Progress and pitfalls in Shigella vaccine research.
ABSTRACT Renewed awareness of the substantial morbidity and mortality that Shigella infection causes among young children in developing countries, combined with technological innovations in vaccinology, has led to the development of novel vaccine strategies in the past 5 years. Along with advancement of classic vaccines in clinical trials and new sophisticated measurements of immunological responses, much new data has been produced, lending promise to the potential for production of safe and effective Shigella vaccines. Herein, we review the latest progress in Shigella vaccine development within the framework of persistent obstacles.
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ABSTRACT: Shigella are Gram-negative bacteria which cause a diarrheal disease, known as shigellosis, by invading and destroying the colonic mucosa and inducing a robust inflammatory response. With no vaccine available, shigellosis annually kills over 600,000 children in developing countries. This study demonstrates the utility of combining high-throughput bioinformatic methods with in vitro and in vivo assays to provide new insights into pathogenesis. Comparisons of in vivo and in vitro gene expression identified genes associated with intracellular growth. Additional bioinformatics analyses identified genes that are present in S. flexneri isolates, but not in the other three Shigella species. Comparison of these two analyses revealed nine genes that were differentially expressed during invasion and specific to S. flexneri. One gene, a DeoR family transcriptional regulator, with decreased expression during invasion was further characterized and is now designated intracellular growth regulator, icgR. Deletion of icgR caused no difference in growth in vitro, but resulted in increased intracellular replication in HCT-8 cells. Further in vitro and in vivo RNAseq studies of an isogenic ΔicgR mutant identified 34 genes that were up-regulated in both growth conditions. This combined informatics and functional approach has allowed the characterization of a gene and pathway previously unknown in Shigella pathogenesis and provides a framework for further identification of novel virulence factors and regulatory pathways.Infection and immunity 06/2013; DOI:10.1128/IAI.00537-13 · 4.16 Impact Factor
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ABSTRACT: Despite intensive research efforts for more than 60 years, utilizing diverse vaccine strategies, a safe and efficacious vaccine against shigellosis is not available yet. We are currently witnessing innovative approaches based on elucidation of the virulence mechanisms of Shigella, understanding the immune response to the pathogen and progress in molecular technology for developing Shigella vaccines. It is hoped that these will lead to a licensed effective Shigella vaccine to protect humans against the significant worldwide morbidity and mortality caused by this microorganism.09/2013; 1(3):113-23. DOI:10.1177/2051013613500428
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ABSTRACT: Shigellosis is an important disease in the developing world where about 90 million people become infected with Shigella spp. each year. We previously demonstrated that the type three secretion apparatus (T3SA) proteins IpaB and IpaD are protective antigens in the mouse lethal pulmonary model. In order to simplify vaccine formulation and process development, we now evaluate a vaccine design that incorporates both of these previously tested Shigella antigens into a single polypeptide chain. To determine if this fusion protein (DB Fusion) retains the antigenic and protective capacities of IpaB and IpaD, we immunized mice with the DB Fusion and compared the immune response to that elicited by the IpaB/IpaD combination vaccine. Purification of the DB Fusion required co-expression with IpgC, the IpaB chaperone, and after purification it maintained the highly α-helical characteristics of IpaB and IpaD. The DB Fusion also induced comparable immune responses and retained the ability to protect mice against S. flexneri and S. sonnei in the lethal pulmonary challenge. It also offered limited protection against S. dysenteriae challenge. Our results show the feasibility of generating a protective Shigella vaccine comprised of the DB Fusion.Infection and immunity 09/2013; 81(12). DOI:10.1128/IAI.00859-13 · 4.16 Impact Factor