Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden.
Department of Parasites and Insect Vectors, Institut Pasteur, 25-28 Rue du Dr Roux, 75015, Paris, France.
BMC Med. 2019 Jan 30;17(1):22. doi: 10.1186/s12916-019-1255-3.
Antibodies against merozoite antigens are key components of malaria immunity. The naturally acquired antibody response to these antigens is generally considered short-lived; however, the underlying mechanisms remain unclear. Prospective studies of travellers with different levels of prior exposure, returning to malaria-free countries with Plasmodium infection, offer a unique opportunity to investigate the kinetics and composition of the antibody response after natural infection.
Adults diagnosed with P. falciparum malaria in Stockholm, Sweden (20 likely malaria naïve and 41 with repeated previous exposure during residency in sub-Saharan Africa) were sampled at diagnosis and 10 days and 1, 3, 6, and 12 months after treatment. Total and subclass-specific IgG responses to P. falciparum merozoite antigens (AMA-1, MSP-1, MSP-2, MSP-3, and RH5) and tetanus toxoid were measured by multiplex bead-based immunoassays and ELISA. Mathematical modelling was used to estimate the exposure-dependent longevity of antibodies and antibody-secreting cells (ASCs).
A majority of individuals mounted detectable antibody responses towards P. falciparum merozoite antigens at diagnosis; however, the magnitude and breadth were greater in individuals with prior exposure. In both exposure groups, antibody levels increased rapidly for 2 weeks and decayed thereafter. Previously exposed individuals maintained two- to ninefold greater antibody levels throughout the 1-year follow-up. The half-lives of malaria-specific long-lived ASCs, responsible for maintaining circulating antibodies, ranged from 1.8 to 3.7 years for merozoite antigens and were considerably short compared to tetanus-specific ASCs. Primary infected individuals did acquire a long-lived component of the antibody response; however, the total proportion of long-lived ASCs generated in response to infection was estimated not to exceed 10%. In contrast, previously exposed individuals maintained substantially larger numbers of long-lived ASCs (10-56% of total ASCs).
The short-lived nature of the naturally acquired antibody response, to all tested merozoite antigens, following primary malaria infection can be attributed to a combination of a poor acquisition and short half-life of long-lived ASCs. Greater longevity is acquired with repeated infections and can be explained by the maintenance of larger numbers of long-lived ASCs. These insights advance our understanding of naturally acquired malaria immunity and will guide strategies for further development of both vaccines and serological tools to monitor exposure.
针对裂殖子抗原的抗体是疟疾免疫的关键组成部分。针对这些抗原的自然获得性抗体反应通常被认为是短暂的；然而，其潜在机制尚不清楚。具有不同先前暴露水平的旅行者返回无疟疾国家并感染疟原虫，为研究自然感染后抗体反应的动力学和组成提供了独特的机会。
在瑞典斯德哥尔摩诊断出患有恶性疟原虫疟疾的成年人（20 名可能为疟疾初发者和 41 名在撒哈拉以南非洲居住期间有重复先前暴露史者）在诊断时以及治疗后 10 天和 1、3、6 和 12 个月时进行采样。采用基于微珠的多重免疫分析和 ELISA 测定针对恶性疟原虫裂殖子抗原（AMA-1、MSP-1、MSP-2、MSP-3 和 RH5）和破伤风类毒素的总 IgG 和亚类特异性 IgG 反应。数学模型用于估计与暴露相关的抗体和抗体分泌细胞（ASC）的寿命。
大多数个体在诊断时对恶性疟原虫裂殖子抗原产生了可检测的抗体反应；然而，先前暴露的个体的幅度和广度更大。在两个暴露组中，抗体水平在 2 周内迅速增加，此后下降。先前暴露的个体在整个 1 年的随访期间保持了 2 至 9 倍的更高抗体水平。负责维持循环抗体的疟疾特异性长寿命 ASC 的半衰期范围为裂殖子抗原的 1.8 至 3.7 年，与破伤风特异性 ASC 相比相当短。初次感染的个体确实获得了抗体反应的长寿命成分；然而，据估计，感染引起的长寿命 ASC 的总比例不会超过 10%。相比之下，先前暴露的个体维持了大量的长寿命 ASC（总 ASC 的 10-56%）。
初次感染后，所有测试的裂殖子抗原的自然获得性抗体反应的短暂性质可归因于长寿命 ASC 的获得和半衰期短的组合。随着重复感染，获得了更长的寿命，这可以通过维持大量长寿命 ASC 来解释。这些见解增进了我们对自然获得性疟疾免疫的理解，并将指导进一步开发疫苗和血清学工具以监测暴露的策略。
