Defining and Manipulating B Cell Immunodominance Hierarchies to Elicit Broadly Neutralizing Antibody Responses against Influenza Virus.
Defining and Manipulating B Cell Immunodominance Hierarchies to Elicit Broadly Neutralizing Antibody Responses against Influenza Virus.
复制标题
定义和操纵B细胞免疫优势层次结构，以广泛中和针对流感病毒的抗体反应。
DOI：
10.1016/j.cels.2020.09.005
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发表时间：
2020-12-16
期刊：
影响因子：
9.3
通讯作者：
Chakraborty AK
中科院分区：
文献类型：
--
作者：
Amitai A;Sangesland M;Barnes RM;Rohrer D;Lonberg N;Lingwood D;Chakraborty AK
抗体库具有几乎无限的多样性，使适应性免疫系统能够适应基本上任何抗原。然而，这种多样性不平等地探索了抗原空间，使一些病原体（如流感病毒）能够施加复杂的免疫优势层次结构，将抗体反应从病毒脆弱的关键部位分散开。我们开发了一个亲和力成熟的计算模型，以绘制免疫优势的模式，这些模式在用天然和工程化的血凝素（HA）（流感疫苗抗原）进行免疫接种后演变。基于这一知识，我们设计了免疫方案，颠覆免疫干扰和集中血清抗体反应的功能保守，但免疫隐性，目标的人广泛中和抗体。我们通过对转基因小鼠接种疫苗来测试计算机预测，其中抗体多样性被人源化以反映临床相关的体液输出。总的来说，我们的研究结果表明，抗体免疫原性的复杂模式可以合理地定义，然后操纵引发工程免疫。针对流感病毒的血凝素（HA）刺突蛋白的抗体天然地靶向免疫分散性特征，而不是赋予广泛中和的保守位点。Amitai等人通过计算解决了免疫优势的驱动因素，然后将这些知识应用于体内，以重新聚焦针对“通用”疫苗靶标的体液应答。
The antibody repertoire possesses near limitless diversity, enabling the adaptive immune system to accommodate essentially any antigen. However, this diversity explores the antigenic space unequally, allowing some pathogens like influenza virus to impose complex immunodominance hierarchies that distract antibody responses away from key sites of virus vulnerability. We developed a computational model of affinity maturation to map the patterns of immunodominance that evolve upon immunization with natural and engineered displays of hemagglutinin (HA), the influenza vaccine antigen. Based on this knowledge, we designed immunization protocols that subvert immune distraction and focus serum antibody responses upon a functionally conserved, but immunologically recessive, target of human broadly neutralizing antibodies. We tested in silico predictions by vaccinating transgenic mice in which antibody diversity was humanized to mirror clinically relevant humoral output. Collectively, our results demonstrate that complex patterns in antibody immunogenicity can be rationally defined and then manipulated to elicit engineered immunity. Antibodies against the hemagglutinin (HA) spike protein of influenza virus naturally target immunodistractive features rather than conserved sites that confer broad neutralization. Amitai et al. resolve drivers of immunodominance computationally and then apply this knowledge in vivo to refocus humoral responses against a ‘universal’ vaccine target.
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DOI：
10.1084/jem.20200206
发表时间：
2020-10-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cassotta A;Paparoditis P;Geiger R;Mettu RR;Landry SJ;Donati A;Benevento M;Foglierini M;Lewis DJM;Lanzavecchia A;Sallusto F
通讯作者：
Sallusto F
影响因子：
17.1
作者：
Andrews SF;Huang Y;Kaur K;Popova LI;Ho IY;Pauli NT;Henry Dunand CJ;Taylor WM;Lim S;Huang M;Qu X;Lee JH;Salgado-Ferrer M;Krammer F;Palese P;Wrammert J;Ahmed R;Wilson PC
通讯作者：
Wilson PC
影响因子：
15.3
作者：
Dosenovic, Pia;Pettersson, Anna-Klara;McGuire, Andrew T.
通讯作者：
McGuire, Andrew T.
影响因子：
2.2
作者：
Altman, Meghan O.;Angeletti, Davide;Yewdell, Jonathan W.
通讯作者：
Yewdell, Jonathan W.
影响因子：
19.7
作者：
HANLEY, JA;MCNEIL, BJ
通讯作者：
MCNEIL, BJ