1. Rationalizing the design of a broad coverage Shigella vaccine based on evaluation of immunological cross-reactivity among S. flexneri serotypes
- Author
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Simona Rondini, Gianmarco Gasperini, Laura B. Martin, Renzo Alfini, Maria Grazia Aruta, Francesca Mancini, Allan Saul, Rino Rappuoli, Francesca Necchi, Francesca Micoli, Omar Rossi, and Francesco Citiulo
- Subjects
Bacterial Diseases ,Serotype ,Physiology ,RC955-962 ,Pathology and Laboratory Medicine ,medicine.disease_cause ,Biochemistry ,Cross-reactivity ,Shigella flexneri ,Mice ,Medical Conditions ,Shigella Vaccines ,Immune Physiology ,Arctic medicine. Tropical medicine ,Medicine and Health Sciences ,Public and Occupational Health ,Shigella ,Shigella vaccine ,Cross Reactivity ,Vaccines ,Immune System Proteins ,Bacterial Gastroenteritis ,O Antigens ,Antibodies, Bacterial ,Vaccination and Immunization ,Bacterial Pathogens ,Body Fluids ,Gastroenteritis ,Blood ,Infectious Diseases ,Medical Microbiology ,Shigellosis ,Female ,Rabbits ,Pathogens ,Anatomy ,Antibody ,Public aspects of medicine ,RA1-1270 ,Research Article ,Neglected Tropical Diseases ,Infectious Disease Control ,Immunology ,Shigella sonnei ,Gastroenterology and Hepatology ,Cross Reactions ,Biology ,Serogroup ,Microbiology ,Antibodies ,Antigen ,Vaccine Development ,medicine ,Animals ,Humans ,Antigens ,Microbial Pathogens ,Dysentery, Bacillary ,Bacteria ,Organisms ,Public Health, Environmental and Occupational Health ,Biology and Life Sciences ,Proteins ,Blood Serum ,biochemical phenomena, metabolism, and nutrition ,Tropical Diseases ,medicine.disease ,biology.organism_classification ,Virology ,digestive system diseases ,biology.protein ,bacteria ,Preventive Medicine ,Immune Serum - Abstract
No vaccine to protect against an estimated 238,000 shigellosis deaths per year is widely available. S. sonnei is the most prevalent Shigella, and multiple serotypes of S. flexneri, which change regionally and globally, also cause significant disease. The leading Shigella vaccine strategies are based on the delivery of serotype specific O-antigens. A strategy to minimize the complexity of a broadly-protective Shigella vaccine is to combine components from S. sonnei with S. flexneri serotypes that induce antibodies with maximum cross-reactivity between different serotypes. We used the GMMA-technology to immunize animal models and generate antisera against 14 S. flexneri subtypes from 8 different serotypes that were tested for binding to and bactericidal activity against a panel of 11 S. flexneri bacteria lines. Some immunogens induced broadly cross-reactive antibodies that interacted with most of the S. flexneri in the panel, while others induced antibodies with narrower specificity. Most cross-reactivity could not be assigned to modifications of the O-antigen, by glucose, acetate or phosphoethanolamine, common to several of the S. flexneri serotypes. This allowed us to revisit the current dogma of cross-reactivity among S. flexneri serotypes suggesting that a broadly protective vaccine is feasible with limited number of appropriately selected components. Thus, we rationally designed a 4-component vaccine selecting GMMA from S. sonnei and S. flexneri 1b, 2a and 3a. The resulting formulation was broadly cross-reactive in mice and rabbits, inducing antibodies that killed all S. flexneri serotypes tested. This study provides the framework for a broadly-protective Shigella vaccine which needs to be verified in human trials., Author summary A strategy to optimize the composition for a broadly-protective Shigella vaccine is to combine components directed against S. sonnei with S. flexneri serotypes to induce antibody responses with the maximum cross-reactivity between different serotypes. Based on mouse and rabbit immunogenicity, we selected 4 GMMA-immunogens, derived from S. sonnei and S. flexneri 1b, 2a and 3a, able to induce antibodies that were broadly bactericidal against most epidemiologically significant S. flexneri strains in mice and rabbits. This was not predicted on the basis of O-antigen modifications conferring serotype or group specificities and allowed revisiting the dogma of cross-protection among S. flexneri serotypes. Overall, this study provides a framework for the rational design of a broadly-protective vaccine that will be evaluated in upcoming human vaccine trials. It also tackles a key issue regarding Shigella vaccine development that is balancing a sufficient number of antigenic components in the vaccine to provide adequate coverage of serotype diversity while minimizing complexity.
- Published
- 2021