Anti-SARS-CoV-2 Monoclonal Antibodies

 The SARS-CoV-2 genome encodes four major structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N), as well as nonstructural and accessory proteins. The spike protein is further divided into two subunits, S1 and S2, that mediate host cell attachment and invasion. Through its receptor-binding domain (RBD), S1 attaches to angiotensin-converting enzyme 2 (ACE2) on the host cell; this initiates a conformational change in S2 that results in virus-host cell membrane fusion and viral entry.1 Monoclonal antibodies that target the spike protein have been shown to have a clinical benefit in treating SARS-CoV-2 infection (as discussed below). Preliminary data suggest that monoclonal antibodies may play a role in preventing SARS-CoV-2 infection in household contacts of infected patients2 and during skilled nursing and assisted living facility outbreaks.3

Anti-SARS-CoV-2 Monoclonal Antibodies That Received Emergency Use Authorizations From the Food and Drug Administration

Three anti-SARS-CoV-2 monoclonal antibody products currently have Emergency Use Authorizations (EUAs) from the Food and Drug Administration (FDA) for the treatment of mild to moderate COVID-19 in nonhospitalized patients with laboratory-confirmed SARS-CoV-2 infection who are at high risk for progressing to severe disease and/or hospitalization. The issuance of an EUA does not constitute FDA approval. These products are:

Bamlanivimab plus etesevimab: These are neutralizing monoclonal antibodies that bind to different but overlapping epitopes in the spike protein RBD of SARS-CoV-2.

The distribution of bamlanivimab plus etesevimab was paused on June 25, 2021, because both the Gamma (P.1) and Beta (B.1.351) variants of concern (VoC) that are currently circulating in the United States have reduced susceptibility to bamlanivimab and etesevimab.4

Casirivimab plus imdevimab: These are recombinant human monoclonal antibodies that bind to nonoverlapping epitopes of the spike protein RBD of SARS-CoV-2.

Sotrovimab: This monoclonal antibody was originally identified in 2003 from a SARS-CoV survivor. It targets an epitope in the RBD of the spike protein that is conserved between SARS-CoV and SARS-CoV-2.

The FDA also updated the EUA for casirivimab plus imdevimab as post-exposure prophylaxis for certain individuals who are at high risk of acquiring SARS-CoV-2 infection and, if infected, are at high risk of progressing to serious illness. See the FDA EUA Fact Sheet for details.

Recommendations

The COVID-19 Treatment Guidelines Panel (the Panel) recommends using one of the following anti-SARS-CoV-2 monoclonal antibodies, listed in alphabetical order, to treat nonhospitalized patients with mild to moderate COVID-19 who are at high risk of clinical progression (see below for criteria and discussion):

Casirivimab plus imdevimab; or

Sotrovimab 500 mg intravenous (IV) infusion

When using casirivimab plus imdevimab, the Panel recommends:

Casirivimab 600 mg plus imdevimab 600 mg IV infusion (AIIa)

If IV infusions are not feasible or would cause a delay in treatment, casirivimab 600 mg plus imdevimab 600 mg administered by four subcutaneous (SQ) injections (2.5 mL per injection) can be used as an alternative (BIII).

When using monoclonal antibodies, treatment should be started as soon as possible after the patient receives a positive result on a SARS-CoV-2 antigen or nucleic acid amplification test (NAAT) and within 10 days of symptom onset.

At this time, the Panel recommends against the use of bamlanivimab plus etesevimab (AIII) because the Gamma (P.1) and Beta (B.1.351) VoC, which have reduced susceptibility to both agents, are circulating in the United States.

The use of anti-SARS-CoV-2 monoclonal antibodies should be considered for patients with mild to moderate COVID-19 who are hospitalized for a reason other than COVID-19 if they otherwise meet the EUA criteria for outpatient treatment.

Anti-SARS-CoV-2 monoclonal antibodies are not currently authorized for use in patients who are hospitalized with severe COVID-19; however, they may be available through expanded access programs for patients who have not developed an antibody response or who are not expected to mount an effective immune response to SARS-CoV-2 infection.

Rationale for the Use of Anti-SARS-CoV-2 Monoclonal Antibodies

In randomized, placebo-controlled trials of nonhospitalized patients who had mild to moderate COVID-19 symptoms and certain risk factors for disease progression, the use of anti-SARS-CoV-2 monoclonal antibody products reduced the risk of hospitalization and death (see Table 3a).5-7 It is worth noting that these studies were conducted before the widespread circulation of VoC. The potential impact of these variants on susceptibility to different anti-SARS-CoV-2 monoclonal antibodies is discussed below.

Casirivimab Plus Imdevimab

On June 3, 2021, the FDA updated the EUA for casirivimab plus imdevimab.6 The authorized dosages were reduced from a single IV infusion of casirivimab 1,200 mg plus imdevimab 1,200 mg to casirivimab 600 mg plus imdevimab 600 mg. In addition, these lower doses of casirivimab and imdevimab may now be administered by SQ injection if IV infusions are not feasible or may delay treatment. It should be noted that SQ administration requires four injections (2.5 mL per injection) at four different sites (see the FDA EUA for details).

The recommendation for using the lower dose of casirivimab 600 mg plus imdevimab 600 mg IV is based on the Phase 3 results from the R10933-10987-COV-2067 study (ClinicalTrials.gov Identifier NCT04425629). This study is a double-blind, placebo-controlled randomized trial in outpatients with mild to moderate COVID-19. The modified full analysis set included participants aged ≥18 years who had a positive SARS-CoV-2 polymerase chain reaction result at randomization and who had one or more risk factors for progression to severe COVID-19. The primary outcome of COVID-19-related hospitalization or death from any cause was reported in 7 of 736 participants (1.0%) in the casirivimab 600 mg plus imdevimab 600 mg IV arm and in 24 of 748 participants (3.2%) in the placebo arm (P = 0.0024), demonstrating a 2.2% absolute reduction and a 70% relative reduction in hospitalization or death among the casirivimab plus imdevimab recipients compared to the placebo recipients. These results are comparable to the results observed for IV infusions of casirivimab 1,200 mg plus imdevimab 1,200 mg. The primary outcome of COVID-19-related hospitalization or death from any cause was reported in 18 of 1,355 patients (1.3%) who received casirivimab 1,200 mg plus imdevimab 1,200 mg IV, compared with 62 of 1,341 patients (4.6%) who received placebo (P < 0.0001). These findings represent a 3.3% absolute reduction and a 71% relative reduction in hospitalization or death among patients who received this dose of casirivimab plus imdevimab.

The recommendation for using SQ injections is based on safety data from the Phase 1 R10933-10987-HV-2093 study (ClinicalTrials.gov Identifier NCT04519437), a double-blind, placebo-controlled randomized trial that compared casirivimab plus imdevimab administered by SQ injection to placebo in healthy volunteers who did not have SARS-CoV-2 infection. Injection site reactions were observed in 12% of the 729 casirivimab plus imdevimab participants and in 4% of the 240 placebo participants. According to the FDA EUA, in a separate trial among symptomatic participants, there were similar reductions in viral load between the IV and SQ arms.6 Because the safety and efficacy data for casirivimab plus imdevimab administered by SQ injection are limited, this route of administration should only be used when IV infusions are not feasible or would lead to a delay in treatment (BIII).

Sotrovimab

The data that support the EUA for sotrovimab come from the Phase 3 COMET-ICE trial (ClinicalTrials.gov Identifier NCT04545060). The COMET-ICE trial included outpatients with mild to moderate COVID-19 who were at high risk for progression to severe disease and/or hospitalization. A total of 583 participants were randomized to receive sotrovimab 500 mg IV (n = 291) or placebo (n = 292). The primary endpoint was the proportion of participants who were hospitalized (for ≥24 hours) or who died from any cause by Day 29. Endpoint events occurred in 3 of 291 participants (1%) in the sotrovimab arm and 21 of 292 participants (7%) in the placebo arm (P = 0.002), resulting in a 6% absolute reduction and an 85% relative reduction in hospitalizations or death among the sotrovimab recipients compared to the placebo recipients.7

Bamlanivimab Plus Etesevimab

This antibody combination has been shown to have a clinical benefit in people with mild to moderate COVID-19 who are at high risk for progression to severe disease and/or hospitalization (see Table 3a). At this time, however, the Panel recommends against the use of bamlanivimab plus etesevimab for the treatment of COVID-19 (AIII) because the Gamma (P.1) and Beta (B.1.351) VoC, which have reduced susceptibility to both bamlanivimab and etesevimab, are circulating in the United States; distribution of this agent has consequently been paused.8 See the Centers for Disease Control and Prevention (CDC) COVID-19 Data Tracker website for the latest information on variant proportions by region in the United States. Casirivimab plus imdevimab and sotrovimab are expected to remain active against these variants.

Criteria for Using Anti-SARS-CoV-2 Monoclonal Antibodies Under the Emergency Use Authorizations

The FDA EUAs for the anti-SARS-CoV-2 monoclonal antibodies originally included a list of specific conditions that placed patients at high risk for clinical progression. On May 14, 2021, the FDA broadened these criteria.5,6 Notable changes included lowering the body mass index (BMI) cutoff from ≥35 to >25 and adding other conditions and factors (e.g., pregnancy, race or ethnicity). There are no longer any age criteria (other than being aged ≥12 years) for using these agents in patients with the following conditions: sickle cell disease, neurodevelopmental disorders, medical-related technological dependence, asthma, cardiovascular disease, hypertension, and chronic lung disease.

Recommendations

The strength of the evidence for using anti-SARS-CoV-2 monoclonal antibodies varies depending on the factors that place patients at high risk for progression to severe COVID-19 and/or hospitalization. The recommendations for treatment are based on the following criteria from the FDA EUAs.

Medical Conditions or Other Factors That Were Represented in Clinical Trials That Evaluated Anti-SARS-CoV-2 Monoclonal Antibodies

Aged ≥65 years (AIIa)

Obesity (BMI >30) (AIIa)

Diabetes (AIIa)

Cardiovascular disease (including congenital heart disease) or hypertension (AIIa)

Chronic lung diseases (e.g., chronic obstructive pulmonary disease, moderate-to-severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension) (AIIa)

Other Conditions or Factors That Had Limited Representation in Clinical Trials but Are Considered Risk Factors for Progression to Severe COVID-19 by the Centers for Disease Control and Prevention

An immunocompromising condition or immunosuppressive treatment (AIII). Many experts strongly recommend therapy for patients with these conditions, despite their limited representation in clinical trials.

Being overweight (BMI 25–30) as the sole risk factor (BIII)

Chronic kidney disease (BIII)

Pregnancy (BIII)

Sickle cell disease (BIII)

Neurodevelopmental disorders (e.g., cerebral palsy) or other conditions that confer medical complexity (e.g., genetic or metabolic syndromes and severe congenital anomalies) (BIII)

Medical-related technological dependence (e.g., tracheostomy, gastrostomy, or positive pressure ventilation that is not related to COVID-19) (BIII)

It is important to note that the likelihood of developing severe COVID-19 increases when a person has multiple high-risk conditions or comorbidities.9-11 Other factors (e.g., race or ethnicity) or medical conditions may also place individual patients at high risk for progression to severe COVID-19. The current EUAs state that the use of anti-SARS-CoV-2 monoclonal antibodies may be considered for many of these other patients. For additional information on medical conditions and factors that are associated with increased risks for progression to severe COVID-19, see the CDC webpage Extra Precautions: People With Certain Medical Conditions. Health care providers should consider the benefits and risks of using anti-SARS-CoV-2 monoclonal antibodies for each individual patient.7

The Panel’s recommendations for using anti-SARS-CoV-2 monoclonal antibodies according to the updated EUA criteria are based on preliminary results from the clinical trials that evaluated these products. The details on the study designs, methods, and follow-up periods for these trials are currently limited. When peer-reviewed data from the Phase 3 trials become publicly available, the Panel will review the results and update the recommendations if necessary.

See the Considerations in Children section below for additional information on using these products in nonhospitalized children with COVID-19.

Using Anti-SARS-CoV-2 Monoclonal Antibodies in Patients Hospitalized for COVID-19

The FDA EUAs do not authorize the use of anti-SARS-CoV-2 monoclonal antibodies for the following patients:

Those hospitalized for COVID-19,

Those who require oxygen therapy due to COVID-19, or

Those who are on chronic oxygen therapy due to an underlying non-COVID-19-related comorbidity and who require an increase in oxygen flow rate from baseline because of COVID-19.

The FDA EUAs do permit the use of these agents in patients who are hospitalized for a diagnosis other than COVID-19, provided they have mild to moderate COVID-19 and are at high risk for progressing to severe disease.12-14

Anti-SARS-CoV-2 monoclonal antibodies have been evaluated in hospitalized patients with severe COVID-19. A substudy of the ACTIV-3 trial randomized patients who were hospitalized for COVID-19 to receive bamlanivimab 7,000 mg or placebo, each in addition to remdesivir. On October 26, 2020, following a prespecified interim futility analysis, enrollment into this study was stopped due to the lack of a clinical benefit.15,16

There are now data that support the use of casirivimab 4,000 mg plus imdevimab 4,000 mg in hospitalized patients with COVID-19 who are seronegative for the anti-spike protein antibody. In the RECOVERY study, hospitalized patients with COVID-19 were randomized to receive standard of care with casirivimab 4,000 mg plus imdevimab 4,000 mg IV or standard of care alone. There was no difference in 28-day all-cause mortality between the casirivimab plus imdevimab arm and the standard of care arm; 944 of 4,839 patients (20%) in the casirivimab plus imdevimab arm died versus 1,026 of 4,946 patients (21%) in the standard of care arm (rate ratio 0.94; 95% CI, 0.86–1.03; P = 0.17). However, in the subgroup of patients who were seronegative for the anti-spike protein antibody, there was a significant reduction in 28-day all-cause mortality in the casirivimab plus imdevimab arm: 396 of 1,633 patients (24%) died in the casirivimab plus imdevimab arm compared to 451 of 1,520 patients (30%) in the standard of care arm (rate ratio 0.80; 95% CI, 0.70–0.91; P = 0.001).17 It should be noted that this higher dose of casirivimab plus imdevimab is not available through the current EUA, and at this time, casirivimab plus imdevimab is only authorized for use in nonhospitalized patients with COVID-19. In addition, rapid serology testing that can identify seronegative individuals is currently not widely available.

Anti-SARS-CoV-2 monoclonal antibodies may be available through expanded access programs for the treatment of immunocompromised patients who are hospitalized because of COVID-19. It is not yet known whether these antibodies provide clinical benefits in people with B-cell immunodeficiency or other immunodeficiencies.

SARS-CoV-2 Variants of Concern or Interest and Their Susceptibility to Anti-SARS-CoV-2 Monoclonal Antibodies

In laboratory studies, some CDC SARS-CoV-2 VoC or variants of interest (VoI) that harbor certain mutations have markedly reduced susceptibility to a number of the FDA EUA monoclonal antibody therapies.18 However, the impact of these mutations on the patient’s clinical response to anti-SARS-CoV-2 monoclonal antibody combinations varies, as do the proportions of these variants in different geographic regions.

Some of the key variants that have been identified are:

Alpha (B.1.1.7) variant: This VoC retains in vitro susceptibility to all the anti-SARS-CoV-2 monoclonal antibodies that are currently available through EUAs.5,6

Beta (B.1.351) variant: This VoC includes the E484K and K417N mutations, which results in a marked reduction in in vitro susceptibility to bamlanivimab and etesevimab.5 In vitro studies also suggest that this variant has markedly reduced susceptibility to casirivimab, although the combination of casirivimab and imdevimab appears to retain activity; sotrovimab appears to retain activity as well.6,7

Gamma (P.1) variant: This VoC includes the E484K and K417T mutations, which results in a marked reduction in in vitro susceptibility to bamlanivimab and etesevimab.5,19,20 This variant also has reduced susceptibility to casirivimab, although the combination of casirivimab and imdevimab appears to retain activity; sotrovimab appears to retain activity as well.6,7

Delta (B.1.617.2) variant: This is the predominant VoC in the United States. The Delta variant contains the L452R mutation, which results in a modest decrease in in vitro susceptibility to the combination of bamlanivimab and etesevimab, although the clinical implications of this finding are not fully known. Sotrovimab and casirivimab plus imdevimab appear to retain activity.6,7,21

Epsilon (B.1.429/B.1.427) variant: This VoI (also called 20C/CAL.20C) includes the L452R mutation. There appears to be a modest decrease in in vitro susceptibility to the combination of bamlanivimab and etesevimab, although the clinical implications of this finding are not fully known.5 Sotrovimab and casirivimab plus imdevimab appear to retain activity.6,7,21

Iota (B.1.526) variant: This VoI includes the E484K mutation and is associated with a reduced in vitro susceptibility to the combination of bamlanivimab and etesevimab, although the clinical implications of this finding are not fully known.5 In vitro studies suggest that the E484K mutation may reduce susceptibility to casirivimab, although the combination of casirivimab and imdevimab appears to retain activity; sotrovimab appears to retain activity as well.6,7,21

Click here to view this table.

Table A. SARS-CoV-2 Variants of Concern and Interest and Susceptibility to Anti-SARS-CoV-2 Monoclonal Antibodies

Ongoing population-based genomic surveillance of the types and proportions of circulating SARS-CoV-2 variants, as well as studies on the susceptibility of different variants to available anti-SARS-CoV-2 monoclonal antibodies, will be important in defining the utility of specific monoclonal antibodies in the future.

Clinical Trials

See Table 3a for information on the clinical trials that are evaluating the safety and efficacy of anti-SARS-CoV-2 monoclonal antibodies in patients with COVID-19. Health care providers are encouraged to discuss participation in anti-SARS-CoV-2 monoclonal antibody clinical trials with patients who have mild to moderate COVID-19.

SARS-CoV-2 Vaccination

SARS-CoV-2 vaccination should be deferred for ≥90 days in people who have received anti-SARS-CoV-2 monoclonal antibodies. This is a precautionary measure, as the antibody treatment may interfere with vaccine-induced immune responses.22

For people who develop COVID-19 after receiving SARS-CoV-2 vaccination, prior vaccination should not affect treatment decisions, including the use of and timing of treatment with monoclonal antibodies.22

Monitoring

These anti-SARS-CoV-2 monoclonal antibodies should be given as either IV infusions or SQ injections and should only be administered in health care settings by qualified health care providers who have immediate access to emergency medical services and medications that treat severe infusion reactions.

Patients should be monitored during the IV infusion or SQ injections and for at least 1 hour after the infusion or injections are completed.

Adverse Effects

Hypersensitivity, including anaphylaxis and infusion-related reactions, has been reported in patients who received anti-SARS-CoV-2 monoclonal antibodies. Rash, diarrhea, nausea, dizziness, and pruritis have also been reported.6,7,13

Drug-Drug Interactions

Drug-drug interactions are unlikely between the authorized anti-SARS-CoV-2 monoclonal antibodies and medications that are renally excreted or that are cytochrome P450 substrates, inhibitors, or inducers (see Table 3c).

Considerations in Pregnancy

The use of anti-SARS-CoV-2 monoclonal antibodies can be considered in pregnant people with COVID-19, especially those who have additional risk factors for severe disease (see the EUA criteria for the use of these products above).

As immunoglobulin (Ig) G monoclonal antibodies, the authorized anti-SARS-CoV-2 monoclonal antibodies would be expected to cross the placenta. There is no pregnancy-specific data on the use of these monoclonal antibodies; however, other IgG products have been safely used in pregnant people when their use is indicated. Therefore, these products should not be withheld in the setting of pregnancy. When possible, pregnant and lactating people should be included in clinical trials that are evaluating the use of anti-SARS-CoV-2 monoclonal antibodies.

Considerations in Children

Please see Special Considerations in Children for therapeutic recommendations for children.

Drug Availability

Casirivimab plus imdevimab and sotrovimab are available through FDA EUAs. Currently, distribution of bamlanivimab plus etesevimab has been halted in the United States. Updates on the distribution of bamlanivimab plus etesevimab are available from the U.S. Department of Health and Human Services Bamlanivimab/Etesevimab website. Efforts should be made to ensure that the communities that are most affected by COVID-19 have equitable access to these monoclonal antibodies.