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GSK's abandoned maternal respiratory syncytial virus (RSV) vaccine protected infants from severe RSV, final results of a phase III trial indicated, but those positive outcomes came at the expense of an unexplained higher risk for preterm birth.

For newborns up to 6 months of age, efficacy with the RSV prefusion F protein-based vaccine (RSVPreF3-Mat) during pregnancy arrived at 65.5% (95% credible interval [CrI] 37.5-82.0) and 69% (95% CrI 33.0-87.6), respectively, against either any or severe RSV-associated lower respiratory tract disease, according to Philip Dormitzer, MD, PhD, of GSK in Waltham, Massachusetts, and colleagues.

But a 37% increased risk of preterm birth in the vaccination arm led the company to halt the trial in February 2022 and cease further development of the maternal vaccine, the researchers reported in the .

In total, 6.8% of infants in the vaccination arm were born preterm, as compared with 4.9% of those in the placebo group (RR 1.37, 95% CI 1.08-1.74). For every 54 infants born to women who received the vaccine, one additional preterm birth occurred.

"No other safety signal has been observed among infant or maternal participants in any trial of RSVPreF3-Mat," the study authors wrote, adding that a previous and unpublished data from a phase III trial found no association between the vaccine and preterm births.

Dormitzer and investigators also considered potential effects of additional vaccines received during pregnancy -- such as vaccines for COVID, the flu, tetanus, and tetanus-diphtheria, none of which have been linked to an increased risk for preterm birth. Receipt of additional vaccines during pregnancy was associated with a lower incidence of preterm birth in both the vaccine and placebo groups, but the reduction in risk was greater in the placebo group.

RSV is the leading cause of hospitalization among infants in the U.S., with 2% to 3% of infants younger than 6 months of age hospitalized for RSV infection annually, noted Sonja Rasmussen, MD, of Johns Hopkins University School of Medicine in Baltimore, and Denise Jamieson, MD, MPH, of the University of Iowa Carver College of Medicine in Iowa City, in .

"Whether the safety signal in the RSVPreF3-Mat trial is real or occurred by chance is unknown," they wrote.

Currently, only Pfizer's bivalent RSV vaccine (Abrysvo) is approved and for use during pregnancy to protect newborns from serious RSV-related outcomes. However, concerned with a possible risk for preterm birth, the FDA restricted its use to between weeks 32 and 36 of gestation. (The monoclonal antibody nirsevimab [Beyfortus] is also recommended for use in newborns entering their first RSV season, provided the mother did not receive an RSV vaccine during pregnancy.)

With more maternal vaccines in development, the editorialists said that "continued focus on balancing the benefits with the potential risks of maternal vaccination will be essential as we move forward to protect infants from the severe effects of infectious diseases."

The current study, , was a phase III double-blind trial that enrolled 5,328 pregnant women ages 18-49 across 24 countries. Women were randomized 2:1 to receive the RSV vaccine or placebo between 24 and 34 weeks of gestation.

Most of the women (80%) were between the ages of 18 and 34 years, with 17% ages 35 to 39 and the remaining over 40. When it came to race and ethnicity, 47% were white, 33% were Hispanic or Latino, and 14% were Black. About half were of low to middle income.

At day 43 after birth, data were available for 3,494 infants in the vaccine group and 1,739 in the placebo group. Of infants in the vaccine group, 237 were born prematurely (<37 weeks of gestation) versus 86 in the placebo group. The overall gestational age of infants was approximately 39 weeks and 97% had an Apgar score of 7 to 10 at 5 minutes.

Very preterm (28 to <32 weeks) or extremely preterm (<28 weeks) births occurred among 5.5% of infants in the vaccine group and 2.3% in the placebo group.

Neonatal deaths occurred in 0.4% of infants in the vaccine group and 0.2% of those in the placebo group (RR 2.16, 95% CI 0.62-7.56). This imbalance was probably attributable to the higher rate of preterm births in the vaccine group, the authors posited.

In post hoc analyses, Dormitzer and colleagues attempted to identify how the vaccine may have led to the increased risk of preterm birth, but noted that the mechanisms for the phenomenon remain unknown. "The intervals from vaccination to preterm delivery generally ranged from weeks to months," they wrote, "which suggests the absence of a direct effect of vaccination on mechanisms that initiated preterm birth." They found no association between inflammatory processes, as measured by cytokine levels in the mothers, and preterm birth.

Of note, the relative risk of preterm births in the vaccine group was highest among low- and middle-income countries (RR 1.56, 95% CI 1.17-2.09), where there is the greatest need for effective maternal RSV vaccines. Also, the greatest difference occurred when the Delta variant of the COVID pandemic was most pronounced, peaking between August and December 2021, the authors pointed out.

SARS-CoV-2 infection, especially during the Delta wave, has been associated with an increased risk of preterm birth, but that fact alone still could not account for the higher incidence of preterm births in the vaccine group, they said.

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