Life Sciences, Burnet Institute, Melbourne, VIC, Australia.
Department of Immunology and Pathology, Monash University, Melbourne, VIC, Australia.
Front Immunol. 2021 Dec 1;12:775659. doi: 10.3389/fimmu.2021.775659. eCollection 2021.
The circumsporozoite protein (CSP) forms the basis of leading subunit malaria vaccine candidates. However, the mechanisms and specific targets of immunity are poorly defined. Recent findings suggest that antibody-mediated complement-fixation and activation play an important role in immunity. Here, we investigated the regions of CSP targeted by functional complement-fixing antibodies and the antibody properties associated with this activity. We quantified IgG, IgM, and functional complement-fixing antibody responses to different regions of CSP among Kenyan adults naturally exposed to malaria (n=102) and using a series of rabbit vaccination studies. Individuals who acquired functional complement-fixing antibodies had higher IgG, IgM and IgG1 and IgG3 to CSP. Acquired complement-fixing antibodies targeted the N-terminal, central-repeat, and C-terminal regions of CSP, and positive responders had greater antibody breadth compared to those who were negative for complement-fixing antibodies (p<0.05). Using rabbit vaccinations as a model, we confirmed that IgG specific to the central-repeat and non-repeat regions of CSP could effectively fix complement. However, vaccination with near full length CSP in rabbits poorly induced antibodies to the N-terminal region compared to naturally-acquired immunity in humans. Poor induction of N-terminal antibodies was also observed in a vaccination study performed in mice. IgG and IgM to all three regions of CSP play a role in mediating complement-fixation, which has important implications for malaria vaccine development.
环子孢子蛋白（CSP）是主要亚单位疟疾疫苗候选物的基础。然而，免疫的机制和特定靶点尚未明确。最近的研究结果表明，抗体介导的补体固定和激活在免疫中发挥重要作用。在这里，我们研究了功能性补体固定抗体靶向的 CSP 区域以及与该活性相关的抗体特性。我们定量了肯尼亚成年人自然感染疟疾（n=102）和一系列兔疫苗接种研究中对 CSP 不同区域的 IgG、IgM 和功能性补体固定抗体反应。获得功能性补体固定抗体的个体对 CSP 的 IgG、IgM 和 IgG1 和 IgG3 的反应更高。获得的补体固定抗体靶向 CSP 的 N 端、中央重复和 C 端区域，与补体固定抗体阴性的个体相比，阳性反应者的抗体广度更大（p<0.05）。使用兔疫苗接种作为模型，我们证实针对 CSP 的中央重复和非重复区域的 IgG 特异性可有效固定补体。然而，与人类自然获得的免疫力相比，兔中的全长 CSP 疫苗接种对 N 端区域的抗体诱导作用较差。在在小鼠中进行的疫苗接种研究中也观察到 N 端抗体的诱导作用较差。针对 CSP 的所有三个区域的 IgG 和 IgM 都在介导补体固定中发挥作用，这对疟疾疫苗的开发具有重要意义。
