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Non-protective immune imprint underlies failure of Staphylococcus aureus IsdB vaccine
Cell Host & Microbe ( IF 30.3 ) Pub Date : 2022-07-07 , DOI: 10.1016/j.chom.2022.06.006
Chih-Ming Tsai , J.R. Caldera , Irshad A. Hajam , Austin W.T. Chiang , Chih-Hsiung Tsai , Haining Li , María Lázaro Díez , Cesia Gonzalez , Desmond Trieu , Gislâine A. Martins , David M. Underhill , Moshe Arditi , Nathan E. Lewis , George Y. Liu

Humans frequently encounter Staphylococcus aureus (SA) throughout life. Animal studies have yielded SA candidate vaccines, yet all human SA vaccine trials have failed. One notable vaccine “failure” targeted IsdB, critical for host iron acquisition. We explored a fundamental difference between humans and laboratory animals—natural SA exposure. Recapitulating the failed phase III IsdB vaccine trial, mice previously infected with SA do not mount protective antibody responses to vaccination, unlike naive animals. Non-protective antibodies exhibit increased α2,3 sialylation that blunts opsonophagocytosis and preferentially targets a non-protective IsdB domain. IsdB vaccination of SA-infected mice recalls non-neutralizing humoral responses, further reducing vaccine efficacy through direct antibody competition. IsdB vaccine interference was overcome by immunization against the IsdB heme-binding domain. Purified human IsdB-specific antibodies also blunt IsdB passive immunization, and additional SA vaccines are susceptible to SA pre-exposure. Thus, failed anti-SA immunization trials could be explained by non-protective imprint from prior host-SA interaction.



中文翻译:

非保护性免疫印记是金黄色葡萄球菌 IsdB 疫苗失败的原因

人类一生中经常会遇到金黄色葡萄球菌(SA)。动物研究已经产生了 SA 候选疫苗,但所有人类 SA 疫苗试验都失败了。一项值得注意的疫苗“失败”针对的是 IsdB,它对于宿主铁的获取至关重要。我们探索了人类和实验动物之间的根本区别——天然 SA 暴露。回顾失败的 III 期 IsdB 疫苗试验,先前感染 SA 的小鼠不会对疫苗接种产生保护性抗体反应,这与初次感染的动物不同。非保护性抗体表现出增加的 α2,3 唾液酸化,从而减弱调理吞噬作用并优先靶向非保护性 IsdB 结构域。SA 感染小鼠的 IsdB 疫苗接种会唤起非中和体液反应,通过直接抗体竞争进一步降低疫苗功效。通过针对 IsdB 血红素结合域的免疫接种,克服了 IsdB 疫苗干扰。纯化的人 IsdB 特异性抗体也会削弱 IsdB 被动免疫,并且其他 SA 疫苗对 SA 预暴露敏感。因此,失败的抗 SA 免疫试验可以用先前宿主与 SA 相互作用的非保护性印记来解释。

更新日期:2022-07-07
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