【桑葛石原研翻译系列】疫苗抗体与自然感染抗体的相似性和潜在差

2021
06/30

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作者:Ruth Jessen Hickman,医学博士;审阅者:AnjuGoel医学博士
更新于2020年12月24日

目前,许多人对抗体感兴趣——免疫系统对感染或疫苗接种产生的蛋白质。抗体反应是一个人以前感染(或接种疫苗)感染covid-19等疾病的关键症状之一。抗体是保护一个人免受未来感染的一种信号。

什么是抗体?

抗体是存在于免疫系统重要细胞表面的蛋白质,称为B细胞。B细胞也会释放抗体,部分借助于另一种免疫细胞T细胞的帮助。

在击败初始感染中的作用

抗体在击败某些类型的感染中起着关键作用,通过各种不同的机制,与免疫系统的其他部分相协调,一些抗体可以失活并帮助消除病原体,这包括导致Covid-19的病毒(SARS-CoV-2)。然而,这需要一段时间才能奏效。如果人的免疫系统以前从未处理过特定的病毒,它就不会有病毒抗体。抗体非常精确地结合到特定病毒上的特定部位。所以人的免疫系统需要一段时间才能弄清楚是什么确切的抗体可以中和病毒(或其他类型的病原体)。这就是人在感染了一种新病毒后需要一段时间才能好转的原因之一。根据抗体类型的抗体,需要几周左右才能大量产生合适的抗体。一种被称为IgM抗体的特异性抗体类型通常是首先产生的。检测IgM抗体有时可以作为对最近感染的测试。例如,一种特定蛋白的IgM抗体通常用于检查最近感染的乙肝病毒。其他类型的抗体通常会在稍晚一点才产生。一种特别重要的类型是IgG抗体,它往往比IgM抗体更长寿。这种亚型抗体不仅对控制初始疾病至关重要,而且对预防未来的疾病,如果人将来再次暴露,也至关重要。

在预防未来的感染中所发挥的作用

感染后,某些能够识别病毒的T细胞和B细胞会在周围停留很长一段时间。如果它们再次暴露于病毒(或其他病原体),这些特殊的记忆细胞会迅速识别出病毒并开始做出反应。这有助于免疫系统更加有效。这样人就不会生病了。或者,如果人真的生病了,人通常只会得到一种非常轻微的疾病。当这种情况发生时,据说人对一种疾病有保护性免疫力。根据情况,豁免权可能会持续几个月或数年。人也可能有部分免疫力,这为人提供了一定程度的保护(如果人再次暴露和再次感染,就会开始进入免疫系统),但不是完全的保护。

新冠肺炎病毒病毒中的抗体

正是由于它在治疗感染和预防疾病中的关键作用,科学家们才对covid-19中抗体的作用非常感兴趣。作为临床试验的一部分,对一些covid-19患者提供的治疗方法之一是由从疾病中康复的患者捐赠的血浆。其想法是,血浆中含有对病毒的抗体,可以帮助个体从感染中更快地恢复。研究人员也在努力开发尖端的合成抗体疗法,这可能最终成为治疗的重要组成部分。抗体产品已经获得了FDA的紧急使用授权,这些在病程早期可能特别有用。研究抗体在covid-19中如何工作也对开发一种成功的疫苗至关重要,对抗体的知识对于评估新冠病毒感染或疫苗的免疫力如何随着时间的推移而降低很重要。由此将了解到人们什么时候可能需要注射强化疫苗来增强他们的免疫力。尽管抗体可能是诱导covid-19免疫的最重要手段,但它们可能并不是免疫系统中唯一发挥重要作用的部分,例如,某些T细胞在对某些感染的保护性免疫力中发挥了作用。随着时间的推移,这一点将变得更清晰。

中和抗体与非中和抗体

一件令人困惑的事情是,尽管抗体对消除和预防多种感染都很重要,但并不是所有身体产生的针对病毒的抗体都是有效的。体内不同的B细胞会产生多种不同的抗体,并与身体上的不同位点结合。但只有与这些位点结合才会使病毒失活。要使疫苗正常工作,它必须产生这种类型的中和抗体。

那么来自自然感染的抗体呢?

当人通过自然感染产生抗体时,人的免疫系统会通过识别病毒并最终产生有效的抗体。人的B细胞会对病毒的不同部位产生抗体,其中一些很有效,而有些则无效。这些功能可以帮助人体消除病毒和恢复,希望这些抗体也能帮助人免受未来的感染。因为导致covid-19的病毒很新,但感染covid-19似乎给了人一个相对较高的保护,防止再感染,至少在短期内是这样,全世界几乎很少有SARS-CoV-2再感染病例。这种病毒传播的太广泛,如果被感染没有提供一些保护,人们会期望更多的人二次感染。此外有研究表明,被covid-19感染的人似乎会产生有效的“中和”抗体(在实验室评估)。从使用其他病毒的经验来看,这意味着感染covid-19可能至少有一定程度的防止未来感染。对动物试验研究表明,抗体有一定程度的保护。

自然免疫力能持续多久?

免疫力持续多久是一个非常重要的问题,不同类型的病毒在感染后的保护性免疫力持续时间上有所不同。有些病毒突变得很快,当人接触到一种新的病毒株时,以前的抗体可能不起作用。对某些类型的冠状病毒的免疫性可能是短暂的,因为人们会因为某些冠状病毒而出现类似感冒的症状。但冠状病毒的突变速度不像导致流感的病毒那么快,这可能意味着Covid-19的保护性免疫力可能比流感的时间更长。对covid-19的抗体在感染后的几个月里似乎确实有所减少。然而,这种情况都发生在所有的传染病上,这并不一定意味着免疫保护正在减少,积极释放相关抗体的B细胞可能会在感染后的几个月内降低其产量,但记忆B细胞在其他类型的感染中可以继续在血液中循环多年。据推测,如果这些B细胞再次暴露于病毒中,它们可能会再次开始释放相关的抗体。在研究了一种病毒很长一段时间后,科学家们可以根据实验室标准来确定特定的免疫标准,这些标准可以通过血液测试来检查(例如,特定浓度的特定抗体)。然而,还没有为covid-19建立起来相关标准。因为病毒太新,随着时间的推移,必须看看它是什么样子。在经历了covid-19症状的三个月后,一项研究发现在大多数人身上都存在抗体。根据相关病毒的信息,一些科学家估计,对自然感染的免疫力可能会持续一到三年。但这种病毒存在的时间还不够长,科学家才能充分评估这一点。无症状、轻度或严重感染也可能会有影响。

那么接种疫苗的抗体呢?

疫苗接种是人的身体建立保护性免疫力的一种方式,而不用先生病。不同类型的疫苗也有不同的方式,但在所有情况下,免疫系统都暴露于来自病毒(或其他病原体)的一种或多个蛋白质中。这允许人的免疫系统制造B细胞,产生特定的抗体来中和特定的病毒。疫苗接种的过程允许形成记忆B细胞,就像它们在自然感染中一样。如果人曾经接触过病毒,这些B细胞会立即发挥作用,并释放出可以针对病毒的抗体。或者在某些情况下,人可能会生病,但情况要温和得多。这是因为人的免疫系统已经有了一个开端,如果没有接种疫苗,它就不会存在了。与自然感染相比,它们有很多相似之处,包括人通过疫苗接种所得到的抗体的类型和免疫反应,但有时也有一些不同。作为对活病毒的反应,IgM型抗体通常首先出现,其次是IgG和其他一些类型的抗体。就像自然感染一样,保护性免疫并不是从人接种疫苗就开始的。人的免疫系统需要几周左右的时间才能形成它所需的抗体和B细胞组。这就是为什么人不能立即从接种疫苗中得到完整的保护范围。在大多数情况下,人接种疫苗后形成的抗体就是人从自然感染中获得的相同类型的抗体。一个区别是,某些类型的疫苗只显示相关病毒的免疫系统部分。正因为如此,免疫系统并不像在自然感染过程中那样形成那么多不同类型的抗体。然而,这并不意味着形成的抗体比在天然感染中形成的抗体更有效。为了制作疫苗,研究人员非常仔细地选择临床前研究中证明的病毒的特定部分,以触发抗体有效中和病毒的反应。只是从理论上说,一个被自然感染的人可能也有额外的抗体(其中许多可能是无效的)。有时,研究人员可以利用这种理解来帮助做出诊断决策。例如,某些抗体的差异有时可以用来确定一个人是否有主动或慢性感染乙型肝炎,或他们是否已成功接种疫苗。通过自然感染获得抗体的人有一种在接种疫苗的人中找不到的特定抗体(这对发展免疫力并不重要)。大多数正在开发的covid-19疫苗只显示了病毒的免疫系统部分,这是一种被选为促进强烈免疫反应的蛋白质。因此,一个自然感染了病毒的人可能还有一些在成功接种了疫苗的人身上没有发现的其他抗体类型。

评估自然免疫与疫苗诱导免疫之间的差异

事实上,对研究人员来说,一个重要的话题是自然感染者和接种疫苗者之间的保护性免疫反应(包括抗体)方面的潜在差异。这是一个非常复杂的话题。人不能仅仅将自然感染与疫苗接种进行比较,因为并不是每种疫苗都有相同的特性,也不是每种疫苗都会触发完全相同的免疫反应。在某些情况下,一种特定的疫苗可能不能提供像被自然感染那样有效的抗体反应。但在其他时候,情况可能会相反,尤其是当一种疫苗被特别设计来引起强烈反应的时候。如果不长期研究特定的数据,就不能做出假设。

抗体的潜在风险

研究人员通常会考虑抗体在消除感染和提供保护性免疫力方面的好处。然而,在罕见的情况下,抗体的结合实际上可能会使感染更加恶化。例如,抗体可能与病毒结合,帮助病毒更容易进入细胞。这意味着一个人在最初的轻微感染后重新感染,然后可能会有更严重的疾病。或者,理论上可能意味着,如果一个人之前已经接种了疫苗,他们可能会对covid-19的潜在感染有更糟糕的反应。这种情况被称为“抗体依赖性增强”。它在登革热等病毒中被发现,登革热使成功疫苗的研制变得复杂。在一些(但不是全部)动物研究中,冠状病毒也与冠状病毒密切相关,冠状病毒会导致SARS。由于意识到这种理论上的可能性,研究人员一直在非常仔细地研究这是否可能是在covid-19中的一种可能性。然而,在covid-19中并没有发现抗体依赖性增强的迹象,这包括临床前研究和临床研究,现在已经超过10万名患者。研究人员将继续监测这种可能性,还将继续了解免疫力和抗体反应如何随时间的变化——在自然感染后和接种不同类型的covid-19疫苗之后。

【原文】


Antibodies From Vaccines vs. Antibodies From Natural Infection Similarities and Potential DifferencesBy Ruth Jessen Hickman, MDMedically reviewed by Anju Goel, MD, MPHUpdated on December 24, 2020

Currently, many people are interested in antibodies—proteins made by the immune system in response to an infection or vaccination. Antibody response is one of the key signs that a person was previously infected (or vaccinated) for a disease such as COVID-19. And sometimes, but not always, antibodies are a signal that an individual is protected from future infection.

What Are Antibodies?

Antibodies are proteins present on the surface of important cells of your immune system called B cells. B cells also release antibodies, partly with the help of another type of immune cell, T cells.

Role in Defeating Initial Infections

Antibodies play a key role in defeating certain types of infections. Through a variety of different mechanisms, in coordination with other parts of your immune system, some antibodies can inactivate and help eliminate pathogens. We think that includes the virus that causes COVID-19 (SARS-CoV-2).However, it takes a while for this to work. If your immune system has never dealt with a particular virus before, it won't have antibodies to the virus ready to go. Antibodies bind very precisely to a specific spot on a given virus. So it takes your immune system a while to figure out what exact antibody will work to neutralize a virus (or other type of pathogen).That's one of the reasons it takes you a while to get better after you are infected with a new virus. Depending on the specific type of antibody, it can take a couple of weeks or so to get the right antibodies produced in large amounts.A specific antibody type called IgM antibodies are usually the first to be produced. Detection of IgM antibodies can sometimes be used as a test for recent infection. For example, an IgM antibody to a specific protein is commonly used to check for recent infection with the hepatitis B virus.Other types of antibodies are usually produced a little later. A particularly important type is IgG antibodies, which tend to be more long-lived than IgM antibodies. This subtype of antibodies is critical not just for controlling initial disease but for preventing future disease if you are re-exposed in the future.

Role in Preventing Future Infections

After an infection, certain T cells and B cells that can recognize the virus stick around for a long time. If they are ever re-exposed to the virus (or other pathogen) again, these special memory cells recognize it quickly and start to respond.This helps the immune system be effective much more quickly. This way, you don't get sick. Or, if you do get sick, you usually only get a very mild version of an illness.When this happens, you are said to have protective immunity to a disease. Depending on the situation, immunity might last for months or years. You might also have partial immunity which offers you some degree of protection, (and a head start to the immune system if you get re-exposed and reinfected) but not total protection.

Antibodies in COVID-19

It's because of this key role in both treating infection and preventing disease that scientists have been so interested in the role of antibodies in COVID-19.One of the treatments being given to some COVID-19 patients as a part of clinical trials is the plasma donated from people who have recovered from the illness. The idea is that that plasma contains antibodies to the virus that might help individuals recover more quickly from infection.Researchers are also hard at work developing cutting-edge synthetic antibody therapies that might end up being an important part of treatment. Antibody products have already received Emergency Use Authorization by the FDA.5 These might be especially helpful early in the disease course.Studying how antibodies work in COVID-19 has also been critical for developing a successful vaccine. Knowledge about antibodies will be important for assessing how immunity to COVID-19—either from infection or from a vaccine—might decrease over time. From this we will learn when people might need booster vaccine shots to re-up their immunity.Even though antibodies are probably the most important means of inducing immunity in COVID-19, they may not be the only part of the immune system with an important role. For example, certain T cells play a role in protective immunity for some infections.6 This will become clearer with time.

Neutralizing vs. Non-Neutralizing Antibodies

One confusing thing is that even though antibodies are important for eliminating and preventing many kinds of infections, not all antibodies the body produces against a virus are effective.Different B cells in the body will produce multiple different antibodies that bind to different sites on the body. But only binding to some of these sites will actually inactivate the virus. For a vaccine to work, it must produce this type of neutralizing antibodies.

What About Antibodies From Natural Infection?

When you develop antibodies through natural infection, your immune system goes through this process of identifying the virus and eventually making effective antibodies. Your B cells make antibodies to different parts of the virus, some of which are effective and some of which are not. These help you eliminate the virus and recover.Hopefully, some of these antibodies also help protect you from future infection. Because the virus that causes COVID-19 is so new, there is still a lot that we don't know about it. But it seems like infection with COVID-19 gives you a relatively high degree of protection from being re-infected, at least in the short term.Very few cases of reinfection with SARS-CoV-2 have been documented worldwide. Because the virus is so widespread, if getting infected didn't give at least some protection, you'd expect many more people to have gotten the virus twice.Also, studies have indicated that people with symptoms of COVID-19 seem to produce antibodies—effective, “neutralizing” antibodies (as assessed in a lab). From our experience with other viruses, we think that that means that getting infected with COVID-19 probably leads to at least some level of protection against future infection.Additionally, studies in animals suggest at least some level of protective immunity, with at least some of this coming from antibody protection.

How Long Might Natural Immunity Last?

How long that immunity lasts is a very important question. Different types of viruses differ in how long protective immunity lasts after infection.Some viruses mutate rather quickly; when you are exposed to a new strain of the virus, your previous antibodies might not work. Immunity to some types of coronavirus may be short-lived, as people can get cold-like symptoms from certain coronaviruses season after season.But coronaviruses don't mutate as rapidly as viruses like influenza, which cause the flu. This might mean that protective immunity might last longer for COVID-19 than it does for something like the flu.Antibodies to COVID-19 do seem to decrease in the months after infection. However, that happens for all infectious diseases. It doesn't necessarily mean that immune protection is decreasing.The B cells actively releasing the relevant antibody may decrease their production in the months after an infection. But memory B cells can continue to circulate in the bloodstream for years in other types of infections. Presumably, these B cells could again start releasing the relevant antibody if they were again exposed to the virus.After they have studied a virus for a long time, scientists can establish certain standards for whether a person is immune based on laboratory standards that can be checked with a blood test (e.g., a certain concentration of a specific antibody). However, this hasn't been established for COVID-19 yet.Because the virus is so new, we'll have to see what it looks like over time. Three months after experiencing symptoms from COVID-19, one study found antibodies in the majority of people.Based on information from related viruses, some scientists estimate that immunity from natural infection might last one to three years.11 But the virus hasn't been around long enough for scientists to fully assess this. It might also make a difference whether one had an asymptomatic, mild, or a severe infection.

What About Antibodies From Vaccination?

Vaccination is a way for your body to build protective immunity without having to get sick first. Different types of vaccines do this in different ways. But in all cases, the immune system is exposed to one or more proteins from the virus (or other pathogen). That allows your immune system to make B cells that make specific antibodies that can neutralize that specific virus.The process of vaccination allows the formation of the memory B cells, just like they do in natural infection. If you are ever exposed to the virus, these B cells go into action right away and release antibodies that can target the virus. They inactivate the virus before you get sick. Or, in some cases, you might get sick but with a much milder case.That's because your immune system already has a head start, one it wouldn't have had if you hadn't been vaccinated.There are a lot of similarities but also sometimes some differences in the type of antibody and immune response you get from vaccination compared to a natural infection. As in response to a live virus, IgM type antibodies usually come first, followed by IgG and some other types of antibodies.And just like in a natural infection, protective immunity doesn't begin the moment you get vaccinated. It takes a couple of weeks or so for your immune system to form the antibodies and groups of B cells that it needs. That's why you don't get full protective coverage from a vaccination right away.For the most part, the antibodies that you form from getting vaccinated are the same kind of antibodies you would get from a natural infection. One difference is that certain types of vaccines only show the immune system part of the relevant virus. Because of that, the immune system doesn't form as many different types of antibodies as it would in the course of a natural infection.However, this doesn't mean that the antibodies formed are any less effective than those formed in a natural infection. To make a vaccine, researchers very carefully select a specific part of the virus that has been demonstrated in pre-clinical studies to trigger an antibody response that effectively neutralizes the virus. It's just that theoretically, someone who has been naturally infected might also have additional antibodies (many of which might be ineffective).Sometimes researchers can use this understanding to help make diagnostic decisions. For example, differences in certain antibodies can sometimes be used to determine if a person has an active or chronic infection with hepatitis B or if they have been successfully vaccinated. People who got the antibodies through natural infection have a specific antibody not found in people who got vaccinated (one not important for developing immunity).Most of the vaccines under development for COVID-19 only show the immune system part of the virus, a protein chosen to prime a strong immune response. (This includes the Pfizer mRNA vaccine.) So, someone who had naturally been infected with the virus might have some additional antibody types not found in someone who had been successfully vaccinated.COVID-19 Vaccines: Stay up to date on which vaccines are available, who can get them, and how safe they are.

Assessing Differences in Natural vs. Vaccine-Induced Immunity

In fact, an important topic for researchers are these potential differences in the protective immune response (including antibodies) between people who got an infection naturally and people who got a vaccine.It is a very complex topic. You can't just compare natural infection to vaccination, because not every vaccine has the same properties, and not every vaccine will trigger exactly the same immune response.In some cases, a specific vaccine might not provide as effective of an antibody response as being naturally infected. But other times, the reverse might be the case, especially if a vaccine has been especially designed to provoke a strong response. We can't make assumptions without studying the specific data over the long-term.

Potential Risks of Antibodies

We usually think about the benefits of antibodies in terms of eliminating infections and providing protective immunity. However, in rare circumstances, binding of an antibody might actually worsen an infection. For example, antibodies might bind to a virus in such a way that help it enter cells more easily.This might mean that a person re-infected after an initial mild infection might then have more severe disease. Or, it theoretically might mean that a person could have a worse response to a potential infection with COVID-19 if they have previously been vaccinated for the disease.This scenario has been called “antibody dependent enhancement.”It has been found in viruses such as dengue, in which it complicated the creation of successful vaccines. In some (but not all) animal studies, it has also been observed in a coronavirus closely related to the one that causes COVID-19—the virus that causes SARS.Because they were aware of this theoretical possibility, researchers have been looking very carefully to see whether this might be a possibility in COVID-19. However, no signs of antibody dependent enhancement have been found in COVID-19.This includes pre-clinical studies and clinical studies that have now included well over 100,000 patients. This has been very reassuring to researchers, but they will continue to monitor for this possibility.This includes the Pfizer mRNA vaccine for COVID-19, the only vaccine as of mid-December 2020 that has been released under an Emergency Use Authorization by the FDA. Researchers will continue to monitor the effects of this vaccine and the others under development. With time, we'll get more data that will hopefully definitively quash this theoretical concern.We'll also continue to learn how immunity and the antibody response changes over time—both after natural infection and after vaccination with different types of COVID-19 vaccines. 

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关键词:
免疫系统,免疫力,抗体,疫苗,感染,细胞

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