Novel vita-vaccine formula combines safety of dead and efficacy of live vaccines

新型维生素疫苗配方结合了死疫苗的安全性和活疫苗的功效

• 批准号: 9357501
• 负责人: Julie Magarian Blander
• 金额: $ 41.93万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9357501
• 关键词: Adjuvant; Advanced Development; Agonist; Anthrax Vaccines; Anthrax disease; Antibodies; Antibody Response; Area; Attenuated Live Virus Vaccine; Attenuated Vaccines; B-Lymphocyte Subsets; B-Lymphocytes; Bacillus anthracis; Bacteria; Bacterial Infections; Bacterial RNA; Bacterial Vaccines; Biological Preservation; Biothrax; CASP1 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation process; Cells; Chitosan; Communicable Diseases; DNA; Developing Countries; Elderly; Escherichia coli; Evaluation; Formulation; Fright; Health; Helper-Inducer T-Lymphocyte; Hematopoietic; Human; IRF3 gene; Imiquimod; Immune; Immune response; Immune system; Immunity; Immunization; Immunocompromised Host; Immunoglobulin Class Switching; Immunoglobulin G; Inactivated Vaccines; Individual; Inflammasome; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Injection of therapeutic agent; Innate Immune System; Interferon Type I; Interferon-beta; Interleukin-1 beta; Interleukins; Knowledge; Ligands; Mediating; Memory; Messenger RNA; Molecular; Mus; Nature; Pathway interactions; Pattern; Pattern Recognition; Performance; Play; Poly I-C; Population; Production; Receptor Signaling; Risk; Role; Safety; Secondary Immunization; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; Subunit Vaccines; Supplementation; Testing; Time; Toll-like receptors; Vaccinated; Vaccines; Virulence Factors; Virus Diseases; Wild Type Mouse; Work; adaptive immunity; attenuated microorganism; cytokine; improved; influenza virus vaccine; insight; killings; live attenuated influenza vaccine; microbial; microorganism; novel; pathogen; receptor; response; vaccine development

PROPOSAL SUMMARY Live attenuated vaccines have proven to be the most efficient human vaccines for many serious infectious diseases. When compared to their dead counterparts, live vaccines induce superior immune protection and lasting memory. But despite the efficacy of live vaccines, concerns over their safety have led to vaccine refusal by some and withholding their administration to the very young, the elderly and immunocompromised. Preservation and delivery of live vaccines especially to impoverished areas in developing countries is difficult and expensive. Understanding the molecular basis for the efficacy of live vaccines is significant because it would enable targeting of the relevant immune pathways that induce optimal and long-lasting protective immunity. Importantly, it would set the stage for the development of vaccines that are safe and afford the same protection as live vaccines, alleviating public fears and increasing the segment of the population that is vaccinated. We began our work eight years ago with the hypothesis that innate immune cells sense microbial viability as a distinct set of pathogen associated molecular patterns (PAMPs), and we identified bacterial messenger RNA (mRNA) as a vita-PAMP that signifies bacterial viability and mobilizes a tailored immune response not warranted for dead microorganisms. The Toll-like receptor (TLR) signaling adaptor TRIF plays a central role here upstream of inflammatory type I interferon and NLRP3 inflammasome pathways. Adding bacterial mRNA to dead bacteria recapitulates these innate responses, and supplementing a dead vaccine with bacterial mRNA (what we call a vita-vaccine) augments its performance in mice. A vita-vaccine performed similarly to a live vaccine in uniquely eliciting a follicular T helper cell response (that helps B cells), germinal center formation, and B cell isotype class switching, all in a TRIF-dependent manner. These studies provide strong evidence that vita-vaccine versions of existing vaccines could represent a significant advance in being able to combine the efficacy of live vaccines with the safety of dead vaccines. The three overlapping areas we will investigate in this project are: 1. We will determine how adaptive immunity elicited by the supplementation of a dead bacterial vaccine with the vita-PAMP bacterial mRNA compares to that elicited by PAMPs such as bacterial lipopeptides and others. 2. We will investigate how bacterial mRNA impacts the performance of subunit vaccines. We will test vita- vaccine versions of the licensed anthrax subunit vaccine and Influenza A virus monovalent subunit vaccine. 3. We will test a vita-vaccine version of a trivalent inactivated Influenza virus vaccine and compare it to the live attenuated influenza vaccine. The completion of these studies should provide sufficient experimental evidence to warrant the use of bacterial mRNAs as superior vita-adjuvants that restore the signatures of microbial viability to dead vaccines and improve existing inactivated and subunit vaccines for protection against either bacterial or viral diseases.

提案摘要 减毒活疫苗已被证明是针对许多严重传染病的最有效的人类疫苗 疾病。与死疫苗相比，活疫苗能产生更好的免疫保护， 持久的记忆。尽管活疫苗有效，但对其安全性的担忧导致人们拒绝接种疫苗 一些人拒绝给幼儿、老年人和免疫功能低下的人服用。 活疫苗的保存和运送很困难，尤其是向发展中国家的贫困地区运送 而且很贵。了解活疫苗功效的分子基础非常重要，因为它 将能够靶向相关的免疫途径，从而产生最佳且持久的保护作用 免疫。重要的是，这将为开发安全且负担得起的疫苗奠定基础 活疫苗的保护，减轻公众的恐惧并增加受感染的人群 接种疫苗。八年前，我们开始了我们的工作，假设先天免疫细胞能够感知微生物 活力作为一组独特的病原体相关分子模式（PAMP），并且我们鉴定了细菌 信使 RNA (mRNA) 作为一种 vita-PAMP，表示细菌活力并动员定制的免疫 对于死亡的微生物，反应不成立。 Toll 样受体 (TLR) 信号适配器 TRIF 发挥着 在炎症 I 型干扰素和 NLRP3 炎症小体通路的上游发挥核心作用。添加 死细菌的细菌 mRNA 概括了这些先天反应，并用 细菌 mRNA（我们称之为维生素疫苗）增强了其在小鼠体内的表现。进行了维他疫苗 与活疫苗类似，它能独特地引发滤泡 T 辅助细胞反应（帮助 B 细胞）、生发疫苗 中心形成和 B 细胞同种型类别转换，全部以 TRIF 依赖性方式进行。这些研究提供 强有力的证据表明，现有疫苗的维他疫苗版本可能代表着在疫苗研发方面的重大进步。 能够将活疫苗的功效与死疫苗的安全性结合起来。我们的三个重叠区域 该项目将调查的是： 1. 我们将确定如何通过补充死细菌疫苗来引发适应性免疫 vita-PAMP 细菌 mRNA 与 PAMP（如细菌脂肽等）引起的 mRNA 进行比较。 2. 我们将研究细菌mRNA如何影响亚单位疫苗的性能。我们将测试vita- 已获得许可的炭疽亚单位疫苗和甲型流感病毒单价亚单位疫苗的疫苗版本。 3. 我们将测试三价灭活流感病毒疫苗的维生素疫苗版本，并将其与 减毒活流感疫苗。 这些研究的完成应提供足够的实验证据来保证使用 细菌 mRNA 作为优质生命佐剂，可恢复死疫苗的微生物活力特征 并改进现有的灭活疫苗和亚单位疫苗，以预防细菌或病毒性疾病。