Immunization Against Bacterial Diseases of the Intestine

More than two thirds of the world’s infants and children live in less developed countries, often in conditions in which the unavailability of potable water and sanitation and of refrigeration for foods fosters the transmission of enteric pathogens. In such areas, bacterial enteric pathogens are common causes of infant diarrhea, dysentery in toddlers, and enteric (typhoid and paratyphoid) fever in school age children. Whereas many bacterial pathogens have been identified as causes of diarrheal disease during the past 25 years, a relative few are cumulatively responsible for the majority of disease of public health importance. Several of these have been targeted as priorities for the development of new or improved vaccines, including: Vibrio cholerae O1 and O139 (causes of epidemic and pandemic dehydrating diarrhea); Shigella (the most common etiologic agent of dysentery); enterotoxigenic Escherichia coli (the second most common cause of dehydrating infant diarrhea, after rotavirus); and, Salmonella enterica serovar Typhi (S. Typhi, the etiologic agent of typhoid fever) (1). If optimal vaccines against these infectious agents could be delivered to the pediatric populations at risk, the global burden of enteric infections could be greatly diminished. Other than Shigella, these enteric infections rarely pose a problem for children in the industrialized countries of North America and Europe, unless they travel to developing areas of the world. On the other hand, as a consequence of animal husbandry, mass food processing and fast food practices, a bacterial pathogen of particular importance in the industrialized countries, enterohemorrhagic E. coli (EHEC; also called Shiga toxin–producing E. coli [STEC]), has emerged (2). Although the need for an EHEC vaccine has been controversial, a few EHEC vaccines are in early development (3–5). This review covers in depth the vaccines against cholera, shigellosis, enterotoxigenic E. coli (ETEC) diarrhea, and typhoid fever, and, in addition, briefly mentions vaccines against enteropathogenic E. coli (EPEC), enteroaggregative E. coli (EAggEC), Campylobacter jejuni, and Helicobacter pylori. A common motif that will emerge is how the development of modern vaccines against bacterial enteric pathogens has depended extensively on advances in mucosal immunology, bacterial pathogenesis, and host–parasite interaction. Rather than recount in depth the pathogenesis of each bacterial enteropathogen, specific salient features are cited to illustrate how they have influenced vaccine development strategies. The bacterial enteric pathogens exhibit distinct pathogenetic themes in relation to the gut mucosa. For example, V. cholerae O1 and ETEC are noninvasive organisms that colonize the proximal small intestine where they adhere by means of fimbrial attachment factors and elaborate enterotoxins that result in net secretion (6,7). A second theme is exemplified by Shigella, which initially elaborates one or more enterotoxins (depending on their serotype) that are active in the small intestine (8–11), but then invades the mucosa of the distal ileum and colon, initially through M cells overlying the gut-associated lymphoid tissue (GALT) (12,13). Shigella induces intense mucosal inflammation characterized by a profligate influx of polymorphonuclear leukocytes and mucosal ulcerations and microabscesses. Demonstrating yet another motif, Salmonella enterica serovar Typhi results in a generalized infection of the GALT, reticuloendothelial system, and gall bladder. S. Typhi invades the mucosa through both M cells and enterocytes, becomes engulfed by macrophages, enters the lymph and then the blood circulation, and is filtered by fixed macrophages in the reticuloendothelial system, including the liver, spleen, and bone marrow (14). After a rather long incubation of 8 to 14 days, clinical illness begins, accompanied by persistent low-level secondary bacteremia. The most prominent site of disease is the ileum where grossly swollen Peyer’s patches are noted. Received March 3, 2000; revised June 29, 2000; accepted June 30, 2000. Address correspondence and reprint requests to Dr. Myron M. Levine, Center for Vaccine Development, Division of Infectious Diseases and Tropical Pediatrics, University of Maryland School of Medicine, 685 W. Baltimore Street, Baltimore, MD 21201. This invited review is accompanied by an editorial. Please see Bass DM. Vaccines for bacterial enteritis: what is new and why it matters. J Pediatr Gastroenterol Nutr 2000;31:365–6. Journal of Pediatric Gastroenterology and Nutrition 31:336–355 © October 2000 Lippincott Williams & Wilkins, Inc., Philadelphia