Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine rollout has coincided with the spread of variants of concern. We investigated whether single-dose vaccination, with or without prior infection, confers cross-protective immunity to variants. We analyzed T and B cell responses after first-dose vaccination with the Pfizer/BioNTech messenger RNA vaccine BNT162b2 in health care workers (HCW) followed longitudinally, with or without prior Wuhan-Hu-1 SARS-CoV-2 infection. After one dose, individuals with prior infection showed enhanced T cell immunity, antibody-secreting memory B cell response to the spike protein, and neutralizing antibodies effective against variants B.1.1.7 and B.1.351. By comparison, HCW receiving one vaccine dose without prior infection showed reduced immunity against variants. B.1.1.7 and B.1.351 spike mutations resulted in increased, abrogated, or unchanged T cell responses, depending on human leukocyte antigen (HLA) polymorphisms. Single-dose vaccination with BNT162b2 in the context of prior infection with a heterologous variant substantially enhances neutralizing antibody responses against variants.