The Ad26.COV2.S vaccine1–3 has shown clinical efficacy against symptomatic COVID-19, including variant B.1.351, which is partially resistant to neutralizing antibodies1. However, the immunogenicity of this vaccine in humans against the SARS-CoV-2 variant of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from a phase 1/2 clinical trial of COV10012 against the original strain SARS-CoV-2 WA1 / 2020, as well as against the respective variants B.1.1.7, CAL.20C, P.1. and B.1.351. Ad26.COV2.S induced median titers of neutralizing pseudoviruses of antibodies that were 5.0- and 3.3-fold lower, respectively, than variants B.1.351 and P.1, compared to WA1 / 2020 on day 71
. after vaccination. The median antibody titers were 2.9- and 2.7-fold lower, respectively, compared to variants B.1.351 and P.1, compared to WA1 / 2020. Antibody-dependent cellular phagocytosis, complement deposition, and activation responses were NK cells are largely conserved relative to variant B.1.351. CD8 and CD4 T cell responses, including central and effector memory responses, are comparable between variants WA1 / 2020, B.1.1.7, B.1.351, P.1 and CAL.20C. These data indicate that the neutralizing antibody responses induced by Ad26.COV2.S are reduced compared to variants B.1.351 and P.1, but the functional non-neutralizing responses of antibodies and T-cell responses are largely preserved compared to variants of SARS-CoV-2. These findings have implications for vaccine protection against SARS-CoV-2 concerned variants.