First step toward vaccine approval
Madhi and colleagues5 were among the first to conduct a large well-designed study to evaluate the effectiveness of maternal vaccination in preventing neonatal infection in the first few months of life. The authors enrolled more than 4,500 healthy pregnant women at 28 to 36 weeks of gestation and assigned them to receive either a single intramuscular dose of an RSV fusion (F) protein vaccine or placebo in a ratio of 2:1. The primary end point was a “medically significant lower respiratory tract infection” within the first 90 days of life. The percentage of infants who met the primary end point was low in both groups: 1.5% in the vaccine group and 2.4% in the placebo group (efficacy 39.4%). The efficacy of the vaccine in preventing lower respiratory tract infection with severe hypoxemia was 48.3% and 44.4% in preventing hospitalization. Although there were differences between the 2 groups, they did not meet the prespecified success criterion for efficacy. Vaccine recipients had more local injection site reactions (40.7% vs 9.9%); however, there was no difference in the frequency of other adverse effects.
Intermediate step: Continued assessment of vaccine safety and immunogenicity
The next important step in the development of the RSV vaccine was a study by Simoes et al,6 who conducted a phase 2b trial to determine the safety and immunogenicity of the RSVpreF vaccine. The authors randomly assigned pregnant women at 24 to 36 weeks of gestation to receive either 120 or 240 µg of RSVpreF vaccine or placebo. The key endpoints were the following: maternal and infant safety; the maternal-to-infant transplacental transfer ratio; and the presence of RSV A, B, and combined A/B neutralizing antibody in maternal serum and umbilical cord blood at delivery. The authors conducted a planned interim analysis that included 327 mothers who received the vaccine. The incidence of adverse effects was similar in mothers and infants in the vaccine compared with the placebo group. None of the adverse effects were judged to be serious. The transplacental neutralizing antibody transfer ratios ranged from 1.4 to 2.1 across a range of gestational ages. The vaccine elicited meaningful neutralizing titers of antibody in maternal serum even up to 7 weeks after immunization. The levels of neutralizing antibodies in umbilical cord blood did not vary substantially with respect to gestational age. A post hoc analysis showed that the transferred antibodies prevented medically-attended RSV-associated lower respiratory tract illnesses in the infants.
Final step: Convincing proof of efficacy
The most recent of the 3 studies, and the one that had the greatest impact in convincing the FDA to approve the vaccine, was the report by Kampmann and colleagues.7 The authors conducted a phase 3 prospective, randomized, double-blind trial in 18 different countries over 4 RSV seasons: 2 in the northern hemisphere and 2 in the southern hemisphere. They enrolled healthy pregnant women with singleton gestations at 24 to 36 weeks of gestation and assigned them in a 1:1 ratio to a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. They excluded patients with any recognized risk factor for an adverse pregnancy outcome, including preterm labor. The 2 primary efficacy endpoints were a medically-attended severe RSV–lower respiratory tract infection and any medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth.
The efficacy of the vaccine in preventing severe lower respiratory tract illness within 90 days of delivery was 81.8% (99.5% confidence interval [CI], 40.6–96.3). The efficacy within 180 days of delivery was 69.4% (97.58% CI, 44.3–84.1). These differences reached the study’s pre-established statistical criteria for success. The overall rate of lower respiratory tract infections was not significantly different. The frequencies of adverse effects in mothers and infants were similar in the vaccine and placebo groups. In particular, the frequency of preterm delivery in the vaccine group was 0.8%, compared with 0.6% in the placebo group (P = NS).
In previous reports to the FDA,4 the frequency rate of preterm delivery in RSV vaccine recipients was slightly increased in vaccine recipients compared with patients who received placebo. The difference among the groups was too small to infer a causal relationship; however, as a condition of vaccine approval, the FDA has required Pfizer to conduct a postmarketing study to be certain that administration of the vaccine does not increase the risk for preterm delivery.
Practical details
The new vaccine is a bivalent recombinant vaccine that elicits a robust antibody response against the F (fusion) protein of the virus. In addition to the F antigen, the vaccine contains the following buffer ingredients: tromethamine, sucrose, mannitol, polysorbate, and sodium chloride.8 There are no preservatives in the vaccine.
The vaccine should be administered in a single, 0.5 mL, intramuscular injection at 32 to 36 weeks of gestation. Patients who are allergic to any of the components of the vaccine should not be vaccinated. Patients with a mild upper respiratory tract infection may receive the vaccine. Administration should be delayed in patients who are moderately to severely ill. The vaccine may be administered at the same time as other vaccines, such as influenza or Tdap.
The most common side effects of the vaccine are local injection site reactions, such as pain, redness, or swelling. Some patients may experience mild systemic manifestations, including fatigue, fever, headache, nausea, diarrhea, arthralgias, and myalgias. According to the Centers for Disease Control and Prevention, the approximate wholesale acquisition cost of the vaccine is $320 for 1 injection.
CASE Resolution
This patient is healthy and has no contraindication to the new RSV vaccine. According to the FDA, the optimal time for administration of the vaccine is 32 to 36 weeks of gestation. The patient should anticipate very few side effects following the vaccination, and the vaccine has approximately 80% efficacy in preventing severe lower respiratory tract infection in her neonate. ●
KEY POINTS
- RSV is the most common cause of acute lower respiratory tract infection in infants younger than 6 months of age.
- In low- and middle-resource countries, RSV is a leading cause of infant death.
- In late August 2023, the FDA approved the first RSV vaccine that can be administered to pregnant women to provide protection for the infant in the first few months of life.
- The vaccine specifically targets the F protein of the virus, a protein which is essential for facilitating fusion between the viral and host cell membranes, resulting in penetration of the virus into the host cell.
- The vaccine should be administered as a single intramuscular injection at 32 to 36 weeks’ gestation.
- The vaccine is approximately 82% effective in preventing severe lower respiratory tract infection in infants within the first 6 months of life.
- To exercise an abundance of caution, because of a possible association between administration of the vaccine and an increased risk for preterm delivery, vaccination should be delayed until 36 weeks in patients clearly identified as at-risk for preterm delivery.