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

新生儿流感病毒感染可导致危及生命的疾病。LRTI相关性 1岁以下儿童的住院率是1至4岁儿童的4倍 年龄小于6个月的婴儿特别容易发生严重的 疾病由于以下原因，目前市场上的流感疫苗未被批准用于<6个月的婴儿 他们在这个年龄段的有效性有限。要克服这种反应能力差的问题，就需要开发 免疫原性更强的疫苗。调查的另一个重要领域是 婴儿对旨在提供多种流感病毒株保护的通用疫苗产生反应。 虽然通过疫苗接种靶向产生这些抗体是非常可取的，但我们对如何产生这些抗体的理解是非常重要的。 新生儿可以有效地产生它们，或者可以最佳地引发这些抗体的辅助信号， 未知本申请中提出的研究的最终目标是确定一种疫苗方法， 流感病毒是安全和广泛的保护时，交付给新生儿。为了评估潜在的战略，我们 将使用我们建立的非洲绿色猴（AGM）非人灵长类新生动物模型。利用这个模型，我们 先前发现TLR 7/8激动剂R848与灭活流感病毒的缀合促进了显著的 产生病毒特异性IgG和IFNγ的T细胞应答增加，为持续的 在新生儿中探索这种佐剂。我们将使用R848与异源加强或HA茎 构建体作为引发广泛反应性抗体的方法。作为我们分析的一部分，我们将评估 Tfh在调节广泛反应性抗体数量和质量中的反应。这些研究的结果将 提供机制以及实际的信息，可能会导致改进的疫苗设计， 在脆弱的新生儿群体中有效。

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.