Engineering an intranasal universal influenza vaccine

设计鼻内通用流感疫苗

基本信息

批准号：
9526306
负责人：
Harvinder Singh Gill
金额：
$ 58.43万
依托单位：
TEXAS TECH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-09 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9526306
关键词：
Adjuvant Agonist Amino Acid Sequence Amino Acids Antibody Response Antigens Avian Influenza Avian Influenza A Virus B-Lymphocytes Binding Biodistribution Birds C57BL/6 Mouse California Cells Child Consensus Consensus Sequence Data Development Dose Economic Burden Elderly Electron Microscopy Engineering Epitopes Exhibits Extracellular Domain Family suidae Freeze Drying Genes Gills Goals Gold Grant Haemophilus influenzae Haplotypes Histocompatibility Histopathology Human IgG2 Immobilization Immune Immune response Immunization Immunoglobulin G Inbred BALB C Mice Inbreeding Inflammation Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Influenza A Virus, H7N9 Subtype Influenza A virus Integral Membrane Protein Investigation Kidney Knock-out Liver Longevity M2 protein Measures Monitor Morbidity - disease rate Mouse Strains Mus Mutation Nasal Epithelium National Institute of Allergy and Infectious Disease Pathogenicity Pattern Phase I Clinical Trials Population Heterogeneity Porcine Influenza A Virus Protein Isoforms Reassortant Viruses Safety Serum Signal Transduction Single-Stranded DNA System T-Lymphocyte T-Lymphocyte Epitopes TLR9 gene Testing Tissues Transgenic Organisms Vaccinated Vaccination Vaccine Design Vaccines Vietnam Viral Virulent Virus Zoonoses base circulating biomarkers design genetic makeup immunogenic immunogenicity influenza virus vaccine influenzavirus lymph nodes mouse model nanoparticle novel pandemic disease pandemic influenza respiratory response swine influenza uptake vaccination strategy vaccine safety

项目摘要

Engineering an intranasal universal influenza vaccine Influenza virus causes serious respiratory illness. Due to the high mutation rate in influenza genes, antigenic drift can create a new strain each year. Consequently there is significant economic burden to monitor virus activity and to create and distribute new influenza vaccines to the public each year. Furthermore, due to gene reassortment, a novel influenza subtype could emerge, which is virulent and has never circulated amongst humans, and could cause a devastating pandemic. It is therefore crucial that unlike current vaccines, more universal vaccination strategies be developed against influenza A that can protect against all influenza A subtypes. The 23 amino acid-long extracellular domain of the viral transmembrane protein M2 (M2e) found on human (h) influenza A viruses has remained highly conserved since the 1918 pandemic; and hM2e is thus considered a good candidate for the development of a universal influenza A vaccine. However, hM2e is poorly immunogenic. We have designed an intranasal delivery system for hM2e. Our studies show that by attaching hM2e to virus-mimicking gold nanoparticles (AuNPs) and by using CpG as a soluble adjuvant (AuNP- hM2e+sCpG vaccine) a broad heterosubtypic protection can be observed in Balb/c mice against human H1N1 and H3N2 influenza A strains, and the highly pathogenic avian influenza strain H5N1. However, the consensus amino acid sequence of M2e in human (h), avian (a), and swine (s) influenza viruses shows variability. Indeed our preliminary study shows that mice vaccinated intranasally by the AuNP-hM2e+sCpG vaccine are only partially protected against a lethal challenge by Anhui/1/2013 (H7N9), which is an avian reassortant virus, and whose M2e sequence has more homology to avian aM2e than hM2e. Amazingly, our vaccine can also induce M2e antibody response in C57BL/6 mice and CD-1 mice (an outbred strain), thus demonstrating an ability to be applicable to a genetically diverse population. We thus hypothesize that a multivalent vaccine based on AuNP—M2e+sCpG and comprising of hM2e, aM2e, and sM2e consensus sequences as antigens can be developed in to a broadly cross-protective, durable and safe influenza A vaccine that is effective in a genetically diverse population. Our specific aims are: (i) Establish breadth of cross-protection in genetically diverse mouse strains and evaluate long term vaccine protection. (ii) Determine mechanism of immune stimulation by the vaccine. (iii) Determine biodistribution and safety of the vaccine. If successful these studies will provide the efficacy and safety data necessary to support moving the vaccine in to phase-I clinical trials.

设计鼻内通用流感疫苗流感病毒由于流感基因的高突变率、抗原性而引起严重的呼吸道疾病。每年都会产生新的病毒株，监测病毒会带来巨大的经济负担。此外，由于基因的原因，每年都会开发和向公众分发新的流感疫苗。重组后，可能会出现一种新的流感亚型，这种亚型具有致命性，并且从未在全球范围内被废除过。人类，并可能导致毁灭性的大流行，因此与目前的疫苗不同，更多的疫苗至关重要。制定针对甲型流感的通用疫苗接种策略，可以预防所有甲型流感病毒跨膜蛋白 M2 (M2e) 的 23 个氨基酸长的胞外结构域。自 1918 年大流行以来，人类 (h) 甲型流感病毒一直保持高度保守，因此 hM2e 是高度保守的； hM2e 被认为是开发通用甲型流感疫苗的良好候选者。我们的研究表明，通过附着，我们设计了一种鼻内递送系统。 hM2e 转化为模拟病毒的金纳米粒子 (AuNP) 并使用 CpG 作为可溶性佐剂 (AuNP- hM2e+sCpG 疫苗）在 Balb/c 小鼠中观察到针对人 H1N1 流感的广泛异亚型保护和H3N2甲型流感毒株，以及高致病性禽流感毒株H5N1。人流感病毒 (h)、禽流感病毒 (a) 和猪流感病毒 (s) 的 M2e 氨基酸序列确实表现出变异性。我们的初步研究表明，小鼠鼻内接种 AuNP-hM2e+sCpG 疫苗仅部分保护免受安徽/1/2013 (H7N9)（一种禽重配病毒）的致命挑战，以及其M2e序列与禽类aM2e的同源性高于hM2e，令人惊讶的是，我们的疫苗也可以诱导。 C57BL/6 小鼠和 CD-1 小鼠（远交品系）中的 M2e 抗体反应，从而证明了能够因此，我们寻求一种基于基因多样性的多价疫苗。 AuNP-M2e+sCpG 并包含 hM2e、aM2e 和 sM2e 共有序列作为抗原，可以是开发成一种具有广泛交叉保护性、持久且安全的甲型流感疫苗，可有效预防我们的具体目标是： (i) 建立遗传交叉保护的广度。 (ii) 确定免疫系统的机制 (iii) 确定疫苗的生物分布和安全性。如果成功，这些研究将提供支持疫苗接种所需的功效和安全性数据至 I 期临床试验。