Current HIV-1 vaccine candidates based on recombinant adenovirus serotype 5 (rAd5) vectors are promising but may prove limited by the high prevalence of pre-existing anti-Ad5 immunity in the developing world. To overcome this problem, we have constructed a series of novel serotype and novel chimeric rAd vectors that effectively circumvent anti-Ad5 immunity. We have also demonstrated that heterologous rAd prime-boost regimens utilizing two serologically distinct rAd vectors elicit remarkably potent immune responses, particularly regimens involving rAd26 priming and rAd5 or rAd5HVR48 boosting. In addition, we have generated rAd Vectors expressing optimal C clade, M consensus, and M mosaic HIV-1 antigens designed to minimize genetic distance and to optimize T cell epitope coverage among global HIV-1 sequences. We propose to develop a practical, two-injection, heterologous rAd26 prime, rAd5HVR48 boost regimen expressing antigens optimized for global coverage as a novel candidate HIV-1 vaccine. The goals of Project 1 are to select the optimal antigens for our multivalent HIV-1 vaccine candidate and to evaluate the immunogenicity and protective efficacy of the rAd26 prime, rAd5HVR48 boost regimen in rhesus monkeys to support the clinical program in Project 2 and the manufacturing program in Project 3. In Project 1, we hypothesize that M consensus or M mosaic HIV-1 antigens will prove superior to naturally occurring C clade and VRC multiclade antigens for immunologic coverage of diverse global virus sequences. We further hypothesize that the optimal vaccine regimen expressing SIV antigens will afford significant protection against both homologous and heterologous SIV challenges in rhesus monkeys. To explore these hypotheses, we propose the following four Specific Aims: 1. To compare the magnitude and breadth of immune responses elicited by optimal C clade, M consensus, M mosaic, and VRC multiclade antigens in rhesus monkeys; 2. To determine the protective efficacy of the optimal vaccine regimen expressing various sets of SIV antigens against homologous SIV challenges in rhesus monkeys with anti-Ad5 immunity; 3. To evaluate the protective efficacy of the optimal vaccine regimen against heterologous SIV challenges in rhesus monkeys with anti-Ad5 immunity;and 4. To assess the mucosal immunogenicity and protective efficacy of the optimal vaccine regimen against multiple, low-dose, mucosal SIV challenges in rhesus monkeys with anti-Ad5 immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI078526-05
Application #
8379262
Study Section
Special Emphasis Panel (ZAI1-CCH-A)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$588,107
Indirect Cost
$946,603
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Penaloza MacMaster, Pablo; Shields, Jennifer L; Alayo, Quazim A et al. (2017) Development of novel replication-defective lymphocytic choriomeningitis virus vectors expressing SIV antigens. Vaccine 35:1-9
Ackerman, Margaret E; Barouch, Dan H; Alter, Galit (2017) Systems serology for evaluation of HIV vaccine trials. Immunol Rev 275:262-270
Provine, Nicholas M; Badamchi-Zadeh, Alexander; Bricault, Christine A et al. (2016) Transient CD4+ T Cell Depletion Results in Delayed Development of Functional Vaccine-Elicited Antibody Responses. J Virol 90:4278-88
Stephenson, Kathryn E; Neubauer, George H; Bricault, Christine A et al. (2016) Antibody Responses After Analytic Treatment Interruption in Human Immunodeficiency Virus-1-Infected Individuals on Early Initiated Antiretroviral Therapy. Open Forum Infect Dis 3:ofw100
Handley, Scott A; Desai, Chandni; Zhao, Guoyan et al. (2016) SIV Infection-Mediated Changes in Gastrointestinal Bacterial Microbiome and Virome Are Associated with Immunodeficiency and Prevented by Vaccination. Cell Host Microbe 19:323-35
Larocca, Rafael A; Provine, Nicholas M; Aid, Malika et al. (2016) Adenovirus serotype 5 vaccine vectors trigger IL-27-dependent inhibitory CD4+T cell responses that impair CD8+T cell function. Sci Immunol 1:
Provine, Nicholas M; Larocca, Rafael A; Aid, Malika et al. (2016) Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells. J Immunol 197:1809-22
Tartaglia, Lawrence J; Chang, Hui-Wen; Lee, Benjamin C et al. (2016) Production of Mucosally Transmissible SHIV Challenge Stocks from HIV-1 Circulating Recombinant Form 01_AE env Sequences. PLoS Pathog 12:e1005431
Barouch, Dan H; Ghneim, Khader; Bosche, William J et al. (2016) Rapid Inflammasome Activation following Mucosal SIV Infection of Rhesus Monkeys. Cell 165:656-67
Gandhi, Rajesh T; Kwon, Douglas S; Macklin, Eric A et al. (2016) Immunization of HIV-1-Infected Persons With Autologous Dendritic Cells Transfected With mRNA Encoding HIV-1 Gag and Nef: Results of a Randomized, Placebo-Controlled Clinical Trial. J Acquir Immune Defic Syndr 71:246-53

Showing the most recent 10 out of 87 publications