Reference: N Engl J Med. 2023 Apr 20;388(16):1451-1464
Practice Point: Consider the newly FDA-approved maternal RSV vaccination at 24-36 weeks’ gestation to prevent severe RSV infection in infants.
EBM Pearl: Lack of transparency about whether an intention-to-treat or per-protocol analysis was done often suggests the latter, and demands a thorough review of appendices.
The Pfizer respiratory syncytial virus (RSV) vaccine was recently approved for pregnant women in an effort to protect infants. The vaccine targets RSV surface glycoproteins from both RSV A and RSV B (therefore bivalent) and triggers the body to produce antibodies which prevent RSV fusion and infection in human cells. Vaccination during late pregnancy gives newborns passive immunity through the transfer of maternal antibodies, similar to Tdap and influenza vaccination. The FDA’s decision was supported by an interim analysis of a phase 3 randomized control trial published in the NEJM.
From June 2020 through October 2022, investigators randomized 7,392 healthy pregnant adults with uncomplicated singleton pregnancies at 24-36 weeks’ gestation to one dose of RSV vaccine IM vs. placebo. RSV infection was monitored via weekly contact with parents of infants ≤ 6 months old and also with RT-PCR swabs for RSV collected during all visits for respiratory infections. The trial was conducted over four RSV seasons and infants were followed for up to 2 years. The primary efficacy outcomes were laboratory confirmed, medically-attended (i.e., seen by a healthcare provider) severe RSV and RSV of any severity within 90, 120, 150, and 180 days after birth.
At the time of interim analysis, 77% of pregnant adults had given birth and 79% of infants had completed 6-month follow-up. Infants in the vaccinated group were significantly less likely to develop severe RSV infection at 6 months, with only 19 cases in the vaccinated group compared to 62 cases in the placebo group (0.5% vs. 1.85%, vaccine efficacy 69.4%, 97.58% CI, 44.3%-84.1%). RSV infection of any severity was also significantly lower in the vaccinated group at 6 months (1.6% vs. 3.4%). Additionally, fewer hospitalizations for RSV occurred in infants born to mothers in the vaccinated group. In terms of safety, maternal recipients of the vaccine experienced more local reactions, muscle pain, and headaches than in the placebo group. Otherwise, there were similar rates of serious adverse events in maternal and infant participants in both groups. Premature delivery rates were also similar, while a higher number of deaths occurred in infants born to mothers in the placebo group.
We think the overall results are promising. One rub, however, is that the authors never specify whether they did an intention-to-treat or per-protocol analysis. After some digging into the supplementary data, we found language stating that evaluable participants had “no major protocol violations”, strongly suggesting that a per-protocol analysis was done instead of the more conservative and preferred intention-to-treat. The confidence intervals were also wide and the generalizability is somewhat limited given the exclusion of adults with high-risk pregnancies. Despite these considerations, however, it appears the benefits of maternal vaccination outweigh the risks. We estimate an NNT of ~70 to prevent 1 case of severe RSV, though we will need the final analysis to confirm. For a potentially severe illness with no treatment other than supportive care, we are generally on board with vaccinating pregnant women.
For more information, see the topic Respiratory Syncytial Virus (RSV) Infection in Infants and Children in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Nicole Jensen, MD, Family Physician at WholeHealth Medical. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, Deputy Editor at DynaMed; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; Elham Razmpoosh, PhD, Postdoctoral fellow at McMaster University; and Sarah Hill, MSc, Associate Editor at DynaMed.