The benefits and risks of maternal RSV vaccination on mortality in South Africa: a modelling study

BackgroundMaternal respiratory syncytial virus (RSV) vaccine, RSV prefusion F protein vaccine (RSVpreF (Abrysvo(R))), was found to be safe and efficacious in its phase III trial. However, post-hoc stratified analyses identified an excess of preterm births in the intervention arm in two upper middle-income countries, most prominently in South Africa. This study weighs the potential benefits and risks in mortality associated with maternal RSV vaccination in South Africa, assuming the increased risk of preterm births observed in the trial was caused by vaccination. Methods and FindingsWe compared the estimated RSV-associated infant deaths averted by vaccination (benefits) and neonatal mortality potentially associated with vaccine-associated risk in preterm birth (risks) in South Africa. The benefit model estimated the South African RSV disease burden in 2011-16 and waning vaccine protection during infancy. The risk model estimated excess neonatal mortality using gestational age (GA)-specific mortality data from a South African cohort study and the GA-specific birth distribution in South Africa in the trial, but did not incorporate the mortality risk found in the vaccine trial in which no excess deaths occurred. The benefit model estimated that vaccination would reduce RSV-associated infant deaths by 31 (95% Credible Interval (Crl): 27, 35) per 100,000 live births born to vaccinated mothers in South Africa. The risk model suggested that neonatal deaths would increase by 44 (95%CrI: -43, 210) with vaccination at 24-36 GA weeks, totaling 1.4 (95%CrI: -1.4, 7.0) excess neonatal deaths for every infant RSV death prevented. Using the data for infants born to mothers vaccinated at 27-36 GA weeks, the predicted risks sharply dropped and in 98% of the simulations the benefits outweighed the risks. ConclusionsIf RSVpreF increases preterm birth risk, and if this increases neonatal mortality, then the benefit-risk analysis did not show that the direct benefits of vaccination in reducing RSV-associated infant mortality would substantially outweigh the risks of preterm birth-associated neonatal mortality in South Africa with vaccination from 24 GA weeks. There was large uncertainty in the analyses due to small numbers of preterm births. With vaccination from the third trimester, the benefit-risk analysis favoured vaccination.