Clinical Studies of Vaccines for Pandemic H1N1 Influenza

甲型H1N1流感疫苗的临床研究

• 批准号: 9161665
• 负责人: Kanta Subbarao
• 金额: $ 73.6万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9161665
• 关键词: Adult; Age-Years; American; Antibody Response; Attenuated; California; Centers for Disease Control and Prevention (U.S.); Child; Clinical Research; Clinical Trials; Collaborations; Data Analyses; Dose; Elderly; Family suidae; Frequencies; Gene Combinations; Genetic; Goals; Hemagglutination; Human; Immune; Immune response; Immunity; Immunoglobulin A; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Licensing; Life; Molecular; Mucosal Immune Responses; Natural History; Nature; Nose; Porcine Influenza A Virus; Recovery; Regulation; Reporting; Schedule; Serum; System; Systems Biology; United States; Universities; Upper respiratory tract; Vaccines; Viral; Virus; Virus Diseases; Virus Replication; World Health Organization; base; cell type; disorder prevention; imprint; influenza virus vaccine; influenzavirus; neutralizing antibody; novel; pandemic disease; pandemic influenza; preclinical study; programs; response

Antigenic and genetic characterization of the novel influenza A H1N1 virus indicated that the virus contained a unique combination of gene segments from North American and Eurasian lineages of swine influenza viruses. The viruses isolated from human cases of the 2009 pandemic H1N1 (pH1N1) virus infection were antigenically homogeneous and antigenically similar to North American swine H1N1 viruses, but distinct from seasonal human influenza A H1N1 viruses. The hypothesis of original antigenic sin (OAS) states that the imprint established by an individuals first influenza infection governs the antibody response thereafter. Subsequent influenza virus infections result in an antibody response against the original infecting virus, impairing the immune response against a newer influenza virus. A live attenuated influenza virus (LAIV) vaccine is licensed for healthy adults 2-49 years of age. This vaccine is administered by nasal spray. Neutralizing antibody in the serum has been found to be a correlate of protection for TIV, but the immune correlates of protection for LAIV are not known. Defining the origin and nature of transcriptional responses to LAIV in upper respiratory tract will be a highly informative first step in a systems approach toward understanding the molecular basis of viral replication restriction and the regulation of the local mucosal immune responses following LAIV administration. In FY13, in collaboration with colleagues at Stanford University, we undertook a natural history study using a systems biology approach to identify LAIV replication niches among a variety of URT cell types and characterize the host immune response to LAIV. Data analysis is in progress. Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are available for children. Local and systemic immunity induced by LAIV followed a month later by LAIV and IIV followed by LAIV were investigated with virus recovery after LAIV doses as surrogates for protection against influenza on natural exposure. Fifteen children received IIV followed by LAIV, 13 an initial dose of LAIV, and 11 a second dose of LAIV. The studies were done during autumn 2009 and autumn 2010 with the same seasonal vaccine containing A/California/07/09 H1N1, A/Perth/16/09 H3N2, B/Brisbane/60/08. Twenty-eight of 39 possible influenza viral strains were recovered after the initial dose of LAIV. When LAIV followed IIV, 21 of 45 viral strains were identified. When compared to primary LAIV infection, the decreased frequency of shedding with the IIV-LAIV schedule was significant (P = .023). With LAIV-LAIV, the fewest viral strains were recovered (3/33)numbers significantly lower (P < .001) than shedding after initial LAIV and after IIV-LAIV (P < .001). Serum hemagglutination inhibition antibody responses were more frequent after IIV than LAIV (P = .02). In contrast, more mucosal immunoglobulin A responses were seen with LAIV. In conclusion, LAIV priming induces greater inhibition of virus recovery on LAIV challenge than IIV priming. The correlate(s) of protection are the subject of ongoing analysis.

新型甲型H1N1流感病毒的抗原性和基因特征表明，该病毒包含来自北美和欧亚猪流感病毒谱系的独特基因片段组合。从2009年大流行H1N1(PH1N1)病毒感染的人类病例中分离出的病毒在抗原性上是同质的，与北美猪H1N1病毒相似，但与季节性人类甲型H1N1流感病毒不同。原始抗原性原罪(OAS)假说表明，个体首次感染流感时形成的印记支配着随后的抗体反应。随后的流感病毒感染会导致对原始感染病毒的抗体反应，削弱对较新流感病毒的免疫反应。 减毒活流感病毒(LAIV)疫苗是为2-49岁的健康成年人获得许可的。这种疫苗是通过鼻腔喷雾注射的。血清中的中和抗体已被发现与TIV的保护作用有关，但对LAIV的保护作用的免疫相关性尚不清楚。确定上呼吸道对LAIV的转录反应的来源和性质将是了解病毒复制限制的分子基础和LAIV给药后局部粘膜免疫反应调节的系统方法的第一步。在2013财年，我们与斯坦福大学的同事合作，使用系统生物学方法进行了一项自然历史研究，以确定各种URT细胞类型中的LAIV复制生态位，并表征宿主对LAIV的免疫反应。数据分析正在进行中。 儿童可获得减毒活流感疫苗(LAIV)和灭活流感疫苗(IIV)。1个月后用LAIV诱导局部和系统免疫，1个月后用LAIV和IIV诱导的局部和系统免疫，以LAIV剂量后的病毒恢复作为预防流感自然暴露的替代方案。15名儿童接受了静脉注射，随后接受了LAIV，13名儿童接受了第一剂LAIV，11名儿童接受了第二剂LAIV。这些研究是在2009年秋季和2010年秋季使用含有A/California/07/09 H1N1、A/Perth/16/09 H3N2、B/Brisbane/60/08的相同季节性疫苗进行的。39个可能的流感病毒株中的28个在初始剂量LAIV后恢复。当LAIV和IIV相继时，45株病毒中有21株被鉴定出来。与原发LAIV感染相比，IIV-LAIV方案的脱落频率显著降低(P=.023)。在LAIV-LAIV中，回收的病毒株最少(3/33)，与最初LAIV和IIV-LAIV后的脱落病毒数(P&lt；.001)相比，差异显著(P&lt；.001)。静脉注射后血清血凝抑制抗体反应比静脉注射后更频繁(P=0.02)。相反，LAIV有更多的粘膜免疫球蛋白A反应。 综上所述，LAIV启动对LAIV攻击的病毒恢复的抑制作用大于IIV启动。保护的相关性(S)是正在进行的分析的主题。