Controlling Vaccine Kinetics with Small Molecule Drugs

用小分子药物控制疫苗动力学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要艾滋病毒、疟疾、结核病和季节性流感等传染病的流行和新冠病毒的出现新的流行病仍然是全球主要健康问题，凸显了疫苗创新方法的必要性众所周知，相对抗原暴露于炎症信号的精确动力学在其中发挥着关键作用。形成协调的细胞免疫和体液免疫，从而增强疫苗的免疫原性和然而，当前的疫苗接种策略不包括抗原的时间控制机制。在这里，我们建议结合合成生物学方法。创造基于核酸的疫苗，其中疫苗（抗原和佐剂）暴露的动力学可以使用经 FDA 批准的口服小分子药物进行控制。自我复制的RNA称为复制子，编码抗原和细胞因子分子佐剂并涵盖监管机制由 FDA 批准的小分子药物甲氧苄啶 (TMP) 控制。允许通过单次推注在体内递送编码抗原和细胞因子的复制子，然后通过口服 TMP 控制抗原和细胞因子表达的幅度和持续时间。 RNA 复制子平台具有以下几个优点：(i) 它允许在它们的天然构象；(ii) 它能够自我复制，因此在细胞内的存在时间比 mRNA 长维持“新鲜”抗原和佐剂的稳定供应；(iii) 与 DNA 疗法不同，它不存在风险基因组整合，也不需要传递到细胞核进行转基因表达。被称为工程外域（eOD-GT8）的包膜免疫原将用作模型抗原，细胞因子分子佐剂采用白细胞介素2和白细胞介素12。该项目的具体目标是： (1) 生成小分子响应性 RNA 复制子疫苗，使 (2) 确定抗原的最佳时间模式和佐剂暴露最大化复制子疫苗引起的保护性免疫。将建立一个疫苗平台，可以调节和促进 T 细胞的数量和质量，通过服用口服药丸形式的药物进行免疫接种后产生抗体反应，作为一种简单的临床方法此外，还阐明了最佳细胞因子和增强疫苗诱导免疫力的可转化策略。提供保护的抗原暴露模式将为受孕提供关键信息和见解更好的疫苗设计策略。