Considerations for development of whole cell bacterial vaccines to prevent diarrheal diseases in children in...

Enteric pathogens constitute a major pediatric threat in the developing world through their impact on morbidity and mortality, physical and cognitive development and cause and effect relationship with malnutrition. Although many bacterial pathogens can cause diarrheal diseases, a group of less than 10 including Shigella spp., enterotoxigenic Escherichia coli (ETEC), Vibrio cholerae, and possibly, Campylobacter jejuni account for a significant percentage of these diseases in developing countries. Rotavirus is also a major cause of diarrheal diseases. Vaccines against these agents offer a potentially effective control measure against these diseases, but safe, practical, and effective vaccines for many of these agents have yet to be realized. Many vaccine development approaches are under investigation, but the one that is currently most advanced and that has been most widely applied to enteric pathogens is the use of orally administered live or killed whole pathogen preparations. If inactivated, these vaccines will probably be administered as multiple doses with approximately 10(10) to 10(11) total particles per dose, but they are relatively safe for oral administration. Further, they may not require a buffer for delivery and can be stored in liquid formulations. Fewer doses may be required for some live attenuated pathogen vaccines, but a buffer will most likely be required for oral delivery and the product must be stored in a dried formulation. Also, safety becomes more of a concern with live pathogens depending on the degree of attenuation, host immunocompetence, and the total number and kinds of attenuated pathogens which may be present in a combined agent vaccine. Both live and killed whole pathogen vaccines can be immunogenic and have the possibility to serve as vectors for other antigens. Although many organisms and serotypes are clinically important, by exploiting antigenic cross reactivity and using some pathogen components as vectors for cloned antigens of other pathogens, it could be possible to induce immunity against major enteric pathogens/serotypes with <10 whole pathogen components in a multi-agent vaccine. Safe and effective mucosal adjuvants may in the future be useful in whole pathogen vaccines, but they do not seem to be essential for immunization. Further, dietary supplements such as zinc, mixed routes of delivery and new regimens are under study which may in the future enhance further the effectiveness of the whole pathogen vaccines which now seem realizable in the near term. For this to happen, however, a coordinated and committed effort is necessary now to address the immunologic, regulatory, manufacturing, testing and implementation issues which will be involved in the realization of this important product to benefit children's health worldwide.