Clinical Summary | Paediatrics & Neonatology | Infectious Disease | Vaccines
Prefusion F Protein–Based Respiratory Syncytial Virus Immunization in Pregnancy
Time to read: 04:32
Time to read: 08:27
Type of article: Clinical Trial Summary
MedED Catalogue Reference: MPN007
Sources: NEJM
Category: Paediatrics & Neonatology
Cross-Category: Infectious Diseases, Vaccines
Keywords: RSV, Immunisation, pregnancy,
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Overview | Participants | Method & Measurement | Objectives & Endpoints | Findings | Conclusion
Overview
Each year, approximately 118,200 children die from infection with Respiratory Syncytial virus (RSV): most are infants younger than six months, and more than half of those deaths occur in developing countries.3
Currently, there is no vaccine or therapy to prevent RSV infection. Palivizumab (Synagis), a humanised monoclonal antibody, is most often administered prophylactically to high-risk infants, although its efficacy is only 45-55% in these cases. The multiple-dose regimen and the expense of the drug additionally hamper full-scale adoption of the treatment. In 2013, novel research conducted by McLellan et al. determined the effectiveness of the prefusion structure of the RSV-F protein, which revitalised efforts to develop a vaccine.
RSV-F protein is a “… membrane-anchored glycoprotein that mediates viral entry into host cells” 5 McLellan et al. found that antibodies specific to the prefusion form were highly effective at blocking virus infection, suggesting a prefusion F-based vaccine may confer optimal protection against RSV.1,4
Based on these findings, pharmaceutical company Pfizer set out to develop the first bivalent RSV prefusion F protein-based vaccine candidate (RSVpreF vaccine). The vaccine was accepted for review by the FDA in March 2022, having conferred it Breakthrough Therapy Designation.2
This study presents interim phase 2b trial results for pregnant women in their late second or third trimester. It focuses on the RSVpreF vaccine's safety, immunogenicity, and transplacental transfer of RSV-neutralising antibodies, serving as groundwork for upcoming phase 3 efficacy trials. The study did not set out to establish the vaccine's efficacy.
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Participants
The trial is a multicounty, observer-blinded, randomized, placebo-controlled, proof-of-concept conducted in the United States, Chile, Argentina, and South Africa. This report details the interim results from the United States; research continues in the Southern Hemisphere cohort.
A cohort of 407 women (403 infants) were selected. The median age of the women was 27 years (Range: 18-42 years)
327 women (80.5%) received the RSVpreF vaccine
The median gestation age was 31 weeks, three days (Range: 24 weeks, 0 days – 36 weeks, six days)
Study Design
The 407 women were randomly assigned at 24 through to 36 weeks gestation, to receive either 120 or 240 μg of RSVpreF vaccine (with or without aluminium hydroxide) or a placebo
Safety was monitored using an electronic diary for one week after vaccination and during planned visits at two and four weeks after delivery and at one, six, and twelve months after birth.
Umbilical cord blood was obtained, and infants were randomly assigned to two phlebotomy cohorts for blood draws at 1 and 4 months or 2 and 6 months.
Objectives & Endpoints
The primary safety endpoints of the trial were as follows:
Maternal:
Solicited local and systemic reactions were recorded within seven days after vaccination.
Unsolicited adverse events that occurred during the month after vaccination
Infant:
Unsolicited local and system reactions that occurred during the first month of life
Adverse events of special interest included congenital anomalies and developmental delay
Serious adverse events, medically attended adverse events, and adverse events of special interest that occurred throughout the observation period, from the first participant’s vaccination through January 31, 2020, were considered.
The immunogenicity endpoints in this interim analysis included 50% titres of RSV A, B, and combined A/B neutralising antibodies in maternal serum at delivery and umbilical cord blood, as well as maternal-to-infant transplacental transfer ratios.
Findings
Adverse Events
Maternal:
Less than 5% of participants reported a serious adverse event in the month following vaccination.
None of the reported events was considered to be related to the vaccine; rather, they were complications of pregnancy, labour, delivery, and the immediate postpartum period.
Post-vaccination reactions were mild to moderate, with a higher incidence of local reactions observed in women who received the RSVpreF vaccine containing aluminium hydroxide compared to those who received the vaccine without it.
Infants:
Of the 403 infants reviewed, 170 (42.2%) had an adverse event in the first month of life, the most common of which were neonatal jaundice or hyperbilirubinemia, delivery complications and minor GIT and infectious conditions common in neonates, none of which resulted from maternal vaccination.
15 (3.7%) preterm births were recorded, mostly in the 36th week: these were reported as adverse events, regardless of the outcome
Immunogenicity
The interim analysis showed that RSVpreF vaccine-elicited neutralising titres in maternal serum were achieved at delivery, approximately seven weeks after immunisation. Notably, RSV-neutralising titres in umbilical cord blood remained consistent regardless of gestational age at immunisation (24 to 36 weeks).
These findings support a three-month immunisation window during pregnancy, potentially simplifying prenatal immunisation by reducing the need to administer the RSV vaccine alongside other vaccines like tetanus–diphtheria–acellular pertussis or influenza during routine prenatal visits.
Vaccine efficacy
This phase 2b trial analysis was not intended to assess vaccine efficacy. However, a post hoc exploratory efficacy analysis revealed an efficacy of 84.7% for medically attended RSV-associated lower respiratory tract illness and 91.5% for severe medically attended cases.
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Conclusion
The researchers concluded that neutralizing titers were transferred across the placenta efficiently without serious side effects. Furthermore, while not the requirement of this report, their analysis suggests that the antibody transfer prevented medically attended RSV lower respiratory tract infection in infants.
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References:
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