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 carrier 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. 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. Among the isolated human monoclonal antibodies, two neutralizing antibodies, 4-C06 and 4-C09 were characterized. Though derived from distinct lineages, both antibodies utilized similar modes of recognition to target the fusion-peptide site of vulnerability, suggesting vaccine elicitation of fusion-peptide directed neutralizing antibodies is feasible. 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. 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 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 are exploring the use of alternative adjuvants including 3M-052, CpG and LNP in preclinical studies now. mRNA vaccines are also being tested for Env with transmembrane domain and mRNA vaccine for FP-lumazine synthase. On the other hand, FP-prime and SHIV infected monkeys developed broad and potent HIV-1 neutralizing activities. SHIV infection was able to boost pre-existing FP-directed neutralizing activities to high levels in 8 weeks. Further studies are planned to mimic the SHIV infection to potentiate such FP antibody lineages. 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. In addition, we have made novel bispecific antibodies that can be used for both HIV-1 prevention and treatment. 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 established a model system where human antibodies can be infused multiple times in non-human primates without the appearance of any anti-drug antibody (ADA) responses. This model is now been used to assess the efficacy of potent HIV-1 bNAbs in suppressing viral rebound in virally infected animals. 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.