Bronchiolitis is a common respiratory infection affecting children under two years old. It accounts for almost a fifth of all infant hospital admissions in the UK. Respiratory syncytial virus (RSV) causes about 80% of cases.
Infants with various cardio/respiratory conditions, immunodeficiencies and prematurity are at higher risk of severe bronchiolitis, which can result in an intensive care admission. RSV infection itself causes a lower respiratory tract infection (LRTI) and increases the risk of a secondary bacterial LRTI. It is also strongly associated with recurrent wheeze in childhood.
The impact of RSV infections
RSV infections have a significant impact on children, their families and health services. In the UK, conservative estimates suggest that each year, paediatric RSV infections result in 110,000 GP consultations, 75,000 A&E visits, 20,000 hospitalisations (including 900 PICU admissions), and 22 deaths.
Regarding annual treatment burdens, RSV infections are estimated to result in 11,000 children receiving nasogastric fluids, 3,500 IV fluids, 11,000 low-flow oxygen, 4,500 high-flow oxygen, 1,200 non-invasive ventilation, and nearly 6,000 receiving antibiotics.
Bronchiolitis in young children is estimated to cost £80 million annually in healthcare costs and productivity losses.
Effectively reducing or managing RSV infections in infants has received significant attention because of its widespread implications.
Vaccines vs immunoglobulins
Primary prevention of RSV infections has recently improved substantially through passive immunisation.
At present, two options exist:
- A monoclonal antibody to be given to infants
- Immunisation of pregnant women to build an antibody response, which is then transiently conferred to their newborn
What about active immunity – i.e., vaccinating infants?
There is nothing on the immediate horizon regarding an RSV vaccine for babies. Several vaccine technologies are approved for market or in phase three trials for immunising pregnant women or the elderly. Five vaccine candidates are currently being developed for children, all in phase two trials.
Figure 1: RSV vaccine and prophylaxis candidates (Jan 2024). Reproduced from the PATH website at www.path.org, May 2024.
Monoclonal antibodies
The mainstay at the moment: Palivizumab
This monoclonal antibody binds to the RSV F protein, preventing it from fusing with the host cell membrane. Palivizumab is well established, with many trials demonstrating its effectiveness in protecting premature babies against RSV infections and their associated complications. It is given intramuscularly (IM) monthly for 6 months, with courses commencing at the start of the RSV season. It is currently given to infants most at risk of severe bronchiolitis.Â
Its effectiveness has been well demonstrated. The IMpact-RSV study, a double-blind placebo-controlled RCT on infants with a gestation under 35 weeks, showed that palivizumab reduced hospitalisation by 55%. Additionally, a double-blind, placebo-controlled RCT in late preterms, the MAKI trial, showed that palivizumab reduced days spent wheezing by 60% compared with placebo and reduced episodes of recurrent wheeze by 10% even after the course finished.Â
The new therapy: Nirsevimab
Nirsevimab also binds to the RSV F protein and is given intramuscularly. However, its half-life averages 70 days, meaning one dose provides protection for up to 6 months. From a practical perspective, this increases appeal because it enables a wider rollout than palivizumab.
Nirsevimab antibody levels are higher at 1 year post-vaccination than anti-RSV antibodies of infants who were infected by RSV.
The HARMONIE trial was an RCT of over 8,000 infants with a gestation of ≥29 weeks. Nirsevimab had an 83% efficacy in preventing hospitalisations with RSV-associated LRTIs, with severe RSV-associated LRTIs reduced by 76%. Importantly, the HARMONIE trial excluded patients eligible to receive palivizumab, allowing a wider population of infants not currently eligible for RSV prophylaxis to be studied.
The MELODY study, a placebo-controlled RCT, complements this by evaluating nirsevimab in late-preterm (gestation ≥35 weeks) and term infants who did not meet criteria for palivizumab. It showed that nirsevimab was 75% effective in preventing RSV-associated LRTIs and 62% effective in preventing admissions with RSV-associated LRTIs.
Maternal Vaccine
The RSV prefusion F protein-based vaccine (RSVpreF)
This is an IM injection given to pregnant women. It needs to be given at least 2 weeks before delivery to take effect. It works by stimulating the production of neutralising antibodies. These then bind to the F protein before it attaches to cells (Pre-F). Newborn protection occurs through transplacental transfer of maternal antibodies, providing passive immunity for the first six months of life. This covers the period when newborns are most vulnerable.Â
The MATISSE study, a placebo-controlled RCT, enrolled over 7,000 pregnant women in 18 countries and four RSV seasons. The primary endpoints examined vaccine efficacy at preventing severe (hospitalisation) and non-severe (requiring a physician review) RSV-associated LRTIs requiring medical attention from 90 to 180 days after birth. The study team defined success as the lower limit of the vaccine efficacy confidence interval being at least 20%.Â
The study found vaccine efficacy of 82% and 69% for preventing severe LRTIs at 90 and 180 days, respectively, and 57% and 51% for non-severe LRTIs at 90 and 180 days. The study team met its success criteria for preventing severe LRTIs but not for non-severe LRTIs. While the statistical definition of success was not met at 90 days for non-severe LRTIs, the data, regardless, show a clinically significant impact of the vaccine in both outcomes at all stages.Â
Real-world data
Several examples of real-world observational data are emerging from countries which have rolled out RSV prophylaxis, showcasing its effectiveness. One example is from the Spanish province of Galicia. They achieved a 92% uptake of nirsevimab.
It was given to 3 cohorts:
- Newborns on their first day of life if born during RSV season
- Infants aged <6 months during the RSV season
- High-risk infants aged 6-24 months during the RSV season
They found that nirsevimab was 82% effective overall in reducing RSV-associated LRTIs, 87% effective in preventing severe RSV-related LRTIs requiring oxygen, and 66% effective against all-cause hospitalisations. This yields an NNT of 25 to prevent one RSV-associated hospitalisation.Â
Observational data from the USA also show the impact RSV prophylaxis can have. The CDC recommended nirsevimab in August 2023 and maternal RSV vaccines in September 2023, advising that infants should be protected by one of these methods. Their observational data indicate that babies who received nirsevimab (and did not have mothers who took the RSV vaccine) had RSV-associated admissions reduced by 90%. Similar data on the impact of the maternal vaccine in the USA has yet to be published.
Some points to consider
There have been no head-to-head comparisons between nirsevimab and the maternal RSV vaccine, so the primary endpoints of the studies mentioned are not directly comparable.
The half-life of maternal antibodies is approximately 30 days, compared to nirsevimab’s 70 days. However, nirsevimab is a monoclonal antibody to one specific antigenic site. This contrasts with the maternal vaccine, which produces a polyclonal response with affinity maturation
Babies who are born prematurely would have a reduced amount of maternal antibodies transferred and would still likely require a monoclonal antibody postnatally. Most transplacental antibody transfer occurs near term.
Where does this leave the UK?
The JCVI reviewed the evidence for monoclonal antibodies and maternal vaccination to protect infants against RSV. In late 2023, they concluded that they support a year-round, universal monoclonal antibody or maternal vaccination programme.
Following the JCVI’s decision, parents and doctors are now waiting on the UK government to provide the funding and infrastructure to roll out an immunisation programme for infants in time for the 2024 RSV season. A petition led by the RCPCH was signed by over 2000 paediatricians.
The Treasury and Department of Health must now decide quickly to ensure appropriate procurement and give primary care and paediatric departments enough notice to set up the necessary service provisions to implement the vaccine roll-out in time for September 2024.
Delays in decision-making could be immensely costly for children and health services alike, given we now have highly effective interventions within reach that could change the lives of many infants and significantly reduce acute paediatric admissions by turning RSV LRTIs into a preventable infection for many.
References
Ares-Gómez et al. Effectiveness and impact of universal prophylaxis with nirsevimab in infants against hospitalisation for respiratory syncytial virus in Galicia, Spain: initial results of a population-based longitudinal study. Lancet Infect Dis. 2024 Apr 30:S1473-3099(24)00215-9. doi: 10.1016/S1473-3099(24)00215-9.
Blanken et al. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med. 2013 May 9;368(19):1791-9. doi: 10.1056/NEJMoa1211917.
Drysdale SB et al. Nirsevimab for Prevention of Hospitalizations Due to RSV in Infants. N Engl J Med. 2023 Dec 28;389(26):2425-2435. doi: 10.1056/NEJMoa2309189.
Fusco et al. The burden of respiratory syncytial virus: Understanding impacts on the NHS, society and economy. RAND Corporation, 2022. https://www.rand.org/pubs/research_reports/RRA1895-1.html.
Green et al. Admission to hospital for bronchiolitis in England: trends over five decades, geographical variation and association with perinatal characteristics and subsequent asthma. Arch Dis Child. 2016 Feb;101(2):140-6. doi: 10.1136/archdischild-2015-308723. Epub 2015 Sep 4.
Hammitt LL at al. Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants. N Engl J Med. 2022 Mar 3;386(9):837-846. doi: 10.1056/NEJMoa2110275.
The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group. Pediatrics. 1998 Sep;102(3 Pt 1):531-7.
JCVI. Respiratory syncytial virus (RSV) immunisation programme for infants and older adults: JCVI full statement, 11 September 2023. https://www.gov.uk/government/publications/rsv-immunisation-programme-jcvi-advice-7-june-2023/respiratory-syncytial-virus-rsv-immunisation-programme-for-infants-and-older-adults-jcvi-full-statement-11-september-2023 September 2023.
Kampmann B et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. N Engl J Med. 2023 Apr 20;388(16):1451-1464. doi: 10.1056/NEJMoa2216480.
Moline et al. Early Estimate of Nirsevimab Effectiveness for Prevention of Respiratory Syncytial Virus-Associated Hospitalization Among Infants Entering Their First Respiratory Syncytial Virus Season – New Vaccine Surveillance Network, October 2023-February 2024. MMWR Morb Mortal Wkly Rep. 2024 Mar 7;73(9):209-214. doi: 10.15585/mmwr.mm7309a4.
RCPCH. Over 2,000 paediatricians and healthcare professionals call on Government to introduce game-changing vaccine. https://www.rcpch.ac.uk/news-events/news/over-2000-paediatricians-healthcare-professionals-call-government-introduce-game March 2024.
https://www.path.org/our-impact/resources/rsv-vaccine-and-mab-snapshot/
