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. 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 (FP on a carrier protein and clade C consensus trimer) were identified as vaccine candidates for prime/boost regimens and GMP manufacture is in progress. GMP manufacture of the adjuvant, Adjuplex, used in these studies is also on-going. We have identified two clinical regimens, one with FP prime and the other with FP plus trimer cocktail prime, and both regimens elicited FP directed neutralizing activities in more than 50% of immunized guinea pigs. The clinical trial VRC019 to test these vaccines will start in Mar 2022. Studies to understand the development of broadly neutralizing antibodies using human immunoglobulin knock-in mice are also ongoing. These studies are testing novel immunogens designed to generate neutralizing antibodies to HIV-1 vulnerable sites: the CD4 binding site, V2 apex and membrane-proximal external region (MPER). We have demonstrated that VRC designed vaccine regimen induced maturation of VRC01-class precursors to HIV-1 neutralizing antibodies with >50% breadth on a large virus panel. 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 have developed a novel 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. In addition, 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 preliminary results suggests that B cell depletion limits ADA responses and allows for multiple infusions with a bNAb. This will allow assessment of in vivo anti-viral efficacy of bNAbs, combinations 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 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. In another collaborative effort, we are developing improved N6-like antibodies for use in HIV-1 therapy. 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.