A Phase 2a Randomized Study to Evaluate the Safety and Immunogenicity of the 1790GAHB Generalized Modules for Membrane Antigen Vaccine against Shigella sonnei Administered Intramuscularly to Adults from a Shigellosis-Endemic Country

Abstract

Shigellosis is a mild-to-severe diarrheal infection, caused by the genus Shigella, and is responsible for significant morbidity and mortality worldwide. We evaluated the safety and immunogenicity of an investigational Shigella sonnei vaccine (1790GAHB) based on generalized modules for membrane antigens (GMMA) in Kenya, a Shigella-endemic country. This phase 2a, observer-blind, controlled randomized study (NCT02676895) enrolled 74 healthy adults aged 18–45 years, of whom 72 were vaccinated. Participants received, in a 1:1:1 ratio, two vaccinations with the 1790GAHB vaccine at doses of either 1.5/25 μg of O antigen (OAg)/protein (group 1.5/25 μg) or 5.9/100 μg (group 5.9/100 μg) at day (D) 1 and D29, or vaccination with a quadrivalent meningococcal vaccine at D1 and tetanus, diphtheria, and acellular pertussis vaccine at D29 (control group). Solicited and unsolicited adverse events (AEs), serious AEs (SAEs), and AEs of special interest (neutropenia and reactive arthritis) were collected. Anti-S. sonnei lipopolysaccharide (LPS) serum immunoglobulin G (IgG) geometric mean concentrations (GMC) were evaluated at D1, D29, and D57 and compared to anti-S. sonnei LPS antibody levels in convalescent patients naturally exposed to S. sonnei. The percentages of participants with seroresponse were also calculated. The most frequently reported solicited local and systemic AEs across all groups were pain and headache, respectively. Only one case of severe systemic reaction was reported (severe headache after first vaccination in group 5.9/100 μg). Seven and three episodes of neutropenia, assessed as probably or possibly related to vaccination respectively, were reported in the investigational and control groups, respectively. No other SAEs were reported. Despite very high baseline anti-S. sonnei LPS serum IgG levels, the 1790GAHB vaccine induced robust antibody responses. At D29, GMC increased 2.10- and 4.43-fold from baseline in groups 1.5/25 and 5.9/100 μg, respectively, whereas no increase was observed in the control group. Antibody titers at D57 were not statistically different from those at D29. Seroresponse was 68% at D29 and 90% at D57 in group 1.5/25 μg, and 96% after each vaccination in group 5.9/100 μg. The 1790GAHB vaccine was well tolerated and highly immunogenic in a population of African adults, regardless of the GMMA OAg/protein content used.

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

“…In order to determine the possibility to assess serum bactericidal activity of human sera against S. sonnei by L-SBA, NVGH2863, an anti- S. sonnei IgG human standard serum already in use to assess quantity of human antibodies raised upon vaccination with S. sonnei GMMA in clinical trials (17, 18), has been used to set-up the assay conditions with human sera and characterise the assay prior moving on with testing the functionality of clinical samples. Initial experiments were conducted to test the behaviour in L-SBA of NVGH2863 under experimental conditions already established with pre-clinical sera (20% exogenous baby rabbit complement (BRC) and S. sonnei with stabilized LPS expression in vitro as target bacteria).…”

“…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.…”

“…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).…”

Update on vaccines for enteric pathogens

“…A novel bioconjugate technology was utilized to develop a prototype conjugate vaccine [71], which has also recently shown evidence of efficacy in a controlled human infection model study [72]. Meanwhile, an outer membrane vesicle approach (termed GMMA: generalized modules for membrane antigens) has been tested in two phase I studies [73] and a phase IIa trial in Kenyan adults [74]. Other vaccine approaches are also in early clinical development [75].…”

Sustainable vaccine development: a vaccine manufacturer's perspective

“…Though no established correlates of protection exist, Shigella vaccine development is facilitated by generally accepted immunological associations with protection. Two promising approaches already evaluated in Phase 2 studies include the bioconjugate S. flexneri 2a vaccine (Flexyn2a) supported by The Wellcome Trust, and a monovalent S. sonnei vaccine (1790GAHB) based on genetically-derived outer membrane vesicles of Shigella, generated using the Generalized Modules for Membrane Antigens (GMMA) technology ( [20,21] and NCT02646371). The latter vaccine is being developed with funding from the European Commission's FP7 program.…”