Independent report

Respiratory syncytial virus (RSV) immunisation programme for infants and older adults: JCVI full statement, 11 September 2023

Updated 11 September 2023

Introduction

The Joint Committee on Vaccination and Immunisation (JCVI) is an expert scientific advisory committee which advises the UK government on matters relating to vaccination and immunisation.

JCVI has been monitoring products in development for the prevention of respiratory syncytial virus (RSV) disease for several years. Since January 2023, JCVI has been actively reviewing the latest evidence on immunisation products in the late stages of development or which are newly licensed which could protect both newborns or infants and older adults against RSV infection and disease. A series of meetings of the JCVI RSV subcommittee have taken place in 2023. JCVI has reviewed evidence from manufacturers on the efficacy, safety and duration of protection of these immunisation products alongside clinical and epidemiological data on the burden of RSV in infants and older adults. JCVI has also considered programme delivery including ensuring high uptake in different population groups and clinical settings. Modelling of the impact and cost effectiveness of potential immunisation strategies by the London School of Hygiene and Tropical Medicine (LSHTM) has been used to inform JCVI’s advice, along with second opinion modelling by other expert academic groups. Cost effectiveness is a key factor in JCVI’s considerations to ensure that the finite resources of the health service are used to maximise the health of the population.

JCVI recognises that there is a significant burden of RSV illness in the UK population and unmet public health need which has a considerable impact on NHS services during the winter months. Following the 7 June 2023 meeting, JCVI issued a short statement of its advice on a RSV immunisation programme. JCVI advised that a RSV immunisation programme that is cost effective should be developed for both infants and older adults. This comprehensive statement provides the detail on the evidence considered and the key discussions and conclusions of the committee.

Background

RSV is a common respiratory virus that usually causes mild, cold-like symptoms. Globally, RSV infects up to 90% of children within the first 2 years of life and frequently reinfects older children and adults. For most people, RSV infection causes a mild respiratory illness. Babies under one year of age and the elderly are at the greatest risk of hospitalisation with more severe RSV. The clinical significance of RSV in infants is that it can cause bronchiolitis which leads to the inflammation of the small airways and significant breathing difficulties. In older adults, RSV is an important cause of acute respiratory illness, particularly those living with frailty and co-morbidities.

There is a significant burden of RSV illness in the UK population which has a considerable impact on NHS services during winter months. A typical RSV season in the UK starts in October, peaks in December and declines by March. In recent years, the RSV season has been interrupted by control measures against the COVID-19 pandemic which has resulted in unseasonal RSV activity; this included significant rebound activity in summer 2021 and summer 2022 and a very prolonged period of virus activity in 2022. RSV accounts for approximately 33,500 hospitalisations annually in children aged under 5 years old. It is a leading cause of infant mortality globally, resulting in 20 to 30 deaths per year in the UK. RSV-related mortality in low-income countries is considerably higher, and in some analyses is the second commonest cause of death (after malaria) in infancy.

The burden of RSV in older adults is less well understood and considered to be underestimated by existing routine surveillance. Sharp (reference 1) estimated the average annual hospital admission rate in England related to RSV infection to be 71 and 251 per 100,000 for those aged 65 to 74 and those over 75 years, respectively. Fleming (reference 2) estimated RSV mortality rates in the UK as high as 58 per 100,000 and 178 per 100,000 in high-risk groups and 9 per 100,000 and 133 per 100,000 in low-risk groups aged 65 to 74 and those over 75 years, respectively. Hardelid (reference 3) estimated in each winter season there are 1,200 deaths in persons aged 45 to 74 years and 4,000 deaths in those aged over 75 years.

Tables 1 and 2 show data from the Severe Acute Respiratory Infection (SARI-Watch) surveillance system on the cumulative incidence of RSV and influenza hospitalisations by season and age group.

Notes on table 1 and table 2:

• ‘age group’ is the sum of weekly rates from week 40 to week 20 in the following year
• data for adults over 65 years of age was split into 3 categories: 65 to 74 years, 75 to 84 years and over 85 years from October 2020

Table 1: cumulative incidence per 100,000 population of RSV hospitalisation by season and age group in England

Years	Under 1 year of age	Under 5 years of age	Over 65 years of age	Over 75 years of age
2022 to 2023	1,055.99	295.34	42.91	65.15
2019 to 2020	2,088.55	549.94	53.79	-
2018 to 2019	1,972.40	500.07	42.13	-
2017 to 2018	2,040.09	544.99	33.51	-

Table 2: cumulative incidence of influenza hospitalisation per 100,000 population by season and age group in England

Years	Under 1 year of age	Under 5 years of age	Over 65 years of age	Over 75 years of age
2022 to 2023	305.51	200.83	180.60	275.52
2019 to 2020	178.77	109.99	94.62	-
2018 to 2019	199.69	154.58	88.89	-
2017 to 2018	135.49	91.81	240.70	-

Programme to protect neonates and infants

Clinical studies

The committee reviewed data from 2 ongoing clinical studies (Stop RSV and BronchStart) to assess the burden of RSV.

Stop RSV (reference 4) is an observational surveillance study designed to assess the number of children with respiratory symptoms and laboratory confirmed RSV swabs under 3 years of age in primary and secondary or tertiary healthcare settings in Merseyside and Bristol (United Kingdom). The study also seeks to determine the health economic burden to the family and healthcare. The study covers the geographical areas of Bristol, Chester and Liverpool and has 13 primary care sites and 2 secondary and tertiary care sites. The study aims to improve the understanding of the burden of RSV in infants and young children to provide data to inform future vaccination strategies. Interim data for 723 children recruited up to August 2022 were presented:

• 48% of participants were less than one year old and 18% were premature (less than 37 weeks)
• RSV positivity was 48% and highest in those aged under 6 months (60%) with a peak of 71% positivity in the month of November
• 35% of RSV positive patients had a co-infection, with rhinovirus the most commonly identified
• 92% of children attending hospital had attended a previous primary care appointment
• health economic analyses were pending based on EQ 5D 3LE (questionnaire) and paediatric quality of life (PedsQL) measurement

BronchStart (reference 5) is a prospective multicentre cohort study. Paediatric emergency departments (PED) within PERUKI (Paediatric Emergency Research in the UK and Ireland) submit data on all children under 2 years of age who visit a PED with symptoms of an acute lower respiratory tract infection (LRTI) (diagnosed as bronchiolitis, LRTI or first episode of acute wheeze). Follow up information is submitted 7 days later, and study data is made available on a live online dashboard.

17,914 attendances were captured from the beginning of May 2021 to the end of April 2022. 16.8% of cases had a comorbidity, 11% were premature (less than 37 weeks) and 1.5% had congenital heart disease. The most common diagnosis was bronchiolitis, followed by first episode of wheeze and LRTI at 90%, 10% and 8.5%, respectively. RSV was identified in 48.7% of children aged 0 to 11 months and 27.4% in those aged 12 to 23 months.

Prematurity was a risk factor for all outcomes; admission, low flow or high flow oxygen, invasive mechanical ventilation, breathing support (continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP), or admission to a high dependency unit or paediatric intensive care unit). Although congenital heart disease numbers were small this was also a risk factor for all outcomes. The proportion of patients with a comorbidity increased as the level of care increased, going from emergency department to the highest level of care in a paediatric intensive care unit (PICU), with 49.7% of cases admitted to a PICU having one or more comorbidities. Overall, those with no comorbidity made up the highest proportion for emergency department care (80%).

Using the results generated from the study, estimates were made of the national burden attributable to RSV using Hospital Episode Statistics data for the mean admissions from 2016 to 2019. Results indicated RSV infections would account for the following number of infants less than 12 months old receiving the following treatments:

• nasogastric fluids: 11,000
• IV fluids: 3,500
• low flow oxygen: 11,000
• high flow oxygen: 4,500
• CPAP or BiPAP: 1,188
• antibiotic prescriptions: 5,725

The study also collected data from Public Health Scotland on uptake of vitamin K in newborns which might be considered as a proxy measure for the potential uptake of nirsevimab (monoclonal antibody) if administered soon after birth. Uptake of vitamin K was approximately 95% with no difference by ethnicity and socio-economic status.

Manufacturer products and data

Sanofi, in partnership with AstraZeneca, have developed a new long-acting monoclonal antibody (MAB) Beyfortus® (nirsevimab) for passive immunisation against RSV infection and disease. Nirsevimab was licensed by the Medicines and Healthcare products Regulatory Agency (MHRA) on 9 November 2022.

The committee has reviewed data presented by Sanofi from their clinical trials. Top line results from the phase 3 MELODY trial (reference 6) were:

• efficacy against medically attended RSV-associated LRTI was 76.4% (95% CI, 62.3 to 85.2)
• efficacy against hospitalisation for RSV-associated LRTI was 76.8% (95% CI, 49.4 to 89.4)
• efficacy against very severe medically attended RSV-associated LRTI was 78.6% (95% CI, 48.8 to 91.0)

An exploratory analysis based on a small number of cases from the MELODY South Africa cohort (primary cohort) from day 151 to day 361 indicated there was potentially protection beyond 150 days with an efficacy of 51% (95% CI, −52.0 to 84.0) for medically attended RSV-LRTI.

Interim results provided from the phase 3b HARMONIE study were also in line with the phase 3 clinical trial results and showed:

• efficacy against hospitalisation for RSV-associated LRTI was 83.2%
• efficacy against severe RSV disease was 75.7%
• efficacy against all cause LRTI hospitalisation was 58.0%

Pfizer have developed a bivalent RSV prefusion F maternal vaccine candidate, RSVpreF, which has undergone clinical trials and has a potential licensing timeline in 2023.

The committee reviewed data presented by Pfizer from their phase 3 clinical trial (reference 7). The 2 primary efficacy end points were RSV-associated medically attended LRTI and medically attended severe LRTI in infants within 90, 120, 150 and 180 days after birth:

• efficacy against medically attended severe LRTI was 81.8% (99.5% CI, 40.6 to 96.3) and 69.4% (99.5% CI, 44.3 to 84.1) within 90 and 180 days after birth, respectively
• efficacy against medically attended LRTI was 57.1% (99.5% CI, 14.7 to 79.8) and 51.3% (99.5% CI, 29.4 to 66.8) within 90 and 180 days after birth, respectively

The committee noted that data presented to the United States Food and Drug Administration (US FDA) on vaccination relatively early in pregnancy (before week 28 gestation) was less compelling (interim analysis efficacy medically attended LRTI 55.1 (−26.6, 86.0), 20.7 (−44.6, 57.0); efficacy severe medically attended LRTI 64.6 (−19.4, 91.8), 43.7 (−24.6, 75.8) at 90 and 180 days respectively). Data from a vaccination study in non-pregnant women also indicates a possible blunting of the immune response to some components of the pertussis vaccine which suggests that the 2 vaccines should ideally not be co-administered in pregnancy though the clinical significance of this effect was unknown.

Safety

An important issue that concerned the subcommittee in May 2023 was a potential safety signal for 2 developmental maternal vaccines. The clinical trial for the GSK maternal vaccine candidate reported a 1.5 increase in risk of preterm births in the vaccinated cohort. The product was withdrawn from further development because the preterm births from the intervention arm were associated with a 2-fold higher risk of mortality. Stratification by economic region showed that the increase in preterm births was only observed in low income countries (LICs) and not in high income countries (HICs).

The published Pfizer results also showed an excess of preterm births in the vaccinated group. A more detailed scrutiny of the Pfizer data by the committee showed no excess of preterm birth in HIC, with the excess confined to the study sites in the upper middle income countries (UMIC), South Africa and Brazil. Further scrutiny showed that gestational age at vaccination was similar between the 2 income settings and that this was unlikely to be the reason for the observed disparity in premature births. Further plots of gestational age at vaccination against gestational age at birth stratified by income setting did not show a relationship between time of vaccination and prematurity.

The committee is relatively reassured that there is not an obvious signal of preterm births in HICs. There is not a full understanding of the cause of the signal in UMIC settings and whether this was driven by data from South Africa alone or South Africa and Brazil. No difference in neonatal deaths was observed between intervention and control groups, and in fact deaths were lower in the vaccinated group compared with the control group. Potentially, vaccinating later in pregnancy might mitigate any potential risks of prematurity. The committee notes that in the trial of the Novavax maternal RSV vaccine candidate, which is also an F protein vaccine, no signal for preterm births was observed and the study included South Africa among its study sites.

The Pfizer maternal vaccine candidate was approved by the US FDA on 21 August 2023. The committee notes that FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted that the available data supports the efficacy and safety of the unadjuvanted bivalent RSV prefusion F vaccine candidate RSVpreF (Abrysvo). The committee voted 14 to 0 on effectiveness and 10 to 4 on safety.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended granting a marketing authorisation in the European Union (EU) for Abrysvo.

Subject to MHRA approval, the UK regulator responsible for vaccine safety which will consider the safety profile of the product as part of this process, JCVI is reassured that the safety data for the Pfizer vaccine does not raise significant concerns on its potential use in an RSV programme to protect newborns and infants.

Comparison of the phase 3 clinical trials for nirsevimab with RSVpreF

At the RSV subcommittee in May 2023, expert opinion was sought on the comparison of the above RSV vaccine trials end points as well as an immunological perspective with regards to assay comparisons and persistence of protection. The key points noted were:

• comparison of the 2 phase 3 clinical trials showed that background attack rates in the control groups were higher for RSV medically attended LRTI and RSV hospitalisation in the MELODY trial (nirsevimab) compared with the MATISSE trial (RSVpreF maternal vaccine). The seasonal recruitment to MELODY (nirsevimab) versus year-round recruitment to MATISSE (maternal vaccine), together with interruptions in RSV transmission during the pandemic and the different populations included might all have contributed to the difference in background rates
• both studies required cases to be confirmed RSV positive by PCR while the Pfizer trial also required some respiratory signs or symptoms. Median age at immunisation was 2.6 months in the MELODY trial, ranging from 0.03 to 11 months of age, meaning that on average infants were protected from 2.6 months of age. In the maternal vaccine trial, babies were born with maternal antibody and therefore protected from birth. The primary end points for RSV medically attended LRTI were considered similar between the trials. However, the definitions for severe or very severe LRTI were considered very different. In the secondary end points for hospitalisation, MELODY included LRTI hospitalised cases plus hospitalised cases with any respiratory illness due to RSV while Pfizer included all RSV confirmed hospitalised illness but not all met the severe LRTI criteria. Therefore, the secondary end points of hospitalisation were not strictly comparable but there was an exploratory analysis in the MELODY trial which had similar criteria to the secondary end point on the Pfizer trial. The HARMONIE definition for hospitalisation was not comparable to the definition used in the MELODY trial and nor with the hospitalisation definition in the Pfizer trial. The definitions for hospitalisation for severe RSV were also not comparable between HARMONIE, MELODY and the Pfizer trials

The committee also noted that:

• there were no head-to-head data for the 2 products on protection using the same end points nor on durability of protection
• there was no harmonisation of the neutralisation assays used in each trial for a direct comparison of the observed kinetics of antibody decay
• no correlates for protection were identified (as yet)
• both products were effective at preventing infection over 6 months which would be adequate to cover the duration of the RSV season, but it was difficult to assess what the effectiveness might be year-round
• premature birth would compromise the amount of maternal antibody available to the infant, hence supplemental MAB would likely be needed for the most premature infants
• for nirsevimab, infants just below the 5kg weight cut off might be disadvantaged if given the lower 50mg dose compared to infants weighing 5kg and over who receive the 100mg dose, as dose per kg is likely to relate to the duration of protection
• neutralising titres in infants born to vaccinated mothers remained high through to 6 months and above the levels seen for palivizumab which are known to provide protection against ICU admission
• durability of nirsevimab antibody also showed waning but remained consistently above antibody levels of infants naturally infected by RSV over a 12-month period
• the extended half-life of nirsevimab was 68 days and that of the maternal antibody was between 28 and 35 days
• the monoclonal antibody was very specific to one antigenic site whereas the maternal vaccine part of the immune response was driven by the mother’s immune memory to RSV and generated a polyclonal antibody response which is likely to be affinity matured
• based on the experience with other maternal vaccines (for example, pertussis) the maternal vaccine would need to be administered at least 2 weeks before birth to achieve satisfactory antibody levels in the baby
• vaccinating early in pregnancy might also improve avidity of antibody

In summary, the committee’s view is that both products appear to give at least 150 days protection, there is no correlate of protection, there is considerable uncertainty about efficacy beyond 150 days, and the clinical trials for the products are not directly comparable because they use different end points or case definitions and assays, and there are no head-to-head studies.

Modelling

Modelling of the impact and cost effectiveness of potential immunisation strategies was undertaken by LSHTM to inform JCVI’s advice. Second opinion modelling was requested by JCVI for assurance because of the financial and operational implications of a large scale passive or maternal programme.

Modellers at LSHTM developed a large dynamic transition model to try and characterize the transmission of RSV in England and Wales (reference 8). This was fitted to respiratory data mart system data from between 2010 and 2017. An estimate of the burden from a synthesis of published studies was made to calculate quality adjusted life year (QALY) loss for a number of different health outcomes including symptomatic cases, hospital admissions and deaths. Annual estimates for GP hospitalizations and hospital bed days were used to estimate healthcare costs.

The model has been used to provide published estimates on the cost effectiveness of a nirsevimab programme (reference 9).

The committee also noted that the manufacturer Sanofi had raised concerns over the LSHTM model with regards to the latter’s exponential decline in efficacy. This was a key point highlighted by the manufacturer which would impact on the cost effectiveness of the product. The burden estimates used in the manufacturers model, based on Taylor (reference 10), also contrasted with the estimates used in the LSHTM model which were based on Reeves (references 11 and 12). The LSHTM model did not include outpatient follow up visits and A&E visits and had a much lower estimate for primary care visits. The Sanofi model also included primary care visits related to recurrent wheezing, but the committee considered that there was insufficient evidence to confirm RSV as the primary cause of this condition for inclusion in the LSHTM model. It was noted that both models gave roughly similar results in terms of impact if the LSHTM efficacy waning was used in the Sanofi model. However, the Sanofi model base case with no waning of vaccine efficacy over 150 days predicted 65% of hospitalisations could be prevented, compared with the LSHTM model using exponential waning prediction of 28% hospitalisations prevented.

After reviewing the model at the RSV subcommittee in January 2023, including the points raised by the manufacturer, it was agreed that the LSHTM model was conservative in its estimates and should be updated with more recent additional data. Further work was initiated to assess the impact and cost effectiveness of a maternal programme based on the published estimates of efficacy from the Pfizer MATISSE trial. The updated model was presented at the May 2023 RSV subcommittee and the June 2023 JCVI meetings. The main findings of the work presented at the June meeting are outlined below.

In those aged less than one year, the annual incidence of the different outcomes included in the model were approximately:

• 270,000 symptomatic cases
• 108,000 GP consultations
• 74,000 A&E visits
• 20,000 hospitalised cases
• 900 ICU admissions
• 22 deaths

For the maternal product 2 options were simulated: a seasonal programme between July and the end of December (assuming an even distribution of uptake between 28 to 36 weeks gestation in pregnancy) and a year-round programme. Mothers were vaccinated during a gestational window and acquired protection and then, within the timeframe of maternal protection, newborns were protected. Coverage was estimated to be 60% based on uptake data for maternal pertussis vaccination.

The duration of protection was modelled to wane over time with an efficacy similar to the published estimates for LRTI and severe LRTI for 6 months. Due to the lack of available data beyond 6 months, protection was assumed to wane so that by 360 days approximately 10% of babies still had protection.

Three scenarios were modelled for the monoclonal programme with a 90% uptake: seasonal from September to February; seasonal with catch up for children aged less than 6 months at the beginning of the season; and a year-round birth dose offer from March to February. Duration of protection was modelled to fit the published estimates for the first 150 days and beyond that point was assumed to wane.

The model showed a small increase in incidence of RSV infections in those aged over one year in the following season as they were no longer protected by the monoclonal antibody. The model did factor in some innate immunity effects and if a child was not infected in the first year, then they were more susceptible in the second. This effect also applied to the maternal vaccine but to a smaller degree. The model also included QALY losses in mothers due to non-medically attended symptomatic infection. This was a small QALY loss for the individual but large in total due to the numbers involved and there were also indirect effects related to prevention of RSV transmission from mothers to other adults.

Cases averted and the QALY gains for each programme were estimated and the healthcare cost savings determined. Comparison of impact was presented in terms of QALYs and costs averted and the numbers needed to vaccinate (NNV), a measure of efficiency, for seasonal and year-round maternal and seasonal, seasonal with catch up and year-round monoclonal programmes. The biggest impact was seen with the seasonal with catch up and year-round monoclonal programmes while the most efficient in terms of NNV were the seasonal programmes, both maternal and monoclonal (without catch up). For both products, the estimates for waning of protection beyond the published data are very uncertain and could have major impacts on their cost effectiveness.

Cost effectiveness analysis for the different strategies, supplementary to the current palivizumab programme, were presented as the willingness to pay combined cost of purchasing and administration (CCPA) at £20,000 per QALY (50% certainty). The main findings were:

• if both products were priced low the monoclonal product was the best option because of its bigger impact
• if the monoclonal product was priced high and the maternal vaccine low, then a maternal programme was the best option
• if the monoclonal product was priced low and the maternal vaccine high, then a monoclonal programme was the best option
• if they were both expensive, then it was difficult to discern which would be the better option and above a certain maximum price neither were cost effective
• there was only a small cost differential in the maximum CCPA price between a seasonal maternal programme and seasonal monoclonal programme
• the willingness to pay for a maternal year-round programme was approximately half that compared with that for a seasonal maternal programme
• the willingness to pay for a seasonal monoclonal programme was higher compared with that for a seasonal with catch up monoclonal programme
• the CCPA for a year-round monoclonal programme was much lower than that for a seasonal monoclonal programme
• using a 70% coverage for both the maternal and monoclonal programmes showed that threshold prices did not change

In summary the most cost-effective programmes were seasonal for either product followed by seasonal with catch up for the monoclonal product and then year-round programmes for either product. If the products were priced similarly then it was difficult to differentiate between the 2, based on cost effectiveness.

Comparison with second opinion model

University of Antwerp (UA) conducted the second opinion modelling using a model developed for the REspiratory Syncytial virus Consortium in EUrope (RESCEU) project. UA has conducted work on the cost effectiveness of monoclonal antibody and maternal immunization against RSV in infants (references 13 and 14) as well as contributing to a model comparison study which included LSHTM’s transmission dynamic model (reference 15).

The second opinion model was presented at the May 2023 RSV subcommittee. The second opinion model was slightly more conservative in its estimates but in general, there was good agreement between the first and second opinion modelling considering differences in burden of disease estimates used and model structures (transmission dynamic modelling versus static models). Based on the discussion, further adjustments to the models were required in time for the JCVI meeting on 7 June 2023.

A comparison of the UA and LSHTM models showed that the cost effectiveness results in terms of the CCPA compared well for the seasonal monoclonal programme but were slightly lower compared with the LSHTM results. The second opinion model had higher hospitalisation costs and QALYs lost per RSV episode (including non-medically attended symptomatic cases, GP consultations and hospitalisation) were also slightly higher compared with the LSHTM model. In the base case, efficacy was also modelled differently as the second opinion model was a static design and modelled the full efficacy over 150 days for the monoclonal followed by a sudden drop, whereas the LSHTM model assumed some efficacy beyond this period. Similarly, the published estimates for the maternal vaccine efficacy end points for the 3 month and 6 month period were used followed by a drop to zero efficacy after 6 months whereas the LSHTM modelled waning efficacy over that period. Alternative assumptions on various aspects (such as alternative efficacy estimates including both exponential and stepwise waning beyond 6 months), were also explored by the second opinion and presented in the May 2023 RSV subcommittee meeting but did not change the overall conclusions.

The LSHTM baseline disease burden was more than twice as high compared with the UA estimates, as was the number of GP consultations in those aged less than 2 months. No A&E estimates were included in the UA model. Hospitalisation estimates were similar for the 2 models but only the LSHTM model included deaths which, although small in number, accounted for a large QALY loss. Taking these differences into account meant the total QALY losses estimated by LSHTM were approximately double that of the UA model, but in the LSHTM model treatment costs were lower in those aged 0 to 2 months and higher for those aged 3 to 5 months and 6 to 11 months.

The QALY losses and treatment costs therefore tended to balance out between the 2 models. However, the LSHTM model was a transmission dynamic model and therefore also estimated a QALY gain in the vaccinated mothers and some additional indirect effects, both positive and negative. If these additional effects were excluded in the LSHTM model the maximum CCPA or willingness to pay for the maternal vaccine decreased and the maximum CCPA for the monoclonal increased; the LSHTM results were then very similar to those of the UA model. Overall, when considering the impact during the first 6 months of life in the dynamic model the LSHTM results aligned with the second opinion model.

Considerations

At the JCVI meeting on 7 June 2023, the committee agreed that overall, the modelling had provided the necessary information to support providing advice from an impact and cost effectiveness perspective and helped identify the important areas where more data is needed. The second opinion modelling had been very useful in ensuring the modelling was robust, and it was reassuring that the results were similar between the 2 models considering the different approaches used.

There were still significant uncertainties, particularly around the differences in the programmes which made it difficult to have a preference for one product over the other. There were some potential theoretical benefits in the monoclonal product as it may have a slightly higher efficacy, but this remains uncertain.

The question was raised whether existing and future maternal vaccines for other diseases (for example pertussis, influenza, COVID-19 and group B streptococcus (GBS)) might make maternal vaccination a crowded space. On the horizon was a potential maternal vaccine against GBS and additional prevention of stillbirths caused by GBS might raise the acceptability of maternal vaccination. Acceptability, scheduling to confer optimal protection, and co-administration will require careful consideration and planning in anticipation of potentially more vaccines being added to the maternal vaccination schedule.

The committee agreed that it did not prefer one product over the other and that, subject to licensure of the maternal vaccine, it was likely to come down to a tender process with the 2 products competing against each other if that was the policy decision.

There are also major operational differences between the 2 products in how they might be delivered which needed consideration by the committee. At the February 2023 JCVI meeting, the committee had agreed that both products (monoclonal antibody and maternal vaccination) could potentially be further assessed by a service type evaluation in selected sites or regions. However, there are major challenges in implementing different modes of delivery at scale and operationally the pilot approach with different types of delivery could be problematic. Similarly, regular switching of products from one year to the next would also be difficult to operationalise and communicate to healthcare providers and the public.

The committee also agreed that the anticipated uptake rate was an important factor, and that the uptake of vitamin K given to infants may not be a good example on which to base the anticipated uptake rate of a new monoclonal vaccine product. The level of uptake for a maternal programme was also uncertain. Therefore, it would be useful to assess the realistic potential uptake rate for the monoclonal product in a small study that would be relatively easy to organise. In addition, in January 2023 the RSV subcommittee agreed that attitudinal research on the acceptability for both the public and healthcare workers of a passive immunisation programme and a maternal programme was necessary. At the June 2023 JCVI meeting it was noted that UKHSA attitudinal work was in progress to better understand the acceptability of the 2 products.

All of the programmes were potentially cost effective and had a roughly similar impact, with some advantages and disadvantages and what was operationally the most straightforward to deliver could influence the eventual programme selected. NHS England indicated that although they could support whatever operational delivery the committee advised, a year-round programme was simpler to deliver. Year-round delivery would be most effective if the duration of protection lasted significantly longer than 150 days. Longer term protection data was expected from the previous trials and should help clarify the present uncertainty of the level of protection beyond 6 months.

The merits of having both products in an RSV programme in different parts of the UK was considered as a way of assessing the options in practice but this was deemed not to be practical. In terms of a seasonal with catch up for the monoclonal programme, a July to February programme would be easier to implement than a catch up within the season September to February. A seasonal maternal programme as modelled would take place from July to the end of December.

In summary, the committee agreed at present there was a preference for a year-round programme of either vaccine or monoclonal antibody but that a seasonal programme was also an option. This allows the potential for a competitive tender between the products for both a year-round and a seasonal programme basis. It was noted that the advice for a maternal programme was subject to authorisation of the vaccine.

RSV passive immunisation programme

At the JCVI meeting on 1 February 2023, the committee advised that palivizumab should be replaced by nirsevimab for the currently eligible cohort because of its extended half-life and high efficacy with only one dose required during the season compared with monthly doses for palivizumab. The committee noted that it should be a simple decision to switch to nirsevimab as long as it is no more expensive than palivizumab for the current groups without requiring further modelling; it was for specialised commissioning to work towards replacing palivizumab with nirsevimab this year.

JCVI also discussed augmenting the current groups eligible for palivizumab because there are other clinical risk groups who may be at similar risk of severe RSV infection. For example, the secretariat had received correspondence about young children with spinal muscular atrophy (SMA) type 1 who were considered to be at particular risk and potentially could be included in the eligible cohort based on clinical judgement. The Green Book allows for clinical discretion to include individuals who are deemed to be at equivalent risk, such as SMA. However, it was noted there was no easy system for obtaining RSV vaccination using clinical judgement in the NHS. Specialised commissioning had indicated that the issue of clinical discretion was problematic and difficult to implement via the current system and that there were concerns about inconsistencies and inequalities of uptake. Identifying specific eligible cohorts is a much more effective way of ensuring access to passive immunisation against RSV. However, to add to the current eligible groups requires a more formal assessment of potential at risk populations to ensure all comorbidities that are potentially susceptible to RSV are considered. Given the likelihood of the introduction of a universal programme that would cover all risk groups in the near future, the committee agreed that efforts should be concentrated on formulating the advice towards introduction of a universal programme as soon as possible.

At the JCVI meeting on 7 June 2023, it was noted that the question of offering passive immunisation to other risk groups not specified in the current passive immunisation for palivizumab should be resolved once there was a policy for a universal programme covering all infants. For the coming season it was for specialised commissioning to work within the current guidance as to how this might be applied for those considered to be at equivalent risk based on clinical judgment. JCVI was in favour of considering other risk groups based on clinical assessment as per the current guidance but could not provide specific advice for named clinical conditions without a formal analysis.

Programme for older adults

Three RSV vaccine products have been in development with potential licensure timelines for 2023 or early 2024:

• GSK adjuvanted PreF protein vaccine
• Pfizer PreF protein vaccine
• Moderna PreF mRNA

The GSK product was recently licensed by the EMA on 6 June 2023 and by the MHRA on 7 July 2023. As of 22 July 2023, Bavarian Nordic has discontinued its RSV program for a Modified Vaccinia virus Ankara (MVA-BN) vaccine due to the trial not meeting all the specified primary endpoints for RSV LRTD. A product developed by Janssen, Ad26.RSV.preF-RSVpreF Protein Vaccine, has been withdrawn from further development.

The committee reviewed data presented by GSK, Pfizer, and Moderna at the RSV subcommittee meeting on 7 March 2023. Pfizer (reference 16) and GSK (reference 17) have published their phase 3 results and Moderna (reference 18) have released phase 3 top line results.

Tables 3a, 3b and 3c summarise the efficacy data from the products reviewed by the JCVI. In reviewing the data, the committee considered there was uncertainty in comparing the efficacy of the products based on their trial results owing to the different case definitions and end points used and how these were measured. There are no head-to-head studies. The data from the GSK adjuvanted vaccine suggests that it might have a better efficacy, which might be attributed to the adjuvant, but there remained uncertainty about this. Overall, there does not appear to be any major safety concerns for the products at this stage.

Table 3a: summary of the GSK (RSVPreF3 OA) vaccine efficacy data reviewed

Outcome	Efficacy (%, 96.95 CI)
RSV ARI (see note)	71.1 (55.0 to 82.0)
RSV LRTD (see note)	82.6 (57.9 to 94.1)
RSV LRTD with 2 or more lower respiratory signs or assessed as severe by investigator	94.1 (62.4 to 99.9)

Acute respiratory illness (ARI) here means either:

• 2 or more respiratory symptoms or signs for 24 hours or more
• 1 respiratory symptom or sign plus 1 systemic sign for 24 hours or more

Lower respiratory tract disease (LRTD) here means either:

• 2 or more respiratory symptoms or signs for 24 hours or more including 1 or more lower respiratory signs
• 3 or more lower respiratory symptoms for 24 hours or more

Table 3b: summary of the Pfizer (RSVPreF3) vaccine efficacy data

Outcome	Efficacy (%, 95 CI)
RSV ARI (see note)	62.1 (37.1 to 77.9)
RSV LRTI 2 or more symptoms (see note)	66.7 (32.5 to 84.8)
RSV LRTI 3 or more symptoms (see note)	85.7 (37.9 to 98.4)

Acute respiratory illness (ARI) here means 1 or more respiratory symptoms or signs for 24 hours or more.

Lower respiratory tract infection (LRTI) here means an ARI with 2 or more or 3 or more lower respiratory symptoms or signs for 24 hours or more.

Table 3c: summary of the Moderna (mRNA-1345) vaccine efficacy data

Outcome	Efficacy (%, 95.88 CI)
RSV LRTD 2 or more symptoms	83.7 (66.1 to 92.2)
RSV LRTD 3 or more symptoms	82.4 (34.8 to 95.3)

Modelling

The LSHTM dynamic transmission model was used to assess the impact and cost effectiveness of an older adult RSV vaccination programme. Second opinion modelling was provided by the University of Groningen who have developed a static model and published an exploratory assessment based on a hypothetical vaccine (reference 19) as part of the RESCEU project.

The GSK phase 3 results provided the most comprehensive read out of the data available and were therefore used for the LSHTM impact and cost effectiveness assessment.

At the May 2023 RSV subcommittee meeting, discussion centred around the underestimation of the burden in older adults in relation to hospitalisations and deaths. Therefore, 2 scenarios were modelled for the 7 June 2023 JCVI meeting: a base case with a conservative estimate of deaths using a case fatality rate of 0.064 per hospitalised case from Li (reference 20) and a higher more liberal estimate of the number of deaths based on Fleming (reference 2).

The conservative estimate of annual deaths was 741 (95% CI 644 to 870) which only took account of hospital deaths and not those in the wider community and was therefore likely to be an underestimate. The Fleming (reference 2) estimate was much higher at 6,472 (95% CI 5,102 to 7,929) and approximately twice the number of estimated ICU admissions; this estimate has been used by other modellers as well as the manufacturers. Estimates of symptomatic cases, GP consultations, hospitalisations and ICU admissions were similar for both the conservative and liberal scenarios.

Implementation of programmes for those aged over 65 years and over 75 years were assessed for impact and cost effectiveness with a coverage of 70% (based on the uptake for influenza vaccine in the elderly). Efficacy against acute respiratory infection (ARI) and severe LRTI was modelled to fit published estimates to cover one season. Data on multi season protection is expected for some products soon and the model will then be updated.

Burden reduction for the 2 programmes under the conservative estimates and liberal estimates were similar except with regards to mortality. Vaccination prevented approximately 90,000 and 36,000 GP consultations, 8,000 and 4,600 hospitalisations, and 2,000 and 1,000 ICU admissions in those aged over 65 years and over 74 years, respectively. In the conservative estimate 500 and 300 deaths - and in the liberal estimate 4,000 and 2,800 - were prevented for those over 65 years and over 75 years, respectively.

Results showed a programme for those over 75 years would be more efficient in terms of NNV and would cover those at greater risk, but a programme for those over 65 years would have the greatest impact on burden. A programme for those over 75 years would therefore be more cost effective with the maximum CCPA willingness to pay a price higher under the liberal burden estimate compared with the conservative burden estimate.

Second opinion modelling

Hospitalisation and GP costs were similar in the 2 models while the second opinion model had much higher QALY loss estimates for hospitalisation based on a proxy from an influenza study (reference 21). The second opinion model, which was static in design, assumed the efficacy stayed the same for a whole year but this did not make much difference between the 2 models as most transmission occurred over the winter period. Total QALY gains on cases averted were higher in the second opinion model, as were total treatment costs. The second opinion model also looked at 2 scenarios: one which used the Fleming primary care and mortality estimates, the other a more conservative estimate similar to the LSHTM model. Overall, the maximum cost per dose for the conservative estimates were similar between the 2 models, while in the liberal estimates those of the second opinion model were approximately double the maximum price of the LSHTM model. It was noted that the second opinion model had a lot more primary care consultations averted using the Fleming estimates for disease burden than the LSHTM model, which was based on estimates of disease burden by Sharp (reference 1) using a methodology based on Cromer (reference 22). It was noted that the higher burden estimate of GP consultations could account for the larger QALY gain in the second opinion results.

Considerations

At the JCVI meeting on 7 June 2023, the committee agreed that more work was required to obtain better estimates of the RSV burden in adults. It was noted that the hospital case fatality rate used in the LSHTM model was consistent across a number of publications, so it was likely that either the number of hospitalisations was being underestimated or there was an excess of community cases with deaths outside hospitals. Both models indicated that a programme could have a substantial impact and be cost effective and that several products were expected to be available, subject to licensure, with the potential to have more than one product in the programme. It was also noted that there were emerging second season data from GSK. The GSK data showed that one dose over 2 seasons was comparable to 2 annual doses and that one dose gave similar vaccine efficacy estimates in the second season when compared with 2 doses, with a substantial benefit. This would change the cost effectiveness estimates towards a higher willingness to pay threshold price. The implication of these results suggested that one dose could protect for more than one season and that vaccination could occur year-round rather than seasonally. Protection for more than one season would make the decision more complicated as it would not be an annual vaccination programme, but vaccination could initially be offered to a larger cohort and then annually to those turning the eligible age.

There was more certainty that a programme in those aged over 75 years would be cost effective, but that as more data accumulated, the cost effectiveness on those aged over 65 years could be kept under review. It was suggested that the programme could potentially be delivered initially to those aged 75 to 80 years, similar to how the shingles programme was implemented, and then for those turning 75 years in subsequent years.

The committee agreed that the conservative estimate for deaths was too low and that a factor was needed to adjust for this. All cause excess mortality estimates could be explored to estimate those deaths attributable to RSV, as had been done for influenza. This could then be compared with the estimate for deaths in hospitals.

In summary, the committee was strongly in favour of having an impact on RSV and advised a programme for those aged over 75 years. The committee suggested an initial programme to potentially vaccinate a cohort aged from 75 to 80 years old, and then for those turning 75 years in subsequent years. Advice for the programme would be guided by emerging evidence on duration of protection and disease incidence. An extension to the initial programme would be considered when there is more certainty about protection in the very elderly and the real-world impact of the programme in the 75 to 80 year olds. Immunisation might ideally be delivered to time with the RSV season, but it was for NHS England and the devolved administrations to work out how best to operationalise this.

Conclusions and advice

JCVI’s early advice on 22 June 2023 was issued for the Department of Health and Social Care (DHSC) to consider developing policy on RSV interventions and to allow sufficient lead in time for the necessary planning for a potential RSV immunisation programme.

Once there is a policy, the procurement process for a tender can have a long lead in time with all the processes required by HM Treasury. Alongside this there needs to be the necessary work for the planning and effective implementation of an RSV programme by NHS England and the devolved administrations in collaboration with DHSC and UKHSA. This is a significant and complex undertaking involving the coordination of multiple work streams and organisations to ensure the optimal delivery of immunisation services.

As well as delivery, the necessary surveillance needs to be in place to closely monitor the uptake of immunisations and the impact of a programme on the incidence of RSV and on the NHS. JCVI has worked at pace to review the necessary scientific and clinical information to issue advice as early as possible while being mindful that this needs to be as robust as possible and based on the latest available information. This is a fast-moving area with numerous products in development and new data emerging on a frequent basis. The committee will continue to keep its advice under close review and will update this when appropriate. JCVI’s current advice for an RSV immunisation programme remains the same as that issued in the short statement and is outlined below.

Programme to protect neonates and infants

The committee notes a seasonal, seasonal with catch-up or year-round passive immunisation (monoclonal antibody) programme for newborns could be cost effective over a range of potential prices that combine the cost of the product and its administration.

The committee notes a seasonal or year-round maternal active immunisation programme could be cost effective over a range of potential prices that combine the cost of the product and its administration.

JCVI advises that both products are suitable for a universal programme to protect neonates and infants from RSV.

JCVI does not have a preference for either product or whether a maternal vaccination or a passive immunisation programme should be the programme chosen to protect neonates and infants. Therefore, subject to licensure of the maternal vaccine, both options should be considered for a universal programme.

JCVI advises a preference for a year-round offer for a passive immunisation or maternal immunisation programme to ensure high uptake and for reasons of operational effectiveness because this would be less complex and resource intensive to deliver, compared with running seasonal campaigns.

Programme for older adults

The committee notes an RSV vaccine programme for adults aged 75 years and above could be cost effective at a potential price that combines the cost of the product and its administration, noting that this would be influenced by multi-year protection from a single dose.

JCVI advises a programme for older adults aged 75 years old and above. JCVI currently favours a one-off campaign as the strategy for this programme with the initial offer covering several age cohorts and then a routine programme for those turning 75 years old, with its delivery and implementation to be determined through further consultation between NHS England, DHSC, UKHSA and the devolved administrations.

JCVI currently does not have a preference among the products it has reviewed as efficacy is broadly comparable and there are no head-to-head studies to allow direct comparison, and so subject to licensure, they can be considered equally suitable for an older adult RSV immunisation programme at this time.

Conclusion

In summary, JCVI advises that a RSV immunisation programme, that is cost effective, should be developed for both infants and older adults.

Stakeholder engagement

JCVI also issued their early advice statement on 22 June 2023 to encourage feedback from key stakeholders, providing the opportunity for engagement on its advice via the JCVI secretariat. Responses so far have been in line with the JCVI discussion on the potential differences in the products and the committee’s advice. The committee remains open to engagement with key stakeholders via the secretariat.

References

1. Sharp A and others. Estimating the burden of adult hospital admissions due to RSV and other respiratory pathogens in England. Influenza and Other Respiratory Viruses 2022: 16(1),125-131.

2. Fleming DM and others. Modelling estimates of the burden of respiratory syncytial virus infection in adults and the elderly in the United Kingdom. BMC Infectious Diseases 2015: 15, 443.

3. Hardelid P, Pebody R and Andrews N. Mortality caused by influenza and respiratory syncytial virus by age group In England and Wales 1999 to 2010. Influenza and Other Respiratory Viruses 2012: 1(7), 35-45.

4. Fyles F and others. Surveillance towards preventing paediatric incidence of respiratory syncytial virus attributable respiratory tract infection in primary and secondary/tertiary healthcare settings in Merseyside, Cheshire and Bristol, UK. BMJ Open Respiratory Research 2023: 10, e001457.

5. Williams T, Marlow R, Hardelid P and others. The clinical impact of serious respiratory disease in children under the age of 2 during the 2021 to 2022 bronchiolitis season in the United Kingdom and Ireland. Preprint: medRxiv 2023.02.22.23285616.

6. Muller WJ and others. Nirsevimab for prevention of RSV in term and late-preterm infants. New England Journal of Medicine 2023: 388(16), 1533-1534.

7. Kampmann B and others. Bivalent prefusion F vaccine in pregnancy to prevent RSV illness in infants. New England Journal of Medicine 2023: 388(16), 1451-1464.

8. Hodgson D and others. Evaluating the next generation of RSV intervention strategies: a mathematical modelling study and cost-effectiveness analysis. BMC Medicine 2020:18, 348.

9. Hodgson D and others. Optimal respiratory syncytial virus intervention programmes using nirsevimab in England and Wales. Vaccine 2022: 40(49), 7151-7157.

10. Taylor S and others. Modelling estimates of the burden of respiratory syncytial virus infection in children in the UK. BMJ Open 2016: 6(6), e009337.

11. Reeves RM and others. Estimating the burden of respiratory syncytial virus (RSV) on respiratory hospital admissions in children less than 5 years of age in England, 2007 to 2012. Influenza and Other Respiratory Viruses 2017: 11(2), 122-129.

12. Reeves RM and others. Burden of hospital admissions caused by respiratory syncytial virus (RSV) in infants in England: a data linkage modelling study. Journal of Infection 2019: 78(6), 468-475.

13. Li X and others. Cost effectiveness of respiratory syncytial virus disease prevention strategies: maternal vaccine versus seasonal or year-round monoclonal antibody program in Norwegian children. Journal of Infectious Diseases 2022: 226 (Supplement 1), S95-S101.

14. Getaneh AM and others. Cost effectiveness of monoclonal antibody and maternal immunization against respiratory syncytial virus (RSV) in infants: evaluation for 6 European countries. Vaccine 2023: 41(9),1623-1631.

15. Li X and others. Cost effectiveness of respiratory syncytial virus preventive interventions in children: a model comparison study. Value in Health 2023: 26(4), 508-518.

16. Walsh EE and others. Efficacy and safety of a bivalent RSV prefusion F vaccine in older adults. New England Journal of Medicine 2023: 388, 1465-1477.

17. Papi A and others. Respiratory syncytial virus prefusion F protein vaccine in older adults. New England Journal of Medicine 2023: 388, 595-608.

18. Moderna announces mRNA-1345, an investigational respiratory syncytial virus (RSV) vaccine, has met primary efficacy endpoints in phase 3 trial in older adults. Press release, 17 January 2023.

19. Zeevat F and others. Exploratory analysis of the economically justifiable price of a hypothetical RSV vaccine for older adults in the Netherlands and the United Kingdom. Journal of Infectious Diseases 2022: 226 (Supplement 1), S102-S109.

20. Li Y and others. Adjusting for case under-ascertainment in estimating RSV hospitalisation burden of older adults in high income countries: a systematic review and modelling study. Infectious Diseases and Therapy 2023: 12, 1137-1149.

21. Thommes EW and others. Cost effectiveness evaluation of quadrivalent influenza vaccines for seasonal influenza prevention: a dynamic modeling study of Canada and the United Kingdom. BMC Infectious Diseases 2015; 15, 465.

22. Cromer D and others. Burden of paediatric respiratory syncytial virus disease and potential effect of different immunisation strategies: a modelling and cost effectiveness analysis for England. Lancet Public Health 2017: 2(8), 367-374.

Further references and evidence JCVI considered

JCVI

Respiratory syncytial virus (RSV) immunisation programme: JCVI advice, 7 June 2023, published 22 June 2022.

Joint Committee on Vaccination and Immunisation (2023) minutes of the meeting on 7 June 2023

Joint Committee on Vaccination and Immunisation (2023) minutes of the meeting on 1 February 2023

Burden in children

van Houten CB and others. Antibiotic overuse in children with respiratory syncytial virus lower respiratory tract infection. Pediatric Infectious Disease Journal 2018: 37(11), 1077-1081.

Raes M and others. The burden and surveillance of RSV disease in young children in Belgium - expert opinion. European Journal of Pediatrics 2023: 182, 451-460.

Noble M and others. Respiratory syncytial virus-associated hospitalisation in children aged ⩽5 years: a scoping review of literature from 2009 to 2021. ERJ Open Research 2022: 8, 00593-2021.

Wingert A and others. Burden of illness in infants and young children hospitalized for respiratory syncytial virus: a rapid review. Canada Communicable Disease Report 2021: 47(9), 381-396.

Roland D and others. Features of the transposed seasonality of the 2021 RSV epidemic in the UK and Ireland: analysis of the first 10,000 patients. Archives of Disease in Childhood 2022: 107(11), 1062-1063.

Burden in adults

Savic M and others. Respiratory syncytial virus disease burden in adults aged 60 years and older in high-income countries: a systematic literature review and meta-analysis. Influenza and Other Respiratory Viruses 2023: 17(1), e13031.

Maggi S and others. Rate of hospitalizations and mortality of respiratory syncytial virus infection compared to influenza in older people: a systematic review and meta-analysis. Vaccines 2022: 10(12), 2092.

Belongia EA and others. Clinical features, severity, and incidence of RSV illness during 12 consecutive seasons in a community cohort of adults ≥60 years old. Open Forum Infectious Diseases 2018: 5(12), ofy316.

Shi T and others. Global disease burden estimates of respiratory syncytial virus-associated acute respiratory infection in older adults in 2015: a systematic review and meta-analysis. Journal of Infectious Diseases 2020: 222 (Supplement 7), S577-S583.

Nguyen-Van-Tam JS and others. Burden of respiratory syncytial virus infection in older and high-risk adults: a systematic review and meta-analysis of the evidence from developed countries. European Respiratory Review 2022: 31, 220105.

Manufacturers

Janssen

Falsey AR and others. Efficacy and safety of an Ad26.RSV.preF-RSV preF protein vaccine in older adults. New England Journal of Medicine 2023: 388(7), 609-620.

Pfizer

FDA approves first vaccine for pregnant individuals to prevent RSV in infants. 21 August 2023.

Vaccines and Related Biological Products Advisory Committee, 18 May 2023 meeting summary minutes (pdf, 174kb)

First RSV vaccine to protect infants up to 6 months of age and older adults. European Medicines Agency, 21 July 2023.

Bavarian Nordic

Samy NR and others. Safety and immunogenicity of novel modified vaccinia Ankara-vectored RSV vaccine: a randomized phase I clinical trial. Vaccine 2020: 38 (11), 2608-2619.

Jordan EG and others. Reduced respiratory syncytial virus load, symptoms and infections: a human challenge trial of MVA-BN-RSV vaccine. Journal of Infectious Diseases 2023: jiad108.

Jordan E and others. Broad antibody and cellular immune response from a phase 2 clinical trial with a novel multivalent poxvirus based RSV vaccine. Journal of Infectious Diseases 2021: 223(6), 1062-1072.

Sanofi

Hammitt LL and others. Nirsevimab for prevention of RSV in healthy late-preterm and term infants. New England Journal of Medicine 2022: 386(9), 837-846.

Domachowske J and others. Safety of nirsevimab for RSV in infants with heart or lung disease or prematurity. New England Journal of Medicine 2022: 386(9), 892-894.

Griffin MP and others. Single-dose nirsevimab for prevention of RSV in preterm infants. New England Journal of Medicine 2020: 383(5), 415-425. Erratum in: New England Journal of Medicine 2020: 383(7), 698.

Simões EAF and others. Efficacy of nirsevimab against respiratory syncytial virus lower respiratory tract infections in preterm and term infants, and pharmacokinetic extrapolation to infants with congenital heart disease and chronic lung disease: a pooled analysis of randomised controlled trials. Lancet Child & Adolescent Health 2023: 7(3), 180-189.