Controlling Vaccine Kinetics with Small Molecule Drugs

用小分子药物控制疫苗动力学

• 批准号: 10464208
• 负责人: Parisa Yousefpour
• 金额: $ 6.98万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464208
• 关键词: Address; Adjuvant; Antibodies; Antibody Response; Antigen Presentation; Antigens; Bolus Infusion; Cell Nucleus; Cells; Cellular Immunity; Communicable Diseases; Complex; Cues; Cytoplasm; DNA; DNA-Directed RNA Polymerase; Development; Dose; Engineering; Epidemic; Exposure to; FDA approved; Gene Expression Regulation; Genes; Genome; Genomics; HIV; HIV-1; HIV/TB; Health; Humoral Immunities; Immune response; Immunity; Immunization; Immunologic Memory; Infection; Inflammatory; Injections; Interleukin-12; Interleukin-2; Kinetics; Laboratories; Lymphocyte; Lymphoid Tissue; MHC Class I Genes; Malaria; Mediating; Messenger RNA; Methods; Modeling; Molecular; Molecular Conformation; Nucleic Acid Vaccines; Nucleic Acids; Oral; Oral Administration; Outcome; Pattern; Pharmaceutical Preparations; Play; Production; Proteins; RNA; RNA vaccine; Replicon; Reporter; Risk; Role; Schedule; Shapes; Subunit Vaccines; T cell response; T-Lymphocyte; Therapeutic; Trimethoprim; Tuberculosis; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Work; clinically translatable; compliance behavior; cytokine; design; global health; immunoengineering; in vivo; influenza epidemic; innovation; insight; interest; lymph nodes; novel; pandemic disease; pill; replicon vaccine; response; seasonal influenza; small molecule; synthetic biology; therapeutic DNA; tool; transgene expression; translatable strategy; translation to humans; vaccination strategy; vaccine development; vaccine efficacy; vaccine immunogenicity; vaccine platform; vaccine strategy; vaccine-induced immunity

PROJECT SUMMARY Infectious diseases such as HIV, malaria, tuberculosis, and seasonal influenza epidemics and emergence of new pandemics remain major global health problems highlighting the need for innovative approaches in vaccine design. The precise kinetics of antigen exposure relative to inflammatory cues is known to play a critical role in shaping a coordinated cellular and humoral immunity and thereby enhancing the vaccine immunogenicity and efficacy. Current vaccination strategies, however, do not include mechanisms for the temporal control of antigen and adjuvant exposure to lymphoid tissues. Here, we propose incorporating synthetic biology approaches to create nucleic acid-based vaccines where the kinetics of vaccine (antigen and adjuvant) exposure can be controlled using orally-available FDA-approved small molecule drugs. This strategy is enabled using self-replicating RNAs termed replicons that encode antigens and cytokine molecular adjuvants and encompass regulatory mechanisms governed by the FDA-approved small molecule drug, trimethoprim (TMP). This strategy allows the delivery of replicons encoding antigens and cytokines in vivo with a single bolus injection and then controlling the amplitude and duration of antigen and cytokine expression by oral administration of TMP. Using the RNA replicon platform provides several advantages: (i) it allows antigens and cytokines to be produced in their native conformation; (ii) it self-replicates and therefore persists inside the cells longer than mRNA and sustains a steady supply of “fresh” antigen and adjuvant; (iii) unlike DNA therapeutics, it does not harbor the risk of genome integration and also does not require delivery to the nucleus for transgene expression. An HIV envelope immunogen, known as the engineered outer domain (eOD-GT8), will be used as the model antigen, and interleukine-2 and interleukine-12 will be used as the cytokine molecular adjuvants. The Specific Aims of this project are: (1) Generate small molecule-responsive RNA replicon vaccines enabling control over the dynamics of antigen and adjuvant expression. (2) Identify optimal temporal patterns of antigen and adjuvant exposure maximizing the protective immunity elicited by replicon vaccines. Results from this project will establish a vaccine platform that allows modulating and promoting the magnitude and quality of T cell and antibody responses following immunization by taking a drug available as an oral pill, as a simple and clinically- translatable strategy to enhance vaccine-induced immunity. In addition, elucidating the optimal cytokine and antigen exposure patterns that confer protection will provide critical information and insights for use in conceiving better vaccine design strategies.

项目摘要 艾滋病毒、疟疾、结核病和季节性流感等传染病的流行以及 新的流行病仍然是主要的全球卫生问题，突出了疫苗创新方法的必要性 设计已知抗原暴露相对于炎性线索的精确动力学在炎症反应中起关键作用。 形成协调的细胞和体液免疫，从而增强疫苗免疫原性， 功效然而，目前的疫苗接种策略不包括暂时控制抗原的机制。 和佐剂暴露于淋巴组织。在这里，我们建议将合成生物学方法 以产生基于核酸的疫苗，其中疫苗（抗原和佐剂）暴露的动力学可以 使用FDA批准的口服小分子药物进行控制。此策略通过以下方式启用： 称为复制子的自我复制RNA编码抗原和细胞因子分子佐剂， 由FDA批准的小分子药物甲氧苄啶（TMP）管理的调节机制。这一战略 允许用单次推注在体内递送编码抗原和细胞因子的复制子， 通过口服TMP控制抗原和细胞因子表达的幅度和持续时间。使用 RNA复制子平台提供了几个优点：（i）它允许抗原和细胞因子在细胞内产生， 它们的天然构象;（ii）它自我复制，因此在细胞内持续的时间比mRNA长， 维持“新鲜”抗原和佐剂的稳定供应;（iii）与DNA治疗剂不同，它不存在 并且也不需要递送到细胞核用于转基因表达。一个艾滋病毒 被称为工程化外结构域（eOD-GT 8）的包膜免疫原将被用作模型抗原， 白细胞介素-2和白细胞介素-12将用作细胞因子分子佐剂。 本项目的具体目标是：（1）制备小分子应答RNA复制子疫苗， 控制抗原和佐剂表达的动力学。(2)识别抗原的最佳时间模式 和佐剂暴露使复制子疫苗引发的保护性免疫最大化。本项目的成果 将建立一个疫苗平台，允许调节和促进T细胞的数量和质量， 免疫后的抗体反应，通过服用口服药丸，作为一种简单的和临床上- 增强疫苗诱导免疫力的可翻译策略。此外，阐明了最佳细胞因子和 提供保护的抗原暴露模式将为怀孕提供关键信息和见解， 更好的疫苗设计策略。