Safety and Immunogenicity of a Second Dose of an Investigational Maternal Trivalent Group B Streptococcus Vaccine in Nonpregnant Women 4-6 Years After a First Dose: Results From a Phase 2 Trial

Abstract

Background: Maternal immunization against group B streptococcus (GBS) could protect infants from invasive GBS disease. Additional doses in subsequent pregnancies may be needed. We evaluated the safety and immunogenicity of a second dose of an investigational trivalent CRM197-glycoconjugate GBS vaccine (targeting serotypes Ia/Ib/III), administered to nonpregnant women 4-6 years postdose 1.

Methods: Healthy women either previously vaccinated with 1 dose of trivalent GBS vaccine 4-6 years before enrollment (n = 53) or never GBS vaccinated (n = 27) received a single trivalent GBS vaccine injection. Adverse events (AEs) were recorded. Serotype-specific (Ia/Ib/III) anti-GBS antibodies were measured by multiplex immunoassay prevaccination and 30/60 days postvaccination.

Results: AEs were reported with similar rates after a first or second dose; none were serious. Of previously GBS-vaccinated women, 92%-98% had anti-GBS concentrations that exceeded an arbitrary threshold (8 µg/mL) for each serotype 60 days postdose 2 vs 36%-56% postdose 1 in previously non-GBS-vaccinated women. Of previously GBS-vaccinated women with undetectable baseline (predose 1) anti-GBS levels, 90%-98% reached this threshold postdose 2. For each serotype, anti-GBS geometric mean concentrations (GMCs) 30/60 days postdose 2 in previously GBS-vaccinated women were ≥200-fold higher than baseline GMCs. Among women with undetectable baseline anti-GBS levels, postdose 2 GMCs in previously GBS-vaccinated women exceeded postdose 1 GMCs in previously non-GBS-vaccinated women (≥7-fold).

Conclusions: A second trivalent GBS vaccine dose administered 4-6 years postdose 1 was immunogenic with a favorable safety profile. Women with undetectable preexisting anti-GBS concentrations may benefit from a sufficiently spaced second vaccine dose.

Clinical trials registration: NCT02690181.

Keywords: group B streptococcus; immunogenicity; maternal immunization; safety; second dose.

Figure 1.

Study design. Abbreviations: alum, aluminum hydroxide-adjuvanted formulation; GBS, Group B streptococcus; MF59 full, full-dosage MF59-adjuvanted formulation; MF59 half, half-dosage MF59-adjuvanted formulation (a full dosage of MF59 contained 9.75 mg squalene, 1.18 mg polysorbate 80, 1.18 mg sorbitan trioleate, 0.66 mg sodium citrate dehydrate, and 0.04 mg citric acid monohydrate); no adj, nonadjuvanted formulation. ^aFor the parent study, only interventions relevant to the current analyses are presented. Vials indicate blood sampling for immunogenicity assessment. Syringes indicate vaccination in the parent or extension study. Braces indicate how the groups are pooled.

Figure 2.

Participant flow diagram. Abbreviations: alum, aluminum hydroxide-adjuvanted formulation; GBS, group B streptococcus; MF59 full, full-dosage MF59-adjuvanted formulation; MF59 half, half-dosage MF59-adjuvanted formulation; no adj, nonadjuvanted formulation. ^aOne woman in the prior group B streptococcus (GBS) no adj group was excluded from the day 31 and day 61 immunogenicity analyses because she received a vaccine forbidden by the protocol on day 21 and no blood was drawn on day 61. One woman in the prior placebo group was excluded from the day 61 immunogenicity analysis because of noncompliance with the blood draw schedule. One woman in the prior GBS alum group and 1 in the prior GBS MF59 full-dosage group were excluded from the day 31 and day 61 immunogenicity analyses because the sample concentrations for serotypes III and Ia, respectively, could not be calculated due to nontitrable mean fluorescence intensity signals. Two women in the prior placebo group had no parent study baseline sample available.

Figure 3.

Reverse cumulative distribution curves of serotype-specific anti-GBS antibody concentrations at baseline and 60 days postvaccination (per protocol immunogenicity set). Analyses on all women regardless of their baseline lower limit of quantitation status. Baseline refers to the prevaccination time point in the parent study for the prior GBS and prior placebo groups and to the prevaccination time point (day 1) in the extension study for the naïve group. Abbreviations: alum, aluminum hydroxide-adjuvanted formulation; GBS, group B streptococcus; MF59 full, full-dosage MF59-adjuvanted formulation; MF59 half, half-dosage MF59-adjuvanted formulation; N, number of women with available results in each group; no adj, nonadjuvanted formulation.

Figure 4.

Serotype-specific geometric mean anti-GBS antibody concentrations at different time points for the pooled groups (per protocol immunogenicity set). See Figure 1 for group names. Analyses on all women regardless of their baseline lower limit of quantitation (LLQ) status (“all,” left side) and on women with baseline serotype-specific anti-GBS antibody concentrations below the LLQs (“