Key messages
Pre-exposure prophylaxis of COVID-19:
– tixagevimab/cilgavimab probably reduces number of people infected with COVID-19 and development of COVID-19 symptoms, and may reduce number of people admitted to hospital;
– casirivimab/imdevimab may reduce number of people infected with COVID-19 and development of COVID-19 symptoms, and may increase number of unwanted effects (any severity) slightly.
Postexposure prophylaxis of COVID-19:
– bamlanivimab probably reduces number of people infected with COVID-19;
– casirivimab/imdevimab reduces number of people infected with COVID-19 and development of COVID-19 symptoms, and reduces number of unwanted effects (any severity).
What are 'monoclonal' antibodies?
The body makes antibodies to defend against disease. However, they may be produced in a laboratory from cells taken from people who have recovered from a disease.
Antibodies that target only one specific protein – in this case, a protein on the SARS-CoV-2 virus (that causes COVID-19) – are 'monoclonal'. They attach to the virus and stop it from entering and replicating in human cells to prevent and fight infection. They are relevant for people who do not respond or respond poorly to vaccinations.
What did we want to find out?
We wanted to know if COVID-19-specific monoclonal antibodies are effective at preventing COVID-19 in people exposed to the virus or are at high risk of being exposed to the virus. We looked at:
– confirmed COVID-19 infections;
– development of COVID-19 symptoms;
– death from any cause;
– hospital admission;
– quality of life;
– unwanted effects, such as infections and cardiac disorders;
– serious unwanted effects, such as life-threatening, hospitalisation, disability, or death.
What did we do?
We searched for studies comparing monoclonal antibodies (e.g. bamlanivimab, tixagevimab/cilgavimab, and casirivimab/imdevimab) with placebo (sham treatment), another treatment, or no treatment to prevent COVID-19 in people of any age, gender, or ethnicity.
We summarised data and rated our confidence in the evidence, based on factors such as study methods and size.
What did we find?
Four studies including 9749 people; two investigated people before being exposed to SARS-CoV-2 (pre-exposure prophylaxis) and two investigated people who were in contact with an infected person (postexposure prophylaxis). Studies were conducted before the emergence of the Omicron variant and before or during widespread vaccine roll-out. Participants were unvaccinated at baseline.
Pre-exposure prophylaxis
One study (5197 people) compared tixagevimab/cilgavimab to placebo. Participants had been exposed to wild-type, Alpha, Beta, and Delta variants.
Tixagevimab/cilgavimab:
– reduces development of symptoms;
– probably reduces number of people infected;
– may reduce number of hospital admissions;
– may have little or no effect on deaths from any cause, unwanted effects (any severity), and serious unwanted effect.
We found no data for quality of life, or mild and severe unwanted effects.
One study (969 people) compared casirivimab/imdevimab to placebo. Participants may have been exposed to wild-type, Alpha, and Delta variants.
Casirivimab/imdevimab:
– may reduce number of people infected and development of symptoms;
– resulted in no deaths;
– may increase unwanted effects (any severity) slightly;
– we are uncertain whether casirivimab/imdevimab may have an effect on severe and serious unwanted effects.
We found no data for number of people with COVID-19 within 30 days, development of symptoms within 30 days, hospital admissions within 30 days, quality of life, and mild unwanted effects.
Postexposure prophylaxis (two studies)
One study (966 people) compared bamlanivimab to placebo. Participants may have been exposed to wild-type variants.
Bamlanivimab:
– probably reduces number of people infected;
– may have little or no effect on deaths from any cause;
– may increase unwanted effects (any severity) and serious unwanted effects slightly.
We found no data for number of people who developed symptoms, hospital admissions, quality of life, mild, and severe unwanted effects.
One study (2617 people) compared casirivimab/imdevimab to placebo. Participants may have been exposed to wild-type, Alpha, and potentially, but unlikely Delta variants.
Casirivimab/ imdevimab:
– reduces number of people infected, development of symptoms, and unwanted effects (any severity);
– may slightly reduce severe unwanted effects;
– may have little or no effect on deaths, hospital admissions, and serious unwanted effects.
We found no data for quality of life and mild unwanted effects.
What are the limitations of the evidence?
One study reported each comparison. All participants were unvaccinated at the beginning of the studies, which were conducted prior to the occurrence of Omicron. Our confidence in the evidence is high to very low. Although we have high confidence in the evidence found for relevant outcomes, the findings are not transferable to vaccinated people and variants that occurred outside the study periods, such as Omicron. Although laboratory studies have shown that tixagevimab/cilgavimab is effective against Omicron, there are no data from clinical studies. The other monoclonal antibodies included in this review were ineffective against Omicron in laboratory studies.
Four ongoing studies are likely to change our conclusions and may help us understand how new variants and COVID-19 vaccines affect the effectiveness of monoclonal antibodies in preventing COVID-19.
How up to date is this evidence?
The evidence is up-to-date to 27 April 2022.
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.
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.