ABSTRACT
Patients with haematological malignancies are prioritized for COVID-19 vaccine due to their high risk for SARS-CoV-2 infection related disease severity and mortality. Immune defects associated with malignancy and their treatment could influence vaccine driven immune response in these cancer patients. Thus, to understand T cell immunity, its long-term persistence, and correlation with antibody response, we evaluated the BNT162b2 SARS-CoV-2 mRNA vaccine-specific immune response in chronic lymphocytic leukaemia (CLL) and myeloid dysplastic syndrome (MDS) patients. Longitudinal analysis of CD8+ T cells using DNA-barcoded peptide-MHC multimers covering the full SARS-CoV-2 spike-protein showed vaccine-specific T cell activation and persistence of memory T cells up to 6 months post-vaccination. Surprisingly, a higher frequency of vaccine-induced antigen-specific CD8+ T cell was observed in the patient group compared to the healthy donor group. Furthermore, and importantly, immunization with the second booster dose significantly increased the frequency of antigen-specific CD8+ T cells as well as the total number of T cell specificities. Altogether, 23 immunogenic epitopes were identified and a strong immunodominance was observed for the two of the spike-specific T cell epitopes restricted to HLA-A24 (NYNYLYRLF) and HLA-A2 (YLQPRTFLL) with a prevalence of 100% and 80% respectively. In summary, we mapped the vaccine-induced antigen-specific CD8+ T cells and showed a booster-specific activation and enrichment of memory T cells that could be crucial for long-term disease protection for this patient group.
ABSTRACT
introduction. hla alleles play a fundamental role in the development of the immune response against viral infections. objective. Gather the information available on the association of different hla alleles with increased protection or susceptibility;furthermore, the impact on complications associated with sars-cov-2 infection. methodology. An information search was carried out in the Scopus, PubMed/Medline, lilacs and Academic Google databases that answered the research question: What is the association between hla and sars-cov-2 infection and the severity of the illness? Records of clinical trials from the databases of the who International Clinical Trials Platform were included. results. It was found that the hla-a* 25: 01, hla-b* 46: 01 and hla-c* 01: 02 alleles were associated with greater susceptibility to infection, while the hla-a* 02: 01 alleles, hla-a* 24: 02 and hla-b*27: 07 were associated with greater severity of the disease and the alleles hla-a* 02: 02, hla-b* 15: 03 and hla-c* 12: 03 as protective factor in covid-19. conclusions. The association between susceptibility, protection and severity with the different types of hla are mainly reported in silico analysis, and its precision is limited, requiring support based on in vitro and in vivo experimental studies and clinical trials in different populations. A greater focus is needed on the affinity of the various hla alleles by the sars-cov-2 proteome to elucidate the immunopathogenesis of the disease.
ABSTRACT
SARS-COV-2 (COVID-19) has resulted in over 4 million deaths worldwide. While vaccination has decreased mortality, there remains a need for curative therapies for active infections. Uncertainties regarding the duration of post-vaccination immunity and the rapidity of mutational evolution by this virus suggest that it is unwise to rely on preventative measures alone. Humoral and cellular immunity provide selective pressure for the emergence of variant strains which have eliminated target epitopes. Elimination of immunodominant epitopes provides the strongest advantage to newly emerging strains and, consequently, immunodominant epitopes would be expected to be preferentially eliminated compared to subdominant epitopes in emerging variants. Immunologic treatments for SARS-COV-2 need to be continuously reassessed as new sequence information becomes available. TVGN-489 is a clinical grade product consisting of highly enriched, highly potent CD8+ CTLs recognizing peptides derived from COVID-19 gene/ORF products in an HLA restricted manner. CTLs are generated from apheresis products from individuals who have recovered from COVID-19 infections. Lymphocytes are serially primed and selected using APCs from these donors pulsed with small numbers of peptides encoded by the COVID-19 genome predicted or demonstrated to bind to specific HLA class I alleles. The resulting products are typically >95% CD3+/CD8+, >60% positive by tetramer staining and demonstrate strong cytolytic activity with >60% lysis of peptide pulsed targets typically at an effector to target ratio of 3:1 (See Figure). Given the immunologic pressure to lose dominant target epitopes, we assessed whether the peptides derived from genomic sequences from early SARS-COV-2 strains (and successfully used to generate CTLs from donors infected with these early strains) were still present in the more recently evolved Delta variant. Seven peptides were used to generate CTL products restricted by HLA-A*02:01, the most common allele worldwide. These peptides are derived from the spike (S) and nucleocapsid (N) proteins as well as ORF3a and ORF1ab. The contributions of these peptides to the overall cytotoxicity and tetramer staining range from 2% to 18% without clear immunodominance by one of these peptides. Though identified in early viral strains, these sequences persist in 97.5%-100% of the more than 120 Delta variant sequences present in the NIH database. For HLA-A*01:01, eight peptides derived from the matrix (M) protein as well as ORF1ab and ORF3a were utilized to generate CTLs. Seven of the eight peptides showed binding similar to what was seen with the HLA-A*02:01 peptides (1% to 18%). However, in contrast to HLA-A*02:01, an immunodominant peptide (TTDPSFLGRY, ORF1ab 1637-1646) was noted which was responsible for over half of the observed tetramer binding. This region of ORF1ab was mutated in the Delta variant resulting in loss of this immunodominant epitope from nearly 93% of the Delta genomic sequences in the NIH database. The remaining subdominant peptides were all preserved in 100% of the sequences. Given the growing number of Delta cases, it will be essential to remove this peptide from the HLA-A*01:01 peptide pool used to stimulate SARS-COV-2-specific CD8+ CTLs to avoid encouraging the expansion of cells which would recognize early strains of the virus, but not Delta variants. The remaining CTLs, generated in the absence of TTDPSFLGRY, should be capable of eradicating Delta as well as the earlier prototypic strains of COVID-19. The loss of immunodominant epitopes is not surprising in a virus such as SARS-COV-2, with a high frequency of mutation. This provides an example of immunologic escape similar to what has been described for the Delta variant in the case of HLA-A24. These data are consistent with the hypothesis that immunodominant epitopes will be preferentially eliminated as the virus continues to evolve. They further illustrate the need to monitor viral sequences and to tune the production of CTLs in order to ensure that they can continue to recognize and e fectively treat newly emerging variants of COVID-19. [Formula presented] Disclosures: No relevant conflicts of interest to declare. OffLabel Disclosure: The drug is Cytotoxic T lymphocytes that are specific to COVID-19. Preclinical data.