Mosaic HIV-1 Vaccines Expand the Breadth and Depth of Cellular Immune Responses in Rhesus Monkeys

The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development. Antigens derived from natural HIV-1 sequences have elicited only a limited breadth of cellular immune responses in nonhuman primate studies and clinical trials to date. Polyvalent 'mosaic' antigens, in contrast, are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity. Here we show that mosaic HIV-1 Gag, Pol and Env antigens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors markedly augmented both the breadth and depth without compromising the magnitude of antigen-specific T lymphocyte responses as compared with consensus or natural sequence HIV-1 antigens in rhesus monkeys. Polyvalent mosaic antigens therefore represent a promising strategy to expand cellular immunologic vaccine coverage for genetically diverse pathogens such as HIV-1.

[1]  Peter B Gilbert,et al.  Peptide selection for human immunodeficiency virus type 1 CTL-based vaccine evaluation. , 2006, Vaccine.

[2]  D. Montefiori,et al.  Evaluating Neutralizing Antibodies Against HIV, SIV, and SHIV in Luciferase Reporter Gene Assays , 2004, Current protocols in immunology.

[3]  David C Montefiori,et al.  Dynamic immune responses maintain cytotoxic T lymphocyte epitope mutations in transmitted simian immunodeficiency virus variants , 2005, Nature Immunology.

[4]  D. Montefiori,et al.  Immune Control of an SIV Challenge by a T Cell-Based Vaccine in Rhesus Monkeys , 2008, Nature.

[5]  J. Kublin,et al.  Safety and immunogenicity of a replication-incompetent adenovirus type 5 HIV-1 clade B gag/pol/nef vaccine in healthy adults. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  J. Safrit,et al.  Depletion of CD8+ Cells in Sooty Mangabey Monkeys Naturally Infected with Simian Immunodeficiency Virus Reveals Limited Role for Immune Control of Virus Replication in a Natural Host Species1 , 2007, The Journal of Immunology.

[7]  Alan S. Perelson,et al.  The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection , 2009, The Journal of experimental medicine.

[8]  James Theiler,et al.  Web-based design and evaluation of T-cell vaccine candidates , 2008, Bioinform..

[9]  K. Mansfield,et al.  Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity , 2006, Nature.

[10]  B. Korber,et al.  Expanded Breadth of the T-Cell Response to Mosaic Human Immunodeficiency Virus Type 1 Envelope DNA Vaccination , 2008, Journal of Virology.

[11]  K. Mansfield,et al.  Comparative Seroprevalence and Immunogenicity of Six Rare Serotype Recombinant Adenovirus Vaccine Vectors from Subgroups B and D , 2007, Journal of Virology.

[12]  Devan V Mehrotra,et al.  Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial , 2008, The Lancet.

[13]  Donald K Carter,et al.  HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case–cohort analysis , 2008, The Lancet.

[14]  B. Korber,et al.  A centralized gene-based HIV-1 vaccine elicits broad cross-clade cellular immune responses in rhesus monkeys , 2008, Proceedings of the National Academy of Sciences.

[15]  James Theiler,et al.  Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants , 2007, Nature Medicine.

[16]  D. Douek,et al.  Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts , 2009, Nature Medicine.

[17]  David Heckerman,et al.  CD8+ T-cell responses to different HIV proteins have discordant associations with viral load , 2007, Nature Medicine.

[18]  Norman L. Letvin,et al.  T-Cell Vaccine Strategies for Human Immunodeficiency Virus, the Virus with a Thousand Faces , 2009, Journal of Virology.

[19]  D. Barouch,et al.  Challenges in the development of an HIV-1 vaccine , 2008, Nature.

[20]  V. Carey,et al.  Mixed-Effects Models in S and S-Plus , 2001 .