A tale of two bacterial enteropathogens and one multivalent vaccine

Abstract

Shigella and enterotoxigenic Escherichia coli (ETEC) are among the top four enteric pathogens that cause diarrheal illness in young children in developing countries and are major etiologic agents of travellers' diarrhoea. A single vaccine that could target both of these pathogens would have significant public health impact. In this review, we highlight the many pivotal contributions of Phillippe Sansonetti to the identification of molecular mechanisms of pathogenesis of Shigella that paved the way for the development of rationally designed, novel vaccines candidates. The CVD developed a series of live attenuated Shigella vaccine strains based on the most prevalent serotypes associated with disease. Shigella vaccine strains were engineered to express critical ETEC antigens to form a broadly protective Shigella‐ETEC multivalent vaccine.

A bivalent vaccine confers immunogenicity and protection against Shigella flexneri and enterotoxigenic Escherichia coli infections in mice

“…Further, the protection against ETEC-induced disease outcomes in this model may have been facilitated by anti-LT antibody responses, not measured here. The capacity of CVD 1208S-122 to induce strong serum and mucosal antibody responses against the ETEC antigens expressed in the vaccine was recently reported in guinea pigs 7,8 and will need to be evaluated in future studies utilizing these mouse models.…”

“…The ETEC CFA/I-encoding operon and the LT A2 and B subunits were engineered into the chromosome of the CVD 1208S. This new bivalent vaccine (CVD 1208S-122) has been reported to be safe and immunogenic in guinea pigs 7,8,19 .…”

“…The lack of small animal models that fully recapitulate clinical outcomes of infection has been one of the major barriers for development of Shigella and ETEC vaccines 5,6 . Recently, a combined Shigella-ETEC vaccine (CVD 1208S-122), consisting of an attenuated S. flexneri 2a strain expressing the ETEC colonization factor antigen-1 (CFA/1) and the heat labile-enterotoxin (LTb), has been shown to be safe and immunogenic in guinea pigs 7,8 . In order to provide stronger evidence of its pre-clinical effects, we evaluated whether CVD 1208S-122 could induce antibody responses and confer protection against diarrhea and weight loss using two murine models of orally administered S. flexneri and ETEC infections in C57BL/6 mice 9,10 .…”

“…Following antibiotic treatment, these models enable the study of clinical outcomes that mimic human disease in children induced by oral infection and enable the testing of interventions. In this study, we used antibiotic pre-treated nourished mice as they closely mimic the disease most often seen in humans with optimal, self-limited diarrhea and weight decrements as reported 6,7 .…”

Development of vaccines at the time of COVID-19

“…Such approaches have been extensively applied, mainly to enterotoxigenic pathogens such as Salmonella enterica subsp. enterica Serovar Typhi, Vibrio cholera and Shigella strains (Barry and Levine 2019 ). Although very promising, no vaccines based on this technology have so far been licensed, suggesting that the right balance between reduced virulence and immunogenicity continues to be a challenge.…”