for whom sufficient demographic details had been captured were identified. The GPs of these patients were contacted to confirm patient details and diagnosis. The parents of the patients were then contacted with a letter explaining the project and a questionnaire. The questionnaire contained questions on clinical course including pre-existing and subsequent conditions, as well as the standardised EQ-5DY QoL questions. The project was performed as part of Public Health England’s responsibilities for on-going surveillance and control of communicable disease and was endorsed by meningitis charities.
Results: There was a response rate of 43% (110/254) and the gender and age profile of responders and non-responders appears similar. Preliminary results show 98% of cases required admission to hospital and 47% admission to PICU/ICU or other high care unit. Around one third of cases had at least one new health condition following their Men B illness, with hearing loss being the most common. EQ5DY responses indicate the majority of cases had large loss of QoL during the illness, but many had recovered at least some, or all of that loss in the months following the illness. Discussion: This study demonstrates that short term QoL loss is a major problem for children following Men B infection, and although some of that loss is regained over time, a significant proportion of cases have sequelae that can cause long term disability. The study is limited as the QoL measure used, which is that recommended by NICE, is not validated in younger age groups and some questions are difficult to apply to the youngest cases. These results add to the available evidence on Men B disease, and may help with future policy decisions.
E18 The epidemiology of invasive meningococcal disease serogroup B in Scotland 1999-2012 Eisin McDonald1, Barbara Denham2, Alison SmithPalmer1, Giles Edwards2, Claire Cameron1 1
ealth Protection Scotland, Meridian Court, 5 Cadogan Street, H Glasgow, G2 6QE; 2The Scottish Haemophilus Legionella Meningococcus and Pneumococcus Reference Laboratory (SHLMPRL), Stobhill Hospital, 133 Balornock Road, Glasgow, G21 3UW
Email: firstname.lastname@example.org Keywords: Epidemiology, Meningococcal disease, Serogroup B, Clinical presentation, Case fatality ratio Meningococcal disease is a notifiable disease caused by infection with the bacterium Neisseria meningitidis. It is a significant cause of morbidity and mortality, particularly in children and young people. Meningococcal Invasive Disease Augmented Surveillance (MIDAS) was introduced in Scotland in 1999 to monitor the impact of the meningococcal C vaccine. This poster presents the epidemiology of invasive meningococcal disease serogroup B in Scotland from 1999-2012 and discusses the potential implications for meningococcal B vaccine introduction.
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Epidemiology & Surveillance Laboratory confirmed cases of invasive meningococcal disease submitted to the Scottish Haemophilus, Legionella, Pneumococcal and Meningococcal Reference Laboratory (SHLMPRL) are routinely serogrouped and MLST typed. There has been an average of 70 cases of meningococcal disease serogroup B reported each year in Scotland. This has decreased steadily from 117 cases (2.3 cases per 100,000 population) in 2000 to 38 cases (0.7 cases per 100,000) in 2012 and serogroup B is now the most commonly reported serogroup in Scotland, accounting for 73% of laboratory confirmed cases in 2012. Just over half of all cases reported are in children under five years of age (535/989; 54.1%) and the most commonly reported clinical presentation for cases was meningitis (320 cases; 43%), followed by septicaemia (222 cases; 30%) and both meningitis and septicaemia (177 cases; 24%). There were 55 deaths reported in the time period equating to an overall case fatality ratio (CFR) of 5.5%. However, CFR was found to vary by age and clinical presentation. The most commonly circulating MLST types were 413 (27 cases), 213 (25 cases), 275 (19 cases) and 269 (14 cases). In summary, meningococcal disease serogroup B has declined in recent years in Scotland but remains a significant source of morbidity and mortality, especially among young children. As serogroup B disease now accounts for the majority of laboratory confirmed cases, any ability to prevent these infections could have a substantial impact on overall incidence of disease.
E19 Meningococcal seroepidemiology in Burkina Faso, one year after the MenAfriVac® mass campaign Yaro S1, Tall H2, Ouangraoua S1, Kpoda H1, Trotter C3, Njanpop Lafourcade B2, Martin C2, Findlow H4, Bosco JB5, Gessner BD2, Borrow R4, Mueller JE6 Centre Muraz, Bobo-Dioulasso, Burkina Faso; 2Agence de Médecine Préventive, Paris, France; 3Cambridge University, Cambridge, UK; 4Vaccine Evaluation Unit, Public Health England, Manchester, UK; 5Institut de Recherche en Science et Santé, Bobo-Dioulasso, Burkina Faso; 6EHESP French School of Public Health, Paris, France 1
Email: Judith.email@example.com Keywords: African Meningitis Belt, serogroup A conjugate vaccine (MenAfriVac®), seroepidemiology, immunisation coverage, vaccine impact assessment
Background: To eliminate meningococcal meningitis epidemics, a meningococcal serogroup A conjugate vaccine (MenAfriVac) has been introduced in Burkina Faso via mass campaigns in December 2010, targeting the 1- to 29-year-old population. This study describes specific antibody titre in the population 11 months after vaccine introduction and compares them to pre-introduction data obtained during 2008 using the same protocol (Trotter et al. 2013). Methods: During October-November 2011, we included a representative sample of the population of urban Bobo-Dioulasso aged 6-months to 29-years. Participants were examined using standardized questionnaires and blood draws. Using rabbit complement, serum bactericidal antibody (SBA) titres were measured against two serogroup A strains: reference strain F8238 of immunotype L11 (all sera) and strain 3125 (L10; 200 randomly selected sera). Results: Among the 562 participants, 477 were ≥23-months-old and had been eligible for the MenAfriVac campaign. Among them, 204 (43%) reported vaccination and 160 (34%) could provide a vaccination card. No systematic difference in SBA titre was found between persons reporting vaccination or not; therefore, overall data are reported. GMT was 8 among the 85 children under 23 months, 1458 among vaccine-eligible children up to 4 years (2100 if vaccination confirmed), and 2355 (2494) among vaccine-eligible older persons. Titre <128 or <1024 were found with 5% and 23%, respectively, of 2- to 4-year-old children and with 1% and 12%, respectively, of 5- to 29-year-old persons. Compared to the 2008 pre-introduction data, GMTs against the reference strain and 3125 strain were 11 and 42 fold higher, respectively, among 2- to 4-yearold children, and 8 and 78 fold higher, respectively, among 5- to 29-year-old persons. Discussion: Since the MenAfriVac mass campaign, serogroup A meningococcal SBA titres in the targeted population of Burkina Faso have substantially increased. The increase is more pronounced with SBA against strain 3125 than against the reference strain, possibly as the latter is sensitive to natural immunity, as suggested by high pre-vaccination titre. SBA-3125 should therefore be included in studies on antibody persistence after meningococcal vaccination in populations with substantial natural immunity. Further studies are planned to evaluate longer term antibody persistence. This study was funded by Meningitis Research Foundation.
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Epidemiology & Surveillance E20 Neisseria meningitidis: Epidemiological markers and antimicrobial susceptibility of invasive strains. Cuba, 2002-2011 Suarez E1, Martinez I2, Llanes R1, Feliciano O1, Gutierrez O1 Pedro KourĂ Institute (IPK), Havana, Cuba; 2Finlay Institute (IPK), Havana, Cuba
Email: firstname.lastname@example.org Keywords: Epidemiology, antimicrobial susceptibility Introduction: Neisseria meningitidis is one of the main causative agents of bacterial meningitis and sepsis. The study of epidemiological markers and antimicrobial susceptibilities of the circulating strains constitute the main activities of meningococcal disease surveillance. Aims: To investigate epidemiological markers and the antimicrobial susceptibility patterns of invasive isolates of N. meningitidis in Cuba for ten years (2002-2011). Methods: A transversal descriptive study was conducted to characterise invasive meningococcal isolates received at the National Reference Laboratory of Pathogenic Neisseria during 10 years. A total of 69 viable meningococcal strains were studied. Conventional laboratory methods were used to identify the species and serogroups; PCR technique was used when the latter was doubtful. Phenotypic characterisation was carried out using ELISA of whole cells with monoclonal antibodies, while antimicrobial susceptibility was determined by the E-test method. Results: Strains of serogroup B (98.6%) were predominant, with only one strain belonging to serogroup C (1.4%); strains of serotype 4 were the most frequent (55.1%), followed by non-typable and serotype 2a (15.9% and 8.7%), respectively. The more frequent subtypes were P1.15 (42.0%), P1.19 (20.3%) and non subtypable strains (10.1%). Of serogroup B strains, phenotype B:4:P1.15 was predominant (26.1%), and phenotype C:2a:P1.5 was detected for the first time in Cuba. Susceptible meningococci strains were predominant: ceftriaxone (100.0%), rifampicin (98.2%), chloramphenicol (92.8%), ciprofloxacin (89.3%), and penicillin (87.5%), except for cotrimozaxol, to which however 92.8% of isolates were resistant.
Conclusions: Our data provide valuable epidemiological information for a better understanding and control of meningococcal disease in Cuba.
E21 Development of a multiplex assay to determine IgG binding to Group B streptococcus and evaluation of anti-Group B Streptococcus IgG in the UK Stephen Taylor, Sophie Arthur, Jenny Herbert, Stephen Thomas and Andrew Gorringe Public Health England, Porton Down, Salisbury SP4 0JG
Keywords: GBS, immunity, flow-cytometry, multiplex-assay, seroprevalence Streptococcus agalactiae (Group B Streptococcus, GBS) is now the most frequent cause of sepsis and infectious death in neonates in England. Risk of GBS infection is highest during the first few days of life through intrapartum contamination of the neonate from maternal flora. The organism possesses a polysaccharide capsule that defines the serotype and serotypes III and Ia are isolated from the majority of early onset neonatal cases, with disease also caused by serotypes V, Ib and II (Lamagni at al., 2013, Clin Infect Dis). In the last 20 years the distribution of serotypes varied according to patient age and serotype III has increased among early-onset cases and decreased in adults. To facilitate understanding of immunity to GBS in the UK population we have developed a multiplexed flow cytometry assay to determine concentrations of IgG against GBS serotypes Ia, Ib, II, III and V. Formaldehyde-fixed GBS strains representing each of these serotypes were stained with a different live/dead fluorescent stain. IgG binding to the five distinct GBS populations was determined using an anti-human IgG FITC conjugate. Initial assays compared IgG binding to the bacteria determined in single and multiplexed assays with good correlation of values obtained. The multiplexed assay was then used to determine naturally-acquired antibody to GBS serotypes Ia, Ib, II, III and V in a panel of 1852 age-stratified sera collected in the year 2000 from male and female donors. Nearly all samples (99%) had detectable IgG binding to GBS of at least one serotype, with 87% of individuals having detectable IgG that bound to GBS of all five serotypes examined. The distribution of IgG binding to GBS in the entire serum panel was serotype III > V > Ib > II > Ia. The serotype distribution of anti-GBS IgG varied with age. In
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Epidemiology & Surveillance children under 1 year the distribution was II > III > Ib > V > Ia and in individuals over 60 years it was III> II > Ib > V > Ia. The second most common disease serotype is Ia, whereas IgG binding to this serotype is the lowest across all ages, indicating that either it is poorly immunogenic or is more pathogenic than other serotypes. Conversely, serotype II is rarely isolated from disease but elicits the highest levels of IgG in children less than 1 year of age.
E22 Bacterial load and host cytokine response in the CSF of adults with pneumococcal meningitis Emma C Wall1,2,3, Jenna Gritzfeld2, Matthew Scarborough4, Katherine Adjukiewcz5, Mavuto Mukaka1, Caroline Corless6, David G Lalloo1,2, Stephen B Gordon1,2 1
Malawi-Liverpool-Wellcome Trust clinical research programme, Malawi; 2Clinical Group, Liverpool School of Tropical Medicine, Liverpool, UK; 3College of Medicine, Department of Medicine,
University of Malawi, Malawi; 4Infectious Diseases Department, John Radcliffe Hospital, Oxford, UK; 5Infectious Diseases department, North Manchester NHS Trust, Manchester, UK; 6Clinical Microbiology, Institute of Global Heal, University of Liverpool, UK
Keywords: Meningitis, pneumococcus, pneumolysin, bacterial load, cytokine Specific objective of the study: Bacterial meningitis in sub-Saharan Africa is predominately caused by Streptococcus pneumoniae and is associated with mortality rates double those seen in well-resourced settings, which reach 50-60% in adults. We undertook a study to investigate bacteria and host response in the CSF compartment to identify potential causes of poor outcome. No published data currently quantify the host cytokine response by outcome in adults with meningitis from a high HIV prevalence country in sub-Saharan Africa, and there are no published data quantifying the CSF pneumococcal load in adult meningitis. Methods: We quantified the number of copies of pneumococcal DNA using real time PCR and six common pro-inflammatory cytokines using bead array in the cerebrospinal fluid (CSF) of adults with culture proven pneumococcal meningitis in Malawi. We correlated the results to outcome at discharge from hospital and 6 week follow up.
Results: The median age was 32 years, 82% of patients were HIV antibody-positive and the mortality rate by six week follow up was 49%. The median CSF white cell count was 730 cells/mm3, with significantly lower WCC in non-survivors p=0.02. Bacterial loads were high (median 6.5x105 copies/ml CSF) and there was no significant variation in bacterial load by outcome at ten days or six weeks. All proinflammatory CSF cytokines were elevated in the CSF, with a trend towards a more intense response in nonsurvivors reaching marginal statistical significance for IL8 and IL10 on multivariate analysis p=0.034 and 0.029 respectively. There were no differences in the CSF bacterial load or cytokine response between adults who were HIV-infected and non HIV-infected. Conclusion: Mortality from pneumococcal meningitis in adults in sub-Saharan Africa is not related to pneumococcal bacterial load. Anti-cytokine therapies are unlikely to be effective adjunctive treatment to improve mortality. We have previously shown that pneumolysin persists in the CSF of non-survivors of pneumococcal meningitis. This finding, with the altered WCC response presents an opportunity for exploring pathogenesis and potential anti-pneumococcal toxin adjunctive therapy further. More research is needed to understand the very high mortality from meningitis in this region.
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Clinical Diagnosis, Treatment & Sequelae C23 Feverish illness in children: discordance between British, Italian and Swedish clinical guidelines Inge Axelsson Mid Sweden University and Östersund Hospital, Östersund, Sweden
Email: email@example.com Keywords: fever, children, meningococcal disease, Kawasaki disease, encephalitis Object: In 2007, NICE published Feverish illness in children (CG47), a clinical guideline (CG) based on systematic review of the scientific literature. A second, revised edition, Feverish illness in children (CG160), was published in 2013, after extensive peer review. In 2013, the Swedish Institute for Communicable Disease Control (SMI) published a national CG for Signs of serious infections in children (in Swedish), also after extensive peer review. I was coeditor. The SMI paper was partly based on NICE CG160. In 2009, the Italian Pediatric Society published Management of Fever in Children: Summary of the Italian Pediatric Society Guidelines (Chiappini E et al., Clin Ther. 2009;31:1826-1843). However, these three CGs are in part discordant. I will here identify these differences and discuss their importance. Method: The three guidelines were read and compared. The British, Italian and Swedish CGs are called UK, IT and SE, respectively. Discordance was documented in a summary of findings table. Results: UK and SE had different definition of fever; IT had no definition. UK and IT recommended electronic measurement of fever in an axilla or an ear while SE still recommended rectal thermometer. Children should be screened for Kawasaki disease if they have fever lasting more than 5 days (UK) or 5 days or more (SE). According to British studies, pain in arm or leg is an early sign of meningococcal disease. This was mentioned in SE but not in UK or IT. Herpes simplex encephalitis should be considered in children with fever and focal neurological signs, focal seizures or decreased level of consciousness according to UK but herpes simplex encephalitis was not mentioned in IT or SE. UK and SE used ‘traffic lights’ and recommended ‘safety nets’; IT did not. UK recommended teaching parents how to detect signs of dehydration by looking for the following features: sunken fontanelle, dry mouth, sunken eyes, absence of tears and poor overall appearance.
Also, UK recommended health staff to teach parents to identify a non-blanching rash. IT or SE had no such recommendations. Conclusions: This comparison may be used to improve revisions of the clinical guidelines.
C24 The management of suspected childhood bacterial meningitis in a UK district general hospital Doyle K1, Houseman C1, Makwana N2 1
Foundation year 2 trainee, West Midlands Deanery, UK; Consultant Paediatrician, Department of Child Health, Sandwell and West Birmingham NHS Trust
Keywords: Paediatrics, bacterial meningitis, antibiotics, management Background and aims: To compare the management of suspected bacterial meningitis at the Sandwell and West Birmingham NHS Trust with that recommended by the National Institute for Health and Care Excellence (CG102 Guideline, 2010.)† Method: Retrospective case note based analysis. Notes were requested for admissions within the trust coded as meningitis. This included all children aged between 4 weeks to 16 years admitted between 2006 and 2011. Of the 42 notes received, 34 fitted inclusion criteria. 22 were male, 6 patients were less than 3 months. Results: 100% of patients were expected to have; 1) Initial investigations (detailed in Table). Table: Initial investigations for suspected bacterial meningitis
% Investigations Completed (N)
% Abnormal results (N)
Blood PCR (n=30)
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Clinical Diagnosis, Treatment & Sequelae 2) A lumbar puncture (LP) if no contraindications (N=26): 26 LPs were attempted (8 excluded.) 4 attempts failed. Of those completed 86% (N=19) of results were abnormal. In 3 cases LP was contraindicated but performed. 3) A laboratory blood glucose at time of LP (N=22). 36.4% (N=8) had a laboratory glucose. Of the remaining 14, 78.6% (N=11) had a capillary glucose level. 3 cases did not have a blood glucose at the time of LP. 4) Received the recommended empirical antibiotics. Of those aged <3 months (N=6), 4 received antibiotics as recommended by NICE (cefotaxime/ ceftriaxone and amoxicillin/ampicillin). All ≥3 months (N=28) received recommended antibiotics (Ceftriaxone). 5) Received antibiotics for recommended duration (N=31) Out of the 31 eligible patients 45.2% received antibiotics for the duration recommended by NICE. 83.9% received antibiotics for the duration recommended by trust guidelines. 6) Follow up (N=31): 87.1% had a documented plan for audiological referral and 77.4% for paediatric referral upon discharge. There were no deaths from meningitis. Conclusions: The NICE guidelines were followed in the majority of cases. There are several areas that can be developed within the department including a review of departmental guidelines. Education for junior doctors about the NICE guidelines is planned and improved communication between paediatrics and microbiology needed. References: † National Institute for Health and Care Excellence. CG102. Bacterial meningitis and meningococcal septicaemia in children and young people younger than 16 years in primary and secondary care. 2010.
C25 The Orthopaedic Sequelae of Childhood Meningococcal Septicaemia Tomos Edwards1, Fiona Bintcliffe2, Lowri Bowen1, James Aird2, Fergal Monsell2 University of Bristol Medical School, Bristol, UK; 2Department of Paediatric Orthopaedic Surgery, Bristol Children’s Hospital, Bristol, UK 1
Email: firstname.lastname@example.org Keywords: Meningococcal, septicaemia, orthopaedic, sequelae, limb-reconstruction
Objective: Meningococcal septicaemia is a potentially devastating disease that can result in a variety of disabling complications. The aim of this study is to use a defined population as a common denominator enabling correct identification of the incidence of orthopaedic sequelae as well as to investigate the specific complications developed. Methods: Clinic letters and radiographs were analysed retrospectively of all patients admitted to the Paediatric Intensive Care Unit (PICU) of the Bristol Royal Hospital for Children from 01/01/2001 to 31/12/2012 with a primary diagnosis of meningococcal septicaemia. Results: 138 patients with meningococcal septicaemia were identified, 130 of which were alive at PICU discharge. Of these, 10 developed orthopaedic sequelae, representing an overall incidence in this patient population of 7.7%. Those who developed orthopaedic complications were admitted to PICU at a significantly younger age (P < 0.05) and for a longer time period (P < 0.001). This study is the first to report a greater proportion of boys than girls developing orthopaedic complications (risk ratio: 3.1; 95% CI: 0.69 – 14.14). 9 patients required an amputation, and these were much more common in the lower limb, 16/22 (72.7%). Each patient requiring an amputation had multiple limb involvement. Amputations most often occurred distally, however a more proximal revision amputation was required in 2 patients. A total of 48 growth plate abnormalities were identified in 8 patients. 39 (81.3%) of the affected growth plates were in the lower limb, and the most commonly affected growth plate in both right (40%) and left (36.8%) lower limbs was the distal tibia. Of the 6 patients with documented angular deformity, 10 ankles were identified as having a varus malalignment. Partial fusion across the distal tibia with relative fibular overgrowth was the most common causative factor. 6 patients had documented leg length discrepancy that was most commonly due to significant shortening of the tibia. All 10 patients had documented skin scarring and had suffered skin necrosis or purpura fulminans. Additionally, 3 patients required a fasciotomy. Conclusion: This study has identified a relatively high incidence of orthopaedic sequelae following meningococcal septicaemia. The data collected suggests the most common complications as well as those patients at greatest risk of developing them. We recommend considering the cost benefit implications of a yearly review of these patients to enable early identification of potentially treatable complications.
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Clinical Diagnosis, Treatment & Sequelae C26
Fluorescence immunoassay for procalcitonin hormone in whole blood Eun Seon Yoon1, Do Won Kim2, Eui Yul Choi1,2
Outbreak of Serotype W135 Neisseria meningitidis in Central River Region (CRR) of the Gambia - A Clinical perspective Osuorah Donatus1, Bilques Shah1, Manjang Ahmed1, Ebba Secka2
Department of Biomedical Science, Hallym University, Chuncheon, South Korea 200-702; 2Boditech Med Inc. Chuncheon, South Korea 200-702
Email: email@example.com Keywords: Procalcitonin (PCT), calcitonin, katacalcin The determination of blood level of TSH is an important biomarker for the clinical assessment of sepsis status. Here, we presented a new fluorescence (FL) immunochip PCT assay system, which was developed with a platform of point-ofcare test (POCT) for clinical applications. The assay system modified a later-flow immunochromatographic technology and consisted of anti-PCT-mAb coated strip in a disposable chip, a detection buffer containing FL-labeled anti-PCT-poly Ab, a chip for the calibration curve, and a laser FL scanner. The analytical performance of FL immunochip PCT assay system was evaluated by linearity, interference, recovery, and imprecision tests. The comparability of the developed assay was examined with automated reference assay. The developed assay system exhibited an excellent linearity in working range of 0.25 â€“50 ng/ml. The analytical mean recovery of control was 97.6% in a dynamic working range and the imprecision of intra- and inter-assay of CVs was less than 10%. There was highly significant correlation between the developed PCT assay and automated Beckman Coulter Access 2 reference assay with r = 0.989 (p < 0.001). The developed FL immumo assay is the only method that quantifies PCT concentration in whole blood, which meets the criteria of POCT, including affordable cost, a disposable device, and requiring minimum maintenance to perform test.
Pneumococcal Surveillance Project (Central River Region Research site), Child survival unit, Medical research council UK, The Gambia unit; 2Regional Health Authority, Central River Region, The Gambia Ministry of Health and Social Welfare The Gambia
Email: firstname.lastname@example.org or chidi.osuorah@gmail. com Keywords: Neisseria meningitis, W135 strain, Central river region, Bansang hospital Background: Meningitis still accounts for many deaths in children especially during epidemics in countries within the African meningitis belt. The Gambia recently witnessed another outbreak with the W135 strain of Neisseria meningitidis. There have been studies on similar outbreaks in Africa but only a few have looked specifically into the clinical and child perspective of these outbreaks that usually and unfortunately are most affected. This study therefore presents a clinical perspective of the most recent outbreak in the Central River Region of the Gambia and evaluated predisposing and risk factors associated with acquiring the infection among children. Methods: This is a descriptive and prospective cohort study using the nested case-control design. Suspected cases of meningitis presenting to the paediatric ward of the Bansang Hospital in the Central River Region of the Gambia during the outbreak period were employed for the study. Eightynine (89) confirmed cases of N. meningitidis were enrolled as cases and 108 matching controls with negative blood cultures admitted for other reason during the same period were recruited as controls. Result: Between February and May 2012, over 250 suspected cases presented to the Bansang hospital of whom more than 95% were children. The outbreak had a double peak period in weeks 5 and 8 during which the epidemic threshold of 10 cases/100,000 per week was exceeded. The W135 strain of Neisseria meningitidis was responsible for 98.9% of meningitis infection during the 2012 outbreak in the Central River Region of the Gambia with an incidence rate of 47.9 per 100,000 and a case fatality rate of 7.9%.
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Clinical Diagnosis, Treatment & Sequelae Highest attack rate was seen in the 12-49 months age group. Atypical signs such as conjunctivitis and joint swelling were seen in cases. Aside from environmental conditions, contact with cases was the most important identified risk factor for acquiring and transmitting the organism. Adjusted regression analysis showed 0.13 less likelihood of infection without a positive contact history [RR 0.13 CI (0.060.30)]. There was no significant difference in mortality rate between cases and controls [HR 0.78 CI (0.292.13)]. Conclusion: Effective district level surveillance and contact tracing should be put in communities and residents should be educated before or around outbreak seasons to isolated suspected cases as soon as possible to the nearest health facility. Vaccination with meningococcal vaccine for epidemic strain should be incorporated into the EPI schedule of the Gambia and yearly booster dose given to children especially prior or during the epidemic seasons.
C28 A review of the management of paediatric sepsis on the University Paediatric Ward in the Karapitiya Teaching Hospital, Galle, Sri Lanka Quicke E1, Last A2, Jayantha UK3 1
University of Birmingham Medical School, Birmingham, UK; London School of Hygiene & Tropical Medicine, Clinical Research Department, London, UK; 3Department of Paediatrics, Karapitiya Teaching Hospital, Galle, Sri Lanka 2
Email: email@example.com Keywords: Sepsis, Paediatric, Audit, Resourcelimited, Management Background: Sepsis is a leading cause of death in both the developed and developing world. In 2008, 70% of the 9 million paediatric deaths worldwide were from sepsis. Following the Surviving Sepsis campaign, guidelines were independently written in 2012 by the World Federation of Paediatric Intensive and Critical Care Societies which were adjusted for low/middle income countries. These guidelines provide a modified, evidence based system for management of sepsis, severe sepsis and septic shock in resource limited settings. This audit aimed to compare the management of cases of paediatric sepsis to these guidelines.
Methods: A prospective audit of 45 cases of confirmed/suspected paediatric sepsis admitted to the University Paediatric Ward of the Karapitiya Teaching Hospital in 10 days of May 2013. Several aspects of the management of each case including fluid management, oxygen administration, antimicrobial administration, and the use of appropriate microbiological investigations were compared to the guidelines written by the World Federation of Paediatric Intensive and Critical Care Societies. Results: The most common infection was a lower respiratory tract infection (60%, 27/45), with other sources of infection being meningitis or suspected meningitis (6.7%, 3/45), abscesses (8.9%, 4/45) and urinary tract infections (8.9%, 4/45). Fluid management: 24% (11/45) cases received fluids. The rate at which fluids were administered varied between cases. Oxygen: 13% (6/45) were given oxygen on admission. Of the 42 cases where oxygen saturations were recorded, 95% (40/42) had saturations >90%. Antibiotics: 91% cases (41/45) received empirical antibiotic therapy, 43.8% (14/32) were within one hour. Appropriate Microbiological Investigations: 40% (18/45) cases had appropriate cultures taken, 55.5% (10/18) were taken before the administration of antibiotics. Conclusion: This audit has highlighted that many of the recommended standards are not being met. Despite 91% receiving antibiotics, in only 43.8% cases was this within one hour. This is likely to be a factor that could significantly affect patient outcomes. Similarly, only 40% had cultures taken which can affect the ability to identify and later treat the causative organism. Both these issues could be addressed by introducing a policy of giving antibiotics at the time of taking cultures thereby prompting the clinician to undertake both management steps quickly. In addition, awareness should be raised amongst clinical staff about the guidelines to ensure that they are aware of the current problems and the appropriate management steps. A plan to re-audit should be implemented to ensure that any measures introduced are effective.
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Clinical Diagnosis, Treatment & Sequelae C29 Audit of UHCW Paediatric Departmentâ€™s management of meningitis against the NICE quality standards Tan Y, Jorge P, Wallace C, Manias K Department of Paediatrics, University Hospitals Coventry Warwickshire (UHCW) NHS Trust, Coventry
Email: firstname.lastname@example.org Keywords: Meningitis, meningococcal, children, NICE, guidelines Background: Bacterial meningitis is an infection of meninges by bacteria that travel from mucosal surfaces via the bloodstream. Invasive meningococcal disease describes meningococcal meningitis and meningococcal septicaemia, which can lead to multiorgan failure and death. The incidence of meningococcal disease and bacterial meningitis has decreased over the last 20 years, primarily due to meningitis C vaccination. Meningococcal disease remains the leading cause of death from infection in early childhood in the UK (mortality rate 10%). Prompt recognition of symptoms and signs is key to preventing death or disability. In 2012, 41/443 of patients with invasive meningococcal infection were from the West Midlands, accounting for 9% of the UK population. In June 2012 NICE published a quality standard QS19 for bacterial meningitis and meningococcal septicaemia in children and young people. Aim: The aim of this audit was to assess UHCW Paediatric Departmentâ€™s management of meningococcal disease against the NICE QS19. Methods: A proforma listing the 14 quality standards was created. Prospective data was collected from May 1st-June 12th 2013. Results: Seventeen patients were suspected of having bacterial meningitis or meningococcal sepsis. The average age was 12 months. All patients were admitted, with an average inpatient stay of 5 days. One patient required intubation & ventilation and transfer to PICU. Four patients had confirmed bacterial meningitis or meningococcal sepsis.
All patients with petechial rash received appropriate antibiotics. The average time before administering the first antibiotic dose was 3 hours. All patients with suspected bacterial meningitis, unless clinically unstable, had an LP with CSF results available within 4 hours. Intubation & transfer were performed by adequately trained healthcare professionals. All confirmed cases of meningococcal disease were discharged with appropriate information and follow up. The following recommendations were made. An advice sheet (including a picture of a petechial rash) should be given to parents sent home with febrile children. Temperature, respiratory rate, pulse, blood pressure, urine output, oxygen saturation and neurological condition should be monitored hourly until stable. Patients should receive intravenous or intraosseous antibiotics within an hour of arrival. Meningococcal PCR testing should be performed. Children should have an audiological assessment before discharge. Conclusions: The majority of patients with suspected meningococcal disease in UHCW were managed in accordance with the NICE QS19. There were, however, areas for improvement, particularly in terms of advice sheets given to parents of febrile children and time taken to commence antibiotics.
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Public Health Management PH30 A cluster of four cases of meningococcal disease in a single nuclear family Peter Acheson1, Ruth Barron2, Ray Borrow3, Steve Gray3, Csaba Marodi4, Mary Ramsay5, Julia Waller1, Terry Flood6 1
North East Public Health England Centre, Newcastle upon Tyne, UK; 2Department of Paediatrics, South Tees Hospitals NHS Foundation Trust, Middlesborough, UK; 3Meningococcal Reference Unit, Public Health England, Manchester, UK; 4 Department of Clinical Microbiology, South Tees Hospitals NHS Foundation Trust, Middlesborough, UK; 5Public Health England, London, UK; 6Department of Paediatric Immunology and Infectious Diseases, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
All family members were subsequently investigated for complement deficiency. Despite this, no obvious abnormality in the family group has been identified to date and no further significant infections have been recognised. A cluster of meningococcal disease of this nature and timescale is highly unusual. Details of the cluster, investigation and implications for health protection practice are discussed.
Email: email@example.com Keywords: meningococcal disease, family, cluster, prophylaxis A cluster of four confirmed cases of meningococcal disease was seen in the same nuclear family in the North East of England across a 15 week period in 2010. The first two cases presented within 48 hours of each other, followed by a gap of 40 days to the next case and a further 63 days to the fourth. The cases were three siblings and a parent. All cases recovered well from their illness. The first case was confirmed by meningococcal PCR only (serogroup not determined) but the subsequent three cases were due to indistinguishable strains of Group B disease (B:NT:P1.19-1,15-11). Contact tracing was initially undertaken and reviewed in detail after each subsequent case. Antibiotic prophylaxis was administered to close family contacts on three separate occasions, including switching of antibiotic agents. The family reported having taken full courses of prophylaxis each time this was prescribed. Throat swabs were undertaken after the final round of prophylaxis to try to establish that carriage had been eliminated from the family group. No throat swab sample grew Neisseria meningitidis.
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Vaccinology V31 Physico-chemical and immunological investigation into the thermal stability of meningococcal MenACWY-TT conjugate vaccine Nicola Beresford & Barbara Bolgiano Division of Bacteriology, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK
Keywords: Conjugate, vaccine, stability, physicochemical, immunogenicity The thermal stability of a meningococcal serogroup ACWY tetanus toxoid (TT) conjugate vaccine was analysed following exposure to four storage temperatures (-20˚C, +4˚C, +37˚C, +56˚C) and repeated freeze-thawing cycles (FT) for 28 days. Both the bulk conjugates and the final fill were analysed for their molecular integrity, free saccharide content and carrier protein folding by size exclusion chromatography (HPLC-SEC), high performance anion exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD) and fluorescence spectroscopy. The data shows that the molecular integrity of the bulk conjugates is significantly altered at high temperatures leading to degradation into small molecular weight material. This observation is most profound in MenA bulk conjugate above +37˚C. The MenY bulk conjugate was most resistant with degradation only observed at +56˚C. Following +56˚C incubation the percentage free saccharide content in the bulk conjugates also increased for MenACW ranging from 38% to complete depolymerisation (100%). Only minor changes were observed in the pH of the bulk conjugates and final fill with the exception of MenA which resulted in a significant drop in the pH associated with depolymerisation and instability. Neither the molecular integrity nor the percentage free saccharide of the lyophilised final fill was significantly affected by FT or by storage at high temperatures. Correlates between physico-chemical characterisation and immunogenicity measuring the total IgG responses against serogroup specific polysaccharides were analysed. A reduction in the immunogenicity was observed in the IgG response to all polysaccharides at high temperatures. There was a significant drop in the anti-MenA IgG response when incubated above +37˚C and a similar response was seen for anti-MenC IgG when incubated at +56˚C.
Although the same trend extends to anti-MenW and anti-MenY IgG responses stored at high temperatures these were not significant. In conclusion the immunogenicity correlated with the physicochemical analysis of the bulk conjugates with MenA and MenC being the most prone to instability at high temperatures and MenY the most stable in adverse storage conditions.
V32 Serum Bactericidal Antibody Levels Following Quadrivalent Conjugate (MenACWY-CRM) or Serogroup B (4CMenB) Meningococcal Vaccines in a Phase 3 Study to Evaluate the Effect of Vaccination on Pharyngeal Carriage of N. meningitidis in Young Adults Peter Dull1, Xilian Bai2, Rohit Bazaz3, Kate Nolan2, Abida Nazir3, Annette Karsten1, Ellen Ypma1, Daniela Toneatto1, Robert Read3, Ray Borrow2 1
Novartis Vaccines and Diagnostics, Cambridge, Inc., Massachusetts, USA; 2Vaccine Evaluation Unit, Public Health England, Manchester Royal Infirmary, Manchester, UK; 3Sheffield University, and Royal Hallamshire Hospital Sheffield, Department of Infection & Immunity, Sheffield School of Medicine and Biomedical Science, Sheffield, UK
Email: firstname.lastname@example.org Keywords: vaccine, meningococcal, serogroup B, quadrivalent, immunogenicity Background: Immunogenicity of a quadrivalent meningococcal conjugate vaccine, MenACWYCRM (Menveo®) and a serogroup B meningococcal vaccine, 4CMenB (Bexsero®) were assessed in a subset of subjects in a carriage study among English university students (NCT01214850). Methods: There were 2968 subjects enrolled to receive either MenACWY-CRM/placebo, 4CMenB or Japanese encephalitis vaccine (Ixiaro®). At the Sheffield site, immunogenicity of MenACWY-CRM and 4CMenB was evaluated in a subject (n~200 per group) by serum bactericidal antibody using human complement (hSBA) response at time points up to one year after initial vaccination. Subjects from the immunogenicity subset were tested by hSBA against serogroups C and Y, and MenB strains 44/76-SL, 5/99, and NZ98/254.
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Vaccinology Results: At baseline across all vaccine groups, 38–71% of subjects had hSBA titres ≥ 4 against 44/76-SL, 5/99, and NZ98/254. One month after the second dose of 4CMenB, 99–100% of subjects had hSBA titres ≥ 4 against each of the MenB strains. Eleven months after the second vaccination, 85–97% of these subjects maintained hSBA titres ≥ 4. The MenACWY-CRM and control groups showed no substantial increase in hSBA titres ≥ 4 against MenB strains. At baseline, 80–90% and 72–78% of subjects across all vaccine groups showed hSBA titres ≥ 8 against serogroups C and Y, respectively. Against serogroup C, most subjects maintained hSBA titres ≥ 8 at all post-vaccination time points across all groups. Against serogroup Y, there were further increases in subjects with hSBA titres ≥ 8 from baseline in the MenACWY-CRM group, while in the 4CMenB and control groups the percentage of subjects with hSBA titres ≥ 8 was similar to baseline. The carriage rate in seropositive subjects was generally higher than in seronegative subjects at baseline; however, no clear association between carriage rates and post-vaccination hSBA levels was shown against MenB or serogroup C or Y strains. In subjects with documented prior vaccination with a serogroup C conjugate vaccine, evidence of an anamnestic response was demonstrated among MenACWY-CRM recipients with a mean serogroup C hSBA GMT of 1905 two months after vaccination (baseline GMT 91) Conclusion: High percentages of MenACWY-CRM and 4CMenB recipients maintained bactericidal antibodies 11-12 months post-vaccination. No clear association between carriage rates and postvaccination hSBA levels was observed.
V33 Functional expression of the capsule polymerase of Neisseria meningitidis serogroup X: A new perspective for vaccine development Timm Fiebig1, Francesco Berti2, Friedrich Freiberger1, Vittoria Pinto2, Heike Claus3, Maria Rosaria Romano2, Daniela Proietti2, Barbara Brogioni2, Katharina Stummeyer1,4, Monika Berger1, Ulrich Vogel3, Paolo Costantino2, Rita Gerardy-Schahn1
Institute for Cellular Chemistry, Hannover Medical School, 30625 Hannover, Germany; 2Novartis Vaccines and Diagnostics, Research, Via Fiorentina 1, 53100 Siena, Italy; 3Institute for Hygiene and Microbiology, University of Würzburg, 97080 Würzburg, Germany; 4Present address: GRS - Gesellschaft für Anlagen- und Reaktorsicherheit, Schwertnergasse 1, 50667 Köln, Germany
Email: email@example.com Keywords: capsule polymerases, Neisseria meningitidis serogroup X, NMR, recombinant protein production, vaccine development Neisseria meningitidis (Nm) is a leading cause of bacterial meningitis and sepsis. A key feature in pathogenicity is the capsular polysaccharide (CPS) that negatively impacts complement activation and thus supports bacterial survival in the host. Twelve serogroups characterised by immunologically and structurally different CPS have been identified. Meningococcal CPS elicit bactericidal antibodies and consequently are used for the development of meningococcal vaccines. Vaccination against the epidemiologically most relevant serogroups was initially carried out with purified CPS and later followed by conjugate vaccines which consist of CPS covalently linked to a carrier protein. Of increasing importance in the African meningitis belt is NmX for which no vaccine is currently available. Here we describe the molecular cloning, recombinant expression, and purification of the capsule polymerase of NmX called CsxA. The protein expressed with N- and/or C-terminal epitope tags was soluble and could be purified to near homogeneity. With short oligosaccharide primers derived from the NmX capsular polysaccharide, recombinant CsxA produced long polymer chains in vitro that in immunoblots were detected with NmX specific antibodies. Moreover, the chemical identity of in vitro produced NmX polysaccharides was confirmed by NMR. Besides demonstration that the previously identified gene csxA encodes the NmX capsule polymerase CsxA, the data presented in this study pave the way for the use of the recombinant capsule polymerase as a safe and economic way to generate the NmX capsular polysaccharide in vaccine developmental programs.
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Vaccinology V34 The MenC content of meningococcal conjugate vaccines using the WHO 1st International Standard for Serogroup C Polysaccharide does not necessarily correlate with their immunogenicity Fang Gao, Nicola Beresford, Kay Lockyer, Karena Burkin, Angela Martino and Barbara Bolgiano Division of Bacteriology, National Institute for Biological Standards and Control, Medicines and Healthcare products Regulatory Agency, South Mimms, Potters Bar, Herts, EN6 3QG, UK
Keywords: meningococcal serogroup C, polysaccharide, conjugate vaccine, HPAEC-PAD, resorcinol Introduction: The meningococcal serogroup C (MenC) saccharide content in monovalent and multivalent meningococcal conjugate vaccines was determined using various standards for their licensure and batch release control testing before the establishment of an international standard. The WHO 1st International Standard for Meningococcal Serogroup C Polysaccharide (NIBSC code 08/214) was adopted in 2011, based on the MenC content as determined by eight laboratories participating in a collaborative study (Vipond et. al., 2012). At NIBSC, it has been used in this study as the ‘gold standard’ to determine MenC content in meningococcal vaccines including a MenC-Hib combination, three monovalent MenC conjugates, and three MenACWY tetravalent vaccines. The aim of this study was to compare the content of MenC saccharide in currently licensed conjugate vaccines. The immunogenicity of the vaccines was also evaluated in a mouse model. Method: The MenC content was determined by either high performance anion exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD) or for the MenC-TT vaccine, the resorcinol assay, using the MenC PS 1st International Standard. The MenC-specific IgG of the vaccines following 2 doses of 1/10 SHD in Balb/C mice was measured by ELISA titre, using an anti-MenACWY-DT reference sera. Results: When the WHO 1st International Standard for MenC polysaccharide was applied as the quantitative standard, varying amounts of MenC content were found in the different vaccines, which did not precisely correspond with their labelled contents. The highest MenC content was in a monovalent MenC-TT conjugate with 12.1 µg/dose. The lowest
contents were found from the MenC-TT components in a MenC-Hib and a MenACWY combination, with 2.9 and 3.0 µg/dose, respectively. The MenC content of all other tested vaccines were as expected based on their labelled contents. The post-2 geometric mean titres of MenC PS-specific IgG were not significantly different from each other. Conclusions: The 1st International Standard for MenC PS provided a powerful tool to compare the ‘true’ MenC content in different vaccines. The three MenCTT conjugates were found containing variant MenC contents. The GMTs from a 2-dose mouse model showed statistically-comparable MenC responses from all the vaccines tested, suggesting that the MenC response did not necessarily correlate with the dosage given.
V35 Vaccines against MenB disease: over-expression of factor H-binding protein (fHbp) in native outer membrane vesicles elicits broader strain-coverage than recombinant fHbp Johan Holst1, Peter T. Beernink2,Rolando Pajón2 1
Department of Bacteriology and Immunology, Division of Infectious Diseases Control, Norwegian Institute of Public Health, Oslo, Norway; 2Center for Immunobiology and Vaccine Development, Children’s Hospital Oakland Research Institute, Oakland, California, USA
Email: firstname.lastname@example.org; email@example.com; firstname.lastname@example.org One of the most promising vaccine candidates against serogroup B (MenB) meningococcal disease is factor H-binding protein (fHbp). At present this antigen is a key component in two different vaccines; one with a recent marketing authorisation in Europe and the other in late-stage clinical trials. These vaccine formulations are based on recombinant fHbp molecules with differences in sequence and lipidation state. Another vaccine strategy is to use native outer membrane vesicles (nOMV) prepared from strains with genetically over-expressed fHbp. In the present study, we immunised mice with a nOMV vaccine with over-expressed fHbp ID 9 from subfamily B (OE-nOMV-fHbp; ID 9). We measured human complement-mediated bactericidal activity against 12 invasive case isolates from Norway with different sub-family B fHbp sequence variants. As controls, we used sera raised to non-lipidated recombinant fHbp vaccines, whose sequences were matched to each of the test strains (identical fHbp sequence identification
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Vaccinology (ID) numbers. Antibodies to the recombinant fHbp vaccines elicited bactericidal activity against most of the strains. However, three strains with moderate to high expression of different fHbp sequences, as measured by flow cytometry, were resistant to these antisera. Antibodies to the OE-nOMV-fHbp ID 9 vaccine elicited high bactericidal titres against 11 of the 12 strains tested. The cross-protective responses were primarily elicited by anti-fHbp antibodies, since a control vaccine prepared from an isogenic fHbp knock-out strain (KO-nOMV) elicited no bactericidal activity against any of the strains. Thus, antibodies elicited by the nOMV-fHbp vaccine had broader functional reactivity against the strains overall than antibodies elicited by the matched recombinant fHbp vaccines. Our findings illustrate the promise of using an OE-nOMV-fHbp formulation as an improved next generation MenB vaccine, for achieving a better functional immune response, with broader strain-coverage, than by using recombinant fHbp in various vaccine formulations.
V36 Addressing knowledge gaps around Serogroup B Invasive Meningococcal Disease Vaccination: Development of an Evidence-Based Reference document for use by Canadian Health Care Professionals Tajdin Jadavji1, Ronald Gold2, Gregory Tyrrell3,4, Marc Lebel5,6, Simon Dobson7, Ian Gemmill8, Allan Ronald9, James A.Mansi10 1
Alberta’s Children’s Hospital, Calgary, AB; 2University of Toronto, Toronto, ON; 3University of Alberta, Edmonton, AB; 4Division of Medical Microbiology , Edmonton, AB; 5Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC; 6Université de Montréal, Montreal, QC; 7British Columbia Children’s Hospital, Vancouver, BC; 8Kingston, Frontenac and Lennox & Addington Public Health Unit, Kingston, ON; 9University of Manitoba, Winnipeg, MB; 10 Novartis Vaccines & Diagnostics, Dorval, QC
Email: email@example.com Keywords: Invasive Meningococcal Disease (IMD), Meningitis B, MenB Vaccine, Immunisation Practice, Knowledge Translation Background: Since the implementation of Meningococcal C (MenC) vaccine programs in Canada, significant reductions in MenC disease have been seen. With the introduction of quadrivalent meningococcal conjugate A, C, W-135, Y (MenACWY) vaccines, we hope to observe similar reductions in invasive meningococcal disease (IMD) due to serogroups Y and W. In Canada Meningococcal B (MenB) accounts for the majority of invasive
meningococcal disease (IMD). A MenB vaccine will soon be available. In order to facilitate the introduction and use of MenB vaccines, existing gaps in understanding of these vaccines and immunisation recommendations will need to be addressed. We developed an evidence-based reference document to bridge to guidelines and address the immediate need for answers to commonly asked questions. Methods: A Steering Committee of experts in IMD, infectious diseases and vaccinology was established to provide oversight and governance. Questions were collected from accredited continuing medical education (CME) events and through the Novartis Medical Information Centre support line. An Advisory Committee was convened to obtain consensus on reference based responses and their relevance from an immunisation perspective. Consensus was obtained on Frequently Asked Questions (FAQs) and evidence based answers, generating an open source document. Results: Over an 18 month period, 8 different CMEs occurred. Of these 2 were focused on MenACWY vaccines and 6 on MenB vaccines. Questions posed during these CMEs, including those sent through the Medical Information Centre, were grouped according to the following categories: epidemiology and burden of IMD (35%), IMD pathophysiology and vaccine clinical data (45%) and IMD immunisation recommendations (20%). Conclusion: There remain gaps in understanding of current IMD epidemiology, vaccine clinical data and vaccine guidelines. This evidence-based reference document will help bridge to upcoming guidelines and recommendations, addressing the immediate need for answers to commonly asked questions from a scientific, clinical and practical perspective. Conflict of Interest: The development of this document was made possible through funding provided by Novartis Vaccines & Diagnostics, a business unit of Novartis Pharmaceuticals Canada Inc. (‘’Novartis’’), and was conducted under a collaborative agreement between Novartis and the project’s scientific steering committee, which comprised Drs Tajdin Jadavji, Ron Gold, Gregg Tyrell, Marc Lebel, Simon Dobson, Ian Gemmill, Alan Ronald and James A. Mansi. The scientific steering committee was responsible for the development of the document and for the direction of the project. Novartis does not have any ownership rights to the project. The scientific steering committee has absolute discretion and the final decision over the contents, educational materials and presentations.
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Vaccinology V37 The successful development of an efficient OMV vaccine process with the potential for producing a broad protective immune response against Neisseria meningitidis Michael Joachim, Claire Entwisle, Ann McIlgorm, Sue Hill, Sally Harris, Lucy Blandford, Paola Cecchini, Yin Pang, Chris Bailey, Camilo Colaco ImmunoBiology Ltd, Cambridge, UK
Email: Michael.firstname.lastname@example.org Keywords: Neisseria meningitidis, OMV, Fermentation, Process, Immunogenicity Outer membrane vesicles (OMVs) are naturally produced by Neisseria meningitidis bacteria by vesiculation or â€˜blebbingâ€™ from the bacterial membrane. The composition of OMVs makes them significant activators of host innate and acquired immune response pathways. In addition to the potent immunomodulatory molecule LPS, vesicles contain porins and other important innate immune-activating ligands. Together, vesicle components appear to act synergistically to modulate the host response in ways that can either stimulate the clearance of the pathogen, enhance the virulence of the infection, or both. The current method of OMV production involves the use of detergents to extract the OMVs which gives a good yield but can change the conformation and immunogenicity from the native OMV. Whilst these detergent-extracted OMVs have been used as vaccines to control epidemics they are only protective against the homologous strain, although they have also been used in vaccines to increase the breadth of the immune response. ImmBio has investigated the use of a non-detergent method of OMV production using a 1L fermentation scale process. The aim of the study was to produce spontaneously released OMVs (sOMV) which are released into the culture supernatant and an extracted OMV (eOMV). OMVs were produced from wild type N. meningitidis strains 44/76-SL and M01-240149 which were grown in 1L fermenters and the effect of different culture conditions on the production process was assessed. Following downstream processing, the resultant eOMV and sOMV were assessed by SDS PAGE gels, Western blot, ELISAs and electron microscopy and compared with OMVs produced by detergent extraction.
The sOMV and eOMV were also used in an in vivo study to assess immunogenicity. Following analysis it was found that there was a high yield of sOMVs derived from the 44/76-SL strain compared with that derived from the M01-240149 strain and that the yield of eOMVs was similar for both strains. Using SDS-PAGE and Western blot analysis both eOMV and sOMV were found to have similar protein profiles and in vivo, both the eOMV and sOMV were immunogenic and induced a good antibody response. This study shows that this 1L scale fermentation of N. meningitidis can successfully and efficiently produce both soluble and extracted OMVs which are immunogenic in vivo.
V38 Structure-antibody recognition studies of currently licensed tetanus toxoid-conjugated bacterial polysaccharide vaccines Kay Lockyer, Fang Gao, Laura Coombes, Paul Stickings, Barbara Bolgiano Division of Bacteriology, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Herts. EN6 3QG, UK
Email: Kay.Lockyer@nibsc.org Keywords: conjugate, SEC-MALLS, epitope recognition, tetanus toxoid, monoclonal antibody A comparison of structural features of nine different currently licensed polysaccharide-tetanus toxoid (TT) conjugate vaccines was made to determine if the accessibility of neutralising epitopes on the conjugated carrier protein was affected by the degree of polysaccharide (PS) loading or size of the conjugate. T-cell epitope accessibility and integrity is critical in conjugate vaccines so that glyco-peptides can be processed and presented to antigenpresenting cells for an effective immune response. The conjugates used included vaccine components to protect against disease caused by Haemophilus influenzae type b (Hib), Neisseria meningitidis groups A, C, W and Y and Streptococcus pneumoniae serotype 18C. Conformation and structural analysis included size exclusion chromatography with multiangle light scattering (SEC-MALS) to determine size, and intrinsic fluorescence spectroscopy and fluorescence quenching to evaluate the protein folding and exposure of Trp residues. A capture ELISA measured the recognition of TT epitopes in the conjugates, using four rat monoclonal antibodies, 2 localised to the Hc (cell-binding) subunit, and 2 which
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Vaccinology were conformation-dependent (and not localised to a particular subunit). All TT conjugates were found to be well-folded, and did not have spectral features typical of aggregated TT. They ranged in size from 1.5 to > 10 MDa. The panel of bulk conjugates showed a correlation between PS loading (mol PS: mol protein) and the recognition of neutralising Hc epitopes (antibodies TT04 and TT10); somewhat surprisingly, increased protein epitope recognition was observed in conjugates which had higher PS loading/mol protein. In general, Trp residues were also more surface exposed and quenched by acrylamide in the larger conjugates. Low or no correlation was found for the conformational, holotoxin epitopes. Although manufactured by different conjugation chemistries, this panel of TT conjugates has been useful in establishing the concept that high PS conjugation to carrier proteins need not necessarily mask or prevent immune system recognition of key vaccine epitopes.
V39 Attitudes towards vaccination against Group B streptococcus in pregnancy Fiona McQuaid1,2, Christine E Jones3, Zoe Stevens1,2, Jane Plumb4, Rhona Hughes5, Helen Bedford6, Paul T Heath3, Matthew D Snape1,2 Department of Paediatrics, University of Oxford, UK; 2NIHR Oxford Biomedical Research Centre, Oxford, UK; 3Paediatric Infectious Diseases Research Group, St Georges, University of London, London, UK; 4Group B Strep Support, Haywards Heath, West Sussex, UK; 5Simpson Centre for Reproductive Health, Royal Infirmary, Edinburgh, UK; 6Centre for Epidemiology and Child Health, University College London Institute of Child Health, London, UK 1
Email: Fiona.email@example.com Keywords: Group B Streptococcus, vaccination, pregnancy, attitudes Introduction: Group B streptococcus (GBS) remains the most common cause of serious infection, including meningitis, in infants under three months of age. GBS vaccines are currently in development, and their use in pregnancy has the potential to prevent early and late onset disease. However, women may be reluctant to accept antenatal vaccination. The objective of this survey was to assess the knowledge and attitudes of British women regarding GBS and the acceptability of a potential GBS vaccine.
Methods: An online questionnaire distributed to 1,013 women aged 18-44 in Great Britain by a market research company (ComRes, London, 13th-17th September 2013) assessed level of awareness of, and attitudes towards vaccination in pregnancy against pertussis, influenza and GBS. Information about GBS was then presented and questions about GBS immunisation repeated with an additional question about GBS vaccine research. Respondents were also asked to rate the importance of immunisation advice from a list of sources. The survey was funded by Meningitis UK. Results: Nearly two thirds (63%) of women aged 18-44 years reported they either had never heard of GBS or didnâ€™t know what it was, compared to 28% for pertussis and 40% for influenza in pregnant women. However, the level of knowledge about the condition did not affect the willingness to receive a vaccine against it during pregnancy with 75% being likely to accept pertussis vaccine, 72% influenza and 72% GBS. Once additional information was provided about GBS, the latter percentage rose to 82%. Thirty-two percent responded that they would be likely to take part in GBS vaccine research during pregnancy if the vaccine had been tested in 500 pregnant women without significant safety concerns, rising to 43% if the vaccine had been tested in 5000. Seventy-nine percent reported they would be happy to receive the vaccine if it was licensed and recommended for use by the NHS. GPs were rated the most important source of advice on maternal immunisation (considered important by 87% of women aged 18-44 years) followed by midwives (84%). Conclusions: Despite the low level of knowledge about GBS, those completing the survey were open to the idea of immunisation during pregnancy and over a third showed interest in being involved in research. While these results are encouraging in terms of the feasibility of conducting future GBS vaccine trials in pregnancy, more work is required to establish the specific concerns of pregnant women and how these may be overcome.
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Vaccinology V40 Knowledge and attitudes towards meningitis and vaccination: a survey of parents and health professionals in Ireland Andy Cochrane, Diane McConnell, Caroline O’Connor Meningitis Research Foundation Dublin
Keywords: knowledge and attitudes; questionnaires; parents; GPs and practice nurses Email: Caroline@meningitis-ireland.org Aims: In the past two decades the introduction of vaccines to control Hib disease, meningococcus C and some types of pneumococcus has resulted in a dramatic reduction in the number of cases each year. For example, cases of invasive meningococcal disease (IMD) caused by serogroup C has reduced from 135 in 1999 to just 2 in 2010. Nevertheless, meningitis has not ‘gone away’ and Ireland still has the highest rates of confirmed cases of IMD in Europe for both of the age groups most at risk (under 5 years: 21 per 100,000; 15-24 year olds: 5.7: 100,000). A vaccine uptake rate of ≥ 95% is needed to achieve herd immunity. However, following the change to the immunisation schedule in July 2008, the uptake of the Men C and Hib vaccines due at 13 months fell to as low as 80% in some parts of the country. While there is some evidence of improved uptake rates there is a need to understand attitudes towards vaccination and knowledge about meningitis to inform health promotion initiatives. Method: Telephone surveys were conducted with (1) a nationally representative sample of parents (n = 350) with one or more child under the age of two years; and (2) GPs and practice nurses (n = 150) with direct involvement in vaccination. Results: The findings indicate that meningitis creates a high level of concern for both parents and health professionals, yet some parents are delaying completion of the vaccination schedule without realising that this leaves their child unprotected at a period when they are most at risk from the disease. In addition, over a third of parents mistakenly believed that the current vaccination schedule protects their child against all forms of meningitis.
Conclusions: Recognition and treatment of meningitis and septicaemia has improved but prevention remains critical in reducing the burden of the disease. There is an ongoing need for information about vaccination and meningitis at a national level, and for more tailored individualised information. GPs and Public Health nurses remain the key people that parents turn to for advice and information, and these professionals will be critical in ensuring the uptake rates of the current immunisation schedule continue to improve and to promote the successful introduction of any changes to the childhood vaccination schedule.
V41 Safety and Immunogenicity of a 2-Dose Schedule (12 Months and 18 Months of Age) of a Quadrivalent Meningococcal Conjugate Vaccine Noya F1, McCormack D1, Reynolds DL2, Neame D2, Oster P3 1 McGill University Health Centre, Montreal, QC Canada; 2Sanofi Pasteur Ltd., Toronto, ON, Canada; 3Sanofi Pasteur, Lyon, France
Email: firstname.lastname@example.org Keywords: Neisseria meningitidis; conjugate vaccine; meningococcal disease; safety; immunogenicity Background: Monovalent serogroup C meningococcal conjugate vaccine (MCC) has been provided through Quebec vaccination programs since 2001. A 2-dose schedule of a quadrivalent meningococcal conjugate vaccine (MenACYW-D) at 12 and 18 months of age would fit current programmes and broaden coverage. Methods: Eligible toddlers received MMRV and PCV13 at 12 months and MMR and DTaP-IPV-Hib at 18 months in a 2-armed, open-label, parallel descriptive study. Participants were randomised to receive a 2-dose schedule of MenACYW-D at 12 and 18 months of age (MenACYW-D arm) or one dose of MCC at 12 months of age (MCC arm). Blood samples were collected pre-Dose 2 at 18 months and 1 month post-Dose 2 in the MenACYW-D arm and at 1 and 7 months post-MCC in the MCC arm. Immune responses to meningococcal vaccines (via baby rabbit serum bactericidal assay [SBA-BR]) and DTaP-IPV-Hib vaccine were analysed and safety data collected
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Vaccinology Results: Participants in the MenACYW-D arm (n=61) achieved high rates of seroprotective levels (SBA-BR ≥8 1/dil) post-Dose 2: A (100% [95% CI, 93.0%– 100%]), C (96.1% [95% CI, 86.5%–99.5%]), Y (100% [95% CI, 93.0%–100%]), W (98.0% [95% CI, 89.6%– 100%]). In the MCC arm (only serogroup C response was expected; n=62), 66.7% [95% CI, 53.3%–78.3%] of participants achieved seroprotective levels 1 month postvaccination, declining to 25.9% (95% CI, 15.3%–39.0%) 7 months postvaccination. In the MenACYW-D arm, geometric mean titres for all serogroups were high post-Dose 2: 1740 (A), 957 (C), 719 (Y) to 970 (W). All titre increased from the 18-month pre-Dose 2 vaccination. Seroprotection rates for diphtheria, tetanus, PRP and polio types 1, 2, and 3 were 100%. Pertussis booster response rates in the MenACYW-D and MCC arms were 100% versus 94.3% (PT), 92.7% versus 78.8% (PRN), 97.7% versus 88.0% (FHA), and 100% versus 95.8% (FIM), and were within the range of historical rates. Both vaccines were well tolerated. Three SAEs were reported. None were related to vaccination, and no participants withdrew due to AEs. Conclusion: Two doses of MenACYW-D resulted in higher serogroup C immune responses at 19 months than a single dose of MCC and broadened serogroup coverage. MenACYW-D administered as a 2-dose series, concomitantly with a booster dose of DTaPIPV-Hib at 18 months of age demonstrated good immunogenicity and safety profiles. MenACYW-D can be used as an alternative to MCC in vaccination programs. Study funded by Sanofi Pasteur (NCT01359449).
V42 Single Priming Dose of NeisVac-C® in Infants Eva Maria Poellabauer, Borislava G. Pavlova, Sandor Fritsch, Julia Singer, Christian Neubauer, Jennifer Doralt, Barbara Valenta-Singer, Robert Petermann, Hartmut J. Ehrlich Global R&D, Baxter BioScience, Industriestrasse 67, A-1220 Vienna, Austria
Keywords: meningitis, vaccination, infants, single dose, schedule The currently licensed infant immunisation schedule for meningococcal serogroup C conjugated vaccines requires two doses, followed by a booster dose in the second year of life. Several clinical studies with NeisVac-C® demonstrated high seroprotection rates in infants after a single priming dose.
The aim of the present study was to assess the feasibility of a single priming dose of NeisVac-C® given at 4 months or 6 months of age compared to a two-dose priming schedule. 956 subjects were randomly assigned to receive a single dose of NeisVac-C® at 4 or 6 months of age, or two doses at 2 and 4 months of age. All subjects received a booster between 12 and 13 months of age. Concomitant vaccinations with Infanrix® hexa and Prevenar 13® were administered to all subjects at all timepoints. Primary endpoint of the study was to demonstrate non-inferiority of seroprotection rates following a single priming dose compared to a two-dose priming one month after the primary vaccination (rSBA ≥8), prior to the booster (rSBA ≥8), and one month after the booster (rSBA ≥128). The non-inferiority margin was set to 10% and 5%, for the first two and the third time points, respectively. Rates of subjects with rSBA ≥ 8 one month after primary vaccination were 99.6% in the 4 month dose group, 99.2% in the 6 month dose group, and 99.6% in the two-dose group. Prior to the booster, 78.0% and 90.7% of subjects had seroprotective antibody titre in the single dose groups (month 4 or month 6, respectively), compared to 67.8% in the two dose group. One month after the booster, > 98.5% of subjects in all three dose groups showed rSBA titre ≥ 128, with no differences between the groups. Non-inferiority of the single dose regimen vs. two doses could be demonstrated. Thus, a single priming dose given at age ≥ 4 months, followed by a booster early in the second year of life, is expected to offer protection, which is comparable to that of a two-dose priming schedule. This finding is in line with several previous studies which demonstrated seroprotection rates of 92%-100% after one dose of NeisVac-C® given at two - or three months of age. Reducing the number of doses in infancy from two doses to one provides greater flexibility in the already crowded infant vaccination schedules, and allows transfer of one MCC vaccine dose into adolescence in a cost neutral way.
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Vaccinology V43 - Oral Presentation, day two Impact of Quadrivalent Conjugate (MenACWYCRM) and Serogroup B (4CMenB) Meningococcal Vaccines on Meningococcal Carriage in English University Students Robert C. Read1, David Baxter2, David R. Chadwick3, Saul N. Faust4, Adam Finn5, Stephen B. Gordon6, Paul T. Heath7, David J.M. Lewis8, Andrew J. Pollard9, David P.J. Turner10, Rohit Bazaz1, Amitava Ganguli11, Tom Havelock4, Keith R. Neal10, Ifeanyichukwu O. Okike7, Begonia Morales-Aza5, Kamlesh Patel12, Matthew D. Snape9, John Williams3, Stefanie Gilchrist13, Stephen J. Gray13, Huajun Wang14, Maggie McCarthy14, Daniela Toneatto14, Peter M Dull14, Ray Borrow13 1
Sheffield University, and Royal Hallamshire Hospital Sheffield, Department of Infection & Immunity, Sheffield School of Medicine and Biomedical Science, Sheffield, UK; 2Division of Epidemiology and Health Sciences, Medical School, The University of Manchester, UK; 3The James Cook University Hospital, Middlesborough, UK; 4NIHR Wellcome Trust Clinical Research Facility, Faculty of Medicine, University Hospital Southampton NHS Foundation Trust, University of Southampton, UK; 5University of Bristol & Bristol Royal Hospital for Children, University Hospitals, Bristol NHS Foundation Trust, Bristol, UK; 6Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK; 7Vaccine Institute & Paediatric Infectious Diseases Research Group, Division of Clinical Sciences, St. Georges, University of London, London, UK; 8Clinical Research Centre, Institute of Biosciences and Medicine, FHMS, University of Surrey, Guildford, UK; 9 Oxford Vaccine Group, Department of Paediatrics, University of Oxford, UK; 10University of Nottingham, and Nottingham University Hospitals NHS Trust, Derby Road, Nottingham, UK; 11 Royal Liverpool University Hospital and Institute of Translational Medicine, University of Liverpool, UK; 12NIHR/Wellcome Trust Clinical Research Facility, Manchester Royal Infirmary, Manchester, UK; 13Meningococcal Reference Unit, Public Health England, Manchester Public Health Laboratory, Manchester Royal Infirmary, Manchester, UK; 14Novartis Vaccines and Diagnostics, Inc., Cambridge, Massachusetts, USA
Email: email@example.com Keywords: vaccine, meningococcal, serogroup B, carriage, quadrivalent Background: Successful introduction of serogroup C meningococcal conjugate vaccination was underpinned by a significant impact on oropharyngeal carriage. With the recent introduction of ACWY meningococcal conjugate vaccines and EMA approval of a serogroup B meningococcal vaccine, we investigated the effect of these two vaccines on carriage in university students,
a potential target population for meningococcal vaccination (NCT01214850). Methods: From September–December 2010, 2968 students (mean age ± SD, 19.9 ± 1.6 years) from ten English universities were enrolled into a phase III observer-blind, randomised, controlled study. Three equal groups received two vaccinations one month apart: a MenACWY-CRM group (n=956) given one dose of quadrivalent meningococcal conjugate vaccine (Menveo®) followed by saline placebo; a 4CMenB group (n=932) who received two doses of meningococcal serogroup B vaccine (Bexsero®); and controls (n=947) given two doses of Japanese Encephalitis vaccine (Ixiaro®). Oropharyngeal samples were taken before vaccination and at five subsequent visits over one year. Primary analysis compared cross-sectional carriage one month after the vaccine course; secondary analysis compared cumulative carriage in the period commencing after primary analysis until study termination. Results: Before vaccination, 981 (33%) of 2941 evaluable samples yielded Neisseria cultures, mostly (98%; n=930) N. meningitidis, mainly capsular groups B and Y. The primary analysis showed no significant differences in carriage between controls and MenACWY-CRM (p=0.593) or 4CMenB (p=0.393) groups. In secondary analyses from three months after dose two 4CMenB showed significantly lower carriage of any N. meningitidis than controls at any timepoint; efficacy 18.2% (95% CI: 3.4–30.8), and lower carriage of genogroups B, C, W and Y combined: efficacy 26.6% (95% CI: 10.5–39.9). Genogroups B, C, W, and Y carriage was significantly lower in 4CMenB subgroups associated with increased susceptibility to de novo acquisition: subjects enrolled within 30 days of semester start (p=0.012), smokers (p=0.009), and subjects < 21 years-old (p=0.004). In further secondary analysis from two months after first dose, the MenACWYCRM group showed significantly lower carriage of genogroups and serogroups A, C, W, and Y combined (p=0.011 and p=0.002, respectively) compared with controls, largely attributable to a carriage-reduction efficacy of 39% (95% CI: 17.3– 55.0) against serogroup Y strains. Conclusion: MenACWY-CRM and 4CMenB both show impact on carriage during 12 months postvaccination, particularly in sub-groups associated with increased risk of meningococcal disease, raising the possibility of an impact on transmission, which may translate into herd protection in settings where the vaccines are implemented broadly.
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Vaccinology V44 Five-Year Persistence of Immune Responses to Two Licensed Quadrivalent (MenACWY) Conjugate Meningococcal Vaccines in Adolescents Roger Baxter1, Keith Reisinger2, Stan L Block3, Sandra Percell4, Tatjana Odrljin4, Peter M Dull4, Igor Smolenov4 1
Kaiser Permanente Vaccine Study Center, Oakland, CA, USA; Primary Physicians Research, Pittsburgh, PA, USA; 3Kentucky Pediatric and Adult Research, Bardstown, KY, USA; 4Novartis Vaccines and Diagnostics, Inc., Cambridge, MA, USA 2
Email: firstname.lastname@example.org Keywords: vaccine, meningococcal, persistence, booster, quadrivalent Background: Meningococcal conjugate ACWY vaccines are recommended for all US adolescents, with one of two currently licensed vaccines, Menveo® (MenACWY-CRM, Novartis Vaccines) and Menactra® (MenACWY-D, Sanofi Pasteur). Having previously compared immune responses to these two vaccines in adolescents, we assessed antibody persistence at five years post-vaccination (clinicaltrials.gov NCT00856297). Methods: In this open-label, multi-center, US-based study, antibody persistence was assessed in healthy 11−18 year-old adolescents five years after vaccination (March 2007) with one dose of either MenACWY-CRM or MenACWY-D; some subjects also received a booster dose of MenACWY-CRM three years after primary vaccination. Age-matched vaccine-naïve subjects were recruited as controls. Immune responses, assessed by serum bactericidal activity with human complement (hSBA), were expressed as percentages of seropositive subjects (hSBA titer ≥ 8) and geometric mean titre (GMT) against the four serogroups. Results: A total of 389 subjects participated in five groups: MenACWY-CRM (n=131); MenACWYD (n=76); MenACWY-CRM + MenACWY-CRM booster (n=44); MenACWY-D + MenACWY-CRM booster (n=31); vaccine-naïve (n=107). Mean ages were 18.8–19.7 years across all groups. Five years after primary vaccination, the percentages of seropositive subjects against serogroup A in the MenACWY-CRM and MenACWY-D groups were both significantly (p < 0.001) higher than in vaccine-naive subjects (32%, 34% and 8%, respectively).
For serogroups C, W and Y, the respective seropositivity rates in the MenACWY-CRM, MenACWY-D and vaccine-naïve groups were: serogroup C (59% vs 60% vs 38%), serogroup W (82% vs 73% vs 66%) and serogroup Y (64% vs 54% vs 39%). All comparisons between MenACWY-CRM and control groups were statistically significant (p ≤ 0.004). For Men-ACWY-D, only the serogroup C rate was significantly higher than controls (p = 0.004). MenACWY-CRM vaccinees had significantly higher GMTs against all four serogroups than controls, but in the MenACWY-D group only serogroup A and C GMTs were significantly higher than controls. Two years after a booster dose of MenACWY-CRM, 77–79% of subjects had hSBA titre ≥ 8 against serogroup A, 87–95% against serogroup C, 97–100% against serogroup W, and 93–95% against serogroup Y, after primary vaccination with MenACWY-CRM or MenACWY-D. Conclusion: Both MenACWY-CRM and MenACWY-D showed evidence of substantial seropositivity rates 5 years after a single vaccination, although only the MenACWY-CRM group had significantly higher rates than controls for all serogroups. A booster dose of MenACWY-CRM three years after either vaccine maintained high rates of seropositive subjects two years later.
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Vaccinology V45 Development of a serum bactericidal antibody (SBA) assay for Haemophilus influenzae serotype b Kelly Townsend1, Helen Findlow1, Xilian Bai1, Shamez Ladhani2, Mary Slack3, Ray Borrow1 1
Vaccine Evaluation Unit, Public Health England, Manchester Royal Infirmary, Manchester, UK; 2Immunisation, Hepatitis and Blood Safety Department, Public Health England, London, UK; 3 Respiratory and Systemic Infection Laboratory, Public Health England, London, UK
Keywords: Hib, SBA assay, anti-PRP IgG, glycoconjugate vaccines, assay validation Background: Prior to routine conjugate vaccination, Haemophilus influenzae serotype b (Hib) was a major cause of serious bacterial infections, particularly in young children. The introduction of the Hib conjugate vaccine into national childhood immunisation programmes resulted in a rapid and sustained reduction in invasive Hib disease across all age groups. Evaluation of the immune response to Hib conjugate vaccines includes the measurement of serum antibodies against the Hib capsular polysaccharide, polyribosyl-ribitol-phosphate (PRP), by ELISA, with accepted short term and long term levels of ≥0.15 µg/mL and ≥1.0 µg/mL, respectively. The relevance for protection in children who have been primed with glycoconjugate vaccines remains unclear, as these levels were derived from passive immunisation, or immunisation with pure polysaccharide. The serum bactericidal antibody (SBA) assay measures functional antibodies that bind to a specific target strain and fix complement onto the bacterial surface, initiating complement mediated lysis. Previous SBA methodologies have been published for Hib which have shown good correlation between IgG antibody concentrations against the Hib capsular polysaccharide (PRP) with SBA titres in adult sera. This correlation, however, has not been established and evaluated in vaccinated UK infants. The objective of this study, therefore, was to develop an SBA assay to assess the functional activity of Hib antibodies induced by Hib conjugate vaccines.
Methods: A Hib SBA assay was developed and optimised using previous knowledge and understanding of the N. meningitidis SBA, and subsequently tested on sera from vaccinated adults (n=39), and from infants immunised under the current UK accelerated immunisation schedule at two, three and four months (n = 486). SBA titres were compared to previously determined anti-PRP IgG concentrations determined by a Hib Bioplex assay for correlation and the Pearson`s correlation coefficients (r value) were calculated. Results: Validation of the Hib SBA assay was deemed acceptable in all assay parameters tested. In vaccinated adults, a strong correlation (r=0.81) between anti-PRP IgG concentrations and SBA titres were shown. In vaccinated infants, too, good correlations between anti-PRP IgG concentration and SBA titres were observed (r=0.64 post primary, r=0.75 post-booster). A predictive SBA titre of 8 was calculated using the established long-term correlate of protection (1.0 μg/mL). Conclusions: The Hib SBA assay was shown to be reliable and reproducible when evaluating the humoral response following Hib vaccination. An SBA titre of 8 was estimated to confer long-term protection against invasive Hib disease.
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Vaccinology V46 Assessment of non-functional variant 3 factor H binding proteins as meningococcal vaccine candidates Stijn van der Veen, Christoph M. Tang Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford, OX1 3RE, UK
Email: email@example.com Keywords: Neisseria, fHbp, vaccine, factor H, immunogenicity Neisseria meningitidis is a human specific pathogen and the leading cause of meningitis and septicaemia. Capsule-based vaccines are available against several serogroups of N. meningitidis, but not against serogroup B strains because its capsule mimics a human molecule, affecting immunogenicity and raising concerns of autoimmunity. Consequently, N. meningitidis serogroup B is the main cause of disease in developed countries. Therefore, vaccines containing outer-membrane proteins are currently being developed. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against meningococcus, and is currently being assessed in several phase II/III clinical trials. However, the interaction of fHbp with the host complement regulator factor H (fH) could impair the immunogenicity of this antigen and has led to the development of non-functional fHbps as vaccine candidates. Furthermore, fHbp can be divided into three variant groups (V1, 2 and 3) based on its amino-acid sequence and immunological crossreactivity between these variant groups is limited. So far, nothing is known about the immunogenicity of non-functional V3 fHbps, while this variant group is expressed by approximately 10% of the clinical isolates.
In this study, we investigated the non-functional V3 fHbp mutants fHbpT228A and fHbpE255A, to establish their suitability for an fHbp-based vaccine. The binding affinity of the wild-type and mutant proteins for fH was determined by surface plasmon resonance, ELISA and far-Western and both mutants showed a marked reduction in affinity. Reduced binding by the non-functional fHbps could be the consequence of misfolding or reduced stability and unstable proteins are undesirable for vaccine development. Therefore, we investigated the structural integrity and stability of the non-functional fHbps using circular dichroism spectroscopy (overall folding), differential scanning calorimetry (thermal stability) and trypsin digestion assays (local folding disturbances) and confirmed that both nonfunctional fHbps are stable fully folded proteins. The immunogenicity of our non-functional fHbps was assessed by immunising transgenic mice in which the mouse fH domains involved in binding to fHbp were replaced by human fH domains. No differences in anti-fHbp antibody titre were observed between wild-type or non-functional fHbps. To determine whether these antibodies are able to elicit protective immunity, the serum bactericidal activity of the antibodies was investigated against N. meningitidis M1239, which naturally expresses the homologous 3.P28 fHbp. Equivalent or improved bactericidal activity was observed after immunisation with nonfunctional fHbps. These findings provide the basis for the rational design of next generation vaccines containing non-functional V3 fHbps.
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Vaccinology V47 Antibody persistence 12 months following booster vaccination with a quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy children Timo Vesikari1, Aino Forsten1, Veronique Bianco2, Marie Van der Wielen2, Jacqueline M Miller3 1
Vaccine Research Center, University of Tampere Medical School, Tampere, Finland; 2Vaccine Discovery and Development, GlaxoSmithKline Vaccines, Wavre, Belgium; 3Vaccine Discovery and Development, GlaxoSmithKline Vaccines, King of Prussia, PA, USA
Email: firstname.lastname@example.org Keywords: MenACWY-TT, MenC-CRM197, persistence, SBA, 1-year post-booster follow-up Background and aims: This study evaluated antibody persistence 12 months after booster vaccination with a meningococcal serogroups A, C, W-135, Y conjugate vaccine (MenACWY-TT, GlaxoSmithKline Vaccines) compared to a meningococcal serogroup C conjugate vaccine (MenC-CRM197, Wyeth LLC), in healthy children. Methods: In this phase III, open-label, controlled, multi-centre study in Finland (NCT00955682), children previously randomised (3:1) and primed with a single dose of MenACWY-TT or MenC-CRM197
at age 12–23 months (NCT00474266) received a booster dose of the same vaccines 48 months postpriming. Immunogenicity was evaluated at month (M) 60 (12 months post-booster) with serum bactericidal antibody assays using rabbit (rSBA; cut-off 1:8) and human (hSBA; cut-off 1:4) complement. Vaccinerelated serious adverse events (SAEs) were recorded until M60. Results: Of 293 boosted children, 286 returned at M60, with 277 included in the according-to-protocol cohort for persistence at M60 (MenACWY-TT: N=231; MenC-CRM197: N=46). At M60, all MenACWY-TT recipients retained rSBA titres ≥1:8 (except for MenC, 97.4%) and hSBA titres ≥1:4 (except for MenA, 95.5%) (Table). hSBA geometric mean antibody titres (GMTs) at M60 declined compared to M49 (1 month post-booster), but were higher than after primary vaccination. MenC seropositivity rates and GMTs (rSBA, hSBA) were comparable between groups. No vaccine-related SAEs were reported. Conclusion: Antibodies evaluated by rSBA and hSBA assays persisted for each serogroup in >95% of children 12 months after MenACWY-TT booster vaccination. These data indicate that additional booster doses of MenACWY-TT could extend the duration of vaccine-induced protection. Funding: GlaxoSmithKline Biologicals SA
Table: Percentage of children with rSBA titres ≥1:8 and hSBA titres ≥1:4 and corresponding GMTs (ATP cohort for persistence at M60)
Antibody Group N % ≥1:8 GMT N % ≥1:4 GMT (95% CI) (95% CI) (95% CI) (95% CI) MenA MenACWY-TT 231 100
978.9 221 95.5 88.0 (98.4-100) (860.2-1114.0) (91.8-97.8) (73.6-105.1)
MenC MenACWY-TT 231 97.4
226.4 228 100 1342.3 (94.4-99.0) (183.7-279.0) (98.4-100) (1134.6-1588.1) MenC-CRM197 46 97.8 320.9 33 100 931.1 (88.5-99.9) (201.1-512.2) (89.4-100) (572.8-1513.4)
MenW-135 MenACWY-TT 231 100
1390.7 218 100 2196.6 (98.4-100) (1203.2-1607.3) (98.3-100) (1955.7-2467.2)
MenY MenACWY-TT 231 100
1071.1 206 100 1110.8 (98.4-100) (924.9-1240.5) (98.2-100) (987.5-1249.6) GMT = geometric mean antibody titre; ATP = according-to-protocol; M60 = Month 60, 12 months post-booster; N = number of subjects with available results; 95% CI = 95% confidence interval; rSBA assay performed at Public Health England; hSBA assay at GlaxoSmithKline Vaccines
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Vaccinology V48 - Oral Presentation, day two Safety, Tolerability, and Immunogenicity of an Investigational Meningococcal Serogroup B Bivalent rLP2086 Vaccine in Healthy Adolescents When Administered in Regimens of 2 or 3 Doses in Healthy Subjects aged 11 to 18 Years Timo Vesikari, MD, PhD,1 Javier Diez-Domingo, MD, PhD,2 Lars Ostergaard, MD, PhD3, Johannes Beeslaar, MD4, Joseph Eiden, MD, PhD4, Qin Jiang, PhD5, Kathrin U. Jansen, PhD4, Thomas R. Jones, PhD4, Laura J. York, PhD4, and John L. Perez, MD4 1 University of Tampere Medical School, Tampere, Finland; 2Área de Investigación en Vacunas, Centro Superior de Investigación en Salud Pública (CSISP), Universidad Católica de Valencia, Valencia, Spain; 3Arhus Universitetshospital, Skejby, Arhus, Denmark; 4 Pfizer Vaccine Research, Collegeville, PA, USA
Email: email@example.com Keywords: Vaccine, Meningitis B, rLP2086, fHBP, adolescents Background: Neisseria meningitidis serogroup B (MnB) is a major cause of invasive disease in infants, adolescents, and young adults. A conserved, surface-exposed lipoprotein, LP2086 (a factor H binding protein [fHBP]), is a promising MnB vaccine target. Safety, tolerability, and immunogenicity of an investigational bivalent, recombinant vaccine (rLP2086) were studied in healthy adolescents 11–18 years of age using 5 dose regimens comprising 2 or 3 vaccinations (Table). Each 120-µg dose contained 60 µg of LP2086 from 1 subfamily A and 1 subfamily B variant.
Methods: All subjects in this phase 2, randomised, placebo-controlled, single-blind study attended vaccination visits at months 0, 1, 2 and 6. For blinding, a saline control was given when vaccine was not scheduled. Serum bactericidal assays using human complement (hSBA) were performed with 4 MnB test strains expressing fHBP variants A22, A56, B24 and B44, all of which are different from the variants in the vaccine. Unsolicited adverse events (AE), solicited local and systemic reactions, and antipyretic use were assessed. Results: 1 month after the last vaccine dose, 86–99% subjects (after 3 doses; P<0.001) and 69–100% of subjects (after 2 doses) had hSBA titre ≥8 to each MnB test strain. After study dose 1, 19–27% (1.1–4.3% severe) and 23–27% (0.0–1.0% severe) of rLP2086 recipients experienced redness and swelling, respectively, by group. Injection site pain was the most common local reaction after study dose 1 (7.6–13.1% severe). Fever ≥38ºC after the first study dose of rLP2086 was experienced in 3.3–6.5% by group compared to 2.1% in saline recipients. Local and systemic reactions were generally more frequent after dose 1 than after subsequent doses. 43 of 1712 subjects (2.5%) reported 51 serious AEs; 2 cases were considered related (1 case of vertigo, chills and headache and 1 case of fever and vomiting). No deaths were reported. Conclusions: Bivalent rLP2086 had an acceptable safety profile. All 5 dosing regimens yielded hSBA titre ≥8 against all 4 test strains in a high proportion of subjects.
Table: Statistical Analysis on Proportion of Evaluable Study Subjects Achieving hSBA Titer ≥8* for Each Primary Strain 1 Month After Last Dose of Bivalent rLP2086 – Evaluable Immunogenicity Population
Strain n†/N‡ %§(95% CI)¶ n†/N‡ %§(95% CI)¶ [variant]
n†/N‡ %§(95% CI)¶ n†/N‡
%§(95% CI)¶ n†/N‡
330/3 91.7¶ 60 (88.3,94.3)
339/ 95.0¶ 357 (92.1,97.0)
345/ 93.5¶ 369 (90.5,95.8)
102/ 91.9 111 (85.2, 96.2)
360/3 99.4¶ 62 (98.0,99.9)
355/ 98.9¶ 359 (97.2,99.7)
364/ 98.4¶ 370 (96.5,99.4)
112/ 99.1¶ 113 (95.2, 100.0)
315/ 89.0¶ 354 (85.2,92.0)
313/ 88.4¶ 354 (84.6,91.6)
291/ 81.1¶ 173/ 73.0¶ 359 (76.6,85.0) 237 (66.9, 78.5)
76/ 69.1¶ 110 (59.6, 77.7)
315/ 88.5¶ 356 (84.7,91.6)
303/ 86.1¶ 352 (82.0,89.5)
276/ 77.5¶ 356 (72.2,82.3)
81/ 73.0¶ 111 (63.7, 81.0)
*Lower limit of quantification for all strains=8 †Number of subjects with hSBA titer ≥8. ‡Number of subjects with valid hSBA titre. §P<0.001 using one-sided exact test based on binomial distribution; values<0.0125 are considered significant. ¶ Exact 2-sided confidence interval (Clopper and Pearson) based upon the observed proportion of subjects.
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Vaccinology The higher proportions against some test strains after 3 doses compared with 2 doses indicate that 3 doses may provide the broadest protection against diverse MnB clinical strains. Global phase 3 clinical trials are underway with the bivalent rLP2086 vaccine. Acknowledgments: This study was sponsored by Pfizer Inc. Editorial/medical writing support was provided by Nicole Gudleski, PhD, of Complete Healthcare Communications, Inc., and was funded by Pfizer Inc.
V49 Sensitivity Analysis of a Model Used to Predict the Cost Effectiveness of Bexsero for Immunisation against Meningococcal Disease in the United Kingdom Jasper Huels1, Jim Wassil2, Lars Bonefeld3, Phil Watson3* 1
Novartis Vaccines & Diagnostics AG, Basel, Switzerland; Novartis Vaccines, Cambridge, USA; 3Novartis Vaccines & Diagnostics Limited, Frimley, UK
Email: firstname.lastname@example.org Keywords: JCVI, Meningococcal, cost-effectiveness, sensitivity, Bexsero Background and aims: Neisseria meningitidis remains a major cause of bacterial meningitis and sepsis in the UK. Bexsero, a multicomponent vaccine approved by EMA for individuals >2 months, is the only licensed MenB vaccine. In July 2013, the Joint Committee on Vaccination and Immunisation (JCVI) concluded that routine infant or toddler immunisation using Bexsero is highly unlikely to be cost effective at any vaccine price, and that adolescent immunisation is highly unlikely to be cost effective if the vaccine has little or no impact on meningococcal carriage. These conclusions contradict recently published, peer-reviewed findings*. To demonstrate the impact of changing key inputs on cost effectiveness, we repeated the cost effectiveness sensitivity analysis and examined the effect of changing input parameters, in particular when multiple parameters were adjusted simultaneously.
Methods: A published mathematical and economic model estimated the impact of introducing Bexsero and determined the cost effectiveness of several vaccination strategies. Published input parameters from Christensen et al were used as a base case and varied 40% lower to represent the likely JCVI input parameters. Results: Assuming 3.5% discounting of costs and benefits and a QALY threshold of ÂŁ20,000, infant and adolescent Bexsero vaccination programmes would be cost effective with the published input parameters. Using 40% lower estimates of key input parameters, infant Bexsero programs were not cost effective at any vaccine price and adolescent programs only at a low price. Disease incidence, vaccine strain coverage, and frequency and quality of life impact of long-term sequelae among IMD survivors had the greatest impact on cost effectiveness. Adjustments to individual input assumptions had no substantive effect on cost effectiveness while maintaining low estimates for remaining parameters. Modest adjustments to two input parameters together had compounded effects and cost effectiveness markedly improved. Simultaneous adjustments to three key input assumptions, using plausible evidence-based data, had a profound effect. Conclusion: The model used in this analysis is similar to JCVIâ€™s, showing similar potential for cost effectiveness and sensitivity to changing inputs. Consistently populating this model using conservative parameters for all key inputs leads to Bexsero not being cost effective. Maintaining these low assumptions and increasing key parameters one at a time, leads to a similar conclusion. If the model is populated with evidence-based data which reflects the devastating impact and cyclical epidemiology of MenB disease, UK-wide immunisation of infants and adolescents with Bexsero could be cost-effective. *Reference: Christensen H, Hickman M, Edmunds JW, Trotter C. Introducing vaccination against serogroup B meningococcal disease: An economic and mathematical modeling study of potential impact. Vaccine. 2013;31;2638-2646.
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Vaccinology V50 Meningococcal vaccination in immunodeficiency â€“ is a targeted approach sufficient? Jo Anne Welsch, E. David McIntosh, William Egan, Theodore Tsai
into cross coverage by proteins contained in the multicomponent protein-based meningococcal B vaccine that may provide an opportunity to cover non-B serogroups including rarely occurring serogroups that threaten cohorts with primary immunodeficiencies.
Novartis Vaccines and Diagnostics, Cambridge MA, USA
Email: email@example.com Keywords: meningococcal disease; immunodeficiency; meningococcal vaccine; serogroup B; complement deficiency Objective: The UK JCVI recommends meningococcal ACWY conjugate and meningococcal B vaccines for children and adults with immunodeficiency, such as asplenia, splenic dysfunction or complement deficiency â€“ conditions that may be inherited as well as acquired. Immunodeficiency is associated with increased risk for meningococcal disease. A hallmark of inherited deficiencies in complement pathway proteins is an increased risk for and repeated episodes of meningococcal disease. Treatment with the monoclonal antibody eculizumab, a targeted complement inhibitor (to the C5 complement protein), and illnesses such as membranous glomerulonephritis, also are associated with the development of invasive meningococcal disease. Methods: We reviewed literature on meningococcal disease and immunodeficiency. Results: Complement deficiency is difficult to detect and may have as its first manifestation an episode of invasive meningococcal disease caused by any serogroup, including those rarely seen in healthy individuals. Additionally, patients with acquired complement disorders, including patients treated with eculizumab, are susceptible to meningococcal infections. Although these individuals are recommended to receive meningococcal vaccine, the effectiveness of vaccination has not been demonstrated clinically and protection against disease may, to some degree, be limited by the complement deficiency. Discussion: Protecting individuals with immunodeficiency indirectly, by herd effects achieved through universal and catch up vaccination programmes may be the most efficient means to protect these cohorts, as well as infants who cannot be vaccinated early enough in life to achieve direct protection. Further investigation is warranted
V51 Novel approach towards the development of vaccine candidates against pneumococcal meningitis Marie Yang1, Hansjuerg Engel2, Chrispin Chaguza1, Jen Corninck1, Lucy Hathaway2, Dean Everett1, Aras Kadioglu1 1 Institute of Global Health, Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK; 2Institute for Infectious Diseases, University of Bern, Bern, Switzerland
Keywords: pneumococcal meningitis, vaccine candidates, virulence factors Streptococcus pneumoniae is the most common cause of bacterial meningitis in children, the elderly and immunocompromised individuals. The propensity of pneumococci to progress to the brain and cause meningitis remains highly enigmatic, though current literature strongly suggests that pneumococcal meningitis is preceded by nasopharyngeal colonisation. This project is based on the rationale that virulence factors preferentially expressed during meningitis could serve as potential targets for vaccine development and therapeutic interventions. The objectives of the study are three-fold: 1) to identify meningitis-specific virulence factors by analysing the differential gene expression of pneumococci in the cerebrospinal fluid relative to the blood of human diseased patients, 2) to elucidate the functional role of these virulence genes in the pathogenesis of pneumococcal meningitis by creating a series of clinical strain deletion mutants, and 3) to develop an in vivo mouse model of meningitis that closely mimics the human situation in order to dissect out immune responses and test the protective immunogenicity of the virulence gene products. Here, we present a detailed outline of our study plan supported by promising preliminary results, and we discuss the implications of these results for the design of the subsequent stages of the study.
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Sponsors & Exhibitors Meningitis Research Foundation is very grateful to our major sponsors Baxter, Novartis Vaccines and Diagnostics and Pfizer. Thanks to their generous support, we are able to hold the conference here at the Royal Society of Medicine (RSM). Thanks also to Public Health England and GSK for supporting us and the RSM and its staff for making us all so welcome.
Baxter is dedicated to improving public health worldwide. Baxter currently has vaccines licensed against: n Meningococcal C disease n Tick-borne encephalitis (TBE) n Pandemic influenza and pre-pandemic influenza n Seasonal influenza Baxter’s mission is the prevention of a broad spectrum of infectious diseases, including meningitis C, in infants, children and adults. NeisVac-C is Baxter’s vaccine against Meningitis C: n High immunogenicity after the first dose1-3 n Proven field effectiveness4 n Licensed for all age groups from 2 months of age1 References: 1. Summary of Product characteristics for NeisVac-C
Public Health England’s mission
is to protect and improve the nation’s health and to address inequalities through working with national and local government, the NHS, industry and the voluntary and community sector. PHE is an operationally autonomous executive agency of the Department of Health. Public Health England’s Immunisation Hepatitis and Blood Safety Department and Meningococcal Reference Unit (MRU) work together in country-wide surveillance of invasive meningococcal disease (IMD), the national programme to vaccinate against Group C meningococcal disease and the development of national guidelines for the public health management of IMD. Staff in both Departments advise on the investigation and management of individual cases and outbreaks. The MRU and Immunisation Department provide surveillance and other scientific information to support policy decisions relating to IMD both nationally and internationally and are actively involved in world-leading research in this area. www.gov.uk/phe
2. Southern J. et al., Immunogenicity of a reduced schedule of meningococcal group C conjugate vaccine given concomitantly with the Prevenar and Pediacel vaccines in healthy infants in the United Kingdom, Clin. Vaccine Immunol. 2009; 16(2); 194-199. 3. Richmond P. et al., Ability of 3 different meningococcal C conjugate vaccines to induce immunologic memory after a single dose in UK toddlers, J Infect. Dis. 2001; 183 (1): 160-163. 4. Kaajik P., et al. Is a single dose of meningococcal serogroup C conjugate vaccine sufficient for protection? Experience from the Netherlands, BMC Infectious Disease, 2012, 12:35, http:www. biomedcentral.com/1471-2334/12/35.
BS-VA-561 10/2013 For UK residents: Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Any adverse events relating to Baxter products can also be reported direct to Baxter Pharmacovigilance on 01635 206360, or For UK residents: Surecall – Baxter Medical Information, Baxter Healthcare Ltd, Wallingford Road, Compton, Newbury, Berkshire, RG20 7QW Tel: 01635 206345 Fax: 01635 206071 Email: firstname.lastname@example.org
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Sponsors & Exhibitors Novartis Vaccines and Diagnostics
(NVD) is the world’s fifth largest manufacturer of vaccines and a leader in providing products to fight more than 20 vaccine-preventable viral and bacterial diseases worldwide. With around 800 million doses of vaccines produced annually by NVD, which are shipped to 85 countries around the globe, it is estimated that 25 people worldwide receive a NVD vaccine every second. Meningococcal disease has been highlighted as a priority for NVD. Globally, meningococcal disease is estimated to cause approximately 50,000 deaths a year1 with most cases of infection caused by five serogroups – A, B, C, W-135 and Y. NVD is dedicated to delivering vaccines that provide broad coverage, with the potential to protect all at-risk age groups against this devastating disease. The current NVD portfolio includes the following vaccines that protect against these key serogroups: n Menjugate®is a meningococcal serogroup C conjugate vaccine and a key part of the UK vaccination programme which has prevented over 9,000 cases and 1,000 deaths since 19992. n Menveo® is a quadrivalent conjugate vaccine providing protection against meningococcal serogroups A, C, Y and W-135. n Bexsero®is the first and only vaccine to be approved in Europe to provide protection against a broad range of meningococcal serogroup B strains, the leading cause of meningococcal disease in Europe. NVD also works closely with stakeholders supporting global initiatives to help combat epidemics in infectious diseases, particularly within meningococcal disease. These partnerships are crucial to NVD’s overall commitment to vaccine-preventable diseases and to achieving its mission to help alleviate human suffering. 1. World Health Organization. Control of epidemic meningococcal disease. WHO practical guidelines. 2nd edition. Available at: www.who.int/csr/resources/publications/meningitis/ whoemcbac983.pdf. Accessed Sep 2013.
At Pfizer, we apply science and our global resources to improve health and well-being at every stage of life. We strive to set the standard for quality, safety and value in the discovery, development and manufacturing of medicines. Our diversified global health care portfolio includes medicines and vaccines, as well as many of the world’s best-known consumer healthcare products. Every day, Pfizer colleagues work to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we also collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us. In the UK, Pfizer has its business headquarters in Surrey and is a major supplier of medicines to the NHS. To learn more about our commitments, please visit us at www.pfizer.co.uk. Pfizer Vaccines has a long history and strong heritage in public health. Through innovative research, we have pioneered the development, licensing and manufacture of several vaccines to improve the nation’s health. Our commitment to vaccines spans well into the future with research and development currently looking across a broad range of diseases and populations, including infants, children, adolescents, and adults. For further information please visit www.pfizervaccines.co.uk
GlaxoSmithKline Biologicals GSK has contributed to the funding to allow delegates from developing countries to attend this conference. Thanks to their generosity we are able to welcome delegates from Belarus, Cameroon, Chad, Ethiopia, the Gambia and the Ukraine.
2. Health Protection Agency. Vaccination for Meningococcal disease. Available at: www.hpa.org.uk/web/ HPAweb&HPAwebStandard/HPAweb_C/1296682977081. Accessed Sep 2013.
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Photograph credits: Group – Robert Eagleton, No.10 – Nicky McClure