Article
Author: Carpp, Lindsay N  ; Hejazi, Nima S.  ; Fong, Youyi  ; Struyf, Frank  ; Gilbert, Peter B  ; Douoguih, Macaya  ; McDermott, Adrian B  ; Donis, Ruben O.  ; Bekker, Linda-Gail  ; Schuitemaker, Hanneke  ; Lu, Yiwen  ; Houchens, Christopher R  ; Luedtke, Alex  ; McDermott, Adrian B.  ; O’Connell, Sarah  ; Koup, Richard A.  ; Gaur, Aditya H  ; Follmann, Dean  ; Petropoulos, Christos J  ; Naisan, Mursal  ; Hyrien, Ollivier  ; Petropoulos, Christos J.  ; Amoa-Awua, Obrimpong  ; Wang, Jennifer  ; Donis, Ruben O  ; Gray, Glenda E.  ; Martins, Karen  ; Stieh, Daniel J.  ; Lin, Bob C.  ; Van Dromme, Ilse  ; Gray, Glenda E  ; Serebryannyy, Leo  ; Lin, Bob C  ; Van Roey, Griet A.  ; Benkeser, David  ; Narpala, Sandeep  ; Andrasik, Michele P  ; Veloso, Valdilea G  ; Hejazi, Nima S  ; Veloso, Valdilea G.  ; Kublin, James G  ; Roels, Sanne  ; Goepfert, Paul A.  ; O'Connell, Sarah  ; Juraska, Michal  ; Houchens, Christopher R.  ; Randhawa, April K  ; Neuzil, Kathleen M  ; Moore, Christopher  ; Goepfert, Paul A  ; Yu, Chenchen  ; Corey, Lawrence  ; Wolfe, Daniel N  ; Randhawa, April K.  ; Castellino, Flora  ; Gilbert, Peter B.  ; Kublin, James G.  ; Flach, Britta  ; Hendriks, Jenny  ; Truyers, Carla  ; Mueller, Allen  ; Kenny, Avi  ; Vandebosch, An  ; Sadoff, Jerald  ; Grinsztejn, Beatriz  ; Wolfe, Daniel N.  ; Castro, Mike  ; Koup, Richard A  ; Carpp, Lindsay N.  ; Huang, Ying  ; Stieh, Daniel J  ; Neuzil, Kathleen M.  ; Basappa, Manjula  ; Naqvi, Muhammed  ; Jayashankar, Lakshmi  ; Andrasik, Michele P.  ; Van Roey, Griet A  ; Gaur, Aditya H.  ; Carone, Marco 
AbstractAssessment 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 90th 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.