Long-Term Immunogenicity Study of an Aluminum Phosphate-Adjuvanted Inactivated Enterovirus A71 Vaccine in Children: An Extension to a Phase 2 Study

Background EV-A71 causes hand, foot, and mouth disease with potentially fatal complications such as encephalitis and acue flaccid myelitis in infants and children. This study examined the long-term immunity conferred by EV71vac, an inactivated EV-A71 vaccine based on the B4 subgenotype adjuvanted with aluminum phosphate, in children from the age of > 2 months to < 6 years for up to 5 years after the first immunization. Methods A total of 227 subjects from age of 2 months to 6 years who had previously received either EV71vac or placebo in the phase 2 clinical study were enrolled. Subjects were split into age groups: 2 years to < 6 years (Group 2b), 6 months to < 2 years (Group 2c), and 2 months to < 6 months (Group 2d). Serum samples were taken periodically for up to five years after the first dose for immunogenicity against EV-A71. Results At year 5, the neutralizing antibody titers against B4 subgenotype remained high at 621.38 to 978.20, 841.40 to 1159.93, and 477.71 to 745.07 for Groups 2b, 2c, and 2d, respectively. Cross-neutralizing titers at year 5 were 99.14 to 444.30 and 341.94 to 998.20 against B5 and C4a subgenotypes, respectively. Nearly all subjects remained seroprotected at year five (95.8 to 100%). No long-term safety issues were reported. Conclusion This study shows that using the current dosing regimen, EV71vac conferred persistent immunity against EV-A71 for at least five years after the first vaccination in children from the age of two months to six years. Summary EV-A71 neutralizing antibody persisted at high level throughout five years post vaccination in children of two months to six years old. ### Competing Interest Statement C. C., H.-Y. C., E.-F. H., and L. T.-C. L. are employees of Medigen Vaccine Biologics Corporation. Other authors have no conflict of interest to declare. All authors have reviewed and approved the final version of the manuscript. ### Clinical Trial NCT04072276 ### Funding Statement Medigen Vaccine Biologics Corporation was the study sponsor and had a role in study design, data analysis, and data interpretation, but had no role in data collection, or writing of the clinical study report. ### 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: The trial protocol and informed consent form were approved by the Taiwan Food and Drug Administration and the ethics committee of each investigation sites: National Taiwan University Research Ethics Committee, Chang Gung Medical Foundation Institutional Review Board, and MacKay Memorial Hospital Instituional Review Board. The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. An independent data and safety monitoring board (DSMB) was established to monitor safety data and the trial conduct. 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 Data produced in the study are available upon reasonable request to the authors