To develop human CD4 and CD8 lymphocyte stimulating Herpes simplex viral lipopeptides as vaccine candidates

Summary

To join an experienced team of researchers in the Westmead Millennium Institute to study the human immunology of Herpes Simplex Virus (HSV) to facilitate vaccine development. Such a vaccine would have impact on the spread of both HSV and HIV.

Supervisor(s)

Professor Tony Cunningham, Dr Min Kim

Research Location

Westmead - Westmead Institute for Medical Research

Program Type

PHD

Synopsis

Herpes Simplex Viruses type 1 and 2 (HSV) can cause cold sores, genital herpes, keratitis/blindness, encephalitis and neonatal herpes. 70-80% of the Australian population is infected with HSV-1 and 12% with HSV-2. Once it infects the human body, it persists throughout life. HSV-2 infection increases the acquisition of HIV by 2-3 fold. Current vaccine candidates are inadequate and need boosted and immunogenicity through better knowledge of the initial immune response.

There is no effective HSV vaccine currently available, with the most efficacious vaccine candidates in clinical trials to date failing to induce protective CD8 T cell immunity and yet CD4 and CD8 T cells play a major role in controlling HSV infection in humans. Recently we defined an immunodominant CD8 T cell glycoprotein D peptide D from HSV-2 when combined with the TLR-2 agonist Pam2Cys (a lipopeptide). It was restricted to HLA A*02:01 and HLA B*44:02The 12AA peptide had been previously shown by us to also stimulate CD4 T cell interferon gamma responses. Furthermore, it synergistically enhanced the total T cell response. The CD8 T cell stimulation occurred through dendritic cell cross presentation. This Pam2Cys-gD 12 mer peptide with both CD4 and CD8 T cell stimulating activity thus provides a paradigm for a powerful immunogen for HLA-A2 people. For this to be a practical vaccine further such peptides able to stimulate CD4 and CD8 T cells from 95% of the population is required i.e. lipopeptides restricted by HLA A1, A3, A24, B7 in addition to this lipopeptide.

Research Plan:
1. Define HLA-A1/A3//A24 and B7 restricted 9-10 mer peptide epitopes contained within a (promiscuous) CD4 T cell epitope peptide by multiple predictive algorithms (already found)
2. Conjugate to the TLR2 agonist Pam2Cys and test for human CD4 and CD8 T cell responses in HSV immune subjects
3. Check that the efficacy is not lost when combined with other defined stimulatory lipopeptides
4. Examine uptake of fluorescein labeled lipopeptides in epithelial dendritic cells after topical and intradermal injection of human foreskin explants
5. Test in non-human primates

Additional Information

Our lab has been continuously funded by NHMRC for studies of the human immunology of HSV to facilitate vaccine development since 1985. Our studies determined the composition of the partly successful GSK Simplirix vaccine candidate which stimulates CD4 T lymphocytes and neutralizing antibody but not CD8 T lymphocytes. We will provide a stipend of 28,800 p.a. up to 3 years.

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Keywords

Herpes simplex virus. Human immunology, skin, Vaccines, CD8 T cells, toll like receptors

Opportunity ID

The opportunity ID for this research opportunity is: 1924

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