Antibody Feedback Limits the Expansion of B Cell Responses to Malaria Vaccination but Drives Diversification of the Humoral Response
Antibody Feedback Limits the Expansion of B Cell Responses to Malaria Vaccination but Drives Diversification of the Humoral Response
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DOI：
10.1016/j.chom.2020.07.001
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发表时间：
2020-10-07
影响因子：
30.3
通讯作者：
Cockburn, Ian A.
中科院分区：
文献类型：
--
作者：
McNamara, Hayley A.;Idris, Azza H.;Cockburn, Ian A.
产生足够的抗体来阻断感染是疟疾疫苗的关键挑战。在这里，我们展示了针对关键靶点的抗体滴度，即恶性疟原虫环子孢子蛋白(PfCSP)的重复区域，在辐射减弱子孢子疫苗的临床试验中，该抗体在两次免疫后稳定下来。为了了解限制疫苗反应的机制，我们建立了免疫球蛋白(Ig)敲打小鼠，其PfCSP结合B细胞的数量增加。我们确定召回反应被抗体反馈抑制，可能是通过免疫优势的PfCSP重复区域的表位掩蔽。重要的是，阻止增强的抗体量低于保护所需的抗体量。最后，虽然抗体反馈限制了接种疫苗的志愿者对PfCSP重复区域的反应，但对PfCSP C末端区域的潜在保护性亚显性反应随着随后的增强而扩大。这些数据表明，抗体反馈推动了免疫反应的多样化，疟疾疫苗接种将需要靶向多种抗体。
Generating sufficient antibody to block infection is a key challenge for vaccines against malaria. Here, we show that antibody titers to a key target, the repeat region of the Plasmodium falciparum circumsporozoite protein (PfCSP), plateaued after two immunizations in a clinical trial of the radiation-attenuated sporozoite vaccine. To understand the mechanisms limiting vaccine responsiveness, we developed immunoglobulin (Ig)-knockin mice with elevated numbers of PfCSP-binding B cells. We determined that recall responses were inhibited by antibody feedback, potentially via epitope masking of the immunodominant PfCSP repeat region. Importantly, the amount of antibody that prevents boosting is below the amount of antibody required for protection. Finally, while antibody feedback limited responses to the PfCSP repeat region in vaccinated volunteers, potentially protective subdominant responses to PfCSP C-terminal regions expanded with subsequent boosts. These data suggest that antibody feedback drives the diversification of immune responses and that vaccination for malaria will require targeting multiple antigens.Y