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什么是抗體檢測?檢測結果有什么意義?

什么是抗體檢測?檢測結果有什么意義?

Sy Mukherjee 2020年05月16日
美國FDA緊急授權了12個新冠病毒抗體血液檢測項目,這種檢測對識別高危人群特別有用。

抗體是一種奇特的生物怪獸。這些Y形蛋白質的存在表明,人體免疫系統對生物入侵者作出了反應。它們能夠粘附在病毒或其他敵人的特定部位,集結力量將病原體殺死,使其失去效力。在實驗室,研究人員可以通過誘導免疫反應來制造抗體,從而創造出藥物來對抗從癌癥到新冠病毒本身在內的一切疾病。至關重要的是,在新冠病毒肆虐期間,意識到抗體的存在對于遏制疫情、探索經濟和社會的重啟之策意義重大。

新冠疫情危機引發了一系列問題,觸及到科學、流行病學和公共衛生機制的痛處。我們對病毒的傳播了解多少?哪些治療方法可能有效,哪些無效?回歸“正?!钡淖罴巡呗允鞘裁??

接受《財富》采訪的政府高官、制藥業資深人士和學術專家都表示,抗體檢測將是回答這些問題的關鍵工具。但是,就像所有與這種陰險病毒相關的事情一樣,這件事很復雜。我們需要時間分析信息,制定出適當的監管方針,以確定哪種檢測最有效,并搞清楚這些檢測究竟揭示了新冠病毒和相關免疫力的哪些性質。

抗體檢測亟需審查

任何診斷方式都面臨一個很簡單的關鍵問題:這東西真的管用嗎?但令人沮喪的是,回答這個問題的難度或許遠超你的想象。在一場流行病疫情期間,監管機構必須設法平衡在患者身上快速試驗的需求,同時還要評估其療效。

到目前為止,美國食品與藥品管理局(FDA)已經緊急授權了12個新冠病毒抗體血液檢測項目。最初采取的全權委托方式招致了醫學界的批評。一些人警告說,這可能會引來一些狗皮膏藥叫賣者,給公眾留下不準確的信息。

就像西部淘金潮再現一樣,70多家公司蜂擁而至,爭相開發實驗性的新冠病毒抗體檢測。相較于其他類型的冠狀病毒診斷方案,這種測試往往更容易進行。兩位FDA高級官員解釋說,對緊急授權的審查級別低于根據監管準則授予的“完全批準”或許可。

其他種類的冠狀病毒檢測,包括所謂的聚合酶鏈反應(PCR)技術,通常需要鼻腔或咽喉拭子(或兩者都需要),而且需要花費更長的時間。它們可能需要在專門的實驗室,非常特殊的設備上進行。這些測試可以告訴醫療專家某人是否有“急性感染”,即病毒是否在他們的系統內活躍傳播。

但抗體檢測是一種血清學測試,可以通過簡單的抽血來幫助確定某人是否曾經感染過新冠病毒。從理論上講,康復患者可以安全地返回工作崗位或者進入公共場合,而不會出現把病毒傳播給易感人群的風險。

麻煩在于,我們仍然不確定冠狀病毒抗體的存在意味著什么。這是否表示就像大多數感染SARS(這是一種不同類型的冠狀病毒)的患者那樣,擁有長達兩年的免疫期?或者是更短的免疫期?有報道稱,一些患者在首次感染后再次檢測呈陽性,但尚不清楚這是否是最初的假陽性結果所致。具體來說,哪些公司的檢測將提供最準確的信息?

“其中一大挑戰是,這是一種新病毒?!狈鹆_里達大學生物統計學助理教授、流行病學專家納塔利·迪恩說,“或許會有某種程度的免疫力,但我們不知道這種免疫力能持續多久。我們必須對患者的抗體進行長期追蹤?!?/p>

FDA高級官員指出,就抗體檢測而言,這是一個雞生蛋還是蛋生雞的難題。該機構在3月確定的初始工作重點是,提供廣泛的抗體檢測渠道。上述官員強調稱,非緊急情況下的診斷需要提交更多的數據。

本月早些時候,FDA更新了3月首次就抗體檢測發布的指導意見,以打擊做出誤導性聲明的公司,并明確其質量控制責任。

FDA 在5月發布的公開聲明寫道:“3月16日發布政策時,我司認為,相較于旨在檢測新冠病毒是否存在的分子檢測,對抗體檢測采用更高靈活性是合適的,因為它并不是用來診斷活躍的新冠病毒感染的?!痹撀暶餮a充說,超過200種抗體檢測正在走緊急使用前授權或授權流程。他們還表示,FDA正在與美國國立衛生研究院及美國疾病控制中心合作,以確定某些檢測的有效性。

在4月投放市場的許多抗體檢測,甚至還沒有獲得FDA的批準,更不用說對其準確性進行更廣泛的評估了。

最有希望的抗體檢測是什么?

作為此次美國疫情的震中城市,紐約市已經啟動了一項免費且廣泛的抗體檢測計劃,最多可能惠及14萬居民。問題在于,即使冠狀病毒抗體最終能在一段時間內帶來免疫力,但檢測無法成為讓人們重返工作崗位的可靠工具,除非采用一個基準來衡量這種測試的有效性。

在確定抗體檢測的準確性方面,有兩個關鍵指標:其一是所謂的“敏感性”,它顯示一項測試能夠多么準確地識別那些確實有抗體,并由此判斷感染過新冠病毒的人(也被稱為真實的陽性率)。其二是“特異性”,它提供的是數據的另一面,即沒有抗體的人。

羅氏診斷公司的首席醫療官艾倫·賴特說:“敏感性旨在識別那些感染過病毒的人,而特異性是發現過去或最近沒有感染的人?!痹摴韭暦Q擁有最精確的新冠病毒抗體檢測之一,已獲得緊急使用授權。

羅氏公司表示,其診斷方法擁有高達100%的敏感性和超過99.8%的特異性。其競爭對手、獲得兩項緊急授權的雅培實驗室也宣稱,它的抗體檢測擁有類似的準確性。

FDA官員和羅氏公司的賴特都強調了結合使用多種檢測手段,以及跨機構共享數據的重要性,因為這有助于真正理解免疫范圍和公眾的感染率。在過去幾個月,加州大學伯克利分校、加州大學舊金山分校和其他學術機構組建的研究團隊,一直在竭力驗證市場上測試的準確性,其結果明顯好壞參半。

“這是一系列測試的一部分?!辟囂卣f,“我們不會孤立地進行診斷?!崩?,羅氏等公司可能需要在PCR測試確定感染冠狀病毒的幾周后,才能對其抗體檢測的敏感性和特異性進行評估。

這些測試的準確性還有助于制藥商了解研發新冠藥物和疫苗的最佳方法。關于免疫力和新冠病毒抗體持久力的長期數據可能預示著,未來的新冠疫苗是一次性的(比如麻疹疫苗)還是季節性的(比如流感疫苗)。但這一過程需要更長時間才能完成。

“診斷方法有兩個部分需要獲得批準?!辟囂卣f,“一個是分析證據,或者只是一般性的數據收集。另一個是臨床證據,它可以加速藥物開發過程,并告訴我們更多關于免疫和病毒對健康系統長期影響的信息?!?/p>

這些是了解一個新病原體的基本方面?!翱贵w檢測讓我們對疾病的范圍有了更全面的了解?!鄙锝y計學家迪恩表示,“這種檢測對識別高危人群特別有用,有助于我們觀察風險最高的職業,比如人們近距離相處的工廠。但你必須從一堆來源中把這些東西拼湊起來?!保ㄘ敻恢形木W)

譯者:任文科

抗體是一種奇特的生物怪獸。這些Y形蛋白質的存在表明,人體免疫系統對生物入侵者作出了反應。它們能夠粘附在病毒或其他敵人的特定部位,集結力量將病原體殺死,使其失去效力。在實驗室,研究人員可以通過誘導免疫反應來制造抗體,從而創造出藥物來對抗從癌癥到新冠病毒本身在內的一切疾病。至關重要的是,在新冠病毒肆虐期間,意識到抗體的存在對于遏制疫情、探索經濟和社會的重啟之策意義重大。

新冠疫情危機引發了一系列問題,觸及到科學、流行病學和公共衛生機制的痛處。我們對病毒的傳播了解多少?哪些治療方法可能有效,哪些無效?回歸“正?!钡淖罴巡呗允鞘裁??

接受《財富》采訪的政府高官、制藥業資深人士和學術專家都表示,抗體檢測將是回答這些問題的關鍵工具。但是,就像所有與這種陰險病毒相關的事情一樣,這件事很復雜。我們需要時間分析信息,制定出適當的監管方針,以確定哪種檢測最有效,并搞清楚這些檢測究竟揭示了新冠病毒和相關免疫力的哪些性質。

抗體檢測亟需審查

任何診斷方式都面臨一個很簡單的關鍵問題:這東西真的管用嗎?但令人沮喪的是,回答這個問題的難度或許遠超你的想象。在一場流行病疫情期間,監管機構必須設法平衡在患者身上快速試驗的需求,同時還要評估其療效。

到目前為止,美國食品與藥品管理局(FDA)已經緊急授權了12個新冠病毒抗體血液檢測項目。最初采取的全權委托方式招致了醫學界的批評。一些人警告說,這可能會引來一些狗皮膏藥叫賣者,給公眾留下不準確的信息。

就像西部淘金潮再現一樣,70多家公司蜂擁而至,爭相開發實驗性的新冠病毒抗體檢測。相較于其他類型的冠狀病毒診斷方案,這種測試往往更容易進行。兩位FDA高級官員解釋說,對緊急授權的審查級別低于根據監管準則授予的“完全批準”或許可。

其他種類的冠狀病毒檢測,包括所謂的聚合酶鏈反應(PCR)技術,通常需要鼻腔或咽喉拭子(或兩者都需要),而且需要花費更長的時間。它們可能需要在專門的實驗室,非常特殊的設備上進行。這些測試可以告訴醫療專家某人是否有“急性感染”,即病毒是否在他們的系統內活躍傳播。

但抗體檢測是一種血清學測試,可以通過簡單的抽血來幫助確定某人是否曾經感染過新冠病毒。從理論上講,康復患者可以安全地返回工作崗位或者進入公共場合,而不會出現把病毒傳播給易感人群的風險。

麻煩在于,我們仍然不確定冠狀病毒抗體的存在意味著什么。這是否表示就像大多數感染SARS(這是一種不同類型的冠狀病毒)的患者那樣,擁有長達兩年的免疫期?或者是更短的免疫期?有報道稱,一些患者在首次感染后再次檢測呈陽性,但尚不清楚這是否是最初的假陽性結果所致。具體來說,哪些公司的檢測將提供最準確的信息?

“其中一大挑戰是,這是一種新病毒?!狈鹆_里達大學生物統計學助理教授、流行病學專家納塔利·迪恩說,“或許會有某種程度的免疫力,但我們不知道這種免疫力能持續多久。我們必須對患者的抗體進行長期追蹤?!?/p>

FDA高級官員指出,就抗體檢測而言,這是一個雞生蛋還是蛋生雞的難題。該機構在3月確定的初始工作重點是,提供廣泛的抗體檢測渠道。上述官員強調稱,非緊急情況下的診斷需要提交更多的數據。

本月早些時候,FDA更新了3月首次就抗體檢測發布的指導意見,以打擊做出誤導性聲明的公司,并明確其質量控制責任。

FDA 在5月發布的公開聲明寫道:“3月16日發布政策時,我司認為,相較于旨在檢測新冠病毒是否存在的分子檢測,對抗體檢測采用更高靈活性是合適的,因為它并不是用來診斷活躍的新冠病毒感染的?!痹撀暶餮a充說,超過200種抗體檢測正在走緊急使用前授權或授權流程。他們還表示,FDA正在與美國國立衛生研究院及美國疾病控制中心合作,以確定某些檢測的有效性。

在4月投放市場的許多抗體檢測,甚至還沒有獲得FDA的批準,更不用說對其準確性進行更廣泛的評估了。

最有希望的抗體檢測是什么?

作為此次美國疫情的震中城市,紐約市已經啟動了一項免費且廣泛的抗體檢測計劃,最多可能惠及14萬居民。問題在于,即使冠狀病毒抗體最終能在一段時間內帶來免疫力,但檢測無法成為讓人們重返工作崗位的可靠工具,除非采用一個基準來衡量這種測試的有效性。

在確定抗體檢測的準確性方面,有兩個關鍵指標:其一是所謂的“敏感性”,它顯示一項測試能夠多么準確地識別那些確實有抗體,并由此判斷感染過新冠病毒的人(也被稱為真實的陽性率)。其二是“特異性”,它提供的是數據的另一面,即沒有抗體的人。

羅氏診斷公司的首席醫療官艾倫·賴特說:“敏感性旨在識別那些感染過病毒的人,而特異性是發現過去或最近沒有感染的人?!痹摴韭暦Q擁有最精確的新冠病毒抗體檢測之一,已獲得緊急使用授權。

羅氏公司表示,其診斷方法擁有高達100%的敏感性和超過99.8%的特異性。其競爭對手、獲得兩項緊急授權的雅培實驗室也宣稱,它的抗體檢測擁有類似的準確性。

FDA官員和羅氏公司的賴特都強調了結合使用多種檢測手段,以及跨機構共享數據的重要性,因為這有助于真正理解免疫范圍和公眾的感染率。在過去幾個月,加州大學伯克利分校、加州大學舊金山分校和其他學術機構組建的研究團隊,一直在竭力驗證市場上測試的準確性,其結果明顯好壞參半。

“這是一系列測試的一部分?!辟囂卣f,“我們不會孤立地進行診斷?!崩?,羅氏等公司可能需要在PCR測試確定感染冠狀病毒的幾周后,才能對其抗體檢測的敏感性和特異性進行評估。

這些測試的準確性還有助于制藥商了解研發新冠藥物和疫苗的最佳方法。關于免疫力和新冠病毒抗體持久力的長期數據可能預示著,未來的新冠疫苗是一次性的(比如麻疹疫苗)還是季節性的(比如流感疫苗)。但這一過程需要更長時間才能完成。

“診斷方法有兩個部分需要獲得批準?!辟囂卣f,“一個是分析證據,或者只是一般性的數據收集。另一個是臨床證據,它可以加速藥物開發過程,并告訴我們更多關于免疫和病毒對健康系統長期影響的信息?!?/p>

這些是了解一個新病原體的基本方面?!翱贵w檢測讓我們對疾病的范圍有了更全面的了解?!鄙锝y計學家迪恩表示,“這種檢測對識別高危人群特別有用,有助于我們觀察風險最高的職業,比如人們近距離相處的工廠。但你必須從一堆來源中把這些東西拼湊起來?!保ㄘ敻恢形木W)

譯者:任文科

Antibodies are curious biological beasts. These Y-shaped proteins—telltale markers that indicate a body's immune system has responded to a biological intruder—can neutralize pathogens by sticking to specific sites on a virus or other adversary and marshaling the forces that can kill them off. They can be manufactured in labs by inducing immune responses in order to create medicines which fight everything from cancer to COVID-19 itself. And, critically, during the coronavirus pandemic, sensing the presence of antibodies will be essential to containing the outbreak and inform how we can reopen the economy and society at large.

The COVID-19 crisis has whipped up a storm of questions which cut to the heart of science, epidemiology, and the broad mechanisms of public health. What do we know about the virus' spread? Which treatments may or may not be effective? What's the best strategy for returning to something approaching "normal"?

Antibody testing will be a key tool for answering those questions, according to senior government officials, pharmaceutical industry veterans, and academic experts who spoke with Fortune. But, as with everything linked to this insidious scourge, it's complicated. It will take time to parse the information and develop the appropriate regulatory guidance we need to figure out which tests work best—and what, exactly, they're telling us about the nature of the coronavirus and immunity to this pathogen.

The 'Wild West' of antibody testing gets a checkup

The key question for any diagnostic is fairly straightforward: Does this thing actually work? But answering it is, frustratingly, trickier than you might think. And in the midst of a pandemic, regulators have to balance the need to rush experimental tests to patients while also gauging their efficacy.

The Food and Drug Administration (FDA) has granted emergency authorization to a dozen COVID-19 antibody blood tests to date. The initial carte blanche approach has elicited criticism from the medical community, with some warning of a "Wild West" scenario that may galvanize snake oil salesmen and leave the public with inaccurate information.

More than 70 companies have flocked to the gold rush that is developing experimental COVID-19 antibody tests, which can be conducted more easily than other types of coronavirus diagnostics. Emergency authorizations come with a lower scrutiny level than full approvals or clearances under regulatory guidelines, two senior FDA officials explained.

Other kinds of coronavirus tests, including so-called polymerase chain reaction (PCR) technology, often require a nasal or throat swab (or both) and take longer to conduct. They may require very specific equipment at specialized labs. These tests can tell medical professionals if someone has an "acute infection"—if the virus is actively circulating in their system.

But antibody tests are serological tests that can be done with a simple blood draw and help determine if someone has had a previous COVID-19 infection they've recovered from. Someone who has recovered could, theoretically, safely return to work or go out in public without risking spreading the coronavirus to more vulnerable people.

The trouble is we're still not sure just what the presence of coronavirus antibodies means. Would they suggest immunity for up to two years, as was the case with most patients who contracted SARS, a different type of coronavirus? Or might it be a shorter immunity period? There have been reports that some patients have re-tested positive after initial infection, though it's unclear whether that's due to an initial false positive result. And which companies' tests, specifically, will provide the most accurate information?

"One of the challenges is that it's a new virus," says Natalie Dean, an assistant professor of biostatistics at the University of Florida and expert in epidemiology. "What's probably going to happen is there's going to be some level of immunity, but we don't know for how long. We're going to have to do followups of patients over time for antibodies."

In the case of antibody tests, this presents a chicken-and-egg dilemma, according to the senior FDA officials. The agency's initial focus in March was on providing widespread access to antibody tests. The officials emphasized that far more data would be required for diagnostics in a non-emergency situation.

The FDA updated its initial March guidance for antibody testing earlier this month in an effort to crack down on companies making misleading claims and to clarify its quality control responsibilities.

"At the time we issued our March 16 policy, a higher level of flexibility was appropriate for antibody tests than for molecular tests that detect the presence of the virus that causes COVID-19, since antibody tests are not meant for use to diagnose active SARS-CoV-2 infection," wrote regulators in a public statement in May, adding that more than 200 antibody tests are going through the pre-emergency authorization or authorization process. They also stated that the FDA is working with the National Institutes of Health (NIH) and Centers for Disease Control (CDC) to determine how effective certain tests are.

Back in April, many of the antibody tests hitting the market hadn't even received FDA authorization, much less a wider accounting of their accuracy.

What are the most promising antibody tests?

New York City, the epicenter of the pandemic, has launched a free and widespread antibody testing effort that could reach up to 140,000 residents. The trouble is that even if coronavirus antibodies ultimately confer immunity for some time, testing can't become a reliable tool for getting people back to work unless there's a baseline of how effective such tests are.

There are two key metrics to determining the accuracy of an antibody test. The first is something called "sensitivity"—this is a measure that tells you how accurate a test is in identifying people who actually have antibodies and thus have been exposed to infection (otherwise known as the the true positive rate). The second is "specificity," which provides the flip side of the data—who doesn't have antibodies.

"Sensitivity is sensing those who have been sick, specificity is spotting the lack of past or recent infection," says Alan Wright, the chief medical officer at Roche Diagnostics, which claims to have one of the most accurate COVID-19 antibody tests cleared for emergency use.

Roche has said that its diagnostic has a staggering 100% sensitivity rate and a more than 99.8% specificity rate. Rival Abbott Laboratories has received two emergency authorizations with similar accuracy claims for its own antibody test.

FDA officials and Roche's Wright underscored the importance of using a combination of tests—and sharing data across agencies—to truly understand the scope of immunity and the infection rate across the public. In the past few months, a team of researchers from UC Berkeley, UCSF, and other academic institutes have been working to validate the accuracy of tests on the market with decidedly mixed results.

"This is part of a suite of tests," says Wright. "We don't approach diagnostics in isolation." For instance, the sensitivity and specificity of an antibody test such as Roche's may have to be done several weeks after an initial coronavirus PCR test which confirms an active infection.

The accuracy of these tests will also help inform drug makers of the best approaches to COVID-19 drug and vaccine development. Longer-term data about immunity and the staying power of COVID-19 antibodies may spell the difference between a one-time vaccine like with measles or a seasonal one such as influenza. But that process will take even longer to play out.

"There are two components to approval for a diagnostic," says Wright. "One is analytical evidence, or just general data-gathering. The other is clinical evidence that can fuel the drug development process and tell us more about immunity and the virus' long-term effects on the health system."

Those are fundamental aspects of understanding a new pathogen. "Antibody tests give us a bigger picture of the range of disease," says Dean, the biostatistician. "They're especially useful for identifying high-risk groups. [They] let us see at the highest-risk occupations such as factories where people are in close quarters. But you have to piece these things together from a bunch of different sources."

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