Immune Correlates Analysis of the PREVENT-19 COVID-19 Vaccine Efficacy Clinical Trial
Authors: Fong Youyi , Huang Yunda , Benkeser David , Carpp Lindsay N. , Áñez Germán , Woo Wayne , McGarry Alice , Dunkle Lisa M. , Cho Iksung , Houchens Christopher R. , Martins Karen , Jayashankar Lakshmi , Castellino Flora , Petropoulos Christos J. , Leith Andrew , Haugaard Deanne , Webb Bill , Lu Yiwen , Yu Chenchen , Borate Bhavesh , van der Laan Lars W. P. , Hejazi Nima S. , Randhawa April K. , Andrasik Michele P. , Kublin James G. , Hutter Julia , Keshtkar-Jahromi Maryam , Beresnev Tatiana H. , Corey Lawrence , Neuzil Kathleen M. , Follmann Dean , Ake Julie A. , Gay Cynthia L. , Kotloff Karen L. , Koup Richard A. , Donis Ruben O. , Gilbert Peter B. ,   the Immune Assays Team,   the Coronavirus Vaccine Prevention Network (CoVPN)/2019nCoV-301 Principal Investigators and Study Team,   the United States Government (USG)/CoVPN Biostatistics Team
Published: June 2022

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 3rdpercentile, 6934 is the 97.5thpercentile), 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 5thpercentile, 7230 the 97.5thpercentile), 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.