Optimized second-generation recombinant mycobacteria vaccine vectors against HIV

优化的第二代重组分枝杆菌HIV疫苗载体

• 批准号: 9052695
• 负责人: Mark Cayabyab
• 金额: $ 9.69万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052695
• 关键词: AIDS Vaccines; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adenovirus Vector; Animals; Antibodies; Antigens; Attenuated; BCG Vaccine; Bacillus (bacterium); Child; Clinical; Clinical Trials; Cytotoxic T-Lymphocytes; DNA; Data; Development; Disease; Engineering; Failure; Funding; Future; Generations; Genus Mycobacterium; Goals; HIV; HIV Antigens; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Human; Human Volunteers; Immune response; Immunity; Infection; Laboratories; Laboratory Animals; Macaca mulatta; Miliary Tuberculosis; Modeling; Molecular; Monkeys; Mucosal Immunity; Mus; Mycobacteriophages; Mycobacterium bovis; Mycobacterium smegmatis; Plasmids; Preclinical Testing; Preventive vaccine; Public Health; Recombinants; Regimen; SIV; Safety; System; Systems Integration; T cell response; Techniques; Testing; Transgenes; Tuberculosis; Vaccinated; Vaccine Antigen; Vaccines; animal data; base; efficacy trial; human data; immunogenic; immunogenicity; improved; innovation; neutralizing antibody; nonhuman primate; novel; overexpression; pathogen; phase I trial; pre-clinical; preclinical evaluation; preclinical study; prevent; protective efficacy; prototype; public health relevance; rBCG; recombinant adenovirus; research clinical testing; response; tool; transmission process; vaccine candidate; vaccine delivery; vector; vector vaccine; vector-based vaccine; vector-induced

 DESCRIPTION (provided by applicant): HIV/AIDS afflicts 33 million people and a preventive vaccine that will stop transmission of HIV is desperately needed. Recombinant BCG (rBCG) and M. smegmatis (rSmeg) are promising vaccine vectors that were shown to induce protective immunity against a number of pathogens in laboratory animals. However, there is ample evidence demonstrating that current mycobacteria vaccine vectors have limitations. rBCG and rSmeg vectors that are immunogenic are unstable since they are transformed with multi-copy and episomal expression plasmids. Those mycobacteria vaccine vectors that are produced by integrative single-copy plasmids are stable but do not express sufficient amounts of the vaccine antigen to induce an immune response in mice and monkeys. In this proposal, we will explore an innovative approach by exploiting mycobacteriophages to generate integration-proficient expression plasmids for engineering second-generation rBCG and rSmeg vaccine vectors that are not only stable but also have markedly higher expression of vaccine antigens. Preclinical immunogenicity testing in mice will be conducted to assess whether the second generation mycobacteria vaccine vectors will outperform old prototypes in inducing anti-SIV immune responses. We will partner the new rBCG and rSmeg vectors with recombinant adenovirus vectors for eliciting robust systemic and mucosal antibody and T cell responses. These preclinical studies are a critical step towards developing new and improved recombinant BCG and M. smegmatis as potential candidate vaccine vectors against AIDS and other diseases.

 描述（由申请人提供）：艾滋病毒/艾滋病折磨着3300万人，迫切需要一种预防性疫苗来阻止艾滋病毒的传播。重组卡介苗（rBCG）和M. smeglatin（rSmeg）是有前途的疫苗载体，其显示在实验室动物中诱导针对许多病原体的保护性免疫。然而，有充分的证据表明，目前的分枝杆菌疫苗载体有局限性。具有免疫原性的rBCG和rSmeg载体是不稳定的，因为它们用多拷贝和附加型表达质粒转化。由整合单拷贝质粒产生的那些分枝杆菌疫苗载体是稳定的，但不表达足够量的疫苗抗原以在小鼠和猴中诱导免疫应答。在这项提案中，我们将探索一种创新的方法，通过利用分枝杆菌噬菌体产生整合熟练的表达质粒，用于工程化第二代rBCG和rSmeg疫苗载体，这些载体不仅稳定，而且具有明显更高的疫苗抗原表达。将在小鼠中进行临床前免疫原性测试，以评估第二代分枝杆菌疫苗载体在诱导抗SIV免疫应答方面是否优于旧原型。我们将新的rBCG和rSmeg载体与重组腺病毒载体合作，以引发强大的全身和粘膜抗体和T细胞应答。这些临床前研究是开发新的和改进的重组BCG和M的关键一步。作为对抗艾滋病和其他疾病的潜在候选疫苗载体。