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INTRODUCTION: Shigellosis is a major health concern among children < 5 years of age from developing countries, and there are no widely available vaccines to prevent it. The GMMA-based 1790GAHB investigational vaccine against Shigella sonnei was well tolerated and immunogenic in phase 1 and 2 studies conducted in healthy adults from Shigella endemic and non-endemic populations. Based on pooled data of five individual trials, we assessed the association between vaccine administration and the risk of neutropenia as well as the overall safety profile of 1790GAHB. METHODS: The risk ratio (RR) of neutropenia was evaluated between participants receiving 1790GAHB (vaccinees) and active comparator/placebo (controls) using different ethnicity-specific absolute neutrophil count (ANC) thresholds established to define neutropenia. Safety was assessed in terms of solicited, unsolicited, and serious adverse events (AEs). RESULTS: Of the 279 participants, 11 (5.5%) vaccinees and 4 (5.0%) controls had ANC below the appropriate threshold within 7 days post-vaccination. RR was 0.96 [95% confidence interval (CI) 0.54-1.70]. When neutrophil counts of participants of African descent were measured against an ethnicity non-specific threshold, they resulted in neutropenia episodes in 30 (37.0%) vaccinees and 16 (30.2%) controls, while only 2 (2.5%) vaccinees and 1 (1.9%) control had neutropenia when the ethnicity-specific threshold was applied. RRs were 0.98 (95% CI 0.75-1.28) and 1.30 (95% CI 0.1-17.6), respectively. Solicited and unsolicited AEs were slightly more frequent among vaccinees than controls. No serious AEs, other than neutropenia cases, were recorded in the vaccine group. CONCLUSION: By applying the appropriate threshold, no increased risk of neutropenia was identified in vaccinees compared with the controls. The frequency of neutropenia events varied drastically when ethnicity-appropriate thresholds were applied. This observation highlights the importance of selecting appropriate cut-off values according to the correct population reference. Overall, the 1790GAHB vaccine demonstrated an acceptable safety profile.
RESUMEN
BACKGROUND: Shigellosis accounts for substantial morbidity and mortality worldwide and is the second most common cause of moderate and severe diarrhoea in children. METHODS: This phase 2b study (NCT03527173), conducted between August 2018 and November 2019, evaluated vaccine efficacy (VE), safety, and immunogenicity of a Shigella sonnei GMMA candidate vaccine (1790GAHB) in adults, using a S. sonnei 53 G controlled human infection model. Participants (randomized 1:1) received two doses of 1790GAHB or placebo (GAHB-Placebo), at day (D) 1 and D29, and an oral challenge of S. sonnei 53 G at D57. VE was evaluated using several endpoints, reflecting different case definitions of shigellosis. For the primary endpoint, the success criterion was a lower limit of the 90% confidence interval >0. FINDINGS: Thirty-six and 35 participants received 1790GAHB or placebo, respectively; 33 and 29 were challenged, 15 and 12 developed shigellosis. VE was not demonstrated for any endpoint. Adverse events were more frequent in 1790GAHB versus placebo recipients post-vaccination. Anti-S. sonnei lipopolysaccharide (LPS) IgG responses increased at D29 and remained stable through D57 in group 1790GAHB; no increase was shown in placebo recipients. INTERPRETATION: 1790GAHB had an acceptable safety profile and induced anti-LPS IgG responses but did not demonstrate clinical efficacy against shigellosis. Baseline/pre-challenge antibody levels were higher in participants who did not develop shigellosis post-challenge, suggesting a role of anti-LPS IgG antibodies in clinical protection, although not fully elucidated in this study. For further vaccine development an increased S. sonnei O-antigen content is likely needed to enhance anti-LPS immune responses. FUNDING: GlaxoSmithKline Biologicals SA, Bill and Melinda Gates Foundation.
