Safety and immunogenicity of an investigational maternal trivalent group B streptococcus vaccine in healthy women and their infants: a randomised phase 1b/2 trial

Maternal group B streptococcus (GBS) serotype-specific capsular antibody concentrations are correlated with susceptibility to neonatal GBS invasive disease. Maternal immunisation against GBS during pregnancy might protect infants across the period of susceptibility to invasive disease, but no licensed vaccine exists. This study assessed the safety and immunogenicity of a CRM197-conjugated trivalent GBS vaccine in non-pregnant and pregnant women, and antibody transfer to their infants. We did a phase 1b/2, randomised, observer-blind single-centre study of an investigational trivalent GBS vaccine in healthy non-pregnant women (cohort 1), and a dose-ranging study in healthy pregnant women (cohort 2). The study was done at the Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Participants were healthy non-pregnant or pregnant (28–35 weeks' gestation) women aged 18–40 years. In cohort 1, non-pregnant women were randomly assigned (2:1) to receive the investigational vaccine (two injections, 1 month apart, of a 20 μg dose [of each serotype] of aluminium hydroxide-adjuvanted investigational vaccine) or placebo. In cohort 2, pregnant women were randomly assigned (1:1:1:1) to receive one injection at 28–35 weeks' gestation of 0·5 μg, 2·5 μg, or 5·0 μg of the non-adjuvanted investigational vaccine (for each serotype), or placebo. All study participants and study staff not involved with vaccine preparation were masked to the randomisation group. The vaccine contained an equal dose (0·5 μg, 2·5 μg, 5·0 μg, or 20 μg) of each of three glycoconjugates (serotypes Ia, Ib and III). Reactogenicity was monitored to day 7 and unsolicited adverse events (adverse events) and infant safety were recorded throughout the study. The primary outcomes were tolerability and GBS-specific antibody response (measured as geometric mean concentrations [GMCs] in μg/mL) following the two injections for cohort 1, and selection of one vaccine dose based on analysis of serotype-specific antibody responses at delivery (+72 h) for use in subsequent studies. These outcomes were assessed in participants or infants of participants who correctly received the study vaccine with no major protocol deviations, and provided evaluable serum samples at day 1 and the scheduled timepoints throughout the study. This study is registered with ClinicalTrials.gov, NCT01193920. Between Oct 5, 2010, and Sept 21, 2011, we screened 75 non-pregnant and 417 pregnant healthy South African women. Of these, 60 non-pregnant women were enrolled in cohort 1 (40 randomly assigned to the GBS 20 μg group and 40 randomly assigned to the placebo group) and 320 pregnant women were enrolled in cohort 2 (80 in each of the four groups). Among the randomised groups of pregnant women, 33–40% experienced at least one local and 54–71% one systemic solicited adverse event, less than 4% of which were severe, and the rate did not differ by study group. Also, 2% of the pregnancies resulted in stillbirth and 3·5% of the liveborn babies died by 12 months age, none of these deaths were attributed to vaccination. There was one death in a GBS-vaccine recipient, which too was unrelated to vaccination. For cohort 1, serotype-specific antibody concentrations were significantly higher, as evident by no overlap of the 95% CIs of GMCs against all three serotypes in the vaccinated group than the placebo group. For cohort 2, pregnant women in all vaccine groups had significantly higher GMCs than did those in the placebo group at delivery (eg, GMCs against serotype Ia were 11 μg/mL [95% CI 7·0–18] for the GBS vaccine 0·5 μg group, 18 μg/mL [11–29] for the GBS vaccine 2·5 μg group, 22 μg/mL [13–35] for the GBS vaccine 5·0 μg group, and 0·64 μg/mL [0·42–0·98] for the placebo group) and at all measured timepoints. GMCs did not differ significantly between the vaccine doses at any of the measured timepoints (p>0·05). The vaccine was well tolerated and induced capsular-specific antibody responses, in non-pregnant and pregnant women. Maternal vaccination led to higher GBS serotype-specific antibody concentrations in infants than did placebo, with both interventions resulting in similar safety profiles. Novartis Vaccines and Diagnostics division, now part of the GlaxoSmithKline group of companies.