Abstract
Many pathogens establish infection at mucosal surfaces such as the enteric pathogen Enterotoxigenic E. coli (ETEC). Thus, there is a pressing need for effective vaccination strategies that promote protective immunity at mucosal surfaces. Toll-like receptor (TLR) ligands have been extensively developed as vaccine adjuvants to promote systemic immunity, whereas attenuated bacterial toxins including cholera toxin and heat-labile toxin (LT) have initially been developed to promote mucosal immunity. Here we evaluate the ability of the TLR4 agonist second-generation lipid adjuvant formulated in a stable emulsion (SLA-SE) to augment functional mucosal antibodies elicited by intramuscular immunization with a recombinant ETEC vaccine antigen. We find that, in mice, parenterally delivered SLA-SE is at least as effective as the double-mutant LT (LTR192G/L211A, dmLT) adjuvant in promoting functional antibodies and eliciting intestinal IgA responses to the vaccine antigen. In addition, SLA-SE enhanced both the IgG2a response in the mucosa and serum, and the production of LT neutralizing serum antibodies elicited by dmLT four to eightfold. These results reveal unexpected mucosal adjuvant properties of this TLR4 agonist adjuvant when delivered intramuscularly. This may have a substantial impact on the development of vaccines against enteric and other mucosal pathogens.
Highlights
Enterotoxigenic E. coli (ETEC) is a noninvasive enteric pathogen, being one of the leading causes of moderate-to-severe diarrhea in children under the age of 5 in the developing world and is the leading cause of travelers’ diarrhea
second-generation lipid adjuvant (SLA)-stable emulsion (SE) augments mucosal antibodies to a parenteral immunization To determine whether a parenterally delivered TLR4 agonist immunity against nonvaccine bacterial strains (Fig. 3e)
We found that two immunizations of dmLT were required to produce significant labile toxin (LT) neutralizing titers in the serum adjuvant can elicit a similar mucosal immune response as an A-B5 class of adjuvant, BALB/c mice were immunized intramuscularly with an ETEC candidate vaccine antigen, CfaEB, adjuvanted with dmLT, SLA–SE or both
Summary
Enterotoxigenic E. coli (ETEC) is a noninvasive enteric pathogen, being one of the leading causes of moderate-to-severe diarrhea in children under the age of 5 in the developing world and is the leading cause of travelers’ diarrhea. Prior exposure to ETEC may provide highly significant protection against reinfection with the homologous strain or with an ETEC strain expressing the same or related CFs as demonstrated in animal models and in human volunteers.[4,5] the cholera vaccine Dukoral® (Valneva) provides short-term protection against LT-expressing ETEC by eliciting cholera toxin (CT)-specific antibodies that are cross-reactive to LT.[6] oral passive immunization studies with antibodies directed against the colonization factor CFA/I or the tip adhesin of CFA/I, CfaE, were protective against the CFA/I+ ETEC strain H10407 in a controlled human challenge trial.[5,7,8] These human challenge studies are especially important for ETEC vaccine development as the pathogenicity and specificity of ETEC strains differ between hosts (i.e., human and porcine ETEC strains express different CFs) Despite these observations suggesting that an ETEC vaccine is feasible, eliciting protective antibodies against mucosal pathogens such as ETEC has proven more difficult than for many systemic infections because the most common routes of immunization, including intramuscular and subcutaneous, are relatively ineffective in eliciting mucosal antibody responses. Addition of dmLT and/or SLA-SE together did produce a robust HAI titer against this heterologous ETEC strain, suggesting that one benefit of these adjuvants may be to increase protective
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