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

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

展开

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.

新生儿的流感病毒感染会导致威胁生命的疾病。 LRTI相关的速率与1至4岁之间的儿童相比，小于1岁的儿童的住院率高4倍年龄和6个月大的婴儿特别容易受到严重发展疾病。当前的影响疫苗对市场的影响未批准<6个月大的婴儿他们在这个年龄段的有限效力。克服这种不良反应能力将需要发展该人群中具有更大免疫原性的疫苗。另一个重要的投资领域是婴儿应对旨在提供多种影响菌株保护的通用疫苗。高度希望通过疫苗靶向这些抗体生产这些抗体，但我们对有效地，新生儿可以产生它们或可以最佳引起这些抗体的附属信号未知。本应用中提出的研究的最终目标是确定一种疫苗方法流感是安全且广泛保护的，当传递给新生儿。为了评估潜在策略，我们将使用我们既定的非洲绿猴（AGM）非人类灵长类动物新生儿模型。使用此模型我们以前发现TLR7/8激动剂R848的结合会灭活影响重大影响病毒特异性IgG和IFNγ产生的T细胞反应的增加，为继续对新生儿中这种佐剂的探索。我们将使用R848与异源提升或HA茎一起使用构造作为引起广泛反应抗体的方法。作为分析的一部分，我们将评估调节广泛反应性抗体的数量和质量时的TFH反应。这些研究的结果将提供机械和实用信息，这些信息可能会导致疫苗的改进设计在脆弱的新生儿人群中有效。