Preplanned Studies: SARS-CoV-2 Omicron Variant is Expected to Retain Most of the Spike Protein Specific Dominant T-Cell Epitopes Presented by COVID-19 Vaccines — Worldwide, 2021

The World Health Organization (WHO) categorized the new B.1.1.529 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant (Omicron) as a variant of concern (VOC) on November 26, 2021. Since then, this newly emerged variant has placed the world on high alert. Compared to other VOCs, Omicron has an unusual constellation of mutations. It contains over 50 mutations in various locations of its genome. In the spike protein gene, Omicron has over 30 mutations, doubling the number associated with the Delta variant. In the receptor binding domain (RBD) alone, Omicron has over 10 mutations while Delta only has 2. Many of these mutations have been shown to enhance the interaction between the viral spike and the cellular receptor angiotensin-converting enzyme 2 (ACE2). Based on this observation, it is predicted that the Omicron variant could be highly contagious.

In general, a vaccine provides two arms of immune protection. On one hand, the vaccine results in the production of neutralizing antibodies (NAbs) by B cells. These NAbs bind to the spike protein of the virus and inhibit its ability to infect the host cells. For previously immunized people, the memory humoral immune response is the first line of defense against Omicron infection. Unfortunately, Omicron variant carries many mutations on the spike protein that neutralizing antibodies recognize, reducing vaccinated individuals’ immunity to this variant. The human body’s second line of defense is heavily reliant on the human leukocyte antigen (HLA)-restricted T-cell response mechanism, in which viral epitopes are presented by dendritic cells to CD8+ T lymphocytes through interactions with HLA class I alleles and CD4+ T lymphocytes through HLA class II alleles. Viral epitope presentation by HLA class I leads to clonal expansion of HLA-restricted CD8+ cytotoxic T lymphocytes (CTLs), which are primed to perform antiviral defense during acute infection. Subsequently, reinfection of the virus is controlled by memory CTLs. The recognition of viral epitope-HLA class II complexes by CD4+ T cell enhances cell-mediated immune response by inducing cytokines and facilitates antibody production by activating B cells. The urgent question right now is how many of the memory CTLs and T helper (Th) epitopes remain in the heavily mutated Omicron variant.

T-cell epitopes were predicted in this paper using IEDB recommended 2020.09 and SYFPEITHI for major histocompatibility complex Class I (MHC Class I), and IEDB recommended 2.22 and Propred for MHC Class II, before real-world data were available to answer this question.

Wuhan-Hu-1 (NCBI Reference Sequence: YP_009724390.1) was obtained from the GenBank database of the National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov/). EPI ISL:EPI_ISL_6640916 sequence (Omicron) was obtained from the GISAID database (https://www.gisaid.org/).

IEDB recommended 2020.09 (NetMHCpan 4.1EL) (http://tools.immuneepitope.org/mhci/, National Institute of Allergy and Infectious Diseases, USA) and SYFPEITHI (http://www.syfpeithi.de/, BMI Biomedical Informatics, Heidelberg, Germany) were used to predict HLA-A*02:01, HLA-A*11:01 restricted epitopes. NetMHCpan4.1 based on artificial neural network (ANN) applied binding affinity (BA) and mass spectrometry (MS) eluted ligands (EL) data as a model to analyze the affinity between target peptides and their ligands (MHC). This algorithm not only integrates affinity data and mass spectrometry eluted ligand data, but also covers information in the process of antigen processing and presentation (1–2). The smaller the value, the higher the prediction score of the corresponding random natural peptide. SYFPEITHI is based on the motif matrix algorithm (3), according to the natural ligands, T-cell epitopes, or the frequency of amino acids in the binding peptides to predict the target peptides. The anchors and their auxiliary anchors that appear frequently get higher scores in the prediction results. The higher the score, the greater the possibility that the peptide will become an antigenic peptide.

IEDB recommended 2.22 (http://tools.immuneepitope.org/mhcii/, National Institute of Allergy and Infectious Diseases, USA) and Propred (http://www.imtech.res.in/raghava/propred/, Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India) were used to predict HLA-DRB1*01:01 and HLA-DRB1*15:01 restricted epitopes. IEDB recommended 2.22 apply Consensus combined with Combinatorial library (4), SMM-align (5), NN-align (6) to analyze the target peptides and combine their predicted values to obtain more accurate results. Propred based on an algorithm called quantitative affinity matrix (QAM) predicted the score of the sequence by comparing the degree of match between the target sequence and the binding pocket of HLA (7).

In this study, we analyzed 4 representative HLA alleles (including HLA-A*02:01, HLA-A*11:01, HLA-DRB1*01:01, and HLA-DRB*15:01) restricted peptides among which HLA-A*02:01 and HLA-DRB1*01:01 represented the dominant HLA alleles in the world population, HLA-A*11:01 and HLA-DRB*15:01 represent the dominant HLA alleles in the Chinese population (8-9). Various bio-information software was used to predict the HLA restricted CTL or Th epitopes, and the top ten dominant epitopes were finally screened. The comparison between Wuhan-Hu-1 and Omicron was performed.

There were 17 dominant HLA-A*02:01 restricted CTL epitopes (ranking in the top 10) derived from spike (S) protein of Wuhan-Hu-1, among which 2 epitopes mutated in Omicron variant (Table 1). These mutations in Omicron variant exhibited minor decline in epitope rank and may slightly impair corresponding CTL response in viral clearance. However, 15 dominant HLA-DRB1*01:01 restricted Th epitopes in S protein of Wuhan-Hu-1 (ranking in the top ten) remain consistent in Omicron (Table 1). These results indicate that dominant protective CTL and Th epitopes derived from original Wuhan-Hu-1 strain or vaccines constructed based on Wuhan-Hu-1 still provided good T cell protection for convalescents or vaccinated individuals, although limited mutations were found within dominant CTL epitopes in a large proportion of the world’s population.

There were 12 dominant HLA-A*11:01-restricted CTL epitopes (ranking in the top 10) in the S protein of Wuhan-Hu-1, of which 3 epitopes mutated in Omicron variant (Table 2). Similarly, three of the top-ten dominant HLA-DRB1*15:01 restricted Th epitopes of Wuhan-Hu-1 strain S protein mutated in Omicron variant (Table 2). The mutations in the CTL epitopes may lead to a decrease in CTL against Omicron variant, while the mutated Th epitopes, may alter its capacity to promote T cell mediated immune response via cytokines and antibody generation via B cell activation, thus may have some impact on protective effect of vaccine against Omicron variant.