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许多严重传染性疾病的最有效的人用疫苗。 疾病与死疫苗相比，活疫苗诱导上级免疫保护， 永恒的记忆但是，尽管活疫苗有效，但对其安全性的担忧导致了疫苗拒绝 一些人拒绝给年幼者、老年人和免疫功能低下者服用。 保存和运送活疫苗，特别是向发展中国家的贫困地区运送活疫苗是困难的 而且很贵了解活疫苗效力的分子基础是重要的，因为它 将能够靶向相关的免疫途径，诱导最佳的和持久的保护， 免疫力重要的是，它将为开发安全且负担得起的疫苗奠定基础。 保护作为活疫苗，减轻公众的恐惧，并增加人口的一部分， 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感知微生物， 作为一组独特的病原体相关分子模式（PAMPs），我们确定了细菌 信使RNA（mRNA）作为维生素PAMP，标志着细菌的活力和动员定制的免疫 对于死亡微生物，无需作出响应。Toll样受体（TLR）信号转导衔接子TRIF起着重要的作用。 在炎性I型干扰素和NLRP 3炎性体途径的上游起中心作用。添加 细菌mRNA对死亡细菌的反应重演了这些先天反应，并补充了死亡疫苗， 细菌mRNA（我们称之为维生素疫苗）增强了它在小鼠中的表现。一种维生素疫苗 类似于活疫苗，在独特地引发滤泡性T辅助细胞应答（帮助B细胞）方面， 中心形成和B细胞同种型类别转换，所有这些都以TRIF依赖性方式进行。这些研究提供 强有力的证据表明，现有疫苗的维生素疫苗版本可能代表了一个重大的进步， 能够将活疫苗的有效性与死疫苗的安全性联合收割机结合起来。三个相互重叠的领域， 将在本项目中调查的是： 1.我们将确定如何通过补充死亡的细菌疫苗引起适应性免疫， vita-PAMP细菌mRNA与PAMP如细菌脂肽等引起的mRNA相比。 2.我们将研究细菌mRNA如何影响亚单位疫苗的性能。我们要测试一下- 已获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，以保证使用 细菌mRNA作为上级维生素佐剂， 并改进现有的灭活疫苗和亚单位疫苗以保护免受细菌或病毒疾病的侵害。