Inferring vaccine efficacy and mode of action from human challenge studies

To assess the long-term effect of a vaccination programme, understanding both the efficacy and the mode of action of the vaccine is crucial. The actual mode of action is difficult to infer from field trials, because of the heterogeneity of exposure to infection. Here we show an approach to determine both vaccine efficacy and the mode of action of vaccines from human challenge studies. Our approach reveals how vaccines alter an individual's susceptibility, and identifies a mixture of different modes of action as a function of the challenged dose. By applying the proposed method to influenza challenge data, we illustrate that potentially the lowest vaccine efficacy may occur at intermediate doses, suggesting a hypothesis that moderate transmission intensities might be optimal for establishing infections in vaccinated individuals. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by JSPS KAKENHI (FM, Grant number 20J00793). This project has received funding from the European Union's Horizon 2020 research and innovation programme - project EpiPose (JW and DK, Grant agreement number 101003688). This work reflects only the authors' view. The European Commission is not responsible for any use that may be made of the information it contains. ### 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: Source data are publicly available from published articles. All analyzed data are available at the authors' GitHub link (https://github.com/fmiura/VacMoA_2023). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All codes and analyzed data are available at the authors' GitHub link (https://github.com/fmiura/VacMoA_2023).