Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Transfusion Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
Cochrane Database Syst Rev. 2022 Jun 17;6(6):CD014945. doi: 10.1002/14651858.CD014945.pub2.
Monoclonal antibodies (mAbs) are laboratory-produced molecules derived from the B cells of an infected host. They are being investigated as potential prophylaxis to prevent coronavirus disease 2019 (COVID-19).
To assess the effects of SARS-CoV-2-neutralising mAbs, including mAb fragments, to prevent infection with SARS-CoV-2 causing COVID-19; and to maintain the currency of the evidence, using a living systematic review approach.
We searched the Cochrane COVID-19 Study Register, MEDLINE, Embase, and three other databases on 27 April 2022. We checked references, searched citations, and contacted study authors to identify additional studies.
We included randomised controlled trials (RCTs) that evaluated SARS-CoV-2-neutralising mAbs, including mAb fragments, alone or combined, versus an active comparator, placebo, or no intervention, for pre-exposure prophylaxis (PrEP) and postexposure prophylaxis (PEP) of COVID-19. We excluded studies of SARS-CoV-2-neutralising mAbs to treat COVID-19, as these are part of another review.
Two review authors independently assessed search results, extracted data, and assessed risk of bias using Cochrane RoB 2. Prioritised outcomes were infection with SARS-CoV-2, development of clinical COVID-19 symptoms, all-cause mortality, admission to hospital, quality of life, adverse events (AEs), and serious adverse events (SAEs). We rated the certainty of evidence using GRADE.
We included four RCTs of 9749 participants who were previously uninfected and unvaccinated at baseline. Median age was 42 to 76 years. Around 20% to 77.5% of participants in the PrEP studies and 35% to 100% in the PEP studies had at least one risk factor for severe COVID-19. At baseline, 72.8% to 82.2% were SARS-CoV-2 antibody seronegative. We identified four ongoing studies, and two studies awaiting classification. Pre-exposure prophylaxis Tixagevimab/cilgavimab versus placebo One study evaluated tixagevimab/cilgavimab versus placebo in participants exposed to SARS-CoV-2 wild-type, Alpha, Beta, and Delta variant. About 39.3% of participants were censored for efficacy due to unblinding and 13.8% due to vaccination. Within six months, tixagevimab/cilgavimab probably decreases infection with SARS-CoV-2 (risk ratio (RR) 0.45, 95% confidence interval (CI) 0.29 to 0.70; 4685 participants; moderate-certainty evidence), decreases development of clinical COVID-19 symptoms (RR 0.18, 95% CI 0.09 to 0.35; 5172 participants; high-certainty evidence), and may decrease admission to hospital (RR 0.03, 95% CI 0 to 0.59; 5197 participants; low-certainty evidence). Tixagevimab/cilgavimab may result in little to no difference on mortality within six months, all-grade AEs, and SAEs (low-certainty evidence). Quality of life was not reported. Casirivimab/imdevimab versus placebo One study evaluated casirivimab/imdevimab versus placebo in participants who may have been exposed to SARS-CoV-2 wild-type, Alpha, and Delta variant. About 36.5% of participants opted for SARS-CoV-2 vaccination and had a mean of 66.1 days between last dose of intervention and vaccination. Within six months, casirivimab/imdevimab may decrease infection with SARS-CoV-2 (RR 0.01, 95% CI 0 to 0.14; 825 seronegative participants; low-certainty evidence) and may decrease development of clinical COVID-19 symptoms (RR 0.02, 95% CI 0 to 0.27; 969 participants; low-certainty evidence). We are uncertain whether casirivimab/imdevimab affects mortality regardless of the SARS-CoV-2 antibody serostatus. Casirivimab/imdevimab may increase all-grade AEs slightly (RR 1.14, 95% CI 0.98 to 1.31; 969 participants; low-certainty evidence). The evidence is very uncertain about the effects on grade 3 to 4 AEs and SAEs within six months. Admission to hospital and quality of life were not reported. Postexposure prophylaxis Bamlanivimab versus placebo One study evaluated bamlanivimab versus placebo in participants who may have been exposed to SARS-CoV-2 wild-type. Bamlanivimab probably decreases infection with SARS-CoV-2 versus placebo by day 29 (RR 0.76, 95% CI 0.59 to 0.98; 966 participants; moderate-certainty evidence), may result in little to no difference on all-cause mortality by day 60 (R 0.83, 95% CI 0.25 to 2.70; 966 participants; low-certainty evidence), may increase all-grade AEs by week eight (RR 1.12, 95% CI 0.86 to 1.46; 966 participants; low-certainty evidence), and may increase slightly SAEs (RR 1.46, 95% CI 0.73 to 2.91; 966 participants; low-certainty evidence). Development of clinical COVID-19 symptoms, admission to hospital within 30 days, and quality of life were not reported. Casirivimab/imdevimab versus placebo One study evaluated casirivimab/imdevimab versus placebo in participants who may have been exposed to SARS-CoV-2 wild-type, Alpha, and potentially, but less likely to Delta variant. Within 30 days, casirivimab/imdevimab decreases infection with SARS-CoV-2 (RR 0.34, 95% CI 0.23 to 0.48; 1505 participants; high-certainty evidence), development of clinical COVID-19 symptoms (broad-term definition) (RR 0.19, 95% CI 0.10 to 0.35; 1505 participants; high-certainty evidence), may result in little to no difference on mortality (RR 3.00, 95% CI 0.12 to 73.43; 1505 participants; low-certainty evidence), and may result in little to no difference in admission to hospital. Casirivimab/imdevimab may slightly decrease grade 3 to 4 AEs (RR 0.50, 95% CI 0.24 to 1.02; 2617 participants; low-certainty evidence), decreases all-grade AEs (RR 0.70, 95% CI 0.61 to 0.80; 2617 participants; high-certainty evidence), and may result in little to no difference on SAEs in participants regardless of SARS-CoV-2 antibody serostatus. Quality of life was not reported.
AUTHORS' CONCLUSIONS: For PrEP, there is a decrease in development of clinical COVID-19 symptoms (high certainty), infection with SARS-CoV-2 (moderate certainty), and admission to hospital (low certainty) with tixagevimab/cilgavimab. There is low certainty of a decrease in infection with SARS-CoV-2, and development of clinical COVID-19 symptoms; and a higher rate for all-grade AEs with casirivimab/imdevimab. For PEP, there is moderate certainty of a decrease in infection with SARS-CoV-2 and low certainty for a higher rate for all-grade AEs with bamlanivimab. There is high certainty of a decrease in infection with SARS-CoV-2, development of clinical COVID-19 symptoms, and a higher rate for all-grade AEs with casirivimab/imdevimab. Although there is high-to-moderate certainty evidence for some outcomes, it is insufficient to draw meaningful conclusions. These findings only apply to people unvaccinated against COVID-19. They are only applicable to the variants prevailing during the study and not other variants (e.g. Omicron). In vitro, tixagevimab/cilgavimab is effective against Omicron, but there are no clinical data. Bamlanivimab and casirivimab/imdevimab are ineffective against Omicron in vitro. Further studies are needed and publication of four ongoing studies may resolve the uncertainties.
单克隆抗体（mAbs）是源自受感染宿主 B 细胞的实验室产生的分子。它们正在被研究作为预防 2019 年冠状病毒病（COVID-19）的潜在方法。
评估 SARS-CoV-2 中和 mAbs，包括 mAb 片段，用于预防感染导致 COVID-19 的 SARS-CoV-2；并使用循证医学的方法来保持证据的时效性。
我们检索了 Cochrane COVID-19 研究注册库、MEDLINE、Embase 和另外三个数据库，检索日期为 2022 年 4 月 27 日。我们检查了参考文献、引用文献，以及联系了研究作者，以确定其他研究。
我们纳入了评估 SARS-CoV-2 中和 mAbs，包括 mAb 片段，单独或联合使用，用于预防（PrEP）和暴露后预防（PEP）COVID-19 的随机对照试验（RCTs），与活性对照、安慰剂或不干预进行比较。我们排除了用于治疗 COVID-19 的 SARS-CoV-2 中和 mAbs 的研究，因为这些研究属于另一项综述。
两名综述作者独立评估了检索结果、提取数据，并使用 Cochrane RoB 2 评估了偏倚风险。优先考虑的结局是感染 SARS-CoV-2、发展为有临床症状的 COVID-19、全因死亡率、住院、生活质量、不良事件（AEs）和严重不良事件（SAEs）。我们使用 GRADE 评估证据的确定性。
我们纳入了四项共 9749 名之前未感染且未接种疫苗的参与者的 RCTs。中位年龄为 42 至 76 岁。在预防研究中，约 20%至 77.5%的参与者和预防后研究中 35%至 100%的参与者有发生严重 COVID-19 的至少一个危险因素。在基线时，72.8%至 82.2%的参与者 SARS-CoV-2 抗体阴性。我们发现了四项正在进行的研究和两项待分类的研究。替加珠单抗/西加珠单抗与安慰剂 一项研究评估了替加珠单抗/西加珠单抗与安慰剂在暴露于 SARS-CoV-2 野生型、Alpha、Beta 和 Delta 变体的参与者中的效果。由于揭盲和 13.8%因接种疫苗，约 39.3%的参与者在 6 个月内被排除在疗效分析之外。在 6 个月内，替加珠单抗/西加珠单抗可能降低感染 SARS-CoV-2 的风险（风险比（RR）0.45，95%置信区间（CI）0.29 至 0.70；4685 名参与者；中等确定性证据）、降低发展为有临床症状的 COVID-19 的风险（RR 0.18，95%CI 0.09 至 0.35；5172 名参与者；高确定性证据），并可能降低住院风险（RR 0.03，95%CI 0 至 0.59；5197 名参与者；低确定性证据）。替加珠单抗/西加珠单抗可能导致 6 个月内死亡率、全级别的 AEs 和 SAEs 无差异或差异很小（低确定性证据）。生活质量未报告。卡瑞利珠单抗/西米珠单抗与安慰剂 一项研究评估了卡瑞利珠单抗/西米珠单抗与安慰剂在可能接触过 SARS-CoV-2 野生型、Alpha 和 Delta 变体的参与者中的效果。约 36.5%的参与者选择接种 SARS-CoV-2 疫苗，并且在干预措施和接种疫苗之间的平均时间为 66.1 天。在 6 个月内，卡瑞利珠单抗/西米珠单抗可能降低感染 SARS-CoV-2 的风险（RR 0.01，95%CI 0 至 0.14；825 名 SARS-CoV-2 抗体阴性参与者；低确定性证据）和降低发展为有临床症状的 COVID-19 的风险（RR 0.02，95%CI 0 至 0.27；969 名参与者；低确定性证据）。我们不确定卡瑞利珠单抗/西米珠单抗是否会影响 SARS-CoV-2 抗体阳性或阴性参与者的死亡率。卡瑞利珠单抗/西米珠单抗可能会略微增加全级别的 AEs（RR 1.14，95%CI 0.98 至 1.31；969 名参与者；低确定性证据）。关于 6 个月内的 3 级至 4 级 AEs 和 SAEs 的影响，证据非常不确定。住院和生活质量未报告。巴姆洛单抗与安慰剂 一项研究评估了巴姆洛单抗与安慰剂在可能接触过 SARS-CoV-2 野生型的参与者中的效果。与安慰剂相比，巴姆洛单抗可能在第 29 天降低感染 SARS-CoV-2 的风险（RR 0.76，95%CI 0.59 至 0.98；966 名参与者；中等确定性证据），在第 60 天可能导致死亡率无差异（RR 0.83，95%CI 0.25 至 2.70；966 名参与者；低确定性证据），在第 8 周可能导致全级别的 AEs 增加（RR 1.12，95%CI 0.86 至 1.46；966 名参与者；低确定性证据），并可能导致 SAEs 略有增加（RR 1.46，95%CI 0.73 至 2.91；966 名参与者；低确定性证据）。发展为有临床症状的 COVID-19、30 天内住院和生活质量未报告。卡瑞利珠单抗/西米珠单抗与安慰剂 一项研究评估了卡瑞利珠单抗/西米珠单抗与安慰剂在可能接触过 SARS-CoV-2 野生型、Alpha 和可能，但不太可能接触到 Delta 变体的参与者中的效果。在 30 天内，卡瑞利珠单抗/西米珠单抗降低感染 SARS-CoV-2 的风险（RR 0.34，95%CI 0.23 至 0.48；1505 名参与者；高确定性证据）、发展为有临床症状的 COVID-19（广义定义）的风险（RR 0.19，95%CI 0.10 至 0.35；1505 名参与者；高确定性证据），可能导致死亡率无差异（RR 3.00，95%CI 0.12 至 73.43；1505 名参与者；低确定性证据），并可能导致住院无差异。卡瑞利珠单抗/西米珠单抗可能导致 3 级至 4 级 AEs 略有减少（RR 0.50，95%CI 0.24 至 1.02；2617 名参与者；低确定性证据），全级别的 AEs 减少（RR 0.70，95%CI 0.61 至 0.80；2617 名参与者；高确定性证据），并可能导致 SARS-CoV-2 抗体阳性或阴性参与者的 SAEs 无差异。生活质量未报告。
对于预防，替加珠单抗/西加珠单抗可降低发展为有临床症状的 COVID-19、感染 SARS-CoV-2 和住院的风险（高确定性证据）；卡瑞利珠单抗/西米珠单抗可能增加全级别的 AEs（低确定性证据）。对于暴露后预防，巴姆洛单抗可降低感染 SARS-CoV-2 和发展为有临床症状的 COVID-19 的风险（中等确定性证据），并可能增加全级别的 AEs（低确定性证据）。卡瑞利珠单抗/西米珠单抗可能降低感染 SARS-CoV-2、发展为有临床症状的 COVID-19 和全级别的 AEs 的风险（高确定性证据）。虽然有高到中等确定性的证据，但不足以得出有意义的结论。这些发现仅适用于未接种 COVID-19 疫苗的人群。它们仅适用于研究中流行的变体，而不适用于其他变体（如 Omicron）。在体外，替加珠单抗/西加珠单抗对 Omicron 有效，但尚无临床数据。巴姆洛单抗和卡瑞利珠单抗/西米珠单抗对 Omicron 无效。需要进一步的研究，四项正在进行的研究的发表可能会解决这些不确定性。
