Viruses (Sep 2023)
Stochastic Interventional Vaccine Efficacy and Principal Surrogate Analyses of Antibody Markers as Correlates of Protection against Symptomatic COVID-19 in the COVE mRNA-1273 Trial
- Ying Huang,
- Nima S. Hejazi,
- Bryan Blette,
- Lindsay N. Carpp,
- David Benkeser,
- David C. Montefiori,
- Adrian B. McDermott,
- Youyi Fong,
- Holly E. Janes,
- Weiping Deng,
- Honghong Zhou,
- Christopher R. Houchens,
- Karen Martins,
- Lakshmi Jayashankar,
- Britta Flach,
- Bob C. Lin,
- Sarah O’Connell,
- Charlene McDanal,
- Amanda Eaton,
- Marcella Sarzotti-Kelsoe,
- Yiwen Lu,
- Chenchen Yu,
- Avi Kenny,
- Marco Carone,
- Chuong Huynh,
- Jacqueline Miller,
- Hana M. El Sahly,
- Lindsey R. Baden,
- Lisa A. Jackson,
- Thomas B. Campbell,
- Jesse Clark,
- Michele P. Andrasik,
- James G. Kublin,
- Lawrence Corey,
- Kathleen M. Neuzil,
- Rolando Pajon,
- Dean Follmann,
- Ruben O. Donis,
- Richard A. Koup,
- Peter B. Gilbert,
- on behalf of the Immune Assays,
- Moderna, Inc.,
- Coronavirus Vaccine Prevention Network (CoVPN)/Coronavirus Efficacy (COVE),
- United States Government (USG)/CoVPN Biostatistics Teams
Affiliations
- Ying Huang
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- Nima S. Hejazi
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- Bryan Blette
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA 19104, USA
- Lindsay N. Carpp
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- David Benkeser
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
- David C. Montefiori
- Department of Surgery, Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA
- Adrian B. McDermott
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Youyi Fong
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- Holly E. Janes
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- Weiping Deng
- Moderna, Inc., Cambridge, MA 02139, USA
- Honghong Zhou
- Moderna, Inc., Cambridge, MA 02139, USA
- Christopher R. Houchens
- Biomedical Advanced Research and Development Authority, Washington, DC 20201, USA
- Karen Martins
- Biomedical Advanced Research and Development Authority, Washington, DC 20201, USA
- Lakshmi Jayashankar
- Biomedical Advanced Research and Development Authority, Washington, DC 20201, USA
- Britta Flach
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Bob C. Lin
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Sarah O’Connell
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Charlene McDanal
- Department of Surgery, Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA
- Amanda Eaton
- Department of Surgery, Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA
- Marcella Sarzotti-Kelsoe
- Department of Surgery, Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA
- Yiwen Lu
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- Chenchen Yu
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- Avi Kenny
- Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
- Marco Carone
- Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
- Chuong Huynh
- Biomedical Advanced Research and Development Authority, Washington, DC 20201, USA
- Jacqueline Miller
- Moderna, Inc., Cambridge, MA 02139, USA
- Hana M. El Sahly
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Lindsey R. Baden
- Brigham and Women’s Hospital, Boston, MA 02115, USA
- Lisa A. Jackson
- Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA
- Thomas B. Campbell
- Division of Infectious Diseases, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Jesse Clark
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Michele P. Andrasik
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- James G. Kublin
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- Lawrence Corey
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- Kathleen M. Neuzil
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Rolando Pajon
- Moderna, Inc., Cambridge, MA 02139, USA
- Dean Follmann
- Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Ruben O. Donis
- Biomedical Advanced Research and Development Authority, Washington, DC 20201, USA
- Richard A. Koup
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Peter B. Gilbert
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- on behalf of the Immune Assays
- Moderna, Inc.
- Coronavirus Vaccine Prevention Network (CoVPN)/Coronavirus Efficacy (COVE)
- United States Government (USG)/CoVPN Biostatistics Teams
- DOI
- https://doi.org/10.3390/v15102029
- Journal volume & issue
-
Vol. 15,
no. 10
p. 2029
Abstract
The COVE trial randomized participants to receive two doses of mRNA-1273 vaccine or placebo on Days 1 and 29 (D1, D29). Anti-SARS-CoV-2 Spike IgG binding antibodies (bAbs), anti-receptor binding domain IgG bAbs, 50% inhibitory dilution neutralizing antibody (nAb) titers, and 80% inhibitory dilution nAb titers were measured at D29 and D57. We assessed these markers as correlates of protection (CoPs) against COVID-19 using stochastic interventional vaccine efficacy (SVE) analysis and principal surrogate (PS) analysis, frameworks not used in our previous COVE immune correlates analyses. By SVE analysis, hypothetical shifts of the D57 Spike IgG distribution from a geometric mean concentration (GMC) of 2737 binding antibody units (BAU)/mL (estimated vaccine efficacy (VE): 92.9% (95% CI: 91.7%, 93.9%)) to 274 BAU/mL or to 27,368 BAU/mL resulted in an overall estimated VE of 84.2% (79.0%, 88.1%) and 97.6% (97.4%, 97.7%), respectively. By binary marker PS analysis of Low and High subgroups (cut-point: 2094 BAU/mL), the ignorance interval (IGI) and estimated uncertainty interval (EUI) for VE were [85%, 90%] and (78%, 93%) for Low compared to [95%, 96%] and (92%, 97%) for High. By continuous marker PS analysis, the IGI and 95% EUI for VE at the 2.5th percentile (519.4 BAU/mL) vs. at the 97.5th percentile (9262.9 BAU/mL) of D57 Spike IgG concentration were [92.6%, 93.4%] and (89.2%, 95.7%) vs. [94.3%, 94.6%] and (89.7%, 97.0%). Results were similar for other D29 and D57 markers. Thus, the SVE and PS analyses additionally support all four markers at both time points as CoPs.
Keywords
- binding antibody assay
- immune correlates of protection
- modified treatment policy
- neutralizing antibody assay
- principal stratification
- principal surrogate
