Asian Flush Gene Variant Enhances Cellular Immunogenicity of COVID-19 Vaccine: Prospective Observation in the Japanese General Population

Abstract

We previously reported a reduced humoral immune response to the COVID-19 vaccines. Subsequently, we observed a lower susceptibility to COVID-19 in individuals carrying the ALDH2 rs671 variant through a web-based retrospective survey. Based on these findings, we hypothesized that rs671 variant was beneficial for cellular immunity against COVID-19. Using the IFN-γ enzyme-linked immunospot (ELISPOT) assay, we assessed cellular immunity before and after COVID-19 vaccination in two subcohorts of a previously reported cohort. Subcohort 1 (26 participants) had six repeated observations at baseline after one to three doses, whereas subcohort 2 (19 participants) had two observations before and after the third dose. ELISPOT counts at six months after the second dose increased from baseline in carriers of the rs671 variant but not in non-carriers. A positive effect of rs671 on ELISPOT counts was estimated using a mixed model (183 observations from 45 participants), including the random effect of subcohort, repeated measures, and fixed effects of vaccine type, age, sex, height, lifestyle, steroid use, and allergic disease. There was no association between ELISPOT counts and specific IgG levels, suggesting a limitation in estimating protective potential by humoral response. Our sequential observational studies suggest a beneficial effect of the rs671 variant in SARS-CoV-2 infection via enhanced cellular immune response, providing a potential basis for optimizing preventive measures and drug development.

Keywords: ALDH2; COVID-19; T cell; cellular immunity; enzyme-linked immunospot; rs671.

Figure 1

SARS-CoV-2 S1 protein-specific IFN-γ⁺ cell counts after COVID-19 vaccination. (A) Study design. Subcohort 1 included 26 participants who completed two doses of mRNA-1273 (100 µg) and a booster dose of BNT162b2 (30 µg). Subcohort 2 included 19 male students who received three doses of BNT162b2. The green and blue syringe icons indicate mRNA-1273 and BNT 162b2, respectively. Blood samples were collected as indicated in red triangles. (B) SARS-CoV-2 S1 protein specific IFN-γ+ cell counts. IFN-γ ELISPOT counts after immunological activation with 315-peptide mixtures of SARS-CoV-2 spike glycoprotein of the original strain were plotted. Grey circles indicate the individual ELISPOT counts. Black circles indicate the median ELISPOT count for each time point, with error bars representing the interquartile range.

Figure 2

Association between humoral and cellular immunity. Anti-SARS-CoV-2 S1 IgG and IFN-γ+ PBMC count per 1 µL whole blood are plotted for 1 month after the second and third dose of the COVID-19 vaccine (blue and red dots represent subcohort 1 and 2, respectively). SFC: spot-forming cells. PBMC, peripheral blood mononuclear cells. Spearman’s rank correlation coefficients (ρ) and p-values are presented.

Figure 3

Cross-reactivity to SARS-CoV-2 delta and omicron variants. Cross-reactivity was assessed between the original and delta variants in PBMCs from 74 blood samples from subcohort 1 (three weeks after the first dose and one and three months after the second dose), subcohort 2, and between the original and omicron variants in PBMCs from 55 samples from subcohort 1 (six months after the second dose and one month after the third dose). PBMC, peripheral blood mononuclear cells.