PDF(Pubmed)
Abstract：
The Plasmodium falciparum 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.
摘要：
恶性疟原虫环子孢子蛋白（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标定义不清。最近的发现表明，抗体介导的补体固定和激活在免疫中起重要作用。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IgG，IgM,在自然暴露于疟疾的肯尼亚成年人（n=102）中，以及对CSP不同区域的功能性补体固定抗体反应，并使用一系列兔疫苗接种研究。获得功能性补体结合抗体的个体具有较高的IgG，IgM和IgG1和IgG3对CSP。获得的补体固定抗体靶向N端，中央重复，和CSP的C端区域，与补体固定抗体阴性者相比，阳性应答者的抗体宽度更大（p<0.05）。以兔子接种疫苗为模型，我们证实CSP中央重复区和非重复区特异性IgG能有效固定补体.然而,与人的自然获得性免疫相比，用接近全长的CSP疫苗在兔子中诱导的N末端区域抗体较差。在小鼠中进行的疫苗接种研究中也观察到N-末端抗体的不良诱导。CSP的所有三个区域的IgG和IgM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。
