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

ABSTRACT: 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 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.

SUBMITTER: Shimanovich AA

PROVIDER: S-EPMC5299116 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Shimanovich Avital A AA Buskirk Amanda D AD Heine Shannon J SJ Blackwelder William C WC Wahid Rezwanul R Kotloff Karen L KL Pasetti Marcela F MF

Clinical and vaccine immunology : CVI 20170206 2

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 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 ...[more]

PMID: 27927680

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Project description:Inhalation of the biothreat agent, ricin toxin (RT), provokes a localized inflammatory response associated with pulmonary congestion, edema, neutrophil infiltration, and severe acute respiratory distress. The extreme toxicity of RT is the result of the toxin's B chain (RTB) promoting rapid uptake into alveolar macrophages and lung epithelial cells, coupled with the A chain's (RTA) potent ribosome-inactivating properties. We previously reported that intramuscular vaccination of rhesus macaques with a lyophilized, alum-adsorbed recombinant RTA subunit vaccine (RiVax®) was sufficient to confer protection against a lethal dose of aerosolized RT. That study implicated RT-specific serum IgG, toxin-neutralizing activity (TNA), and epitope-specific responses as being associated with immunity. However, it was not possible to define actual correlates of protection (COP) because all vaccinated animals survived the RT challenge. We addressed the issue of COP in the current study, by vaccinating groups of rhesus macaques with RiVax® following the previously determined protective regimen (100 µg on study days 0, 30 and 60) or one of two anticipated suboptimal regimens (100 µg on study days 30 and 60; 35 µg on study days 0, 30, and 60). Two unvaccinated animals served as controls. The animals were challenged with ~5 × LD50s of aerosolized RT on study day 110. We report that all vaccinated animals seroconverted prior to RT challenge, with the majority also having measurable TNA, although neither antibody levels nor TNA reached statistical significance with regard to a correlation with protection. By contrast, survival correlated with pre-challenge, epitope-specific serum IgG levels, derived from a competitive sandwich ELISA using a panel of toxin-neutralizing monoclonal antibodies directed against distinct epitopes on RiVax®. The identification of a species-neutral, competitive ELISA that correlates with vaccine-induced protection against RT in nonhuman represents an important advance in the development of medical countermeasures (MCM) against a persistent biothreat.

Dataset Information

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

Publications

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

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