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

 说明(申请人提供)流感病毒每年造成约100万名儿童严重感染。尽管进行了深入的研究，但关于儿童免疫力的发展和预防流感感染的相关性仍存在许多问题。为了对儿童对流感病毒感染的免疫力的发展进行详细的调查，我们对尼加拉瓜儿童的流感进行了8年多的大规模儿科队列研究。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流感病毒感染以及所有儿童的人口和营养状况的详细信息。我们的儿科队列研究提供了一个难得和宝贵的机会来研究儿童交叉反应免疫反应的发育阶段。我们的中心假设是，与同源HA抗体反应一样，交叉反应HA抗体反应是预防流感感染的关键免疫机制，并且交叉反应抗体反应是儿童免疫成熟过程的一部分。我们将利用前所未有的完整性和质量的流行病学数据和生物样本的创新使用，以及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，我们将根据年龄和性别来描述血凝素抗体反应获得强度、交叉反应和持久性的发展阶段。在目标2中，我们将调查血凝素抗体反应的强度、交叉反应性和持久性的发育获得是否依赖于早期的流感暴露。在目标3中，我们将评估血凝素抗体应答与儿童持续性、反复流感感染风险和严重程度的关系。这项建议 解决儿童交叉保护性抗体及其对流感感染风险和疾病严重性的影响方面的主要知识差距。目前，疫苗接种是减轻儿童流感沉重负担的最好方法。然而，目前的疫苗对儿童的效力明显较低，疫苗效力受到抗原漂移的强烈影响。更好地了解儿童中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指导，并将进一步扩大疫苗接种所提供的好处。这一点尤其重要，因为儿童感染的风险很高，而且免疫系统仍在发育中。此外，至关重要的是，我们必须进一步了解儿童在免疫发育方面的感染和传播风险。因此，我们拟议的研究是及时的，并已做好充分准备，将对公共卫生和科学产生重大影响。

 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.