Safety and immunogenicity of a novel hexavalent group B streptococcus conjugate vaccine in healthy, non-pregnant adults: a phase 1/2, randomised, placebo-controlled, observer-blinded, dose-escalation trial

Abstract

Background: Group B streptococcus (GBS) is a major cause of invasive disease in young infants. Infants born to women with sufficient pre-existing anti-GBS capsular IgG antibodies are at reduced risk of GBS disease, making maternal immunisation a potential strategy for prevention. We aimed to assess the safety and immunogenicity of a novel hexavalent (serotypes Ia, Ib, II, III, IV, and V) GBS conjugate vaccine (GBS6).

Methods: This phase 1/2, placebo-controlled, observer-blinded, dose-escalation trial, was done at four clinical research centres in the USA (Kentucky, Georgia, and two sites in Utah). Healthy, non-pregnant adults aged 18-49 years were randomly assigned using an interactive, web-based response technology system. Within each dose group (low, medium, or high), participants in sentinel cohorts were randomly assigned 2:2:1 and expanded cohort participants were randomly assigned 4:4:1 to receive GBS6 with aluminium phosphate (AlPO₄), GBS6 without AlPO₄, or placebo (saline control). One 0·5 mL dose of either saline placebo or 5 μg capsular polysaccharide per serotype in the low-dose group, 10 μg capsular polysaccharide per serotype in the medium-dose group, or 20 μg capsular polysaccharide per serotype in the high-dose group was administered by intramuscular injection into the deltoid muscle on day 1. The primary outcome was safety up to 6 months after vaccination, including the proportion of sentinel cohort participants with clinical laboratory abnormalities at 1 week, the proportion of all participants reporting solicited local reactions, systemic events, or use of antipyretic or pain medication within 14 days, adverse events up to 1 month, and medically attended or serious adverse events up to 6 months. The secondary outcome was GBS immunogenicity (serotype-specific IgG geometric mean concentrations at 1 month). This study is registered with ClinicalTrials.gov, NCT03170609.

Findings: Between June 5, 2017, and June 25, 2018, 365 participants were randomly assigned and 364 (52 in each dose group) were vaccinated and included in the safety analysis. Unsolicited adverse events were reported by 15 (29%) participants in the 5 μg with AlPO₄ group, 13 (25%) in the 5 μg without AlPO₄ group, 22 (42%) in the 10 μg with AlPO₄ group, 12 (23%) in the 10 μg without AlPO₄ group, 25 (48%) in the 20 μg with AlPO₄ group, 21 (40%) in the 20 μg without AlPO₄ group, and 20 (38%) in the placebo group. The most common unsolicited adverse events were in the system organ class of infections and infestations in any dose or formulation of GBS6 (ranging from six [12%] in the 10 μg without AlPO₄ group to 15 [29%] in the 20 μg with AlPO₄ group and placebo group). Three participants reported at least one serious adverse event during the study, one each in the 5 μg GBS6 with AlPO₄ group (diabetic ketoacidosis, two events; resolved), 10 μg GBS6 with AlPO₄ group (died by suicide), and 20 μg GBS6 with AlPO₄ group (metrorrhagia; resolved). None of these serious adverse events were considered related to the vaccine. 11 of the 365 participants were excluded from the evaluable immunogenicity population, including one participant who did not receive the vaccine, and ten who at 1 month after vaccination were withdrawn for various reasons. GBS serotype-specific IgG geometric mean concentrations increased by 1 week after vaccination for all GBS6 groups, peaked at 2 weeks, stabilised by 1 month, and declined gradually but remained higher than placebo at 6 months.

Interpretation: GBS6 was well tolerated in healthy adults and elicited robust immune responses for all dose levels and formulations that persisted 6 months after vaccination. This study supports further evaluation of GBS6 in pregnant women.

Funding: Pfizer.

Figure 1

Trial profile In the sentinel cohort, 16 patients in each dose group were assigned to receive GBS6 with AlPO₄, and 16 patients in each dose group were assigned to receive GBS6 without AlPO₄. 24 patients were assigned to receive placebo in the sentinel cohort. AlPO₄=aluminium phosphate. GBS6=group B streptococcus-containing vaccine with serotypes Ia, Ib, II, III, IV, and V.

Figure 2

Participants reporting local reactions, by maximum severity, within 14 days after study vaccination Solicited injection-site (local) reactions were: pain at injection site (mild: does not interfere with activity; moderate: interferes with activity; severe: prevents daily activity; grade 4: emergency department visit or hospital admission) and redness and swelling (mild: 2·5–5·0 cm in diameter; moderate: 5·5–10·0 cm in diameter; severe: more than 10·0 cm in diameter; grade 4: necrosis or exfoliative dermatitis for redness, and necrosis for swelling). Data were collected with the use of electronic diaries for 14 days after each vaccination. AlPO₄=aluminium phosphate. GBS6=group B streptococcus-containing vaccine with serotypes Ia, Ib, II, III, IV, and V.

Figure 3

Participants reporting systemic events, by maximum severity, within 14 days after study vaccination Grading of solicited systemic events is described in the appendix (p 9). AlPO₄=aluminium phosphate. GBS6=group B streptococcus-containing vaccine with serotypes Ia, Ib, II, III, IV, and V.

Figure 4

Group B streptococcus serotype-specific IgG geometric mean concentrations The IgG assay lower limit of quantitation for each serotype was: Ia 0·008 μg/mL, Ib 0·011 μg/mL, II 0·009 μg/mL, III 0·010 μg/mL, IV 0·005 μg/mL, and V 0·075 μg/mL. GBS6 IgG antibody concentrations more than the lower limit of quantitation and their quantitated values were reported. Values below the lower limit of quantitation were set to 0·5 times the lower limit of quantitation for all analyses. Error bars represent 95% CIs. AlPO₄=aluminium phosphate. GBS6=group B streptococcus-containing vaccine with serotypes Ia, Ib, II, III, IV, and V.