Safety and immunogenicity of the group B streptococcus vaccine AlpN in a placebo-controlled double-blind phase 1 trial

Abstract

Group B streptococcus (GBS) is a leading cause of life-threatening neonatal infections and subsets of adverse pregnancy outcomes. Essentially all GBS strains possess one allele of the alpha-like protein (Alp) family. A maternal GBS vaccine, consisting of the fused N-terminal domains of the Alps αC and Rib (GBS-NN), was recently demonstrated to be safe and immunogenic in healthy adult women. To enhance antibody responses to all clinically relevant Alps, a second-generation vaccine has been developed (AlpN), also containing the N-terminal domain of Alp1 and the one shared by Alp2 and Alp3. In this study, the safety and immunogenicity of AlpN is assessed in a randomized, double-blind, placebo-controlled, and parallel-group phase I study, involving 60 healthy non-pregnant women. AlpN is well tolerated and elicits similarly robust and persistent antibody responses against all four Alp-N-terminal domains, resulting in enhanced opsonophagocytic killing of all Alp serotypes covered by the vaccine.

Keywords: Bacteriology; Immunology; Microbiology.

Graphical abstract

Figure 1

Trial profile of the clinical study Subject disposition of the clinical Alp-N vaccine study, outlining cohorts, dose regimens, and evaluation of immunogenicity and safety. See also Table S1.

Figure 2

IgG responses against the vaccine constituent GBS-NN and GBS-NN2 Subjects were immunized with two doses of 25 or 50 μg of Alp-N together with the adjuvant AlOH as indicated in the legend (n = 23 per dose level). The second dose was administered 28 days after primary vaccination. Subjects in the placebo group received two doses of adjuvant only (n = 12). (A and B) GBS-NN- and GBS-NN2-specific IgG GMC (A) and fold change relative to pre-vaccination level (B) for indicated time points. Error bars show 95% CI. (C and D) Paired t-test analyses of individual pre-boost (day 29) and post-boost (day 85) levels of IgG against GBS-NN (C) and GBS-NN2 (D) for indicated dose levels. (E and F) Pearson correlation plots with 95% CI bands, showing the associations between concentration of pre-existing and pre-boost (day 29) IgG concentrations (E) and between pre-boost IgG concentrations (day 29) and boost effect of a second dose (fold change day 85 relative to day 29) (F). Pearson correlation analyses performed on all subjects combined from the 25 μg and 50 μg cohorts (n = 46). All statistical analyses performed on logarithmically transformed data. See also Figure S1.

Figure 3

IgG and IgA responses against individual Alp-N domains (A and B) Serum concentrations of IgG (A) and IgA (B) against indicated Alp-N domains were determined by ELISA separately for the cohorts receiving 25 μg and 50 μg of the vaccine as indicated (n = 23 for each cohort). Results show individual subject concentrations and GMCs before vaccination (day 0), after the first dose (day 29), and four weeks after the second dose (day 57). Paired t-tests were used for intra-cohort comparisons. Unpaired t-tests were used for inter-cohort comparisons. (C) Serum concentrations of IgG1 and IgG2 against indicated Alp-N domains four weeks after the second dose (day 57). Paired t-tests performed on all subjects combined from the 25 μg and 50 μg cohorts, showing individual subject concentrations and GMCs (n = 46). All statistical analyses performed on logarithmically transformed data.

Figure 4

OPk responses against all four Alp-N serotypes covered by the Alp-N vaccine Pre- and day 57 post-vaccination sera from all subjects of the 50-μg dose cohort (n = 23) and placebo (n = 12) were assessed for the ability to mediate OPk of the indicated GBS strains. OPkA titer is defined as the reciprocal serum dilution required to mediate 50% bacterial killing relative to killing in the absence of human serum. (A) Total OPk titers achieved against indicated GBS strains. Results show paired t-tests for individual pre- and post-vaccination sera. Unpaired t-tests were used for comparison of placebo versus active pre-vaccination sera. (B) ΔOPkA titers (derived by subtracting the pre-vaccination titer from the paired post-vaccination titer) against indicated strains. Results show individual ΔOPkA titers and ΔOPkA GMTs. (C) Pearson correlation plots with 95% CI bands, showing ΔOPkA titers versus the Alp-N homologous IgG response induced by the vaccine (ΔIgG) for the indicated GBS target strains. (D) Percent of subjects reaching the OPkA titer thresholds >100 and >500 against indicated GBS strains before (striped bars) and after (solid bars) two 50 μg doses of AlpN. All statistical analyses performed on logarithmically transformed data. See also Table S3.