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Published on: March 25, 2014
A decaepitope polypeptide primes for multiple CD8+ IFN-gamma and Th lymphocyte responses: evaluation of multiepitope
Jeff Alexander1, Carla Oseroff, Carol Dahlberg
1Epimmune, San Diego, CA 92121, USA. jalexander@epimmune.com
Insights
Multiepitope polypeptide vaccines effectively induce CD8(+) T cell and T helper lymphocyte responses. These vaccines show promise for future vaccine development, outperforming naked DNA immunization in sustained immune memory.
Area of Science:
- Immunology
- Vaccinology
- Molecular Biology
Background:
- Proteins are typically poor immunogens for CD8(+) cytotoxic T lymphocyte (CTL) responses.
- Developing effective vaccines against T cell epitopes remains a challenge.
Purpose of the Study:
- To evaluate a 100-mer decaepitope polypeptide's ability to induce CD8(+) interferon-gamma (IFN-γ) and T helper lymphocyte (HTL) responses.
- To determine the optimal size and aggregation properties for polypeptide immunogenicity.
- To compare the immunogenicity of the polypeptide vaccine with traditional methods like adjuvant emulsification and naked DNA immunization.
Main Methods:
- Synthesis of a 100-mer decaepitope polypeptide containing multiple CTL and HTL epitopes.
- Immunization of HLA transgenic mice with the polypeptide, truncated forms, and controls (adjuvant, naked DNA).
- Assessment of in vitro recall responses (IFN-γ production) and ex vivo responses.
- Solubility analysis to correlate aggregate formation with immunogenicity.
Main Results:
- A single immunization with the decaepitope polypeptide induced significant IFN-γ recall responses for all included epitopes.
- Optimal immunogenicity for IFN-γ responses was observed for polypeptides of 30-40 residues (3-4 epitopes).
- Polypeptide immunogenicity correlated with its propensity to form particulate aggregates.
- The decaepitope polypeptide demonstrated superior priming for long-term in vitro recall CD8(+) T cell responses compared to naked DNA immunization.
Conclusions:
- Multiepitope polypeptide vaccines are effective inducers of CD8(+) IFN-γ and HTL responses.
- Polypeptide size and aggregation are critical factors for immunogenicity.
- Polypeptide vaccines offer a promising alternative to naked DNA immunization for generating robust and sustained T cell immunity.
Abstract:
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-gamma and Th lymphocyte (HTL) responses in HLA transgenic mice. Following a single immunization in the absence of adjuvant, significant IFN-gamma 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-gamma 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-gamma and HTL responses.
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