Complement-mediated serum bactericidal activity of antibodies elicited by the Shigella sonnei GMMA vaccine in adults from a shigellosis-endemic country: Exploratory analysis of a Phase 2a randomized study

Abstract

Shigella is associated with a significant burden of disease worldwide among individuals of all ages and is the major cause of moderate and severe diarrhea in children under five years of age in low- and middle-income countries. Several candidate vaccines against Shigella species are currently under clinical development. The investigational 1790GAHB vaccine against Shigella sonnei is based on GMMA (Generalized Modules for Membrane Antigens) technology. The vaccine was well tolerated and induced high antibody levels in early-phase clinical trials in both Shigella-endemic and non-endemic settings. The present analysis assessed the bactericidal activity of antibodies induced by 1790GAHB in healthy Kenyan adults during a phase 2a, controlled, randomized study (NCT02676895). Participants received two doses of 1790GAHB 4 weeks apart containing either 1.5/25 µg or 6/100 µg O antigen/protein, or active comparator vaccines (Control). Serum bactericidal activity (SBA) against S. sonnei was assessed at pre-vaccination (D1), 28 days post-first dose (D29) and 28 days post-second dose (D57), using a luminescence-based assay. Most participants had SBA titers above the lower limit of quantification of the assay at D1. SBA geometric mean titers increased 3.4-fold in the 1.5/25 µg group and 6.3-fold in the 6/100 µg group by D29 and were maintained at D57. There was no increase in SBA geometric mean titers in the Control group. A strong correlation was observed between SBA titers and anti-S. sonnei lipopolysaccharide serum immunoglobulin G antibody concentrations (Pearson correlation coefficient = 0.918), indicating that SBA can effectively complement enzyme-linked immunosorbent assay data by indicating the functionality of 1790GAHB-induced antibodies.

Editorial: Pattern recognition receptors at the crosstalk between innate and adaptive immune systems and implications for vaccine development

“…These vaccines have been proven to be immunogenic and efficacious in animal models (Micoli et al, 2018;Gasperini et al, 2021). Similar approaches are being used for the development of novel vaccines against Shigella, where GMMA from bacteria with msbB or htrB deletions (Rossi et al, 2014;Gerke et al, 2015) were safe (Launay et al, 2017;Obiero et al, 2017) and able to elicit functional antibodies in humans (Micoli et al, 2021;Kapulu et al, 2022). Other examples of bacterial vaccines based on this strategy are those against Neisseria meningitidis, with pentacylated LPS obtained via deletion of lpxL1, which have been tested preclinically (Koeberling et al, 2014) and clinically (Keiser et al, 2011).…”

Towards establishing correlates of protection against shigellosis: assessing immunological endpoints across immune responses to the Shigella sonnei Generalized Modules for Membrane Antigens (GMMA) candidate vaccine (1790GAHB).

“…39 Interestingly, in the same study, when assessing correlation with other immunomarkers, bactericidal activity showed the strongest correlation with α4β7+ IgG responses, followed by serum IgG1 responses. 39 We also previously reported a strong correlation between the 1790GAHB elicited SBA titers and anti-S. sonnei LPS serum IgG levels in adults from both Shigella-endemic 29 and non-endemic countries, 18 indicating the functionality of antibodies induced by vaccination. The magnitude of antibody responses may play a less signi cant role in protection than their functionality; for instance, ndings from a CHIM study suggest that Shigella-speci c serum IgG1 may play an important role in protection from shigellosis after parenteral immunization even at relatively low levels elicited post-vaccination, 39 due to their high e ciency in activating the complement cascade.…”

Towards establishing a correlate of protection against shigellosis: assessing immunological endpoints across immune responses to the Shigella sonnei 1790GAHB GMMA investigational vaccine

“…38 Interestingly, in the same study, when assessing correlation with other immunomarkers, bactericidal activity showed the strongest correlation with α4β7 + IgG responses, followed by serum IgG1 responses. 38 We also previously reported a strong correlation between the 1790GAHB elicited SBA titers and anti-S. sonnei LPS serum IgG levels in adults from both Shigella-endemic 29 and non-endemic countries, 18 indicating the functionality of antibodies induced by vaccination. The magnitude of antibody responses may play a less signi cant role in protection than their functionality; for instance, ndings from a CHIM study suggest that Shigellaspeci c serum IgG1 may play an important role in protection from shigellosis after parenteral immunization even at relatively low levels elicited post-vaccination, 38 due to their high e ciency in activating the complement cascade.…”

“…18,30,31 Moreover, serum IgG antibodies were bactericidal and 1790GAHB showed ability to boost the response in individuals preimmunized or naturally exposed to Shigella. 29,32 While the vaccine did not show clinical e cacy against shigellosis after challenge with S. sonnei in this CHIM trial, 33 the study design allowed us to explore the role of several immunomarkers in predicting the risk of shigellosis.…”