Improved Vaccines for Influenza B Virus

描述(申请人提供)：流感是世界各地发病率和死亡率的主要原因。在美国，流感的季节性流行发生在晚秋到初春，影响到所有年龄段的人，但儿童的感染率特别高。严重疾病和死亡是老年人、幼儿和患有其他疾病的人感染流感的后果，这些疾病容易使他们形成流感并发症。接种疫苗是对抗流感感染和疾病的有效方法，但一些科学和技术方面的考虑可能会对目前针对这种病毒的疫苗接种战略产生负面影响。 由于流感病毒有相当大的抗原漂移倾向，每个季节的疫苗中包括的病毒株经常发生变化，以反映当前正在传播的病毒。抗原漂移的问题可能是生产“通用”或广泛交叉保护的流感疫苗的最大障碍。克服流感毒株多样性的努力一直是许多努力的重点。 在这项提案中，我们将尝试解决FDA已经确定的与季节性疫苗的B型流感病毒成分有关的一个特殊问题。与甲型流感病毒不同，乙型流感几乎只感染人类，是幼儿住院率高的严重流行病的罪魁祸首。多年来，B型流感的两种谱系已经被认识到。虽然每个谱系都存在抗原漂移，但序列多样性相对有限。然而，事实证明，很难预测哪个谱系将在给定的流感季节占据主导地位，FDA建议将这两种毒株都包括在季节性疫苗中，因此需要开发一种四价疫苗。 一个更简单的解决方案是创造一种B型流感免疫原，诱导对这两个血统的交叉保护性免疫。我们建议使用定向分子进化方法来解决这个问题。B型流感血凝素的许多变种将利用编码以前疫苗中使用的各种血凝素蛋白的基因在体外进行DNA重组而产生。用这些变种免疫小鼠，并分析产生的血清的中和能力，将用于筛选符合所需标准的免疫原。虽然我们认识到流感血凝素序列的变化主要是通过点突变引起的，但有几种可能性支持通过重组创造新的多样性可以提高免疫原性的想法。重组可能会将不同病毒变异体的表位结合在一起，或者将保守的中和表位暴露在一个免疫原中，从而能够引发更广泛的保护性反应。我们的主要目标是获得一种新的B型流感免疫原的完全交叉反应的中和反应；然而，次要目标是扩大反应范围，覆盖同一谱系的所有病毒。 公共卫生相关性：每年的流感季节导致相当多的疾病和死亡，特别是在人口中较脆弱的成员中。由于流感毒株每年都会发生变化，因此一种广泛发挥作用的疫苗将具有很大的价值。我们建议对季节性疫苗的一种成分进行改进，以提供对某些流感病毒的更好保护。

DESCRIPTION (provided by applicant): Influenza is a major cause of morbidity and mortality around the world. In the United States, seasonal epidemics of flu occur from late fall to early spring affecting all age groups but with especially high rates of infection in children. Serious illness and death are consequences of influenza infection among the elderly, young children, and individuals with other illnesses that predispose them form complication of influenza. Vaccination is an effective way to counter influenza infection and illness, but several scientific and technical considerations can negatively impact the current strategies for vaccination against this virus. Because of the antigenic drift for which the influenza virus has a considerable propensity, the strain of virus included in each season's vaccine is frequently change to reflect the current circulating virus. The issue of antigenic drift is perhaps the most significant impediment to the production of a "universal" or broadly cross- protective vaccine to influenza. Attempts to overcome the diversity of influenza strains have been the focus of many efforts. In this proposal we will attempt to solve a particular problem that has been identified by the FDA related to the influenza B virus component of the seasonal vaccine. Unlike influenza A viruses, influenza B infects almost exclusively humans and has been responsible for severe epidemics with high rates of hospitalization for young children. Two lineages of influenza B have been recognized for many years. Although there is antigenic drift within each lineage, the sequence diversity is relatively limited. However, it has proven to be difficult to forecast which lineage will dominate a given flu season and the FDA has suggested that both strains be included in the seasonal vaccine, thus requiring a quadrivalent vaccine to be developed. A simpler solution would be to create an influenza B immunogen that induces cross-protective immunity to both lineages. We propose to use a directed molecular evolution approach to address this problem. Many variants of influenza B hemagglutinin will be created using in vitro DNA recombination of the genes encoding the various hemagglutinin proteins that have been used in previous vaccines. Immunization of mice with many of these variants and analysis of the neutralizing capability of the resulting serum will be used to screen for immunogens that meet the desired criteria. Although we are cognizant of the fact that changes in influenza hemagglutinin sequences arise largely through point mutation, several possibilities support the idea that creation of novel diversity by recombination can improve immunogenicity. Recombination might combine epitopes from different viral variants or expose conserved neutralizing epitopes into one immunogen capable of eliciting broader protective responses. Our primary objective is to have a fully cross-reactive neutralizing response from a novel influenza B immunogen; however, a secondary objective is to broaden the response to cover all viruses of one lineage. PUBLIC HEALTH RELEVANCE: The annual influenza season is responsible for considerable sickness and death, especially among the more vulnerable members of the population. Since flu strains change from year to year, a vaccine that acts broadly would be of great value. We propose to create an improved version of one of the components of the seasonal vaccine that can provide better protection against some of the flu viruses.