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

新生儿感染流感病毒可导致危及生命的疾病。与LRTI相关的比率 1岁以下儿童的住院率是1岁至4岁儿童的4倍 6岁和6个月以下的婴儿特别容易发展为严重的 疾病。目前市场上的流感疫苗没有被批准用于6个月大的婴儿和婴儿，因为 他们在这个年龄段的效果有限。克服这种糟糕的响应性将需要开发 在这一人群中具有更强免疫原性的疫苗。另一个重要的调查领域是 婴儿对通用疫苗做出反应，该疫苗旨在为多种流感病毒株提供保护。 虽然通过接种疫苗来靶向产生这些抗体是非常可取的，但我们对如何 有效地，新生儿可以产生它们，或者可以最佳地诱导这些抗体的辅助信号是 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 当传染给新生儿时是安全和广泛保护的流感。为了评估潜在的战略，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。使用此模型，我们 先前发现，TLR7/8激动剂R848与灭活流感的结合显著促进了 病毒特异性免疫球蛋白和干扰素γ产生的T细胞反应增加，为继续 探索这种佐剂在新生儿中的应用。我们将结合使用R848和异源Boost或HA茎 构建作为诱导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在调节广谱反应性抗体数量和质量方面的反应。这些研究的结果将 提供可能导致改进疫苗设计的机械和实用信息，从而 对脆弱的新生儿群体有效。

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.