After the failure of the Merck STEP trial that appears to have enhanced the rate of infection in vaccinees, the need for new vectors for HIV vaccine development has become urgent. We believe a solution might be found in the live-attenuated yellow fever vaccine. This vaccine has proven to be one of the most successful and safe vaccines ever created. It has been used in more than 400 million people worldwide. Moreover several aspects of the biology of the yellow fever vaccine 17D (YF-17D) make it an outstanding candidate vector for delivering HIV genes. Recent attempts to elucidate the mechanism of action of the YF-17D vaccine have found that immunization induces a vast network of antiviral genes involved in virus innate sensing and polyfunctional immune responses. Neutralizing antibodies develop rapidly and can be detected as early as one week after inoculation. YF-17D vaccination also elicits robust CD8+ T cell responses that peak at around day 15 after immunization, when roughly 10% of all circulating CD8+ T cells exhibit an activated phenotype. Studies of virus-specific CD4+ T cells have shown that this vaccine induces a mixed T helper 1 (THI) and TH2 profile that persists for at least one year after immunization. Additionally, YF-17D triggers several innate immune pathways, which are likely to contribute to its well-documented immunogenicity and YF-17D replication activates several dendritic cell subsets via Toll-like receptors (TLRs). Taken together, these data demonstrate that the yellow fever vaccine YF-17D induces broad and robust adaptive immune responses, including the generation of effector CD8+ T cells and mixed TH1/TH2 CD4+ T cell responses. Thus, given all of the outstanding qualities of YF-17D listed above, we now hypothesize that recombinant yellow fever can be an efficacious priming agent in a vaccine regimen designed to control replication of the AIDS virus. We plan to test the efficacy of a recombinant yellow fever prime/boost regimen in a monkey model of AIDS. We will improve yellow fever vaccine vector and insert stability. Finally, we will synthesize rYF-17D constructs encoding multiple SIVmac239 inserts for a prime/boost and SIVmac251 and SIVsmE660 repeated low dose challenge study.

Public Health Relevance

We will be determining whether the yellow fever vaccine virus can serve as a vector for HIV vaccine development. Should the results of our experiments be successful, recombinant yellow fever vaccine virus could be part of an eventual HIV vaccine regimen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI094420-02
Application #
8497611
Study Section
Special Emphasis Panel (ZAI1-JBS-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$247,562
Indirect Cost
$6,757
Name
University of Miami School of Medicine
Department
Type
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Magnani, Diogo M; Rogers, Thomas F; Maness, Nicholas J et al. (2018) Fetal demise and failed antibody therapy during Zika virus infection of pregnant macaques. Nat Commun 9:1624
Shin, Young C; Bischof, Georg F; Lauer, William A et al. (2018) A recombinant herpesviral vector containing a near-full-length SIVmac239 genome produces SIV particles and elicits immune responses to all nine SIV gene products. PLoS Pathog 14:e1007143
Magnani, Diogo M; Ricciardi, Michael J; Bailey, Varian K et al. (2017) Dengue Virus Evades AAV-Mediated Neutralizing Antibody Prophylaxis in Rhesus Monkeys. Mol Ther 25:2323-2331
Magnani, Diogo M; Rogers, Thomas F; Beutler, Nathan et al. (2017) Neutralizing human monoclonal antibodies prevent Zika virus infection in macaques. Sci Transl Med 9:
Rainho, Jennifer N; Martins, Mauricio A; Cunyat, Francesc et al. (2015) Nef Is Dispensable for Resistance of Simian Immunodeficiency Virus-Infected Macrophages to CD8+ T Cell Killing. J Virol 89:10625-36
de Santana, Marlon G Veloso; Neves, PatrĂ­cia C C; dos Santos, Juliana Ribeiro et al. (2014) Improved genetic stability of recombinant yellow fever 17D virus expressing a lentiviral Gag gene fragment. Virology 452-453:202-11
Neves, Patricia C C; Santos, Juliana R; Tubarao, Luciana N et al. (2013) Early IFN-gamma production after YF 17D vaccine virus immunization in mice and its association with adaptive immune responses. PLoS One 8:e81953