Nature Communications (Nov 2024)

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 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 N. Wolfe,
  • Jerald Sadoff,
  • Glenda E. Gray,
  • Beatriz Grinsztejn,
  • Paul A. Goepfert,
  • Linda-Gail Bekker,
  • Aditya H. Gaur,
  • Valdilea G. 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,
  • Ruben O. Donis,
  • Peter B. Gilbert,
  • On behalf of the Immune Assays Team,
  • the Coronavirus Vaccine Prevention Network (CoVPN)/ENSEMBLE Team,
  • the United States Government (USG)/CoVPN Biostatistics Team

DOI
https://doi.org/10.1038/s41467-024-53727-y
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 18

Abstract

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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 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.