The humoral and cellular response tomRNA SARS‐CoV‐2 vaccine is influenced byHLApolymorphisms

Abstract

Host genetic variability contributes to susceptibility to SARS‐CoV‐2 infection and COVID‐19 evolution and the role of HLA system has not clearly emerged, suggesting the involvement of other factors. Studying response to vaccination with Spyke protein mRNA represents an ideal model to highlight whether the humoral or cellular responses are influenced by HLA. Four hundred and sixteen workers, vaccinated with Comirnaty beginning 2021, were selected within the Azienda Ospedaliera Universitaria “Città della Salute e della Scienza di Torino.” The humoral response was determined with the LIAISON® kit, while the analysis of the cellular response was performed with the Quantiferon SARS‐CoV‐2 assay, for the S1 (receptor‐binding domain; Ag1) and S1 and S2 (Ag2) subunits of the Spyke protein. Six HLA loci were typed by next‐generation sequencing. Associations between HLA and vaccine response were performed with univariate and multivariate analyses. An association was found between A*03:01, B*40:02 and DPB1*06:01 and high antibody concentration and between A*24:02, B*08:01 and C*07:01 and low humoral responses. The haplotype HLA‐A*01:01 ~ B1*08:01 ~ C*07:01 ~ DRB1*03:01 ~ DQB1*02:01 conferred an increased risk of low humoral response. Considering cellular responses, 50% of the vaccinated subjects responded against Ag1 and 59% against Ag2. Carriers of DRB1*15:01 displayed a higher cellular response both to Ag1 and Ag2 compared to the rest of the cohort. Similarly, DRB1*13:02 predisposed to a robust cellular response to Ag1 and Ag2, while DRB1*11:04 showed an opposite trend. Cellular and humoral responses to Comirnaty are influenced by HLA. Humoral response is mainly associated to class I alleles, with A*03:01, previously associated to protection against severe COVID‐19, and response to vaccination, standing out. Cellular response predominantly involves class II alleles, with DRB1*15:01 and DPB1*13:01 prevailing. Affinity analysis for Spyke peptides is generally in line with the association results.

Genome‐wide association studies of response and side effects to the BNT162b2 vaccine in Italian healthcare workers: Increased antibody levels and side effects in carriers of the HLA‐A*03:01 allele

“…While our manuscript was under review, another study was published online, which confirmed our association between the HLA-A*03:01 allele and high antibody concentrations in the Italian population, using a different approach. 43 Another interesting result that emerged from our study is the association of the HLA-A*03:01 allele with an increased risk of experiencing specific side effects such as fever, chills and myalgia after vaccination with BNT162b2. In fact, the analysis showed side effects associated with the BNT162b2 vaccine to be more frequent in young and female subjects, but also in HLA-A*03:01 carriers.…”

Five doses of the mRNA vaccination potentially suppress ancestral-strain stimulated SARS-CoV2-specific cellular immunity: a cohort study from the Fukushima vaccination community survey, Japan

“…However, in this study, none of these factors were significant. Identifying specific groups unable to acquire cellular immunity based on HLA types remains a future research challenge ( 10 ).…”

Molecular Mimicry and HLA Polymorphisms May Drive Autoimmunity in Recipients of the BNT-162b2 mRNA Vaccine: A Computational Analysis

“…Some of the HLA alleles that showed associations with COVID-19 progression or response to the vaccine were predicted in this analysis to bind to self-epitopes showing 90% BLAST homology with the BNT-162b2 mRNA vaccine protein. For example, the HLA-DRB1*15:01 allele, predicted to bind epitopes of MEAF and ZFHX2, was positively correlated with enhancement of both anti-spike B and T cell responses in Caucasian and Japanese BNT-162b2 mRNA vaccine recipients [ 39 , 41 , 42 ]. Conversely, the allele HLA-A*24:02, which possibly recognizes epitopes of CHL1, was negatively related to the production of anti-spike antibodies after BNT-162b2 mRNA vaccination in an Italian study [ 41 ].…”

“…For example, the HLA-DRB1*15:01 allele, predicted to bind epitopes of MEAF and ZFHX2, was positively correlated with enhancement of both anti-spike B and T cell responses in Caucasian and Japanese BNT-162b2 mRNA vaccine recipients [ 39 , 41 , 42 ]. Conversely, the allele HLA-A*24:02, which possibly recognizes epitopes of CHL1, was negatively related to the production of anti-spike antibodies after BNT-162b2 mRNA vaccination in an Italian study [ 41 ]. However, it is unclear whether T-cell responses are equally impaired in carriers of this HLA allele.…”

“…The results of this computational analysis show that some epitopes of the protein product of the BNT-162b2 mRNA vaccine could be efficiently presented by nucleated cells and antigen-presenting cells (APCs) through preferential binding of some class I or class II HLA molecules. Importantly, research shows that HLA polymorphisms may also dictate the clinical course of COVID-19 or response to vaccines by influencing epitope presentation to protective T cells [39][40][41][42][43][44], as shown in Table 5. In addition to molecular homology and cross-reactivity, allelic variants of the HLA are of paramount importance in the development of autoimmunity.…”