HIV/AIDS Vaccine and Antibody Development

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

During the past year, we have created and tested new vaccine candidates, including envelope proteins and fusion peptides displayed on carrier proteins. In addition, we have continued our work testing different methods and routes of administration as well as prime/boost combinations to further optimize HIV vaccine strategies. Proteins with different adjuvants and nanoparticles were also tested. Several candidate vaccines that elicited promising immunogenicity data in preliminary studies are being tested further. Human clinical trial VRC018 testing the safety and immunogenicity of BG505 trimer has been finished. We have demonstrated that BG505 trimer elicited strong anti-trimer base response. As the trimer base is not surface exposed on the native spike, these off-target responses do not result in high neutralizing activities. Although serum neutralizing titer was low, autologous BG505 virus neutralizing human monoclonal antibodies were isolated from PBMC post vaccination. A new effort was initiated to reduce the trimer base responses. In collaboration with Structural Biology Section, we have introduced glycosylation sites at the trimer base to add glycans to cover the immune dominant surface. Such BG505 trimers with glycan covered base were tested in guinea pigs to show reduced autologous neutralizing activity due to neoepitopes introduced with the glycosylation sites. Second generation designs are on-going. On the other hand, broadly HIV-1 neutralizing activity directed to fusion peptide (FP), which is an essential component of HIV fusion machinery, was elicited in multiple vaccine-test animal models including mouse, guinea pig and non-human primate. Based on these preclinical data, two immunogens (FP8 with the amino acid sequence of AVGIGAVF on a carrier protein rTTHc and clade C consensus trimer) were identified as vaccine candidates and manufactured at GMP grade. GMP lot of the adjuvant, Adjuplex, used in these studies was also made. Two clinical regimens, one with FP prime and the other with FP plus trimer cocktail prime were designed, and both regimens elicited FP directed neutralizing activities in more than 50% of immunized guinea pigs. The clinical trial VRC019 to test these two regimens will start in 2022. At the same time, we also demonstrated that variation of the FP length for priming to enhance HIV neutralizing activity. We are now planning to test these new priming regimens in NHP. For antibody development, we have applied targeted mutations to several broadly neutralizing anti-HIV-1 antibodies (bNAbs) that have been isolated from HIV+ donors. The mutations are designed to increase breadth, potency and half-life to improve potential efficacy for therapeutic application and to decrease immunogenicity to allow for more effective and longer lasting in vivo function. There are also structure-based mutations designed to improve affinity and neutralization potency. Additionally, mutations to improve biophysical properties and manufacturability have been designed with plans for further development and use in clinical trials. These bNAb variants have been assessed for both their neutralization potency and in vivo half life in human FcRn transgenic mice models. We are using an ex vivo assay to assess the selection for specific resistance mutations in HIV-1 viruses derived from viremic HIV+ patients. This assay may be an useful tool for predicting resistance to bNAbs in HIV+ patients and help in the selection of bNAbs that can be used to treat such patients. The results from these assays have been encouraging and predictive of clinical trial outcomes that use bNAbs to treat viremic HIV+ patients. In addition, we have been performing neutralization assays for these outgrowth viral sequences to understand resistance signatures for each bNAb. We are now adapting this assay to look at outgrowth viruses from ART suppressed HIV+ patients and assess the resistance signatures to different bNAbs in that population. That will help identify next generation bNAbs that can be used for treatment of such patients. In terms of in vivo studies, we have tested the ability of B cell depletion in rhesus macaques to limit induction of anti-drug antibodies (ADA) against bNAbs that develop after the animals are infused with bNAbs. The results from the first set of animal studies suggests that B cell depletion limits ADA responses and allows for multiple infusions with a bNAb. This has allowed us to compare in an ongoing larger animal study the anti-viral efficacy of bNAbs and multispecific bNAbs, which will guide selection of best bNAb candidates for further development. We are also working with collaborators to develop multispecific anti-HIV-1 antibodies that combine three or four different anti-HIV-1 specificities in one IgG-like molecule for both HIV-1 prevention and therapy, one of which has advanced to phase I clinical trials. The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. Elimination of latently infected cells could therefore reduce treatment duration and facilitate immune reconstitution. We have developed immunomodulatory proteins referred to as T cell engagers (TCEs) that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor. These TCEs could potentially help to eliminate latently infected cells and deplete the viral reservoir in HIV-1-infected individuals. In addition, we have started collaborative work to develop TCEs that activate T cells to lyse HIV-1 infected cells.