Background Limited information exists on nursing home (NH) residents regarding BNT162b2/Pfizer vaccine efficacy in preventing SARS-CoV-2 and severe Covid-19, and its association with post-vaccine humoral response. Methods 396 residents from seven NHs suffering a SARS-CoV-2 B.1.1.7 (VOC-α) outbreak at least 14 days after a vaccine campaign were repeatedly tested using SARS-CoV-2 real-time reverse-transcriptase polymerase chain reaction on nasopharyngeal swab test (RT-PCR). SARS-CoV-2 Receptor-Binding Domain (RBD) of the S1 subunit (RBD-IgG) was measured in all residents. Nucleocapsid antigenemia (N-Ag) was measured in RT-PCR-positive residents, and serum neutralizing antibodies in vaccinated residents from one NH. Results The incidence of positive RT-PCR was lower in residents vaccinated by two doses (22.7%) vs one dose (32.3%) or non-vaccinated residents (43.7%)(p<0.01). Covid-19-induced deaths were observed in 10.4% of the non-vaccinated residents, in 6.4% of those who had received one dose, and in 0.9% with two doses (p=0.0007). Severe symptoms were more common in infected non-vaccinated (21.0%) vs vaccinated residents (47.6%, p=0.002). Higher levels of RBD-IgG (n=325) were associated with a lower SARS-CoV-2 incidence. No in vitro serum neutralization activity was found for RBD-IgG levels below 1,050 AU/mL. RBD-IgG levels were inversely associated with N-Ag levels, found as a risk factor of severe Covid-19. Conclusions Two BNT162b2/Pfizer doses are associated with a 48% reduction of SARS-CoV-2 incidence and a 91.3% reduction of death risk in residents from NHs facing a VOC-α outbreak. BNT162b2/Pfizer efficacy was partly predicted by post-vaccine RBD-IgG levels.