Vaccines for Protecting Infants from Bacterial Causes of Diarrheal Disease

Abstract

The global diarrheal disease burden for Shigella, enterotoxigenic Escherichia coli (ETEC), and Campylobacter is estimated to be 88M, 75M, and 75M cases annually, respectively. A vaccine against this target trio of enteric pathogens could address about one-third of diarrhea cases in children. All three of these pathogens contribute to growth stunting and have demonstrated increasing resistance to antimicrobial agents. Several combinations of antigens are now recognized that could be effective for inducing protective immunity against each of the three target pathogens in a single vaccine for oral administration or parenteral injection. The vaccine combinations proposed here would result in a final product consistent with the World Health Organization's (WHO) preferred product characteristics for ETEC and Shigella vaccines, and improve the vaccine prospects for support from Gavi, the Vaccine Alliance, and widespread uptake by low- and middle-income countries' (LMIC) public health stakeholders. Broadly protective antigens will enable multi-pathogen vaccines to be efficiently developed and cost-effective. This review describes how emerging discoveries for each pathogen component of the target trio could be used to make vaccines, which could help reduce a major cause of poor health, reduced cognitive development, lost economic productivity, and poverty in many parts of the world.

Keywords: Campylobacter vaccine; ETEC vaccine; Shigella vaccine; adjuvants; disease burden; models of disease; mucosal immunity; multi-pathogen enteric vaccines; stunting.

Figure 1

Percent of total cases of diarrheal disease caused by specific pathogens. Cholera shows as negligible in the chart because of the low number of cases compared with the other causes of enteric diseases shown. These are data for 2016 cited in [5].

Figure 2

Immune response to Shigella and ETEC CS3 antigens in a combined vaccine as shown in Figure 3. CS6 and CFA/I in combination with dmLT or Invaplex had significantly higher anti-CS3 antibody titers compared with titers after immunization with CS3, CS6, and CFA/I alone (Panel A). The immune response to CS6 was similarly enhanced, but the immune response to CFA/I was unaffected. Serum IgG titers directed in Invaplex (Panel B) were comparable in guinea pigs immunized with CS3, CS6, and CFA/I delivered alone or in combination with Invaplex, indicating that the ETEC antigens did not interfere with the Shigella antigen-specific immune responses. For these unpublished data (R. Kaminski), Guinea pigs (Hartley strain; six pigs/grp) were immunized intradermally on study days 1, 22, and 43 with either 6.25 µg of CFA/I, CS3, and CS6 delivered with and without dmLT (500 ng) or Invaplex (25 µg). Blood collected on days 1, 22, 43, and 57 were assayed by ELISA for serum IgG titers directed to CS3 (A) and Invaplex (B). Data represents the geometric mean titer and 95% confidence interval.

Figure 3

Presentation options for oral enteric vaccine delivery. Oral vaccine presentations can be made up of a combination of dry and liquid vaccine components that can be combined as shown.