OUCRU Annual Report 2023

Local Research, Global Impact.

OUCRU Annual Report - 2023

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CROSS-REFERENCING Throughout this report we have cross-referenced to both OUCRU’s Strategic Goals and the Wellcome Outcomes Framework Indicators

The descriptions of corresponding goals and indicators are included in the Appendix.

This is an interactive PDF

TABLE OF CONTENTS DIRECTOR’S WELCOME

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EXECUTIVE SUMMARY

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CASE STUDIES

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1. Reducing death and disability from Tuberculous Meningitis

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2. Antimicrobial resistance in community settings

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3. First malaria vaccine trial in Indonesia

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4. Advances in the prevention and treatment of typhoid fever in Nepal

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5. Climate and Health

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6. Enriching research with Public and Community Engagement

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7. Make a Difference - A long-term investment in people and capabilities

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8. Promoting our research culture with supported communications

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9. Enhancing research capabilities

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APPENDICES

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1. Publications

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2. Clinical Trials

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3. Make a Difference Programme

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4. Our People

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5. Communication and Policy Engagement

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6. OUCRU Strategic Priorities - Coding

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7. Wellcome Outcomes Framework - Coding

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DIRECTOR’S WELCOME Welcome to the OUCRU programme annual report.

In January 1991, the Wellcome Trust awarded a small grant to set up a clinical research ward within the Hospital for Tropical Diseases (HTD). The objective was to conduct a clinical trial of a new Chinese antimalarial drug, artemether, for the treatment of severe malaria, a common cause of death in Vietnam at the time. Thirty-three years later, that ward – now called ‘Viet Anh’ ward (or ‘Vietnam England’ ward) – is still Malaria research team in 1991, including conducting practice-defining clinical studies. But as I Professor Nick White (left), Dr Nguyen Hoan write in May 2024, in a very hot Ho Chi Minh City, little Phu (second from the left), and others. else from those early days is recognisable.

Out of that early partnership between HTD, Oxford University and Wellcome, has grown a research programme that spans Vietnam, Nepal, and Indonesia. OUCRU now has more than 550 people across those three countries, all focused on delivering our mission to have local, regional and global impact on health by leading a locally driven research programme on infectious diseases.

The increase in the size and scale of OUCRU over the last three decades has mirrored the remarkable Original Sign in the Malaria Research Ward development of Asia. OUCRU now works within a (now Viet-Anh Ward) population of more than 400 million people, which brings both challenge and opportunity. Controlling and treating infectious diseases in such a large population is difficult and constantly changing, especially as the climate warms. The need for a locally driven and embedded research programme that aims to better understand and reduce the burden of infectious diseases remains paramount, but it is also a major opportunity for improving health at scale.

Fortunately, there are also large numbers of seriously talented people; their development is as important to OUCRU as the challenges they address.

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OUCRU Annual Report 2023

OUCRU Nepal

OUCRU Hanoi

OUCRU Ho Chi Minh

OUCRU Indonesia

This annual report highlights some of the successes of the programme in the year from October 2022 to 2023. Inevitably, it is just a snapshot of our activities. There is much that we have not included but in which we are equally proud. It is also tempting to see the highlighted projects in isolation, which hides the years building partnerships and, critically, the trust between local institutions, governments and communities that inform and support all of OUCRU’s work. Of course, none of it would be possible without the vision and transformative effects of Wellcome’s thirty-three years of continuous funding.

Our successes belong to teams, not individuals. Everyone in OUCRU - in Vietnam, Nepal, and Indonesia - and whether they are from operations and finance, clinical trials units, public engagement, or the research groups, contributes to that success. All are essential to delivering our mission, and all deserve credit and thanks for what you will read in these pages.

I hope that you enjoy reading the report.

Professor Guy Thwaites OUCRU Director

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EXECUTIVE SUMMARY This report highlights activities across the entire OUCRU programme (Vietnam, Nepal, Indonesia) from October 2022 to 2023, the first year of our Wellcome core grant award.

The report is indebted to two relatively recent developments within OUCRU: a new metrics system that captures data that defines and tracks how OUCRU meets its objectives; and a communications team with expertise in using data, text and images to communicate our outcomes efficiently and effectively.

The report uses case studies, metrics data, and brief statements that summarise how we have addressed OUCRU’s four main aims: 1. Reduce the burden of infectious diseases through research 2. Strengthen our research culture 3. Strengthen our networks and partnerships 4. Increase the local, regional, and global impact of our research Throughout the report, we have cross-referenced the text to OUCRU’s strategic goals and Wellcome’s Outcomes Framework Indicators. Our grants data reveals the close alignment between OUCRU’s research and Wellcome’s Infectious Diseases and Discovery Research programmes.

Mapping OUCRU research themes against the Wellcome Outcomes Framework shows that our clinical trials and surveillance research is a clear entry point to further Discovery Research. OUCRU has long used clinical trials to address important clinical questions concerning the diagnosis and treatment of infectious disease (as described in the TB meningitis case study), concurrently using the well-characterised patients and their associated clinical specimens (e.g. blood and bacteria) to address questions concerning disease and therapeutic mechanisms (Discovery Research).

Community and policy engagement are also highlighted within the report, as they are essential activities that inform and support OUCRU’s research activities. OUCRU’s research priorities are locally-driven, therefore we require mechanisms that enable continuous and bidirectional consultation and engagement with patients, the public, and policy makers.

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Case Studies OUCRU Annual Report 2023

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Reducing death and disability from Tuberculous Meningitis

The reasons for the poor outcomes in Tuberculous Meningitis (TBM), and the best strategies to improve them, have been the subject of OUCRU’s research for almost 25 years. Globally, TBM kills around 150,000 people each year, and it is now the most common form of bacterial meningitis given the success of vaccines against other meningitis-causing bacteria.

TBM is the most dangerous form of tuberculosis, causing death or permanent disability in half of sufferers, despite current recommended four-drug anti-TB therapy.

However, these recommendations are based on pulmonary TB treatment; there are few data to support current TBM treatment regimens.

In 2004, OUCRU researchers demonstrated that adjunctive corticosteroids1 reduced mortality from tuberculous meningitis by around 30%, although without any reduction in disability. As a result, WHO and other national tuberculosis treatment guidelines recommended all patients with TBM should receive corticosteroids2.

Today, our TBM research strategy is focused around four questions, addressed through several studies. Key projects for each are highlighted below: Do corticosteroids improve outcomes in HIV-positive patients?

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ACT-HIV trial

Will alternative host directed therapies further improve outcomes for TBM patients?

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INTERCEPT project

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SURE trial

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LAST-ACT trial

Why and how to corticosteriods reduce death, but not disability?

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HARVEST trial

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ULTIMATE project

Why do people get TBM, and how can we identify it earlier?

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A novel, microbiological assay-independent diagnostic model for adult TBM

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Host blood transcriptional signatures identify those with TBM

3.1, 3.2

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D4.2, ID3.2, PC4.2, EE1

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Do corticosteroids improve outcomes in HIV-positive patients?

Adjunctive Corticosteroids for TBM In HIV-Infected Adults (The ACT HIV Trial)

OUCRU Grant number: 271 CTU Study Code: 26TB

The ACT-HIV trial investigated the role of corticosteroids in those with HIVassociated TBM. 520 adults with HIV and TBM were randomised to receive standard anti-tuberculosis antibiotics with 6 - 8 weeks of dexamethasone (a corticosteroid) or an identical placebo.

The trial was conducted in Ho Chi Minh City and Jakarta under the operational direction and expertise of the OUCRU Clinical Trials Unit.

The trial results were reported in the New England Journal of Medicine3 in October 2023. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a clear benefit from dexamethasone, although the drug was safe and caused no additional adverse effects compared to placebo. Previous OUCRU studies have shown that people with HIV and TBM have higher intra-cerebral concentrations of inflammatory molecules than those without HIV. Therefore, we suspect that to improve the terrible outcomes from HIV-associated TBM, we need to use immunemodulating drugs that target the inflammatory response more effectively than corticosteroids alone. We are now working to identify these targets and to develop new clinical trials of potentially effective drugs.

The study underscores the urgent global need for better detection and treatment of HIV and tuberculosis. It also shows the importance of crosscountry collaboration between researchers in Vietnam and Indonesia in delivering practice-defining trials.

“WHO recommends the use of Dexamethasone for all TBM patients, regardless of their HIV status. This clinical trial provides important evidence for WHO to revise their recommendations for TBM/HIV positive patients, which will change the practice at local hospitals.”

Dr Nguyen Huu Lan, Director of Pham Ngoc Thach Hospital

1.1, 2.1, 3.2, 3.1 OUCRU Annual Report 2023

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Will alternative host directed therapies further improve outcomes for TBM patients?

OUCRU Grant number: 271

Last-ACT Trial

CTU study code: 27TB

In collaboration with researchers at the University of Cambridge, OUCRU researchers have shown that polymorphisms in the gene encoding leukotriene A4 hydrolase (LTA4H), an enzyme responsible for the production of pro- and anti-inflammatory eicosanoids, influence intra-cerebral inflammation and predict survival response to corticosteroids in HIV-uninfected individuals with TBM4-6.

These findings have introduced the possibility of personalised therapy for TBM (and other forms of tuberculosis), which has been the subject of a second OUCRU trial. The LAST-ACT trial (LTA4H genotype-stratified randomised controlled trial of adjunctive corticosteroids) completed enrolment and follow-up of 720 HIV-negative Vietnamese adults in March 2024. The analysis is planned for June/July 2024 and we anticipate presenting the results at the International Union against TB and lung disease conference in Bali in November 2024.

1.1

D1.1,1.3; ID1.1,1.4; EE6

OUCRU Grant number: 590,

INTERCEPT

also using data from 149

TBM disproportionally affects young children. INTERCEPT, funded by NIH, aims to better understand the biological pathways that determine death or survival from TBM, both in children and adults, and how they might be manipulated therapeutically with better-directed or novel host directed therapeutic strategies.

We will combine unique access to some of the largest clinical studies in TBM globally with exceptional expertise in integration of multi-omics and deepphenotyping data. Our strong preliminary data, access to two large bioarchives from adult TBM, an on-going randomised controlled trial in pediatric TBM, and expertise in integration of large-scale clinical and multi-layer ‘omics’ data promises to provide a step-change in understanding childhood TBM pathogenesis and discovery of new targets for future host-directed therapies.

Community advisory groups, involving parents of children with TBM, are being set up in each study site, to collaborate on the studies.

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Short intensive anti-tuberculosis and antithrombosis treatment for children with TBM (SURE)

OUCRU Grant number: 149 Clinical Trials ref: 31TB

This is a randomised controlled trial to shorten treatments for children with TBM, funded by Wellcome, MRC and others through the Joint Global Health Trials scheme..

A total of 400 children will be recruited to this study (360 to date).

The World Health Organization currently advises 12 months of treatment for children with TBM. This randomised trial aimed to answer two questions: 1. Is it safe and effective to treat children with TBM for 6 months as opposed to 12 months?

2. Does aspirin reduce the risk of disability in children with TBM? OUCRU is a major partner in this study. We contributed to the design of the trial and helped to secure funding. More children have been recruited in Vietnam than any other participating country (around 50% from Vietnam) – the study is also conducted in India, Uganda, Zambia and Zimbabwe.

Engagement work integrated in this trial included: 1. Pilot child and adolescent advisory group 2. Patient and Public Involvement - Including a Vietnamese survivor of TBM, who is a TB patient advocate and volunteers for a number of people living with disability groups.

3. Formal community advisory board to engage with marginalised populations in our research.

Results from this trial are expected to be reported in 2026 1.1, 4.2, 3.1, 6.1.3

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ID1.1 ,1.2; CH1.1; EE4,6

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Why and how do corticosteriods reduce death, but not disability?

Identifying new targets: ULTIMATE

OUCRU Grant number: 393, using data from 271

Clinical trials allow important clinical questions to be addressed (e.g. whether or not to give corticosteroids for TBM treatment), but they also provide an opportunity to better understand disease and therapeutic mechanisms. We have therefore used data from the ACT-HIV and LAST-ACT trials and from the IBIS study in the NIH-funded study ULTIMATE to investigate how and why TBM is so deadly.

Objectives To define transcriptomic and metabolism in TBM & their genetic regulation using state-ofthe-art LC-MS platforms and a combination of genome-wide SNP-typing of DNA from the same patient group and whole genome sequencing of a subset.

To identify biomarkers predicting the effect of corticosteroids and discover potential new targets for host-directed therapy by integrating clinical and neuro-radiological data with CSF transcriptomics, metabolomics, and host genotype.

Study design This study integrated data and specimens from large studies in Vietnam and Indonesia (including ACT-HIV and LAST-ACT) with state-of-the-art omics technology and systems biology in the Netherlands and USA, including: •

Genome-wide SNP-array;

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Metabolomics;

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Whole genome sequencing;

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Proteomics;

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RNA sequencing and transcriptomics;

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Antibodies.

The results, published in Elife7 in May 2023, showed that high cerebrospinal fluid concentrations of an essential amino acid called tryptophan were strongly associated with death from TBM in both HIV-negative and positive patients. Low cerebrospinal fluid tryptophan concentrations were associated with survival from TBM, indicating a possible mechanism for novel therapeutic approaches.

This project is an example of the benefit of having a long-running core-funded programme with a supported network of long-term partnerships in multiple countries. Because of our unique positioning as a Wellcome Programme, we have been able to leverage substantial funding from other agencies from Wellcome funded work – amplifying the potential impacts of our programme, our funding and our partnerships.

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OUCRU Grant number: 368

HARVEST Trial

CTU report: 13IND

HARVEST Investigator Meeting in Oxford, August 2022

This double-blinded randomised controlled Phase III trial aims to determine if high dose rifampicin is safe and improves 6-month survival compared to standard of care for patients with TBM. Secondary objectives are to compare the high dose rifampicin regimen to the standard of care regimen for 12-month survival; neurological disability and functional outcomes from TBM; safety and tolerability; hospital outcomes related to TBM; subsequent neurologic deterioration; management of drug-induced liver injury.

Tertiary objectives are to describe the pharmacokinetics (PK) of high dose rifampicin in plasma and CSF, assess predictors of exposure to rifampicin in plasma and CSF, assess PK-PD relationships also considering exposures to the other first-line TB drugs and ART in HIV-infected patients, and determine the minimally desired rifampicin exposure for optimal treatment of TBM. This trial is funded by Wellcome and the Joint Global Health Trials Scheme. It is being conducted in Indonesia with collaborating sites in southern Africa.

1.1 OUCRU Annual Report 2023

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Why do people get TBM, and how can we identify it earlier?

A novel, microbiological assay-independent diagnostic model for Adult TBM

Funder: Wellcome 204904/Z/16/Z, 225167/Z/22/Z, 225167/A/22/Z, and 217650/Z/19/Z

In this Core-funded project, we analysed data from 659 individuals aged 16 years and above with suspected brain infections admitted to the Hospital for Tropical Diseases in Ho Chi Minh City, Viet Nam. The team developed a tool that uses early clinical, biochemical and haematological features to estimate the likelihood of TBM in patients before Mtb confirmatory test results are available.

Implications for Clinical Practice The simplified diagnostic model8, which includes a scoring table for early screening using only clinical information and chest X-ray results, could be particularly useful in settings where comprehensive CSF analysis is not feasible.

Both models are also accessible as a free app.

Principal Investigator Dr Dong Huu Khanh Trinh emphasises the model’s potential impact: “Our diagnostic tool holds the promise of being a crucial decision assistant for clinicians across different settings. It can help in rapidly identifying TBM cases, thereby facilitating timely and appropriate treatment interventions that can save lives.”

1.1, 2.3, 3.1, 4.2

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Host blood transcriptional signatures identify those with TBM TBM is difficult to diagnose. We investigated whether a 3-gene (dual specificity phosphatase 3 [DUSP3], guanylate-binding protein [GBP5], krupple-like factor 2 [KLF2]) host response signature in blood can distinguish TBM from other brain infections.

The outcomes of this study 9 showed that the 3-gene host response has the ability to discriminate TBM from other brain infections, including in HIV-positive individuals. GBP5 expression is the most discriminatory, and may provide comparable or better TBM diagnostic performance than the tuberculosis score. HIV coinfection appears to improve the diagnostic performance of GBP5 and the tuberculosis score, which is an important finding given TBM is more common and more lethal in those with HIV. We also showed that GBP5 is the most discriminatory of the 3-gene host response and should be further explored.

Large, prospective studies further defining the diagnostic utility of the 3-gene test are needed.

This study leveraged funding from multiple Wellcome awards (206724/Z/17/Z, 204904/Z/16/Z, 110971/Z/15/Z, 309272/Z/24/Z) and enrolled patients from Ho Chi Minh City, Viet Nam who were already enrolled in either LAST-ACT or ACTHIV. A strength of our study is that the RNA sequencing data generated will allow us to explore other gene sets or combinations of genes as potential diagnostic signatures – a current focus of our TBM programme.

1.1, 3.1, 4.2, 5.3.2 D1.1,1.2,1.3,1.4, 3.1, 3.2; ID1.1,1.2,1.4,1.5,2.1; PC2.1,4.1; EE4,5,6

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TBM international research consortium

Following a meeting in Cape Town in 2008, we formed an international TBM research consortium, with the aim of promoting collaborative TBM research that increases understanding of the disease and improves clinical outcomes. Subsequent meetings have been held in Dalat, Vietnam (2015); Lucknow, India (2019); online (2020); and in Oxford (2022). The next meeting will be in Bali, Indonesia in 2024. There has been a substantial increase in funded research activity surrounding TBM in the last few years, much of which has been stimulated and led by the consortium and its membership, and the landscape of TB meningitis research is more dynamic now that at any time in its history. It is therefore important that the international community – especially those from low and middleincome countries – have a supported network to discuss and respond to these advances and opportunities.

The consortium currently has over 100 members, from 50 organisations in 12 countries.

Publications from the consortium are hosted in a collection on Wellcome Open Research.

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ID1.3,1.4, 2.5, PC3.1, PC3.4, EE6

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Public Engagement

Health Research Advisory Board - TB patients and carers discuss TBM

The OUCRU Health Research Advisory Board, established in 2020, fosters dialogue between researchers, healthcare workers, and the community regarding OUCRU’s health research. In August and September 2023, two Board meetings were convened at OUCRU Ho Chi Minh City to discuss future TBM research. Each meeting included 12 community members, two TBM researchers and two public engagement coordinators.

These sessions facilitated researcher understanding of public perspectives and concerns surrounding TBM in Vietnam. Notably, the discussions explored community viewpoints on the impact of disability within Vietnamese families and communities, along with specific views on the Rankin outcome scale and its application in defining “bad outcomes”.

Insights from the discussion of these meetings will significantly inform future TBM research, including upcoming new trials. This engagement activity serves as a model for replication in other countries that this research will be conducted.

2.1,2,2,3.3,6.1.1,6.1.3,6.3

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Conclusion OUCRU’s research has improved outcomes by improving TBM diagnosis, by defining the best combinations of anti-tuberculosis treatment, and by better understanding, and controlling, the intra-cerebral inflammatory response.

Over the last year, we have completed two major trials that further define best clinical practice and enhance understanding of disease mechanisms. Our research has influenced national tuberculosis treatment guidelines throughout the world, including those from the WHO, and OUCRU researchers have led an international consortium for TBM research that has brought coherence and influence to the research field.

References 1. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. DOI: 10.1056/NEJMoa040573 2. WHO consolidated guidelines on tuberculosis. https://iris.who.int/bitstream/ handle/10665/353829/9789240048126-eng.pdf 3. Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults.

DOI: 10.1056/NEJMoa2216218 4. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. DOI: 10.1016/j.cell.2011.12.023 5. Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone. DOI: 10.1073/pnas.2024852118 6. A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis. DOI: 10.7554/eLife.61722 7. Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis. DOI: 10.7554/eLife.85307 8. A novel diagnostic model for tuberculous meningitis using Bayesian latent class analysis. DOI: 10.1186/s12879-024-08992-z 9. The Ability of a 3-Gene Host Signature in Blood to Distinguish Tuberculous Meningitis From Other Brain Infections. DOI: 10.1093/infdis/jiad606

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Antimicrobial resistance in community settings

In much of our research at OUCRU, we look to our communities and our partnerships to identify the direction our research needs to focus. We have a number of longstanding partnerships that support our work in this area, including with the National Hospital for Tropical Diseases (Hanoi), the National Institute for Hygiene and Epidemiology (Hanoi), Hanoi Medical University, the Nam Dinh Department of Health and Sub Department of Animal Health, and the Global Antibiotic Resistance Partnership. Research led by OUCRU Hanoi has shown a high proportion of antibiotic use is in the community1,2. One of the great benefits of these partnerships is they facilitate co-creation of both research and engagement projects with our communities and our policy stakeholders.

This was confirmed by an OUCRU-led study in pharmacies, and followed by the first primary healthcare point-of-care C-reactive Protein test (CRP) trial in Vietnam, led by Dr Do Thi Thuy Nga in 2014 as part of her Wellcome-funded PhD3, 4.

With these strong community partnerships and compelling early results, OUCRU Hanoi moved to further the develop the community AMR programme in 2017 – appointing Senior Epidemiologist Associate Professor Sonia Lewycka to lead and further develop this programme with newly-graduated Dr Nga. Dr Nga went on to coordinate two international programmes on Antibiotic Access and Use (ABACUS, and ABACUS II) in Vietnam, Ghana, Mocambique, Thailand, Bangladesh and South Africa. ABACUS was an assessment, and ABACUS II, which ended in 2023, was focused on figuring out targets for an intervention: recognising antibiotics.

Photovoice exhibition in Northern Vietnam

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ABACUS II This project aimed to build the case for an international system that harmonizes the appearance of antibiotics to facilitate their identification and help efforts aimed at addressing inappropriate antibiotic use.

The multi-national project had three goals: 1. Exploring a standard look for antibiotic drugs - investigating whether having a harmonised physical appearance for antibiotics could help in their correct identification.

2. Studying economic impact looking into the financial burdens caused by the inability to correctly identify antibiotics.

1.2, 3.1, 3.3, 4.1, 4.2, 6.1

OUCRU Grant number: 527

3. Investigating antibiotic quality testing for substandard or fake antibiotics, ensuring the medications people get are safe and effective.

Key outputs from this project have so far included: • Community empowerment: Clear labelling of antibiotics empowers community members to use antibiotics correctly, which is essential for their health and safety.

• Policy brief presentation: At the ABACUS II Conference in Bangkok in June 2023, findings and recommendations were presented to help improve how antibiotics are identified and used.

• And multiple publications5,6,7,8

D1.1,1.2,1.3,1.4,2.3; ID1.1, 1.2, 1.3, 1.4, 2.2, 2.3, 2.6; PC1.1, 2.1, 3.1, 3.2, 3.3; EE1, 2, 3, 4, 6, 7

ICAT Trial

Implementation of CRP Point of Care Testing in Primary Care to Improve Antibiotic Targeting in Febrile and Respiratory Illness: A stepped wedge cluster randomised demonstration study Sonia and Nga rolled out CRP testing in this community health care cluster randomised trial – the largest low- and middle-income CRP trial ever conducted, showing low uptake of testing but significant reduction.

This trial officially ended in December 2021, and is often the case, the impacts of the work are becoming apparent now, a few years later.

In September 2023, results were published in Lancet Infectious Diseases9, and Our findings support previous evidence that CRP testing could be an important component of management strategies for acute respiratory infections in routine care in low-income and middleincome countries.

The ICAT trial was funded by the Foundation for Innovative Diagnostics.

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Generating collective solutions to reduce unnecessary antibiotic use in Vietnam (Co-Act) One of the ways that we ensure relevance and acceptability of our research is by using multidisciplinary participatory learning and action research and engagement methods, such as in the Wellcome-funded Co-Act project.

OUCRU Grant number: 392

This study10 evaluated interventions at three levels of the healthcare system: communities, primary healthcare and hospitals. Partnerships with national and local authorities provided an important foundation for building relationships with communities, and enhanced visibility and credibility of activities.

“A sense of ownership emerged as the study progressed and participants understood more about AMR, how it related to their own concerns, and incorporated their own ideas into activities. Participatory learning and action research can be a powerful way of stimulating community action and bringing people together to tackle a common problem.

Understanding the nuances of local power structures, and allowing time for stakeholder relationship development and consensus-building are important considerations when designing engagement projects.”

First author Cai Ngoc Thien Huong Research Coordinator at OUCRU Ha Noi

1.2, 2.2, 3.1, 3.3, 4.1, 4.2, 6.1 D1.1, 1.2, 1.3, 1.4, 2.2, 2.3; ID1.1, 1.2, 1.3, 1.4, 2.2, 2.3, 2.6; PC1.1, 3.1, 3.2; EE1, 2, 3, 4, 6, 7

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LMIC AWaRe system based Primary Care Antimicrobial Stewardship Quality Improvement Trial and related research (AWARE1)

OUCRU Grant number: 699

In 2023, we obtained funding to roll out the WHO AWaRe guidance for treatment of Acute Respiratory Infection in primary health care in Vietnam, Indonesia, Bangladesh, Nigeria and Ghana, and this will be a major project for this team in 2024.

The AWARE1 project aims to: • Develop and test a new framework for how antibiotics are prescribed and used in primary care settings.

• Establish and evaluate an educational tool for healthcare providers, helping them prescribe antibiotics more effectively based on the WHO AWaRe system.

• Conduct a practical clinical trial to assess the effectiveness of these interventions in reducing the misuse of broad-spectrum antibiotics.

This involves creating simple, traffic-light coded tools (green for Access, yellow for Watch, red for Reserve), based on the 2022 WHO Essential Medicines List AWaRe Antibiotic Handbook, that can easily be used by healthcare professionals to make better prescribing decisions.

By educating healthcare providers and implementing a structured antimicrobial stewardship program, the trial seeks to significantly reduce inappropriate prescriptions of broad-spectrum antibiotics, thereby lowering the risk of antibiotic resistance. This approach not only aims to improve health outcomes but also to establish sustainable practices that can be adopted in similar settings worldwide.

1.2, 3.1, 3.3, 4.1, 4.2, 6.1 D1.1, 1.2, 1.3, 1.4, 2.3; ID1.1, 1.2, 1.4, 1.5, 2.2, 2.3, 2.6; PC3.1, 3.2, 3.3; EE1, 2, 3, 4, 6, 7

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PhD Projects with Community AMR Focus Our Community AMR programme has supported the work of several PhD students

Vu Thi Quynh Giao is expected to defend her DPhil dissertation at Oxford University in July 2024. Titled Farm antibiotic use and resistance: Account from a Red River Delta province of Vietnam, her dissertation reports several paradoxes in this northern part of the country, including the fact that there is a high level of antibiotic resistance in livestock and an overall low prevalence of antibiotic use among farmers.

Here, drug overuse, including routine antibiotic prophylaxis, is limited to a very specific group of farmers who have joined Vietnam’s new wave of ‘công nghiệp hóa-hiện đại hóa’ (modernization and industrialization). Such overuse causes high levels of resistance on certain farms and has externalities for neighboring farms, a problem amplified by the northern region’s situation of ‘too many people and too little land.’

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In 2023 OUCRU PhD graduate Dr Nguyen Vinh Nam published his thesis: Antibiotic Access and Use in the Community and the Feasibility to Implement Pharmacy Targeted Interventions11. In this project, Dr Nam worked with pharmacists and community members to determine the feasibility of introducing CRP testing in pharmacists, and people’s willingness to pay for CRP tests.

Nguyen Thi Hong Yen is a final year PhD student at the University of Oxford exploring the social, cultural and political context of antibiotics with focus on antibiotic use, dispensing and management in rural communities. Yen uses anthropological approach to identify dilemma situations in which the willingness to address antibiotic resistance faces cultural and structural challenges that hamper behaviour change. The study is expected to provide an in-depth contextual understanding of antibiotics and antibiotic resistance to better inform policy making.

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Focus on Researcher

Dr Do Thi Thuy Nga Post Doctoral Researcher OUCRU Hanoi

Dr Do Thi Thuy Nga has more than 15 years of experience working in the field of AMR, co-leading a number of large-scale, complex community-based observational/interventional studies targeting inappropriate antibiotics prescribing, dispensing and use behaviours in primary care settings in low– and middle-income countries (LMICs).

Research Goals and Methods Dr Nga’s research aims to improve how antibiotics are prescribed, dispensed, and used. She explores how communities access and utilize antibiotics to pinpoint areas where changes are needed. Through her studies, she identifies why antibiotics may be overused or misused and develops strategies to correct these behaviors.

One of her notable approaches involves examining the role of vaccines. By understanding how vaccines can reduce the need for antibiotics, Nga’s work helps to decrease the likelihood of developing antibiotic resistance.

Nga has developed her career with the support of OUCRU, and is a graduate of OUCRU’s PhD programme, via the Open University (2017). She has 19 publications, with six as first or last author.

1.2, 2.3, 3.1, 3.3, 5.1.1, 6.1.1 D1.3; ID1.1,1.2,1.3; PC1.1,2.1, 4.1, 4.4; EE1,2,4,7

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Community Engagement around AMR in Nepal

Singing the Song of Antibiotics YouTube playlist In 2023, OUCRU Nepal engaged with 224 community health volunteers for a project called Singing the songs of antibiotics. These volunteers then composed six songs on AMR awareness. Out of those songs, two have been produced as videos and we have been using them for public and community engagement activities. Through Singing the songs of antibiotics, we produced two videos on AMR awareness and a booklet to use for inperson engagement activities.

Public events During this period, the we hosted five public events: • Fighting AMR with youth: A series of 3 workshops from April to September 2023. The workshop engaged with 83 young people (59 female/24 male).

• Flashmob on handwashing: Young people (68 female/67 male) engaged with our teams performed a public flashmob about handwashing in a busy street.

• Cycle rally: We held a cycle rally as part of the World Antimicrobial Awareness Week in 2022. It had 90 attendees (30 female/60 male).

• Doodle competition: We held an online art competition for young people as part of World Antimicrobial Awareness Week in 2022. The artworks, published on social media, received high engagement levels (reactions, comments, and shares), with the highest shares on social media (1,700 shares).

• AMR movie screening: We also hosted a movie screening during World Antimicrobial Awareness Week in 2022. It had 136 attendees (66 female/70 male).

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Conclusion Since our first studies 10 years ago, AMR in the community has become core focus of our work across the programme, but particularly in OUCRU Hanoi. By investing in our people, capacity, and introducing new research methods we have been able to build a portfolio of projects in this area with diverse funding, and respond to local as well as global questions.

References 1. Situation Analysis: Antibiotic Use and Resistance in Vietnam. https://onehealthtrust.org/ wp-content/uploads/2017/06/vn_report_web_1_8.pdf 2. Antibiotic use and resistance in emerging economies: a situation analysis for Viet Nam. doi: 10.1186/1471-2458-13-1158 3. Antibiotic sales in rural and urban pharmacies in northern Vietnam: an observational study. doi: 10.1186/2050-6511-15-6.

4. Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial. doi: 10.1016/S2214-109X(16)30142-5. Epub 2016 Aug 3.

5. Community-level antibiotic access and use (ABACUS) in low- and middle-income countries: Finding targets for social interventions to improve appropriate antimicrobial use - an observational multi-centre study. doi: 10.12688/wellcomeopenres.11985.1. eCollection 2017.

6. Community-based antibiotic access and use in six low-income and middle-income countries: a mixed-method approach. doi: 10.1016/S2214-109X(21)00024-3.

7. “I can make more from selling medicine when breaking the rules” - understanding the antibiotic supply network in a rural community in Viet Nam. doi: 10.1186/ s12889-019-7812-z 8. Is this pill an antibiotic or a painkiller? Improving the identification of oral antibiotics for better use. doi: 10.1016/S2214-109X(23)00258-9 9. Implementation of point-of-care testing of C-reactive protein concentrations to improve antibiotic targeting in respiratory illness in Vietnamese primary care: a pragmatic cluster-randomised controlled trial. DOI: 10.1016/S1473-3099(23)00125-1 10. Challenges and Lessons Learned in the Development of a Participatory Learning and Action Intervention to Tackle Antibiotic Resistance: Experiences From Northern Vietnam. DOI: 10.3389/fpubh.2022.822873 11. Antibiotic Access and Use in the Community and the Feasibility to Implement Pharmacy Targeted Interventions. doi: 10.21954/ou.ro.0001725f 23

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First malaria vaccine trial in Indonesia

Safety, Tolerability, Immunogenicity and Protective Efficacy Against Naturally-Transmitted Malaria in Eastern Indonesia of Two Plasmodium Falciparum Sporozoite Vaccines (IDSPZV1) OUCRU Grant number: 322 CTU ref: 07IND

Principal investigator: Prof. Erni J. Nelwan, MD, PhD, University of Indonesia Responsible Investigator: Prof. Kevin Baird

Background • WHO estimated that there were 249 million malaria cases, with more than 600,000 deaths1, globally in 2022 • The WHO’s Global Technical Strategy for Malaria Control and Elimination2 aims to reduce malaria cases and deaths by 90% by 2030 compared with 2015.

• Cases in Indonesia in 2022: 1,156,0001.

• Indonesia has set a target to eliminate malaria by 20303.

By September 2023, OUCRU Indonesia was close to completing its study on the Indonesian Army base at Bangkinang, Riau Province, Sumatra after a 2-year effort to evaluate the safety, tolerability, immunogenicity, and protective efficacy of two distinct live, attenuated sporozoite vaccines (irradiation attenuated PfSPZ-Vac & chloroquineattenuated PfSPZ-CVac) sponsored by manufacturer Sanaria Inc. This randomized, double-blind and saline placebo-controlled trial, IDSPZ1, reached all of its targets of enrolment, retention, adherence, and malaria attack rates sufficing to ascertain protective efficacy with good precision.

The Indonesian soldier model offers unique and powerful analytical advantages in malaria prevention and treatment clinical trials. Young and healthy non-immune soldiers are temporarily exposed to very high risk of malaria in connection with their security duties in remote areas of Indonesia. We are able to conduct definitive trials using fewer subjects, for shorter duration, with lower costs and greater certainty compared to similar trials in endemic populations.

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The trial is now complete and under analysis. Results are expected to be reported and available in 2024. This trial was an example of the extraordinary complexities that can be involved in OUCRU’s clinical research – especially where fieldwork and collaboration with local partners is imperative to study success.

Urgency of vaccines/the ones tested in controlling or ending malaria.

Many trial challenges were overcome with thorough preparation, close coordination, and strong collaboration: The trial involved a total of 111 site staff in Bangkinang, Riau, alone.

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OUCRU Indonesia provided GCP, research & lab training, and malaria diagnostics, to staff, collaborators, and army doctors.

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Trial clearances were granted in 2018 and 2019. But, due to COVID-19 and other delays, the study team resubmitted all applications in 2021, including a new application to the Gatot Soebroto Army Hospital Medical Committee in Jakarta, for renewals and relevant protocol amendments. In March 2022, the Indonesian Food and Drug Authority gave the second approval and import licenses.

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In addition to dealing with Covid-19, one of the toughest aspects of preparing for the trial was picking the right battalion to work with and adapting to their schedule and activities. Deployment details were usually kept secret, which made it hard for the study team to choose a battalion that fit the expected study timeline. Once we picked one, we had to stay flexible to keep up with their activities. For instance, they had training sessions in the jungle before leaving, but we still needed to do regular checkups. We had to adjust our plans and follow along with the soldiers without causing too much disruption to their schedule, all while ensuring the trial was still carried out properly. This highlights the importance of thorough preparation and strong collaboration with all parties involved for the trial’s success.

Getting access to the soldier subjects was a nearly two-year (COVID-delayed) engagement process between our Indonesian partner institutions and the most senior health and commanding officers of the Indonesian Army. Approval for the project came from the 4-star general Commander-in-Chief of the Army. This level of attention and approval elevated the local importance and stature of our host institutions, and considerably deepened their relationship to the Indonesian Army and its own research culture and needs.

Our Malaria vaccine trial has many firsts

First malaria vaccine trial in Indonesia

First vaccine trial by OUCRU Indonesia

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First trial directly comparing PfSPZ-Vac vs.

PfSPZ-CVac

First malaria vaccine trial in Asia-Pacific in the past 30 years

First trial of these vaccines for naturallyacquired Asian P. falciparum and P. vivax

First trial of these vaccines in a nonAfrican population

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One challenge in this trial was ensure that this research in infantry soldiers (a vulnerable population) was free of coercion and thus ethical. This trial spurred the creation of the Indonesian Army medical research ethics board at Gatot Subroto Army Hospital in Jakarta.

Before that board, the University of Indonesia Faculty of Medicine Ethics Committee, OxTREC, and the US government’s Human Research Protections Office.

The vaccines were administered from cryopreserved sporozoites manufactured in the USA. The shipping to the field site in Sumatra and the storage on site was all done under liquid nitrogen holding. Thawing and direct intravenous inoculation followed during early June to late September 2022, when we enrolled and vaccinated a total of 350 soldiers, all members of the same combat infantry battalion based at Bangkinang in Sumatra. Less than an hour before boarding their troopship that would carry them to Papua, the trial team collected at portside the last post-vaccination blood sample from the last soldier vaccinated.

After a 3-week, 4500km journey by ship, the soldiers disembarked from their ship at Jayapura, Papua to begin their 9-month tour of duty along the highly malarious frontier border with Papua New Guinea. The OUCRU Indonesia team had flown in to greet and follow them through their tour of duty. During those months, the research team would diagnose and treat over one thousand cases of acute malaria among the soldier subjects.

When their duties were complete, the battalion returned to their base on Sumatra and the OUCRU team was again there to greet and follow them for a 6-month post-exposure follow up period.

We are exceptionally proud of the large team that did this extraordinarily challenging trial, especially the Principal Investigator from the Faculty of Medicine Universitas Indonesia, Prof Erni J Nelwan (who earned the Professor title whilst the trial was in progress).

1.1,1.2,3.1,4.1,5.3.3,5.4 ID1.1,1.2,1.4,2.2,2.5,3.1; PC1.2,1.3,3.1,3.2,3.3,3.4; EE4,6,7,8

References 1. World Malaria Report 2023. https://www.who.int/teams/global-malaria-programme/ reports/world-malaria-report-2023 2. Global Technical Strategy for Malaria 2016-2030, 2021 Update. https://www.who.int/ publications/i/item/9789240031357 3. Decision of Minister of Health Number 293 Year 2009. http://hukor.kemkes.go.id/hukor/ kepmenkes/2009/7

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Advances in the Treatment of Typhoid Fever in Nepal It can take a long time for our research outcomes to be directly visible as impacts on health in the countries where we work. However, the phenomenon of research leading to policy change and improved health outcomes for people is clearly visible in our typhoid research – which has been a key focus for OUCRU Nepal for more than 20 years.

For the past two decades, OUCRU Nepal has been actively involved in conducting clinical treatment trials for typhoid fever. Our research efforts have not only influenced international treatment guidelines but have also played a crucial role in vaccine development and implementation strategies.

Typhoid fever is characterised by fever and abdominal symptoms. It affects more than 14 million children and adults globally each year. Between one and two million of these patients may progress to severe and life-threatening complications. Up to 1% of patients who get typhoid may die of the disease. A typhoid illness can be followed by a relapse 2-3 weeks later and lead to a prolonged period of ill health and catastrophic financial cost to the family with a resulting burden on the health system and society. In South Asia, which is the largest typhoid hub in the world, the annual burden of disease is estimated at 7 million cases.

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Impact on Treatment Guidelines: Our clinical trials have significantly impacted treatment guidelines since our founding in 2004. Notably, our research findings led to recommendations by the World Health Organization (WHO) against the use of fluoroquinolones in the treatment of uncomplicated typhoid fever in South Asia. This change in guidelines aimed to combat the emergence of antimicrobial resistance and optimize treatment outcomes for patients.

Vaccine Trials and Implementation: In addition to our contributions to treatment guidelines, we conducted a groundbreaking vaccine trial for typhoid fever – the TyVAC study - evaluating the efficacy of the Typhoid Conjugate Vaccine (TCV)1. Following successful clinical trials, the TCV was incorporated into the national immunisation schedule for children in 2020. By October 2023, over 8 million children have been vaccinated, marking a significant milestone in the prevention of typhoid fever.

Our research2, which demonstrated the evolution of multidrug antibiotic resistance in Salmonella Typhi, was taken up by WHO in its 2020 recommendation: Target product profile for therapy of uncomplicated enteric fever3, and helped to lay the groundwork for our ACT South Asia treatment trial currently underway (more details below).

Emergence of Antimicrobial Resistance: During our clinical trials, we observed a concerning trend of increasing antimicrobial resistance among Salmonella strains responsible for typhoid fever. This observation underscores the urgent need for alternative treatment strategies to combat multidrug-resistant strains. In response to this challenge, OUCRU Nepal has initiated trials exploring combination therapy approaches to enhance treatment efficacy and reduce the risk of further antimicrobial resistance development, including the ACT South Asia study.

This study was also linked to Dr Pham Thanh Duy’s Wellcome Fellowship work, which identified azithromycin-resistant Salmonella Typhi isolates in Nepal in 20204.

Enhancements in Clinical Trials Unit and Surveillance: OUCRU Nepal has leveraged the opportunities presented by multiple research projects to make significant advancements in the clinical trials unit. We have invested in training experienced staff to conduct highquality trials and equipped our laboratories to perform comprehensive surveillance for antimicrobial resistance. This enhanced surveillance allows for the early detection of resistant bacteria and informs treatment strategies accordingly.

1.1, 1.2, 1.3, 2.1, 4.1, 4.2, 5.2.1, 5.4, 6.3 ID1.1,1.2,1.3,1.4,1.5,2.1,2.2,2.3,3.1,3.2,4.1.4.2,4.3; PC3.2,3.3,4.1,4.2, EE1,3,4,7,8

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Assessing The Impact Of A Vi-Polysaccharide Conjugate Vaccine In Preventing Typhoid Infections Among Nepalese Children – A Phase III Trial (TyVAC) TyVAC-Nepal was a participant- and observer-blind, 1:1 individually randomised trial of the typhoid conjugate vaccine (TCV) that aimed to study the impact of TCV in an endemic setting.

The study was a part of the Typhoid Vaccine Acceleration Consortium (TyVAC), which aimed to reduce the global burden of typhoid fever by accelerating the introduction of TCV in low-resource settings. As a part of the TyVAC consortium, independent impact studies have also been conducted in Dhaka, Bangladesh and Blantyre, Malawi.

This study ran in Nepal between 2017 and 2021, and enrolled more than 20,000 children between the ages of nine months and 16 years. The children came from a predefined catchment area in Lalitpur, Kathmandu which comprises 17 wards of Lalitpur.

The children were randomised to receive either TCV or a control vaccine (Group A meningococcal vaccine). At the same time, a subset of 1500 consenting participants (1,000 TCV, 500 control vaccine) was sub-randomised to have blood samples collected to study immunogenicity.

Participants were followed up in fever clinics set up at all 17 wards of the Lalitpur area and Patan hospital, the main study hospital, to capture confirmed typhoid fever cases. All participants presenting with a fever after two or more days and/ or a temperature higher than 38 degrees C consented to blood culture and had their blood samples taken for confirmation of the diagnosis of typhoid fever. The parents or guardians of participants were contacted every three months either via telephone call or an in-person visit to collect information about mortality and morbidity endpoints, including fever, antibiotic use, school/work absenteeism etc.

At the end of the study, all participants were unblinded and offered the alternate vaccine. After the campaign, a census and Global Water, Sanitation, & Hygiene (WASH) survey were also conducted in the catchment area. The final results of this study showed that the TCV is efficacious, safe and immunogenic5.

1.1, 2.2, 3.1, 3.3, 4.1, 4.2, 5.5.1, 6.1.1, 6.1.2, 6.1.3 ID1.1, 1.2, 1.3, 1.4, 1.5, 2.1, 2.2, 2.3, 2.6, 3.1, 3.2, 4.1, 4.2, 4.2, 4.4

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Assessing The Medium Term Impact Of A Vi-Polysaccharide Conjugate Vaccine In Preventing Typhoid Infections Among Nepali Children (TyVOID)

TyVOID was an important continuation of the TyVAC study, and provided further evidence for the Nepalese government that TCV was both safe and effective for use in children. This study aimed to assess the medium-term efficacy of the vaccine by comparing the relative risk of typhoid fever in a cohort initially vaccinated in 2017 and 2018 with cohorts vaccinated in 2020 and 2021.

TyVOID Nepal was a prospective cohort study, and ran alongside the continuation of a community surveillance study, which included conducting healthcare facility-based passive surveillance for typhoid fever in children (vaccinated and unvaccinated), and an immunogenicity study to assess waning immunity to the

vaccine. At the same time, we ran WASH surveys, which look at Water, Sanitation and Hygiene in the study areas, as well as demographic analysis.

To assist with uptake and acceptability, the TyVOID study included a qualitative component to assess the perception of the community regarding typhoid conjugat vaccination. All the participants who were enrolled in the initial TyVAC study were eligible for inclusion in this study. As with TyVAC, the entire population within a selected geographical catchment area of Lalitpur, Kathmandu (17 wards of Lalitpur) was included in the background typhoid surveillance and WASH assessment.

This enabled the study teams to be very embedded in the local context6.

1.1, 2.2, 3.1, 3.3, 4.1, 4.2, 5.5.1, 6.1.1, 6.1.2, 6.1.3 ID1.1, 1.2, 1.3, 1.4, 1.5, 2.1, 2.2, 2.3, 2.6, 3.1, 3.2, 4.1, 4.2, 4.2, 4.4

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ACT South Asia Trial: Cefixime & azithromycin vs azithromycin alone for the out-patient treatment of typhoid fever in South Asia; a randomised comparative controlled trial

The primary objective of ACT-South Asia is to determine if the combination of azithromycin and cefixime for seven days results in significantly fewer treatment failures when compared with the current standard regimen of azithromycin alone for seven days in the out-patient treatment of children and adults with uncomplicated typhoid fever (infection due to Salmonella Typhi and Salmonella Paratyphi A) in South Asia7.

Antimicrobial resistance has become a massive problem in tacking typhoid in South Asia. When antimicrobial treatment works, the patient gets better with in 4-6 days, and is significantly less likely to develop life-threatening complications.

And, if the antimicrobial treatment works, then the treament is inexpensive, and can be given in an out-patient setting. In the last 20 years fluoroquinolones, such as ciprofloxacin, have been successfully used. However, in South Asia resistance to ciprofloxacin in typhoid is now widespread.

Resistance limits the choice of effective antimicrobials and increases the risk of patients developing severe disease.

Because of these concerns Salmonella was listed as Priority 2: HIGH on the WHO Priority Pathogens List in 20178.

A current standard regimen, recommended by the WHO, is a 7-day course of the oral antimicrobial azithromycin. Emerging evidence from small studies suggests that a combination of azithromycin

1.2, 3.1, 4.1, 4.2 OUCRU Annual Report 2023

OUCRU Grant number: 414 CTU ref: 25NP

and cefixime may achieve a better cure than azithromycin alone. In this trial, we have recruited 1,500 patients across multiple sites in typhoid-endemic areas of Bangladesh, Nepal and Pakistan. Our aim is to assess whether treatment outcomes are better with the combination regime at completion of the one week of treatment and again at follow-up one and three months after treatment was started. Both of these antimicrobials are widely used and have an excellent safety profiles, but we will carefully monitor for side effects. This project also includes a health economics component to assess the financial implications for families and the health system.

If the combination treatment is better than the single antibiotic treatment, the involvement of three countries in the study will allow generalisation of the results across South Asia and other typhoid endemic areas. Considering the high burden of typhoid fever in this region even small improvements in the treatment success will translate into a benefit for many individuals and families and the health system as a whole. For example, a reduction in treatment failures in the 7 million patients with typhoid fever in South Asia from 15% (with azithromycin alone) to 10% using the antimicrobial combination, will mean at least 350,000 patients will experience a faster cure, fewer hospital admissions with less financial impact.

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Conclusion Our dedication to advancing the treatment of typhoid fever has led to impactful contributions in both clinical practice and public health policy. We have influenced treatment guidelines, facilitated the development and implementation of effective vaccination strategies, and initiated innovative approaches to combat antimicrobial resistance. Moving forward, we remain committed to furthering our understanding of typhoid fever and improving patient outcomes through evidence-based interventions.

References 1. Phase 3 Efficacy Analysis of a Typhoid Conjugate Vaccine Trial in Nepal. DOI: 10.1056/NEJMoa1905047 2. The Evolution of Antimicrobial Resistance in Salmonella Typhi. DOI: 10.1097/ MOG.0000000000000406 3. Target Product Profile for Therapy of Uncomplicated Enteric Fever. https://iris.who.int/ bitstream/handle/10665/332247/9789240003835-eng.pdf 4. The emergence of azithromycin-resistant Salmonella Typhi in Nepal. DOI: 10.1093/ jacamr/dlaa109 5. Phase 3 Efficacy Analysis of a Typhoid Conjugate Vaccine Trial in Nepal. DOI: 10.1056/NEJMoa1905047 6. Public Engagement During a Typhoid Conjugate Vaccine Trial in Lalitpur, NepalExperience, Challenges and Lessons Learnt. DOI: 10.1080/21645515.2022.2043104 7. Azithromycin and Cefixime Combination Versus Azithromycin Alone for the Out-patient Treatment of Clinically Suspected or Confirmed Uncomplicated Typhoid Fever in South Asia: A Randomised Controlled Trial Protocol. DOI: 10.12688/wellcomeopenres.16801.2 8. WHO Publishes List of Bacteria for Which New Antibiotics Are Urgently Needed. https:// www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-newantibiotics-are-urgently-needed

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Climate and Health

Climate and Health is an emerging research focus at OUCRU. Southeast Asia is recognised as one of the most vulnerable regions to climate change, and faces rising sea levels, heat waves, floods and droughts, and increasingly intense and unpredictable weather events. In clinical practice, we see the impact of this in the expanding range of vector-borne illnesses such as dengue and malaria, contamination of water sources leading to water-borne illnesses such as typhoid, and high-risk of emerging pathogens.

In 2021, we set priorities for our research focus on climate and health, aligned with other AAPs. Climate impacts on health are not limited to any one country, or any one discipline, and therefore there are opportunities for cross-disciplinary and multicountry responses in our climate and health programme. We have selected two key projects that were conducted at OUCRU in the last year to demonstrate this, and highlight some of our researchers who are leading our response to climate emergency.

Photo stories: Exploring the Impacts of Changing Climates on Health and Wellbeing in Indonesia, Nepal, & Vietnam. Conducted by researchers at OUCRU Hanoi, OUCRU Indonesia, and OUCRU Nepal.

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Dengue Advanced Readiness Tools (DART) Dengue is the most important arboviral infection affecting humans and presents a major global challenge for public health services. In endemic areas like Vietnam, seasonal epidemics of varying size and intensity can overwhelm health service capacity. Thus, the ability to identify the precise location, size and duration of a dengue outbreak is important to target mitigation efforts effectively.

Compared to previous initiatives on dengue forecasting, and addressing the need of our public health officer partners in Vietnam, our goal is to provide shortterm probabilistic forecasting at high spatial resolution. To achieve this goal, we are developing an innovative forecasting tool that combines agnostic and flexible machine learning algorithms with mechanistic mathematical models.

OUCRU Grant number: 703

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Climate, weather and hydrolical data forcasting;

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Human demographic, socio-economic and population movement data;

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Case report and virological, entomological and environmental data.

Integrating weather forecast data in the system at the initial design phase of DART will enable the subsequent extension of the system to provide stakeholders with relevant information on longer timescales (from months, to decades).

This addition will allow the exploration of if and how remote climatic drivers may affect dengue outbreaks in Vietnam, leading to a greater understanding of weather and climate impacts on dengue and subsequently improving dengue forecasts.

We will consider as many potential predictors as possible and include:

Two global health challenges: a multi-country analysis to explore the implications of climate change for antibiotic resistance In this project, we conducted community engagement to support climate change research using the participatory method of community-led photography. This was part of a multi-country study to understand experiences of climate change and its impacts on health and wellbeing in Indonesia, Vietnam, and Nepal, led by Associate Professor Sonia Lewycka.

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OUCRU Grant number: 682 CTU study code: 221GR

The participants used photography and storytelling to capture their individual experiences. Those photographs were then collaboratively interpreted through discussions to develop narratives that explain the impact of climate change.

The photographs have been displayed at several public events internationally.

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How are our researchers looking at Climate and Health?

Dr Marc Choisy – OUCRU Ho Chi Minh Using machine-learning forecastingbased approaches, Marc is working to understand the effects of environmental and climatic variables on the epidemiology of infectious diseases, including dengue fever, respiratory infections and diarrheal diseases.

Associate Professor Sonia Lewycka – OUCRU Hanoi Sonia uses population datasets to analyse global distributions and determinants of antibiotic use. By linking these population datasets with climate data, she is building geospatial models to look at the relationship between climate and AMR, as well as mathematical models to identify intervention points with the largest potential for impact on antibiotic use and resistance.

Dr Iqbal Elyazar – OUCRU Indonesia Iqbal uses digital and spatial tools such as for assessing the effects of climate change on infectious disease incidences among Indonesia’s climate vulnerable populations. In his work, he uses predictive artificial intelligence models, Earth observation data, and serological and epidemiological data to forecast the climate impact on health effects among vulnerable populations, quantifying the economic costs, identifying gaps and offering recommendations on climate change policy, collaborating with national, local authorities and community leaders to develop communication and advocacy strategy and tools to facilitate informed policy action.

Associate Professor Sophie Yacoub – OUCRU Ho Chi Minh Under Sophie’s leadership, OUCRU’s Dengue group is investigating the impact of climate change and global heating on dengue and other climate-sensitive diseases in Southeast Asia through the integration of novel digital technologies, remote patient monitors, mHealth initiatives and artificial intelligence methodologies. The overall aim of the group is to improve dengue clinical outcomes in Viet Nam and globally.

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Enriching research with Public and Community Engagement Public and Community Engagement initiatives at OUCRU are designed to bridge the gap between scientific research and the general public by facilitating meaningful interactions and discussions. We aim to make science accessible and relevant to diverse communities, enhancing their understanding and involvement in healthrelated research.

This report encapsulates data from our initiatives across Indonesia, Nepal, and Vietnam in 2023. The first section presents a comprehensive summary of activities conducted and the scope of audience engagement. Detailed insights into the impact of these initiatives are further explored through three case studies focusing on mental health, engagement with community members affected by tuberculosis (TB), efforts to enhance awareness about antimicrobial resistance (AMR), and initiatives aimed at empowering young people.

Public and Community Engagement teams from Vietnam, Indonesia, Nepal

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Research Enrichment Supporting researchers to do engagement • Seed Awards for researcher-led engagement projects: 5 awarded in 2022-23 with a total value at £15,799.

• Collaborating on PCE events: 59 events included the participation of researchers, involving 240 people – 87 as facilitators, 153 as audience.

Supporting healthcare workers (HCW) Training for HCWs in our partnered hospitals and to the wider audience through online webinars and training sessions.

• 30 training sessions with 28 inperson, two online events in partnership with Medisetter (videos).

• A total of 546 HCWs received training on soft skills topics such as: Dealing with angry patients, Non-verbal communication skills, Presenting vaccine information to rural communities.

“Before the training was implemented, 52 out of 184 communes in Dak Lak fell behind on vaccination. This is an area of concern for us. After the Covid-19 pandemic, the vaccination rate fell significantly. Capacity building for frontline health workers is now more important than ever.”

Dr Le Phuc, Vice Director of Dak Lak CDC

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“This is the first time I’ve attended a workshop where community members were included. They have been able to present their research and offer vital information on the community’s challenges in accessing care and treatment for HepC. This model [of engagement] should be applied to HIV/AIDS and other infectious diseases.”

Dr Cao Hue Chi, Specialist, Vietnam Authority on HIV/AIDS Control

Empowering communities to be involved in OUCRU research We worked with five advisory groups including a total of 79 people: Youth advisory group (Nepal), Hepatitis C stakeholder working group (HCMC), Hepatitis C community advisory group (HCMC), Health research advisory group (HCMC), and CONNECT website advisory group (international).

• One example is the Health Research Advisory Board (HCMC). This board has 14 members of the general public and held six meetings this year to discuss research with five OUCRU research groups. Topics they discussed included: death & dying, DART study (dengue forecasting), TBM, and use of routine data.

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Involving policy makers and stakeholders In 2023, we held two policy engagement events.

1. Accessing care for underserved populations at risk from Hepatitis C: This event convened more than 70 attendees, including senior stakeholders from the Vietnamese Ministry of Health, Ho Chi Minh CDC, international and local organisations, community-based organisations’ members and OUCRU researchers.

2. Supporting frontline vaccine staff serving rural, ethnic minority communities at Dak Lak province, Central Highlands, Vietnam. In May 2023, we worked with 51 participants from local Vietnamese organisations, together with health collaborators, district and commune vaccine workers, and OUCRU researchers.

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Partnership with Youth: Collab Lab

Collab Lab was a creation of two groups of Youth Science Ambassadors and has been running since 2022.

The goals of the project are: • Disseminate research findings to the public.

• Bring health scientists and young people together.

Since its beginning, Collab Lab has worked intensively with 15 young people and 12 scientists. Together, they have created 11 explainer videos which summarize published research papers, and other science communication materials. They have also hosted two Meet The Scientists interactive events. Collab Lab videos have gained over 21,300 reach.

• Host a platform for young people to feedback on the work of scientists and for scientists to listen to young people’s perspectives.

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Youth and school children

This year we have held nine events involving 1,660 schoolchildren (784 female/876 male).

Young people were involved as collaborators in ongoing activities: 46 young people contributed to 77 meetings, including the Youth Advisory Group (Nepal), Science Ambassadors and Collab Lab team.

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Engaging communities and stakeholders affected by TB See also – TBM case study which has a PCE component.

Scoping review of engagement practice to address TB stigma The experience of stigma is one of the barriers that can prevent people living with TB from accessing treatment. Stigma usually comes from the patients’ families or the public and can also be internalised by patients themselves. Addressing and reducing stigma contributes to improved health outcomes for TB patients. We are currently conducting a literature review of engagement activities related to TB stigma. Our teams in Nepal, Indonesia, and Vietnam will use the results to design appropriate, localised activities for the TB patient communities in different TB research projects at OUCRU. 3.2, 3.3, 5.5.1, 6.3

EE7

Engagement to Support Mental Health OUCRU does not have a research focus on mental health. However, we recognise that it is a health issue that affects our research communities, collaborators and research staff.

Therefore, across our programme, we actively engage with communities and partners about mental health.

Social media activities •

Content aiming to raise awareness about mental health: a total of 10 posts, including a campaign for World Mental Health Day 2022 (October).

Podcasts •

The impact of stigma for people with infectious diseases, in particular leprosy (Indonesia) - Destigmatisation Leprosy (Memanusiakan Penyintas Kusta) (Spotify).

•

Savouring Your Life (Seni Menikmati Hidup) (Spotify) discussed Dr Fred Bryant’s article on boosting happiness through positive reminiscence and other similar topics.

Public events:

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•

OUCRU Nepal held three events for World Mental Health Day involving 188 members of the public (112 female/76 male).

•

Indonesia: Five-day photo exhibition and launch event on leprosy and stigma: 274 members of the public (122 female/152 male). A public talk about progress and challenge of leprosy research in Indonesia at Kala Gallery, Central Jakarta for 56 participants (29 female/27 male).

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•

Vietnam: A series of public events ‘Talks at the Café: Exploring mental health’, with talks from people with lived experience and open discussion. Two events (in this period, out of 4 of the series) with total of over 50 participants from different backgrounds including young people, office workers, and mental health experts.

Mental healthcare training In recognition that communication challenges contribute to the stress and anxiety experienced by healthcare workers, we conduct regular participatory trainings for staff at the Hospital for Tropical Diseases (Ho Chi Minh City), and through online webinars to a wider audience across Vietnam. These trainings were particularly useful and relevant during the pandemic.

Training topics include: how to share bad news, conflict management and dealing with angry patients. In 2023, we organised seven in-person sessions with total of 169 participants including office staff, pharmacists, doctors, and nurses. Online workshops were attended by 379 medical staff.

Mental health services directory

We have created an online directory of professional mental health services and healthrelated support groups, compiled in consultation with mental health experts in Vietnam.

We also organised public events in collaboration with our partners to share the directory and raise awareness about mental health. We continue to update the online content and share the resource. We have had 253 views, scans, and downloads for the directory1.

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Building good engagement practice By documenting and publishing our initiatives, we can monitor progress, measure effectiveness and impact, and pinpoint areas that need improvement. Our goal is to share our experiences, insights, and success stories with the broader scientific community and public, particularly with countries in similar contexts. We aim to improve our transparency and accountability, and we hope our results will help set the best practice for involving the public in research.

We produced a number of academic publications and resources for our communities, and these are openly available on our website.

References 1. Stakeholder engagement to develop a directory of COVID-19 related mental health services in Vietnam: reflections on a participatory approach. DOI: 10.12688/ wellcomeopenres.20491.1

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Make a Difference Programme: a long-term investment in people and capabilities For the past 10 years, OUCRU has been running the Make a Difference (MAD) development programme with excellent results for both individual participants and for the broader organisation.

Staff members who participate in the MAD programme get the opportunity to develop their independent thinking, communication skills and leadership approaches. Many participants have gone on to hold leadership positions within OUCRU. The Programme is led by Rob Hale, an Executive Performance coach with over 30 years’ professional experience designing, developing and delivering courses with a key focus on leadership and coaching.

Make A Difference - The 10-year Anniversary Film

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“For me personally, I learned a lot. It was so much fun, too, and very different from an academic, scientific environment that I’m used to. I discovered a different energy and confidence within myself, and this course helped me discover my potential.”

Dr Pham Thanh Duy Head of Molecular Epidemiology at OUCRU Ho Chi Minh

“Leadership is not just about guiding others; it’s about understanding yourself first. The Make a Difference programme taught me different ways to lead myself and others. I learned that sometimes it’s okay for a leader to step back. This new understanding changed how I think about leading. It’s important to look at your own actions and make your own improvements before asking others to change. Good leadership starts with you and affects everyone around you.”

Dr Suwarti Infectious Disease Scientist at OUCRU Indonesia

“In my previous role in disaster management, I have seen people work like Superman - quick, decisive, and unerring, with no room to show weakness during a crisis. Commanding was the rule. [After the MAD Programme] I’ve realised that my leadership style isn’t entirely fit for my current role.

Today, it’s about being present, supportive, and having those challenging, necessary discussions with the team.”

Bachtiar Andy Musaffa Senior Research Data Manager at OUCRU Indonesia

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“The programme has been extremely beneficial. Often as researchers, we’re so engrossed in our work that we don’t pause to consider our leadership styles; we just act. Leadership training isn’t something most of us, myself included, have formally received. This programme encourages you to reflect on your personal leadership style and the impact you’re making. It addresses many aspects, from enhancing leadership skills to boosting confidence.”

Associate Professor Jennifer van Nuil Head of Social Science and Implementation Research at OUCRU Ho Chi Minh

“The programme helped me develop the confidence and abilities to lead my team effectively. I learned how to increase my credibility, motivate my staff, and create a cohesive and productive work environment.”

Dr Vu Thi Lan Huong Senior Research Fellow at OUCRU Hanoi

“At times, challenging conversations are necessary. There are moments when you might not see eye to eye with your team or senior management. It’s important to acknowledge these differences. The Make a Difference Programme has proven invaluable to me in that regard. It has equipped me with various strategies for effective communication. Being open and transparent is crucial in addressing these communication challenges, I believe.”

Dr Sabina Dongol Research Microbiologist at OUCRU Nepal

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Currently working with its 8th cohort, the Make A Difference Programme consists of 6 face-to-face taught modules, each lasting 2 days, plus 9 hours of individual coaching for participants during a 2-year period.

“The Make a Difference leadership programme is a hugely valuable development opportunity for our staff and has been beneficial to the whole OUCRU programme, probably beyond our expectations,” said Sarah Barton, Director of Operations at OUCRU. “The aim was always to create a programme to support ambitious individuals and to build a network of confident, creative people who could go on to lead, motivate and influence others to support the work of OUCRU.” “The fundamental elements focus participants on three areas: making a difference to Self, a difference to Others and a difference to the Organisation,” she added. “Across all the cohorts, we have seen individuals developing outstanding personal effectiveness, encompassing empathy, strategic vision, emotional intelligence, and inspiring all levels of the organisation with their engagement and contribution. It has been very satisfying to see colleagues grow and fulfil their potential through participation in the MAD Programme.”

We have collected some interesting metrics about participants in the MAD programme – see Appendix.

2.2,2.3,5.1.3,5.1.4

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Promoting our research culture with supported communications Public-facing Communications

The strategic objective of OUCRU’s public-facing communications activities is to increase our impact by sharing timely, relevant, and evidence-based information about our research with our key stakeholders - including policymakers, the press, and the wider public.

Our centrally-managed comms assets include our branding, our website and diverse social media accounts. Metrics are collected quarterly and shared with relevant teams to monitor performance and tailor our strategy to fit with each audience’s needs.

On April 30, 2023, OUCRU’s redesigned website went online. The new website has accessibility features, and provides comprehensive information about our research, people, and publications. From April to December 2023, we published 22 stories on the website to promote OUCRU’s work, attracting 6,800 site visitors.

Currently, OUCRU maintains a social media presence on six platforms, including Facebook, Instagram, X (formerly known as Twitter), LinkedIn, YouTube, and Spotify.

In addition to promoting OUCRU’s research outputs, we also have a focus on public and community engagement activities and a dedicated Facebook account for our youth communities and schools programme.

@OUCRUVN; @OUCRUID; @OUCRU Nepal; @Khoa Hoc Truong Hoc (School Science)

Oxford University Clinical Research Unit

@OUCRU_Official; @oucruindonesia

Oxford University Clinical Research Unit

@OUCRU_Programme; @OUCRUID

Oxford University Clinical Research Unit

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Capacity Training for Healthcare Workers: Stories from Dak Lak

OUCRU’s campaigns spread our messages via multiple channels to enhance our impact.

For example, to promote a years-long Social science and Public engagement project that raises vaccination uptake in ethnic minority communities in Dak Lak, Viet Nam, we developed a project summary video, featuring the community members and healthcare workers that were involved in the project. The video premiered at a Project Update Event hosted by OUCRU and Dak Lak CDC in May 2023, and was shared on our website and social media channels. On Facebook, the post received 2,500 impressions and 2,100 reach.

On YouTube, the video has received 430 views.

We leverage the latest social media techniques to increase our reach. For example, we made more use of short portrait or square video formats to take advantage of platform algorithms. One effective approach in 2023 has been using YouTube shorts, which accounted for nearly 90% of our video impressions.

A detailed report can be found in the Appendix.

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Internal Communications

The strategic objective of our internal communications activities is to build a healthy, supportive, and inclusive working environment and foster a strong research culture.

Communication and Policy Engagement Team

OUCRU staff are dispersed across a vast geographic area which incorporates multiple languages, cultures and accessibility needs.

In 2023 we invested in developing M365 as the internal communications system for OUCRU staff and students, including SharePoint, Teams and other related apps. Its primary purpose is to help employees securely communicate with each other, store information, and collaborate.

All OUCRU staff can access the centrally-managed intranet, to find OUCRU’s policies and procedures, governance, and research support resources.

Inclusive Communications We are committed to providing inclusive, accessible communications that represent our organisation’s diversity as well as the diversity of our audience.

Our online presence complies with Oxford University’s accessibility requirements.

All our communications, unless specified otherwise, are produced for a general audience.

As such, our writing strives to be simple, straightforward, and easy-to-understand.

OUCRU’s communications (including our website) are developed and translated in: English (all of the time, on all available channels), Vietnamese (when suitable for a Vietnamese audience), Indonesian (when suitable for an Indonesian audience), and Nepali (when suitable for a Nepalese audience).

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Policy Engagement OUCRU’s vision is to have an impact on health, and one way to realise this is through effective policy engagement with stakeholders – locally, regionally, and globally. Our policy engagement goal is to facilitate and enhance continuous engagement across a broad spectrum of opportunities for both researchers and stakeholders.

OUCRU INFECTIOUS DISEASES RESEARCH AND POLICY DISCUSSION FORUM (IDDF) The IDDF provides a sustainable platform and mechanism for OUCRU infectious disease researchers, and key stakeholders working in the areas of infectious disease policy in Viet Nam to meet, share priorities and initiatives, seek advice, and work together in collaborative projects. The IDDF serves to facilitate equal, two-way discussion and sharing - giving both OUCRU researchers and policy stakeholders the opportunity to learn about one another’s priorities, concerns, and opportunities to collaborate. The goals of the Forum are to: • Provide all members a platform to discuss infectious diseases of importance to Vietnam including strategic and action plans for outbreak responses and preparedness.

• Ensure that OUCRU’s research is designed and communicated in a way that quickly generates outcomes that are relevant and useful for defining policy.

• Strengthen the networks between researchers and stakeholders in the policy making environment focused on major infectious diseases at national and international levels.

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Policy engagement research We need our policy engagement practice to be evidence informed. To enable this, we have a policy engagement research programme, which allows us to ask questions about the policy-making environment in the areas where we work, as well as the about the best ways to facilitate effective engagement between researchers and policy stakeholders in those environments.

In 2023 we completed the project: Understanding Wildlife Farming and Zoonotic Disease Management in Vietnam.

The study conducted a literature review and in-depth interviews with stakeholders in Vietnam to support evidence-based policy decisions and measures to tackle the challenges posed by wildlife farming and trade. The findings were presented at a workshop with relevant stakeholders in Hanoi in June 2023.

Full report

Policy metrics and impact management OUCRU aims to have impact on health, and in order to evaluate this we need to manage our policy-related metrics and outputs. The Policy Engagement team at OUCRU tracks and measures data related to our policy engagement outputs and outcomes. Based on the collected data, we produce reports, case studies and data visualization for monitoring and evaluation as well as for supporting our policy engagement practice from an evidenceinformed standpoint.

Some key metrics are included in the Appendix.

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Enhacing Research Capabilities: Strategic Acquisition of Advanced Lab Instruments

In 2023, OUCRU has significantly enhanced its research capabilities through the acquisition of state-of-the-art laboratory instruments to support discovery science and collaborative studies throughout the programme.

OUCRU Ho Chi Minh In April 2023, the acquisition of the ImmunoSpot® S6 Universal M2 added a sophisticated tool for immune monitoring, particularly focusing on B and T cell responses. Configurable for up to 12-colour analysis, its versatility supports a range of applications including ELISPOT assays, PBMC counting, and ELISA analyses, making it an essential asset for advancing immunological research.

With support from the Nuffield Department of Medicine in Oxford, we introduced a Chromium X Single Cell RNA sequencer from 10X Genomics in July 2023. This technology allows for the detailed analysis of individual cell transcriptomes, facilitating the discovery of new biomarkers, profiling gene expressions, and studying cellular responses in diverse infectious diseases.

Additionally, the acquisition of the Real-Time PCR CFX96 model in September 2023 has greatly enhanced the laboratory’s genetic analysis capabilities. Using fluorescencebased PCR, this equipment provides highly sensitive detection and precise quantitation of nucleic acid sequences, essential for the accurate evaluation of biological and medical research data.

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OUCRU Indonesia OUCRU Indonesia lab, established in collaboration with the University of Indonesia, similarly acquired cutting-edge technology that are crucial for understanding infectious diseases, immunology, and genetics. These instruments facilitate precise and detailed analysis, allowing researchers to conduct more efficient and comprehensive studies on a larger scale. Additionally, the enhancements in the lab infrastructure here also support several international research collaborations, including SEACOVARIANTS and INVITE projects, enriching scientific exchanges between the OUCRU units.

Among the key technologies is the Luminex 200 system, which can perform up to 100 immunoassays simultaneously from a single drop of fluid. This system is instrumental in analysing immune responses in diseases such as COVID-19 and Dengue.

The Grid-ION Oxford Nanopore Technology provides high-performance genomic sequencing capabilities. This compact, benchtop sequencer is essential for projects like ACORN, supporting rapid, desktop whole genome analysis.

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For cellular immune response studies, the T-cell ELISPOT analyser and Intracellular cytokine staining (ICS) are critical. The ELISPOT analyser detects immune cells that secrete specific proteins, vital for vaccine response research in COVID-19. Similarly, ICS, used in HIV research, allows for the direct observation and quantification of cytokines within cells, enhancing our understanding of immune cell functions.

The Mass Spectrometry AB SCIEX 4500 TQ Agilent Infinity II 1290 can detect small molecules and metabolic pathways, crucial for pharmacokinetic studies and drug metabolism research. It supports a variety of scientific studies, including the analysis of primaquine metabolism.

The Agena Mass-Array is used extensively for genetic analysis, including CYP2D6 genotyping and Copy Number Variation assays. These analyses are essential for understanding individual responses to drugs and genetic links to diseases, respectively.

Lastly, the Nanodispenser RS1000 is pivotal for the precise handling of nanoliter volume samples in genetic testing, ensuring minimal waste and enhancing laboratory efficiency.

OUCRU Nepal OUCRU Nepal has made strategic enhancements to its laboratory capabilities by integrating advanced automated systems to improve the detection and analysis of pathogens. These systems not only facilitate a quicker diagnostic process but also ensure greater accuracy and reliability in results, which are crucial for effective disease management and research.

The BD BACTEC™ FX40 Automated Blood Culture System and BD Phoenix™ Automated Microbiology System technologies, are capable of rapid detection of organisms in blood samples and perform susceptibility testing of bacteria respectively. Both technologies have dramatically revolutionized the scientific studies approach in Nepal.

1.1, 1.2, 1.3, 3.2, 5.2

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Appendices OUCRU Annual Report 2023

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1. Publications We maintain a database of publications on our website which is publicly accessible. Our publications are linked to research projects and researcher profiles on the website. The database is updated on a fortnightly basis to ensure that new publications are quickly available. In 2023, we published a total of 296 peer-reviewed publications.

Peer-reviewed Publications by Month

Browse our publications database

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2. Active Clinical Trials Study code

Unit

Study title

Clinical trial registration No.

Name of register

26TB

HCMC & Indonesia

A randomized double blind placebo controlled trial of adjunctive dexamethasone for the treatment of HIV-infected adults with tuberculous meningitis (ACT HIV)

NCT03092817

Clinical Trials. gov

27TB

HCMC

A randomized double blind placebo controlled non-inferiority trial of adjunctive dexamethasone for the treatment of HIV-uninfected adults with tuberculous meningitis stratified by Leukotriene A4 hydrolase genotype (LAST-ACT)

NCT03100786

Clinical Trials. gov

35CN

HCMC & Hanoi

VIETNARMS - A strategic post-licensing trial of oral direct acting antiviral Hepatitis C treatment in VIETNam incorporating a novel design with multiple ARMS

ISRCTN61522291

ISRCTN

56DX

HCMC

Metformin as adjunctive therapy in overweight and obese patients with dengue: an open-label safety and tolerability trial

NCT04377451

Clinical Trials. gov

31TB

HCMC & Hanoi

RCT of 6-month intensified anti-TB treatment ISRCTN40829906 versus 12-month WHO standard anti-TB treatment, with or without adjunctive aspirin for children with TB Meningitis (TBM)

ISRCTN

24MA

HCMC

A Phase IV, multi-center, open-label study to determine the safety, tolerability and clinical outcomes following oral administration of EGATENTM (Triclabendazole) in patients (6 years of age or older) with fascioliasis

NCT04230148

Clinical Trials. gov

38C 27NP

HCMC, Hanoi, Indonesia & Nepal

Randomised evaluation of COVID-19 therapy (RECOVERY)

ISRCTN50189673 NCT04381936 2020-001113-21

ISRCTN Clinical Trials. gov EU Clinical Trials

01NVb

HCMC

Developing automated point of care ultrasound for Cardiac, Lung and Muscle examination in critical illness

NCT06034093

Clinical Trials. gov

06NV

HCMC

Evaluation of awake prone positioning effectiveness in moderate to severe COVID-19

NCT05083130

Clinical Trials. gov

60DX

HCMC

Anakinra for dengue patients with hyperinflammation – a randomized double-blind placebo-controlled trial

NCT05611710

Clinical Trials. gov

13IND

Indonesia

High-dose oral rifampicin to improve survival from adult tuberculous meningitis: a double-blinded randomised placebo-controlled Phase III trial (HARVEST)

ISRCTN15668391 INA-EODLQCG

ISRCTN INA-Registry

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Study code

Unit

Study title

Clinical trial registration No.

Name of register

07IND

Indonesia

Safety, Tolerability, Immunogenicity and Protective Efficacy Against Naturally-Transmitted Malaria in Eastern Indonesia of Two Plasmodium Falciparum Sporozoite Vaccines (IDSPZV1)

NCT03503058

Clinicaltrials. gov

20IND

Indonesia

Efficacy and Tolerability of Adjunct Metformin in Combination With Multidrug Treatment for Multibacillary Leprosy: A Randomized Double-blind, Controlled Proof-of-Concept Phase 2 Trial in Indonesia (METLEP)

NCT05243654

Clinicaltrials. gov

24NP

Nepal

Impact of improved diagnostic tools, practices, training and communication package on acute fever case management and antibiotic prescriptions for patients presenting at outpatient facilities in selected health facilities of Kathmandu Valley".

NCT04081051

Clinicaltrials. gov

25NP

Nepal

Azithromycin and cefixime combination versus azithromycin alone for the out-patient treatment of clinically suspected or confirmed uncomplicated typhoid fever in South Asia; a randomised controlled trial

NCT04349826 ISRCTN Registration number: ISRCTN18065452

Clinical Trials.gov ISRCTN

23NP

Nepal

Reducing Antibiotics treatment Duration for Ventilator-Associated Pneumonia (REGARD-VAP)

NCT03382548

Clinical Trials. gov

22NP

Nepal

A Phase IV participant- and observer-blind ISCTRN43385161 randomised-controlled trial to assess the protective impact of a Vi polysaccharide conjugate vaccine (TCV) in preventing typhoid infection in Nepalese children (TyVAC)

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3. Make A Difference Programme

There are limited places available in the MAD programme. Participants are nominated by their supervisors, and must submit an application. We aim to have equitable representation on the programme for many variables including Unit, gender, nationality, career stage and role.

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4. Our People

OUCRU employs around 330 people in Vietnam, and a further 100 people in each of OUCRU Indonesia and OUCRU Nepal. Around 60% of our research groups are led by local researchers, and around half of our group heads are female. We track gender (limited to male/female and undefined, currently) and nationality information for our staff in order to monitor our progress towards providing a supportive, fair and collaborative environment for all of our staff. While the majority of our staff are directly employed in the conduct of research, our research support teams which include operations (HR, procurement, grants, comms, training, IT), finance and clinical trials support, estates and other staff are essential to success of our programme.

In 2023, we were pleased to welcome seven PhD graduates, and four Master’s graduates from our training programme.

Group Heads by Gender

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Support staff by gender

Staff Composition

Masters and PhDs Awarded

University titles and Post-doc by Gender

University titles and Post-doc by Nationality

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5. Communication and Policy Engagement

Number of Activities by Engagement Outcome Engagement Outcome Evidence of positive reception Maintaining/strengthening relationships with existing contacts New policy recommendations New relationships with new contact Secondary publications (citing or incorporating the research)

Most common outcome we observe arising from our policy engagement activities is maintaining or strengthening existing relationships - a key goal of our policy engagement work. The number of new relationships recorded with new contacts has also steadily increased over this period.

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Change of Activities by Research Stage over Time

We track our policy engagement activities against the stage of research. Our aim is to see more engagement at earlier stages in the research cycle - the dark blue colour in this chart. The most common engagement activity type we see is coded here as NA, and most of these reflect professional memberships that can’t be linked to a specific research stage. Nevertheless, maintaining these professional networks is a good way to form and maintain relationships with key stakeholders.

Change of Engagement Types over Time

By tracking the numbers and types of engagement our researchers are undertaking with policy stakeholders, we are able to observe more joint activities and outputs, particularly in co-production of knowledge & event planing.

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Social Media Report Summary from All platforms (Vietnam Accounts)

Best Performing Content

Top performing content was mostly in the people and capabilities category.

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6. OUCRU Strategic Priority Areas

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7. Wellcome Outcomes Framework Coding

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Editorial Team Katrina Lawson

Grants and Communications Manager

Ibrahim Indra

Senior Policy Engagement and Communications Officer Indonesia

Ngo Huyen Chi

Senior Communications Officer

Ngo Phan Bao Tran

Senior Policy Engagement Officer

Nguyen Thuy Ngan Trang

Pham Khanh Binh

Communications Officer

Internal Communications Officer

Huynh Van Nhat Lac

Tran Thi Tuyet Anh

IT Administrator

Tran Van Ai Nhi Graphic Designer

PCE Communications Manager

and contributors

With thanks to all contributors

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Working in partnership with

OUCRU is a Wellcome Major International Programme.

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Oxford University Clinical Research Unit

www.oucru.org