Protein-specific immune response elicited by the <i>Shigella sonnei</i> 1790GAHB GMMA-based candidate vaccine in adults with varying exposure to <i>Shigella</i>

<i>Shigella</i> is a leading cause of diarrheal morbidity and mortality in young children from low- and middle-income countries. Here, we aimed to verify the ability of the generalized modules for membrane antigens (GMMA)-based <i>Shigella sonnei</i> candidate vaccine 1790GAHB to elicit an anti-protein antibody response. Serum samples from previous clinical trials in adults (a dose-escalation study and its extension in France, a vaccine efficacy study after human challenge in the United States, and a study in Kenya) were investigated using pan-proteome microarrays consisting of 3,150 full-length or fragmented <i>Shigella</i> proteins. Pre-/post-vaccination comparisons identified subsets of proteins that were highly immunoreactive and largely overlapped across all trials; the T3SS lipochaperone family protein (expressed on GMMA) was the most reactive in all studies. Responses to several microarray antigens correlated well with <i>S. sonnei</i> LPS serum IgG antibody levels. Overall, we confirmed the ability of GMMA to elicit an anti-protein IgG/IgA response; however, no association with protection against shigellosis was identified. In the challenge study, IgG response to seven antigens (IpaC, IpaB, IpaA, IpaD, IpaH, IpgC, and MxiD; not expressed on GMMA) was associated with a decreased risk of shigellosis. These antigens were observed to also have high IgG responses at baseline in individuals naturally exposed to <i>Shigella</i> and could constitute targets for future vaccine development.IMPORTANCE<i>Shigella</i> remains a major cause of diarrheal disease, especially in children aged under 5 years from low-to-middle-income countries. No vaccine against shigellosis is yet widely available despite the high public health need. An ideal vaccine would provide protection against the most prevalent species, <i>Shigella flexneri</i> and <i>Shigella sonnei</i>; therefore, it could be relevant to identify common antigens. We developed a microarray containing 3,150 full-length or fragmented proteins selected across <i>Shigella</i> species. Sera collected in four clinical trials conducted in three countries of varying endemicity to evaluate a <i>S. sonnei</i> GMMA-based candidate vaccine were tested against these proteins. We identified several <i>Shigella</i> proteins (IpaC, IpaB, IpaA, IpaD, IpaH, IpgC, MxiD) that induced robust antibody response following experimental challenge or natural infection. These proteins correlated with a reduced risk of shigellosis after the <i>S. sonnei</i> challenge. We found no apparent role for anti-GMMA proteins' IgG or IgA response in protection against shigellosis.