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Principal Investigator: Cheng Cheng
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
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 (Env) and fusion peptides (FP) displayed on nanoparticles as protein immunogens or mRNA vaccines. 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. Immunogens with different adjuvants and FP displayed on 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 soluble prefusion BG505 trimer (VRC4571) adjuvanted with alum has been finished. We have demonstrated that soluble 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. Among the isolated human monoclonal antibodies, two neutralizing antibodies were characterized to target the fusion-peptide site of vulnerability. A new effort was initiated to reduce the trimer base responses. In collaboration with VRC Structural Biology Section, we have introduced glycosylation sites at the trimer base to add glycans to cover the immune dominant surface. Such BG505 and ConC trimers with glycan covered base were tested in guinea pigs to show reduced autologous neutralizing activity due to neoepitopes introduced with the glycosylation sites. Using flexible linkers to link three trimers created a new category of trimers, but also generated high off-target responses and failed to improve serum neutralizing activities. Second generation designs using flexible, non-immunogenic sequences to block the access to the base were shown to be feasible and animal studies are on-going.
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. 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 HVTN303 to test these two regimens were started in 2022 and was terminated early due to reactogenicity caused by Adjuplex used as the adjuvants. We explored the use of alternative adjuvants including 3M-052, CpG and LNP in preclinical studies and 3M-052/Alum was chosen for a new clinical trial VRC020 based on the immunogenicity data in guinea pig and NHP. Another clinical trial VRC021 to test glycan base trimer as the boost trimer is also being planned. Furthermore, FP vaccine primed and then SHIV infected monkeys developed broad and potent HIV-1 neutralizing activities. Therefore, SHIV infection was able to boost pre-existing FP-directed neutralizing activities to high levels within 8 weeks (Cell, in press). Further studies to mimic the SHIV infection to potentiate such FP antibody lineages have been explored. Specifically, escalating dose of protein immunogens and mRNA vaccine to mimic SHIV replication improved immune response to FP or CD4 binding site in mice, guinea pigs and NHP. mRNA vaccines are being developed for Env with transmembrane domain and for FP-carrier protein fusion in collaboration with biotech companies.
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 and Fc transgenic mice models. 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. Four of the next generation trispecific antibodies selected based on neutralization breadth and potency have been studied in human FcRn and Fc transgenic mice and in NHP. The pharmacokinetic (PK) parameters will help in the selection of antibodies for further clinical development.
We are using an ex vivo assay to assess the selection for specific resistant in HIV-1 viruses derived from viremic HIV+ patients. This assay is a 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. The assay is also being used to screen multispecific antibodies for their potency to suppress viral outgrowth. 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.
Terms: <7S Gamma Globulin><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adjuvant><Affinity><Alum Adjuvant><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><Antigens><Assay><Autologous><Binding Sites><Bioassay><Biological Assay><Biotech><Biotechnology><Blood Serum><Carrier Proteins><Categories><Cavia><Cell Body><Cells><Chimera Protein><Chimeric Proteins><Clinical><Clinical Trials><Collaborations><Combining Site><Data><Development><Dose><Drug Kinetics><Early-Stage Clinical Trials><Envelope Protein><Evaluation><FcRn><FcRn neonatal transfer protein><Fusion Protein><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><Immune response><Immunes><Immunize><Immunoglobulin G><Immunological response><Infection><LAV-HTLV-III><Link><Lymphadenopathy-Associated Virus><Metabolic Glycosylation><Methods><Mice><Mice Mammals><Modern Man><Monkeys><Murine><Mus><Mutation><Outcome><PBMC><Pathway interactions><Patients><Peptide Vaccines><Peptide antibodies><Peptides><Peripheral Blood Mononuclear Cell><Pharmacokinetics><Phase 1 Clinical Trials><Phase I Clinical Trials><Polysaccharides><Population><Prevention><Preventive><Proteins><RNA vaccine><RNA-based vaccine><Reactive Site><Regimen><Research><Resistance><Route><SHIV><Serum><Site><Specificity><Structure><Surface><T-Cells><T-Lymphocyte><TM Domain><Testing><Therapeutic><Transgenic Mice><Transmembrane Domain><Transmembrane Region><Transport Protein Gene><Transport Proteins><Transporter Protein><Treatment Efficacy><Vaccination><Vaccines><Variant><Variation><Viral><Viral Diseases><Virus><Virus Diseases><Virus-HIV><Work><alum><aluminum sulfate><base><bases><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><clinical development><clinical predictors><design><designing><developmental><env Antigens><env Gene Products><env Polyproteins><env Protein><evaluate vaccines><flexibility><flexible><genome mutation><glycosylation><host response><humAbs><human immunodeficiency virus vaccine><human mAbs><human monoclonal antibodies><human monoclonals><immune system response><immunogen><immunogenicity><immunoresponse><improved><in vivo><intervention efficacy><mRNA vaccine><mRNA-based vaccine><manufacturability><model of animal><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 study><preclinical study><predictive tools><rational design><resistant><response><safety testing><simian HIV><simian human immunodeficiency virus><structural biology><therapeutic efficacy><therapy efficacy><thymus derived lymphocyte><vaccine candidate><vaccine evaluation><vaccine screening><vaccine strategy><vaccine testing><viral infection><viral resistance><virus infection><virus resistance><virus-induced disease>