Efficacy and safety of respiratory syncytial virus vaccines

- Rationale Respiratory syncytial virus (RSV) is a highly transmissible pathogen that causes varying degrees of respiratory illness across all age groups. The safety and efficacy profiles of available RSV vaccines, a critical consideration for their integration into public health strategies and clinical practice, remain uncertain. Objectives To assess the benefits and harms of RSV vaccines compared to placebo, no intervention, vaccines for other respiratory infections, other RSV vaccines, or monoclonal antibodies (mAbs) across all human populations. Search methods We conducted a comprehensive literature search of CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the WHO ICTRP following standard systematic review methodology from 2000 to April 2024. Eligibility criteria We included both randomised controlled trials (RCTs) and non‐randomised studies of interventions (NRSIs) involving all human populations comparing RSV vaccines with placebo, no intervention, vaccines for other respiratory infections, other RSV vaccines, or mAbs. We excluded studies focused on dose‐finding schedules and immunogenicity assessment. Outcomes Benefits included frequency of RSV illness (both lower and upper respiratory illness) confirmed by laboratory tests (RSV‐associated lower respiratory tract illness and RSV‐associated acute respiratory illness); hospitalisation due to RSV disease (both lower and upper respiratory illness) confirmed by laboratory tests; mortality from illness caused by RSV (confirmed by laboratory test); all‐cause mortality; and admission to an intensive care unit. Harms included serious adverse events (SAEs) related to vaccination, including neurological disorders such as Guillain‐Barré syndrome. Risk of bias We assessed risk of bias in RCTs using Cochrane's RoB 2 tool. Synthesis methods We used standard Cochrane methods. Included studies We identified 14 RCTs: five trials (101,825 participants) on older adults; three trials (12,010 participants) on maternal vaccination and effects on infants; one trial (300 participants) on women of childbearing age; and five trials (192 participants) on infants and children. We identified no NRSIs. Synthesis of results RSV prefusion vaccine versus placebo in older adults These vaccines reduced RSV‐associated lower respiratory tract illness with vaccine efficacy (VE) of 77% (95% confidence interval (CI) 0.70 to 0.83; risk ratio (RR) 0.23, 95% CI 0.17 to 0.30; 4 RCTs, 99,931 participants; high‐certainty evidence) and RSV‐associated acute respiratory illness with VE of 67% (95% CI 0.60 to 0.73; RR 0.33, 95% CI 0.27 to 0.40; 3 RCTs, 94,339 participants; high‐certainty evidence). There may be little to no difference in mortality from illness caused by RSV, all‐cause mortality, and SAEs related to vaccination (low‐certainty evidence). RSV postfusion F protein‐based vaccine versus placebo in older adults There is probably little to no difference in RSV‐associated lower respiratory tract illness with VE of − 0.37% (95% CI − 1.96 to 0.37; RR 1.37, 95% CI 0.63 to 2.96; 1 RCT, 1894 participants; moderate‐certainty evidence) and RSV‐associated acute respiratory illness with VE of − 0.07% (95% CI − 1.15 to 0.47; RR 1.07, 95% CI 0.53 to 2.15; 1 RCT, 1894 participants; moderate‐certainty evidence). There may be little to no difference in mortality from illness caused by RSV, all‐cause mortality, and SAEs related to vaccination (low‐certainty evidence). Maternal RSV F protein‐based vaccine versus placebo in infants These vaccines reduced medically attended RSV‐associated lower respiratory tract illness with VE of 54% (95% CI 0.28 to 0.71; RR 0.46, 95% CI 0.29 to 0.72; 3 RCTs, 12,010 participants; high‐certainty evidence), medically attended RSV‐associated severe lower respiratory tract illness with VE of 74% (95% CI 0.44 to 0.88; RR 0.26, 95% CI 0.12 to 0.56; 3 RCTs, 12,010 participants; high‐certainty evidence), and hospitalisation due to RSV disease with VE of 54% (95% CI 0.27 to 0.71; RR 0.46, 95% CI 0.29 to 0.73; 2 RCTs, 11,502 participants; high‐certainty evidence) in infants. There may be little to no difference in mortality from illness caused by RSV, all‐cause mortality, and SAEs related to vaccination in mothers and infants (low‐certainty evidence). Live‐attenuated RSV vaccines versus placebo in infants and children The evidence is very uncertain regarding all‐cause medically attended acute respiratory illness (MAARI) with VE of 26% (95% CI − 0.01 to 0.46; RR 0.74, 95% CI 0.54 to 1.01; 5 RCTs, 171 participants; very low‐certainty evidence) and RSV‐associated MAARI with VE of 38% (95% CI − 0.24 to 0.69; RR 0.62, 95% CI 0.31 to 1.24; 5 RCTs, 192 participants; very low‐certainty evidence). There may be little to no difference in SAEs related to vaccination (low‐certainty evidence). RSV recombinant F nanoparticle vaccine versus placebo in women of childbearing age The evidence is very uncertain regarding new RSV infections with VE of 50% (95% CI 0.08 to 0.73; RR 0.50, 95% CI 0.27 to 0.92; 1 RCT, 300 participants; very low‐certainty evidence). There may be little to no difference in mortality from illness caused by RSV, all‐cause mortality, and SAEs related to vaccination (low‐certainty evidence). Phase III trials consistently demonstrated low risk of bias. Whilst phase I and II trials occasionally raised concerns about selection bias in the randomisation process, the overall evidence was deemed robust. Authors' conclusions RSV prefusion vaccines reduced RSV‐associated lower respiratory tract illness and acute respiratory illness in older adults. There may be little to no difference in SAEs related to vaccination in older adults. Maternal vaccination with RSV F protein‐based vaccines reduced medically attended RSV‐associated lower respiratory tract illness and severe cases in infants. There may be little to no difference in SAEs related to vaccination in mothers and infants. The evidence is very uncertain regarding the effects of RSV vaccine on women of childbearing age, and the effects of live‐attenuated RSV vaccines on infants and children; there may be little to no difference in SAEs related to vaccination. Funding This review was funded by the EU4Health Programme under a service contract with the European Health and Digital Executive Agency (HaDEA). Registration The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42023439128). Plain language summary What are the benefits and harms of respiratory syncytial virus (RSV) vaccines in preventing RSV disease? Key messages Respiratory syncytial virus (RSV) prefusion vaccines reduced RSV illness in older adults. When pregnant women received RSV F protein‐based vaccines, their babies had fewer serious RSV illnesses. This was true for both approved and unapproved vaccines. The effectiveness of RSV vaccines in women of childbearing age and the impact of live RSV vaccines on infants and children remain uncertain. These trials used unapproved vaccines. Further research is needed looking at RSV vaccines in women of childbearing age and the effects of live vaccines on infants and children. What is respiratory syncytial virus (RSV)? RSV is a virus that spreads easily and causes respiratory illnesses. Most people get it when they are very young, and nearly all have had it by the age of two. How is RSV prevented? It can be prevented by getting vaccinated, using special antibodies, washing hands, and avoiding close contact with sick people. What did we want to find out? We wanted to know how well RSV vaccines work in preventing RSV and how safe they are. What did we do? We searched for studies that compared RSV vaccines to placebo (dummy treatment), no treatment, vaccines for other respiratory infections, other RSV vaccines, or monoclonal antibodies (lab‐made proteins that help the immune system fight disease) in all people. We compared and summarised the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes. What did we find? We found five studies on older adults, three on the effect of vaccinating pregnant women on their babies, one on women of childbearing age, and five on infants and children. Main results RSV prefusion vaccine versus placebo in older adults; 4 studies (99,931 people) RSV prefusion vaccines reduced RSV‐related respiratory illness by 77% and RSV‐related acute illnesses by 67% in older adults. We are confident in these results. There may be little to no difference between RSV prefusion vaccine and placebo in numbers of serious unwanted effects, people who die from RSV itself, or people who die from any cause. We have low confidence in these results. The studies did not report RSV‐related hospitalisation or intensive care unit (ICU) admission. RSV postfusion F protein‐based vaccine versus placebo in older adults; 1 study (1894 people) There is probably little to no difference between RSV postfusion F protein‐based vaccine and placebo in RSV‐related respiratory illness or RSV‐related acute illnesses in older adults. There may be little to no difference between RSV postfusion F protein‐based vaccine and placebo in numbers of serious unwanted effects, people who die from RSV itself, or people who die from any cause. We have low confidence in these results. The study did not report RSV‐related hospitalisation or ICU admission. Maternal RSV F protein‐based vaccine versus placebo in infants; 3 studies (12,010 people) Maternal RSV F protein‐based vaccine reduced RSV‐related respiratory illness by 54%, severe RSV‐related respiratory illness by 74%, and hospitalisations due to RSV by 54% in infants. We are confident in these results. There may be little to no difference between maternal RSV F protein‐based vaccine and placebo in numbers of serious unwanted effects, infants who die from RSV itself, or infants who die from any cause. We have low confidence in these results. The studies did not report ICU admission. Live‐attenuated RSV vaccines versus placebo in infants and children; 5 studies (192 infants and children) We are uncertain if live RSV vaccines reduce respiratory illnesses and RSV‐related illnesses in infants and children. There may be little to no difference between live RSV vaccines and placebo in numbers of serious unwanted effects. The studies did not report RSV‐related hospitalisation, numbers of infants and children who died from RSV itself, numbers who died from any cause, or ICU admission. RSV recombinant F nanoparticle vaccine versus placebo in women of childbearing age; 1 study (300 women) We are uncertain if RSV recombinant F nanoparticle vaccine prevents new RSV infections in women of childbearing age. There may be little to no difference between RSV recombinant F nanoparticle vaccine and placebo in numbers of serious unwanted effects, people who die from RSV itself, or people who die from any cause. We have low confidence in these results. The study did not report RSV‐related hospitalisation or ICU admission. What are the limitations of the evidence? We only included articles published in English, and therefore may have missed studies published in other languages. There were occasional issues with the way some studies were done, but overall the studies were well conducted. How up‐to‐date is the evidence? The evidence is current to April 2024.