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Evaluation of pregnancy on vaccine-induced immunity and protection in a pre-clinical model of RSV infection

RSV感染临床前模型中妊娠对疫苗诱导免疫和保护的评价

基本信息

批准号：
10269922
负责人：
Karen A Norris
金额：
$ 77.12万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10269922
关键词：
Accounting Acute Address Adult Affect Animal Model Animals Antibody Response Blood group antigen f Child Childhood Clinical Clinical Research Clinical Trials Disease Environment Etiology Evaluation Evolution Exposure to Failure Female Formalin Goals Human Immune Immune response Immunity Immunization Infant Infection Infiltration Innate Immune System Kinetics Lower Respiratory Tract Infection Lung Lung diseases Lymphocyte Macaca Maternal antibody Maternally-Acquired Immunity Mediating Memory Memory B-Lymphocyte Modeling Molecular Conformation Monoclonal Antibodies Morbidity - disease rate Mothers Mucous body substance Nature Passive Immunity Passive Transfer of Immunity Phenotype Population Pre-Clinical Model Predisposition Pregnancy Prevention Primates Production Public Health Pulmonary Pathology Reproducibility Respiratory Signs and Symptoms Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory syncytial virus Respiratory syncytial virus RSV F proteins Rodent Model Route Second Pregnancy Trimester Serology Specificity T-Lymphocyte Testing Th2 Cells Therapeutic Third Pregnancy Trimester Vaccinated Vaccination Vaccines Virus Virus-like particle base clinically relevant design efficacy testing experience human disease immunopathology improved infant infection maternal vaccination mature animal mortality neonate neutralizing antibody neutrophil nonhuman primate novel novel vaccines offspring perinatal period postnatal period pregnant prevent protective efficacy recombinant virus response seropositive transmission process vaccination strategy vaccine candidate vaccine development vaccine efficacy vaccine-induced immunity

项目摘要

RSV is the leading cause of acute lower respiratory tract infections in children, causing an estimated 33 million new infections each year. Despite this significant global burden, there is no RSV vaccine and there are currently limited therapeutic options for severe RSV infection. Vaccine efforts have been hindered by 1) failure of early vaccine attempts using formalin-inactivated RSV (FI-RSV) which led to the occurrence of enhanced respiratory disease (ERD) in some infants and 2) deficiencies of rodent models that do not to recapitulate critical aspects of human infant RSV infection. Studies have shown that vaccination with FI-RSV and subsequent RSV challenge skews Th2-cell mediated responses towards immunopathology, while prior exposure to live virus properly primes the adaptive and innate immune systems without ERD. Consequently, the potential for subunit and inactivated RSV vaccines to cause ERD remains a particular concern for RSV naïve pediatric population. In this proposal, we offer a novel immunization strategy in a highly relevant, pre-clinical model of RSV that addresses these barriers to vaccine development. We propose to test novel maternal immunization strategies for eliciting protective maternal immunity and test the protective efficacy of passive transfer of neutralizing antibodies. We hypothesize that this approach will provide protective passive immunity in infants during perinatal period of greatest RSV susceptibility. We propose to test this approach in a non-human primate model of RSV infection using recombinant virus-like particle (VLP) vaccines expressing F antigen in appropriate conformation. In addition, we will use this immunization strategy to improve understanding of critical aspects of maternal immunization including 1) the effects of pregnancy on vaccine-induced immunity 2) the kinetics of maternal transfer of neutralizing antibodies responses and 3) the efficacy of maternal immunization and protection in a clinically relevant infant primate model. In addition, we will define innate and adaptive immune correlates of protection in RSV infection in adult macaques, information that will be critical to the understanding of deficiencies in the infant lung environment. We expect these studies will have a catalytic effect on the RSV field by establishing a pre-clinical model of infection for design and testing maternal immunization strategies as well as in a highly relevant, pre-clinical model that most closely mimics human disease.

呼吸道合胞病毒是儿童急性下呼吸道感染的主要原因，估计造成3300万人感染