| Summary: | <i>Shigella</i> infections are one of the top causes of diarrhea throughout the world, with <i>Shigella flexneri</i> being predominant in developing countries. Currently, no vaccines are widely available and increasing levels of multidrug-resistance make <i>Shigella</i> a high priority for vaccine development. The serotype-specific O-antigen moiety of <i>Shigella</i> lipopolysaccharide has been recognized as a key target for protective immunity, and many O-antigen based candidate vaccines are in development. Recently, the Generalized Modules for Membrane Antigens (GMMA) technology has been proposed as an alternative approach to traditional glycoconjugate vaccines for O-antigen delivery. Here, these two technologies are compared for a vaccine against <i>S. flexneri</i> serotype 6. Genetic strategies for GMMA production, conjugation approaches for linkage of the O-antigen to CRM<sub>197</sub> carrier protein, and a large panel of analytical methods for full vaccine characterization have been put in place. In a head-to-head immunogenicity study in mice, GMMA induced higher anti-O-antigen IgG than glycoconjugate administered without Alhydrogel. When formulated on Alhydrogel, GMMA and glycoconjugate elicited similar levels of persistent anti-O-antigen IgG with bactericidal activity. Glycoconjugates are a well-established bacterial vaccine approach, but can be costly, particularly when multicomponent preparations are required. With similar immunogenicity and a simpler manufacturing process, GMMA are a promising strategy for the development of a vaccine against <i>Shigella</i>.
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