Two nonhuman primate efficacy studies have convincingly demonstrated that CMV/SIV vectors can: 1) reinfect CMV+ rhesus macaques (RM), 2) during re-infection, elicit potent and persistent SIV-specific CD4+ and CD8+ T cell responses with a strong """"""""effector memory"""""""" (T{EM}) bias, and 3) completely protect ~50% of vaccinated RM from progressive SIV infection after limiting dose rectal challenge with the highly pathogenic SIVmac239 virus. The protection manifested in these RM is distinct from previous vaccines in its abruptness and extent, with protected RM exhibiting a viral burst in plasma of varying size upon initial infection, followed by immediate control to undetectable levels. Protection correlates with the extent of total SIV-specific CD8+ T cells generated during the vaccine phase, and is stable in the vast majority of protected RM for >12 months. These data indicate a novel pattern of protection consistent with very early control, likely taking place at the site of viral entry and/or early sites of viral replication and amplification, and involving tissue-resident CD8+ T{EM}- Thus, CMV vectors and the """"""""T{EM}"""""""" vaccine concept offer a powerful new approach to HIV/AIDS vaccine development, and have the potential to be developed into a safe and effective HIV/AIDS vaccine. In this Program, we seek to: 1) increase the potency of CMV/SIV vectors so as to achieve rates of protection closer to 100% of vaccines, 2) reduce the pathogenic and shedding potential of CMV vectors, while retaining immunogenicity, so as to achieve an effective vaccine that is safe enough for use in a general human population, and 3) determine immunologic correlates or protection to guide further development of the T{EM}"""""""" vaccine concept. The program is composed of 3 projects, and 5 cores. Projects 1 and 2 will use novel strategies to develop replication-deficient and tropism-modified CMV vectors that will retain immunogenicity, but have reduced shedding and capacity to mediate disease. Project 3 seeks to enhance CMV/SIV vector immunogenicity with both combinatorial vaccine approaches and CMV vector modification, and will determine immunologic correlates ofthe novel """"""""all or none"""""""" protection associated with these vectors. These projects will be assisted by Core A (Administration), Core B (Nonhuman Primate), Core C (Pathogenesis Models), Core D (Virology and Immunology Monitoring), and Core E (Genomics).

Public Health Relevance

Worldwide, ~2.5 million new HIV infections occurred in 2007 (with prevalence rates in some areas of southern Africa exceeding 15%), and it is generally agreed that an effective prophylactic vaccine is the only practical means by which the HIV/AIDS epidemic can be controlled. We have demonstrated that cytomegalovirus (CMV) vectors can harness tissue resident effector memory T cells to combat the AIDS virus very early in infection, and can protect rhesus monkeys from progressive infection after mucosal challenge. The work proposed in this application will enhance the safety of CMV vectors, optimize their efficacy, and provide crucial information for the further clinical development of this novel vaccine approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI094417-04
Application #
8681307
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Pensiero, Michael N
Project Start
2011-07-15
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Portland
State
OR
Country
United States
Zip Code
97239
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McMichael, Andrew J; Picker, Louis J (2018) Corrigendum to 'Unusual antigen presentation offers new insight into HIV vaccine design' [Curr Opin Immunol 46 (2017) 75-81]. Curr Opin Immunol 53:217
Wu, Helen L; Wiseman, Roger W; Hughes, Colette M et al. (2018) The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques. J Immunol 200:49-60
Walters, Lucy C; Harlos, Karl; Brackenridge, Simon et al. (2018) Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. Nat Commun 9:3137
Früh, Klaus; Picker, Louis (2017) CD8+ T cell programming by cytomegalovirus vectors: applications in prophylactic and therapeutic vaccination. Curr Opin Immunol 47:52-56
McMichael, Andrew J; Picker, Louis J (2017) Unusual antigen presentation offers new insight into HIV vaccine design. Curr Opin Immunol 46:75-81
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Hansen, Scott G; Sacha, Jonah B; Hughes, Colette M et al. (2013) Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science 340:1237874
Hansen, Scott G; Piatak Jr, Michael; Ventura, Abigail B et al. (2013) Immune clearance of highly pathogenic SIV infection. Nature 502:100-4
Masopust, David; Picker, Louis J (2012) Hidden memories: frontline memory T cells and early pathogen interception. J Immunol 188:5811-7

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