Manipulating immunodominance in influenza HA

每一种流感血凝素(HA)都是由保守的毒株特异性表位拼接而成，其中一些表位是 被中和抗体识别的。优先产生中和抗体的流感疫苗 识别保守表位的人将比现在使用的表位具有更广泛的保护作用。了解如何 受试者的接触史、流感疫苗抗原的差异以及佐剂的添加使 针对不同HA表位的免疫反应将使我们能够设计出最佳的疫苗。以下三项 假说将会得到检验。(1)非复制型流感疫苗和 感染的多克隆激活程度和中和广度不同。由以下因素引起的剧目 佐剂疫苗和非佐剂疫苗不同，因为佐剂扩大了识别表位的范围。(2) 广泛反应的抗体，包括那些识别异亚型干细胞表位的抗体，在 真正的初级流感疫苗接种后，由于多个HA扩大了反应范围 刺激。(3)有效地诱导针对所需表位的抗体需要：(A)增殖 有利的生殖系抗体和(B)亲和力成熟途径，以达到所需的最终特异性。确实有 针对特定表位的抗体的首选种系前体和成熟途径。 假设1和2将通过绘制由人类受试者的曲目识别的表位来检验 有不同的流感感染接触史和/或接种佐剂或非佐剂疫苗 疫苗。我们将寻找广泛的中和抗体(那些我们想要诱导的抗体)来了解它们的种系。 前体和成熟途径。我们还将绘制结合HA的各种抗体的表位图 以确定体液免疫系统“看到”了什么。从这一映射中获得的见解将被用于 合理设计优良的HA免疫原，通过抗原迭代循环进行优化 工程学、小鼠免疫、谱系分析和抗原重新设计。抗原设计技术将会 包括选择性表位呈现、表位掩蔽和种系抗体靶向，随后是引导 亲和力成熟。这项工作揭示的抗原设计原理可以应用于保护 需要疫苗的多种病原体的决定因素。

Each influenza hemagglutinin (HA) is a mosaic of conserved and strain-specific epitopes, some of which are recognized by neutralizing antibodies. An influenza vaccine that preferentially elicits neutralizing antibodies that recognize conserved epitopes will be more broadly protective than those now in use. Understanding how the exposure history of subjects, differences in influenza vaccine antigens, and the addition of adjuvants bias the immune response towards different HA epitopes will enable us to design optimal vaccines. The following three hypotheses will be tested. (1] The B-cell repertoires elicited by non-replicating influenza vaccines and by infection differ in degree of polyclonal activation and breadth of neutralization. The repertoires elicited by adjuvanted and non-adjuvanted vaccines differ because adjuvant broadens the range of recognized epitopes. (2] Broadly reactive antibodies, including those recognizing the heterosubtypic stem epitope, are less frequent after true primary than after secondary influenza immunization due to broadening of the response by multiple HA stimulations. (3) Efficient induction of antibodies against a desired epitope requires: (a] proliferation of a favorable germline antibody and (b) an affinity maturation pathway to a desired final specificity. There are preferred germline precursors and maturation pathways for antibodies targeting particular epitopes. Hypotheses 1 and 2 will be tested by mapping the epitopes recognized by the repertoires of human subjects with different exposure histories to influenza infection and/or immunization with adjuvanted or un-adjuvanted vaccines. We will seek broadly neutralizing antibodies (those we want to elicit) to understand their germline precursors and maturation pathways. We will also map the epitopes of the full range of antibodies that bind HA to determine what the humoral immune system "sees." The insights obtained from this mapping will be used to rationally design superior HA immunogens that will be optimized through an iterative cycle of antigen engineering, mouse immunization, repertoire analysis, and antigen redesign. Antigen design techniques will include selective epitope presentation, epitope masking, and germ-line antibody targetting followed by guided affinity maturation. The principles of antigen design revealed by this work could be applied to protective determinants of multiple pathogens for which vaccines are needed.