An effective global HIV-1 vaccine is urgently needed. One of the fundamental challenges in HIV-1 vaccine development is the tremendous diversity of HIV-1 strains worldwide. This extreme genetic diversity makes it difficult to design an HIV-1 vaccine that can elicit broadly protective immunity. Vaccines that elicit diverse HIV-1-specific immune responses represent a potential strategy to overcome the challenge of HIV-1 sequence variation. The hypothesis underlying this strategy is that the greater and more diverse the immune responses, the greater the likelihood that there will be a match to the transmitting HIV-1 strain. Currently, we do not know the optimal design of a global HIV-1 vaccine to elicit diverse immune responses. The objective of this K23 Career Development Award is to define HIV-1 vaccine regimens that elicit the greatest diversity of immune responses following immunization. To accomplish this objective, we will use novel cutting-edge immunologic assays to measure how changes in antigen delivery and composition impact the breadth and depth of HIV-1-specific antibodies and T cell responses in humans.
Each aim of this K23 award focuses on a different potential vaccine strategy for increasing immune diversity, including a vaccine that combines viral vectors and proteins for HIV-1 antigen delivery (Aim 1), novel mosaic HIV-1 antigens bioinformatically engineered to optimize coverage of global HIV-1 sequences (Aim 2), and a new replicating viral vector for expressing HIV-1 antigens (Aim 3).
The Specific Aims are as follows:
Specific Aim 1 : To evaluate whether immunization with vectored HIV-1 Env antigens (ALVAC-HIV) plus Env protein (AIDSVAX B/E) elicits greater diversity of Env-specific antibodies than immunization with either vectored Env or Env protein alone in humans.
Specific Aim 2 : To assess if mosaic HIV-1 antigens (MVA-Mosaic) elicit greater diversity of Env-specific antibodies and Gag-specific CD8+ T cells than multi-clade HIV-1 antigens (MVA-Natural) in humans.
Specific Aim 3 : To evaluate the diversity of serum and mucosal Env-specific antibodies in humans vaccinated with an oral, replicating Ad26 vector expressing mosaic HIV-1 Env (rcAd26.Mos1ENV). The findings from this K23 award have the potential to greatly inform HIV-1 vaccine design. Through the above Specific Aims, we will identify which HIV-1 vaccines elicit the greatest diversity of HIV-1-specific immune responses, and will be able to craft novel HIV-1 vaccine regimens that include combinations of our most optimal candidates. In this way, we aim to advance the development of an effective global HIV-1 vaccine.
According to the World Health Organization, 6,300 people are newly infected with HIV every day, and more than 95 % of newly HIV-infected people live in low and middle income countries that have restricted access to antiviral medication. Therefore, an effective vaccine for HIV is urgently needed. Yet, the extreme genetic diversity of HIV poses a major challenge to HIV vaccine development. HIV vaccines that aim to elicit diverse HIV-specific immune responses represent one strategy to overcome this challenge. These novel vaccine strategies should be explored.
|Bricault, Christine A; Kovacs, James M; Badamchi-Zadeh, Alexander et al. (2018) Neutralizing Antibody Responses following Long-Term Vaccination with HIV-1 Env gp140 in Guinea Pigs. J Virol :|
|Baden, Lindsey R; Walsh, Stephen R; Seaman, Michael S et al. (2018) First-in-Human Randomized, Controlled Trial of Mosaic HIV-1 Immunogens Delivered via a Modified Vaccinia Ankara Vector. J Infect Dis 218:633-644|