Abstract
Immunological heterogeneity has long been the major challenge in developing broadly effective vaccines to protect humans and animals against bacterial and viral infections. Enterotoxigenic Escherichia coli (ETEC) strains, the leading bacterial cause of diarrhea in humans, express at least 23 immunologically different colonization factor antigens (CFAs) and two distinct enterotoxins [heat-labile toxin (LT) and heat-stable toxin type Ib (STa or hSTa)]. ETEC strains expressing any one or two CFAs and either toxin cause diarrhea, therefore vaccines inducing broad immunity against a majority of CFAs, if not all, and both toxins are expected to be effective against ETEC. In this study, we applied the multiepitope fusion antigen (MEFA) strategy to construct ETEC antigens and examined antigens for broad anti-CFA and antitoxin immunogenicity. CFA MEFA CFA/I/II/IV [CVI 2014, 21(2):243-9], which carried epitopes of seven CFAs [CFA/I, CFA/II (CS1, CS2, CS3), CFA/IV (CS4, CS5, CS6)] expressed by the most prevalent and virulent ETEC strains, was genetically fused to LT-STa toxoid fusion monomer 3xSTaA14Q-dmLT or 3xSTaN12S-dmLT [IAI 2014, 82(5):1823-32] for CFA/I/II/IV-STaA14Q-dmLT and CFA/I/II/IV-STaN12S-dmLT MEFAs. Mice intraperitoneally immunized with either CFA/I/II/IV-STa-toxoid-dmLT MEFA developed antibodies specific to seven CFAs and both toxins, at levels equivalent or comparable to those induced from co-administration of the CFA/I/II/IV MEFA and toxoid fusion 3xSTaN12S-dmLT. Moreover, induced antibodies showed in vitro adherence inhibition activities against ETEC or E. coli strains expressing these seven CFAs and neutralization activities against both toxins. These results indicated CFA/I/II/IV-STa-toxoid-dmLT MEFA or CFA/I/II/IV MEFA combined with 3xSTaN12S-dmLT induced broadly protective anti-CFA and antitoxin immunity, and suggested their potential application in broadly effective ETEC vaccine development. This MEFA strategy may be generally used in multivalent vaccine development.
Highlights
Virulence heterogeneity among bacterial and viral strains or isolates has long been one major challenge in vaccine development
We immunized mice with the colonization factor antigens (CFAs)/I/II/IV multiepitope fusion antigen (MEFA) combined with toxoid fusion 3xSTaN12S-dmLT, and compared induced antigen-specific antibody responses with those induced by the CFA/I/II/IV-STaN12S-dmLT MEFA to assess whether genetic fusion affected antigenic property of the fused CFA adhesin and toxin antigen components, enabling application of MEFA strategy for multivalent vaccine development
Vaccines inducing anti-CFA antibodies to broadly prevent enterotoxigenic Escherichia coli (ETEC) adherence and colonization and antitoxin antibodies to neutralize both labile toxin (LT) and STa toxins are expected to be broadly effective against ETEC diarrhea
Summary
Virulence heterogeneity among bacterial and viral strains or isolates has long been one major challenge in vaccine development. Field studies showed that the rCTB-CF vaccine induced antibody responses and protected adults traveling from developed countries to ETEC endemic countries against the risk of disease by 60% to 70% [16,17] or against moderate to severe diarrhea [21] This product, provided no protection to children, especially very young children living in endemic areas against ETEC diarrhea, and caused some adverse effects. To create a single antigen inducing antibodies broadly protecting against seven CFA adhesins and both toxins and to explore potential application of such an antigen in ETEC vaccine development, in this study we first genetically fused the CFA/I/II/IV MEFA gene [39] to a LT-STa toxoid fusion gene [38] for a CFA/I/II/IV-STa-toxoid-dmLT MEFA and examined antiCFA and antitoxin immunogenicity in a murine model. We immunized mice with the CFA/I/II/IV MEFA combined with toxoid fusion 3xSTaN12S-dmLT, and compared induced antigen-specific antibody responses with those induced by the CFA/I/II/IV-STaN12S-dmLT MEFA to assess whether genetic fusion affected antigenic property of the fused CFA adhesin and toxin antigen components, enabling application of MEFA strategy for multivalent vaccine development
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