Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA. Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA. Biostatistics Division, Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA. Departments of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA. Department of Statistics, University of Washington, Seattle, WA, USA. Department of Computer Science, Pitzer College, Claremont, CA, USA. University of North Florida, Jacksonville, FL, USA. University of North Carolina at Charlotte, Charlotte, NC, USA. Johnson & Johnson Innovative Medicine, Janssen Vaccines & Prevention B.V, Leiden, The Netherlands. Department of Biochemistry, University of Washington, Seattle, WA, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. South African Medical Research Council, Cape Town, South Africa. Janssen R&D, a division of Janssen Pharmaceutica NV, Beerse, Belgium. Evandro Chagas National Institute of Infectious Diseases-Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil. Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Facultad de Medicina Humana, Universidad Nacional de la Amazonia Peru, Iquitos, Peru. Hospital General de Agudos José María Ramos Mejia, Buenos Aires, Argentina. Division of Infectious Diseases, University of California San Diego, La Jolla, CA, USA. Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA. The Desmond Tutu HIV Centre, University of Cape Town, Observatory, Cape Town, South Africa. Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa. Discipline of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa. Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. pgilbert@fredhutch.org. Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. pgilbert@fredhutch.org. Department of Biostatistics, University of Washington School of Public Health, Seattle, WA, USA. pgilbert@fredhutch.org.

Nature communications. 2024;(1):2175

Abstract

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against the most distant viruses.