Preclinical Characterization of Immunogenicity and Efficacy against Diarrhea from MecVax, a Multivalent Enterotoxigenic E. coli Vaccine Candidate

• Published in: Infection and immunity Vol. 89; no. 7; p. e0010621
• Main Authors: Seo, Hyesuk, Garcia, Carolina, Ruan, Xiaosai, Duan, Qiangde, Sack, David A, Zhang, Weiping
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 16-06-2021
• Subjects: Animals; Antibodies, Bacterial - immunology; Antibodies, Neutralizing - immunology; Antigens, Bacterial - immunology; Bacterial Toxins - immunology; Diarrhea - immunology; Diarrhea - microbiology; Diarrhea - prevention & control; Disease Models, Animal; Enterotoxigenic Escherichia coli - immunology; Epitopes - immunology; Escherichia coli Infections - prevention & control; Escherichia coli Proteins - immunology; Escherichia coli Vaccines - administration & dosage; Escherichia coli Vaccines - adverse effects; Escherichia coli Vaccines - immunology; Mice; Microbial Immunity and Vaccines; Recombinant Fusion Proteins - immunology; Spotlight; Swine; Vaccines, Combined - genetics; Vaccines, Combined - immunology; MecVax; injectable multivalent vaccine; toxoid fusion; multiepitope fusion antigen; enterotoxigenic Escherichia coli; MEFA; pig model; ETEC; diarrhea
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00106-21

There are no vaccines licensed for enterotoxigenic Escherichia coli (ETEC), a leading cause of diarrhea for children in developing countries and international travelers. Virulence heterogeneity among strains and difficulties identifying safe antigens for protective antibodies against STa, a potent but poorly immunogenic heat-stable toxin which plays a key role in ETEC diarrhea, are challenges in ETEC vaccine development. To overcome these challenges, we applied a toxoid fusion strategy and a novel epitope- and structure-based multiepitope fusion antigen (MEFA) vaccinology platform to construct two chimeric multivalent proteins, toxoid fusion 3xSTa
-mnLT
and adhesin CFA/I/II/IV MEFA, and demonstrated that the proteins induced protective antibodies against STa and heat-labile toxin (LT) produced by all ETEC strains or the seven most important ETEC adhesins (CFA/I and CS1 to CS6) expressed by the ETEC strains causing 60 to 70% of diarrheal cases and moderate to severe cases. Combining two proteins, we prepared a protein-based multivalent ETEC vaccine, MecVax. MecVax was broadly immunogenic; mice and pigs intramuscularly immunized with MecVax developed no apparent adverse effects but had robust antibody responses to the target toxins and adhesins. Importantly, MecVax-induced antibodies were broadly protective, demonstrated by significant adherence inhibition against E. coli bacteria producing any of the seven adhesins and neutralization of STa and cholera toxin (CT) enterotoxicity. Moreover, MecVax protected against watery diarrhea and provided over 70% and 90% protection against any diarrhea from an STa-positive or an LT-positive ETEC strain in a pig challenge model. These results indicated that MecVax induces broadly protective antibodies and prevents diarrhea preclinically, signifying that MecVax is potentially an effective injectable vaccine for ETEC.
Enterotoxigenic Escherichia coli (ETEC) bacteria are a top cause of children's diarrhea and travelers' diarrhea and are responsible for over 220 million diarrheal cases and more than 100,000 deaths annually. A safe and effective ETEC vaccine can significantly improve public health, particularly in developing countries. Data from this preclinical study showed that MecVax induces broadly protective antiadhesin and antitoxin antibodies, becoming the first ETEC vaccine candidate to induce protective antibodies inhibiting adherence of the seven most important ETEC adhesins and neutralizing the enterotoxicity of not only LT but also STa toxin. More importantly, MecVax is shown to protect against clinical diarrhea from STa-positive or LT-positive ETEC infection in a pig challenge model, recording protection from antibodies induced by the protein-based, injectable, subunit vaccine MecVax against ETEC diarrhea and perhaps the possibility of intramuscularly administered protein vaccines for protection against intestinal mucosal infection.