Neutralizing antibody correlate of protection against severe-critical COVID-19 in the ENSEMBLE single-dose Ad26.COV2.S vaccine efficacy trial
Lindsay N. Carpp, Ollivier Hyrien, Youyi Fong, David Benkeser, Sanne Roels, Daniel J Stieh, Ilse Van Dromme, Griet A. Van Roey, Avi Kenny, Ying Huang, Marco Carone, Adrian B. McDermott, Christopher R. Houchens, Karen Martins, Lakshmi Jayashankar, Flora Castellino, Obrimpong Amoa-Awua, Manjula Basappa, Britta Flach, Bob C. Lin, Christopher A. Moore, Mursal Naisan, Muhammed Naqvi, Sandeep Narpala, Sarah O’Connell, Allen Mueller, Leo Serebryannyy, Mike Castro, Jennifer Wang, Christos J. Petropoulos, Alex Luedtke, Yiwen Lu, Chenchen Yu, Michal Juraska, Nima S. Hejazi, Daniel Wolfe, Jerald Sadoff, Glenda Gray, Beatriz Grinsztejn, Paul Goepfert, Linda‐Gail Bekker, Aditya H. Gaur, Valdilea Veloso, April K. Randhawa, Michele P. Andrasik, Jenny Hendriks, Carla Truyers, An Vandebosch, Frank Struyf, Hanneke Schuitemaker, Macaya Douoguih, James G. Kublin, Lawrence Corey, Kathleen M. Neuzil, Dean Follmann, Richard A. Koup, Rubén O. Donis, Peter B. Gilbert, On behalf of the Immune Assays Team, the Coronavirus Vaccine Prevention Network (CoVPN)/ENSEMBLE Team, Ilse Van Dromme, Griet A. Van Roey, the United States Government (USG)/CoVPN Biostatistics Team
Abstract
Abstract Assessment of immune correlates of severe COVID-19 has been hampered by the low numbers of severe cases in COVID-19 vaccine efficacy (VE) trials. We assess neutralizing and binding antibody levels at 4 weeks post-Ad26.COV2.S vaccination as correlates of risk and of protection against severe-critical COVID-19 through 220 days post-vaccination in the ENSEMBLE trial (NCT04505722), constituting ~4.5 months longer follow-up than our previous correlates analysis and enabling inclusion of 42 severe-critical vaccine-breakthrough cases. Neutralizing antibody titer is a strong inverse correlate of severe-critical COVID-19, with estimated hazard ratio (HR) per 10-fold increase 0.35 (95% CI: 0.13, 0.90). In a multivariable model, HRs are 0.31 (0.11, 0.89) for neutralizing antibody titer and 1.22 (0.49, 3.02) for anti-Spike binding antibody concentration. VE against severe-critical COVID-19 rises with neutralizing antibody titer: 63.1% (95% CI: 40.0%, 77.3%) at unquantifiable [<4.8975 International Units (IU)50/ml], 85.2% (47.2%, 95.3%) at just-quantifiable (5.2 IU50/ml), and 95.1% (81.1%, 96.9%) at 90 th percentile (30.2 IU50/ml). At the same titers, VE against moderate COVID-19 is 32.5% (11.8%, 48.4%), 33.9% (19.1%, 59.3%), and 60.7% (40.4%, 76.4%). Protection against moderate vs. severe disease may require higher antibody levels, and very low antibody levels and/or other immune responses may associate with protection against severe disease.