HLA Variation and SARS-CoV-2 Specific Antibody Response

Abstract

Differences in SARS-CoV-2-specific immune responses have been observed between individuals following natural infection or vaccination. In addition to already known factors, such as age, sex, COVID-19 severity, comorbidity, vaccination status, hybrid immunity, and duration of infection, inter-individual variations in SARS-CoV-2 immune responses may, in part, be explained by structural differences brought about by genetic variation in the human leukocyte antigen (HLA) molecules responsible for the presentation of SARS-CoV-2 antigens to T effector cells. While dendritic cells present peptides with HLA class I molecules to CD8+ T cells to induce cytotoxic T lymphocyte responses (CTLs), they present peptides with HLA class II molecules to T follicular helper cells to induce B cell differentiation followed by memory B cell and plasma cell maturation. Plasma cells then produce SARS-CoV-2-specific antibodies. Here, we review published data linking HLA genetic variation or polymorphisms with differences in SARS-CoV-2-specific antibody responses. While there is evidence that heterogeneity in antibody response might be related to HLA variation, there are conflicting findings due in part to differences in study designs. We provide insight into why more research is needed in this area. Elucidating the genetic basis of variability in the SARS-CoV-2 immune response will help to optimize diagnostic tools and lead to the development of new vaccines and therapeutics against SARS-CoV-2 and other infectious diseases.

Keywords: COVID-19; HLA; MHC; SARS-CoV-2; antibody; genomics; immunoglobulin; polymorphism.

Figure 1

HLA variation determines SARS-CoV-2-specific antibody response. In this example, we present different scenarios suggesting differential SARS-CoV-2-specific antibody response impacted by variation in the HLA class II molecule. (A) MHC-II molecule binding to SARS-CoV-2 peptides induces efficient CD4+ T cell and antibody response leading to viral neutralization, ADCC, and the death of SARS-CoV-2 infected cells. (B) Polymorphic MHC-II molecule binding to viral peptide fails to stimulate CD4+ T cells and results in low antibody titer, lack of ADCC, and ADP. Abbreviations: Ab: antibody; ADCC: antibody-dependent cellular (NK cell) cytotoxicity; ADP: antibody-dependent phagocytosis; HLA: human leukocyte antigen; MØ: macrophage; MHC: major histocompatibility complex; nAbs: neutralizing antibodies; T_H0: CD4+ helper cells; T_H: T helper; T_FH: T follicular helper cells. Figure made using BioRender.

Figure 2

Heat-map showing the association between HLA variants and antibody responses or epitope binding affinity. Associations are depicted arbitrarily as high (scaled 1, yellow boxes), low (scaled 0.5, red boxes), or no association (scaled 0, dark-blue boxes). Gray boxes indicate undetermined values. References shown are for antibody response* or epitope binding affinity** studies.