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Principal Investigator: Cheng Cheng
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2022
Award: $2,325,099
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <7S Gamma Globulin><AIDS><AIDS Virus><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acquired Immunologic Deficiency Syndrome><Adjuvant><Affinity><Amino Acid Sequence><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><Antigens><Assay><Autologous><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bioassay><Biologic Assays><Biological Assay><Blood Serum><CD3><CD3 Antigens><CD3 Complex><CD3 molecule><Carrier Proteins><Cavia><Cell Body><Cells><Clinical><Clinical Trials><Collaborations><Consensus><Data><Development><Drugs><Early-Stage Clinical Trials><Envelope Protein><Evaluation><FcRn><FcRn neonatal transfer protein><GMP lots><Generations><Genetic Alteration><Genetic Change><Genetic defect><Glycans><Guinea Pigs><Guinea Pigs Mammals><HIV><HIV vaccine><HIV-1><HIV-1 vaccine><HIV-I><HIV/AIDS Vaccines><HIV1><HIV1 vaccine><Half-Life><Hu-mABs><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><IgG><Immune><Immunes><Immunize><Immunoglobulin G><Immunomodulation><Individual><Infection><Infusion><Infusion procedures><LAV-HTLV-III><Length><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><MHC Receptor><Macaca mulatta><Major Histocompatibility Complex Receptor><Medication><Metabolic Glycosylation><Methods><Mice><Mice Mammals><Modern Man><Murine><Mus><Mutation><OKT3 antigen><Outcome><PBMC><Pathway interactions><Patients><Peptides><Peripheral Blood Mononuclear Cell><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase 1 Clinical Trials><Phase I Clinical Trials><Polysaccharides><Population><Prevention therapy><Preventive><Primary Protein Structure><Proteins><Regimen><Research><Resistance><Rhesus Macaque><Rhesus Monkey><Route><Serum><Site><Specificity><Structure><Surface><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><T3 Antigens><T3 Complex><T3 molecule><Testing><Therapeutic><Time><Transgenic Mice><Transport Protein Gene><Transport Proteins><Transporter Protein><Treatment Efficacy><Treatment Period><Vaccination><Variant><Variation><Viral><Viral Diseases><Viral reservoir><Virus><Virus Diseases><Virus reservoir><Virus-HIV><Work><anti-retroviral therapy><anti-retroviral treatment><anti-viral efficacy><antiretroviral therapy><antiretroviral treatment><antiviral efficacy><base><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><clinical predictors><design><designing><developmental><drug/agent><env Antigens><env Gene Products><env Polyproteins><env Protein><evaluate vaccines><genome mutation><glycosylation><good manufacturing practice lot><humAbs><human immunodeficiency virus vaccine><human mAbs><human monoclonal antibodies><human monoclonals><immune modulation><immune reconstitution><immune regulation><immunogen><immunogenicity><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><improved><in vivo><intervention efficacy><manufacturability><model of animal><model organism><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neonatal Fc receptor><neutralizing antibody><new vaccines><next generation><next generation vaccines><non-human primate><nonhuman primate><novel><novel vaccines><pathway><phase I protocol><pre-clinical><preclinical><predictive tools><protein sequence><rational design><resistance mutation><resistant><resistant mutation><response><safety testing><structural biology><therapeutic efficacy><therapy efficacy><thymus derived lymphocyte><treatment days><treatment duration><vaccine antibodies><vaccine candidate><vaccine evaluation><vaccine induced antibodies><vaccine screening><vaccine strategy><vaccine testing><vaccine-induced antibodies><viral infection><viral resistance><virus infection><virus resistance><virus-induced disease>