Development of Adaptive Immunity to Influenza A: A Longitudinal Study of Anti-Hemagglutinin Antibodies, Their Cross-Reactivity and Protection in Children

甲型流感适应性免疫的发展：抗血凝素抗体、其交叉反应性和儿童保护的纵向研究

• 批准号: 9014901
• 负责人: AUBREE L GORDON
• 金额: $ 27.13万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-05 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014901
• 关键词: 14 year old; 2 year old; 5 year old; Acute; Address; Affect; Age-Years; Antibodies; Antibody Response; Antigens; Bayesian Modeling; Biological Assay; Blood specimen; Child; Childhood; Clinical; Cohort Studies; Data; Development; Epitopes; Frequencies; Future; Gender; Growth; Hemagglutination; Hemagglutinin; Immune; Immune response; Immune system; Immunity; Incidence; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Investigation; Knowledge; Laboratories; Life; Longitudinal Studies; Lower Respiratory Tract Infection; Methods; Monitor; Nicaragua; Nutritional status; Persons; Predisposing Factor; Process; Public Health; Recurrence; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Sampling; Serologic tests; Serological; Serum; Severities; Severity of illness; Specificity; Specimen; Staging; Testing; Time; Vaccination; Vaccine Design; Vaccines; Variant; Virus; Virus Diseases; adaptive immunity; age group; aged; cross reactivity; design; epidemiologic data; experience; follow-up; high risk; influenza virus vaccine; influenzavirus; innovation; public health relevance; respiratory; time interval; transmission process; vaccination strategy; vaccine effectiveness; vaccine-induced immunity

 DESCRIPTION (provided by applicant) Influenza virus causes an estimated 1 million severe infections in children each year. In spite of intensive research, many questions remain about the development of immunity and correlates of protection from influenza infection in children. To undertake a detailed investigation of the development of immunity to influenza virus infection in children, we have been conducting a large pediatric cohort study of influenza in children in Nicaragua for over 8-years. In addition to banked longitudinal serum samples, we have detailed information on clinical laboratory-confirmed influenza virus infections and demographic and nutritional status on all children. Our pediatric cohort study presents a rare and invaluable opportunity to study the developmental stages of the cross-reactive immune response in children. Our central hypothesis is that cross-reactive HA antibody response, like homologous HA antibody response, is a key protective immune mechanism against influenza infection and that cross-reactive antibody response is acquired as a part of the immune maturation process in children. We will take advantage of the innovative use of epidemiologic data and biologic samples of unprecedented completeness and quality, and state-of-the-art Bayesian statistical modeling to investigate the development of the immune response to influenza infection in children. In Aim 1, we will characterize the developmental stages of the acquisition of strength, cross-reactivity and persistence of hemagglutinin antibody response by years of age and gender. In Aim 2, we will investigate whether developmental acquisition of strength, cross-reactivity and persistence of hemagglutinin antibody response depends on early life influenza exposure. In Aim 3, we will evaluate the relationship between hemagglutinin antibody response and persistence, and risk of recurrent influenza infections and severity in children. This proposal addresses major gaps in knowledge on cross protective antibodies in children and their effect on influenza infection risk and disease severity. Currently, vaccination is the best method to reduce the heavy burden of influenza in children. However, the efficacy of current vaccines is clearly lower in children and vaccine effectiveness is strongly affected by antigenic drift. A bettr understanding of cross protective antibodies in children will inform strategic use and design of broadly-protective influenza vaccines and will further expand the benefits that vaccination has been providing. This is particularly important since children are at high risk of infection and ther immune system is still undergoing development. In addition it is critical that we further our understanding of children's risk of infection and transmission with respect to their immune development. Our proposed study is thus timely and well-poised to have substantial public health and scientific impact.

 描述（由申请人提供） 流感病毒每年导致约 100 万儿童严重感染，尽管进行了深入研究，但关于儿童免疫力的发展和流感感染防护的相关性仍存在许多问题，需要进行详细调查。为了提高儿童对流感病毒感染的免疫力，我们已经在尼加拉瓜开展了一项大型儿童流感队列研究超过 8 年。除了储存的纵向血清样本外，我们还拥有经临床实验室确认的详细信息。我们的儿科队列研究为研究儿童交叉反应性免疫反应的发展阶段提供了一个难得的宝贵机会，我们的中心假设是交叉反应性HA抗体反应，例如。同源HA抗体反应是针对流感感染的关键保护性免疫机制，并且交叉反应性抗体反应是儿童免疫成熟过程的一部分，我们将利用流行病学数据和前所未有的生物样本的创新使用。完整性和质量，以及采用最先进的贝叶斯统计模型来研究儿童对流感感染的免疫反应的发展。在目标 1 中，我们将通过以下方法来描述血凝素抗体反应的强度、交叉反应性和持久性的获得的发展阶段。在目标 2 中，我们将研究血凝素抗体反应的强度、交叉反应性和持续性的发育获得是否取决于生命早期流感暴露。在目标 3 中，我们将评估血凝素之间的关系。抗体反应和持续性，以及儿童反复感染流感的风险和严重程度。 对儿童交叉保护性抗体及其对流感感染风险和疾病严重程度的影响的认识存在重大差距。 目前，疫苗接种是减轻儿童流感沉重负担的最佳方法，但现有疫苗对儿童的功效明显较低。疫苗的有效性受到抗原漂移的强烈影响，更好地了解儿童的交叉保护性抗体将为广泛保护性流感疫苗的战略使用和设计提供信息，并将进一步扩大疫苗接种所提供的益处，这一点尤其重要，因为儿童是流感疫苗的受益者。处于高感染风险且其免疫系统仍在接受治疗此外，我们进一步了解儿童在免疫发育方面的感染和传播风险也至关重要，因此我们提出的研究是及时且有能力产生重大公共卫生和科学影响的。