Novel Preventive HIV Vaccines

新型预防性艾滋病毒疫苗

• 批准号: 9252789
• 负责人: Baozhong Wang
• 金额: $ 22.7万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252789
• 关键词: Antibodies; Antibody Formation; Antibody Response; Antigenic Variation; Antigens; Avidity; Binding; Cavia; Cellular Immunity; Clinical Trials; Effectiveness; Epitopes; Escape Mutant; Exhibits; Funding; Future; Generations; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Health; Human; Immune; Immune Sera; Immune response; Immune system; Immunization; Immunoglobulin Variable Region; Individual; Infection; Influenza Hemagglutinin; Intramuscular; Investigation; Leucine Zippers; Life; Molecular Conformation; Morphology; Mutation; Outcome; Pathway interactions; Preventive; Process; Production; Proteins; Public Health; Recombinants; Regimen; Route; Structure; Testing; Time; Vaccination; Variant; Viral; Virus; base; content retention; design; env Gene Products; env Glycoproteins; immunogenic; immunogenicity; nanoparticle; neutralizing antibody; nonhuman primate; novel; prevent; protective efficacy; protein structure; response; simian human immunodeficiency virus; success; vaccine candidate; vaccine development

 DESCRIPTION (provided by applicant): Broadly neutralizing antibodies (bnAbs) are ideal components for preventing HIV infection. However, no vaccine candidate investigated so far has induced such "holy grail" components although selected individuals living with HIV have generated bnAbs after a 2 to 4-year delay. We hypothesize that a "sequential induction" pathway is involved in inducing bnAbs in these individuals, and propose new vaccination approaches to mimic the pathway by which HIV induces bnAbs as novel preventive HIV vaccine strategies. We will mimic this process by sequential immunizations with various structure-stabilized chimeric Env gp140 proteins (rEnvs). These rEnvs contain complete different strain-specific epitope profiles but share conserved weakly-immunogenic epitopes for bnAbs. Therefore they will not boost strain-specific immune responses but gradually boost bnAb responses against conserved determinants, mimicking the elicitation of bnAbs by the emerging "new Envs" in evading strain-specific antibody responses in HIV-infected individuals after long term infection, during which strain-specific epitopes undergo continuous antigenic variation. To increase immunogenicity, rEnvs will be constructed to include a trimerization sequence to stabilize their trimeric structures (cs-rEnvs). Highly immunogenic nanoparticles, designated as nanoclusters, will be self-assembled from these trimeric cs-rEnvs and used for immunization. Broadly reactive antibody responses will be evaluated in guinea pigs. Two specific aims will be pursued: 1) Generation and purification of different chimeric cs-rEnvs with conserved regions from the same Env but variable regions from Envs in different subtypes, and fabrication of nanoclusters assembled from the resulting cs-rEnvs; 2) Comparison of sequential-immunization regimens with nanoclusters self-assembled from different cs-rEnvs for induction of broadly reactive antibody, particularly bnAb responses, in guinea pigs by parallel intramuscular and intranasal routes. The long term goal of this proposal is to develop an effective HIV vaccine strategy to achieve preventive broadly neutralizing antibody responses. This project will provide proof of the concept that a sequential-immunization regimen with self-assembled nanoclusters containing different cs-rEnv trimers is a potential approach to develop a preventive HIV vaccine.

 说明(申请人提供)：广谱中和抗体(BNAbs)是预防艾滋病毒感染的理想成分。然而，到目前为止，还没有被调查的候选疫苗产生这样的“圣杯”成分，尽管经过2到4年的延迟，选定的艾滋病毒携带者已经产生了bNAbs。我们假设在这些个体中诱导bNAbs是一种“顺序诱导”途径，并提出了新的疫苗接种方法，以模拟HIV诱导bNAbs的途径，作为新的预防性HIV疫苗策略。我们将通过用各种结构稳定的嵌合环境gp140蛋白(REnv)顺序免疫来模拟这一过程。这些rEnv包含完全不同的菌株特异性表位谱，但共享保守的弱免疫原性bNAbs表位。因此，它们不会增强毒株特异性免疫反应，而是逐渐增强针对保守决定簇的bNab反应，模拟新出现的“新包膜”在长期感染HIV感染者逃避毒株特异性抗体反应时所激发的bNAbs，在此期间毒株特异性表位经历不断的抗原变异。为了提高免疫原性，rEnv将被构建为包括一个三聚化序列来稳定其三聚体结构(cs-rEnv)。高免疫原性纳米粒子，称为纳米簇，将由这些三聚体cs-rEnv自组装并用于免疫。将在豚鼠身上评估广泛反应的抗体反应。 我们将致力于两个具体目标：1)构建和纯化不同嵌合的cs-rEnv，该嵌合cs-rEnv具有来自相同环境的保守区，但来自不同亚型的env的可变区，并由得到的cs-rEnv组装成纳米簇；2)通过平行的肌肉和鼻腔途径，比较不同cs-rEnv自组装的纳米簇在豚鼠体内诱导广谱抗体，特别是bNab反应的序贯免疫方案。 这项提议的长期目标是开发一种有效的艾滋病毒疫苗战略，以实现预防性的广泛中和抗体反应。该项目将证明序贯免疫方案是开发预防性艾滋病毒疫苗的潜在方法，该方案由含有不同cs-rEnv三聚体的自组装纳米簇组成。

项目成果

Incorporation of a GPI-anchored engineered cytokine as a molecular adjuvant enhances the immunogenicity of HIV VLPs.

• DOI: 10.1038/srep11856
• 发表时间: 2015-07-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Feng H;Zhang H;Deng J;Wang L;He Y;Wang S;Seyedtabaei R;Wang Q;Liu L;Galipeau J;Compans RW;Wang BZ
• 通讯作者: Wang BZ