Center for Human Systems Immunology, Duke University, Durham, NC, USA.
Department of Immunology, Duke University, Durham, NC, USA.
Sci Immunol. 2021 Oct 29;6(64):eabj1181. doi: 10.1126/sciimmunol.abj1181.
Vaccine development to prevent Typhi infections has accelerated over the past decade, resulting in licensure of new vaccines, which use the Vi polysaccharide (Vi PS) of the bacterium conjugated to an unrelated carrier protein as the active component. Antibodies elicited by these vaccines are important for mediating protection against typhoid fever. However, the characteristics of protective and functional Vi antibodies are unknown. In this study, we investigated the human antibody repertoire, avidity maturation, epitope specificity, and function after immunization with a single dose of Vi-tetanus toxoid conjugate vaccine (Vi-TT) and after a booster with plain Vi PS (Vi-PS). The Vi-TT prime induced an IgG1-dominant response, whereas the Vi-TT prime followed by the Vi-PS boost induced IgG1 and IgG2 antibody production. B cells from recipients who received both prime and boost showed evidence of convergence, with shared V gene usage and CDR3 characteristics. The detected Vi antibodies showed heterogeneous avidity ranging from 10 μM to 500 pM, with no evidence of affinity maturation after the boost. Vi-specific antibodies mediated Fc effector functions, which correlated with antibody dissociation kinetics but not with association kinetics. We identified antibodies induced by prime and boost vaccines that recognized subdominant epitopes, indicated by binding to the de–-acetylated Vi backbone. These antibodies also mediated Fc-dependent functions, such as complement deposition and monocyte phagocytosis. Defining strategies on how to broaden epitope targeting for Typhi Vi and enriching for antibody Fc functions that protect against typhoid fever will advance the design of high-efficacy Vi vaccines for protection across diverse populations.
在过去的十年中，预防伤寒感染的疫苗研发进展迅速，导致新疫苗获得许可，这些疫苗将细菌的 Vi 多糖（Vi PS）与无关的载体蛋白缀合作为活性成分。这些疫苗引起的抗体对于介导伤寒热的保护至关重要。然而，保护性和功能性 Vi 抗体的特征尚不清楚。在这项研究中，我们研究了人类抗体库、亲和力成熟、表位特异性和接种单价 Vi-破伤风类毒素结合疫苗（Vi-TT）和加强剂量单价 Vi 多糖（Vi-PS）后的功能。Vi-TT 初免诱导 IgG1 优势反应，而 Vi-TT 初免后加强剂量 Vi-PS 诱导 IgG1 和 IgG2 抗体产生。接受初免和加强剂量的受者的 B 细胞显示出收敛的证据，具有共享的 V 基因使用和 CDR3 特征。检测到的 Vi 抗体表现出从 10 μM 到 500 pM 的异质亲和力，加强剂量后没有亲和力成熟的证据。Vi 特异性抗体介导 Fc 效应功能，与抗体解离动力学相关，但与结合动力学无关。我们鉴定了由初免和加强疫苗诱导的识别亚显性表位的抗体，这表明与去乙酰化的 Vi 骨架结合。这些抗体还介导 Fc 依赖性功能，如补体沉积和单核细胞吞噬作用。确定如何拓宽针对伤寒 Vi 的表位靶向并丰富针对伤寒热的抗体 Fc 功能的策略将推进针对不同人群的高效 Vi 疫苗的设计。
