BNT162b2, an mRNA-based SARS-CoV-2 vaccine (Pfizer-BioNTech, New York, NY, USA), is one of the most effective COVID-19 vaccines and has been approved by more than 130 countries worldwide. However, several studies have reported that the COVID-19 vaccine shows high interper-sonal variability in terms of humoral and cellular responses, such as those with respect to SARS-CoV-2 spike protein immunoglobulin (Ig)G, IgA, IgM, neutralizing antibodies, and CD4+ and CD8+ T cells. The objective of this study is to investigate the kinetic changes in anti-SARS-CoV-2 spike IgG (IgG-S) profiles and adverse reactions and their associations with HLA profiles (HLA-A,-C,-B,-DRB1,-DQA1,-DQB1,-DPA1 and-DPB1) among 100 hospital workers from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan. DQA1*03:03:01 (p = 0.017; Odd ratio (OR) 2.80, 95%confidence interval (CI) 1.05–7.25) was significantly associated with higher IgG-S production after two doses of BNT162b2, while DQB1*06:01:01:01 (p = 0.028, OR 0.27, 95%CI 0.05–0.94) was significantly associated with IgG-S declines after two doses of BNT162b2. No HLA alleles were significantly associated with either local symptoms or fever. However, C*12:02:02 (p = 0.058; OR 0.42, 95%CI 0.15–1.16), B*52:01:01 (p = 0.031; OR 0.38, 95%CI 0.14–1.03), DQA1*03:02:01 (p = 0.028; OR 0.39, 95%CI 0.15–1.00) and DPB1*02:01:02 (p = 0.024; OR 0.45, 95%CI 0.21–0.97) appeared significantly associated with protection against systemic symptoms after two doses of BNT162b2 vaccination. Further studies with larger sample sizes are clearly warranted to determine HLA allele associations with the production and long-term sustainability of IgG-S after COVID-19 vaccination.