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Dynamics of the protective vaccine-induced human influenza neuraminidase B cell response

保护性疫苗诱导的人流感神经氨酸酶 B 细胞反应的动态

基本信息

批准号：
9765486
负责人：
James J Kobie
金额：
$ 75.01万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765486
关键词：
Adjuvant Adult Animals Antibodies Antibody Repertoire Antibody Response Antibody Specificity Antiviral Agents B-Lymphocytes Blood Circulation Bone Marrow Cavia Cell Lineage Cells Characteristics Clone Cells Dependence Development Epitopes Evolution Frequencies Future Genetic Glycoproteins Hemagglutinin Human Immune response Immunity Immunization Immunoglobulin G In Vitro Infection Influenza Influenza B Virus Influenza Hemagglutinin Intramuscular Lung Inflammation MF59 Mediating Modality Monoclonal Antibodies Mus Mutation Neuraminidase Phagocytosis Plasma Cells Prevention Process Production Property Proteins Receptors, Antigen, B-Cell Research Resolution Seasons Serum Severity of illness Site Source Specificity Surface Testing Therapeutic Translating Vaccination Vaccines Viral Viral Physiology Virion Virus Virus Shedding antibody-dependent cell cytotoxicity complement pathway deep sequencing flu transmission human monoclonal antibodies immunogenic in vivo influenza virus vaccine insight novel vaccines pandemic influenza peripheral blood prevent resistant strain response transcriptomics transmission process universal vaccine vaccine development

项目摘要

PROJECT SUMMARY The human immune response against influenza is dominated by the production of hemagglutinin (HA)-specific antibodies (Abs). The yearly mutation rate in influenza HA proteins is 1-2% leading to development of new viral strains that are resistant to previous immunity. The other most predominant glycoprotein on the virion surface is neuraminidase (NA). Although immunogenic, predominance of human NA-specific Abs is much lower than HA, probably because NA expression is only one fourth the amount of HA on the virion surface. The yearly rate of mutation of NA is about half that of HA while part of the enzymatic site remains conserved across type A (IAV) and B (IBV) influenza viruses, making NA a potentially effective target for universal vaccine and therapeutic human monoclonal Ab (hmAb) development. Antibody responses targeting NA have demonstrated protective and therapeutic activity against influenza infection in animals, and in humans NA-inhibiting serum Abs have been correlated with effective protection, reduced disease severity, and duration of viral shedding, independent of or more strongly than HA-specific Ab responses, substantiating NA as a valuable target for the prevention and treatment of influenza in humans. Although seasonal human inactivated influenza vaccines (IIV) contain NA, the extent and mechanisms of action of protective human NA-specific humoral responses induced by vaccination are poorly resolved. Our research has demonstrated that IIV in humans does induce both IAV and IBV NA- specific B cells, and that the Ab clonal lineages they encode for include those that have broad and potent ability to protect and treat influenza infection. Further, we have demonstrated that these protective NA-specific B cell clonal lineages are present in long-lived bone marrow plasma cells in humans following IIV and are the likely source for their sustained presence in circulation. We posit that NA-mediated universal humoral protection, like HA, is dependent on B cell receptor/Ab specificity, however, to a greater extent than HA is also highly dependent on the precise Fc/IgG subclass composition of the NA-specific Ab repertoire. Our central hypothesis is that human IIV induces NA-specific B cell responses with broad protective potential, however, those with both the proper specificity and anti-viral activity to confer universal protection are subdominant and sporadically induced, hence at insufficient abundance to confer optimal protection. Through precisely defining the dynamics of those protective human NA-specific B cell clonal lineages, including their induction, frequency, persistence, precise specificity, and mechanisms of action, we expect to obtain insight on how to optimally stimulate them for future human universal vaccine strategies. To that end, we propose 1) define the evolution of human NA-specific B cell clonal lineages in response to seasonal IIV 2) assess the ability of IIV-induced human NA B cell lineages to inhibit infection and transmission and 3) evaluate the Fc-dependence of NA-specific hmAb protection. The process for the development of protective human NA-specific B cell clonal lineages will be defined and strategies to translate this to universal human vaccine-mediated protection from influenza infection identified.

项目总结