Broad spectrum Shigella subunit vaccine based on conserved proteins

ABSTRACT Shigella spp. are a major global cause of diarrhea and dysentery. Children 2-5-years of age in low- and middle- income countries are the most affected. Mortality is second only to rotavirus among diarrheal diseases in young children, and repeated bouts of disease cause lifelong disability. In industrialized nations, Shigella outbreaks

have occurred in day care centers and medical institutions. Shigella spp. rapidly acquire genetic elements that confer antimicrobial resistance. A safe, effective, and affordable vaccine could make a major public health impact, yet none is currently approved. Candidates based on the Shigella-O-antigen are in clinical development.

However, that approach is impractical and costly, requiring multiple vaccines to prevent disease caused by Shigella strains with different O antigens. This proposal seeks to develop a safe, practical, and effective broad- spectrum Shigella vaccine based on highly conserved Shigella Type III secretion system (TTSS) proteins,

invasion plasmid antigen (Ipa) B, IpaH, and the virulence antigen VirG (IcsA). Our laboratory was the first to report the high immunogenic and broad protective capacity of Shigella IpaB in mice, and the association of IpaB- and VirG- serum IgG (IgG1) levels with clinical protection against shigellosis in humans. Preliminary data in this

application demonstrate that VirG also elicits potent and protective immunity. In addition, we have found that adults living in endemic regions who acquire natural immunity to Shigella have high levels of IpaB-, VirG-, and IpaH- serum antibodies. Maternal IgG against these proteins are more efficiently transferred to infants through

the placenta as compared to IgG against the O-polysaccharide. High levels of antibodies are also present in breast milk. This robust maternally-derived immunity is consistent with the low incidence of infection at