《科学》：冠状病毒疫苗的新方向——刺突蛋白

资讯来源：University of Texas at Austin

编辑翻译：奇奇

译文校对：菁菁

本文献于2021年6月发表在国际顶级期刊《科学》（Science）上。文中研究人员揭示了抗体如何抵抗病毒，为设计下一代疫苗以及未来其他冠状病毒疫苗提供了新的理论。               

研究发现人体内会产生有效抵抗SARS-CoV-2的抗体，并揭示了抗体是如何中和引起感染的病毒部分，这是迄今为止最完善的一种见解。德克萨斯大学奥斯汀分校(University of Texas at Austin)的研究人员在《科学》(Science)杂志上发表了这一发现，这对于设计下一代疫苗以抵御病毒变异或未来新出现的冠状病毒来说是个好消息。

四名从SARS-CoV-2感染中康复的患者的血液样本分析表明，血液中循环的大多数抗体（平均约84％）靶向受体结合域之外的病毒刺突蛋白区域 （RBD）。图片来源：德克萨斯大学

此前研究的关注点在一组抗体上，这些抗体靶向冠状病毒刺突蛋白中最明显的部分——受体结合域(RBD)。因为RBD是刺突的一部分，它直接附着在人类细胞上，使病毒能够感染它们，因此被当作是免疫系统的主要目标。但是，研究人员对四名SARS-CoV-2感染患者的血浆样本进行检测后发现，血液中循环的大多数抗体(平均约84%)都是靶向RBD外的病毒刺突蛋白区域。

Greg Ippolito是论文合著者、德克萨斯大学奥斯汀分校分子生物科学系的研究副教授和戴尔医学院的肿瘤学助理教授。他说：“我们发现这些抗体覆盖了整个刺突，包括刺突蛋白的弧线和茎部，形状上看起来像一把伞。免疫系统会发现整个刺突，并试图中和它。”

研究人员发现，很多这种非RBD导向的抗体可以作为对抗病毒的有力武器，它们靶向刺突蛋白的一个区域，该区域位于伞状冠层上，被称为N端结构域（NTD）。这些抗体在细胞培养中中和了病毒，并被证明可以防止小鼠感染适应性致命病毒。

NTD也是经常变异的病毒刺突蛋白的一部分，尤其是在几个受关注的变异中。这表明，变异能够有效避开免疫系统的一个重要原因就是，变异发生在最常见、最有效的一种抗体上。

Jason Lavinder是麦凯塔化学工程系的研究助理，也是该项新研究的合著者。他说：“病毒和我们的免疫系统之间正在进行一场军备竞赛。我们都在开发一种针对该病毒的标准免疫反应，包括了针对病毒的适应性变化以及施加选择性压力。但是病毒随后也会试图突破我们的选择性免疫压力来发挥其进化力量。”

研究人员说，即使SARS-CoV-2遵循这些原则，但大约40%的循环抗体还是针对刺突蛋白的茎，称为S2亚基，这也是病毒似乎无法轻易改变的一部分。

Ippolito说：“这是我们的免疫系统拥有的一个优势。这也意味着我们目前的疫苗可以引出靶向S2亚基的抗体，这可能会为抵抗病毒提供另一层保护。”

这对针对变异设计疫苗增强剂或者新一代疫苗来说是个好消息，甚至对于开发一种疫苗来预防未来其他冠状病毒的大流行也是一个好消息。

Ippolito说：“这意味着我们有充分的理由开发下一代SARS-CoV-2疫苗，甚至是针对每种病毒株的泛冠状病毒疫苗。”

德克萨斯大学奥斯汀分校的研究人员是世界上致力于开发一种单一冠状病毒疫苗的研究团队之一，这种单一疫苗能够对抗所有冠状病毒的感染，不仅仅只是 SARS-CoV-2。

英语原文

Our Immune Systems Blanket the SARS-CoV-2 Spike Protein with Antibodies

The most complete picture yet is shedding light on how antibodies produced in people who effectively fight off SARS-CoV-2 work to neutralize the part of the virus responsible for causing infection. In the journal Science, researchers at The University of Texas at Austin describe the finding, which represents good news for designing the next generation of vaccines to protect against variants of the virus or future emerging coronaviruses.

Previous research focused on one group of antibodies that target the most obvious part of the coronavirus's spike protein, called the receptor-binding domain (RBD). Because the RBD is the part of the spike that attaches directly to human cells and enables the virus to infect them, it was rightly assumed to be a primary target of the immune system. But, testing blood plasma samples from four people who recovered from SARS-CoV-2 infections, the researchers found that most of the antibodies circulating in the blood—on average, about 84%—target areas of the viral spike protein outside the RBD.

"We found these antibodies are painting the entire spike, both the arc and the stalk of the spike protein, which looks a bit like an umbrella," said co-corresponding author Greg Ippolito, who is a research associate professor in UT Austin's Department of Molecular Biosciences and an assistant professor of oncology at the university's Dell Medical School. "The immune system sees the entire spike and tries to neutralize it."

Many of these non-RBD-directed antibodies the team identified act as a potent weapon against the virus by targeting a region in apart of the spike protein located in what would be the umbrella's canopy called the N-terminal domain (NTD). These antibodies neutralize the virus in cell cultures and were shown to prevent a lethal mouse-adapted version of the virus from infecting mice.

The NTD is also a part of the viral spike protein that mutates frequently, especially in several variants of concern. This suggests that one reason these variants are so effective at evading our immune systems is that they can mutate around one of the most common and potent types of antibody in our arsenals.

"There's an evolutionary arms race going on between the virus and our immune systems," said Jason Lavinder, research associate in the McKetta Department of Chemical Engineering andco-corresponding author of the new study. "We're all developing a standard immune response to this virus that includes targeting this one spot and that'sexerting selective pressure on the virus. But then the virus is also exerting its evolutionary strength by trying to change around our selective immune pressures."

Despite these maneuvers by SARS-CoV-2, the researchers said about 40% of the circulating antibodies target the stalk of the spike protein, called the S2 subunit, which is also a part that the virus does not seem able to change easily.

"That's reassuring," Ippolito said. "That's an advantage our immune system has. It also means our current vaccines are eliciting antibodies targeting that S2 subunit, which are likely providing another layer of protection against the virus."

That's also good news for designing vaccine boosters or next-generation vaccines against variants of concern, and even for developing a vaccine that can protect against future pandemics from other strains of the coronavirus.

"It means we have a strong rationale for developing next-generation SARS-CoV-2 vaccines or even a pan-coronavirus vaccine that targets every strain," Ippolito said.

UT Austin researchers are among several in the world now aiming to develop a single coronavirus vaccine to fight infection from all coronaviruses, not just SARS-CoV-2.

参考文献

"Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes," Science(2021).

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