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延迟分次接种 RTS,S/AS01 通过平衡多功能 NANP6- 和 Pf16 特异性抗体来改善疟疾的体液免疫。

Delayed fractional dosing with RTS,S/AS01 improves humoral immunity to malaria via a balance of polyfunctional NANP6- and Pf16-specific antibodies.

机构信息

Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.

出版信息

Med. 2021 Nov 12;2(11):1269-1286.e9. doi: 10.1016/j.medj.2021.10.003.

DOI:10.1016/j.medj.2021.10.003
PMID:35590199
Abstract

BACKGROUND

Malaria remains a key cause of mortality in low-income countries. RTS,S/AS01 is currently the most advanced malaria vaccine, demonstrating ∼50% efficacy in controlled human malaria infection (CHMI) studies in malaria-naive adults and ∼30%-40% efficacy in field trials in African infants and children. However, a higher vaccine efficacy is desirable.

METHODS

Modification of the vaccine regimen in a CHMI trial in malaria-naive individuals resulted in significant increase in protection. While three equal monthly RTS,S/AS01 doses (RRR) were used originally, the administration of a delayed third dose with 20% of the original antigen dose (RRr) resulted in ∼87% protection, linked to enhanced antibody affinity maturation. Here, we sought to identify a novel molecular basis for this higher protective efficacy using Systems Serology.

FINDINGS

We demonstrate that the delayed fractional dose maintains monocyte phagocytosis and NK activation mediated by NANP6-specific antibodies, key correlates of protection for the RRR regimen. However, it is also marked by a higher breadth of C-term Fc effector functions, including enhanced phagocytosis. The RRr regimen breaches immunodominance of the humoral immune response, inducing a balanced response across the C-terminal (Pf16) and NANP region of CSP, both of which were linked to protection.

CONCLUSIONS

Collectively, these data point to an unexpectedly concordant evolution in Fab avidity and expanded C-term Fc effector functions, providing novel insights into the basis for higher protection conferred by the delayed fractional dose in malaria-naive individuals.

FUNDING

This research was supported by PATH's Malaria Vaccine Initiative and the MGH Research Scholars program.

摘要

背景

疟疾仍然是低收入国家的主要死亡原因。RTS,S/AS01 是目前最先进的疟疾疫苗,在疟疾初治成年人的人体疟疾感染对照试验(CHMI)中显示出约 50%的疗效,在非洲婴儿和儿童的现场试验中显示出约 30%-40%的疗效。然而,人们希望疫苗的疗效更高。

方法

在疟疾初治个体的 CHMI 试验中改变疫苗方案导致保护作用显著增加。虽然最初使用了三剂等量的 RTS,S/AS01(RRR),但延迟给予一剂 20%原始抗原剂量的第三剂(RRr)导致约 87%的保护率,这与增强抗体亲和力成熟有关。在这里,我们使用系统血清学方法试图确定这种更高保护效力的新分子基础。

发现

我们证明,延迟的分数剂量维持了 NANP6 特异性抗体介导的单核细胞吞噬作用和 NK 激活,这是 RRR 方案的关键保护相关性。然而,它也以更高的 C 末端 Fc 效应功能的广度为标志,包括增强的吞噬作用。RRr 方案打破了体液免疫反应的优势,在 C 末端(Pf16)和 CSP 的 NANP 区域诱导了平衡的反应,这两者都与保护有关。

结论

总之,这些数据表明 Fab 亲和力和扩展的 C 末端 Fc 效应功能的出乎意料的协调进化,为延迟分数剂量在疟疾初治个体中提供更高保护的基础提供了新的见解。

资助

这项研究得到了 PATH 的疟疾疫苗倡议和 MGH 研究学者计划的支持。

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