Development of vaccine approaches to elicit broadly protective influenza-specific immune responses in infants

开发疫苗方法以在婴儿中引发广泛保护性的流感特异性免疫反应

基本信息

批准号：
10229523
负责人：
Martha Ann Alexander-Miller
金额：
$ 73.91万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-05 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229523
关键词：
1 year old Address Adjuvant Adult Affinity African Green Monkey Age-Months Agonist Animal Model Antibodies Antibody Formation Antibody Response Antigens Area B cell differentiation B-Lymphocytes Biological Assay Cells Centers for Disease Control and Prevention (U.S.)Child Data Development Disease Dose Effectiveness Generations Goals Hospitalization Human Immune Immune response Immune system Immunoglobulin G Individual Infant Influenza Influenza vaccination Interferon Type II Investigation Lead Life Ligands Lower Respiratory Tract Infection MF59 Maintenance Maternal antibody Measures Memory B-Lymphocyte Modeling Mus National Institute of Allergy and Infectious Disease Newborn Infant OX40 Population Positioning Attribute Research Risk Role Signal Transduction Specificity Structure of germinal center of lymph node T cell response TLR7 gene Testing Time Vaccinated Vaccination Vaccine Design Vaccines Virus Vulnerable Populations Work adaptive immune response age group base immunogenicity improved infancy infant animal influenza infection influenza virus strain influenza virus vaccine influenzavirus nanoparticle neonate nonhuman primate pre-clinical response stem universal influenza vaccine universal vaccine vaccine access vaccine candidate vaccine development vaccine response vaccine safety

项目摘要

Influenza virus infection of neonates can lead to life-threatening disease. The rate of LRTI-associated hospitalizations is >4 times higher in children less than 1 year of age compared to those between 1 and 4 years and infants younger than 6 months of age are particularly vulnerable to the development of severe disease. Current influenza vaccines on the market are not approved for infants <6 months of age as a result of their limited effectiveness in this age group. Overcoming this poor responsiveness will require development of vaccines with greater immunogenicity in this population. Another important area of investigation is the ability of infants to respond to universal vaccines designed to provide protection across multiple strains of influenza. While targeting production of these antibodies by vaccination is highly desirable, our understanding of how effectively newborns can produce them or the accessory signals that can optimally elicit these antibodies is unknown. The ultimate goal of the studies proposed in this application is to identify a vaccine approach for influenza that is safe and broadly protective when delivered to neonates. To evaluate potential strategies, we will use our established African green monkey (AGM) nonhuman primate neonate model. Using this model we previously found that conjugation of the TLR7/8 agonist R848 to inactivated influenza promotes significant increases in virus-specific IgG and IFNγ-producing T cell responses, providing rationale for the continued exploration of this adjuvant in neonates. We will utilize R848 together with heterologous boost or an HA stem construct as approaches to elicit broadly reactive antibody. As part of our analyses we will evaluate the role of Tfh responses in modulating broadly reactive antibody quantity and quality. The results of these studies will provide mechanistic as well as practical information that may lead to the improved design of vaccines that will be efficacious in the vulnerable neonate population.

新生儿感染流感病毒可导致危及生命的疾病 LRTI 相关疾病。 1 岁以下儿童的住院率是 1 岁至 4 岁儿童的 4 倍以上岁和 6 个月以下的婴儿特别容易患上严重的疾病由于以下原因，目前市场上的流感疫苗未获批准用于 6 个月以下的婴儿。他们在这个年龄段的有效性有限，需要发展以下能力。研究的另一个重要领域是疫苗在该人群中具有更大免疫原性的能力。婴儿对旨在提供针对多种流感病毒株的保护的通用疫苗有反应。虽然通过疫苗接种来靶向产生这些抗体是非常可取的，但我们对如何实现这些抗体的理解新生儿可以有效地产生这些抗体，或者可以最佳地引发这些抗体的辅助信号是本申请中提出的研究的最终目标是确定一种疫苗方法。为新生儿提供安全且具有广泛保护作用的流感病毒，我们评估了潜在的策略。我们将使用我们建立的非洲绿猴 (AGM) 非人类灵长类新生儿模型。先前发现，TLR7/8 激动剂 R848 与灭活流感病毒的结合可显着促进病毒特异性 IgG 和产生 IFNγ 的 T 细胞反应增加，为持续的研究提供了理由我们将利用 R848 与异源增强剂或 HA 干细胞一起探索这种佐剂。作为引发广泛反应性抗体的方法，我们将评估其作用。 Tfh 在调节广泛反应性抗体数量和质量方面的反应将是这些研究的结果。提供可能导致改进疫苗设计的机制和实用信息对弱势新生儿群体有效。