Shifting immunodominance of humoral immunity against influenza viruses

改变体液免疫对流感病毒的免疫优势

• 批准号: 10720359
• 负责人: Jenna Guthmiller
• 金额: $ 44.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-22 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720359
• 关键词: 2019-nCoV; Adult; Affinity; Antibodies; Antibody Binding Sites; Antibody Response; Antigen Presentation; Antigenic Variation; Antigens; Avidity; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Binding Sites; CD4 Positive T Lymphocytes; Coronavirus; Ebola virus; Epitopes; Exposure to; Flavivirus; Frequencies; Generations; HIV; Hantavirus; Head; Health; Helper-Inducer T-Lymphocyte; Hemagglutinin; Human; Humoral Immunities; Immune; Immune system; Immunity; Immunize; Immunologics; Individual; Infant; Influenza A Virus, H1N1 Subtype; Knowledge; Laboratories; Libraries; Memory B-Lymphocyte; Modeling; Monoclonal Antibodies; Mus; Mutagenesis; Mutate; Mutation; Organoids; Parasites; Plasmodium; Play; Population; Postdoctoral Fellow; Pre-Clinical Model; Recording of previous events; Research; Role; Seasons; Serum; Shapes; Site; Specificity; T cell response; Testing; Titrations; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Variant; Virus; Work; Yeasts; anti-influenza; combinatorial; crosslink; design; emerging pathogen; experimental study; improved; influenza virus vaccine; influenzavirus; lymph nodes; memory recall; monoclonal antibody production; neoantigens; novel; pandemic disease; pathogen; prevent; rational design; recruit; response; seasonal influenza; translational immunology; vaccine candidate; vaccine efficacy; vaccine evaluation

PROJECT SUMMARY Influenza viruses remain a major global threat to human health, which is exacerbated by the lack of an effective vaccine. Humoral immunity does not target all parts of the virus evenly, a phenomenon known as immunodominance. Following seasonal vaccination, humans preferentially generate antibody responses against evolving epitopes of the hemagglutinin (HA) head domain rather than against broadly protective epitopes of the conserved stalk domain. In the absence of preexisting immunity against the HA head, as occurred with the 2009 pandemic H1N1 virus, humans can preferentially recall memory B cells against the stalk domain. However, naïve B cells against novel epitopes of the HA head are induced, populate the memory B cell pool, and are preferentially recalled following exposure to an antigenically similar virus. Therefore, immunodominance of the head domain and the preferential recruitment of naïve B cells against new epitopes remains a major obstacle for the generation of a broadly protective influenza vaccine. In order to generate broadly protective humoral immunity, a vaccine needs to be designed that induces robust and durable antibody responses against the stalk domain but prevents the recruitment of naïve B cells against neoepitopes. Immunodominance is in part dictated by which B cells can acquire antigen and efficiently present antigen to CD4 T cells. B cell avidity, the simultaneous binding of both binding-sites of an antibody with its epitope and the cross- linking of multiple B cell receptors on a B cells, plays a critical role in which B cell specificities are selected. B cells against the head domain have an avidity advantage, as these epitopes are more accessible than those of the stalk domain. We hypothesize that reducing B cell avidity for head epitopes will reduce competition for antigen, limit the induction of anti-head B cells, and preferentially select for B cells against the stalk domain. Using combinatorial mutagenesis and yeast-display, we will generate and select for a library of stable HAs with diverse head epitopes but an identical stalk domain, which we refer to as scrambled HA (Aim 1). By titrating the diversity of scrambled HAs, we will determine the effect of increasing head epitope diversity on which B and T follicular helper cell specificities are induced. We will perform these experiments in naïve and H1N1 immune mice to mimic immune histories in infants and adults, respectively (Aim 2). Moreover, we will immunize human ex vivo lymph node organoids generated from individuals of diverse immune histories to determine if our approach recalls memory B cells against the stalk domain (Aim 3). Together, this study will generate a vaccine that shifts immunodominance towards the stalk domain, which will be proven using multiple models of preexisting immunity. Although this proposal focuses on shifting immunodominance of anti-influenza humoral immunity, the approach taken provides a proof-of-concept that can be applied to other rapidly evolving pathogens for which immunodominance is a key barrier for successful vaccine generation, including HIV and coronaviruses.

项目摘要 流感病毒仍然是对人类健康的主要全球威胁，由于缺乏有效 疫苗。体液免疫并不瞄准病毒的所有部位，这种现象称为 免疫主持。在季节性疫苗后，人类优先生成针对的抗体反应 血凝素（HA）头域的不断发展的表位，而不是针对广泛保护的表位 保守的茎域。在没有预先存在的免疫力对HA头的情况下，2009年发生的 大流行H1N1病毒，人类可以优先召回记忆B细胞与茎结构域。但是，天真 B细胞针对HA头的新表位被诱导，填充记忆B细胞池，并且是 暴露于抗原上相似的病毒后优先召回。因此，免疫力 头部域和对新表位的幼稚B细胞的首选募集仍然是一个主要障碍 广泛保护的影响疫苗的产生。为了产生广泛保护的体液 免疫力，需要设计一种疫苗，以诱导对茎的坚固耐用抗体反应 域但可以防止幼稚的B细胞募集针对neoeppitopes。 免疫主持的部分决定了B细胞可以获取抗原并有效地将抗原呈现给CD4 T细胞。 B细胞的亲和力，两种结合位点的简单结合与其表位和交叉 将多个B细胞接收器连接在B细胞上，在选择B细胞规范的关键作用中起着关键作用。 b 针对头部结构域的单元具有同性优势，因为这些表位比 茎域。我们假设减少头部表位的B细胞亲和力将减少竞争 抗原，限制抗头B细胞的诱导，优先选择B细胞针对茎结构域。 使用组合诱变和酵母 - 播放，我们将生成并选择一个稳定库的库 不同的头部表位，但是一个相同的茎域，我们称之为炒HA（AIM 1）。通过滴定 争夺的多样性具有，我们将确定b和t的头部表位多样性增加的效果 诱导Follic Helper细胞规格。我们将以幼稚和H1N1免疫进行这些实验 小鼠分别模仿婴儿和成人的免疫历史（AIM 2）。而且，我们将使人免疫 从潜水员免疫历史的个体产生的离体淋巴结器官，以确定我们的 接近回忆记忆B细胞针对茎域（AIM 3）。这项研究将共同​​生成疫苗 这将免疫力量转向茎域，将使用多种模型证明这一点 尽管该提案的重点是转移抗Influenza体液免疫史的免疫权力，但 方法采取的概念证明可以应用于其他快速发展的病原体 免疫主导是成功产生疫苗的关键障碍，包括艾滋病毒和冠状病毒。