Long-Term Clinical Protection from Falciparum Malaria Is Strongly Associated with IgG3 Antibodies to Merozoite Surface Protein 3

BackgroundSurrogate markers of protective immunity to malaria in humans are needed to rationalize malaria vaccine discovery and development. In an effort to identify such markers, and thereby provide a clue to the complex equation malaria vaccine development is facing, we investigated the relationship between protection acquired through exposure in the field with naturally occurring immune responses (i.e., induced by the parasite) to molecules that are considered as valuable vaccine candidates. Methods and FindingsWe analyzed, under comparative conditions, the antibody responses of each of six isotypes to five leading malaria vaccine candidates in relation to protection acquired by exposure to natural challenges in 217 of the 247 inhabitants of the African village of Dielmo, Senegal (96 children and 121 older adolescents and adults). The status of susceptibility or resistance to malaria was determined by active case detection performed daily by medical doctors over 6 y from a unique follow-up study of this village. Of the 30 immune responses measured, only one, antibodies of the IgG3 isotype directed to merozoite surface protein 3 (MSP3), was strongly associated with clinical protection against malaria in all age groups, i.e., independently of age. This immunological parameter had a higher statistical significance than the sickle cell trait, the strongest factor of protection known against Plasmodium falciparum. A single determination of antibody was significantly associated with the clinical outcome over six consecutive years in children submitted to massive natural parasite challenges by mosquitoes (over three parasite inoculations per week). Finally, the target epitopes of these antibodies were found to be fully conserved. ConclusionsSince anti-MSP3 IgG3 antibodies can naturally develop along with protection against P. falciparum infection in young children, our results provide the encouraging indication that these antibodies should be possible to elicit by vaccination early in life. Since these antibodies have been found to achieve parasite killing under in vitro and in vivo conditions, and since they can be readily elicited by immunisation in na?ve volunteers, our immunoepidemiological findings support the further development of MSP3-based vaccine formulations.

研究背景：为合理指导疟疾疫苗的研发与开发，人类抗疟疾保护性免疫的替代标志物（surrogate markers）仍是亟需确立的关键工具。为识别此类标志物，进而为破解疟疾疫苗研发面临的复杂困境提供线索，本研究针对野外自然感染所获得的保护力，与天然免疫应答（即由疟原虫诱导的免疫应答）之间的关联展开了探究，其中靶标分子均为被视为极具潜力的疟疾疫苗候选抗原。

研究方法与结果：本研究在标准化对照条件下，对塞内加尔迪埃尔莫（Dielmo）非洲村落247名居民中的217人（含96名儿童、121名青少年及成人）进行了分析，检测了其针对5种主流疟疾疫苗候选抗原的6种抗体同型（isotype）应答，并关联了因野外自然感染疟原虫所获得的保护状态。依托该村落独有的6年长期随访队列，由医护人员每日开展的主动病例监测，确定了研究对象的疟疾易感性与抗性状态。在检测的30项免疫应答指标中，仅针对裂殖子表面蛋白3（merozoite surface protein 3，MSP3）的IgG3同型抗体，在所有年龄组中均与疟疾临床保护力呈显著关联，即该关联不受年龄因素影响。该免疫学指标的统计学显著性甚至高于镰状细胞性状（sickle cell trait）——后者是目前已知的抗恶性疟原虫（Plasmodium falciparum）保护性最强的宿主因素。在每周遭受至少3次蚊虫叮咬自然感染疟原虫的儿童队列中，单次抗体检测结果即可与连续6年的临床结局呈显著关联。最终研究发现，此类抗体的靶表位（epitope）完全保守。

研究结论：由于幼儿体内可自然产生抗MSP3的IgG3抗体，并伴随恶性疟原虫感染的保护性免疫力，本研究结果提示，通过早期疫苗接种即可诱导此类抗体的产生，这一发现令人备受鼓舞。鉴于此类抗体已被证实可在体外（in vitro）与体内（in vivo）环境中实现疟原虫杀伤，且可通过免疫接种在未感染过疟原虫的志愿者体内轻松诱导产生，本免疫流行病学研究结果支持基于MSP3的疫苗制剂的进一步开发。