Manipulating immunodominance in influenza HA

每个流感血凝素（HA）是一个保守的和菌株特异性表位的马赛克，其中一些被中和抗体识别。一种优先诱导识别保守表位的中和抗体的流感疫苗将比目前使用的疫苗具有更广泛的保护作用。了解受试者的暴露史、流感疫苗抗原的差异以及佐剂的添加如何使免疫反应偏向于不同的HA表位，将使我们能够设计出最佳的疫苗。以下三个假设将被检验。(1)非复制型流感疫苗和感染诱导的b细胞库在多克隆激活程度和中和广度上存在差异。引起的演奏

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