Immune Correlates Analysis of the PREVENT-19 COVID-19 Vaccine Efficacy Clinical Trial

In the randomized, placebo-controlled PREVENT-19 phase 3 trial conducted in the U.S. and Mexico of the NVX-CoV2373 adjuvanted, recombinant spike protein nanoparticle vaccine, anti-spike binding IgG concentration (spike IgG) and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured two weeks after two doses were assessed as correlates of risk and as correlates of protection against PCR-confirmed symptomatic SARS-CoV-2 infection (COVID- 19). These immune correlates analyses were conducted in the U.S. cohort of baseline SARS- CoV-2 negative per-protocol participants using a case-cohort design that measured the antibody markers from all 12 vaccine recipient breakthrough COVID-19 cases starting 7 days post antibody measurement and from 639 vaccine recipient non-cases (Mexico was excluded due to zero breakthrough cases with the efficacy data cut-off date April 19, 2021). In vaccine recipients, the baseline risk factor-adjusted hazard ratio of COVID-19 was 0.36 (95% CI: 0.20, 0.63), p<0.001 (adjusted p-0.005) per 10-fold increase in IgG spike concentration and 0.39 (0.19, 0.82), p=0.013 (adjusted p=0.030) per 10-fold increase in nAb ID50 titer. At spike IgG concentration 100, 1000, and 6934 binding antibody units/ml (100 is the 3rd percentile, 6934 is the 97.5th percentile), vaccine efficacy to reduce the probability of acquiring COVID-19 at 59 days post marker measurement was 65.5% (95% CI: 23.0%, 90.8%), 87.7% (77.7%, 94.4%), and 94.8% (88.0%, 97.9%), respectively. At nAb ID50 titers of 50, 100, 1000, and 7230 IU50/ml (50 is the 5th percentile, 7230 the 97.5th percentile), these estimates were 75.7% (49.8%, 93.2%), 81.7% (66.3%, 93.2%), 92.8% (85.1%, 97.4%) and 96.8% (88.3%, 99.3%). The same two antibody markers were assessed as immune correlates via the same study design and statistical analysis in the mRNA-1273 phase 3 COVE trial (except in COVE the markers were measured four weeks post dose two). Spike IgG levels were slightly lower and nAb ID50 titers slightly higher after NVX-CoV2373 than after mRNA-1273 vaccination. The strength of the nAb ID50 correlate was similar between the trials, whereas the spike IgG antibodies appeared to correlate more strongly with NVX-CoV2373 in PREVENT-19, as quantified by the hazard ratio and the degree of change in vaccine efficacy across antibody levels. However, the relatively few breakthrough cases in PREVENT-19 limited the ability to infer a stronger correlate. The conclusion is that both markers were consistent correlates of protection for the two vaccines, supporting potential cross-vaccine platform applications of these markers for guiding decisions about vaccine approval and use. ### Competing Interest Statement All authors have completed the ICMJE uniform disclosure form at [www.icmje.org/downloads/coi_disclosure.docx][1]. P.B.G., Y.F., Y.H., D.B., Y.L., C.Y., B.B., L.W.P.v.d.L., A.K.R., M.P.A., J.G.K., L.C., and L.N.C. declare support (in the form of grant payments to their institutions) from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) for the submitted work. Y.H. additionally declares contract payments to her institution within the past 36 months from the World Health Organization to conduct statistical analysis work related to COVID-19 vaccines (outside the scope of the current work), as well as direct payment (approved by her institute) within the past 36 months from Worcester HIV Vaccine for participation on a Data Safety Monitoring Board or Advisory Board. L.D., G.A., I.C., W.W., and A.M. are stockholders and employees at Novavax, Inc. C.J.P. declares support from BARDA and the US Centers for Disease Control within the past 36 months, for SARS-CoV-2 nAb testing for vaccine trials and surveillance studies, respectively, and is a shareholder in Labcorp (LH) and in Novavax (NVAX). N.S.H. declares a grant from the National Science Foundation within the past 36 months paid to his institution. K.M.N. declares grants within the past 36 months from Pfizer to her institution to conduct clinical trials of COVID-19 vaccines (but receives no salary support from these grants), as well as grants from the NIH to participate in the overall organization of COVID-19 vaccine trials and for participation in vaccine trials. K.L.K. declares support in the form of grant payments to her institution for the submitted work; serving as the PREVENT-19 Trial co-chair, CoVPN, with salary support from the NIH paid to her institution within the past 36 months; as well as PCR Cepheid and Abbott equipment for volunteer testing from CoVPN within the past 36 months (payments to her institution; will be returned). C.L.G. is a site Principal Investigator and a CoVPN protocol co-chair for the Novavax phase 3 trial. Her institution receives grant funding from NIH that includes salary support for her from NIAID for these activities. All other authors declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. ### Clinical Trial NCT04611802 ### Funding Statement Supported by Novavax; the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA) (contracts Operation Warp Speed: Novavax Project Agreement number 1 under Medical CBRN [Chemical, Biological, Radiological, and Nuclear] Defense Consortium base agreement no. 2020-530, Department of Defense no. W911QY20C0077 and Government Contract No. 75A50122C00008 with Labcorp - Monogram Biosciences); and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. The NIAID provides grant funding to the HIV Vaccine Trials Network (HVTN) Leadership and Operations Center (UM1 AI68614), the HVTN Statistics and Data Management Center (UM1 AI68635), the HVTN Laboratory Center (UM1 AI68618), the HIV Prevention Trials Network Leadership and Operations Center (UM1 AI68619), the AIDS Clinical Trials Group Leadership and Operations Center (UM1 AI68636), and the Infectious Diseases Clinical Research Consortium leadership group (UM1 AI148684). This work was also partially supported by NIAID through award no. R37AI054165 and by the Intramural Research Program of the NIAID Scientific Computing Infrastructure at Fred Hutch, under ORIP grant S10OD028685. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the Department of Health and Human Services or its components. ### 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 following Institutional Review Boards (IRBs)/Independent Ethics committees reviewed and approved the study: Western Copernicus Group IRB, US; Great Plains IRB, US; Comite de etica en investigacion del Instituto Nacional de Ciencias Medicas y Nutricion, Salvador Zubiran, Mexico; Comite de etica en investigacion de la Unidad de Atencion Medica e Investigacion en Salud S.C., Mexico; Comite de etica en investigacion del Instituto Nacional de Salud Publica, Mexico; Comite de etica en investigacion de Medica Rio Mayo S.C., Mexico; Comite de etica en investigacion del Hospital La Mision S.A. de C.V., Mexico. 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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 Data are available from . [1]: http://www.icmje.org/downloads/coi_disclosure.docx