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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-03-0926.
Submitted March 27, 2002
Accepted June 21, 2002
Pre-clinical Development of an Adjuvant-Free Peptide Vaccine with Activity Against CMV pp65 in HLA Transgenic Mice
Corinna La Rosa, Zhongde Wang, John Brewer, Simon F Lacey, Maria C Villacres, Rahul Sharan, Radhika Krishnan, Matthew Crooks, Susan Markel, Rebecca Maas, and Don J Diamond*
Laboratory of Vaccine Research, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
* Corresponding author; email: ddiamond{at}coh.org.
Epitope vaccines have shown promise for inducing cellular immune responses in animal models of infectious disease. In cases where cellular immunity was augmented, peptide vaccines composed of covalently linked minimal cytotoxic T lymphocyte (CTL) and T-help (TH) epitopes generally showed the most efficacy. To address a clinical vaccine strategy for CMV in the context of HCT, we made the observation that linking the synthetically-derived PADRE or one of several tetanus TH epitopes to the immuno-dominant HLA A*0201-restricted CTL epitope from CMV-pp65 to create a fusion peptide, caused robust cytotoxic cellular immune responses in HLA A*0201/Kb transgenic mice. Significantly, the fusion peptides are immunogenic when administered in saline solution by either subcutaneous or intranasal routes. CpG-containing single-stranded DNA (ss-ODN) added to the fusion peptides dramatically upregulated immune recognition by either route. Notably, target cells which either expressed full length pp65 protein from vaccinia viruses or were sensitized with the CTL epitope encoded in the vaccine were recognized by splenic effectors from immunized animals. Visualization of murine peptide-specific CTL by flow cytometry was accomplished using an HLA A*0201 tetramer complexed with the pp65495-503 CTL epitope. TH-CTL epitope fusion peptides in combination with CpG ss-ODN represents a new strategy for parenteral or mucosal delivery of vaccines in a safe and effective manner that has applicability for control or prophylaxis of infectious disease, especially in situations such as vaccination of donors or recipients of HCT, where highly inflammatory adjuvants are not desired.
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