Foundation Immunogens for Influenza Vaccines

描述（由申请人提供）：美国每年约有37，000人死于季节性流感爆发。匹配每年流行的流感病毒批次的努力未能预测23%的时间将在美国传播的毒株。2007-2008年的流感季节是预测和实际菌株流行之间不匹配的一个例子。在那个季节，三种流感毒株中的两种与在人群中传播的病毒不匹配，导致接种疫苗的个体感染流感。因此，每年的季节性流感抗原预测不是最佳的。除了季节性流感，更令人不安的是，不可能预测下一次流感大流行的毒株 尽管我们尽了最大努力监控新的爆发即使可以在大流行开始时确定病毒株，开发和生产有效疫苗以供全球分发所需的时间可能太长，无法为世界人口提供保护性疫苗。我们建议创造和测试“集中”流感基因，以产生预防性交叉反应免疫，以对抗季节性流感和大流行性流感。集中抗原是已经被计算工程化以代表由许多或所有当前病毒抗原变体共享的共同或原始抗原序列的抗原。使用集中抗原的优点是疫苗株与攻毒株的遗传距离是随机抗原与攻毒株的一半。因此，与选定的野生型候选抗原不同，集中抗原与所有流感病毒株具有显著更高的一般同源性，从而增加了它们驱动交叉反应性免疫应答以控制流感变体的能力。本研究的具体目的是：1）创建表达集中基因的重组流感病毒。这些将包括H1、H2、H3、H5、N1和N2亚型的血凝素（HA）和神经氨酸酶（NA）。集中的病毒（H1N1-con、H2 N2-con、H3 N2-con和H5 N1-con）将用于生产传统的灭活疫苗。2)为了确定最广泛的保护性疫苗，将用集中和野生型灭活疫苗免疫小鼠。免疫的小鼠将用不同的流感病毒攻击，最好的疫苗将由诱导最广泛保护水平的能力来确定。3)本研究的最终目的是确定在既往抗流感免疫的背景下使用集中流感疫苗的效果。疫苗安全性至关重要，这些研究将确定使用集中疫苗加强是否会导致原始抗原和显性非中和免疫应答。最后的分析将在雪貂中进行，因为雪貂更类似于人类的自然流感感染。该项目的总体目标是确定集中疫苗是否能够诱导针对流感病毒的交叉保护性免疫，其范围是否大于传统流感抗原。 最广泛的保护性抗原，无论是集中型还是野生型，都可以在疫苗错配的情况下用作对抗大流行或“武器化”流感病毒的第一线防御或备用疫苗，或者可以掺入年度疫苗制剂中。

DESCRIPTION (provided by applicant): Approximately 37,000 people die in the U.S. each year just due to seasonal influenza outbreaks. Efforts to match each year's batch of prevailing influenza viruses fail to predict the strains that will spread in the U.S. 23% of the time. The influenza season of 2007-2008 was one example of the mismatch between prediction and actual strain prevalence. In that season, two of the three influenza strains were mismatched with the viruses that spread in the population leading to influenza infections in vaccinated individuals Therefore, year to year seasonal influenza antigen prediction is not optimal. Beyond seasonal influenza, more troubling is that it is impossible to predict the next pandemic strain of influenza despite our greatest attempts to monitor new out breaks. Even if the strain could be determined at the onset of the pandemic, the time needed to develop and produce an effective vaccine for world-wide distribution may take too long to provide a protective vaccine to the world population. We propose to create and test "centralized" influenza genes for the production of prophylactic cross-reactive immunity to combat both seasonal and pandemic influenza. Centralized antigens are antigens that have been computationally engineered to represent common or primordial antigen sequences shared by many or all current viral antigen variants. The advantage of using a centralized antigen is that the genetic distance from the vaccine strain to the challenge strain is half of that of a random antigen and a challenge strain. Therefore, unlike selected wildtype candidate antigens, centralized antigens have substantially higher general homology to all strains of influenza, increasing their ability to drive cross-reactive immune responses to control influenza variants. The specific aims of this study are 1) to create reassorted influenza viruses expressing centralized genes. These will include hemagglutinin (HA) and neuraminidase (NA) for H1, H2, H3, H5, N1 and N2 subtypes. The centralized viruses (H1N1-con, H2N2-con, H3N2-con, and H5N1-con) will be used to make traditional inactivated vaccines. 2) In order to determine the most broadly protective vaccine, mice will be immunized with centralized and wildtype inactivated vaccines. The immunized mice will be challenged with divergent influenza viruses and the best vaccine will be determined by the ability to induce the broadest levels of protection. 3) The final goal of the study is to determine the effects of using a centralized influenza vaccine in the context of prior anti-influenza immunity. Vaccine safety is paramount and these studies will determine if boosting with centralized vaccines results in original antigeni sin and dominant non-neutralizing immune responses. A final analysis will be done in ferrets, since ferrets more closely resemble natural influenza infection in humans. The overall goal of this project is to determine if a centralized vaccine is capable of inducing cross-protective immunity against influenza virus with greater breadth than that of a traditional influenza antigen. The most broadly protective antigens, whether centralized or wildtype, could be used as a first line defense or backup vaccine against pandemic or "weaponized" influenza viruses in the case of vaccine mismatch or could be incorporated into the annual vaccine formulation.