Abstract

BACKGROUND: GBS-AlpN is a novel group B streptococcus maternal vaccine, based on the N-terminal domains of the alpha-like proteins AlphaCN, RibN, Alp1N, and Alp2/3N, which are responsible for 99% of invasive group B streptococcus strains. We aimed to assess the safety and immunogenicity of GBS-AlpN in pregnant women receiving vaccination or placebo. METHODS: This phase 2, observer-blind, randomised, placebo-controlled study was done in ten health-care facilities in South Africa, Denmark, and the UK. Eligible participants were healthy women carrying a singleton pregnancy without detectable congenital abnormalities at 21 weeks and 0 days to 23 weeks and 6 days of gestation at first vaccination. Participants were randomly assigned (2:2:2:2:1) via an electronic case report to receive two GBS-AlpN vaccine doses and one placebo dose (groups 1, 2, and 3), one GBS-AlpN vaccine dose and two placebo doses (group 4), or no vaccine doses and three placebo doses (group 5). Randomisation was stratified by site and within site using blocks of nine. Participants received 0·5 mL GBS-AlpN or placebo (saline) intramuscularly at 22 (placebo), 26 (vaccine), and 30 (vaccine) weeks' gestational age (group 1); 22 (vaccine), 26 (vaccine), and 30 (placebo) weeks' gestational age (group 2); 22 (vaccine), 26 (placebo), and 30 (vaccine) weeks' gestational age (group 3); 22 (placebo), 26 (vaccine), and 30 (placebo) weeks' gestational age (group 4); and 22 (placebo), 26 (placebo), and 30 (placebo) weeks' gestational age (group 5). All individuals (study staff and participants) were masked to group allocation, except those administering vaccines. The primary endpoint was the concentration of AlphaCN, RibN, Alp1N, and Alp2/3N protein-specific IgG in umbilical cord blood or blood obtained from infants within 72 h of birth and the proportion of infants with AlpN-specific IgG concentrations above a range of prespecified descriptive thresholds (0·1, 0·2, 0·5, 1·0, 2·0, 4·0, and 8·0 μg/mL). Safety endpoints were evaluated in participants who received at least one vaccination, and their infants. Immunogenicity analyses included participants in the safety population who provided an evaluable sample following first GBS-AlpN or placebo. This trial is registered with ClinicalTrials.gov, NCT05154578, and is closed to enrolment. FINDINGS: Between Feb 17 and Nov 22, 2022, 400 participants were screened for eligibility, of whom 272 were randomly assigned (group 1 n=61; group 2 n=60; group 3 n=59; group 4 n=62; group 5 n=30). 269 participants received at least one dose of GBS-AlpN or placebo (group 1 n=61; group 2 n=59; group 3 n=59; group 4 n=60; and group 5 n=30). The highest serum IgG concentrations at birth were observed in group 1, followed by the other two dose vaccine groups (groups 2 and 3). Lower IgG concentrations were observed in group 4, although these were at least 21-fold higher than in group 5 (placebo only). The proportion of infants with IgG concentrations greater than 1·0 μg/mL in umbilical cord blood ranged from 33 (87%) of 38 to 34 (94%) of 36 in group 1, 30 (67%) of 45 to 43 (91%) of 47 in group 2, 37 (82%) of 45 to 38 (93%) of 41 in group 3, and 22 (61%) of 36 to 28 (80%) of 35 in group 4. No infants in the placebo group had antibody concentrations greater than 1·0 μg/mL for any of the AlpN proteins. Treatment-emergent adverse events were reported by 56 (92%) of 61 maternal participants in group 1, 54 (92%) of 59 in group 2, 57 (97%) of 59 in group 3, 56 (93%) of 60 in group 4, and 26 (87%) of 30 in group 5; most events were mild-moderate. Nine infant fatalities were reported; none were considered related to vaccination. INTERPRETATION: GBS-AlpN had an acceptable safety profile and was immunogenic when administered to pregnant women, supporting its progression to phase 3 trials, with a flexible two-dose schedule allowing dosing intervals of 4-8 weeks. FUNDING: MinervaX.