Abstract
ABSTRACTShigella 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 by the lack of firm immunological correlates of protection, among other reasons. To address this gap in knowledge, we established quantitative assays to measure Shigella-specific serum bactericidal antibody (SBA) and opsonophagocytic killing antibody (OPKA) activities and investigated their potential association with protection against disease in humans. SBA, OPKA, and Ipa-, VirG (IscA)-, and Shigella flexneri 2a lipopolysaccharide-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 Shigella flexneri 2a. Prechallenge 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 the immunogenicity of leading live attenuated vaccine candidates Shigella CVD 1204 and CVD 1208S in humans. A single oral immunization with CVD 1204 or CVD 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.
Highlights
Shigella causes a severe diarrheal and dysenteric disease that affects primarily young children living in low-resource settings [1]
Bactericidal and macrophage phagocytic activities have been detected in sera from infected individuals living in regions of Shigella endemicity [18,19,20,21]
Antibody-dependent complement-mediated killing and opsonophagocytic activity have been associated with protection against other bacterial pathogens [22,23,24]
Summary
Shigella causes a severe diarrheal and dysenteric disease that affects primarily young children living in low-resource settings [1]. To investigate functional antibody responses and their potential associations with protection against shigellosis in humans, we established quantitative assays to measure Shigellaspecific serum bactericidal antibody (SBA) and opsonophagocytic killing antibody (OPKA) activity and measured SBA and OPKA titers in sera from adult volunteers who had been orally immunized with a Shigella vaccine candidate (EcSf2a-2) or remained unvaccinated and were subsequently challenged with virulent Shigella flexneri 2a [15]. In these same volunteers, we measured levels in serum of IgG and IgG subclasses specific for S. flexneri LPS, IpaB, IpaC, IpaD, and VirG. To demonstrate the applicability of our functional assays to assess immune responses to vaccines, SBA and OPKA titers were measured in sera from human adult volunteers orally immunized with leading live attenuated vaccine candidates CVD 1204 [16] and CVD 1208S [17]
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