T‐Cell epitope discovery for variola and vaccinia viruses

Abstract

Variola major, the causative agent of smallpox, afflicted mankind throughout history until the worldwide World Health Organisation WHO vaccination campaign successfully eradicated the disease. Unfortunately, recent concerns about bioterrorism have renewed scientific interest in this virus. One essential component of our biodefense and preparedness efforts is an understanding of poxvirus immunity. To this end a number of laboratories have sought to discover T- and B-Cell epitopes from select agents such as variola virus. This review focuses on the efforts to identify CD8(+) T-Cell epitopes from poxviruses as a means to develop new vaccines and therapeutics. A wide variety of techniques have been employed by several research groups to provide complementary information regarding cellular immune responses to poxviruses. In the last several years well over 100 T-Cell epitopes have been identified and the work rapidly continues. The information gleaned from these studies will not only give us a greater understanding of immunity to variola virus and other viruses, but also provide a foundation for next generation vaccines and additional tools with which to study host-pathogen interactions.

Memory CD8+ T Cell Responses Expand When Antigen Presentation Overcomes T Cell Self-Regulation

“…One explanation is based on the genomic size of the vaccinia virus. Compared with Flu-ME, which produces 10 proteins, and Ad-CS, which produces 1, VV-SYV is large with ϳ200 different protein products and a corresponding abundance of CD8 ϩ epitopes (44,45). Robust presentation of the SYVPSAEQI epitope after VV-SYV priming takes place alongside similarly strong presentation of many other epitopes.…”

Long-Term Immunity against Actual Poxviral HLA Ligands as Identified by Differential Stable Isotope Labeling

“…One peptide, A48R 187-195 , had been described by Johnson et al (31), and 6 ligands matched known CTL epitopes (references see Table VI). Nine proteins from which HLA ligands were derived are among the 29 previously described immunogenic early proteins (10), and 4 proteins, B19R, E5R, G5.5R, and B15R, were newly identified in this study to contain relevant human CTL epitopes (Table VI). The proteins bearing HLA ligands functionally belong to two groups: proteins with immunomodulatory or host range and virulence function (B8R, B15R, B19R, C7L, and F12L (51,56,57)), and proteins functionally connected to DNA replication or transcription (E5R, A48R, G5.5R, A23R, D12L, and J6R (51)).…”

“…Therefore, modified vaccinia virus Ankara (MVA), an attenuated replication-deficient strain of VACV, is currently being tested as a safer third-generation vaccine (5,(7)(8)(9). A more detailed understanding of the CTL response to MVA allows both the development of epitope-based vaccines promising a safe, stable, and handy alternative to traditional vaccination strategies, as well as the monitoring of clinical trials by following MVA-specific T cell responses (10,11). Furthermore, MVA has been successfully introduced as a highly immunogenic recombinant viral vector vaccine for immunotherapy of infectious diseases and cancer (12), which requires the assessment of T cell epitope-specific responses elicited against vector and recombinant Ags.…”

“…Despite the increasing number of epitopes published, there is an ongoing need for further investigation. First, although thousands of peptides have been screened, covering ϳ35% of the large viral DNA genome that encodes more than 200 nonoverlapping open reading frames (ORF), the published determinants represent only a fraction of the total antiviral CTL response (10). Second, only a small number of the identified epitopes have been validated to date (10).…”

“…First, although thousands of peptides have been screened, covering ϳ35% of the large viral DNA genome that encodes more than 200 nonoverlapping open reading frames (ORF), the published determinants represent only a fraction of the total antiviral CTL response (10). Second, only a small number of the identified epitopes have been validated to date (10). Third, our recent work challenges the indirect strategy to identify epitopes, which is based on the monitoring of T cell responses alone: upon a first vaccination with MVA, T cells were primed against viral peptides that were not necessarily presented by infected cells, but cross-presented by noninfected cells (28).…”