Novel H1N1 influenza protection via cross-reactive immunity

描述（由申请人提供）： 2009年春季爆发的新型H1N1流感让流行病学家、免疫学家和疫苗学家大吃一惊，并激发了全球范围内的大规模努力，生产数百万剂疫苗，以预防这种单一的流感毒株。大流行与w形年龄相关的易感性曲线有关，这在1918年大流行期间也被观察到。由于新型H1N1流感的独特流行病学，我们假设对交叉保守T细胞表位的反应可能有助于减少流感样疾病的报告，并在缺乏交叉反应性体液免疫的情况下证实老年人中的新型H1N1感染。我们最初的计算机模拟分析在2009年3月发表的A/加州/04/2009（H1N1）序列中鉴定了超过16个交叉保守表位，现在我们希望通过本研究计划中描述的测定进一步开展该研究。因此，我们提出的研究，评估的能力，高度保守的HA和NA T细胞表位从循环，季节性H1N1毒株和传统的三价流感疫苗（TIV）引起强大的和持久的免疫反应，在人类和小鼠模型。该项目的目标是：（1）使用可用的流感序列作为我们的出发点，合成并验证“免疫原性共有序列”交叉保守的流感II类表位，（2）鉴定ICS表位在HLA竞争结合测定中结合相关HLA分子的能力，并使用来自TIV的外周血白细胞评价表位的抗原性，季节性流感暴露和新的H1N1暴露的人类受试者。最后，（3）与Richard Webby博士合作，在HLA转基因小鼠模型中评估它们对免疫原性的影响以及在有/没有流感疫苗的情况下用于引发时对新型H1N1的保护效力。我们期望发现，与未致敏的小鼠相比，在用交叉反应性表位致敏的小鼠中，抗体滴度更高，并且流感的表现减弱。我们期望这些研究的结果表明，保守的流感序列，这是重要的病毒适应性，也可能是免疫学价值，因为它们可能有助于防止发病率和通用流感疫苗的设计，导致重新评估替代方法，以“引发”流感免疫反应，减轻疾病和准备下一次大流行。 公共卫生相关性：2009年，猪源性流感病毒的意外出现促使疫苗开发人员生产出一种针对这种新型毒株的疫苗。我们将探索跨毒株免疫原诱导免疫应答的潜力，这可能会导致通用流感疫苗的开发。

DESCRIPTION (provided by applicant): The outbreak of a novel H1N1 influenza in the spring of 2009 took epidemiologists, immunologists and vaccinologists by surprise and galvanized a massive worldwide effort to produce millions of vaccine doses to protect against this single influenza strain. The pandemic has been associated with a w-shaped age-related susceptibility curve, which was also observed during the 1918 pandemic. Because of the unique epidemiology of novel H1N1 influenza, we hypothesize that response to cross-conserved T cell epitopes might have contributed to diminished reports of influenza-like illnesses and confirmed novel H1N1 infection among older adults in the absence of cross-reactive humoral immunity. Our initial in silico analysis identified more than sixteen cross-conserved epitopes in the A/California/04/2009 (H1N1) sequence published in March 2009 and now we wish to take that study further with the assays described in this research plan. We therefore propose studies that evaluate the ability of highly conserved HA and NA T cell epitopes from circulating, seasonal H1N1 strains and the conventional trivalent influenza vaccine (TIV) to elicit robust and durable immune responses in humans and in a murine model. The aims for this project are to: (1) Synthesize and validate "immunogenic consensus sequence" cross-conserved influenza class II epitopes, using available influenza sequences as our point of departure, (2) Validate the ICS epitopes for their ability to bind relevant HLA molecules in HLA competition binding assays and evaluate the epitopes' antigenicity using peripheral blood leukocytes from TIV, seasonal influenza-exposed and novel H1N1-exposed human subjects. Finally, (3) evaluate their effect on immunogenicity and protective efficacy against novel H1N1 in the HLA transgenic mouse model when used to prime with/without flu vaccine, in collaboration with Dr. Richard Webby. We expect to find that antibody titers are higher and manifestations of influenza are attenuated in mice primed with the cross-reactive epitopes, compared to mice not primed. We expect the results of these studies to demonstrate that conserved influenza sequences, which are important to viral fitness, may also be of immunological value in that they may contribute to protection against morbidity and to universal influenza vaccine design, leading to re-evaluation of alternative approaches to "priming" influenza immune responses, attenuating illness and preparing for the next pandemic. PUBLIC HEALTH RELEVANCE: The unexpected emergence of swine-origin influenza virus in 2009 prompted vaccine developers to produce a vaccine specific for the novel strain. We will explore the potential for cross-strain immunogens to induce immune responses that may give rise to development of a universal influenza vaccine.