MVA Prime/Novel Trimeric Cyclically Permuted Envelope Protein Boost Vaccines for HIV

MVA Prime/新型三聚体循环排列包膜蛋白增强 HIV 疫苗

• 批准号: 10219067
• 负责人: Rama Rao Amara
• 金额: $ 76.67万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219067
• 关键词: AIDS/HIV problem; Adjuvant; Affinity; Agonist; Amino Acids; Animal Model; Animals; Antibodies; Antibody Formation; Antibody Response; Antigens; Autologous; Avidity; Binding; Cavia; Cells; Complex; Development; Enterotoxins; Epitopes; Failure; Formulation; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Vaccine Trials Network; HIV vaccine; HIV-1; Human; Humoral Immunities; Immune; Immunization; Infection prevention; Laboratories; Link; Macaca; Macaca mulatta; Modality; Modeling; Modified Vaccinia Virus Ankara; Molecular; Molecular Conformation; Mosaicism; Mucous Membrane; Mutation; Oryctolagus cuniculus; Pathogenicity; Periodicity; Proteins; Regimen; Resistance; SIV; Secondary Immunization; Specificity; TLR7 gene; TNFSF5 gene; Testing; Thailand; Time; Vaccination; Vaccines; Virus; Virus Diseases; aluminum sulfate; base; cartilage matrix protein; cross reactivity; design; disulfide bond; efficacy trial; env Gene Products; immunogenicity; improved; mutant; nanoparticle; neutralizing antibody; nonhuman primate; novel; novel vaccines; prevent; protective efficacy; response; scaffold; simian human immunodeficiency virus; vaccine efficacy

The overall goal of this application is to determine the immunogenicity and protective efficacy of novel trimeric gp120 immunogens against HIV using the rhesus macaque model. Development of an effective vaccine against HIV-1 has been an elusive goal for the past three decades. The results from the RV144 efficacy trial in Thailand provided a first proof in humans that HIV infection can be prevented by vaccination and demonstrated that anti-envelope (Env) antibody response contributes significantly for this protection. The major correlate of protection was found to be non-neutralizing antibodies specific for the variable loops V1V2 of gp120, a finding supported by recent non-human primate (NHP) trials in which protection from neutralization resistant simian immunodeficiency virus (SIV) infection also correlated with anti-V1V2 antibodies. Thus, we hypothesize HIV vaccines that generate a strong and broad anti-V1V2 response, in addition to neutralizing antibody response, will significantly improve protection against diverse HIV-1 isolates. Towards this, we recently described the design, immunogenicity and efficacy of a novel trimeric gp120 immunogen, CycP-gp120. This immunogen is based on a cyclically permuted gp120 in which a de novo N-terminus is generated within the V1 loop region with the native N- and C- termini joined via an amino acid linker chain. To induce a trimeric complex, the human cartilage matrix protein (hCMP) coiled-coil trimerization domain was fused to the de novo N-termini, resulting in a stabilized, disulfide bond linked trimeric gp120. Immunization of guinea pigs with cycP-gp120 showed strong induction of neutralizing antibodies against neutralization resistant (tier-2) HIV-1 isolates from multiple clades. Immunization of rabbits and rhesus macaques showed induction of high levels of high avidity HIV-1 Env specific antibodies with a remarkable anti-gp70-V1V2 specific response, promoting antibodies recognizing V1V2 sequences from a diverse, multi-clade panel of global HIV-1 isolates. More recent studies in rhesus macaque showed that MVA prime/CycP boost regimen confers protection against pathogenic SHIV challenges. In this proposal we will further optimize the CycP immunogen design and the adjuvant for CycP protein boost, and test the ability of CycP-induced antibody response to further enhance protection against HIV using a heterologous pathogenic tier 2 SHIV challenge in rhesus macaques.

本应用的总体目标是确定新型三聚体的免疫原性和保护功效