Germline targeting influenza immunogens

摘要 流感病毒是一种主要的公共卫生负担，目前每年通过 预防针保护作用主要由抗体提供。然而，公共卫生 官员们担心，这种免疫接种可能会错过新出现的病毒或那些 血凝素或神经氨酸酶蛋白的新亚型，具有导致 一场流行病此外，目前做法的费用对 社会最近，人们产生了希望，认为有可能制定一项普遍的 疫苗，能够赋予多种亚型的抗性。稀有单克隆 靶向流感病毒茎区的抗体可以是广泛中和的， 说明了研制通用流感病毒疫苗的可能性， 表明天然应答是有限的或天然流感抗原不 以适当的方式刺激免疫系统。广泛中和人类 对流感病毒干细胞有反应的抗体通常使用中等数量的VH 1 -69 突变，但几乎没有其他共同特征。VH 1 -6+D3-3广泛 中和抗体类以独特的方式靶向干细胞， 独立的病人。在这个RO 1项目中，我们建议研究现有的和新的爆震- 在携带生殖系人VH 1 -69或VH 1 -6+D3-3的小鼠中， 基因座对流感候选疫苗的应答。我们应该理性地隔离新的 通过进化HA变体或对种系具有亲和力的支架设计免疫原， 回复了广泛中和的VH 1 -69和VH 1 -6+D3-3类抗体。这些新颖 然后使用生殖系VH 1 - 1测试免疫原刺激B细胞的能力。 69或VH 1 -6+D3-3的小鼠模型，使用为此目的产生的新小鼠品系。最后， 我们将评估这些免疫原单独或与加强免疫一起 免疫原赋予广泛的中和保护的能力。我们的长期目标 了解天然流感抗体反应的局限性， 如何优化免疫原，并确定候选的通用疫苗免疫原 适合人体试验。

Abstract Influenza virus is a major public health burden that is currently controlled by yearly vaccination. Protection is largely conferred by antibodies. However, public health officials fear that such immunizations might miss newly emerging viruses or those with novel subtypes of hemagglutinin or neuraminidase proteins, with the potential to lead to a pandemic. Moreover, the costs of the current approach represent a major burden to society. Recently, hope has arisen that it may be possible to formulate a universal vaccine, capable of conferring resistance to numerous subtypes. Rare monoclonal antibodies targeting the stem region of influenza virus can be broadly neutralizing, illustrating the possibility of raising a universal influenza virus vaccine, but also indicating that the natural response is limited or natural influenza antigens do not stimulate the immune system in an appropriate way. Broadly neutralizing human antibodies reactive to the stem of influenza usually use VH1-69 with moderate numbers of mutations, but have few other features in common. The VH1-6+D3-3 broadly neutralizing antibody class targets the stem in a distinct way and has been seen in independent patients. In this RO1 project, we propose to study existing and new knock- in mice carrying germline human VH1-69 or VH1-6+D3-3 targeted to the physiological loci for their responses to influenza vaccine candidates. We shall isolate new rationally designed immunogens by evolving HA variants or scaffolds with affinity for germline- reverted broadly neutralizing VH1-69 and VH1-6+D3-3 class antibodies. These novel immunogens will then be tested for the ability to stimulate B cells using germline VH1- 69 or VH1-6+D3-3 in vivo, using novel mouse strains generated for the purpose. Finally, we will assess the ability of these immunogens alone or together with boosting immunogens for the ability to confer broad neutralizing protection. Our long-term goals are to understand the limitations of the natural influenza antibody response, to learn how to optimize immunogens, and to identify candidate universal vaccine immunogens suitable for human trials.