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（由适用提供）：迫切需要艾滋病毒/艾滋病3,300万人和一种预防性疫苗，该疫苗迫切需要停止艾滋病毒的传播。重组BCG（RBCG）和M. smegmatis（RSMEG）有望疫苗载体，这些疫苗向量被证明可诱导受保护的免疫学针对实验动物中的许多病原体。但是，有足够的证据表明当前的分枝杆菌疫苗媒介有局限性。免疫原性的RBCG和RSMEG载体是不稳定的，因为它们被多拷贝和偶发表达质粒转化。由综合单拷贝质粒产生的那些分枝杆菌疫苗载体是稳定的，但没有表达足够量的疫苗抗原以诱导小鼠和猴子的免疫激素。在该提案中，我们将通过利用分枝杆菌噬菌体来探索一种创新的方法，以生成积分效应的表达质粒，用于工程第二代RBCG和RSMEG疫苗媒介，这些疫苗不仅稳定，而且疫苗抗原的表达也明显更高。将进行小鼠的临床前免疫原性测试，以评估第二代分枝杆菌疫苗载体是否在诱导的抗SIV免疫调查中表现优于旧原型。我们将将新的RBCG和RSMEG载体与重组腺病毒载体合作，以引起健壮的全身性和粘膜抗体以及T细胞反应。这些临床前研究是开发新的和改进的重组BCG和Smegmatis的关键步骤，作为针对艾滋病和其他疾病的潜在候选疫苗向量。