Active immunization of pregnant women with investigational vaccine protected infants from RSV from birth through at least 6 months.
An investigational vaccine against respiratory syncytial virus (RSV) administered to pregnant women in a phase 2b trial produced sufficient maternal immunogenic response and transplacental antibody transfer for infants to demonstrate protection from birth to at least 6 months of age. The prepublication, interim results of the trial informed the Food and Drug Administration (FDA) decision in March to designate the vaccine as a Breakthrough Therapy.
Alejandra Gurtman, MD, Vaccine Research and Development, Pfizer, and colleagues employed 2 strategies to improve on an earlier effort, in which inactivated whole-virus vaccine administered directly to infants actually worsened illness when initial RSV exposure occurred after vaccination: They developed an alternative to the inactivated whole-virus; and administered it to pregnant women who, along with all adults, have had previous exposure to RSV.
"Adults have universally had exposure to RSV, so the immunization of pregnant women could circumvent the risk of disease enhancement (ie, increased severity) and passively protect infants before the peak incidence of RSV disease at approximately 6 weeks of age," Gurtman and colleagues explained. "The effect of maternal immunization on protection against influenza, tetanus, and pertussis in infants is well established."
Rather than an inactivated whole virus, the current vaccine candidate exploits the prefusion structure of the RSV F protein, which has been identified as the primary target of neutralizing antibodies. The bivalent RSV prefusion F protein-based (RSVpreF) vaccine is composed of two preF proteins, selected to optimize protection against both RSV A and B.
The investigators sought a dose and formulation which would provoke immunogenicity endpoints and transplacental transfer ratios, while being safe and well tolerated by mother and infant. Two doses (120μg and 240 μg) with and without an aluminum hydroxide adjuvant and placebo were administered on a 1:1:1:1:1 random assignment to participating women in gestation week 24 though 36.
Although the trial is being conducted in the US, Chile, Argentina, and South Africa, the interim analysis, received by the FDA and in the current publication, was based on findings with 406 women and 403 infants in the US, with 327 women having received a formulation of the RSVpreF vaccine. The vaccinations were timed to precede RSV season in each hemisphere, and provide infants protection from likely exposure at 6 months of age or younger.
Mothers were monitored through their electronic diary for 1 week after vaccination, and at visits at 2 and 4 weeks after vaccination, at delivery, and at 1, 6, and 12 months after birth. Infants were evaluated at 1,2,4,6 and 12 months. Most post-vaccination reactions were mild to moderate, although the incidence of local reactions was higher with the aluminum hydroxide adjuvant.
Gurtman and colleagues reported that the geometric mean titer ratios for neutralizing antibodies in the vaccinated maternal participants relative to placebo ranged from 11.0 to 15.1 for RSV A and from 13.7 to 17.5 for RSV B. The corresponding mean titer ratios in umbilical cord ranged from 9.7 to 11.7 for RSV A and 13.6 to 16.8 for RSV B. Transplacental transfer ratios for RSV A or B were 1.68 to 2.10 from vaccine without aluminum hydroxide and 1.41 to 1.67 with the adjuvant. The mean titer ratios for neutralizing antibodies and trans-placental transfer ratios were similar in infants irrespective of dose or the timing of immunization between 24 to 36 weeks gestation.
Although full evaluation of efficacy will await data from the entire cohort, the investigators found that in the 4 RSVpreF vaccine groups in the US relative to placebo, preliminary case distribution corresponds to efficacies of 84.7% (95% CI 21.6-97.6) against medically attended RSV- associated lower respiratory tract illness, and 91.5% (-5.6 to 99.8) against severe RSV-associated lower respiratory tract illness.
"RSVpreF vaccine elicited neutralizing antibody responses with efficient transplacental transfer and without evident safety concerns," concluded Gurtman and colleagues.
Kathrin Jansen, PhD, senior vice president and Head of Vaccine Research and Development, Pfizer, remarked in a statement, "if approved by the FDA, this maternal immunization has the potential to be the first vaccine candidate to help protect infants in their vulnerable first months of life from disease caused by this highly contagious virus."