Efficacy, Safety, and Immunogenicity of the MATISSE (Maternal Immunization Study for Safety and Efficacy) Maternal Respiratory Syncytial Virus Prefusion F Protein Vaccine Trial

Abstract

Objective: To evaluate descriptive efficacy data, exploratory immunogenicity data, and safety follow-up through study completion from the global, phase 3 MATISSE (Maternal Immunization Study for Safety and Efficacy) maternal vaccination trial of bivalent respiratory syncytial virus (RSV) prefusion F protein vaccine (RSVpreF).

Methods: MATISSE was a phase 3, randomized, double-blinded, placebo-controlled trial. Healthy pregnant participants aged 49 years or younger at 24-36 weeks of gestation were randomized (1:1) to receive a single RSVpreF 120 micrograms or placebo dose. Primary efficacy endpoints included newborn and infant severe RSV-associated medically attended lower respiratory tract illness within 180 days after birth. The RSV-A and RSV-B serum neutralizing antibody titers were determined in a subset of pregnant participants and their newborns.

Results: In this final analysis, 7,420 pregnant participants were randomized, and 7,307 children were born (RSVpreF n=3,660, placebo n=3,647). Vaccine efficacy , defined as protection against newborn and infant severe RSV-associated medically attended lower respiratory tract illness, was 82.4% (95% CI, 57.5-93.9) and 70.0% (95% CI, 50.6-82.5) within 90 and 180 days of birth, respectively. The RSVpreF induced robust immune responses in pregnant participants and resulted in highly efficient transfer of maternal antibodies to their newborns across subgroups (by gestational age at delivery and at vaccination, number of days from vaccination to delivery, country, maternal age). Final RSVpreF safety results in pregnant and newborn and infant participants were consistent with the primary analysis with no new safety concerns identified.

Conclusion: This final analysis of MATISSE trial data confirms the primary analysis conclusions: Maternal vaccination with RSVpreF has a favorable safety profile in both pregnant and newborn and infant participants and demonstrates efficacy against RSV-associated lower respiratory tract illness in infants through age 6 months. The RSVpreF induces robust immune responses in pregnant individuals, with corresponding high RSV-neutralizing titers in their newborns.

Clinical trial registration: ClinicalTrials.gov , NCT04424316.

Fig. 1.. Vaccine efficacy in newborns and infants. Vaccine efficacy for severe respiratory syncytial virus (RSV)–associated medically attended lower respiratory tract illness (LRTI) (A) and for RSV-associated medically attended LRTI occurring within 180 days after birth in newborns and infants in the primary and final analyses (B). C and D. Cumulative case curves for severe RSV-associated medically attended LRTI and RSV-associated medically attended LRTI, respectively, for the final analysis. Data are for the evaluable efficacy population. RSV-associated LRTI cases of any severity were confirmed by the Endpoint Adjudication Committee. The criterion for vaccine efficacy with respect to the primary analysis was a lower boundary of the CI of more than 20%. Error bars for the primary analysis are 99.5% CIs for 90 days after birth and 97.58% CIs for later timepoints as described previously. Error bars for the final analysis are 95% CIs. For the primary analysis, 3,495 newborns and infants were in the RSV prefusion F protein vaccine (RSVpreF) group and 3,480 were in the placebo group; corresponding numbers for the final analysis were 3,585 and 3,563. The associated data are provided in Appendix 6 (available online at http://links.lww.com/AOG/D942).

Fig. 2.. Parental (A) and newborn (B) combined respiratory syncytial virus (RSV)-A/RSV-B geometric mean titers by subgroup. Geometric mean titers after delivery (A) or birth (B) and corresponding two-sided Student t distribution CIs and geometric mean fold rises from before vaccination to delivery (A. RSV prefusion F protein vaccine [RSVpreF] only) were calculated by exponentiating the mean logarithm of the titers or fold rises, respectively. Assay results below the lower limit of quantitation were set to 0.5 times the lower limit of quantitation. In both panels, error bars represent 95% CIs. Horizontal dashed purple line in B refers to the 50% RSV-neutralizing titers of a serum palivizumab concentration of 100 mg/mL providing 97.5% or higher protection from pediatric intensive care unit admission for newborns and infants at high risk for severe RSV disease attributed to RSV-A/RSV-B. GA, gestational age (weeks); NT, neutralizing titer.

Fig. 3.. Newborn combined respiratory syncytial virus (RSV)-A/RSV-B–neutralizing titer geometric mean ratios (GMRs) and geometric mean titers (GMTs) by subgroup. The GMTs and GMRs and the corresponding two-sided Student t distribution CIs were calculated by exponentiating the mean logarithm of the titers or the mean differences in the logarithms of the titers (RSV prefusion F protein vaccine [RSVpreF] group – placebo group), respectively. Assay results below the lower limit of quantitation were set to 0.5 times the lower limit of quantitation.

Fig. 4.. Parent-to-newborn placental transfer ratio of combined respiratory syncytial virus (RSV)-A/RSV-B–neutralizing titers by subgroup: RSV prefusion F protein vaccine (RSVpreF) group. For each parent–newborn dyad, the transfer ratio was calculated as the ratio of the newborn's RSV-neutralizing titer to the pregnant individual's with back-transformed Student t distribution CIs. Error bars are 95% CIs. Assay results below the lower limit of quantitation were set to 0.5 times the lower limit of quantitation. GA, gestational age (weeks).

Fig. 5.. Safety in children from birth to age 24 months. A and B. Adverse events of special-interest and newly diagnosed chronic medical conditions, respectively, occurring in 0.1% or more of pediatric participants in either study group. C. Serious adverse events occurring in 1% or more of pediatric participants in either study group. Error bars are two-sided 95% CIs. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; GERD, gastroesophageal reflux disease; RSVpreF, respiratory syncytial virus prefusion F protein vaccine.