Abstract
Diarrhoeal diseases are the second leading cause of death for children under 5 years old in 69 low- and middle-income countries, with an annual economic burden of US$ 4 billion and over 525,000 lives lost. Cholera and enterotoxigenic Escherichia coli (ETEC) traveller's diarrhoea are major diarrhoeal diseases caused by Vibrio cholerae (O1 and O139 serogroups) and ETEC, which have similar pathogeneses and can co-infect. There is no exclusive vaccine for ETEC, but cholera vaccines containing the cholera toxin B (CT-B) component offer short-term cross-protection. However, licensed oral cholera vaccines are expensive due to cold-chain supplies and the need for multiple doses. A cost-effective, dual-protection, live, cold-chain-free vaccine is, therefore, required for vaccination campaigns in low-resource settings, and MyChol - a prototype cold-chain-free live attenuated cholera vaccine, targeting V. cholerae O139 and ETEC H10407 - was developed in this context. The vaccine was evaluated in three animal models (Sprague Dawley [SD] rats, BALB/c mice and New Zealand white rabbits) for safety, colonisation capacity, reactogenicity and immunogenicity against challenge strains. In suckling mice, MyChol displayed high colonisation potential compared to unformulated VCUSM14P (the vaccine candidate) and wild-type O139. In the acute toxicity assessment, the SD rats with the highest MyChol dose (1 × 107 colony-forming unit [CFU]/kg) demonstrated no adverse effects or mortality. Mice vaccinated with MyChol exhibited elevated antibody levels, including anti-CT, anti-heat-labile enterotoxin (LT), anti-CT-B and anti-LT-B. Anti-CT antibodies neutralised LT toxin in ETEC H10407 in challenge studies and cross-protected against ETEC H10407 in both mice and rabbits, preventing weight loss and diarrhoea. Ileal loop experiments in rabbits and BALB/c mice showed no reactogenicity. This review, based on our previous research, therefore provides valuable insights into improving the selection of animal models to advance preclinical evaluations of diarrhoeal vaccines.
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