Clinical Studies of Vaccines for Pandemic H1N1 Influenza

新型甲型H1N1流感病毒的抗原性和遗传特征表明，该病毒含有来自北美和欧亚猪流感病毒谱系的基因片段的独特组合。从2009年H1N1大流行（pH1N1）病毒感染人间病例中分离出的病毒在抗原性上与北美猪H1N1病毒同质且抗原性相似，但与季节性人类甲型H1N1流感病毒不同。原始抗原原罪（OAS）假说指出，由个体首次流感感染建立的印记控制了此后的抗体反应。随后的流感病毒感染会导致针对原始感染病毒的抗体反应，从而削弱针对新流感病毒的免疫反应。

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. We sought evidence of OAS in humans that had prior H1N1 infections with viruses of variable antigenic distance from the 2009 pH1N1 virus, including viruses from 1935 through 1999. Analysis of paired samples of human sera taken before and after vaccination with a monovalent inactivated 2009 pH1N1 vaccine showed a significantly greater fold-rise in antibody titer against the 2009 pH1N1 virus compared to H1N1 viruses that circulated during the childhood of each subject. Thus, prior experience with H1N1 viruses did not result in an impairment of the antibody response against the 2009 pH1N1 vaccine. Our data suggest that prior exposure to H1N1 viruses did not impair the immune response against the 2009 pH1N1 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.