Development of an effective vaccine against HIV-1 has been an elusive goal for the past three decades. As a result it has been a major challenge to stem the tide of the epidemic caused by this virus globally. The results of the RV44 efficacy trial in Thailand have spurred a new level of excitement for the development of HIV vaccine and strongly support the development of vaccination approaches that enhance the titer and functional quality of anti-HIV Env antibody that may significantly enhance protection against HIV. The overall goal of this program is to develop novel vaccination approaches that not only enhance the magnitude but also enhance the functional quality of anti-HIV cellular and humoral immunity. Specifically, we propose to combine two new vaccination approaches developed recently at Emory University that showed great promise in rhesus macaques. The first approach uses CD40L, a co-stimulatory molecule for dendritic cells (DC) and B cells, expressed on the surface of HIV VLPs as a genetic adjuvant for enhancing the magnitude and functional quality of HIV-specific cellular and humoral immunity leading to enhanced protection from acquisition of SIV infection. The second approach uses a new MVA that lacks 4 immune modulatory genes (MVAA4) as a vaccine vector that showed a significant increase in the magnitude of HIV-specific cellular and humoral immunity in rhesus macaques. In this program, we hope to combine these two new complementary approaches to develop a novel vaccination strategy against HIV. This program will be a collaborative effort between scientists at the Emory University (Drs. Amara, Mulligan, Derdeyn, and Velu), NIH (Dr. Moss), International AIDS Vaccine Initiative (lAVI; Dr. Dean), Walter Reed Army Institute of Research (WRAIR; Dr. Michael), Louisiana State University (LSU; Dr. Kozlowski) and CDC (Dr. Garber). This Program has 3 projects and two cores. The proposed program builds upon the enormous experience with our DNA and MVA vaccines in the preclinical and clinical settings and strong preliminary data with the new vaccines in the preclinical model. Successful completion of the program will result in the clinical development of two new vaccine products and a novel HIV vaccine.
WHO estimates that there are currently about 33 million humans living with HIV/AIDS and there is a great need to develop a safe and effective HIV vaccine that prevents infection. The main goal of this program is to develop novel vaccine strategy that prevents infection from a heterologous mucosal HIV infection and to test this vaccine in humans. This program will ultimately lead to the development of a HIV vaccine. Project 1: Manufacture and Regulatory Cd40l Adjuvanted Clade C DNA and MVA HIV Vaccines Project Leader: Mark Mulligan DESCRIPTION: The concepts to be tested are the ability of CD40L (a co-stimulatory molecule for dendritic cells (DC) and B cells) to serve as an adjuvant for protective immune responses and a modified MVA with deletion of four immunomodulatory genes (MVAA4) for boosting the protective immune responses primed by the CD40Ladjuvanted DNA vaccine. CD40L will be expressed in cis by CD40L sequences added to the DNA vaccine. A central hypothesis is that CD40L improves protection by enhancing the functional quality of HIV Env specific antibody responses. The primary goals of this Project are to 1) produce the CD40L-adjuvanted DNA vaccine and conduct a phase I trial to test the safety and immunogenicity of this DNA combined with MVA boost, and 2) to develop and characterize the MVAA4 HIV vaccine for use in preclinical macaque studies (see project 2) and future human studies. This project has the following specific aims: 1. Construction of Clade C MVAA4 HIV vaccine: The VLP-expressing MVAA4 immunogen to match vaccine inserts in our clade C DNA vaccine will be constructed under GLP conditions and characterized for growth, expression and stability. 2. cGMP Manufacturing of CD40L-adjuvanted clade C.DNA HIV Vaccine (pGA1/IN3-CD40L). The aim is to produce sufficient quantities of finished vaccine in a timely manner, in order to supply high quality research materials for GLP pre-clinical safety, immunogenicity and human clinical trials. 3. Regulatory support. The regulatory support will be provided by IAVI. The aim is to establish good communication and coordination of IAVI, IAVI regulatory subcontractors, HVTN and NIAID Regulatory affairs branch. 4. Phase I clinical trial. The aim is to conduct a phase I human trial using pGA1/IN3-CD40L prime and clade C MVA/HIV boost. This trial will be conducted by the HVTN and Dr. Mark Mulligan will serve as the protocol chair. 5. Ancillary assays for Phase I trial. The aim is to measure immune responses in vaccinated humans. RELEVANCE: The acquired immunodeficiency syndrome (AIDS) caused by HIV-1 is the leading cause of death in Africa and the fourth leading cause of death worldwide. This IPCAVD is developing HIV/AIDS vaccines that use DNA for priming and MVA for boosting (DNA/MVA vaccine) as well as a simpler an ultimately easier to deploy form of these vaccines that use MVA for both priming and boosting (MVA/MVA vaccine).
|Mylvaganam, Geetha H; Rios, Daniel; Abdelaal, Hadia M et al. (2017) Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection. Proc Natl Acad Sci U S A 114:1976-1981|
|Kelley, C F; Kraft, C S; de Man, T Jb et al. (2017) The rectal mucosa and condomless receptive anal intercourse in HIV-negative MSM: implications for HIV transmission and prevention. Mucosal Immunol 10:996-1007|
|Kannanganat, Sunil; Wyatt, Linda S; Gangadhara, Sailaja et al. (2016) High Doses of GM-CSF Inhibit Antibody Responses in Rectal Secretions and Diminish Modified Vaccinia Ankara/Simian Immunodeficiency Virus Vaccine Protection in TRIM5?-Restrictive Macaques. J Immunol 197:3586-3596|
|Velu, Vijayakumar; Mylvaganam, Geetha Hanna; Gangadhara, Sailaja et al. (2016) Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells. J Immunol 197:1832-42|
|Cartwright, Emily K; Spicer, Lori; Smith, S Abigail et al. (2016) CD8(+) Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy. Immunity 45:656-668|