Kenya Medical Research Institute, Centre for Geographic Medicine, Coast, Kilifi, Kenya.
PLoS One. 2013 Jul 5;8(7):e68304. doi: 10.1371/journal.pone.0068304. Print 2013.
Antibodies to P. falciparum apical membrane protein 1 (AMA1) may contribute to protective immunity against clinical malaria by inhibiting blood stage growth of P. falciparum, and AMA1 is a leading malaria vaccine candidate. Currently, there is limited knowledge of the acquisition of strain-specific and cross-reactive antibodies to AMA1 in humans, or the acquisition of invasion-inhibitory antibodies to AMA1.
METHODOLOGY/FINDINGS: We examined the acquisition of human antibodies to specific polymorphic invasion-inhibitory and non-inhibitory AMA1 epitopes, defined by the monoclonal antibodies 1F9 and 2C5, respectively. Naturally acquired antibodies were measured in cohorts of Kenyan children and adults. Antibodies to the invasion-inhibitory 1F9 epitope and non-inhibitory 2C5 epitope were measured indirectly by competition ELISA. Antibodies to the 1F9 and 2C5 epitopes were acquired by children and correlated with exposure, and higher antibody levels and prevalence were observed with increasing age and with active P. falciparum infection. Of note, the prevalence of antibodies to the inhibitory 1F9 epitope was lower than antibodies to AMA1 or the 2C5 epitope. Antibodies to AMA1 ectodomain, the 1F9 or 2C5 epitopes, or a combination of responses, showed some association with protection from P. falciparum malaria in a prospective longitudinal study. Furthermore, antibodies to the invasion-inhibitory 1F9 epitope were positively correlated with parasite growth-inhibitory activity of serum antibodies.
CONCLUSIONS/SIGNIFICANCE: Individuals acquire antibodies to functional, polymorphic epitopes of AMA1 that may contribute to protective immunity, and these findings have implications for AMA1 vaccine development. Measuring antibodies to the 1F9 epitope by competition ELISA may be a valuable approach to assessing human antibodies with invasion-inhibitory activity in studies of acquired immunity and vaccine trials of AMA1.
恶性疟原虫顶膜蛋白 1（AMA1）的抗体可能通过抑制疟原虫血期的生长来促进对临床疟疾的保护性免疫，并且 AMA1 是一种主要的疟疾疫苗候选物。目前，人们对人类获得针对 AMA1 的特异性和交叉反应性抗体的情况，或者对获得针对 AMA1 的入侵抑制性抗体的情况了解有限。
方法/发现：我们研究了肯尼亚儿童和成人队列中自然获得的针对特定多态性入侵抑制性和非抑制性 AMA1 表位的人类抗体的获得情况，这些表位分别由单克隆抗体 1F9 和 2C5 定义。通过竞争 ELISA 间接测量了针对入侵抑制性 1F9 表位和非抑制性 2C5 表位的抗体。儿童获得了针对 1F9 和 2C5 表位的抗体，且与暴露相关，并且随着年龄的增长和恶性疟原虫的感染，抗体水平和患病率均升高。值得注意的是，针对抑制性 1F9 表位的抗体的患病率低于针对 AMA1 或 2C5 表位的抗体的患病率。针对 AMA1 外显子、1F9 或 2C5 表位或组合应答的抗体在一项前瞻性纵向研究中显示出与预防恶性疟原虫疟疾有一定的相关性。此外，针对入侵抑制性 1F9 表位的抗体与血清抗体的寄生虫生长抑制活性呈正相关。
结论/意义：个体获得针对 AMA1 的功能性、多态性表位的抗体，这些抗体可能有助于保护性免疫，这些发现对 AMA1 疫苗的开发具有意义。通过竞争 ELISA 测量针对 1F9 表位的抗体可能是评估获得性免疫和 AMA1 疫苗试验中具有入侵抑制活性的人类抗体的一种有价值的方法。
