Impaired immunogenicity of the BNT162b2 mRNA COVID-19 vaccine has been reported in immunocompromised patients treated for solid tumors [8] and with solid organ transplantation [9,10,11]. However, the efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with heart disease has never been investigated. To the best of our knowledge, this is the first study to document a blunt response after a complete cycle of the BNT162b2 mRNA COVID-19 vaccine in patients with CVD.

COVID-19 vaccines demonstrate excellent efficacy in clinical trials [4,5] and effectiveness in real-world data [6], but some individuals still become infected with SARS-CoV-2 after vaccination. A recent study demonstrated that in older adults (≥60 years) who had received their first vaccine dose but not their second, heart disease was associated with post-vaccination infection [12]. Our data showed an inferior serological response to the COVID-19 vaccine after the first vaccine dose, which may be associated with susceptibility to COVID-19 infection after vaccination in patients with heart disease. Therefore, these patients may be highly recommended to receive the complete cycle of the COVID-19 vaccine. Hall et al. reported an increment in the immunogenicity of the COVID-19 vaccine with administration of a third dose in transplant recipients [13]. Our results demonstrated that patients with CVD had lower antibody levels after a booster dose compared to HCWs, suggesting that these patients should be prioritized to receive the third dose of vaccination.

In this study, differences in age and gender were observed between CVD patients and HCWs. Older age has been repeatedly reported to associate with reduced antibody responses after COVID-19 vaccination [14,15,16]. Female gender has also been shown to correlate with antibody responses to COVID-19 vaccination to various degrees [17]. These differences may make it difficult to evaluate the humoral response to COVID-19 vaccination in patients with CVD. In multivariate analyses, however, CVD was independently associated with seropositivity after the first vaccination and RBD−IgG titers after the second vaccination. Furthermore, when we performed multivariate analyses in a subgroup of 16 HCWs over 60 years (median age 65 years; male, 63%) and patients with CVD, similar results were obtained (data not shown). Consequently, we believe that these factors did not significantly affect our results. The mechanisms that emphasize the association between CVD and a poor humoral response to the BNT162b2 mRNA COVID-19 vaccine are still unclear. It is possible that the medications used may be associated with poorer humoral response in patients with CVD. In the present study, there were no significant differences in humoral response according to their medications, such as renin–angiotensin–aldosterone system inhibitors, beta-blockers, and statins. Further investigations are required to clarify this issue.

To date, some COVID-19 vaccines have been approved for emergency use. Diverse platforms have been used to deliver the recombinant SARS-CoV-2 spike, such as mRNA-encapsulating liposomes, adenovirus vectors, and micelle-attached spikes [18]. The humoral response may be different according to the type of vaccine. A notable loss of vaccine efficacy against SARS-CoV-2 variants is reported, likely caused by spike mutations in the RBD, N-terminal domain, and other regions [19,20]. It may be necessary to investigate the neutralizing antibody against variants of SARS-CoV-2.