The effect of human pre-exposure history on antigenic drift of influenza viruses

描述（由申请方提供）：流感病毒在血凝素（HA）和神经氨酸酶（NA）蛋白内的抗体（Ab）结合位点快速积累突变，这一过程称为“抗原漂移”。由于抗原漂移，人类通常会再次感染不同的流感病毒株。尽管大多数人在其一生中相继感染不同的流感毒株，但每年的疫苗毒株是基于血清学研究选择的，该血清学研究利用从原发性流感感染中恢复的雪貂中制备的抗血清。因此，疫苗株的准确选择是基于这样的假设，即在雪貂中产生的参考血清代表在人群中发现的免疫力。我们的初步数据强烈表明，人类流感抗体特异性受到既往流感感染的强烈影响。该提案将检验以下假设：人流感病毒是对连续流感暴露引起的抗体库作出反应而进化的，并且在雪貂中制备的抗血清未能检测到阻止人抗体结合的真正抗原变化。在AIM 1中，我们将确定最近的大流行性H1N1病毒是否已经进化到阻止由连续的H1N1暴露引起的抗体结合。在这些研究中，我们将测试从连续暴露的雪貂和人类中分离的血清是否与大流行性H1N1病毒结合，这些病毒被设计成具有目前存在于大多数流行性H1N1毒株中的新HA突变。在AIM 2中，我们将确定暴露前的历史如何影响抗体对H3 N2病毒的反应。H3 N2病毒已经在人群中传播了45年，这些病毒的遗传和抗原进化得到了很好的研究。我们将用不同的H3 N2毒株依次感染小鼠和雪貂，并确定在这些动物中引发的抗体是否识别在过去45年中在不同抗原位点出现突变的H3 N2病毒。最后，在AIM 3中，我们将确定不同的预暴露如何影响婴儿的疫苗反应性。我们将测量来自接受来自同一季节的2种流感疫苗的婴儿（使用相同抗原的初免-加强）和来自接受来自不同季节的2种抗原性不同的流感疫苗的婴儿（使用不同抗原性不同的抗原的初免-加强）的血清中的Ab特异性。总之，这些研究将进一步加深我们对促进流感病毒抗原漂移的免疫压力的理解。这些研究将阐明为什么流感疫苗在不同的个体中引起无效的反应，也将改善疫苗株的选择过程。

DESCRIPTION (provided by applicant): Influenza viruses rapidly accumulate mutations in antibody (Ab) binding sites within the hemagglutinin (HA) and neuraminidase (NA) proteins, a process termed 'antigenic drift'. Due to antigenic drift, humans are typically re-infected with distinct influenza strains. Although most humans are sequentially infected with different influenza strains over the course of their life, annual vaccine strains are chosen based on serological studies utilizing anti-sera prepared in ferrets recovering from a primary influenza infection. Accurate selections of vaccine strains are therefore based on the assumption that reference sera created in ferrets are representative of immunity found in the human population. Our preliminary data strongly suggest that influenza Ab specificities in humans are strongly influenced by previous influenza infections. This proposal will test the hypothesis that human influenza viruses evolve in response to Ab repertoires elicited by sequential influenza exposures, and that anti-sera prepared in ferrets fail to detect genuine antigenic changes that prevent binding of human Abs. In AIM 1 we will determine if recent pandemic H1N1 viruses have evolved to prevent binding of Abs elicited by sequential H1N1 exposures. For these studies, we will test if sera isolated from sequentially exposed ferrets and humans bind to pandemic H1N1 viruses engineered to possess new HA mutations that are now present in most circulating pandemic H1N1 strains. In AIM 2, we will determine how pre-exposure history influences Ab responses against H3N2 viruses. H3N2 viruses have circulated in the human population for 45 years, and the genetic and antigenic evolution of these viruses is well studied. We will sequentially infect mice and ferrets with different H3N2 strains and determine if Abs elicited in these animals recognize H3N2 viruses engineered to possess mutations that have arisen in distinct antigenic sites over the last 45 years. Finally, in AIM 3 we will determine how different pre-exposures affect vaccine responsiveness in infants. We will measure Ab specificities in sera from infants receiving 2 influenza vaccines from the same season (prime- boost with same antigen) and infants receiving 2 antigenically distinct influenza vaccines from different seasons (prime-boost with different antigenically distinct antigens). Together, these studies will further our understanding of the immunological pressures that promote antigenic drift of influenza viruses. These studies will shed light on why influenza vaccines elicit ineffectve responses in different individuals and will also improve the process by which vaccine strains are chosen.