An unknown pneumonia outbreak was reported by WHO on Dec. 31, 2019, from Wuhan, China. The full-length nucleotide sequence was disclosed several days later and showed 96 % nucleotide homology with morphologically similar severe acute respiratory syndrome (SARS) virus occurred in 2002 and named SARS corona virus-2 (SARS-CoV-2) [1,2]. A few months later, it spread to the EU and US through mostly travelers infected in China, and explosive domestic spread began in several countries [3,4]. The case fatality rate was 2.3 %, being lower than SARS or middle east respiratory syndrome (MERS), but the transmission rate of SARS-CoV-2 is extremely high, with many subjects with asymptomatic infections acting as transmitters [1,5,6]. WHO declared a pandemic on Mar. 11, 2020, and rapid development of effective vaccines was expected [7]. Among several candidates, two mRNA vaccines were developed in a year [8,9].

BNT162b2 (Comirnaty®; Pfizer-BioNTech) and mRNA-1273 (Spikevax®; Moderna), were licensed for emergency use in Dec. 2020 in U.S., based on the results of large-scale phase III trials, showing two doses of both mRNA vaccines 3–4 weeks apart showed unexpectedly high efficacy >95 % [10,11]. They were embedded in lipid nanoparticles (LNP) [12,13]. mRNA, itself, has adjuvant activity through RNA sensor of TLR3, 7, and 8 inducing IFN-α/β for activating cytotoxic T lymphocyte (CTL) and LNPs contribute to stimulate inflammasome to regulate antibody responses through Th1, Th2, and inflammatory cytokines. They induced higher neutralizing antibody (NAb) levels than those observed in the convalescent phase of natural infection of COVID-19 and Th1 cellular responses [14,15]. However, local pain was reported by approximately 80 % of recipients, fatigue and headache were noted in 40–60 %, and febrile illness in <20 % of the recipients as systemic adverse reactions [10,11]. During worldwide expansion of COVID-19, the original Wuhan strain was replaced by subsequent variant strains: α, β, δ, and omicron variants [[16], [17], [18]]. As antigenically different variant strains emerged, vaccine efficacy declined 3–6 months after the primary immunization with two doses [[19], [20], [21]], but mRNA vaccines were still effective on preventing COVID-19 associated hospitalization [22]. Critical features related to vaccine effectiveness involve developing NAb directed at the spike protein. Although NAb levels against variant strains decreased after vaccination, vaccine effectiveness is theoretically explained by cell-mediated immunity to eliminate infected cells by CD8+ cytotoxic T lymphocytes (CTL) induced by mRNA vaccine, preventing further expansion of viruses [23,24].

The CTL assay is complicated using flowcytometry to detect CD8 + and IFN-γ + cells in lymphocyte culture stimulated with spike antigen or peptides and skillful experience is required, not being suitable for a clinical setting. Therefore, there are no data on sequential change on cellular immune responses following mRNA vaccine immunization, with or without having symptomatic or asymptomatic infection. The interferon-γ releasing assay (IGRA) or enzyme linked immunospot (ELISPOT) assay is employed to evaluate the specific cell-mediated immunity against several antigens. In COVID-19 patients and vaccine recipients, the cell-mediated immune response was reported with IGRA using whole-blood cultures stimulated with SARS-CoV-2 spike antigen [[25], [26], [27], [28], [29], [30]]. A mRNA vaccine induced both humoral and cellular immune responses through Th1 and Th2 cytokines [14,23,24]. The incidence of adverse events and the persistence of antibody would be different between the two mRNA vaccines through clinical experience. In the present study, cytokine production in whole-blood cultures stimulated with SARS-CoV-2 spike antigen was compared following primary and booster immunization with BNT162b2 and mRNA-1273 vaccines. Sequential NAb titers against α, δ, and omicron variants were monitored during the study period.