Modified Vaccinia Virus Ankara Can Induce Optimal CD8⁺T Cell Responses to Directly Primed Antigens Depending on Vaccine Design

Abstract

Recombinant vaccines based on vaccinia virus and particularly attenuated strains such as MVA are in human clinical trials, but due to the complexity of these large vectors much remains to be understood about the design parameters that alter their immunogenicity. Previous work had found that MVA vectors should be designed to express stable protein in order to induce robust immunity by CD8+ (cytotoxic) T cells. Here, we found that the primacy of stable antigen is not generalizable to all designs of MVA and may depend where a foreign antigen is inserted into the MVA genome. This unexpected finding suggests that there is an interaction between genome location and the best form of antigen for optimal T cell priming in MVA and thus possibly other vaccine vectors. It also highlights that our understanding of antigen presentation by even the best studied of vaccine vectors remains incomplete.

A protective bivalent vaccine against Rift Valley fever and bluetongue

“…Although comparative (side by side) experiments might be needed, it is reasonable to speculate that the different source of MVA vector and/or the different locus/ promoter used in this work could explain the improved immunogenicity against the encoded RVFV glycoprotein antigens. In this sense, it has been described that genome location and TK function can contribute to the relative immunogenicity of antigens when expressed from rMVA 45 . In addition, in previous rMVA-GnGc vaccine construct 10 , the heterologous gene was cloned under the control of the vaccinia 7.5 k early/late promoter, while in the MVA-GnGc-NS1 describe here the RVFV glycoproteins genes were placed under the control of an optimized strong early/ late promoter 46,47 .…”

Efficient Induction of Cytotoxic T Cells by Viral Vector Vaccination Requires STING-Dependent DC Functions

“…which most likely differ for each ligand. As recently shown ( 64 ), there may be variations between vaccinia virus vaccine delivery platforms such as replication-competent vs. -deficient viruses, different insertion loci for target gene expression or the presence/absence of viral thymidine kinase by which immunodominance can be shaped to a certain degree, but it will not be reversed even in the absence of the immunodominant B8 epitope ( 49 ). In contrast to the systemic i.p.…”

Surprisingly Effective Priming of CD8+T Cells by Heat-Inactivated Vaccinia Virus Virions

“…We started this investigation by following up a previous study that found that VACV virion proteins were overrepresented among immunogenic antigens in mice immunized with infected cells. These experiments used recombinant vaccines based on VACV strain WR, but wild-type virus was not tested and infected cells were injected by the intraperitoneal route ( 22 , 24 ). In our first experiment, MHC-mismatched cells were infected with VACV WR for a total of 6 h, inactivated by heating to 60°C for an hour (here referred to as heat inactivated [HI]), and then used to immunize groups of mice by intradermal injection ( 25 ).…”

“…In our first experiment, MHC-mismatched cells were infected with VACV WR for a total of 6 h, inactivated by heating to 60°C for an hour (here referred to as heat inactivated [HI]), and then used to immunize groups of mice by intradermal injection ( 25 ). This published treatment eliminates infectivity and de novo viral gene expression and presentation in vivo , as shown by the complete loss of responses to VACV-encoded minimal epitope constructs that require direct presentation to prime CD8 + T cells ( 22 , 24 ). The CD8 + T cell response to a well-characterized panel of major VACV epitopes was then measured at the peak of the acute response by ex vivo stimulation of splenocytes with synthetic peptides and intracellular staining for gamma interferon (IFN-γ) ( 19 , 26 – 28 ).…”