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Background Vaccine-induced neutralizing antibodies are key in combating the coronavirus disease 2019 (COVID-19) pandemic. However, delays of boost immunization due to limited availability of vaccines may leave individuals vulnerable to infection and prolonged or severe disease courses. The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC)—B.1.1.7 (United Kingdom), B.1.351 (South Africa), and P.1 (Brazil)—may exacerbate this issue, as the latter two are able to evade control by antibodies. Methods We assessed humoral and T-cell responses against SARS-CoV-2 wild-type (WT), VOC, and endemic human coronaviruses (hCoVs) that were induced after single and double vaccination with BNT162b2. Results Despite readily detectable immunoglobulin G (IgG) against the receptor-binding domain of the SARS-CoV-2 S protein at day 14 after a single vaccination, inhibition of SARS-CoV-2 S-driven host cell entry was weak and particularly low for the B.1.351 variant. Frequencies of SARS-CoV-2 WT and VOC-specific T cells were low in many vaccinees after application of a single dose and influenced by immunity against endemic hCoV. The second vaccination significantly boosted T-cell frequencies reactive for WT and B.1.1.7 and B.1.351 variants. Conclusions These results call into question whether neutralizing antibodies significantly contribute to protection against COVID-19 upon single vaccination and suggest that cellular immunity is central for the early defenses against COVID-19., We assessed single vaccine shot–induced B- and T-cell responses against SARS-CoV-2, variants of concern, and human coronaviruses to determine protection against COVID-19. Our results provide important information about surrogates of protection, test result interpretation, and clinical decision-making.