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 therefore 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 2 are to define the optimal rAd vector combination in phase 1 studies and to advance this novel HIV-1 vaccine candidate into expanded international phase 2a studies in collaboration with the HIV Vaccine Trials Network (HVTN). The clinical studies in Project 2 will build on the preclinical studies in Project 1 and the manufacturing program in Project 3. In Project 2, we hypothesize that the heterologous rAd26 prime, rAd5HVR48 boost regimen will prove safe and highly immunogenic in humans in both the United States and sub-Saharan Africa. We further hypothesize that this HIV-1 vaccine candidate will not be suppressed by pre-existing antivector immunity and will be a promising candidate for further development into advanced phase clinical trials by the end of this project period. To explore these hypotheses, we propose the following three Specific Aims: 1. To perform a phase 1 study assessing the safety and immunogenicity of rAd26 and rAd5HVR48 HIV-1 vaccine regimens in the United States; 2. To perform a phase 1 study assessing the safety and immunogenicity of rAd26 and rAd5HVR48 HIV-1 vaccine regimens in South Africa;and 3. To perform an international phase 2a study evaluating expanded safety and immunogenicity of the heterologous rAd26 prime, rAd5HVR48 boost HIV-1 vaccine regimen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI078526-04
Application #
8320415
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$1,099,479
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Barouch, Dan H; Tomaka, Frank L; Wegmann, Frank et al. (2018) Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19). Lancet 392:232-243
Abbink, Peter; Kirilova, Marinela; Boyd, Michael et al. (2018) Rapid Cloning of Novel Rhesus Adenoviral Vaccine Vectors. J Virol 92:
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
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
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:
Stephenson, Kathryn E; D'Couto, Helen T; Barouch, Dan H (2016) New concepts in HIV-1 vaccine development. Curr Opin Immunol 41:39-46
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
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 90:4278-4288
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

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