Passive immune therapy consists of several different therapies, convalescent plasma, hyperimmune globulin, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing monoclonal antibodies. Although these treatments were not part of any pandemic planning prior to coronavirus disease 2019 (COVID-19), due to the absence of high-quality evidence demonstrating benefit in other severe respiratory infections, a large amount of research has now been performed to demonstrate their benefit or lack of benefit in different patient groups. This review summarizes the evidence up to July 2021 on their use and also when they should not be used or when additional data are required. Vaccination against SARS-CoV-2 is the most important method of preventing severe and fatal COVID-19 in people who have an intact immune system. Passive immune therapy should only be considered for patients at high risk of severe or fatal COVID-19. The only therapy that has received full regulatory approval is the casirivimab/imdevimab monoclonal cocktail; all other treatments are being used under emergency use authorizations. In Japan, it has been licensed to treat patients with mild to moderate COVID-19, and in the United Kingdom, it has also been licensed to prevent infection.

Learning Objectives

• Summarize current evidence on the use of passive immune therapy to prevent infection—whether it reduces risk of death or hospitalization

• Summarize current evidence on the use of passive immune therapy for high-risk patients who have mild COVID-19 symptoms—risk of death

• Can state whether passive immune therapy reduces all-cause mortality for hospitalized patients and whether any subgroups will benefit

A 74-year-old man (case) had a test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after a family gathering for the christening of his granddaughter. He had had the test because he was a close contact for the index case at the christening. His 49-year-old nephew (index case) had been admitted to hospital the day after the christening and was found to be SARS-CoV-2 positive. The nephew had had some symptoms at the time of the christening but had not thought that these were due to coronavirus disease 2019 (COVID-19). The 74-year-old man self-isolated with his wife while awaiting the results of the test.

Passive antibody therapy is one of the oldest treatments for infectious diseases that is still in use. Emil von Behring (1854-1917) was awarded the first Nobel Prize in Medicine “for his work on serum therapy, especially its application against diphtheria.”1  Today, passive antibody therapy involves treatment with polyclonal antibodies derived from humans (convalescent plasma [CP] or hyperimmune globulin), animals (antisera), or antigen-specific monoclonal antibodies (mAbs).2  In this review, I focus on CP and neutralizing mAbs and the current evidence for their use. There are no published trials on the use of hyperimmune globulin in COVID-19.3

CP after infection, particularly after severe illness, may contain high levels of polyclonal pathogen-specific antibodies. These antibodies may confer passive immunity to recipients and in viral diseases are thought to have their main action via neutralization of viral particles.4  Collection and transfusion of CP can occur rapidly after the onset of a pandemic, with collection of plasma occurring from 14 days after a patient has recovered from the infection. The antibody response in CP donors adapts with the virus, either due to donors becoming infected with new variants of the virus or due to vaccination after an initial natural infection. However, the levels of neutralizing antibody can vary significantly from 1 unit to the next, and a minimum threshold of antibody is required within each unit to ensure that the transfusion contains a sufficient level of neutralizing antibody (Table 1).

Table 1.

Comparison between different passive antibody therapies

CharacteristicCPHuman hyperimmune globulinmAb
Speed of production after start of pandemic Rapid—weeks
Can be produced once patients have recovered from infection (14 to 28 days after recovery)
Slow—months
Needs time to collect plasma from a large number of people who have recovered from infection
Slowest—months
Need to identify potential antibodies that would be useful to develop as a mAb and then manufacture antibody
Can adapt to viral variants Yes Yes—more slowly than CP No
Number of anti–SARS-CoV-2 antibodies product contains Many—polyclonal Many—polyclonal One to 2 antibodies
Amount of antibody contained within the product Very variable. Variability can be reduced by using mini-pools—used in Argentina but not all countries allowed to produce mini-pools Fixed amount of total antibody Fixed amount of neutralizing SARS-CoV-2 neutralizing antibody
Route of administration Intravenous Subcutaneous, intramuscular, or intravenous Subcutaneous, intramuscular, or intravenous
Derived from blood* Yes Yes No
Availability Able to be produced in any country in which people have recovered from the infection and are able to produce plasma Not able to be produced in every country but manufacturing requirements are not complex Limited supply due to complex manufacturing requirements
Cost Relatively cheap—$100 to$200 per dose
Can be used in low- and middle-income countries
More expensive than CP but cheaper than mAb—may be able to be produced locally, in low- and middle-income countries Expensive—$1000s per dose Cannot be afforded by low- and middle-income countries Can only be produced at a limited number of manufacturing sites CharacteristicCPHuman hyperimmune globulinmAb Speed of production after start of pandemic Rapid—weeks Can be produced once patients have recovered from infection (14 to 28 days after recovery) Slow—months Needs time to collect plasma from a large number of people who have recovered from infection Slowest—months Need to identify potential antibodies that would be useful to develop as a mAb and then manufacture antibody Can adapt to viral variants Yes Yes—more slowly than CP No Number of anti–SARS-CoV-2 antibodies product contains Many—polyclonal Many—polyclonal One to 2 antibodies Amount of antibody contained within the product Very variable. Variability can be reduced by using mini-pools—used in Argentina but not all countries allowed to produce mini-pools Fixed amount of total antibody Fixed amount of neutralizing SARS-CoV-2 neutralizing antibody Route of administration Intravenous Subcutaneous, intramuscular, or intravenous Subcutaneous, intramuscular, or intravenous Derived from blood* Yes Yes No Availability Able to be produced in any country in which people have recovered from the infection and are able to produce plasma Not able to be produced in every country but manufacturing requirements are not complex Limited supply due to complex manufacturing requirements Cost Relatively cheap—$100 to $200 per dose Can be used in low- and middle-income countries More expensive than CP but cheaper than mAb—may be able to be produced locally, in low- and middle-income countries Expensive—$1000s per dose
Cannot be afforded by low- and middle-income countries
Can only be produced at a limited number of manufacturing sites
*

Any product derived from human blood requires viral testing to ensure that the transfused product does not cause a transfusion-transmitted infection. In high-income countries with good screening systems, transfusion-transmitted infection is very rare. In the United Kingdom, there were no transfusion-transmitted infections reported to the national hemovigilance system in 2020 (https://www.shotuk.org/wp-content/uploads/myimages/TTI-Supplementary-material-2020.pdf).

Hyperimmune globulin is currently used to protect vulnerable individuals from other viral infections, including varicella zoster.5  It is produced by pooling thousands of donations from people who have recovered from an infection or have been vaccinated against an infection and have high levels of antibodies. It produces a consistent product that always has a defined level of antibody within it. However, it takes time to produce, so it cannot be used as early in a pandemic. It will also evolve with changes with the viral variant but not as rapidly as CP.

Neutralizing monoclonal antibody therapy can be derived from humans who have had an infection, or been vaccinated, or from humanized mice that have been exposed to SARS-CoV-2 antigens.2  Monoclonal antibody production can identify antibodies with a high level of neutralizing activity and can be produced without the need for blood donors. mAbs will, however, not adapt to viral variants, and so over time, the virus can become resistant to the monoclonal antibody. This has already happened with the SARS-CoV-2 virus (Table 2). Monotherapy with bamlanivimab has had its emergency use authorization (EUA) withdrawn due to development of viral resistance.6  This may mean that monoclonal cocktails are effective and less likely to lead to resistance than use of a single monoclonal. However, even a monoclonal cocktail could become ineffective in the future, as shown by the prospective mapping of viral variants that detected a potential mutation (E406W) that could escape neutralization by both components of the casirivimab/imdevimab monoclonal cocktail, as well as both components of the bamlanivimab/etesevimab cocktail (Table 2).7  Monoclonal therapy is expensive and requires very specialized manufacturing units. It is therefore a treatment that most low- and middle-income countries cannot afford and will find more difficult to manufacture locally. CP can be produced in many countries and is much more affordable.8  Therefore, when thinking about whether to use passive immunization therapy, consideration needs to be made not just on its effectiveness but also on its accessibility.

Table 2.

Different types of mAb in clinical use

Name of monoclonalSite of actionRoute of administrationClinical trial results*In clinical use (outside of clinical trials)Viral resistance detectedCompetent authority approval
Bamlanivimab Blocks binding of SARS-CoV-2 to the ACE2 receptor by targeting the RBD on the spike protein of SARS-CoV-2 IV Yes Previously—FDA EUA revoked April 2021 Yes
Marked—gamma (P.1) and beta (B.1.351) VoCs
Modest—delta (B.1.617.2) VoC
EUA (now revoked in United States)
Bamlanivimab plus etesevimab Blocks binding of SARS-CoV-2 to the ACE2 receptor by targeting different but overlapping epitopes on the spike protein RBD of SARS-CoV-2 IV Yes Yes—use paused in United States Yes
Marked—gamma (P.1) and beta (B.1.351) VoC
Modest—Delta (B.1.617.2) VoC
EUA
Casirivimab plus imdevimab Blocks binding of SARS-CoV-2 to the ACE2 receptor by targeting different epitopes on the spike protein RBD of SARS-CoV-2 (do not overlap) IV or S/C Yes Yes Yes—only to casirivimab
Marked—beta (B.1.351) VoC
Yes—MHRA and Japanese regulatory agency
Sotrovimab Blocks binding of SARS-CoV-2 to the ACE2 receptor by targeting an epitope on the RBD of the spike protein that is conserved between SARS-CoV and SARS-CoV-2 IV, trialing IM Yes Yes No EUA
Regdanvimab Blocks binding of SARS-CoV-2 to the ACE2 receptor by targeting an epitope on the RBD of the spike protein of SARS-CoV-2 IV Yes Yes Yes
Marked—beta (B.1.351) VoC
EUA
Name of monoclonalSite of actionRoute of administrationClinical trial results*In clinical use (outside of clinical trials)Viral resistance detectedCompetent authority approval
Bamlanivimab Blocks binding of SARS-CoV-2 to the ACE2 receptor by targeting the RBD on the spike protein of SARS-CoV-2 IV Yes Previously—FDA EUA revoked April 2021 Yes
Marked—gamma (P.1) and beta (B.1.351) VoCs
Modest—delta (B.1.617.2) VoC
EUA (now revoked in United States)
Bamlanivimab plus etesevimab Blocks binding of SARS-CoV-2 to the ACE2 receptor by targeting different but overlapping epitopes on the spike protein RBD of SARS-CoV-2 IV Yes Yes—use paused in United States Yes
Marked—gamma (P.1) and beta (B.1.351) VoC
Modest—Delta (B.1.617.2) VoC
EUA
Casirivimab plus imdevimab Blocks binding of SARS-CoV-2 to the ACE2 receptor by targeting different epitopes on the spike protein RBD of SARS-CoV-2 (do not overlap) IV or S/C Yes Yes Yes—only to casirivimab
Marked—beta (B.1.351) VoC
Yes—MHRA and Japanese regulatory agency
Sotrovimab Blocks binding of SARS-CoV-2 to the ACE2 receptor by targeting an epitope on the RBD of the spike protein that is conserved between SARS-CoV and SARS-CoV-2 IV, trialing IM Yes Yes No EUA
Regdanvimab Blocks binding of SARS-CoV-2 to the ACE2 receptor by targeting an epitope on the RBD of the spike protein of SARS-CoV-2 IV Yes Yes Yes
Marked—beta (B.1.351) VoC
EUA
*

Results available in Table 2 for all-cause mortality and need for hospitalization (by day 30) in Table 3 for outpatients.

EUA in the United States as well as other countries. In the United States, the indication is for mild or moderate COVID-19 not requiring oxygen therapy.

EUA in South Korea and Indonesia, but indications for use differ.

FDA, Food and Drug Administration (United States); IM, intramuscular; IV, intravenous; MHRA, Medicines and Healthcare products Regulatory Agency (United Kingdom); RBD, receptor-binding domain; S/C, subcutaneous; VoC, variant of concern.

The mainstay of preventing infection in people with an intact immune system is vaccination. Active immunization against SARS-CoV-2 has been shown to be effective at preventing severe and fatal COVID-19, as well as reducing the risk of symptomatic COVID-19.9  In the United States, by the end of June 2021, vaccination had averted an estimated 279 000 deaths and up to 1.25 million hospitalizations.10  However, vaccination is not as effective in patients with an impaired immune system, either due to immunosuppressive therapy or an underlying disease that affects the immune system. Patients with hematologic malignancies mount blunted antibody responses to SARS-CoV-2 vaccination, and those most at risk appear to be patients who are actively treated with Bruton tyrosine kinase inhibitors, ruxolitinib, venetoclax, or anti-CD20 antibody therapies.11  Consideration therefore needs to be given to preventing infection in people who are unvaccinated or partially vaccinated and are at high risk of developing severe and fatal COVID-19 due to comorbidities or those who have been fully vaccinated but are unable to mount an effective immune response to vaccination. There have been 2 completed trials assessing monoclonal therapy12,13  (Table 3), with 1 trial assessing the effect of 1.2 g of the casirivimab/imdevimab cocktail (subcutaneously via 4 injections) given to household contacts of a positive case.13  However, most of these individuals were not at high risk of severe disease, with fewer than 10% older than 65 years and only 1% with immune suppression. The other trial used bamlanivimab, which showed a benefit in nursing home residents who received the intervention in progression to moderate or severe disease but no evidence of a difference in mortality (Figure 1). However, bamlanivimab is not effective against many of the viral variants currently in circulation. Ongoing studies of CP, hyperimmune globulin, and mAbs assessing high-risk prophylaxis will be assessed within living systematic reviews, so additional information may be available over the next few months.23,24  It is especially important to know their additional impact over and above vaccination for those individuals who have a poor response to vaccination, for example, the immunosuppressed population.11

Table 3.

Completed randomized controlled trials of anti-SARS-CoV-2 mAb therapy

StudyCountryIntervention(s)Number randomized up to data cutoffNumber analyzedPatient populationPrimary outcomeType of analysisViral variants considered in analyses*Mortality at 30 days (GRADE)Need for hospitalization at 30 days or death (GRADE)
Prophylaxis
O'Brien et al13
NCT04452318
Moldova, Romania, United States S/C casirivimab/imdevimab 1.2 g (0.6 g + 0.6 g) 753 1505 Age ≥12 years
Household contact of confirmed SARS-CoV-2 case
SARS-CoV-2 PCR and antibody negative
Incidence of symptomatic COVID-19 Interim
Planned recruitment 3750
No
Recruited
??-January 2021
NR NR
Placebo 752
BLAZE-212
NCT04497987
United States Bamlanivimab (4.2 g) 588 966 Residents and staff at 74 skilled nursing
and assisted living facilities
Within 7 days of a reported confirmed SARS-CoV-2 case
Incidence of COVID-19—virological or clinical Final No
Recruited
August- November 2020
RR, 0.83
95% CI, 0.25-2.70
(low)
NR
Placebo 587
Outpatients (asymptomatic)
O'Brien et al14
NCT04452318
United States S/C casirivimab/imdevimab 1.2 g (0.6 g + 0.6 g) 155 311 Age ≥12 years
Confirmed SARS-CoV-2
SARS-CoV-2 antibody negative
Asymptomatic
Incidence of symptomatic COVID-19 Interim
Planned recruitment 3750
July 2020 to January 2021 NR RR, 0.14
95% CI, 0.01-2.76
(low)
Placebo 156
Outpatients (mild disease)
Weinreich et al (phase 3)15
NCT04425629
Chile, Mexico, Romania, United States Casirivimab/imdevimab 1.2 g (0.6 g + 0.6 g) 838 4057 Adult
Confirmed SARS-CoV-2
≤7 days from onset symptoms
≥1 risk factor COVID-19
Mild symptoms (WHO 2-3)
Excluded
Hospitalized (any reason)
Vaccinated or plan to be vaccinated
Clinical—COVID-related hospitalization or death (day 29) Interim
Planned recruitment 6420
Subgroup—antibody negative
No
Recruited September 2020 to January 2021
RR, 1.02
95% CI, 0.06-16.22
(low)
RR, 0.30
95% CI, 0.13-0.68
(low)
Casirivimab/imdevimab 2.4 g (1.2 g + 1.2 g) 1529 RR, 0.33
95% CI, 0.01-3.94
(low)
RR, 0.29
95% CI, 0.17-0.48
(moderate)
Placebo 1500 — —
COMET-ICE16
NCT04545060
Confirmed SARS-CoV-2
≤5 days from onset symptoms
>55 years or comorbidities
Mild symptoms (WHO 2-3)
Excluded
Likely to require hospitalization ≤24 h
Likely to die ≤7 days
Severely immunocompromised
Vaccinated or plan to be vaccinated within 4 weeks
Clinical—disease progression Interim
Stopped recruitment due to efficacy 1057 participants
No
Recruited August 2020 to March 2021
RR, 0.33
95% CI, 0.01-8.18
(low)
RR, 0.14
95% CI, 0.04-0.48
(low)
Placebo 292
BLAZE-117
NCT04427501
Puerto Rico, United States Bamlanivimab (0.7 g) 104 577 Adult
Confirmed SARS-CoV-2
Mild symptoms (WHO 2-3)
Excluded
Requires oxygen therapy
Any serious concomitant systemic disease
Pregnant or breastfeeding
Virological—viral clearance Interim
Planned recruitment 3160
No
Recruited June-September 2020
No events
(low)
RR, 0.17
95% CI, 0.02-1.33
(low)
Bamlanivimab (2.8 g) 109 RR, 0.32
95% CI, 0.07-1.47
(low)
Bamlanivimab (7.0 g) 104 RR, 0.34
95% CI, 0.08-1.56
(low)
Bamlanivimab/etesevimab (2.8 g + 2.8 g) 114 See updated results below See updated results below
Placebo 161 — —
BLAZE-118
NCT04427501
United States Bamlanivimab/etesevimab (2.8 g + 2.8 g) 518 1035 Adult
Confirmed SARS-CoV-2
Mild symptoms (WHO 2 to 3)
Excluded
Requires oxygen therapy
Any serious concomitant systemic disease
Pregnant or breastfeeding
Clinical—COVID-19–related hospitalization (acute care for ≥24 hours) or death from any cause by day 29 Interim
Planned recruitment 3160
No
September- December 2020
RR, 0.05
95% CI, 0.00-0.81
(low)
RR, 0.30
95% CI, 0.16-0.59
(low)
Placebo 517
Eom et al19
NCT04602000
Romania, South Korea, Spain, United States Regdanvimab 0.04 g/kg 101 327 Adult
Confirmed SARS-CoV-2
≤7 days from onset symptoms
Excluded
Hospitalized
Clinical—time to clinical recovery
Virological—viral clearance
Interim
Planned recruitment 1172
No
Recruited
October-December 2020
No events
(low)
RR, 0.45
95% CI, 0.14-1.42
(low)
Regdanvimab 0.08 g/kg 103 RR, 0.56
95% CI, 0.19-1.60
(low)
Placebo 103 —
Weinreich et al (phase 1/2)20
NCT04425629
Chile, Mexico, Romania, United States Casirivimab/imdevimab 2.4 g (1.2 g + 1.2 g) 92 275 Adult
Confirmed SARS-CoV-2
≤7 days from onset symptoms
Excluded
Hospitalized
Virological—viral clearance Interim No
Recruited
June- August 2020
NR RR, 0.43
95% CI, 0.08-2.19
(low)
Casirivimab/imdevimab 8 g (4 g + 4 g) 90 RR, 0.21
95% CI, 0.02-1.79
(low)
Placebo 93 —
Inpatients (moderate or severe disease)
RECOVERY21
NCT04381936
United Kingdom Casirivimab/imdevimab 8 g (4 g + 4 g) 4839 9185 Any age
Suspected or confirmed COVID-19
Median 9 days symptom onset
>90% requiring oxygen therapy (WHO score ≥5)
Clinical— all-cause mortality day 28 Complete
Subgroup— antibody negative
No
Recruited
September 2020 to May 2021
RR, 0.94
95% CI, 0.87-1.02
(moderate)
NA
Standard care 4946
ACTIV-322
NCT04501978
Denmark, India, Poland, Singapore, Spain, Switzerland, United Kingdom, United States Bamlanivimab (7 g) 314 Inpatients, moderate disease Adult
Confirmed SARS-CoV-2
≤12 days from onset symptoms
Excluded
Requiring organ support
Pregnant/breast feeding
Clinical—time to sustained recovery Interim analysis, bamlanivimab arm stopped for futility, recruitment ongoing for other arms No
Recruited
August to October 2020
RR, 1.39
95% CI, 0.07-1.47
(low)
NA
StudyCountryIntervention(s)Number randomized up to data cutoffNumber analyzedPatient populationPrimary outcomeType of analysisViral variants considered in analyses*Mortality at 30 days (GRADE)Need for hospitalization at 30 days or death (GRADE)
Prophylaxis
O'Brien et al13
NCT04452318
Moldova, Romania, United States S/C casirivimab/imdevimab 1.2 g (0.6 g + 0.6 g) 753 1505 Age ≥12 years
Household contact of confirmed SARS-CoV-2 case
SARS-CoV-2 PCR and antibody negative
Incidence of symptomatic COVID-19 Interim
Planned recruitment 3750
No
Recruited
??-January 2021
NR NR
Placebo 752
BLAZE-212
NCT04497987
United States Bamlanivimab (4.2 g) 588 966 Residents and staff at 74 skilled nursing
and assisted living facilities
Within 7 days of a reported confirmed SARS-CoV-2 case
Incidence of COVID-19—virological or clinical Final No
Recruited
August- November 2020
RR, 0.83
95% CI, 0.25-2.70
(low)
NR
Placebo 587
Outpatients (asymptomatic)
O'Brien et al14
NCT04452318
United States S/C casirivimab/imdevimab 1.2 g (0.6 g + 0.6 g) 155 311 Age ≥12 years
Confirmed SARS-CoV-2
SARS-CoV-2 antibody negative
Asymptomatic
Incidence of symptomatic COVID-19 Interim
Planned recruitment 3750
July 2020 to January 2021 NR RR, 0.14
95% CI, 0.01-2.76
(low)
Placebo 156
Outpatients (mild disease)
Weinreich et al (phase 3)15
NCT04425629
Chile, Mexico, Romania, United States Casirivimab/imdevimab 1.2 g (0.6 g + 0.6 g) 838 4057 Adult
Confirmed SARS-CoV-2
≤7 days from onset symptoms
≥1 risk factor COVID-19
Mild symptoms (WHO 2-3)
Excluded
Hospitalized (any reason)
Vaccinated or plan to be vaccinated
Clinical—COVID-related hospitalization or death (day 29) Interim
Planned recruitment 6420
Subgroup—antibody negative
No
Recruited September 2020 to January 2021
RR, 1.02
95% CI, 0.06-16.22
(low)
RR, 0.30
95% CI, 0.13-0.68
(low)
Casirivimab/imdevimab 2.4 g (1.2 g + 1.2 g) 1529 RR, 0.33
95% CI, 0.01-3.94
(low)
RR, 0.29
95% CI, 0.17-0.48
(moderate)
Placebo 1500 — —
COMET-ICE16
NCT04545060
Confirmed SARS-CoV-2
≤5 days from onset symptoms
>55 years or comorbidities
Mild symptoms (WHO 2-3)
Excluded
Likely to require hospitalization ≤24 h
Likely to die ≤7 days
Severely immunocompromised
Vaccinated or plan to be vaccinated within 4 weeks
Clinical—disease progression Interim
Stopped recruitment due to efficacy 1057 participants
No
Recruited August 2020 to March 2021
RR, 0.33
95% CI, 0.01-8.18
(low)
RR, 0.14
95% CI, 0.04-0.48
(low)
Placebo 292
BLAZE-117
NCT04427501
Puerto Rico, United States Bamlanivimab (0.7 g) 104 577 Adult
Confirmed SARS-CoV-2
Mild symptoms (WHO 2-3)
Excluded
Requires oxygen therapy
Any serious concomitant systemic disease
Pregnant or breastfeeding
Virological—viral clearance Interim
Planned recruitment 3160
No
Recruited June-September 2020
No events
(low)
RR, 0.17
95% CI, 0.02-1.33
(low)
Bamlanivimab (2.8 g) 109 RR, 0.32
95% CI, 0.07-1.47
(low)
Bamlanivimab (7.0 g) 104 RR, 0.34
95% CI, 0.08-1.56
(low)
Bamlanivimab/etesevimab (2.8 g + 2.8 g) 114 See updated results below See updated results below
Placebo 161 — —
BLAZE-118
NCT04427501
United States Bamlanivimab/etesevimab (2.8 g + 2.8 g) 518 1035 Adult
Confirmed SARS-CoV-2
Mild symptoms (WHO 2 to 3)
Excluded
Requires oxygen therapy
Any serious concomitant systemic disease
Pregnant or breastfeeding
Clinical—COVID-19–related hospitalization (acute care for ≥24 hours) or death from any cause by day 29 Interim
Planned recruitment 3160
No
September- December 2020
RR, 0.05
95% CI, 0.00-0.81
(low)
RR, 0.30
95% CI, 0.16-0.59
(low)
Placebo 517
Eom et al19
NCT04602000
Romania, South Korea, Spain, United States Regdanvimab 0.04 g/kg 101 327 Adult
Confirmed SARS-CoV-2
≤7 days from onset symptoms
Excluded
Hospitalized
Clinical—time to clinical recovery
Virological—viral clearance
Interim
Planned recruitment 1172
No
Recruited
October-December 2020
No events
(low)
RR, 0.45
95% CI, 0.14-1.42
(low)
Regdanvimab 0.08 g/kg 103 RR, 0.56
95% CI, 0.19-1.60
(low)
Placebo 103 —
Weinreich et al (phase 1/2)20
NCT04425629
Chile, Mexico, Romania, United States Casirivimab/imdevimab 2.4 g (1.2 g + 1.2 g) 92 275 Adult
Confirmed SARS-CoV-2
≤7 days from onset symptoms
Excluded
Hospitalized
Virological—viral clearance Interim No
Recruited
June- August 2020
NR RR, 0.43
95% CI, 0.08-2.19
(low)
Casirivimab/imdevimab 8 g (4 g + 4 g) 90 RR, 0.21
95% CI, 0.02-1.79
(low)
Placebo 93 —
Inpatients (moderate or severe disease)
RECOVERY21
NCT04381936
United Kingdom Casirivimab/imdevimab 8 g (4 g + 4 g) 4839 9185 Any age
Suspected or confirmed COVID-19
Median 9 days symptom onset
>90% requiring oxygen therapy (WHO score ≥5)
Clinical— all-cause mortality day 28 Complete
Subgroup— antibody negative
No
Recruited
September 2020 to May 2021
RR, 0.94
95% CI, 0.87-1.02
(moderate)
NA
Standard care 4946
ACTIV-322
NCT04501978
Denmark, India, Poland, Singapore, Spain, Switzerland, United Kingdom, United States Bamlanivimab (7 g) 314 Inpatients, moderate disease Adult
Confirmed SARS-CoV-2
≤12 days from onset symptoms
Excluded
Requiring organ support
Pregnant/breast feeding
Clinical—time to sustained recovery Interim analysis, bamlanivimab arm stopped for futility, recruitment ongoing for other arms No
Recruited
August to October 2020
RR, 1.39
95% CI, 0.07-1.47
(low)
NA
*

Was the type of virus (eg, alpha, beta, gamma, delta) detected at baseline taken into consideration as a subgroup analysis?

GRADE assessment—assesses certainty of the evidence. High certainty: very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Pre–peer review.

NA, not applicable; NR, not reported; PCR, polymerase chain reaction; WHO, World Health Organization.

Figure 1.

SARS-CoV-2 mAb vs placebo or standard care—all-cause mortality at 28 days or hospital discharge.

Figure 1.

SARS-CoV-2 mAb vs placebo or standard care—all-cause mortality at 28 days or hospital discharge.

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### CLINICAL CASE (Continued)

The patient and his wife received the results of the polymerase chain reaction test the next day, and both had tested positive for SARS-CoV-2. In total, 15 of the 45 people who attended the christening tested positive for SARS-CoV-2 within the days following the christening. He started to develop symptoms of fever and a dry cough the day after his positive test, but his symptoms were mild, and he treated the fever with paracetamol and rested at home.

Vaccination is known to decrease the risk of progression to moderate or severe COVID-19 disease, although it has less of an impact on the development of asymptomatic or mild symptoms. All of the current evidence for passive immune therapy is prior to vaccination, or patients who were vaccinated or about to be vaccinated were excluded from the trials. Data from Public Health England have shown that vaccination decreases the risk of hospitalization by over 90%, even with the delta variant. It is therefore more difficult to know the real additional effect of passive immune therapy over and above vaccination (Tables 3 and 4).

Table 4.

Completed randomized controlled trials of CP and hyperimmune globulin therapy

StudyCountryIntervention(s)Randomized per armNumber analyzedPatient populationPrimary outcomeNeutralizing antibody titerViral variants considered in analyses*
Prophylaxis
No completed studies
Outpatients (asymptomatic)
No completed studies
Outpatients (mild disease)
Libster et al8
NCT04479163
Argentina 250 mL CP on day 1 80 160 Age >74 or 65 to 74 and comorbidity
Confirmed SARS-CoV-2
Mild illness, not requiring hospitalization
≤48 h from symptom onset
Development of severe disease—defined as RR ≥30 breaths/min or oxygen saturations <93% on air Anti–S IgG SARS-CoV-2 (COVIDAR IgG) minimum titer 1:1000 No
Recruited
June-October 2020
Saline (Placebo) 80
Inpatients (moderate disease (WHO 4 or 5)
Agarwal et al25
CTRI/2020/04/024775
India Two doses 200 mL CP, 24 h apart, preferably different donors 235 464 Adult
Confirmed SARS-CoV-2
SpO2 ≤93% and RR >24/min or PaO2/FiO2 200-300
Excluded
Critically ill (PaO2/FiO2 <200 or shock requiring vasopressors)
Composite all- cause mortality or progression to severe disease (PaO2/FiO2 <100) within day 28 NAb not used to select plasma, tested at end of study—63% of donors had NAb titer >1:20 with median titer 1:40 No
Recruited
April-July 2020
Standard care 229
Simonovich et al26
NCT04383535
Argentina 10-15 mL/kg
Mini-pools (5-10 donors)
Confirmed SARS-CoV-2, requiring hospitalization, pneumonia, plus SpO2 <93% or PaO2/FiO2 <300
Excluded
MV or NIV
Clinical status at day 30 ordinal categories
1: death
2: invasive ventilatory support
3: hospitalized with supplemental oxygen requirements
4: hospitalized without supplemental oxygen requirements
5: discharged without full return of baseline physical function
6: discharged with full return of baseline physical function
Anti–S IgG SARS-CoV-2 (COVIDAR IgG)
Median titer of 1:3200 (IQR, 1:800 to 1:3200)
No
Recruited
May-August 2020
Saline (placebo) 105
Avendaño-Solà et al27
NCT04345523
Spain 250-300 mL CCP on day 1 38 81 Adult
Confirmed SARS-CoV-2
Radiological changes or clinical features plus SpO2 <94%, <12-day symptom onset
Excluded
MV, high-flow O2
Proportion of patients in category 5, 6, or 7 of 7-category COVID-19 ordinal scale at day 15 NAb not available to select plasma, all donation on subsequent testing had VMNT-ID50 > 1:80 No
Recruited
April-July 2020
Standard care 43
AlQahtani et al28
NCT04356534
Bahrain Two doses 200 mL CCP, 24 h apart 20 40 Age ≥21
Confirmed SARS-CoV-2
Pneumonia, plus SpO2 <92% or PaO2/FiO2 <300
Excluded
MV or MOF
Requirement for ventilation (NIV or MV) NR No
Recruited
April-June 2020
Standard care 20
Inpatients (moderate or severe disease—WHO 4 to 7)
RECOVERY 202129
NCT04381936
United Kingdom Two doses 275 mL CCP, 24 h apart 5795 11 558 Any age
Suspected or confirmed COVID-19
Median 9 days symptom onset
>90% requiring oxygen therapy (WHO score ≥5)
Clinical—all-cause mortality day 28 Minimum Euroimmun 6 Partially
Used surrogate of randomized before/after December 2020 for WT/alpha variant
Recruited
May 2020 to January 2021
Standard care 5763
CONCOR-130
NCT04348656
Confirmed SARS-CoV-2
Requiring oxygen therapy (WHO score ≥5)
Excluded
Symptoms >12 days
MV
Intubation or death by day 30 Viral neutralizing antibodies titer >1:160 or antibodies against the RBD of the SARS-CoV-2 spike protein titer >1:100 No
Recruited
May 2020 to January 2021
Standard care 307
O'Donnell et al31
NCT04359810
Brazil, United States 200-250 mL CCP 150 223 Adult
Confirmed SARS-CoV-2
Requiring oxygen therapy (WHO score ≥5)
Clinical status at day 28 following randomization (7-point ordinal scale based on WHO) Anti–SARS-CoV-2 antispike IgG antibody titer ≥1:400 No
Recruited
April-November 2020
200-250 mL nonimmune plasma 73
CAPSID32
NCT04433910
Germany CCP (250-325 mL) on days 1, 3, and 5 53 105 Age 18-75 years
Confirmed SARS-CoV-2
RR >30 or requiring oxygen therapy (WHO score ≥5)
Composite end point of survival and no longer fulfilling criteria of severe COVID-19 (day 21) Median PRNT50 neutralization titer 1:160 (IQR, 1:80 to 1:320) No
Recruited
August-December 2020
Standard care, crossover to CCP at day 14 if not improved 52
Gharbharan et al33
NCT04342182
The Netherlands 300 mL CCP on day 1 43 86 Adult
Confirmed SARS-CoV-2 within 96 h
Excluded
Patients on MV >96 h
Mortality until discharge or maximum of 60 days Minimum of PRNT50 titer of ≥1:80 No
Recruited
April-June 2020
Standard care 43
Ray et al34
CTRI/2020/05/025209
India Two doses 200 mL CCP, 24 h apart 40 80 Adult
Confirmed SARS-CoV-2
RR >30, SpO2 <90%, PaO2/FiO2 <300
Excluded
pregnant, MV
All-cause mortality at 30 days Euroimmun ≥1.5
Standard care 40
Bennett-Guerrero et al35
NCT04344535
United States 480 mL (2 units) CCP 59 74 Adult
Confirmed SARS-CoV-2
Excluded
Pregnant/breastfeeding
Number of days patient remained ventilator free (up to 28 days) Ideally >1:320, but meeting minimum titer per FDA No
Recruited
April-August 2020
480 mL (2 units) nonimmune plasma 15
IRCT20200310046736N1
Iran 500 mL CCP 30 60 Confirmed SARS-CoV-2
WHO score >4
Excluded
Pregnant/breastfeeding
Comorbidities (eg, heart, liver, kidney disease)
Smokers
Improvement in the levels of cytokine storm indices NR No
Recruited
March-May 2020
Standard care 30
Hamdy Salman and Ail Mohamed37
NCT04530370
Egypt 250 mL CP on day 1 15 30 Adult
Confirmed SARS-CoV-2
2 or more of RR ≥24, SpO2 ≤93%, PaO2/FiO2 <300, pulmonary infiltrates
Excluded
MOF, septic shock
At least 50% improvement of the severity of illness at any time during 5-day study period NAb not used to select plasma No
Recruited
June-August 2020
Saline (placebo) 15
Bajpai et al38
NCT04346446
India Two doses 250 mL CCP, 24 h apart 14 29 Age 18-65 years
Confirmed SARS-CoV-2
Pneumonia, plus SpO2 <93% or PaO2/FiO2 <300
Excluded
Comorbidities (kidney, heart or liver disease, COPD)
Proportion of patients remaining free of mechanical ventilation day 7 Variable No
Recruited
April-May 2020
Nonimmune plasma 15
Inpatients (severe disease—WHO 6 to 7)
REMAP-CAP39
NCT02735707
Australia, Canada, United Kingdom, United States Two doses 275 mL CCP, 24 h apart 1084 2000 Adult
Confirmed SARS-CoV-2
≤48 h since admission to ICU
Organ support–free days at day 21 Minimum Euroimmun 6 No
Recruited
May 2020 to January 2021
Standard care 916
Gonzalez et al40
NCT04381858
Mexico Two doses 200 mL CCP, 24 h apart 130 90 Adult (16-90 years)
Suspected or confirmed COVID-19
Severe respiratory failure
Duration of hospitalization
All-cause mortality day 28
NAb not used to select plasma No
Recruited
May-October 2020
IVIg 0.3 g/kg daily for 5 days 60
Li et al41
ChiCTR2000029757
China 4-13 mL/kg of CP 52 103 Confirmed SARS-CoV-2
Excluded
high-titer S-RBD–specific IgG (≥1:640)
Time to clinical improvement (patient discharge or reduction 2 points on 6-point disease severity scale) Minimum of S-RBD–specific IgG of 1:640 (approximately equivalent to NAb of 1:40) No
Recruited
February-April 2020
Standard care 51
StudyCountryIntervention(s)Randomized per armNumber analyzedPatient populationPrimary outcomeNeutralizing antibody titerViral variants considered in analyses*
Prophylaxis
No completed studies
Outpatients (asymptomatic)
No completed studies
Outpatients (mild disease)
Libster et al8
NCT04479163
Argentina 250 mL CP on day 1 80 160 Age >74 or 65 to 74 and comorbidity
Confirmed SARS-CoV-2
Mild illness, not requiring hospitalization
≤48 h from symptom onset
Development of severe disease—defined as RR ≥30 breaths/min or oxygen saturations <93% on air Anti–S IgG SARS-CoV-2 (COVIDAR IgG) minimum titer 1:1000 No
Recruited
June-October 2020
Saline (Placebo) 80
Inpatients (moderate disease (WHO 4 or 5)
Agarwal et al25
CTRI/2020/04/024775
India Two doses 200 mL CP, 24 h apart, preferably different donors 235 464 Adult
Confirmed SARS-CoV-2
SpO2 ≤93% and RR >24/min or PaO2/FiO2 200-300
Excluded
Critically ill (PaO2/FiO2 <200 or shock requiring vasopressors)
Composite all- cause mortality or progression to severe disease (PaO2/FiO2 <100) within day 28 NAb not used to select plasma, tested at end of study—63% of donors had NAb titer >1:20 with median titer 1:40 No
Recruited
April-July 2020
Standard care 229
Simonovich et al26
NCT04383535
Argentina 10-15 mL/kg
Mini-pools (5-10 donors)
Confirmed SARS-CoV-2, requiring hospitalization, pneumonia, plus SpO2 <93% or PaO2/FiO2 <300
Excluded
MV or NIV
Clinical status at day 30 ordinal categories
1: death
2: invasive ventilatory support
3: hospitalized with supplemental oxygen requirements
4: hospitalized without supplemental oxygen requirements
5: discharged without full return of baseline physical function
6: discharged with full return of baseline physical function
Anti–S IgG SARS-CoV-2 (COVIDAR IgG)
Median titer of 1:3200 (IQR, 1:800 to 1:3200)
No
Recruited
May-August 2020
Saline (placebo) 105
Avendaño-Solà et al27
NCT04345523
Spain 250-300 mL CCP on day 1 38 81 Adult
Confirmed SARS-CoV-2
Radiological changes or clinical features plus SpO2 <94%, <12-day symptom onset
Excluded
MV, high-flow O2
Proportion of patients in category 5, 6, or 7 of 7-category COVID-19 ordinal scale at day 15 NAb not available to select plasma, all donation on subsequent testing had VMNT-ID50 > 1:80 No
Recruited
April-July 2020
Standard care 43
AlQahtani et al28
NCT04356534
Bahrain Two doses 200 mL CCP, 24 h apart 20 40 Age ≥21
Confirmed SARS-CoV-2
Pneumonia, plus SpO2 <92% or PaO2/FiO2 <300
Excluded
MV or MOF
Requirement for ventilation (NIV or MV) NR No
Recruited
April-June 2020
Standard care 20
Inpatients (moderate or severe disease—WHO 4 to 7)
RECOVERY 202129
NCT04381936
United Kingdom Two doses 275 mL CCP, 24 h apart 5795 11 558 Any age
Suspected or confirmed COVID-19
Median 9 days symptom onset
>90% requiring oxygen therapy (WHO score ≥5)
Clinical—all-cause mortality day 28 Minimum Euroimmun 6 Partially
Used surrogate of randomized before/after December 2020 for WT/alpha variant
Recruited
May 2020 to January 2021
Standard care 5763
CONCOR-130
NCT04348656
Confirmed SARS-CoV-2
Requiring oxygen therapy (WHO score ≥5)
Excluded
Symptoms >12 days
MV
Intubation or death by day 30 Viral neutralizing antibodies titer >1:160 or antibodies against the RBD of the SARS-CoV-2 spike protein titer >1:100 No
Recruited
May 2020 to January 2021
Standard care 307
O'Donnell et al31
NCT04359810
Brazil, United States 200-250 mL CCP 150 223 Adult
Confirmed SARS-CoV-2
Requiring oxygen therapy (WHO score ≥5)
Clinical status at day 28 following randomization (7-point ordinal scale based on WHO) Anti–SARS-CoV-2 antispike IgG antibody titer ≥1:400 No
Recruited
April-November 2020
200-250 mL nonimmune plasma 73
CAPSID32
NCT04433910
Germany CCP (250-325 mL) on days 1, 3, and 5 53 105 Age 18-75 years
Confirmed SARS-CoV-2
RR >30 or requiring oxygen therapy (WHO score ≥5)
Composite end point of survival and no longer fulfilling criteria of severe COVID-19 (day 21) Median PRNT50 neutralization titer 1:160 (IQR, 1:80 to 1:320) No
Recruited
August-December 2020
Standard care, crossover to CCP at day 14 if not improved 52
Gharbharan et al33
NCT04342182
The Netherlands 300 mL CCP on day 1 43 86 Adult
Confirmed SARS-CoV-2 within 96 h
Excluded
Patients on MV >96 h
Mortality until discharge or maximum of 60 days Minimum of PRNT50 titer of ≥1:80 No
Recruited
April-June 2020
Standard care 43
Ray et al34
CTRI/2020/05/025209
India Two doses 200 mL CCP, 24 h apart 40 80 Adult
Confirmed SARS-CoV-2
RR >30, SpO2 <90%, PaO2/FiO2 <300
Excluded
pregnant, MV
All-cause mortality at 30 days Euroimmun ≥1.5
Standard care 40
Bennett-Guerrero et al35
NCT04344535
United States 480 mL (2 units) CCP 59 74 Adult
Confirmed SARS-CoV-2
Excluded
Pregnant/breastfeeding
Number of days patient remained ventilator free (up to 28 days) Ideally >1:320, but meeting minimum titer per FDA No
Recruited
April-August 2020
480 mL (2 units) nonimmune plasma 15
IRCT20200310046736N1
Iran 500 mL CCP 30 60 Confirmed SARS-CoV-2
WHO score >4
Excluded
Pregnant/breastfeeding
Comorbidities (eg, heart, liver, kidney disease)
Smokers
Improvement in the levels of cytokine storm indices NR No
Recruited
March-May 2020
Standard care 30
Hamdy Salman and Ail Mohamed37
NCT04530370
Egypt 250 mL CP on day 1 15 30 Adult
Confirmed SARS-CoV-2
2 or more of RR ≥24, SpO2 ≤93%, PaO2/FiO2 <300, pulmonary infiltrates
Excluded
MOF, septic shock
At least 50% improvement of the severity of illness at any time during 5-day study period NAb not used to select plasma No
Recruited
June-August 2020
Saline (placebo) 15
Bajpai et al38
NCT04346446
India Two doses 250 mL CCP, 24 h apart 14 29 Age 18-65 years
Confirmed SARS-CoV-2
Pneumonia, plus SpO2 <93% or PaO2/FiO2 <300
Excluded
Comorbidities (kidney, heart or liver disease, COPD)
Proportion of patients remaining free of mechanical ventilation day 7 Variable No
Recruited
April-May 2020
Nonimmune plasma 15
Inpatients (severe disease—WHO 6 to 7)
REMAP-CAP39
NCT02735707
Australia, Canada, United Kingdom, United States Two doses 275 mL CCP, 24 h apart 1084 2000 Adult
Confirmed SARS-CoV-2
≤48 h since admission to ICU
Organ support–free days at day 21 Minimum Euroimmun 6 No
Recruited
May 2020 to January 2021
Standard care 916
Gonzalez et al40
NCT04381858
Mexico Two doses 200 mL CCP, 24 h apart 130 90 Adult (16-90 years)
Suspected or confirmed COVID-19
Severe respiratory failure
Duration of hospitalization
All-cause mortality day 28
NAb not used to select plasma No
Recruited
May-October 2020
IVIg 0.3 g/kg daily for 5 days 60
Li et al41
ChiCTR2000029757
China 4-13 mL/kg of CP 52 103 Confirmed SARS-CoV-2
Excluded
high-titer S-RBD–specific IgG (≥1:640)
Time to clinical improvement (patient discharge or reduction 2 points on 6-point disease severity scale) Minimum of S-RBD–specific IgG of 1:640 (approximately equivalent to NAb of 1:40) No
Recruited
February-April 2020
Standard care 51
*

Was the type of virus (e.g., alpha, beta, gamma, delta, etc.) detected at baseline taken into consideration as a subgroup analysis?

Pre–peer review.

CCP, COVID-19 convalescent plasma; COPD, chronic obstructive pulmonary disease; FDA, Food and Drug Administration; FiO2, fraction of inspired oxygen; ICU, intensive care unit; IQR, interquartile range; IVIg, intravenous immunoglobulin; MOF, multiorgan failure; MV, mechanical ventilation; NAb, neutralizing antibody; NIV, non-invasive ventilation; PaO2, partial pressure of oxygen; PRNT50, 50% reduction in plaque count using the plaque reduction neutralization test; RR, respiratory rate; SpO2, oxygen saturation; VMNT, virus microneutralization test; WT, wild type.

In the studies that assessed bamlanivimab alone or regdanvimab, there were no deaths in any of the study arms; therefore, any effect on all-cause mortality cannot be assessed.42  The only study that showed a reduction in mortality was the BLAZE-1 trial17  arm that used the bamlanivimab/etesevimab monoclonal cocktail (Figure 1); the casirivimab/imdevimab cocktail trial showed a trend in the direction of effect, but it was not clinically significant,15,20  nor was the effect of high-dose CP (Figure 2).3,8  Therefore, although it is suggestive that passive immune therapy if given early could save lives and the reduce risk of severe disease, additional data are required before it can be used in routine practice. None of the studies have performed a cost-effectiveness analysis, but it is likely that those patients who do not respond to vaccination and are at high risk of severe or fatal COVID-19 are the group that will demonstrate a benefit.

Figure 2.

CP vs placebo or standard care—all-cause mortality at 28 days or hospital discharge.

Figure 2.

CP vs placebo or standard care—all-cause mortality at 28 days or hospital discharge.

Close modal

### CLINICAL CASE (Continued)

Seven days after the christening, he developed increasing shortness of breath and called an ambulance. On examination by the paramedics, he was pyrexial (temperature 38.9°C), had a respiratory rate of 25 breaths per minute, and was hypoxic with an oxygen saturation of 91% on room air. He was given oxygen by the paramedics and taken to the local emergency room. In the emergency room, he was given steroids and admitted to the hospital for oxygen therapy.

Two trials have assessed monoclonal antibody use in moderately or severely unwell patients; neither showed a benefit for patients overall (Figure 1), but there was a benefit for patients who had not yet developed a detectable antibody response (Figure 3). Those patients who did not develop an antibody response had a much higher mortality rate than those who did not.19,21  This is partly because patients who have a delayed antibody response are older and have more comorbidities. This does mean that reducing mortality in this group will mean a larger absolute reduction in mortality; for example, based on the RECOVERY data, 54 lives per 1000 patients treated would be saved (95% CI, 24-80 lives saved per 1000 patients treated). Some SARS-CoV-2 variants are resistant to bamlanivimab monotherapy, whereas the current major variants in circulation are still sensitive to neutralization by the casirivimab/imdevimab cocktail. However, this may change with the development of new variants.7  As variant screening cannot be done in real time, passive antibody treatments need to be used that are effective against all current variants in a particular region of the world. CP use does not show a benefit overall for patients with moderate or severe COVID-19.29,30,39  CP has also been assessed in antibody-negative patients in 2 major trials, RECOVERY and REMAP-CAP.29,39  This shows a similar trend in the direction of a possible effect in CP, but it does not reach statistical significance (risk ratio [RR], 0.93; 95% CI, 0.86-1.01). This may partly be because CP is a much more variable product, with some units having much lower antibody levels than others, so even if a minimum titer is used within the trials, this may not have been sufficient. Several trials have shown an effect in a subgroup of participants who received a higher titer product.8,32

Figure 3.

SARS-CoV-2 mAb vs placebo or standard care—all-cause mortality at 28 days or hospital discharge by antibody status at baseline.

Figure 3.

SARS-CoV-2 mAb vs placebo or standard care—all-cause mortality at 28 days or hospital discharge by antibody status at baseline.

Close modal

### CLINICAL CASE (Continued)

Over the next 2 days, the 74-year-old man continued to deteriorate and was admitted to intensive care for noninvasive ventilatory support. An emergency use access request for CP was made, and he received CP on day 10 after the christening.

Fewer trials have specifically assessed interventions for the critically unwell patients (requiring respiratory or cardiovascular organ support) with an intensive care level of care (Tables 1 and 2). Several trials exclude patients requiring mechanical ventilation or organ support of any type. One of the trials that has focused on this patient group is the REMAP-CAP trial.39  It showed no benefit of CP overall (Figure 2), but a prespecified subgroup showed potential benefit of CP. This trial, based on Bayesian statistics, showed an 89.9% posterior probability of benefit in this subgroup. This was a broad group of immunosuppressed patients based on the Acute Physiology and Chronic Health Evaluation (APACHE) score definition of immunosuppression.39  However, as it was a small subgroup, additional research is required to confirm whether or not this is a true finding. The RECOVERY trial did include patients receiving noninvasive and invasive ventilation, and no evidence of a difference was seen for those patients receiving invasive (RR, 0.71; 95% CI, 0.35-1.47; 70 participants) or noninvasive ventilation (RR, 0.86; 95% CI, 0.68-1.08; 673 participants), but the CIs are wide.

### CLINICAL CASE (Continued)

Unfortunately, the 74-year-old man continued to deteriorate and subsequently required invasive ventilation. Fourteen days after the christening, he died due to COVID-19. In total, 5 of the guests at the christening were admitted to hospital, including all 4 of the grandparents of the baby and the uncle (the index case), who had diabetes and hypertension. Both grandfathers died of COVID-19.

Up to now (July 2021), most of the evidence is based on trials performed prior to the introduction of vaccination. Vaccination is likely to be the most cost-effective strategy for preventing infection in the general population, including healthy individuals with high-risk exposure (eg, health care workers). There are insufficient data on the outcomes of prophylactic passive antibody therapy in immunosuppressed individuals.

Passive immune therapy (monoclonal therapy and CP) may be beneficial for high-risk patients who have mild COVID-19 symptoms, but more data are required. Some countries, including the United States, are using passive monoclonal therapy for this indication under EUA.

High-dose passive immune therapy (casirivimab/imdevimab) reduces all-cause mortality for hospitalized patients who have not yet developed a detectable antibody response (SARS-CoV-2 IgG antibody). This monoclonal cocktail has just been approved by the Medicines and Healthcare products Regulatory Agency based on this evidence, but indications for its use are currently not available.

CP may be beneficial for immunosuppressed individuals who are severely or critically unwell, but more data are required.

The virus continues to change, and so although treatments may be effective against current SARS-CoV-2 viral variants of concern, this may not be true in the future. Passive immune therapies will either have to be very broad spectrum or adapt with the virus.

Lise J. Estcourt: author on Cochrane living systematic reviews of monoclonal therapies and CP. Investigator on the RECOVERY and REMAP-CAP trials.

Lise J. Estcourt: nothing to declare.

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