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

• 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
• 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

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.

新生儿感染流感病毒可导致危及生命的疾病。lrti相关的比率