Prefusion F Protein–Based Respiratory Syncytial Virus Immunization in Pregnancy
Type of article: Clinical Trial Summary
MedED Catalogue Reference: MPN007
Sources: NEJM
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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 is now developing 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
In this study, funded by Pfizer, the authors report on the interim results of the phase 2b trial for women in the late second or third trimester of pregnancy. The study is in preparation for phase 3 efficacy trials of (the RSVpreF vaccine). Specifically, the report reviews the interim analysis of the safety and immunogenicity of the RSVpreF vaccine and of the transplacental transfer of RSV-neutralizing antibodies. It did not set out to establish the efficacy of the vaccine.
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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) was selected
• 327 women (80.5%) received the RSVpreF vaccine
• The median age of the women was 27 years (Range: 18-42 years)
• The median gestation age was 31 weeks, three days (Range: 24 weeks, 0 days – 36 weeks, six days)
Method & Measurement
The 407 women were randomly assigned at 24 – 46 weeks gestation to receive 120 or 240 μg of RSVpreF vaccine (with or without aluminium hydroxide) or a placebo.
Women:
• Blood samples were drawn from the women before vaccination, then again 2 and 4 weeks later. Blood samples were retaken at delivery and at 1 and 6 months after birth
• The women were monitored for safety using an electronic diary one-week post-vaccination and at planned visits 2 and 4 weeks later, at delivery, and at 1, 6, and 12 months after birth.
Infants
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Infants were enrolled at birth and were evaluated 1, 2, 4, 6, and 12 months
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Umbilical cord blood was obtained at birth
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The infants were then randomly assigned into two cohorts for blood draws at 1 and 4 months or at 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.
Immunogenicity endpoints that, in this interim analysis, included:
“…50% titers of RSV A, B, and combined A/B neutralizing antibodies in maternal serum at delivery and in umbilical cord blood, as well as maternal-to-infant transplacental transfer ratios.”
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Findings
Adverse Events
Maternal:
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Less than 5% of participants reported a serious adverse event in the month following vaccination.
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Of the reported events, none were considered to be related to the vaccine but rather to“…complications of pregnancy, labour, delivery, and the immediate postpartum period.”
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The authors report that: “Most postvaccination reactions were mild to moderate; the incidence of local reactions was higher among women who received RSVpreF vaccine containing aluminium hydroxide than among those who received RSVpreF vaccine without aluminium hydroxide.”
Infants:
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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.
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According to the researchers, none of the above resulted from maternal vaccination.
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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 indicates that the RSVpreF vaccine-elicited neutralizing titers in maternal serum were obtained at deliveries that occurred, on average, approximately seven weeks after immunization. Most notably:This wide range of gestational ages for immunization may facilitate prenatal immunization, abrogating the need to administer tetanus–diphtheria–acellular pertussis or influenza vaccine concomitantly with RSV vaccine during the recommended prenatal visit schedule.”
Vaccine efficacy
This 2b trial analysis was not designed to determine an assessment of vaccine efficacy. That said, the exploratory efficacy analysis conducted post hoc, showed: “…efficacy of 84.7% and 91.5% for medically attended and severe medically attended RSV-associated lower respiratory tract illness, respectively.”
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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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