MIRNA – Maternal Immunisation Readiness Network in Africa & Asia
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RSV Prefusion F Protein-Based Maternal Vaccine – Preterm Birth and Other Outcomes

Background Vaccination against respiratory syncytial virus (RSV) during pregnancy may protect infants from RSV disease. Efficacy and safety data on a candidate RSV prefusion F protein-based maternal vaccine (RSVPreF3-Mat) are needed. Methods We conducted a phase 3 trial involving pregnant women 18 to 49 years of age to assess the efficacy and safety of RSVPreF3-Mat. […]

Original research2024DOI: 10.1056/nejmoa2305478
Abstract

In this phase 3 trial, pregnant women aged 18 to 49 were randomized 2:1 to receive the candidate maternal RSV vaccine RSVPreF3-Mat or placebo between 24 and 34 weeks' gestation, but enrollment was stopped early (5,328 women and 5,233 infants, versus a target of about 10,000) after a higher rate of preterm birth emerged in the vaccine group. Through 6 months of age, vaccine efficacy was 65.5% against any medically assessed RSV-associated lower respiratory tract disease and 69.0% against severe disease. However, preterm birth occurred in 6.8% of vaccine-group infants versus 4.9% with placebo (relative risk 1.37), and neonatal deaths were also more frequent (0.4% vs 0.2%, not statistically significant), likely reflecting the excess preterm births. The vaccine reduced infant RSV disease but was associated with an increased risk of preterm birth.

Background

Vaccination against respiratory syncytial virus (RSV) during pregnancy may protect infants from RSV disease. Efficacy and safety data on a candidate RSV prefusion F protein-based maternal vaccine (RSVPreF3-Mat) are needed.

Methods

We conducted a phase 3 trial involving pregnant women 18 to 49 years of age to assess the efficacy and safety of RSVPreF3-Mat. The women were randomly assigned in a 2:1 ratio to receive RSVPreF3-Mat or placebo between 24 weeks 0 days and 34 weeks 0 days of gestation. The primary outcomes were any or severe medically assessed RSV-associated lower respiratory tract disease in infants from birth to 6 months of age and safety in infants from birth to 12 months of age. After the observation of a higher risk of preterm birth in the vaccine group than in the placebo group, enrollment and vaccination were stopped early, and exploratory analyses of the safety signal of preterm birth were performed.

Results

The analyses included 5328 pregnant women and 5233 infants; the target enrollment of approximately 10,000 pregnant women and their infants was not reached because enrollment was stopped early. A total of 3426 infants in the vaccine group and 1711 infants in the placebo group were followed from birth to 6 months of age; 16 and 24 infants, respectively, had any medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 65.5%; 95% credible interval, 37.5 to 82.0), and 8 and 14, respectively, had severe medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 69.0%; 95% credible interval, 33.0 to 87.6). Preterm birth occurred in 6.8% of the infants (237 of 3494) in the vaccine group and in 4.9% of those (86 of 1739) in the placebo group (relative risk, 1.37; 95% confidence interval [CI], 1.08 to 1.74; P = 0.01); neonatal death occurred in 0.4% (13 of 3494) and 0.2% (3 of 1739), respectively (relative risk, 2.16; 95% CI, 0.62 to 7.56; P = 0.23), an imbalance probably attributable to the greater percentage of preterm births in the vaccine group. No other safety signal was observed.

Conclusion

The results of this trial, in which enrollment was stopped early because of safety concerns, suggest that the risks of any and severe medically assessed RSV-associated lower respiratory tract disease among infants were lower with the candidate maternal RSV vaccine than with placebo but that the risk of preterm birth was higher with the candidate vaccine.

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Ilse Dieussaert, Joon Hyung Kim, Sabine Luik, Claudia Seidl, Wenji Pu, Jens-Ulrich Stegmann, Geeta K Swamy, Peggy Webster, Philip R DormitzerFrom GSK, Wavre, Belgium (I.D., J.-U.S.); GSK, Rockville, MD (J.H.K., W.P.); GSK, Munich, Germany (S.L., C.S.); the Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC (G.K.S.); and GSK, Waltham, MA (P.W., P.R.D.).
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10.1056/nejmoa2305478
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References

  1. Bénet T, Sánchez Picot V, Messaoudi M, et al. Microorganisms associated with pneumonia in children <5 years of age in developing and emerging countries: the GABRIEL pneumonia multicenter, prospective, case-control study. Clin Infect Dis 2017;65:604-612.
  2. GBD 2016 Lower Respiratory Infections Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis 2018;18:1191-1210.
  3. Li Y, Wang X, Blau DM, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis. Lancet 2022;399:2047-2064.
  4. Buchy P, Badur S, Kassianos G, Preiss S, Tam JS. Vaccinating pregnant women against influenza needs to be a priority for all countries: an expert commentary. Int J Infect Dis 2020;92:1-12.
  5. Maertens K, Orije MRP, Van Damme P, Leuridan E. Vaccination during pregnancy: current and possible future recommendations. Eur J Pediatr 2020;179:235-242.
  6. Vojtek I, Dieussaert I, Doherty TM, et al. Maternal immunization: where are we now and how to move forward? Ann Med 2018;50:193-208.
  7. Vygen-Bonnet S, Hellenbrand W, Garbe E, et al. Safety and effectiveness of acellular pertussis vaccination during pregnancy: a systematic review. BMC Infect Dis 2020;20:136-136.
  8. Esposito S, Abu Raya B, Baraldi E, et al. RSV prevention in all infants: which is the most preferable strategy? Front Immunol 2022;13:880368-880368.
  9. Gunatilaka A, Giles ML. Maternal RSV vaccine development: where to from here? Hum Vaccin Immunother 2021;17:4542-4548.
  10. Schwarz TF, Johnson C, Grigat C, et al. Three dose levels of a maternal respiratory syncytial virus vaccine candidate are well tolerated and immunogenic in a randomized trial in nonpregnant women. J Infect Dis 2022;225:2067-2076.
  11. Stokes AH, Franklin K, Fisher DE, et al. Repeated dose toxicity study and developmental and reproductive toxicology studies of a respiratory syncytial virus candidate vaccine in rabbits and rats. Int J Toxicol 2021;40:125-142.
  12. Pathirana J, Muñoz FM, Abbing-Karahagopian V, et al. Neonatal death: case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine 2016;34:6027-6037.
  13. Bonhoeffer J, Kochhar S, Hirschfeld S, et al. Global alignment of immunization safety assessment in pregnancy — the GAIA project. Vaccine 2016;34:5993-5997.
  14. Quinn J-A, Munoz FM, Gonik B, et al. Preterm birth: case definition & guidelines for data collection, analysis, and presentation of immunisation safety data. Vaccine 2016;34:6047-6056.
  15. Mortality and acute complications in preterm infants. In: Behrman RE, Butler AS, eds. Preterm birth: causes, consequences, and prevention. Washington, DC: National Academies Press, 2007 (https://www.ncbi.nlm.nih.gov/books/NBK11385).
  16. Papi A, Ison MG, Langley JM, et al. Respiratory syncytial virus prefusion F protein vaccine in older adults. N Engl J Med 2023;388:595-608.
  17. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371:75-84.
  18. Boettcher LB, Metz TD. Maternal and neonatal outcomes following SARS-CoV-2 infection. Semin Fetal Neonatal Med 2023;28:101428-101428.
  19. Deng J, Ma Y, Liu Q, Du M, Liu M, Liu J. Association of infection with different SARS-CoV-2 variants during pregnancy with maternal and perinatal outcomes: a systematic review and meta-analysis. Int J Environ Res Public Health 2022;19:15932-15932.
  20. Badell ML, Dude CM, Rasmussen SA, Jamieson DJ. Covid-19 vaccination in pregnancy. BMJ 2022;378:e069741-e069741.
  21. Rahmati M, Yon DK, Lee SW, et al. Effects of COVID-19 vaccination during pregnancy on SARS-CoV-2 infection and maternal and neonatal outcomes: a systematic review and meta-analysis. Rev Med Virol 2023;33(3):e2434-e2434.
  22. Giles ML, Krishnaswamy S, Macartney K, Cheng A. The safety of inactivated influenza vaccines in pregnancy for birth outcomes: a systematic review. Hum Vaccin Immunother 2019;15:687-699.
  23. Perrett KP, Halperin SA, Nolan T, et al. Immunogenicity, transplacental transfer of pertussis antibodies and safety following pertussis immunization during pregnancy: evidence from a randomized, placebo-controlled trial. Vaccine 2020;38:2095-2104.
  24. Bebia Z, Reyes O, Jeanfreau R, et al. Safety and immunogenicity of an investigational respiratory syncytial virus vaccine (RSVPreF3) in mothers and their infants: a phase 2 randomized trial. J Infect Dis 2023;228:299-310.
  25. Madhi SA, Polack FP, Piedra PA, et al. Respiratory syncytial virus vaccination during pregnancy and effects in infants. N Engl J Med 2020;383:426-439.
  26. Simões EAF, Center KJ, Tita ATN, et al. Prefusion F protein-based respiratory syncytial virus immunization in pregnancy. N Engl J Med 2022;386:1615-1626.
  27. Kampmann B, Madhi SA, Munjal I, et al. Bivalent prefusion F vaccine in pregnancy to prevent RSV illness in infants. N Engl J Med 2023;388:1451-1464.
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