Efficacy and safety of respiratory syncytial virus prefusion F protein vaccines in adults
Authors: Zhanwei Du, Shuqi Wang, Ruohan Chen, Songwei Shan, Yuan Bai, Lin Wang, Eric H.Y. Lau, Peng Wu, Benjamin J. Cowling
Journal: Journal of Infection (2024)

•GSK and Pfizer's RSV pre-F vaccines demonstrate promising results in clinical trials of adults with encouraging efficacy.•Approval of RSV pre-F protein vaccines marks a milestone in preventing RSV illnesses in adults.•Continued research is needed for long-term safety and addressing potential risks. Dear Editor, Respiratory syncytial virus (RSV) discovered in 1956 is the most common cause of acute lower respiratory tract infection (ALRTI) worldwide in children under 5 years old and adults at 65 years or above.1Luo Q. et al.Genetic diversity and epidemiological features of respiratory syncytial virus, Beijing, 2015-2019: A multicenter and all-age groups study.J. Infect. 2022; 85: 75-85Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 2Shi T. et al.Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.Lancet. 2017; 390: 946-958Abstract Full Text Full Text PDF PubMed Scopus (1567) Google Scholar Efficacy and safety are essential in the development, testing, and evaluation of vaccines to ensure their effectiveness in preventing diseases while minimizing the potential risks to vaccinated individuals. Here, we performed a systematic review to synthesize data from those published studies estimating the efficacy and safety for RSV prefusion F (pre-F) protein vaccines, which is the only vaccine type that received the FDA approval as of October 2023. The goal of vaccination is to establish immunity in the individual, therefore to prevent disease upon exposure to the infectious pathogen, and provide indirect protection to those unvaccinated. However, RSV vaccine development has faced many challenges including the complex immune response, safety, and viral diversity. One instance of vaccine failure is the use of a formalin-inactivated alum-formulated vaccine for respiratory syncytial virus (FI-RSV) during the 1960s, leading to a syndrome of vaccine-enhanced illness upon subsequent natural RSV infection in the following season.3Graham B.S. The Journey to RSV Vaccines - Heralding an Era of Structure-Based Design.N. Engl. J. Med. 2023; 388: 579-581Crossref PubMed Scopus (0) Google Scholar The availability of structural information for viral surface proteins has revolutionized vaccine antigen design in recent years. The development of RSV vaccines has been greatly accelerated by a study of structure-based design of a fusion glycoprotein vaccine published in 2013 4McLellan J.S. et al.Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus.Science. 2013; 342: 592-598Crossref PubMed Scopus (708) Google Scholar that lead to the two vaccines as of July 2023, Arexvy from GSK and Abrysvo from Pfizer, have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to protect older adults against severe RSV infection. One month later, FDA further approved Abrysvo for use in pregnant women to protect infants from RSV. We identified 59 published articles by searching PubMed, and retrieved 57 related clinical trials of adults, excluding maternal vaccination, from ClinicalTrials.gov on 21, Nov, 2023. After removing 14 duplicates, we identified 102 distinct studies for screening. Of 22 studies meeting the inclusion requirements for this review, 6 reported efficacy results and 22 reported safety results as shown in Figure S1. The efficacy and safety results for four types of RSV pre-F vaccines were included: RSVpreF (MEDI8897), RSVpreF3 OA (GSK3844766A), and Ad26.RSV.preF. Table 1 summarized the efficacy values and the associated RSV infection/illness.Table 1Summary of the efficacy results for the pre-F protein vaccines in development (More details in Table S1, Table S3).VaccinePhase as of 30 August 2023OutcomePopulationEfficacy PeriodYoung and middle-aged adultsaYoung and middle-aged adults aged 18-50.Older adultsbOlder adults, could be aged 60 or older or 65 or older in different studies.GSK's RSVPreF3 OAApproved for older adultsLRTD cRSV-related lower respiratory tract disease (RSV LRTD) were identified by the adjudication committee.82.6 (57.9, 94.1)5Papi A. et al.Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults.N. Engl. J. Med. 2023; 388: 595-608Crossref PubMed Scopus (204) Google Scholar #Follow-up of 6.7 months on averagePfizer's RSVpreFApproved for older adults and maternal vaccinationLRTI dRSV-associated lower respiratory tract illness (RSV-LRTI) is an ARI with 3 or more of the lower respiratory signs/symptoms lasting more than 1 day during the same illness, plus RT-PCR-confirmed RSV infection within 7 days of ARI symptom onset.85.7 (32.0, 98.7)7Walsh E.E. et al.Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults.N. Engl. J. Med. 2023; 388: 1465-1477Crossref PubMed Scopus (146) Google Scholar &Follow-up of 11 months from day 15 after vaccination until the end of season 1Symptomatic infectioneqRT-PCR−confirmed symptomatic RSV infection (Variant 1). Any 2 detectable (quantifiable OR detectable and <LLOQ) qRT-PCR results from nasal swabs obtained on ≥2 consecutive days from Day 2 to Day 12 AND symptoms from 2 different categories (URT, LRT, systemic) or any grade 2 symptom (bothersome but not interfering with daily activity)86.7 (53.8, 96.5)6Schmoele-Thoma B. et al.Vaccine Efficacy in Adults in a Respiratory Syncytial Virus Challenge Study.N. Engl. J. Med. 2022; 386: 2377-2386Crossref PubMed Scopus (54) Google ScholarFollow-up of 12 days after challengeJanssen's Ad26.RSV.preFPhase 2Infection fLiberal RSV infection is defined as ≥2 quantifiable rt-PCR measurements above the LLOQ plus any clinical symptom of any severity.47.06 (2.18, 71.35)9Sadoff J. et al.Prevention of Respiratory Syncytial Virus Infection in Healthy Adults by a Single Immunization of Ad26.RSV.preF in a Human Challenge Study.J. Infect. Dis. 2022; 226: 396-406Crossref PubMed Scopus (44) Google ScholarFollow-up of 12 days after challengeLRTD gRSV LRTD definition is ≥3 symptoms of lower respiratory tract infection (LRTI).80.0 (52.2, 92.9)10Falsey A.R. et al.Efficacy and Safety of an Ad26.RSV.preF-RSV preF Protein Vaccine in Older Adults.N. Engl. J. Med. 2023; 388: 609-620Crossref PubMed Scopus (56) Google Scholar *The CI of the efficacy results are for 94.2% Confidential Interval.Follow-up of 21 months from 1 Sep 2019 to 6 June 2022Note, the values and 95% confidence interval for the efficacy of RSV vaccines against RSV infection/illness were summarized in this table.#The CI of the efficacy results are for 96.5% Confidential Interval.&The CI of the efficacy results are for 96.66% Confidential Interval.a Young and middle-aged adults aged 18-50.b Older adults, could be aged 60 or older or 65 or older in different studies.c RSV-related lower respiratory tract disease (RSV LRTD) were identified by the adjudication committee.d RSV-associated lower respiratory tract illness (RSV-LRTI) is an ARI with 3 or more of the lower respiratory signs/symptoms lasting more than 1 day during the same illness, plus RT-PCR-confirmed RSV infection within 7 days of ARI symptom onset.e qRT-PCR−confirmed symptomatic RSV infection (Variant 1). Any 2 detectable (quantifiable OR detectable and <LLOQ) qRT-PCR results from nasal swabs obtained on ≥2 consecutive days from Day 2 to Day 12 AND symptoms from 2 different categories (URT, LRT, systemic) or any grade 2 symptom (bothersome but not interfering with daily activity)f Liberal RSV infection is defined as ≥2 quantifiable rt-PCR measurements above the LLOQ plus any clinical symptom of any severity.g RSV LRTD definition is ≥3 symptoms of lower respiratory tract infection (LRTI). The CI of the efficacy results are for 94.2% Confidential Interval. Open table in a new tab Note, the values and 95% confidence interval for the efficacy of RSV vaccines against RSV infection/illness were summarized in this table. #The CI of the efficacy results are for 96.5% Confidential Interval. &The CI of the efficacy results are for 96.66% Confidential Interval. The efficacy results of phase 3 clinical trials for the vaccines of RSVPreF for older adults [OA] and RSVpreF show that a range of RSV-associated illnesses were significantly reduced in the vaccine group for all younger, middle-aged and older adults (Table 1). For example, RSVPreF OA in older adults has the vaccine efficacy 82.6% (95% CI: 57.9%, 94.1%) against RSV-related lower respiratory tract disease (RSV LRTD).5Papi A. et al.Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults.N. Engl. J. Med. 2023; 388: 595-608Crossref PubMed Scopus (204) Google Scholar RSVPreF would prevent 86.7% (95% CI: 53.8, 96.5) symptomatic infection in old adults, and 85.7 (96.66% CI: 32.0, 98.7) RSV-associated lower respiratory tract illness (RSV-LRTI) in young and middle-aged adults.6Schmoele-Thoma B. et al.Vaccine Efficacy in Adults in a Respiratory Syncytial Virus Challenge Study.N. Engl. J. Med. 2022; 386: 2377-2386Crossref PubMed Scopus (54) Google Scholar The safety results suggest that the incidence of adverse events (AE) were similar across treatment groups and the control groups (either placebo or vaccines with long-term usage and well-proven safety) in adults (Table S2). For example, in the solicited safety population of older adults, the incidence of unsolicited AEs within 30 days after RSVPreF3 OA injection was similar between the two groups, with rates of 14.9% in the vaccine group and 14.6% in the placebo group.5Papi A. et al.Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults.N. Engl. J. Med. 2023; 388: 595-608Crossref PubMed Scopus (204) Google Scholar In contrast, the RSVpreF vaccine resulted in a non-significant 1% higher risk of systemic AEs in the treatment group than in the placebo group among older adults (aged 60 or older), with 27% experiencing such events,7Walsh E.E. et al.Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults.N. Engl. J. Med. 2023; 388: 1465-1477Crossref PubMed Scopus (146) Google Scholar and a 5.8% incidence rate of AEs in the vaccination group of young and middle-aged adults aged 18-49 years, slightly 0.3% lower than the placebo group.8CTG labs - NCBI. 〈https://beta.clinicaltrials.gov/study/NCT05096208〉.Google Scholar These results from the included studies demonstrated encouraging efficacy and acceptable safety of the two study RSV vaccines. The ideal RSV vaccine would induce a strong and long-lasting immune response without causing significant side effects. It would also need to be effective against different strains of RSV, as the virus can evolve and mutate over time. Although GSK and Pfizer's vaccines have gained significant success, concerns about RSV vaccines still have been raised. The immune response to the virus can be complex and not fully understood. In the past, some vaccine candidates have actually worsened the disease or led to enhanced respiratory disease in animal studies. This is a phenomenon known as vaccine-associated enhanced respiratory disease (VAERD). There is still a need for long-term follow-up to examine safety of the approved RSV vaccines. In conclusion, the development of RSV pre-F protein vaccines has been a result of decades of research and has led to significant advancements in preventing RSV-related illnesses, especially in vulnerable populations. The systematic review of published studies and clinical trials presented in this article demonstrates encouraging efficacy and acceptable safety of the two study RSV vaccines, Arexvy from GSK and Abrysvo from Pfizer. Accurate estimates of vaccine efficacy and effectiveness are crucial to fully understand the potential impact of RSV pre-F vaccination in populations. BJC reports honoraria from AstraZeneca, Sanofi Pasteur, GSK, Moderna and Roche. The authors report no other potential conflicts of interest. This work was supported by grants from the AIR@InnoHK Programme from Innovation and Technology Commission of the Government of the Hong Kong Special Administrative Region, National Natural Science Foundation of China (grant no. 72104208), Health and Medical Research Fund (grant no. 21200632) and HMRF Research Fellowship Scheme (grant no. 07210147), Food and Health Bureau, Government of the Hong Kong Special Administrative Region, and General Research Fund (grant no. 17103122), Research Grant Council, Government of the Hong Kong Special Administrative Region. ZD, SW, RC, SS, and YB: conceived the study, designed statistical and modelling methods, conducted analyses, interpreted results, wrote and revised the manuscript; LW, EL, PW and BJC: interpreted results and revised the manuscript. Code used for data analysis is freely available upon request. 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