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.

产生足够的抗体来阻止感染是疟疾疫苗的一个关键挑战。在这里，我们展示了针对关键目标的抗体滴度，即恶性疟原虫的重复区域环子孢子蛋白 (PfCSP)，在辐射减毒子孢子疫苗的临床试验中两次免疫后趋于稳定。为了了解限制疫苗反应的机制，我们开发了免疫球蛋白 (Ig) 敲入小鼠，其 PfCSP 结合 B 细胞数量增加。我们确定召回反应被抗体反馈抑制，可能是通过免疫显性 PfCSP 重复区域的表位掩蔽。重要的是，防止加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次显性反应随着随后的增强而扩大。