A systems serology analysis of correlates of protection against cholera

Vibriocidal antibodies are the best characterized correlate of protection against cholera and are used to gauge immunogenicity in vaccine trials. However, there is no vibriocidal titer threshold associated with absolute protection against infection with Vibrio cholerae or with symptomatic disease in infected individuals. While other circulating antibody responses have also been associated with a decreased risk of V. cholerae infection, there has been no comprehensive comparison of correlates of protection against cholera. To address this, we analyzed 58 serum antibody biomarkers as correlates of protection against both V. cholerae infection and against cholera diarrhea in infected individuals. The study was performed in two cohorts: (1) household contacts of patients with cholera in Bangladesh, and (2) North American volunteers who were vaccinated with a single dose of CVD 103-HgR live oral cholera vaccine and then challenged with virulent V. cholerae O1 El Tor Inaba. In household contacts, we identified 20 antibody markers that were correlated with protection against V. cholerae infection, though there was overlap between distributions. Conditional random forest models identified serum antibody-dependent complement deposition, targeting the V. cholerae O1 antigen, as the most predictive individual correlate of protection from infection, while vibriocidal antibody titers were less predictive. The model that most accurately predicted protection from infection included five biomarkers, with a cross-validated area under the curve (cvAUC) of 79% (95% CI 73-85). Similarly, in North American volunteers who were challenged with V. cholerae after vaccination, a different five-biomarker model predicted protection from the development of cholera diarrhea with a cvAUC of 78% (95% CI 66-91). Thus, while several new biomarkers predict protection better than vibriocidal titers, it remains difficult to consistently predict whether an individual will be protected from future mucosal infection or symptoms using current serologic markers. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was supported by the icddr,b and extramural grants from the National Institutes of Health, including the National Institute of Allergy and Infectious Diseases, (R01 AI137164 [J.B.H., R.C.C., G.A., F.Q.], R01 AI106878 [E.T.R., F.Q.], R01 AI130378 [T.R.B.], R01 AI135115 [A.S.A, K.E.W.]). icddr,b is thankful to the donors for their support to its research efforts. icddr,b is also grateful to the governments of Bangladesh, Canada, Sweden, and the United Kingdom for providing core/unrestricted support. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by International Centre for Diarrhoeal Disease Research Bangladesh Ethical Review Committee and Massachusetts General Hospital Institutional Review Boards I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript and are available online at https://github.com/HopkinsIDD/cholera-systems-serology