Abstract
The threat posed by severe congenital abnormalities related to Zika virus (ZKV) infection during pregnancy has turned development of a ZKV vaccine into an emergency. Recent work suggests that the cytotoxic T lymphocyte (CTL) response to infection is an important defense mechanism in response to ZKV. Here, we develop the rationale and strategy for a new approach to developing cytotoxic T lymphocyte (CTL) vaccines for ZKV flavivirus infection. The proposed approach is based on recent studies using a protein structure computer model for HIV epitope selection designed to select epitopes for CTL attack optimized for viruses that exhibit antigenic drift. Because naturally processed and presented human ZKV T cell epitopes have not yet been described, we identified predicted class I peptide sequences on ZKV matching previously identified DNV (Dengue) class I epitopes and by using a Major Histocompatibility Complex (MHC) binding prediction tool. A subset of those met the criteria for optimal CD8+ attack based on physical chemistry parameters determined by analysis of the ZKV protein structure encoded in open source Protein Data File (PDB) format files. We also identified candidate ZKV epitopes predicted to bind promiscuously to multiple HLA class II molecules that could provide help to the CTL responses. This work suggests that a CTL vaccine for ZKV may be possible even if ZKV exhibits significant antigenic drift. We have previously described a microsphere-based CTL vaccine platform capable of eliciting an immune response for class I epitopes in mice and are currently working toward in vivo testing of class I and class II epitope delivery directed against ZKV epitopes using the same microsphere-based vaccine.
Highlights
As of Fall 2016, the Zika Virus (ZKV) pandemic continues its northward spread in the Americas
Zika virus (ZKV) is a small enveloped plus strand RNA virus belonging to the genus Flavivirus, which includes many human pathogenic viruses, such as Dengue virus (DNV), yellow fever virus (YFV), West Nile Virus (WNV), and hepatitis C virus (HCV)
The T cell epitope-based vaccine approach may target the immune response only to desirable and relevant epitopes, instead of the whole protein. Relevant epitopes include those that come from conserved viral protein regions, and/or where mutations could lead to reduced viral fitness, and those that bind to multiple Major Histocompatibility Complex (MHC) variant molecules— potentially recognized by the majority of the target population—while avoiding regions that are poorly immunogenic, variable and subject to antigenic drift, or that could cause a harmful response [40]
Summary
As of Fall 2016, the Zika Virus (ZKV) pandemic continues its northward spread in the Americas. The CDC estimates at least 4,100 cases in the United States and up to 29,000 cases in Puerto Rico Those cases in Puerto Rico include 672 pregnant women [1]. Using a data-driven global stochastic epidemic model to project past and future spread of the ZKV in the Americas, it has been estimated that the large population centers of Florida, New York, and New Jersey will be seeing significant numbers of imported cases (acquired by travel) of ZKV infection [2] by the end of Fall 2016. In South America, the new case rate of ZKV infection is tapering off, researchers in Brazil warn that official statistics may significantly underestimate the size of the ZKV epidemic based on improved serological tools that have become recently available. We will highlight details of the vaccines currently under consideration for Phase I and Phase II clinical trials, develop the argument that vaccines that evoke antibody responses need careful scrutiny, outline the rationale why our group is focusing on developing a “pure” CTL vaccine, and enumerate many of the challenges that will need to be overcome to develop an effective ZKV CTL vaccine
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