Booster Vaccination With GVGH Shigella sonnei 1790GAHB GMMA Vaccine Compared to Single Vaccination in Unvaccinated Healthy European Adults: Results From a Phase 1 Clinical Trial

Abstract

The investigational Shigella sonnei vaccine (1790GAHB) based on GMMA (generalized modules for membrane antigens) is immunogenic, with an acceptable safety profile in adults. However, pre-vaccination anti-S. sonnei lipopolysaccharide (LPS) antibody levels seemed to impact vaccine-related immune responses. This phase 1, open-label, non-randomized extension study (ClinicalTrials.gov: NCT03089879) evaluated immunogenicity of a 1790GAHB booster dose in seven adults with undetectable antibodies prior to priming with three 1790GAHB vaccinations 2–3 years earlier (boosted group), compared to one dose in 28 vaccine-naïve individuals (vaccine-naïve group). Anti-S. sonnei LPS serum IgG geometric mean concentrations and seroresponse (increase of ≥25 EU or ≥50% from baseline antibody ≤ 50 EU and ≥50 EU, respectively) rates were calculated at vaccination (day [D]1), D8, D15, D29, D85. Safety was assessed. Geometric mean concentrations at D8 were 168 EU (boosted group) and 32 EU (vaccine-naïve group). Response peaked at D15 (883 EU) and D29 (100 EU) for the boosted and vaccine-naïve groups. Seroresponse rates at D8 were 86% (boosted group) and 24% (vaccine-naïve group) and increased at subsequent time points. Across both groups, pain (local) and fatigue (systemic) were the most frequent solicited adverse events (AEs). Unsolicited AEs were reported by 57% of boosted and 25% of vaccine-naïve participants. No deaths, serious AEs, or AEs of special interest (except one mild neutropenia case, possibly vaccination-related) were reported. One 1790GAHB dose induced a significant booster response in previously-primed adults, regardless of priming dose, and strong immune response in vaccine-naïve individuals. Vaccination was well tolerated.

Characterization of Competitive ELISA and Formulated Alhydrogel Competitive ELISA (FAcE) for Direct Quantification of Active Ingredients in GMMA-Based Vaccines

“…GMMA is a promising technology for the development of affordable vaccines to fight neglected bacterial diseases causing millions of deaths every year. The most advanced GMMA-based vaccine, 1790-GAHB (S. sonnei GMMA formulated on Alhydrogel), has been tested in multiple clinical trials, and was well tolerated and immunogenic in European [8] and Kenyan [9] adults, as well as able to induce a strong anamnestic response after boosting [10]. Results with 1790-GAHB have pushed toward the development of a multicomponent GMMA-based vaccine, in which the S. sonnei component is formulated in Alhydrogel with GMMA from various S. flexneri strains, to cover the majority of the Shigella serotypes epidemiologically relevant worldwide.…”

“…Furthermore, the adsorption of GMMA with Alhydrogel allowed the abrogation of pyrogenicity in rabbits [5]. S. sonnei GMMA have been tested on Alhydrogel in humans, and the results have shown that they are well tolerated, immunogenic [8,9], and able to induce a strong anamnestic response upon boosting [10].…”

Intralaboratory evaluation of luminescence based high-throughput Serum Bactericidal Assay (L-SBA) to determine bactericidal activity of human sera against Shigella

“…The most advanced S. sonnei component (1790GAHB), has been tested in phase I and phase II clinical trials. Immunogenicity has been evaluated so far in terms of anti-LPS IgG response induced (17, 18) (19). The work performed here will allow the analysis of the clinical samples by SBA, confirming if the antibodies elicited by 1790GAHB are able to kill Shigella (i.e.…”

“…The human serum tested was an anti-human S. sonnei IgG standard serum (NVGH2863) that was created by pooling sera from adult subjects immunised with 1790 GAHB in non-endemic European populations (17). NVGH2863 has been already used as standard serum for S. sonnei LPS IgG assessment by ELISA (17–19). Frozen 50 μL working aliquots of the serum were stored at −80°C until use.…”

“…GMMA are easy and inexpensive to produce, and highly immunogenic (10, 13–16). The most advanced GMMA based vaccine, 1790GAHB (10) has been tested in phase I and IIa clinical trials, conducted in European (17) and endemic sites (18), and has been demonstrated to be well tolerated, immunogenic, and able to induce a strong anamnestic response after boosting (19).…”