Antibodies Elicited by the Shigella sonnei GMMA Vaccine in Adults Trigger Complement-Mediated Serum Bactericidal Activity: Results From a Phase 1 Dose Escalation Trial Followed by a Booster Extension

Abstract

Shigella is the second most deadly diarrheal disease among children under five years of age, after rotavirus, with high morbidity and mortality in developing countries. Currently, no vaccine is widely available, and the increasing levels of multidrug resistance make Shigella a high priority for vaccine development. The single-component candidate vaccine against Shigella sonnei (1790GAHB), developed using the GMMA technology, contains the O antigen (OAg) portion of lipopolysaccharide (LPS) as active moiety. The vaccine was well tolerated and immunogenic in early-phase clinical trials. In a phase 1 placebo-controlled dose escalation trial in France (NCT02017899), three doses of five different vaccine formulations (0.06/1, 0.3/5, 1.5/25, 3/50, 6/100 µg of OAg/protein) were administered to healthy adults. In the phase 1 extension trial (NCT03089879), conducted 2-3 years following the parent study, primed individuals who had undetectable antibody levels before the primary series received a 1790GAHB booster dose (1.5/25 µg OAg/protein). Controls were unprimed participants immunized with one 1790GAHB dose. The current analysis assessed the functionality of sera collected from both studies using a high-throughput luminescence-based serum bactericidal activity (SBA) assay optimized for testing human sera. Antibodies with complement-mediated bactericidal activity were detected in vaccinees but not in placebo recipients. SBA titers increased with OAg dose, with a persistent response up to six months after the primary vaccination with at least 1.5/25 µg of OAg/protein. The booster dose induced a strong increase of SBA titers in most primed participants. Correlation between SBA titers and anti-S. sonnei LPS serum immunoglobulin G levels was observed. Results suggest that GMMA is a promising OAg delivery system for the generation of functional antibody responses and persistent immunological memory.

Keywords: 1790GAHB; GMMA; Shigella sonnei; booster response; dose escalation; serum bactericidal activity.

Conflict of interest statement

FM, OR, VC, ASS, MA, UN, EM, RR, LM, FN, and AP are employees of the GSK group of companies and RR, LM, and AP hold shares in the GSK group of companies. AS was an employee of the GSK group of companies at the time of the study and holds shares in the GSK group of companies. FM and AS report grant from the Bill and Melinda Gates Foundation during the conduct of the study. LM reports grant from EU FP7 STOPENTERICS during the conduct of the study and from the Bill and Melinda Gates Foundation and Wellcome Trust outside the submitted work. LM and AS are inventors of patents owned by the GSK group of companies and relevant to Shigella vaccine. OL’s institution received grant from the GSK group of companies for conducting the study. All authors have no non-financial relationships and activities.

Copyright © 2021 Micoli, Rossi, Conti, Launay, Sciré, Aruta, Nakakana, Marchetti, Rappuoli, Saul, Martin, Necchi and Podda.

Figures

Figure 1

Plain Language Summary.

Figure 2

Demographic characteristics of participants. FAS, full analysis set; mFAS, modified FAS; SD, standard deviation; N, number of participants; 0.06/1, group receiving 1790GAHB formulation with 0.06 µg O antigen (OAg) and 1 µg protein; 0.3/5, group receiving 1790GAHB formulation with 0.3 µg OAg and 5 µg protein; 1.5/25, group receiving 1790GAHB formulation with 1.5 µg OAg and 25 µg protein; 3/50, group receiving 1790GAHB formulation with 3 µg OAg and 50 µg protein; 6/100, group receiving 1790GAHB formulation with 6 µg OAg and 100 µg protein; Placebo, group receiving placebo; Booster, group receiving a booster 1790GAHB dose (1.5/25 µg OAg/protein) 2–3 years after primary vaccination; Control, placebo recipients (from the parent study) and vaccine-naïve participants (newly enrolled in the extension study) receiving one dose of 1790GAHB (1.5/25 µg OAg/protein).

Figure 3

SBA geometric mean titers (A) and within-group geometric mean ratios (B). LLOQ, lower limit of quantification; SBA, serum bactericidal activity; Baseline, day of administration of the first dose in the parent study; D29, 28 days post-dose 1; D57, 28 days post-dose 2; D85, 28 days post-dose 3; D225, 6 months post-dose 3; Pre-boost, day of administration of the booster dose (Booster)/vaccine dose (Control) in the extension study; D29 Post-boost; 28 days following booster dose (Booster)/vaccine dose (Control); D85 post-boost, 3 months after the booster dose (Booster)/vaccine dose (Control); N, maximum number of participants with available results; 0.06/1, group receiving 1790GAHB formulation with 0.06 µg O antigen (OAg) and 1 µg protein; 0.3/5, group receiving 1790GAHB formulation with 0.3 µg OAg and 5 µg protein; 1.5/25, group receiving 1790GAHB formulation with 1.5 µg OAg and 25 µg protein; 3/50, group receiving 1790GAHB formulation with 3 µg OAg and 50 µg protein; 6/100, group receiving 1790GAHB formulation with 6 µg OAg and 100 µg protein; Placebo, group receiving placebo; Booster, group receiving a booster 1790GAHB dose (1.5/25 µg OAg/protein) 2–3 years after primary vaccination; Control, placebo recipients (from the parent study) and vaccine-naïve participants (newly enrolled in extension study) receiving one dose of 1790GAHB (1.5/25 µg OAg/protein). *N=4 at D57 and N=6 at D85, D225. **N=6 at D57, D85, D225. Error bars depict 95% confidence intervals.

Figure 4

Pearson correlation between anti-S. sonnei LPS serum IgG antibody concentrations and SBA titers. LPS, lipopolysaccharide; IgG, immunoglobulin G; SBA, serum bactericidal activity; ELISA, enzyme-linked immunosorbent assay; EU, ELISA unit. The lower limit of quantification was 100 (IC50) for SBA and 3.1–4.1 EU/mL (parent study) and 5.5–7.4 EU/mL (extension study) for ELISA. The p-values were <0.0001 for both coefficients.