Vaccine- and infection-derived correlates of protection for cholera

PROJECT SUMMARY Vibrio cholerae causes 3 million cases of cholera and 100,000 deaths annually. It also causes large and deadly epidemics of disease in areas affected by climate and conflict associated humanitarian disasters. Vaccination is a pillar of the World Health Organization's plan to reduce cholera mortality by 90% in 2030. However, cholera vaccine shortages in the face of increasing demand have limited or halted numerous planned vaccination campaigns globally. Although new, low-cost oral cholera vaccines have been developed to improve supply, there is no agreement on how to introduce these new vaccines or evaluate their effectiveness. Traditional randomized trials to test new cholera vaccines require hundreds of thousands of participants, and the availability of other vaccines with proven effectiveness makes such large-scale trails of new vaccines unethical. Case-control studies to gauge vaccine effectiveness are another option for testing new vaccines but these are also resource-intensive and are subject to bias. For these reasons, the lack of 'correlates of protection' (or CoPs) against cholera is a major obstacle to cholera vaccine development. CoPs are measures of immunity which are accepted markers of an effective immune response to vaccination. While other infectious diseases have well established CoPs, there are no widely accepted CoPs for cholera. To overcome this obstacle, we will identify better CoPs for oral cholera vaccines. We will also compare these to CoPs derived from natural infection with V. cholerae. This proposal builds on our preliminary data which shows that several novel antibody-markers distinguish between protected and susceptible individuals after infection with V. cholerae. This evidence supports our premise that vaccination also will produce immune responses that accurately predict subsequent immunity to cholera. To test this hypothesis, we will follow a prospective, longitudinal cohort to identify both natural infection- and vaccine-induced CoPs which distinguish between subsequently protected and susceptible individuals. The study will be performed both in older children and adults, as well as young children, who are less well protected by current cholera vaccines. Ultimately, we expect this study to identify new and better performing CoPs for cholera. The results will improve our understanding of human immunity to cholera, and directly impact human health by accelerating the development and licensure of new and better performing cholera vaccines.