【Cochrane简语概要】实验室培养的COVID-19特异性单克隆抗体是治疗新冠肺炎的有效方法吗？

关键信息

- 我们只评价了6项研究，而这些研究的治疗方案和受试人群不尽相同，因此我们无法确定实验室培育出的抗体（抗体是人体用于抵御疾病的天然产物）及克隆出的 COVID-19特异性（单克隆）抗体是否为治疗COVID-19的有效方法。

- 我们找到了36项正在进行中的研究，这些研究完成后会为我们提供更多的证据。

- 待有新证据出现时，我们会定期更新本综述。

（图片来源于rotunda.ie.com）

什么是“单克隆”抗体？

抗体是人体用于抵御疾病的产物，不过也能从痊愈病人的细胞中提取、在实验室中培养。

单克隆抗体（monoclonal antibodies, mAbs）则是一种专门用来攻击特定蛋白质（在本综述中，这种特定蛋白质就是COVID-19病毒上的蛋白质）的抗体。这些抗体能附着于COVID-19表面，防止其进入人体细胞进一步复制，从而起到抗感染的作用。单克隆抗体已成功运用于其他病毒感染的治疗之中。人们认为单克隆抗体造成的不良影响比恢复期血浆要小，因为血浆中含有各种抗体。

我们想知道什么？

我们想知道COVID-19特异性单克隆抗体是否为治疗 COVID-19的有效方法。我们研究了其是否：

－减少全因死亡人数；

－使症状改善或恶化；

－提高入院率；以及

－产生任何严重不良影响或其他不良影响。

我们做了什么？

我们检索了以安慰剂治疗（假治疗）、其他治疗或无治疗为对照，研究一种或多种单克隆抗体治疗COVID-19 确诊患者效果的研究。研究的地点和对象不限，有来自世界各地的研究，包括了不同年龄阶段、不同性别或种族的轻中重症COVID-19患者。

我们比较和总结了各项研究的结果并根据研究方法和规模评价了证据质量。

我们发现了什么？

我们纳入了6项研究，共计17495名受试者。四项研究调查了无症状或轻症COVID-19非住院患者。二项研究调查了中重症COVID-19住院患者。这些研究在世界各地完成，其中3项研究得到了制药公司的资金支持。研究的单克隆抗体有 bamlanivimab、etesevimab、casirivimab、imdevimab、sotrovimab以及 regdanvimab。我们没有找到有关60日内死亡率或生活质量的数据。

无症状或轻症COVID-19非住院患者（4项研究）

一项研究（465名受试者）调查了安慰剂对照下不同剂量bamlanivimab的疗效。

我们不确信bamlanivimab是否会：

－增加或减少死亡人数，因为在治疗后30日内没有受试者死亡；

－增加或减少严重不良影响，因为几乎没有类似事件。

与安慰剂相比，bamlanivimab可能降低治疗后30日内入院率。

－产生的不良影响可能比安慰剂略少；

－我们没有找到有关症状得到改善或恶化的证据。

一项研究（1035名受试者）调查了安慰剂对照下联合使用bamlanivimab、 etesevimab的疗效。

－联合使用bamlanivimab、etesevimab可能减少死亡人数和入院人数。

－产生的不良影响可能略微更多。

－产生的严重不良影响可能更多。

我们没有找到有关单独使用bamlanivimab或联合使用 bamlanivimab、etesevimab能使症状得到改善或恶化的证据。

一项研究（临床一期／二期，799名受试者）调查了安慰剂对照下联合使用不同剂量的casirivimab、imdevimab的疗效。

－联合使用casirivimab、imdevimab可能减少入院人数和死亡人数。

－由于死亡案例过少，我们无法判断，与安慰剂相比联合使用casirivimab、imdevimab是否会产生更多的不良影响（3-4级）和严重不良影响。

－我们没有找到有关30日内死亡或出现严重症状的数据。

－由于三期临床试验纳入分析的受试者不明确，具有高偏倚风险，我们排除了该项研究的三期结果（5607名受试者）。

一项研究（583名受试者）调查了安慰剂对照下 sotrovimab的疗效。

我们不确信sotrovimab是否会：

－增加或减少死亡人数和有创机械通气治疗的需求量及致死率，由于死亡案例过少，我们无法做出准确判断。

－Sotrovimab可能减少吸氧患者人数、不良影响（3-4级）和严重不良影响。

－可能几乎没有任何程度的不良影响。

另一项研究（327名受试者）调查了安慰剂对照下不同剂量的regdanvimab（40mg/kg 和80 mg/kg）的疗效。

－任何剂量的regdanvimab都可能减少入院人数或死亡人数。

－可能增加不良反应事件（3-4级）。

－80mg/kg 剂量的regdanvimab可能减少不良影响（所有级），40mg/kg 剂量的 regdanvimab 可能几乎没有影响。

－由于死亡案例过少，我们无法判断regdanvimab是否减少死亡人数、有创机械通气治疗的需求量或严重不良影响。

中重症COVID-19住院患者（2项研究）

一项研究（314名受试者）调查了安慰剂对照下的bamlanivimab的疗效。

－由于死亡案例过少（314名受试者中，bamlanivimab组中有6例死亡，安慰剂组中有4例死亡），我们无法判断bamlanivimab是否会增加或减少30日内或90日内的全因死亡人数。

-Bamlanivimab治疗五天后，出现严重COVID-19症状和不良影响的可能性略有增加。

-在出院前，bamlanivimab对病程长短几乎没有影响。

-由于研究规模较小，几乎没有严重不良影响的报告，我们无法确信bamlanivimab是否会在30日内产生严重不良影响。

另一项研究（9785名受试者）调查了标准护理对照下联合使用casirivimab、imdevimab的疗效。

－联合使用casirivimab、imdevimab对死亡人数、有创机械通气治疗需求量和致死率以及出院率可能几乎没有影响。

－我们没有找到有关不良反应或严重不良反应的数据。

证据的局限性是什么？

我们只找到了6篇相关研究，这些研究只部分报告了我们所感兴趣的内容，还有一些结局指标，如60日内死亡人数、生活质量等，则没有报告。我们找到了36项正在进行中的研究，待其发表后，我们会将研究结果纳入到本综述中。这些研究结果很可能会改变我们的结论，帮助我们认识病毒新变体是如何影响单克隆抗体的作用效果的。

证据的时效性如何？

证据更新至2021年6月17日。

结论: 

每项用于比较的证据均基于单项研究。没有研究衡量了生活质量。我们评定非住院患者的证据质量为低质量，住院患者的证据质量为极低质量。我们认为目前的证据还不足以对mAbs中和SARS-CoV-2的疗效下定论。

为证实或反驳这些初步研究结果，为认识SARS-CoV-2 变体的出现是否会影响mAbs中和SARS-CoV-2的有效性，还需进一步的研究以及现有研究基础上更长期的数据。有36项相关研究正在进行之中，这些研究发表后，也许能确定mAbs中和SARS-CoV-2治疗COVID-19的有效性和安全性，以及这种有效性在不同病毒亚组中的差异性。

作者：Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N；译者：毛慧，北京中医药大学2018英语班医学方向；审校：李迅、徐添天，北京中医药大学循证医学中心；编辑排版：索于思、张晓雯，北京中医药大学循证医学中心

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【Cochrane Plain Language Summary】

Key messages

- We do not know whether antibodies (the body’s natural defence against disease) made in a laboratory and all the same as one another (monoclonal) and designed to target COVID-19, are an effective treatment for COVID-19 because we assessed only six studies exploring different treatments in different types of patients.

- We identified 36 ongoing studies that will provide more evidence when completed.

- We will update this review regularly as more evidence becomes available.

What are ‘monoclonal’ antibodies?

Antibodies are made by the body as a defence against disease. However, they can also be produced in a laboratory from cells taken from people who have recovered from a disease. 

Antibodies that are designed to target only one specific protein – in this case, a protein on the virus that causes COVID-19 – are ‘monoclonal’. They attach to the COVID-19 virus and stop it from entering and replicating in human cells, which helps to fight the infection. Monoclonal antibodies have been used successfully to treat other viruses. They are thought to cause fewer unwanted effects than convalescent plasma, which contains a variety of different antibodies.

What did we want to find out?

We wanted to know if COVID-19 specific monoclonal antibodies are an effective treatment for COVID-19. We looked at whether they: 

- reduced the number of deaths from any cause; 

- improved symptoms or made them worse; 

- increased admissions to hospital; and

- caused any serious or other unwanted effects.

What did we do?

We searched for studies that investigated one or more monoclonal antibodies to treat people with confirmed COVID-19 compared with placebo (sham treatment), another treatment or no treatment. Studies could take place anywhere globally and include participants of any age, gender or ethnicity, with mild, moderate or severe COVID-19. 

We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and size.

What did we find?

We found six active studies including a total of 17,495 people. Four studies investigated non-hospitalised people with no symptoms or mild COVID-19. Two studies investigated hospitalised people with moderate to severe COVID-19. Studies took place across the world. Three studies were funded by pharmaceutical companies. The monoclonal antibodies they studied were bamlanivimab, etesevimab, casirivimab and imdevimab, sotrovimab, regdanvimab. We did not identify data for mortality at 60 days and quality of life.

Non-hospitalised people, with no symptoms or mild COVID-19 (four studies)

One study investigated different doses of bamlanivimab (465 people), compared to placebo.

We don’t know whether bamlanivimab:

- increases or reduces the number of deaths because no participants died within 30 days of treatment;

- causes more or fewer serious unwanted effects because there were few events.

Bamlanivimab may reduce the number of admissions to hospital within 30 days of treatment compared to placebo.

- May cause slightly fewer unwanted effects than placebo. 

- We did not find data for improved symptoms or worsened symptoms.

One study investigated a combination of bamlanivimab and etesevimab (1035 people), compared to placebo.

- Bamlanivimab and etesevimab may reduce the number of deaths and admissions to hospital.

- May cause slightly more unwanted effects.

- May cause more serious unwanted effects.

For treatment with bamlanivimab alone or in combination with etesevimab we did not find data for improved symptoms or worsened symptoms.

One study (phase 1/2 with 799 people) investigated different doses of casirivimab combined with imdevimab, compared to placebo.

- Casirivimab combined with imdevimab may reduce the number of hospital admissions or death.

- We don't know whether casirivimab and imdevimab causes more unwanted (grades 3 and 4) and serious unwanted effects than placebo because there were too few deaths to allow us to make a judgment. 

-  We did not find data for the number of people who died at day 30 and development of severe symptoms.

- We did not include results from phase 3 (5607 people) of this study, because of high risk of bias, as it was not clear which participants were included in the analysis.

One study (583 people) investigated sotrovimab, compared to placebo.

We don't know whether sotrovimab: 

- increases or reduces the number of deaths and people requiring invasive mechanical ventilation or dying, because there were too few deaths to allow us to make a judgment.

- Sotrovimab may reduce the number of people requiring oxygen, unwanted (grades 3 to 4) and serious unwanted effects;

- may have little or no effect on unwanted effects (all grades). 

Another study (327 people) investigated different doses of regdanvimab (40 mg/kg and 80 mg/kg), compared to placebo.

- Regdanvimab at either dose may reduce the number of admissions to hospital or death.

- May increase unwanted events (grades 3 to 4).

- Regdanvimab at a dose of 80 mg/kg may reduce unwanted effects (all grades) and 40 mg/kg may have little to no effect.

- We don't know whether regdanvimab increases or decreases the number of deaths, requirement for invasive mechanical ventilation, and serious unwanted effects,  because there were too few events to allow us to make a judgment.

Hospitalised people with moderate to severe COVID-19 (2 studies)

One study (314 people) investigated bamlanivimab compared to placebo.

- We don’t know whether bamlanivimab increases or decreases the number of deaths due to any cause up to 30 or 90 days after treatment because there were too few deaths to allow us to make a judgment (6 deaths with bamlanivimab and 4 deaths with placebo in 314 people). 

- Bamlanivimab may slightly increase the development of severe COVID-19 symptoms five days after treatment and the number of people with unwanted effects.

- Bamlanivimab may have little to no effect on time until discharge from hospital.

- We don’t know whether bamlanivimab causes serious unwanted effects by day 30 because the study was small and reported few serious unwanted effects. 

Another study (9785 people) investigated casirivimab combined with imdevimab, compared to standard of care.

- Casirivimab combined with imdevimab has probably little to no effect on the number of deaths, requirement for invasive mechanical ventilation or death, and hospital discharge alive. 

-  We did not find data for unwanted and serious unwanted effects.

What are the limitations of the evidence? 

Our confidence in the evidence is low because we found only six studies, and they did not report everything we were interested in, such as the number of deaths within 60 days and quality of life. We found 36 ongoing studies. When they are published, we will add their results to our review. These results are likely to change our conclusions and will also help us understand how new variants affect how well monoclonal antibodies work. 

How up to date is this evidence? 

The evidence is up to date to 17 June 2021.

Authors' conclusions: 

The evidence for each comparison is based on single studies. None of these measured quality of life. Our certainty in the evidence for all non-hospitalised individuals is low, and for hospitalised individuals is very low to moderate. We consider the current evidence insufficient to draw meaningful conclusions regarding treatment with SARS-CoV-2-neutralising mAbs.

Further studies and long-term data from the existing studies are needed to confirm or refute these initial findings, and to understand how the emergence of SARS-CoV-2 variants may impact the effectiveness of SARS-CoV-2-neutralising mAbs. Publication of the 36 ongoing studies may resolve uncertainties about the effectiveness and safety of SARS-CoV-2-neutralising mAbs for the treatment of COVID-19 and possible subgroup differences. 

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