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

It is of interest to pinpoint SARS-CoV-2 sequence features defining vaccine resistance. In the ENSEMBLE randomized, placebo-controlled phase 3 trial, estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were measured from 484 vaccine and 1,067 placebo recipients who acquired COVID-19 during the trial. In Latin America, where Spike diversity was greatest, VE was significantly lower against Lambda than against Reference and against all non-Lambda variants [family-wise error rate (FWER) p < 0.05]. VE also differed by residue match vs. mismatch to the vaccine-strain residue at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20). VE 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 different antibody-epitope escape scores and by 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccine recipient sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against viruses with greatest distances. These results help map antigenic specificity of in vivo vaccine protection.

Déclaration de conflit d'intérêts

Competing interests: ALG reports contract testing from Abbott, Cepheid, Novavax, Pfizer, Janssen, and Hologic and research support from Gilead and Merck. JS declares support for the submitted work from the Janssen Pharmaceutical Companies of Johnson & Johnson and partial support (in the form of funding to his institution) from BARDA for the submitted work, declares support within the past 36 months from the Janssen Pharmaceutical Companies of Johnson & Johnson and BARDA funding for part of this work, has patents on invention of the Janssen COVID-19 vaccine, and has Johnson & Johnson stock and stock options. SR had partial support from the Department of Health and Human Services BARDA (in the form of contract payments to his institution) for the submitted work, has stock and/or stock options in Johnson & Johnson, and is an employee of Janssen Pharmaceutica NV. AV had partial support from BARDA (in the form of contract payments to her institution) for the submitted work, had all patent rights transferred to Johnson & Johnson, has stock and/or stock options in Johnson & Johnson, and is an employee of Janssen Pharmaceutica NV. DJS had partial support from the Department of Health and Human Services BARDA (in the form of contract payments to his institution) for the submitted work, has stock and/or stock options in Johnson & Johnson, and is an employee of Janssen. MLG had partial support from BARDA (in the form of contract payments to his institution) for the submitted work, has patents on invention of the Janssen COVID-19 vaccine, has shares in Johnson & Johnson, and is an employee of Johnson & Johnson. JV has stock and stock options in Johnson and Johnson and is an employee of Janssen Pharmaceutica NV. CT and IVD both had partial support from BARDA (in the form of contract payments to their institution) for the submitted work, hold stock in Janssen Pharmaceuticals, and are employees of Janssen Pharmaceutica NV. The views expressed by MR, HB and BLD are those of the authors and should not be construed to represent the positions of the U.S. Army, the Department of Defense, or the Department of Health and Human Services.