This study follows 99 subjects vaccinated with Pfizer/BioNTech COVID-19 vaccines over two years, with particular focus on the last year of observation (between days 360 and 720). The response to the vaccination was assessed with Diasorin’s SARS-CoV-2 TrimericSpike IgG. Screening for SARS-CoV-2 infection was performed with Abbott’s SARS-CoV-2 Nucleocapsid IgG immunoassay. Data from questionnaires were also analyzed. Two years after the first vaccine dose administration, 100% of the subjects were positive for anti-spike SARS-CoV-2 IgG and the median antibody level was still high (3600 BAU/mL), dropping insignificantly over the last year. Simultaneously, a substantial increase in seropositivity in anti-nucleocapsid SARS-CoV-2 IgG was noted, reaching 33%. There was no statistically significant agreement between anti-N seropositivity and reported COVID-19. Higher anti-spike concentrations and lower COVID-19 incidence was seen in the older vaccinees. It was noted that only subjects boosted between days 360 and 720 showed an increase in anti-spike IgG concentrations. The higher antibody concentrations (median 7440 BAU/mL) on day 360 were noted in participants not infected over the following year. Vaccination, including booster administrations, and natural, even unrecognized, contact with SARS-CoV-2 entwined two years after the primary vaccination, leading to high anti-spike antibody concentrations.