Targeting antigen to MHC Class I and Class II antigen presentation pathways for malaria DNA vaccines

Dobaño, Carlota, Rogers, William O., Gowda, Kalpana, and Doolan, Denise L. (2007) Targeting antigen to MHC Class I and Class II antigen presentation pathways for malaria DNA vaccines. Immunology Letters, 111 (2). pp. 92-102.

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An effective malaria vaccine which protects against all stages of Plasmodium infection may need to elicit robust CD8⁺ and CD4⁺ T cell and antibody responses. To achieve this, we have investigated strategies designed to improve the immunogenicity of DNA vaccines encoding the Plasmodium yoelii pre-erythrocytic stage antigens PyCSP and PyHEP17, by targeting the encoded proteins to the MHC Classes I and II processing and presentation pathways. For enhancement of CD8⁺ T cell responses, we targeted the antigens for degradation by the ubiquitin (Ub)/proteosome pathway following the N-terminal rule. We constructed plasmids containing PyCSP or PyHEP17 genes fused to the Ub gene: plasmids where the N-terminal antigen residues were mutated from the stabilizing amino acid methionine to destabilizing arginine, plasmids where the C-terminal residues of Ub were mutated from glycine to alanine, and plasmids in which the potential hydrophobic leader sequences of the antigens were deleted. For enhancement of CD4⁺ T cell and antibody responses, we targeted the antigens for degradation by the endosomal/lysosomal pathway by linking the antigen to the lysosome-associated membrane protein (LAMP). We found that immunization with DNA vaccine encoding PyHEP17 fused to Ub and bearing arginine induced higher IFN-γ, cytotoxic and proliferative T cell responses than unmodified vaccines. However, no effect was seen for PyCSP using the same targeting strategies. Regarding Class II antigen targeting, fusion to LAMP did not enhance antibody responses to either PyHEP17 or PyCSP, and resulted in a marginal increase in lymphoproliferative CD4⁺ T cell responses. Our data highlight the antigen dependence of immune enhancement strategies that target antigen to the MHC Class I and II pathways for vaccine development.

Item ID: 42744
Item Type: Article (Research - C1)
ISSN: 1879-0542
Keywords: Plasmodium yoelii; malaria; DNA vaccines; PyHEP17; PyCSP; ubiquitin; LAMP; MHC; antigen targeting; antibody responses; T cell responses
Funders: United States Army Medical Research and Materiel Command (USAMRMC), Naval Medical Research Centre (NMRC)
Projects and Grants: USAMRMC 62787A.870.F. A0080
Date Deposited: 22 Mar 2016 05:47
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110799 Immunology not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100%
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