A phase 3 trial of a maternal vaccine candidate for respiratory syncytial virus (RSV) has been stopped early because the risk for preterm births is higher in the candidate vaccine group than in the placebo group, said sponsor GSK.
By 25 February 2022 when enrolment was halted because of the safety signal, 5 328 pregnant women had been vaccinated – about half of the intended 10 000 participants.
Of these, 3 557 received the candidate RSV prefusion F protein–based maternal vaccine, and another 1 771 received a placebo.
Data from the trial were immediately made available when recruitment and vaccination were stopped, and investigation of the preterm birth risk followed, reports Medscape.
Results of that analysis, led by Ilse Dieussaert of vaccine development at GSK in Belgium, were published in The New England Journal of Medicine.
“We have discontinued our work on this … and closing out all ongoing trials, with the exception of the MAT-015 follow-on study to monitor subsequent pregnancies,” said a GSK spokesperson.
The trial was conducted in pregnant women aged 18-49 to assess the efficacy and safety of the vaccine. They were randomly assigned 2:1 to receive the candidate vaccine or placebo between 24 and 34 weeks’ gestation.
Preterm births
The primary outcomes were any or severe medically assessed RSV-associated lower respiratory tract infection in infants from birth to six months, and safety in infants from birth to 12 months.
The data showed preterm birth occurred in 6.8% of the infants in the vaccine group and in 4.9% of those in the placebo group (relative risk [RR], 1.37; 95% CI, 1.08-1.74; P = .01).
Neonatal death occurred in 0.4% in the vaccine group and 0.2% in the placebo group (RR, 2.16; 95% CI, 0.62-7.56; P = .23).
To date, only one RSV vaccine (Abrysvo, Pfizer) has been approved for use in pregnancy to protect infants from RSV-associated lower respiratory tract infection.
“It was a very big deal that this trial was stopped, and the new candidate won’t get approval,” said Aaron Glatt, MD, chair of the Department of Medicine and chief of Infectious Diseases and hospital epidemiologist at Mount Sinai South Nassau, New York.
Only one RSV vaccine approved in pregnancy
Glatt said the GSK vaccine is like the maternal vaccine that did get approved. “The data clearly show a slight but increased risk in preterm labour,” he said, “and while not as obvious, there was an increase in neonatal death in the group of very small numbers – but any neonatal death is concerning.”
The implications were disturbing, he added. “You’re giving this vaccine to prevent neonatal death.”
Though the Pfizer vaccine that was granted approval had a slight increase in premature birth, the risk wasn’t statistically significant, he said, “and it showed similar benefits in preventing neonatal illness, which can be fatal”.
Glatt said there is still a lingering concern with the approved vaccine, and that most clinicians would give it closer to the end of the recommended time window of 34 weeks.
“So even if there is a slight increase in premature term labour, you’re probably not going to have a serious outcome because the baby will be far enough along.”
A difference in the incidence of preterm birth between the experimental vaccine and placebo groups was predominantly found in low- and middle-income countries, said Dieussaert’s team, where 50% of the trial population was enrolled and where the medical need for maternal RSV vaccines is the greatest.
The RR was 1.56 (95% CI, 1.17-2.10), for low- and middle-income countries and 1.04 (95% CI, 0.68-1.58) in high-income countries.
“If a smaller percentage of participants from low- and middle-income countries had been enrolled, the relative risk for preterm birth in the vaccine group compared with the placebo group might have been reduced in the overall trial population,” they reported.
The authors said the data do not reveal the cause of the higher risk for preterm birth in the vaccine group.
“GSK completed all necessary steps of product development, including preclinical toxicology studies and clinical studies in non-pregnant women, before starting the studies in pregnant women. There were no safety signals identified in any of the earlier parts of the clinical testing. There have been no safety signals identified in the other phase 3 trials for this vaccine candidate.”
Researchers did not find a correlation between preterm births in the treatment vs control groups with gestational age at time of vaccination or with particular vaccine clinical trial material lots, race, ethnicity, maternal smoking, alcohol consumption, body mass index, or time between study vaccination and delivery.
The GSK spokesperson said the halted vaccine is different from GSK’s currently approved adjuvanted RSV vaccine (Arexvy) for adults over 60.
What's next …
Maternal vaccines have been effective in preventing other diseases in infants, such as tetanus, influenza, and pertussis, but RSV is a very hard virus for which to make a vaccine, Glatt said.
“There is a great to have more than one option for a maternal RSV vaccine, to address any potential supply concerns. And people have to realise how serious RSV can be in infants… It can be fatal disease, and serious even in healthy children.”
Study details
RSV Prefusion F Protein–Based Maternal Vaccine — Preterm Birth and Other Outcomes
Ilse Dieussaert, Joon Hyung Kim, Philip Dormitzer et al.
Published in New England Journal of Medicine on 14 March 2024
Abstract
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, enrolment and vaccination were stopped early, and exploratory analyses of the safety signal of preterm birth were performed.
Results
The analyses included 5 328 pregnant women and 5 233 infants; the target enrolment of approximately 10 000 pregnant women and their infants was not reached because enrolment 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.
Conclusions
The results of this trial, in which enrolment 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.
Medscape article – Risk for Preterm Birth Stops Maternal RSV Vaccine Trial (Open access)
See more from MedicalBrief archives:
Significant drop in newborns’ RSV risk with vaccine for pregnant women
First RSV jab for adults approved by FDA
Conflict over Pfizer RSV vaccine trial informed consent
FDA approves RSV jab for use in pregnant women