Impact of prior influenza exposures on antibody repertoires to new viral strains

先前流感暴露对新病毒株抗体库的影响

• 批准号: 9306754
• 负责人: Scott Eric Hensley
• 金额: $ 35.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306754
• 关键词: Address; Adjuvant; Animals; Antibodies; Antibody Binding Sites; Antibody Repertoire; Antibody Response; Antibody Specificity; Area; Binding; Biological Assay; Chicago; Childhood; Collaborations; Development; Elderly; Enzyme-Linked Immunosorbent Assay; Epitopes; Failure; Ferrets; Goals; Head; Hemagglutination; Hemagglutinin; Human; Immune response; Immune system; In Vitro; Individual; Infection; Influenza; Lung; MF59; Maps; Measures; Methods; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutation; Neuraminidase; Population; Process; Proteins; Puerto Rico; Recording of previous events; Specificity; Update; Vaccinated; Vaccination; Vaccines; Viral; Virus; absorption; anti-influenza; base; enzyme linked immunospot assay; experimental study; in vivo; influenza virus vaccine; influenzavirus; mortality; mouse model; neutralizing antibody; public health relevance; receptor binding; seasonal influenza; vaccine efficacy

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 frequently re-infected with antigenically distinct influenza strains and vaccines must be updated frequently. Influenza vaccines fail to elicit protective Ab responses in some individuals, even when vaccine strains are well matched to predominant circulating strains. Elderly individuals, who typically have extensive influenza exposure histories, respond particularly poorly to influenza vaccines. As early as the 1950's, it was noted that the human immune system preferentially mounts Ab responses to previously circulating influenza strains, as opposed to new Ab responses that exclusively target newer viral strains. This process, termed 'original antigenic sin (OAS)', has been proposed to contribute to vaccine failures in individuals with extensive influenza pre-exposure histories. We hypothesize that strain-specific Abs that recognize variable epitopes located on the top of HA are more efficient at neutralizing virus compared to OAS-induced Abs that recognize epitopes in conserved regions of HA. Previous studies of OAS have utilized influenza strains that have dramatic antigenic differences, however humans are more typically sequentially infected or vaccinated with influenza strains that have subtle antigenic changes compared to previously circulating strains. In this proposal, we will determine if OAS is induced by sequential infections with seasonal influenza strains with moderate antigenic differences. We will sequentially infect mice and ferrets with A/Puerto Rico/8/34 viruses with well defined HA antigenic mutations, and we will identify OAS-induced Abs through hemagglutination-inhibition (HAI), ELISA, ELISPOT, FACS-based Ab binding, and in vitro neutralization assays. We will complete similar vaccination experiments in pre-exposed animals with and without the MF59 adjuvant. We will then map the precise binding footprints of anti-HA mAbs derived from mice sequentially infected with distinct influenza strains. We will also map the binding footprints of a large panel of H3N2 mAbs derived from vaccinated humans with different H3N2 pre- exposure histories. Finally, we will determine in vivo neutralization efficiencies of OAS-induced murine and human mAbs using a mouse model. Collectively, these studies will determine (1) if seasonal vaccines induce OAS, (2) if OAS contributes to decreased vaccine efficacy in pre-exposed populations, and (3) if OAS Ab repertoires can be altered by MF59 adjuvants.

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，人类经常被抗原性不同的流感病毒株再次感染，因此必须经常更新疫苗。流感疫苗不能在某些个体中引起保护性抗体应答，即使疫苗株与主要的流行株很好地匹配。通常有广泛流感暴露史的老年人对流感疫苗的反应特别差。早在20世纪50年代，就注意到人类免疫系统优先对先前流行的流感毒株产生Ab应答，而不是专门靶向较新病毒毒株的新Ab应答。这一过程被称为“原始抗原性缺失（OAS缺失）”，已被认为是导致具有广泛流感前暴露史的个体的疫苗失败的原因。我们假设，与OAS诱导的识别HA保守区表位的抗体相比，识别HA顶部可变表位的菌株特异性抗体在中和病毒方面更有效。OAS的先前研究利用了具有显著抗原差异的流感毒株，然而，与先前流行的毒株相比，人类更典型地依次感染或接种具有细微抗原变化的流感毒株。在本提案中，我们将确定OAS是否由具有中度抗原差异的季节性流感毒株的连续感染引起。我们将用具有明确HA抗原突变的A/波多黎各/8/34病毒依次感染小鼠和雪貂，并将通过血凝抑制（HAI）、ELISA、ELISPOT、基于FACS的Ab结合和体外中和试验鉴定OAS诱导的Ab。我们将在有和没有MF 59佐剂的预暴露动物中完成类似的疫苗接种实验。然后，我们将绘制来自连续感染不同流感病毒株的小鼠的抗HA mAb的精确结合足迹。我们还将绘制一个绑定足迹 来自具有不同H3 N2预暴露史的接种疫苗的人的大组H3 N2 mAb。最后，我们将使用小鼠模型确定OAS诱导的鼠和人mAb的体内中和效率。总的来说，这些研究将确定（1）季节性疫苗是否诱导OAS，（2）OAS是否有助于降低预暴露人群中的疫苗有效性，以及（3）MF 59佐剂是否可以改变OAS Ab库。