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。