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Review

Preventing severe respiratory syncytial virus disease: passive, active immunisation and new antivirals Joanna Murray,1 Sonia Saxena,2 Mike Sharland3 1

Department of Primary Care and Public Health, Imperial College London, London, UK 2 Department of Primary Care and Public Health, Imperial College London, London, UK 3 Paediatric Infectious Diseases Unit, St George’s NHS Trust London, London, UK Correspondence to Professor Mike Sharland, Paediatric Infectious Diseases Unit, St George’s NHS Trust London, London SW17 0QT, UK; mike.sharland@stgeorges. nhs.uk Received 8 October 2013 Revised 29 December 2013 Accepted 30 December 2013 Published Online First 24 January 2014

ABSTRACT In most high-income countries palivizumab prophylaxis is considered safe, efficacious and cost-effective for preventing respiratory syncytial virus (RSV) hospital admissions among specific subgroups of infants born preterm, with chronic lung disease or with congenital heart disease. Virtually all babies acquire RSV during infancy and previously healthy babies are not eligible to receive palivizumab. Emerging evidence suggests some benefit of palivizumab use in reducing recurrent wheeze among infants born preterm. Better longitudinal studies are needed to examine its clinical and cost-effectiveness on recurrent and chronic respiratory illness and associated healthcare burden on resources in the community and hospitals. Since 99% of child deaths attributed to RSV occur in resource poor countries where expensive prophylaxis is not available or affordable, palivizumab has limited potential to impact on the current global burden of RSV lower respiratory tract infection (LRTI). A range of candidate vaccines for active immunisation against RSV are now in clinical trials. Two promising new antivirals are also currently in phase I/II trials to test their effectiveness in preventing severe RSV LRTI. These agents may be effective in preventing severe disease and phase III studies are in development. In the absence of effective active immunisation against RSV infection, population level approaches to prevent severe RSV LRTI should continue to focus on reducing prenatal and environmental risk factors including prematurity, smoking and improving hygiene practices.

INTRODUCTION

To cite: Murray J, Saxena S, Sharland M. Arch Dis Child 2014;99:469–473.

Respiratory syncytial virus (RSV) infection is a major cause of acute respiratory infection worldwide and each year results in an estimated 33.8 million new episodes of lower respiratory tract infections (LRTIs) among children aged less than 5 years.1 Mortality estimates vary from 66 000 to 199 000 child deaths annually thought to be attributed to RSV, 99% of these occurring in resource poor countries.1 In the UK the RSV-attributed death rate in infants has been estimated to be 8.4 per 100 000.2 Most children will have been infected with RSV by 2 years of age and approximately 10% of these episodes are severe enough to require hospital admission.1 In the UK, RSV infection is the leading cause of hospitalisation in children under 1 year of age, with an estimated admission rate of 31 per 1000 children under 1 year admitted in England.3–5 Some infants are at increased risk of hospital admission, including those who are born preterm or have congenital heart defects or chronic lung disease.6 Extensive systematic review evidence suggests there are no available treatments that clearly

Murray J, et al. Arch Dis Child 2014;99:469–473. doi:10.1136/archdischild-2013-303764

shorten the natural course of infection or provide clinical improvements in RSV bronchiolitis symptoms.7–11 Hence, the mainstay of management for infants infected with RSV remains supportive care including nasogastric feeding, oxygen therapy and intensive care for a small proportion (approximately 3%) of more severely affected infants.4 7 12 There is currently no effective vaccine against RSV infection. The only product currently licensed for prophylactic use to provide short-term protection against serious RSV infection among certain high risk infants, is passive immunotherapy with Palivizumab (Synagis, MedImmune), a humanised mouse monoclonal antibody against RSV infection, which targets the surface RSV fusion glycoprotein, preventing RSV entry into host cells and thereby preventing or reducing the severity of RSV infection.13 14 The aim of this article was to review the evidence of the safety, efficacy and costeffectiveness of palivizumab immunoprophylaxis for the prevention of RSV hospital admissions among high-risk infants in the UK and discuss new options under development.

METHODS Relevant articles were identified by searching The Cochrane Library, EMBASE, MEDLINE, Google Scholar and PUBMED databases for studies published from 1 January 1990 to 30 April 2013. Searches were carried out using MeSH terms and various combinations of the following keywords: “respiratory syncytial virus”, “RSV”, “respiratory syncytial virus infections”, “bronchiolitis”, “bronchiolitis, viral”, “palivizumab”, “Synagis”, “immunoprophylaxis”, “efficacy”, “safety”, “costeffectiveness”, “cost benefit analysis”, “cost analysis”, “economic analysis”, “hospital admission”. Relevant publications were identified by title and abstract and full text where required. We included findings from clinical trials, observational studies and postmarketing studies but excluded articles that were not published in English and abstracts that were not available as complete publications. Reference lists from selected papers and recent review articles were also examined.

EFFICACY OF PALIVIZUMAB The efficacy and safety of palivizumab was established through two large randomised, double-blind, placebo-controlled trials, which found palivizumab safely and effectively reduces RSV hospitalisation rates and serious complications among high-risk infants.15–17 The IMpact study was a multicentre, randomised, double-blind placebo-controlled trial in infants aged less than or equal to 35 weeks’ gestational age or those with chronic lung disease aged 469


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Review less than 24 months (n=1502) were randomised to receive five injections of palivizumab (15 mg/kg) or equivalent volume of placebo every 30 days. The trial found that those receiving palivizumab (n=500) had a highly significant 55% reduction in RSV hospital admissions compared to the placebo group (n=1002).15 In addition, secondary outcomes reported showed infants receiving palivizumab spent fewer days in hospital and required fewer days of supplemental oxygen than those receiving placebo, but there was no statistically significant difference in requirement for intensive care or ventilation between the two groups. Another randomised controlled trial (RCT) compared palivizumab use (n=639) to placebo (n=648) among children aged up to 24 months with haemodynamically significant congenital heart disease.14 16 This study reported a 45% reduction in RSV hospital admissions among those receiving palivizumab (5.3% compared with 9.7%). Mortality was also examined as a secondary outcome in both these RCTs, with infants in control groups found to have slightly higher mortality rates, though neither trial was sufficiently powered for examining this outcome. A recent Cochrane systematic review analysed data from three RCTs (including those described above) comparing palivizumab with placebo (n=2831) and four RCTs comparing palivizumab with motavizumab (n=8265), among infants born preterm, with congenital heart disease or chronic lung disease.18 They concluded that prophylaxis compared to placebo was associated with a 51% reduction in risk of RSV hospitalisation (RR=0.49 95% CI 0.37 to 0.64) and a 50% reduction in admissions to intensive care units (RR=0.50 95% CI 0.30 to 0.81). In addition, pooled analysis revealed a reduction in all-cause mortality, though this was statistically non-significant (RR=0.69 95% CI 0.42 to 1.15).18 It is perhaps most useful though to consider the number of children that need to be treated to prevent a hospital episode. It is estimated that 17 preterm infants need to receive prophylaxis to prevent a single RSV hospital admission.19 Methodological limitations of these trials also need to be considered, since some were not designed with sufficient statistical power to confirm efficacy.

MOTAVIZUMAB Motavizumab, another humanised monoclonal IgG antibody, was developed as an alternative passive immunotherapeutic to palivizumab, with the aim of achieving improved binding affinity and virus neutralising activity.20 A phase III double-blinded RCT found motavizumab was non-inferior when compared to palivizumab, with a 26% reduction in RSV hospital admissions compared with palivizumab.21 However, recipients of motavizumab were at increased risk of adverse skin reactions compared with those receiving palivizumab. Motavizumab has therefore not been licensed for use in any country due to concerns over its safety regarding the increased hypersensitivity reactions.15 16 MedImmune have discontinued development of its use for prophylaxis against RSV but are continuing research into its possible use for treatment of RSV infection.17 20

UK GUIDANCE Guidance for the use of palivizumab in the UK is provided by the Joint Committee for Vaccination and Immunisation ( JCVI) RSV subgroup. In 2010 the group released recommendations for palivizumab use but also highlight the limited evidence base on which their decisions were based.17 Current JCVI guidance states that palivizumab is only cost-effective and recommended for use in particular subgroups of infants at most risk of severe disease (see box 1).17 470

COST-EFFECTIVENESS Despite evidence of the safety and efficacy of palivizumab prophylaxis, it remains expensive and difficult to deliver, requiring 5 monthly intramuscular injections. The estimated cost for a single dose of palivizumab for an infant aged 6 months, weighing 7.5 kg, is £1023, meaning the total estimated cost per patient receiving the required five doses is just over £5000 each.14 22 Several economic evaluations have examined the costeffectiveness of palivizumab prophylaxis in high risk children. The most recent review of the economic evidence concluded that the cost-effectiveness of palivizumab is inconsistent across different studies—depending on the threshold used and the consumption of healthcare resources taken into consideration.18 In addition, when interpreting cost-effectiveness studies the different average weights of infants used in the analysis should be carefully examined as this can have a considerable effect on the conclusions reached. A Health Technology Assessment considered population subgroups with different combinations of risk factors for whom the use of palivizumab may be cost-effective. The study reported that at a willingness-to-pay threshold of £30 000 per quality adjusted life year (QALY), prophylaxis with palivizumab is only cost-effective among subgroups of children with no chronic lung disease or congenital heart disease if they have at least two other risk factors besides gestational age at birth (including being male, multiple births, siblings at school, smoking exposure and household overcrowding).23 A Canadian cost-effectiveness study mirrored these recommendations, also concluding that immunoprophylaxis was most cost-effective for infants born at a gestational age of 32–35 weeks with more than two other risk factors for RSV hospital admission.24 Elsewhere in Europe, the undiscounted incremental cost-effectiveness ratio (ICER) for use of palivizumab varies. The ICER is estimated to be €6142 per QALY among all high risk infants in Spain and in the Netherlands is estimated to be €12 738/QALY in infants born preterm or with bronchopulmonary dysplasia and €4256 for infants with congenital heart complications.25 26 We were unable to find any formal cost-effectiveness studies from lower or middle income countries, as the considerable costs prohibit even minimal use in many countries.

OTHER HIGH-RISK INFANTS It is notable that none of the RCTs testing the impact of palivizumab prophylaxis to date have included children with

Box 1 Recommended recipients of palivizumab immunoprophylaxis in the UK. ▸ Children aged <2 years requiring treatment for chronic lung disease within the last 6 months ▸ Children aged <2 years with haemodynamically significant congenital heart disease ▸ Children born at 35 weeks of gestation or less and less than 6 months of age at the onset of the respiratory syncytial virus (RSV) season. ▸ Children who have severe combined immunodeficiency syndrome (SCID), until immune reconstituted. ▸ All long-term ventilated (LTV) children less than 12 months at the start of the RSV season and LTV children aged less than 24 months with additional co-pathology (heart disease/ intrinsic lung disease as reflected by oxygen dependency).

Murray J, et al. Arch Dis Child 2014;99:469–473. doi:10.1136/archdischild-2013-303764


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Review immunodeficiency, chronic neuromuscular diseases, HIV infection or other congenital anomalies. Though these infants at higher risk of RSV infection may benefit from prophylaxis, the impact of passive immunotherapy in these potentially high-risk groups has not been studied, mostly due to the costs of such research and practical limitations of conducting and recruiting for an RCT among infants with such rare conditions. Experts from the American Academy of Pediatrics have highlighted the insufficiency of current evidence for the benefits of prophylaxis particularly in immunocompromised infants (such as solid organ or haematopoietic stem cell transplant recipients, HIV-infected infants and children with other primary and secondary immune deficiencies).27 Experimental studies are currently evaluating the use of palivizumab in infants with cystic fibrosis and immunosuppressed bone marrow transplant recipients.13 23 A large prospective study of over 5000 children in the USA, reported that most children (79%) with severe RSV infection are previously healthy.28 So palivizumab prophylaxis targeting only high risk infants will have a limited impact on total RSV disease burden, as most admissions are babies born at term.28 29 Hall et al28 highlighted the importance of prophylaxis being part of a broader package of care aimed at preventing the spread of viral infections, including the promotion of careful handwashing to reduce child exposure. They conclude that at its current price and clinical outcomes, palivizumab when given in accordance with current recommendations has limited impact on the overall burden of RSV illness seen by hospital paediatricians.28

POTENTIAL LONGER-TERM IMPACT OF PALIVIZUMAB It is not possible to determine from observational studies the complex relationship between RSV infection, recurrent wheeze and pre-existing pulmonary vulnerability.30 The recently published double-blind, placebo-controlled ‘MAKI’ trial has provided interesting and robust evidence on this association. A total of 429 healthy preterm infants born at between 33 and 35 weeks’ gestation were randomly assigned to receive either monthly placebo (n=215) or palivizumab (n=214) injections during the winter RSV season.30 Overall, they reported a 10% lower proportion of infants with recurrent wheeze during the first year of life among those receiving palivizumab (11%) compared with the placebo (21%) group ( p=0.01).30 There was a relative reduction in the total number of wheezing days of 61% in the intervention group compared with the controls (95% CI 56% to 65%). Some caution in interpretation of these findings is required, since the primary outcome relied on parental reporting of wheeze rather than a more definitive clinical diagnosis. However, the reduction in wheezing days beyond the period where treatment was received does appear to suggest RSV plays an active role in the mechanism underlying infant wheeze. Though palivizumab reduced recurrent wheezing by 10%,30 the number needed to treat is estimated to be 24.31 Although this has important implications for the cost-effectiveness of prophylaxis and further health economic analyses measuring all direct and indirect costs are now required, the costs of wheezing in the community are unlikely to be significant compared to current drug costs.

ACTIVE IMMUNISATION A key target in reducing the scale and severity of RSV LRTI among children worldwide is widespread active immunisation. However, this remains a challenge because of the difficulty in eliciting immunity in such young infants and problems with attenuation of live viral vaccine candidates to date.32 33 Furthermore, in this age group waning maternal antibody levels Murray J, et al. Arch Dis Child 2014;99:469–473. doi:10.1136/archdischild-2013-303764

are not sufficient to protect against disease, but can decrease vaccine immunogenicity.34 Considerable safety concerns about inactivated vaccine candidates exist, following the failure of a formalin-inactivated RSV vaccine trialled in the 1960s, which resulted in more severe RSV disease in those who had received the vaccine, and led to two infant deaths due to enhanced disease symptoms.13 35 36 MedImmune37 have developed some potentially promising RSV vaccine candidates. ‘MEDI-559’ has been tested in a phase I/2a multicentre, randomised, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, tolerability, viral shedding and stability of the vaccine.38 The trial included healthy infants aged 1 or 2 months of age irrespective of RSV serostatus and healthy RSV seronegative infants aged 5–23 months. Three doses were given, on a 0, 2 and 4-month schedule, with all enrolled infants being followed up for a full year to ensure they are monitored during an RSV season.38 Results of this trial are not yet publicly available. A phase I study of a single dose, recombinant live-attenuated RSV vaccine (ΔNS2 Δ1313 I1314L) is currently enrolling participants to evaluate vaccine safety and immunogenicity, initially among healthy RSV seropositive infants aged 12–59 months and then also among healthy seronegative infants aged 6–24 months.39 Another phase I study of a recombinant live-attenuated RSV vaccine (RSV ΔM2-2) is also recruiting participants.40 This trial will evaluate the safety of the vaccine in different target groups including adults, RSV-seropositive children aged 12–59 months and healthy RSV-seronegative infants and children aged 6–24 months. Though each of these candidate vaccines is in the early stages of development, these (and other candidate vaccines under development) may represent important advances in the population approaches to the prevention of severe RSV disease. The potential impact of an RSV vaccine in the Netherlands has been modelled, with the results suggesting it could be a cost-effective intervention, although in the absence of clinical trial data many different assumptions about the potential characteristics of an active vaccine had to be made in their analysis.41

ANTIVIRALS Trials of two new antivirals for RSV infection may provide promising new options to prevent severe LRT disease, while other pharmaceutical companies are in the early stages of developing specific antivirals targeting RSV. RSV infects host cells by fusing its envelope with the host cell membrane.42 Attachment is achieved by the actions of the fusion (F) glycoprotein and the G glycoprotein,43 so these proteins are popular targets in the quest to discover and develop new antiviral compounds against RSV. Preliminary trials are under way in healthy adults and infants. Broadly the strategic approach of the new antivirals is primarily focussed on previously healthy babies with early RSV infection, with the aim of secondary prevention of severe LRTI requiring hospital admission. A phase Ib randomised, doubleblind, placebo-controlled trial is currently recruiting, to evaluate the safety and tolerability and pharmacokinetics of the Gilead fusion inhibitor GS-5806 in healthy children <24 months of age, hospitalised with RSV infection, excluding higher risk infants with congenital heart disease or those requiring ventilation.44 Alios has also recently announced the phase 1 study of its new nucleoside analogue ALS-8176 targeting the RSV polymerase45 These antivirals (and others under development) may provide a viable, easily administered intervention for the secondary prevention of severe RSV LRTI among not just the highest risk infants but any infant presenting with RSV RTI in 471


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Review the community. At present there is a paucity of data reporting rates of progression to severe RSV LRTI requiring admission among infants with early mild RSV infection presenting in general practices and emergency departments. More evidence from observational studies to quantify the community burden of RSV illness is needed to consider the potential impact of these agents and to assist in phase 3 study design.

IMPLICATIONS FOR FUTURE RESEARCH As yet no studies have examined the impact of passive immunotherapy beyond the first year of life. Although there is still some debate surrounding the specific relationship between RSV infection in infancy and subsequent wheeze and asthma in child and early adulthood, longer follow-up of infants receiving immunoprophylaxis could help to improve our understanding of the association. Prospective cohort studies are now needed to examine the longer-term effects of palivizumab use on other clinical outcomes including wheezing, as well as asthma and mortality.18 Some evidence of the burden of RSV illness in resource poor countries exists, though this is rarely derived from active case ascertainment so is likely to underestimate incidence in settings with limited access to health services.1 It is estimated that 96% of RSV episodes occur in children living in developing countries, where 90% of the global population of children aged less than 5 years live.1 In the absence of an effective active vaccination or antiviral to prevent RSV LRTI at a population level, prevention efforts should also focus on reducing known environmental risk factors including smoking,46 overcrowded housing and improving hygiene practices to limit transmission among people caring for infants.12 23 The primary focus for reducing nosocomial RSV transmission, particularly in hospital settings, is encouraging good handwashing techniques or glove and gown use among healthcare professionals and those in contact with infected individuals.47 48 This is particularly important for high-risk infants in neonatal units.49 Greater emphasis should be placed on reducing modifiable risk factors for preterm birth including maternal smoking, alcohol consumption and illicit drug use in pregnancy, as well as improved management of chronic health conditions such as diabetes during pregnancy.

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CONCLUSION Almost all babies acquire RSV during infancy and previously healthy babies are not eligible to receive palivizumab. Since 99% of child deaths attributed to RSV occur in resource poor countries where expensive prophylaxis is not available or affordable, palivizumab has limited potential to impact on the current global burden of RSV LRTI. Two new antivirals are currently in phase I/II trials to test their effectiveness in preventing severe RSV LRTI and a range of candidate vaccines for active immunisation against RSV are also now in clinical trials. Until a safe and effective active immunisation against RSV infection is widely available, population level approaches to prevent severe RSV LRTI should continue to focus on reducing prenatal and environmental risk factors including prematurity, smoking and improving hygiene practices. Contributors JM wrote the first draft. All authors reviewed the literature, edited the manuscript and approved the final draft. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.

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Preventing severe respiratory syncytial virus disease: passive, active immunisation and new antivirals Joanna Murray, Sonia Saxena and Mike Sharland Arch Dis Child 2014 99: 469-473 originally published online January 24, 2014

doi: 10.1136/archdischild-2013-303764

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