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.

OBJECTIVE: To describe preterm birth frequency and newborn and infant outcomes overall and among preterm children in the MATISSE (Maternal Immunization Study for Safety and Efficacy) trial of maternal vaccination with bivalent respiratory syncytial virus (RSV) prefusion F protein–based vaccine (RSVpreF) to protect infants against severe RSV-associated illness. METHODS: MATISSE was a global, phase 3, randomized, double-blind trial. Pregnant individuals received single injections of RSVpreF or placebo. Adverse events of special interest, including preterm birth (gestational age less than 37 weeks) and low birth weight (2,500 g or less), were collected through 6 months after delivery (pregnant participants) and from birth through age 12 or 24 months (pediatric participants). RESULTS: Overall, 7,386 pregnant participants received RSVpreF (n=3,698) or placebo (n=3,688); 7,305 newborns and infants were included in the analysis. Most children in both groups were born full term (more than 93%) with normal birth weight (95% or higher). Newborn and infant outcomes, including rates of low birth weight and neonatal hospitalization, were favorable and comparable between groups. Preterm birth rates were 5.7% in the RSVpreF arm and 4.7% in the placebo arm (relative risk [RR] 1.20, 95% CI, 0.98–1.46); most were late preterm. Newborn and infant outcomes, including rates of low birth weight and neonatal hospitalization, were comparable between groups. Twenty-two newborn or infant deaths occurred during the study (RSVpreF n=8, placebo n=14). When stratified by income region, preterm birth rates in RSVpreF and placebo recipients were both 5.0% in high-income countries. Rates in non–high-income countries were 7.0% and 4.0% in the RSVpreF and placebo groups, respectively, and 8.3% and 4.0% in South Africa (RR 2.06, 95% CI, 1.21–3.51). CONCLUSION: In this study of maternal RSVpreF vaccination, no clinically significant increase in adverse events of special interest, including preterm birth, low birth weight, or neonatal hospitalization, was observed among pregnant people in the overall analysis. In subgroup analysis of non–high-income countries, an elevated risk of preterm birth was observed. More research is needed to better ascertain preterm delivery risk factors, particularly aimed at minimizing disparities among geographic regions. FUNDING SOURCE: This study was sponsored by Pfizer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04424316.

Background: Older individuals and adults with certain chronic or immunocompromising health conditions are at increased risk of severe respiratory syncytial virus (RSV) disease. Methods: In this phase 3 randomized trial of RSVpreF safety and immunogenicity in 18–59-year-olds at high risk of severe RSV disease, participants were randomized 2:1 to 1 RSVpreF (120 µg) or placebo dose. Primary safety endpoints included reactogenicity events and adverse events (AEs) through 7 days and 1 month after vaccination, respectively, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) throughout the study. In primary analyses, immunogenicity elicited 1 month after RSVpreF was bridged to a randomly selected subset of ≥60-year-olds receiving RSVpreF from the immunogenicity subset in the pivotal phase 3 RENOIR trial, which demonstrated RSVpreF efficacy. Noninferiority was declared if 95% confidence interval (CI) lower bounds were >.667 (neutralizing titer adjusted geometric mean ratios) and >−10% (seroresponse rate differences) for RSV-A and RSV-B. Results: Overall, 678 participants received RSVpreF (n = 453) or placebo (n = 225). Most reactogenicity events were mild/moderate; severe events occurred in ≤2.0% of participants overall. AE frequencies were similar in RSVpreF (7.1%) and placebo recipients (7.6%). No vaccine-related SAEs or NDCMCs were reported. One month after RSVpreF administration, noninferiority criteria were met in 18–59-year-olds versus ≥60-year-olds for RSV-A and RSV-B neutralizing titers and seroresponse rates. Conclusions: RSVpreF was well tolerated with no safety concerns and demonstrated immunobridging to efficacy in 18–59-year-olds at high risk of severe RSV disease versus ≥60-year-olds in whom efficacy was previously demonstrated, supporting use of RSVpreF to prevent RSV-associated disease in this population. NCT05842967.

Background: Maternal vaccination with respiratory syncytial virus prefusion F vaccine (RSVpreF) is effective at preventing RSV-associated lower respiratory tract illness (LRTI) in newborns/infants. Methods: This subgroup analysis from the global, phase 3, randomized, double-blind, placebo-controlled MATISSE (Maternal Immunization Study for Safety and Efficacy) trial evaluated participants enrolled in Japan. Pregnant women 24–36 weeks’ gestation were randomized 1:1 to receive RSVpreF or placebo. Maternal safety endpoints included local reactions/systemic events within 7 days, adverse events (AEs) through 1 month, and serious AEs (SAEs) through 6 months after vaccination. In infants born to maternal participants, safety endpoints included specific birth outcomes, AEs through 1 month after birth, and SAEs and newly diagnosed chronic medical conditions through 12 or 24 months after birth. Vaccine efficacy in infants was assessed against RSV-positive, medically attended LRTI (RSV-MA-LRTI) and severe RSV-MA-LRTI through 180 days after birth. Results: In Japan, 230 maternal participants received RSVpreF and 232 received placebo; 218 and 216 infants born to these mothers, respectively, were analyzed. Observed vaccine efficacy (95 % CIs) against infant RSV-MA-LRTI within 90 and 180 days after birth was 100.0 % (30.9, 100.0; RSVpreF, 0 cases; placebo, 7 cases) and 87.6 % (7.2, 99.7; RSVpreF, 1 case; placebo, 8 cases), respectively. Vaccine efficacy (95 % CIs) against severe RSV-MA-LRTI within 90 and 180 days was 100.0 % (−140.9, 100.0; RSVpreF, 0 cases; placebo, 3 cases) and 75.1 % (−151.5, 99.5; RSVpreF, 1 case; placebo, 4 cases), respectively. No safety concerns were identified. AE rates ≤1 month after vaccination/birth were similar in the RSVpreF (maternal, 16.1 %; infant, 48.6 %) and placebo (19.8 %; 50.5 %) groups. Preterm birth rates were also similar (RSVpreF, 3.2 %; placebo, 6.0 %). Conclusions: Safety and efficacy data in Japanese participants were consistent with overall MATISSE results, supporting the efficacy of maternal RSVpreF vaccination against severe MA-RSV-LRTI/MA-RSV-LRTI in infants, with no safety concerns. NCT04424316.

Background/Objectives: Individuals with immunocompromising conditions are at high risk of developing severe respiratory syncytial virus (RSV) illness. This phase 3, single-arm study assessed the safety and immunogenicity of the bivalent RSV prefusion F protein−based (RSVpreF) 120-µg vaccine in immunocompromised and renally impaired adults. Methods: Participants were stratified by age group (18−<60-year-olds; ≥60-year-olds) and received two RSVpreF doses 1 month apart (i.e., Dose 1 and Dose 2, respectively). Reactogenicity events were collected for 7 days after each dose; adverse events through 1 month after the last dose; and serious adverse events, adverse events of special interest, and newly diagnosed chronic medical conditions throughout the study. Results: One month after Dose 1, RSVpreF elicited robust immune responses overall and across age and immunocompromised subgroups. Overall, geometric mean fold rises from before to 1 month after Dose 1 were high for RSV A and RSV B (8.3 and 9.0, respectively); no additional increases 1 month after Dose 2 (7.5 and 7.8) were observed. The most frequent local reaction was pain at the injection site, which was more common after Dose 2 than after Dose 1. The most frequent systemic event after any dose was fatigue. Most local reactions and systemic events were mild or moderate in severity. Adverse event and serious adverse event rates were 13.5% and 7.3% among 18−<60-year-olds and 22.4% and 14.0% among ≥60-year-olds, respectively. Conclusions: A single dose of the RSVpreF vaccine conferred robust immune responses in immunocompromised and renally impaired adults with no safety concerns. (ClinicalTrials.gov Identifier: NCT05842967).

Bivalent RSV prefusion F subunit vaccine (RSVpreF), comprised of equal quantities of stabilized prefusion F antigens from the major circulating subgroups (RSV A, RSV B), is licensed for prevention of RSV-associated lower respiratory tract illness (LRTI) in older adults and for maternal vaccination for prevention of RSV-associated LRTI in infants. To support licensure and large-scale manufacturing, this lot consistency study was conducted to demonstrate equivalence in immunogenicity across 3 RSVpreF lots. This phase 3, multicenter, parallel-group, placebo-controlled, randomized (1:1:1:1), double-blind study evaluated immunogenicity, safety, and tolerability of RSVpreF in healthy 18-49-year-old adults. Participants received a single 120-µg injection of 1 of 3RSVpreF lots or placebo. Geometric mean ratio (GMR) of RSV serum 50 % neutralizing geometric mean titers obtained 1 month after vaccination were compared between each vaccine lot for RSV A and RSV B, separately. Equivalence between lots was defined using a 1.5-fold criterion (GMR 95 % CIs for every lot pair within the 0.667-1.5 interval). Safety and tolerability were assessed. Of 992participants vaccinated, 948 were included in the evaluable immunogenicity population. All 3 RSVpreF lots elicited strong immune responses, meeting the 1.5-fold equivalence criterion for all between-lot comparisons for both RSV A and RSV B. Across the 3 lots, RSV A and RSV B 50 % neutralizing geometric mean titers substantially increased from baseline (RSV A, 1671-1795; RSV B 1358-1429) to 1 month after RSVpreF vaccination (RSV A, 24,131-25,238; RSV B, 19,238-21,702), corresponding to ≥14-fold increases in 50 % neutralizing titers for both RSV A and RSV B from before to 1 month after vaccination. Single doses of RSVpreF were safe and well tolerated, with similar safety profiles across the 3 RSVpreF lots. These findings support the reproducibility of RSVpreF vaccine manufacturing with similar safety and reactogenicity profiles (NCT05096208).