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

Abstract

The remarkable variability of response to vaccines against SARS‐CoV‐2 is apparent. The present study aims to estimate the extent to which the host genetic background contributes to this variability in terms of immune response and side effects following the administration of the BNT162b2 vaccine. We carried out a genome wide association study (GWAS) by genotyping 873 Italian healthcare workers who underwent anti‐SARS‐CoV‐2 vaccination with the BNT162b2 vaccine and for whom information about anti‐SARS‐CoV‐2 spike antibodies titers and vaccine side effects were available. The GWAS revealed a significant association between the HLA locus and the anti‐SARS‐CoV‐2 Spike antibodies level at 2 months following the first dose of vaccine (SNP: rs1737060; p = 9.80 × 10−11). In particular, we observed a positive association between the antibody levels and the presence of the HLA‐A*03:01 allele. The same allele was found associated with a 2–2.4‐fold increased risk of experiencing specific side effects such as fever, chills and myalgia and a 1.5–1.8‐fold increased risk of joint pain, nausea, fatigue, headache and asthenia, independently of age and sex. This study confirms that the heterogeneity in the immune response to the BNT162b2 vaccine and in its side effects are at least partially influenced by genetic variants. This information, integrated with individual biological and lifestyle‐related correlates, could be of use in the definition of algorithms aimed at the identification of subjects in which the administration of additional vaccine doses would be particularly beneficial to maintain immunity against the virus.

Strong humoral response after Covid‐19 vaccination correlates with the common HLA allele A*03:01 and protection from breakthrough infection

“…This allele is present in one out of 10 individuals according to the frequencies obtained from the IBMDR and its frequency doubled in our cohort of strong responders. Two independent studies, both conducted on healthcare workers vaccinated with an mRNA vaccine, 8,9 found a significant correlation between HLA*03:01 and humoral response, similarly to ours. Despite some differences in analytical methods, sample selection and timepoints, their results appear consistent and confirm our previous finding of a lower HLA-A*03:01 frequency among weak responders.…”

“…It is perhaps not by chance that the three studies showing significant impact of HLA-A*03:01 on vaccine humoral response so far have been conducted on healthcare workers coming from the same geographical region. 8,9,11 The divergent results obtained with the UK study 21 may be explained by the different study population compared with ours, having thus different expected HLA allele frequencies. In addition, the use of an adenoviral vector-based vaccine in the study by Mentzel and coll.…”

“…[3][4][5][6][7] Similarly, HLA polymorphism has been investigated and appeared to influence vaccine response in recent studies conducted mainly on healthcare workers. 8,9 Explanations of these findings are based on the distinct affinities between HLA alleles and the Spike-derived peptides, synthetized by the dendritic cells and other cells encoding the vaccine-delivered Spike protein. 10 Our group was the first to report an association between the HLA alleles A*03:01, A*33:03, B*58:01, the haplotype A*24:02 C*07:01 B*18:01 DRB1*11:04 and humoral response after BNT162b2 vaccine, supporting the hypothesis of an at least partially genetically-driven responsiveness.…”

Lack of association between HLA and asymptomatic SARS-CoV-2 infection

“…In the large sample study from the COVID-19 Host Genetics Initiative, only one human leukocyte antigen (HLA) class II allele, HLA-DRB1*04:01, has been found to confer a small decrease in the risk of critical COVID-19 (OR = 0.8) 2 . By contrast, we have documented a stronger association between HLA-A*03:01 and side effects following inoculation with the Pfizer-BioNTech COVID-19 mRNA vaccine 13 , which was subsequently replicated 14 .…”

“…13 INSERM UMR 1018, Paris, France. 14 INSERM Sponsor, Paris, France. 15 Centre d'Investigation Clinique, INSERM CIC 1403, Centre Hospitalo universitaire de Lille, Lille, France.…”