Rational design of DNA vaccines for the induction of human papillomavirus type 16 E6- and E7-specific cytotoxic T-cell responses

Many DNA vaccine candidates have been developed for the treatment of human papillomavirus type 16 (HPV16)-induced malignancies. Most of these vaccines consist of a fusion of E7 with a "carrier-protein" that functions to increase the potency of the vaccine. The nature of these carrier-prote...

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Bibliographic Details
Published in:Human gene therapy Vol. 23; no. 12; p. 1301
Main Authors: Oosterhuis, Koen, Aleyd, Esil, Vrijland, Kim, Schumacher, Ton N, Haanen, John B
Format: Journal Article
Language:English
Published: United States 01.12.2012
Subjects:
Animals
CD4-Positive T-Lymphocytes - immunology
Cell Line
Drug Design
Endoplasmic Reticulum - metabolism
Female
Human papillomavirus 16 - immunology
Humans
Male
Mice
Mice, Inbred C57BL
Oncogene Proteins, Viral - genetics
Oncogene Proteins, Viral - immunology
Papillomavirus E7 Proteins - genetics
Papillomavirus E7 Proteins - immunology
Papillomavirus Infections - prevention & control
Papillomavirus Vaccines - genetics
Papillomavirus Vaccines - immunology
Recombinant Proteins - genetics
Recombinant Proteins - immunology
Repressor Proteins - genetics
Repressor Proteins - immunology
T-Lymphocytes, Cytotoxic - immunology
Uterine Cervical Neoplasms - prevention & control
Uterine Cervical Neoplasms - virology
Vaccines, DNA - genetics
Vaccines, DNA - immunology
ISSN:1557-7422, 1557-7422
Online Access:Get more information
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Summary:Many DNA vaccine candidates have been developed for the treatment of human papillomavirus type 16 (HPV16)-induced malignancies. Most of these vaccines consist of a fusion of E7 with a "carrier-protein" that functions to increase the potency of the vaccine. The nature of these carrier-proteins varies widely, and the mechanisms proposed to explain the enhanced immunogenicity of such fusions are often linked to the biological function of the carrier-protein. However, the potentiating effect of these carrier-proteins might also be explained by more general mechanisms, such as the provision of CD4+ T-cell help, increased antigen stability, or altered subcellular localization of the antigen. To assess whether these more generic mechanisms could suffice to generate highly immunogenic DNA vaccines, we evaluated a series of modular HPV16 E7 DNA vaccines in which the presence of CD4+ T-cell help, the presence of an endogenous carrier-protein, and the subcellular localization of the antigen could be systematically altered. Using this approach, we demonstrate that the addition of an element that provides CD4+ T-cell help, elements that enforce endoplasmic reticulum (ER) localization/retention are both necessary and sufficient to create markedly effective HPV16 E7-directed DNA vaccines. Importantly, the resulting design rules also apply to an HPV16 E6-directed DNA vaccine. The developed "HELP(ER)" HPV DNA vaccines encode only very limited additional sequences besides the antigen, thereby reducing the risk of antigenic competition and/or autoimmunity.
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ISSN:1557-7422
1557-7422
DOI:10.1089/hum.2012.101