Early, robust mucosal secretory IgA but not IgG response to SARS-CoV-2 spike in oral fluid is associated with faster viral clearance and COVID-19 symptom resolution

High priority efforts are under way to support the development of novel mucosal COVID-19 vaccines, such as the US Government’s Project NextGen and the Center for Epidemic Preparedness Innovations’ (CEPI) goal to respond to the next pandemic with a new vaccine in 100 days. However, there is limited consensus about the complementary role of mucosal immunity in disease progression and how the immunogenicity of mucosal vaccines will be evaluated. This study investigated the role of oral mucosal antibody responses in viral clearance and in COVID-19 symptom duration. Participants with PCR-confirmed SARS-CoV-2 infection provided oral fluid for testing with SARS-CoV-2 antibody multiplex assays, nasal swabs for RT-PCR and symptom information at up to eight follow-ups from April 2020 to February 2022. High and moderate oral fluid anti-spike (S) SIgA post infection was associated with significantly higher likelihood of viral clearance and of COVID-19 symptom resolution across age groups. Those with high and moderate anti-S SIgA cleared the virus and recovered 14 days (95% CI: 10-18 days) and 9-10 days (95% CI: 6-14 days) earlier, respectively. Delayed but higher oral fluid anti-S IgG was associated with significantly longer time to viral clearance and recovery. The effect size of moderate or high SIgA was equivalent to prior COVID-19 vaccine immunity, which was also associated with faster clearance and recovery. Unvaccinated adults with prolonged COVID-19 symptoms had significantly lower anti-RBD SIgA 15-30 days after infection onset ( p <0.001). Robust mucosal SIgA early post infection appears to support faster clearance of SARS-CoV-2 and recovery from COVID-19 symptoms. This research underscores the importance of harmonizing mucosal immune response assays to evaluate new vaccines that can boost local mucosal immunity. Disclaimer The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding for this study was provided by the Johns Hopkins COVID–19 Research Response Program and the FIA Foundation. N.P., K.K., and C.D.H. were supported by a gift from the GRACE Communications Foundation. C.D.H., N.P., and B.D. were additionally supported by the National Institute of Allergy and Infectious Diseases (NIAID) grants R21AI139784 and R43AI141265 and the National Institute of Environmental Health Sciences (NIEHS) grant R01ES026973. C.D.H. was also supported by NIAID grant R01AI130066 and R01ES026973. C.D.H. was also supported by NIH. grant U24OD023382. YM received support for this work from the Henry M. Jackson Foundation for the Advancement of Military Medicine (contract number 1007957) and the Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases Discovery Program. AA is supported by the National Institutes of Health (grant number K08AI143391). This work was supported by the Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases Discovery Program and the Johns Hopkins University School of Medicine COVID–19 Research Fund. Y.C.M. received salary support from the National Institutes of Health (grant numbers U54EB007958–12, U5411090366, U54HL143541–02S2, UM1AI068613). The SEARCh study was funded by the Centers for Disease Control and Prevention, grant number 75D30120C08737. ### 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 IRB of the the Johns Hopkins University School of Medicine gave ethical approval for this work. The IRB of Johns Hopkins University Bloomberg School of Public Health gave ethical approval for this work. The IRB of the Centers for Disease Control and Prevention gave ethical approval for this work based on the review of the Johns Hopkins University Bloomberg School of Public Health IRB. 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 data produced in the present study are available upon reasonable request to the authors after consultation with and approval of all study PIs.