Dr. Guido Ferrari and Dr. Wilton Williams awarded UM1 grant - Center for Innovative HIV/AIDS Vaccine and Cure Research
Congratulations to Dr. Guido Ferrari, Professor in Surgery, and Dr. Wilton Williams, Associate Professor in Surgery, for receiving NIH funding for their Co-PI grant, “Center for Innovative HIV/AIDS Vaccine and Cure Research (CIAVCR)”. The UM1 award will build upon the development of the team’s vaccine strategy to induce protective immune responses in non-human primate (NHP) models by exploring innovative messenger ribonucleic acid (mRNA) constructs for immunogen delivery that can elicit both protective and therapeutic B and T cell responses.
The program has two main research foci. The first, led by Drs. Wilton Williams and Barton Haynes (Professor of Medicine and Immunology) focuses on vaccine-induced neutralizing antibody protection from HIV-1 infection. The second research focus, led by Drs. Guido Ferrari and Michael Betts (Professor of Microbiology at the University of Pennsylvania), centers on therapeutic vaccine regimen in association with immune modulators for eradication of latent reservoir.
This UM1 presents an exciting opportunity to advance research towards protective and therapeutic vaccine strategies for HIV, which have remained elusive, to leverage the latter to eradicate HIV infection. Building upon recent advances in HIV immunology and vaccine clinical research, the team hypothesizes that a vaccine strategy capable of inducing both polyfunctional neutralizing antibodies (NAbs) and CD8 T cell responses would be the optimal regimen to both prevent and cure HIV-1. The in vivo mechanistic studies will reveal the extent to which NAb and CD8 T cell responses contribute to prevention and eradication of HIV-1 infection. The program will build upon an existing vaccine strategy that can induce protective NAb responses in NHPs by exploring innovative mRNA constructs for immunogen delivery that can elicit both NAb and CD8 T cell responses.
The vaccine regimen will ultimately represent a novel approach for prevention as well as treatment of HIV-1 infection. For treatment, the teams will evaluate the ability of this vaccine regimen to act in concert with the latest generation of latency reversing agents (LRA) that has been recently described as potent and successful in the NHP model in addition to novel anti-HLA-E/ VL9-peptide complex mAbs that can enhance the cytotoxic activity of CD8 T and Natural Killer cells, as well as antibody dependent cellular cytotoxicity (ADCC) mediated by the NK cells.
The team is comprised of dedicated investigators with broad expertise from multiple institutions: Duke University, University of Pennsylvania, University of North Carolina at Chapel Hill, Los Alamos National Laboratory, Harvard University, Oxford University and BIOQUAL Inc.
CIAVCR Announcement - PPT
CIAVCR Specific Aims - PDF
Focus 1 (VACCINES): Overview of research approach. Studies in Aims 1 and 2 were designed to define the best immunization strategy for protection from autologous challenge (SHIV CH505.s2). Aim 1 will test HIV-1 CH505TF SOSIP trimer protein adjuvanted with 3M052 TLR7/8 agonist. Aim 2 will test mRNA-LNP bearing ferritin NPs expressing multiple copies of HIV-1 CH505TF SOSIP trimers as well as mRNA-LNPs bearing SIV Gag. Env viral evolution data from Aims 1 and 2 will also be used to generate boosting Env (CH505 Env variant) for a prime-boost immunization strategy to demonstrate the capacity of vaccine-induced protective B cell responses to develop breadth given the appropriate immunization strategy. Thus, Aim 3 will test our prime-boost immunization strategy to elicit protective B cell responses with breadth against escape variants of the initial TF Env as well as a T cell vaccine capable of eliciting CD8 T cell responses. Both B and T cell vaccines will use the mRNA-LNP delivery platform. We will study RMs for our NHP model.
Focus 2 (CURE): Overview of Research Approach. Studies in focus 2 were designed to test immunization strategies that generate protective immune responses in NHPs (Focus 1) for their ability to reduce the size or eliminate HIV-1 reservoirs. We will study rhesus macaques (RMs) for our NHP model. Aim 1 will test active and passive immunization strategies for depleting viral reservoirs. Active immunization strategy is our established protective vaccine that was also tested in Focus 1-Aim 1. For passive immunization, we will test purified IgG isolated from vaccinated RMs that were protected from SHIV CH505.s2 challenge in Focus 1-Aims 1 and 2 in combination with a candidate protective mAb (DH1028)—an autologous NAb targeting Env CD4-binding site that was previously isolated from a CH505TF SOSIP trimer immunized RM, who was protected from SHIV CH505.s2 challenge (see preliminary data). As a control, additional RMs will receive IgG from SHIV-negative RM in combination with Influenza-specific CH65. In addition to HIV-1 vaccines, we will test the impact of novel therapies that may augment protective vaccine-induced responses in clearing HIV-1 reservoirs. Aim 2 will test the capacity of novel anti-HLA-E/VL9 peptide mAbs to augment vaccine-induced protective B and T cell responses by blocking the inhibitory signal of NK and CD8 T cells, thus enabling them to effectively kill their target cells. Using this approach, we will demonstrate the power of combined B, T and NK cell immunity in eliminating HIV-1 reservoirs. In both aims, LRAs will be used to activate viral reservoirs, thus allowing us to evaluate the effectiveness of our vaccine-induced immune responses or therapies in reducing the size or eliminating HIV-1 reservoirs.
