Safety and immunogenicity of a booster dose of a novel hexavalent group B streptococcus conjugate vaccine in healthy, non-pregnant adults: a phase 2, open-label extension of a phase 1/2 randomised controlled trial

Abstract

Background: A hexavalent group B streptococcus (GBS) polysaccharide conjugate vaccine (GBS6) is being developed to prevent invasive group B streptococcal disease in infants through active maternal immunisation. We previously reported results for GBS6 administered to non-pregnant adults (NCT03170609). Here, we aim to extend these results to determine safety and immunogenicity of a second dose of GBS6 in non-pregnant adults who received a primary dose of GBS6.

Methods: This phase 2, open-label extension of a phase 1/2 randomised controlled trial was done at four sites in the USA to assess the safety, tolerability, and immunogenicity of a booster dose (20 μg capsular polysaccharide per serotype per dose) of GBS6 formulated with and without aluminium phosphate (AlPO₄). Healthy adults who were aged 18-49 years during participation in the phase 1/2 study approximately 2 years before and received one of the six GBS6 formulations were enrolled. Participants received a single dose of GBS6 20 μg capsular polysaccharide (CPS) per serotype on study day 1, with or without AlPO₄ based on the formulation received in the phase 1/2 study. Primary endpoints evaluated GBS6 safety (in participants receiving one or more doses) based on solicited local reactions and systemic events within 14 days, adverse events within 1 month, and unsolicited serious adverse events and medically attended adverse events up to 6 months after vaccination. Secondary immunogenicity endpoints (in the evaluable population of participants in compliance with key protocol criteria) included assessments of GBS serotype-specific IgG geometric mean concentrations (GMCs) and geometric mean fold-rises (GMFRs) in serum samples collected at 1 month after versus before booster vaccination. This study is registered with ClinicalTrials.gov (NCT04258995).

Findings: Of 297 participants who completed the base study, 151 received the GBS6 booster dose (76 participants with and 75 without AlPO₄) and were included in the safety analysis. The median time to booster from primary vaccination was 2·4 years (IQR 2·3-2·5). Most participants were women (114 [75%] of 151) and White (125 [83%] of 151). The mean age was 36·7 years (SD 8·67). Pain at the injection site was the most frequently reported solicited local reaction (52 [68%] of 76 participants who received GBS6 with AlPO₄ and 32 [43%] of 75 without AlPO₄) and was severe in two (3%) of 76 participants who received GBS6 with AlPO₄ and no participant who received the vaccine without adjuvant. Systemic events occurred at similar frequencies in both groups (45 [59%] of 76 with AlPO₄ and 46 [61%] of 75 without AlPO₄), and were mostly mild or moderate in severity. The number of participants reporting any type of unsolicited adverse event was low and similar for GBS6 with AlPO₄ versus GBS6 without AlPO₄ (11 [14%] of 76 vs 12 [16%] of 75). No adverse event was deemed to be related to GBS6. One serious adverse event, assessed as not related to the product being investigated, of thermal burn was reported in a participant who received GBS6 with AlPO₄. Low rates of medically attended adverse events were reported in both groups of participants receiving a booster dose of GBS6 (nine [12%] of 76 with AlPO₄ and seven [9%] of 75 without AlPO₄). For all serotypes, serotype-specific anti-CPS IgG GMCs mostly waned over the 2-year period after the primary vaccination but remained elevated before the booster dose compared with before the primary dose of GBS6. A booster dose of GBS6 elicited robust GBS serotype-specific anti-CPS IgG responses that were two-fold to 18-fold higher 1 month after the booster dose (GMC range 6·025-60·304 μg/mL) than 1 month after the primary dose (0·365-35·173 μg/mL). Anti-CPS IgG GMFRs ranged from approximately ten-fold to 59-fold across the serotypes and formulations from before the booster dose (GMC range 0·130-5·274 μg/mL) to 1 month after the booster dose.

Interpretation: The results of this study showed that a single 20 μg booster dose of GBS6 given approximately 2 years after a primary dose to healthy, non-pregnant adults was safe and elicited robust immune responses that were consistently higher than those after the primary dose. As there is precedent for repeat doses of vaccines to augment or sustain circulating antibodies available for placental transfer with each pregnancy, results from this study might inform decisions around future dosing strategies for GBS6 for maternal immunisation with subsequent pregnancies should GBS6 be approved for use in pregnancy.

Funding: Pfizer.