SARS CTL vaccine candidates; HLA supertype‐, genome‐wide scanning and biochemical validation

Abstract

An effective Severe Acute Respiratory Syndrome (SARS) vaccine is likely to include components that can induce specific cytotoxic T-lymphocyte (CTL) responses. The specificities of such responses are governed by human leukocyte antigen (HLA)-restricted presentation of SARS-derived peptide epitopes. Exact knowledge of how the immune system handles protein antigens would allow for the identification of such linear sequences directly from genomic/proteomic sequence information (Lauemoller et al., Rev Immunogenet 2001: 2: 477-91). The latter was recently established when a causative coronavirus (SARS-CoV) was isolated and full-length sequenced (Marra et al., Science 2003: 300: 1399-404). Here, we have combined advanced bioinformatics and high-throughput immunology to perform an HLA supertype-, genome-wide scan for SARS-specific CTL epitopes. The scan includes all nine human HLA supertypes in total covering >99% of all individuals of all major human populations (Sette & Sidney, Immunogenetics 1999: 50: 201-12). For each HLA supertype, we have selected the 15 top candidates for test in biochemical binding assays. At this time (approximately 6 months after the genome was established), we have tested the majority of the HLA supertypes and identified almost 100 potential vaccine candidates. These should be further validated in SARS survivors and used for vaccine formulation. We suggest that immunobioinformatics may become a fast and valuable tool in rational vaccine design.

A combination of epitope prediction and molecular docking allows for good identification of MHC class I restricted T-cell epitopes

“…In contrast to S no experimental data are available for N protein 9-mer epitopes. Among 23 peptides identified as T-cell epitope from M protein, only peptide m88 was determined experimentally as nonepitope (Sylvester-Hvid et al, 2004), which is consistent with the predictive result of our approach (Table 5), similar to p144 in HIV-1 p24 protein, which is predicted as epitope by 11 epitope prediction methods, but is a non-epitope when analysed experimentally (Table 1). No Unknown a 1: ANNPRED; 2: COMPRED; 3: BIMAS; 4: CTLPRED; 5: MHCPRED; 6: NETMHC; 7: PREDEP; 8: PROPRED-I; 9: RANKPED; 10: SMM; 11: SVMHC; 12: SYFPEITHI.…”

Obstacles and advances in SARS vaccine development

“…Much of the focus has centered towards the humoral response and neutralizing epitopes, but cell-mediated immunity may also be important. CTL epitopes within SARS-CoV that may be presented by 99% of the human leukocyte antigen supertypes were identified by advanced bioinformatics [69]. Further characterization of these epitopes, including their recognition by convalescent serum, should advance the understanding of important immunological features in the control of SARS-CoV.…”

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)

“…Although the receptor-binding region of SARS-CoV is the most important target for neutralizing antibodies, the S2 ''region'' (Leu 803 to Ala 828), conserved across 45 viral isolates and containing a neutralizing antigenic determinant, was able to elicit neutralizing antibodies that protected some but not all small laboratory mammals against infection with SARS-CoV pseudovirus . Over 100 potential cytotoxic T-lymphocyte (CTL) vaccine candidates that cover >99% of all individuals of all major human populations were identified within 6 months of the publication of the virus sequence (Sylvester-Hvid et al, 2004).…”