Correlates of protection for booster doses of the BNT162b2 vaccine

Variants of concern (VOC) of SARS-CoV2 and waning immunity pose a serious global problem. Overall, vaccination and prior infection appear to provide significant protection to the majority of individuals, but some remain susceptible to infection and severe disease. Rigorously identifying a broad spectrum of correlates of protection (COP) is necessary to identify these susceptible populations. The extent to which additional booster doses provide protection is also poorly understood. To address this need, we conducted a multicenter prospective study assessing the association between serological profiles and the risk for SARS-CoV-2 infection, comparing those vaccinated with three to four doses of Pfizer BNT162b2 vaccine. Of 608 healthy adults, 365 received three doses and 243 received four doses. During the first 90 days of followup, 239 (39%) were infected, of whom 165/365 (45%) received 3 doses and 74/243 (30%) four doses. We found that the fourth dose elicited a significant rise in antibody binding and neutralizing titers against multiple variants, and reduced the risk of symptomatic infection by 37% [95% I, 15% - 54%]. We identified several parameters based on IgG and IgA binding that were COPs. The strongest association with infection risk was reduced IgG levels to RBD mutants and IgA levels to VOCs, which was a COP in the three-dose group (HR=6.34, p=0.008) and in the four-dose group (HR=8.14, p=0.018). A combination of two commercially available ELISA assays were also associated with protection in both groups (HR = 1.84, p = 0.002; HR = 2.01, p = 0.025, respectively). Most importantly, we identified a subset of individuals with low antibody levels after three doses of vaccine that responded with a significant boost in neutralizing antibody titers after a fourth dose, but were still at significantly increased susceptibility to infection when compared to those who had pre-existing high levels of neutralizing antibodies. Thus, we identify a highly susceptible population that remains susceptible despite apparent responsiveness to vaccines. Further, we develop several specific and sensitive COPs that show dramatic effect sizes and may be utilized to identify individuals most at risk from future exposures. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The clinical study was funded by Clalit Health Services and the Clinical Research Center at the Soroka University Medical Center. Tomer Hertz was supported by the Israel Science Foundation (ISF) grants no. 882/17 and 2683/21; and NIH award no. 75N93021C00016 subaward# 11308501A-8028280. Ran Taube is supported by the Israeli Ministry of Science and Technology f (MOST; grant #3-16897), the Israel Science Foundation for RT (ISF; Research Grant Application no. 755/17) and the Ben-Gurion University of the Negev COVID-19 Research Task Force for RT. Richard Webby was funded by the Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00016". ### 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: Ethics committee/IRB of the Israeli ministry of health gave ethical approval for this work. Meir Medical Center: 0001-22-mmc-c Emek Medical Center: 0001-22-EMC-C Carmel Medical Center: 0002-22-cmc-c Soroka Medical Center: 0404-21-SOR-C Kaplan Medical Center: 0006-22-kmc-c 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 study are available upon reasonable request to the authors