Weiping Zhang, David A. Sack
strains that produce a heat-labile toxin and/or a heat-stable toxin (STa). ETEC is one of the top four leading causes of diarrhea in children in developing countries (children's diarrhea) and is the most common cause of diarrhea among international travelers (travelers' diarrhea). Remarkable progress has been achieved in understanding disease mechanisms and developing vaccines against ETEC-associated diarrhea. With an understanding of the disease mechanism and identification of virulence determinants, efforts have focused on developing vaccines that target these virulence determinants using either a cellular (whole-cell) vaccine expressing these antigens or an acellular (subunit) approach that primarily targets ETEC adhesins and/or enterotoxins. However, it remains challenging to develop either a cellular or an acellular ETEC vaccine that effectively protects against ETEC strains and associated diarrheal disease, as ETEC strains produce approximately 30 immunologically heterogeneous adhesins and two distinctive enterotoxins, including the potent and poorly immunogenic STa toxin. Additionally, the prevalence of these virulence factors, particularly adhesins, varies over time and across different geographical regions. In this review article, we summarize the ETEC vaccine candidates that have progressed in the last decade and further discuss the potential challenges associated with the leading candidates. We also highlight the novel epitope- and structure-based multiepitope fusion antigen platform and its application in developing cross-protective multivalent precision vaccines.