Functional and Antigen-Specific Serum Antibody Levels as Correlates of Protection Against Shigellosis in a Controlled Human Challenge Study.

Shigella is an important cause of diarrheal disease in young children living in developing countries. No approved vaccines are available, and the development of vaccine candidates has been hindered, among other reasons, by the lack of firm immunological correlates of protection. To address this gap in knowledge, we established quantitative assays to measure Shigella -specific serum bactericidal (SBA) and opsonophagocytic killing antibody (OPKA) activity and investigated their potential association with protection against disease in humans. SBA, OPKA along with Ipa-, VirG(IscA)-, and LPS2a-specific serum IgG titers were determined in adult volunteers who received Shigella vaccine candidate EcSf2a-2 and in unvaccinated controls, all of whom were challenged with virulent S. flexneri 2a. Pre-challenge antibody titers were compared with disease severity after challenge. SBA and OPKA, as well as IpaB- and VirG-specific IgG significantly correlated with reduced illness. SBA and OPKA assays were also used to evaluate immunogenicity of leading live attenuated vaccine candidates Shigella CVD 1204 and 1208S in humans. A single oral immunization with CVD 1204 and 1208S resulted in SBA seroconversion rates of 71% and 47%, and OPKA seroconversion rates of 57% and 35%, respectively. Higher functional antibody responses were induced by CVD 1204, which is consistent with its lower attenuation. This is the first demonstration of SBA, OPKA, and IpaB- and VirG-specific IgG levels as potential serological correlates of protection against shigellosis in humans. These results warrant further studies to establish their capacity to predict protective immunity and vaccine efficacy.