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A Decaepitope Polypeptide Primes for Multiple CD8⁺ IFN- and Th Lymphocyte Responses: Evaluation of Multiepitope Polypeptides as a Mode for Vaccine Delivery¹

Jeff Alexander^2,*, Carla Oseroff^*, Carol Dahlberg^*, Mingsheng Qin^*, Glenn Ishioka^*, Melanie Beebe^*, John Fikes^*, Mark Newman^*, Robert W. Chesnut^*, Phillip A. Morton, Kam Fok, Ettore Appella and Alessandro Sette^*

^* Epimmune, San Diego, CA 92121; Pharmacia, St. Louis, MO 63198; and National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Proteins are generally regarded as ineffective immunogens for CTL responses. We synthesized a 100-mer decaepitope polypeptide and tested its capacity to induce multiple CD8⁺ IFN- and Th lymphocyte (HTL) responses in HLA transgenic mice. Following a single immunization in the absence of adjuvant, significant IFN- in vitro recall responses were detected for all epitopes included in the construct (six A2.1-, three A11-restricted CTL epitopes, and one universal HTL epitope). Immunization with truncated forms of the decaepitope polypeptide was used to demonstrate that optimal immunogenicity was associated with a size of at least 30–40 residues (3–4 epitopes). Solubility analyses of the truncated constructs were used to identify a correlation between immunogenicity for IFN- responses and the propensity of these constructs to form particulate aggregates. Although the decaepitope polypeptide and a pool of epitopes emulsified in IFA elicited similar levels of CD8⁺ responses using fresh splenocytes, we found that the decaepitope polypeptide more effectively primed for in vitro recall CD8⁺ T cell responses. Finally, immunogenicity comparisons were also made between the decaepitope polypeptide and a corresponding gene encoding the same polypeptide delivered by naked DNA immunization. Although naked DNA immunization induced somewhat greater direct ex vivo and in vitro recall responses 2 wk after a single immunization, only the polypeptide induced significant in vitro recall responses 6 wk following the priming immunization. These studies support further evaluation of multiepitope polypeptide vaccines for induction of CD8⁺ IFN- and HTL responses.

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