Conjugate nanoparticle platform development for HIV-1 envelope immunogens

HIV-1 包膜免疫原的共轭纳米颗粒平台开发

• 批准号: 10369067
• 负责人: KEVIN O SAUNDERS
• 金额: $ 471.96万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-17 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369067
• 关键词: 2019-nCoV; Affinity; Amino Acids; Animal Model; Antibodies; Antibody Affinity; Antigens; Avidity; B-Cell Antigen Receptor; B-Lymphocytes; Binding Sites; Biomanufacturing; Cell Line; Cell Lineage; Chimeric Proteins; Clinical Trials; Complex; Consumption; Data; Development; Doctor of Philosophy; Documentation; Electron Microscopy; Ensure; Enzyme Activation; Enzymes; Ferritin; Frequencies; Future; Gene Fusion; Generations; Goals; HIV Antigens; HIV Vaccine Trials Network; HIV vaccine; HIV-1; HIV-1 vaccine; Helicobacter pylori; Human; Immune system; Immunization; Immunologics; Immunology; Industry; Infection; Influenza Hemagglutinin; Investigational New Drug Application; Knock-in Mouse; Lead; Link; Macaca mulatta; Molecular Conformation; Mutation; Nature; Negative Staining; Outcome; Pharmaceutical Preparations; Phase I Clinical Trials; Process; Production; Reaction; Regimen; Series; Serum; Site; Somatic Mutation; Statistical Data Interpretation; Structure; Structure of germinal center of lymph node; Testing; Time; Toxic effect; United States Food and Drug Administration; Vaccine Design; Vaccines; Viral; Virion; activation-induced cytidine deaminase; cross reactivity; design; experience; humanized mouse; immunogenic; immunogenicity; improved; innovation; nanoparticle; neutralizing antibody; nonhuman primate; pandemic disease; phase I trial; process optimization; programs; quality assurance; sortase; trafficking; transpeptidation; vaccination strategy; vaccine evaluation; vaccine platform; vaccine trial

ABSTRACT – OVERALL HIV-1 broadly neutralizing antibodies (bnAbs) are protective in animal models of HIV-1 infection, but are not elicited in humans by current vaccine regimens. To elicit bnAbs, the B cell lineage vaccine design approach aims to administer multiple immunogens in a specific sequence to shepherd bnAb maturation through immunologic roadblocks that typically halt bnAb development. One roadblock we recently identified are somatic mutations that encode key amino acids for antibody function but that are rarely made by the somatic mutation enzyme activation-induced cytidine deaminase. Our central vaccine design hypothesis is that antibodies (Abs) encoding these improbable mutations, will be rare; thus, vaccine immunogens will need to have higher affinity for Abs with these desired amino acid changes than Abs without the amino acid changes in order to select for them. The problem facing this strategy is that the only antigen for HIV-1 bnAbs is HIV-1 envelope (Env), which is poorly immunogenic and for which bnAb precursors generally have low affinity. We and others have found these two obstacles can be overcome by designing Envs with high affinity for bnAb precursors and by multimerizing these Envs on nanoparticles (NPs) to provide avidity and improved antigen trafficking to germinal centers. However, Env trimer NPs can have low expression and present misfolded Env trimers that elicit undesired non-neutralizing Abs. This application is significant because it will establish a cGMP-compliant vaccine platform that rapidly generates higher quality HIV-1 Env trimer NP vaccines without time-consuming iterative immunogen design. This platform uses the sortase A enzyme to site-specifically, covalently-link well- folded HIV-1 Env trimers to intact Helicobacter pylori ferritin NPs. The resultant HIV-1 Env trimer sortase A- conjugated NPs (scNPs) display only well-folded Env trimers, and in preliminary studies, have successfully initiated CD4 binding site bnAb lineages in human bnAb precursor knock-in mice and CD4bs nAbs in rhesus macaques. The scNP platform is universal in nature since it can incorporate diverse viral type I fusion proteins by simply adding a 6-amino acid sortase A tag to their C-terminus. In Specific Aim 1, we will compare the ability of monovalent and bivalent HIV-1 Env scNPs to guide affinity maturation of CD4 binding site bnAbs in humanized mice and rhesus macaques. In Specific Aim 2, we will produce and assemble two CD4 binding site-bnAb- targeting HIV-1 Env trimer scNPs (CH505 TF scNP and a second sequential Env trimer scNP) under cGMP conditions. This program will deliver an optimized cGMP process for making scNPs, two cGMP-produced Env trimer scNPs, and additional ferritin and sortase A components for the manufacture of future immunogens. The CH505 TF Env trimer scNPs will be used in a Phase I trial through the HIV Vaccine Trial Network. Ultimately, the impact of this platform is that it will enable multiple Env trimer scNPs to be made rapidly under cGMP, making it feasible to do iterative testing in clinical trials of complete sequential nanoparticle vaccines that target bnAbs.

摘要-总体