McElrath Vaccine Discovery Consortium

OVERVIEW:

Innate immunity is the body’s first line of defense against pathogens and involves relatively non-specific antibody and T-cell responses. Innate immunity can be elicited through the use of adjuvants, which are formulations that can enhance and direct a vaccine’s immune response. Although widely used, most adjuvants have been discovered empirically.

The McElrath-led VDC is taking a comprehensive approach to understanding how innate immunity can enhance vaccine-induced immunity. The researchers have developed a systematic in vitro and in vivo approach to unraveling the precise molecular pathways of innate immunity that adjuvants and vectors stimulate. Coordinated studies assess the consequence of these activities on the quality and long-term persistence of the HIV-specific adaptive immune response. These findings will rationally guide improved formulations of adjuvants with candidate HIV immunogens.  We have identified two priming regimens, HIV protein with poly I:C and recombinant Listeria/HIV, that induce strong multifunctional T-cell and antibody responses.  We are conducting extensive preclinical testing of these vaccine candidates, and if deemed safe, our current plans are to advance these vaccines into phase I clinical trials. 

RESEARCH OBJECTIVES:

1. Construct or procure a diverse array of adjuvants and vectors, and combine with HIV antigens and genes for evaluation in partnerships with industry, biotech and academia.

2. Standardize and implement an in vitro platform using human peripheral blood mononuclear cells (PBMC) to screen and fully evaluate the innate immune responses induced by vectors and adjuvants alone and in combination; then assess the impact of these innate responses on the phenotype, function and magnitude of HIV-specific T cell responses induced.

3. Elucidate how adjuvants/innate responses shape the quality and persistence of memory T-cells in vivo.

4. Assess innate and adaptive T-cell immune responses upon vaccination of rhesus macaques with SIV immunogens.  

5. Evaluate innate immune responses that drive improved antigen-specific T-cell responses in human trials.

PROGRESS:

For objective 1: The McElrath VDC now has access to all Toll-like receptor (TLR) agonists for in vitro and in vivo preclinical testing alone or in combinations as adjuvants for enhancing antibody and T-cell responses.  A variety of recombinant vectors have been procured, including adenovirus serotype 5, Modified Vaccinia Ankara, Listeria monocytogenes, Newcastle disease virus, and yellow fever virus. Each produced vector expresses HIV-1, SIV, or LCMV genes.

For objective 2: The researchers have identified combinations of TLR agonists that result in quantitative/qualitative differences in activated DCs and responding T cells. Poly I:C appears to be one of the strongest adjuvants in activating dendritic cells and priming T cells.

For objective 3: For protein vaccines, generation of CD4+ T-cell responses alone following primary immunization may not be sufficient to enhance CD8+ T-cell responses after an Ad5 SIV Gag boost. A novel vaccine using PLGA nanoparticles encapsulating TLR4 ligand (monophosphoryl lipid A; MPL) and TLR7 ligand R837 has been successfully designed, characterized, and tested as adjuvants for co-delivery with various recombinant protein-encapsulated PLGA nanoparticles, and has been shown to synergistically enhance the magnitude and quality of antibody responses. For vectors, various approaches were used to improve the quality of the Ad5-induced CD8+ T-cell memory, and co-administration of rapamycin appears to be beneficial for the differentiation and immune function of these memory T cells.

For objective 4: The protein/adjuvant experiment has 54 animals immunized with SIV Gag that is formulated with either TLR3, TLR4, TLR7/8, and TLR9 ligand alone, or in various combinations, followed by an Ad5-Gag boost.  Measurements of innate immune activation, Gag-specific T-cell and antibody responses are mostly complete.  Alterations of gene expression in lymph nodes and PBMCs are being analyzed. The analysis of the SIV challenge phase is in progress. The Listeria prime/boost immunogenicity experiment is also in progress.

For objective 5: Based on the preclinical immunogenicity data, the VDC researchers are moving towards clinical trials to test the concept of priming with HIV Gag and Env protein and Poly I:C adjuvant and boosting with a viral vector. Meanwhile, the researchers are continuing the innate immune analysis of vaccines that are being tested in HVTN trials, including DNA/MVA and DNA/Ad5 vaccines.