COVID-19 Therapies: Monoclonal Antibodies, Convalescent Plasma and Medications: Frequently Asked Questions
While we regularly review and update the information provided here, this FAQ reflects only the best information available at a given point in time. The COVID-19 pandemic is a rapidly evolving global health crisis and new information may have become available since the revision date for each published FAQ.
(Version 9.2; last updated April 7, 2022)
Input from Beth Shaz, MD; Cindy Dunbar, MD; Chris Hillyer, MD; Parameswaran Hari, MD; Terry Gernsheimer, MD; Richard Davey, MD; and Evan Bloch, MD.
Note: Please review ASH's disclaimer regarding the use of the following information. The advent of the Omicron variant is changing the landscape of therapeutics rapidly, and we recommend checking the National Institutes of Health website for updated information.
What monoclonal antibody therapies are available for prevention or treatment of COVID-19 disease?
Multiple engineered monoclonal antibodies directed against the SARS-CoV-2 spike protein have been developed and tested. Initial clinical trials of monoclonal antibody therapies in hospitalized patients with severe COVID-19 disease were stopped due to futility, with no evidence of benefit in preventing ICU admission or death, or other critical disease endpoints. This lack of benefit is not surprising given that passive antibody administration is unlikely to improve clinical status in most patients already making their own anti-COVID antibodies a week or more after infection. In contrast, administration of antibodies to non-hospitalized outpatients has shown promise in preventing hospitalization or progression to severe disease. Additionally, administration of a monoclonal antibody to nursing home residents and staff soon after a high-risk exposure was effective in decreasing the incidence of infection and death. These trials have recently been reviewed.
The U.S. Food and Drug Administration (FDA) has issued sequential emergency use authorizations (EUAs) allowing administration of a series of products consisting of one or two monoclonal antibodies to non-hospitalized individuals (or those hospitalized for an indication other than COVID-19 disease) with a positive SARS-CoV-2 test and one or more risk factors for severe COVID-19 disease, including age and/or a broad list of medical conditions. Several products also received an EUA for post-exposure prophylaxis or pre-exposure prevention in high-risk individuals.
However, with the evolution of viral spike protein mutant strains, particularly Omicron, the majority of available single or even double monoclonal antibody preparations have shown reduced neutralizing activity in the laboratory and are presumed less effective for prevention or protection against disease progression, although clinical studies documenting breakthrough infections or loss of efficacy are lacking. Information and recommendations are constantly evolving and mostly unpublished regarding activity of each preparation against Omicron. A database of information provided by manufacturers, regulators, and academics on the activity of both vaccines and antibody therapies against variants is updated daily by the National Institutes of Health (NIH).
It is critical that clinicians consult updated EUA information from the FDA or other regulatory and health agencies before making any decisions regarding administration of a monoclonal antibody product to any individual patient.
Currently, monoclonal antibody treatment of patients with documented COVID-19 within 10 days of symptom onset is limited to sotrovimab (only in regions with <50% Omicron B.2 variant; though this variant is rapidly overtaking the B.1 variant) and bebtelovimab for all patients including those with Omicron B.2. For pre-exposure prophylaxis in high-risk patients (see below), Evushield (tixagevimab/cilgavimab) remains active; however, the recommended dosing was recently doubled based on decreased activity against Omicron B.2. Patients previously receiving the original dose formulation are asked to return to their health care providers to receive a second dose. Whether the dosing interval will need to be shortened from the current six months is currently under consideration by the FDA and Centers for Disease Control and Prevention (CDC).
In what settings should treatment with monoclonal antibody therapies be considered for immunocompromised or other hematology patients?
The EUAs for monoclonal antibodies include broad criteria for “high risk,” and they are thus eligible for infusion in outpatients (1) following documented SARS-CoV-2 infection, (2) as postexposure prophylaxis, or (3) as pre-exposure prophylaxis. Criteria relevant to hematology patient populations specifically include immunosuppressive disease or immunosuppressive treatment (thus post-allogeneic transplantation, active or recent chemotherapy or immunotherapy, active malignancy) or sickle cell anemia, in patients unlikely to respond optimally to vaccination, or in those not fully vaccinated. The EUAs refer to the CDC website for a current list of high-risk criteria to consider. Patients with moderate to severe immune compromise due to a medical condition or receipt of immunosuppressive treatments who may not mount an adequate response to COVID-19 vaccination are eligible in the EUAs, including for pre-exposure prophylaxis. The list below summarizes a set of indicators tailored to hematology and other immunosuppressed patients:
- Undergoing treatment for cancer
- Solid organ transplant within the past three months or any history of lung transplant
- Bone marrow transplant within the past 12 months or receiving immunosuppressive therapies
- Primary immunodeficiency disorder with profound T- or B-cell dysfunction
- T-cell depleting therapy with CD4 count < 300 cells/mm3 or, for children, <15%
- B-cell depleting therapy within the past six months and no evidence of B-cell recovery
- Hypogammaglobulinemia (IgG by age group: <200 mg/dL [2 mo. - ≤ 12 mo.], <400 mg/dL [> 12 mo. - ≤ 11 years), < 500 mg/dL [≥ 12 years])
- Systemic corticosteroids with prednisone equivalent of ≥ 20 mg/day or ≥ 2 mg/kg/day for ≥ 14 days
- Advanced or untreated HIV
- Other immunocompromised host with absolute lymphocyte count < 300 cells/mm3
Patients should be at least two weeks postvaccination and can be retreated every six months. Prior COVID-19 infection does not preclude monoclonal antibody treatments, nor do immunosuppressive or anticancer therapies. Updated considerations regarding each monoclonal antibody regimen should be referenced before initiating treatment.
Data on vaccine response in many categories of hematology patients are rapidly becoming available. Current information suggests that patients with chronic lymphocytic leukemia, multiple myeloma, lymphoma, or acute leukemias are at the highest risk for a poor response to vaccination. In particular, those patients treated with agents depleting or suppressing the function of B cells or plasma cells, such as rituximab, daratumumab, blinatumomab or related antibodies; recipients of CAR-T cells targeting B cell or plasma cell antigens; allogeneic transplantation patients on immunosuppression or within two years of transplantation; or patients undergoing or recovering from therapies for acute leukemias are at the highest risk. These patients should be considered for pre-exposure prophylaxis, or treatment immediately following a high-risk exposure or a positive SARS-CoV-2 antigen or PCR test, if predicted, effective antibodies are available based on strain considerations in the area.
It is important for hematologists and other providers to discuss the potential benefit of monoclonal antibodies with their patients as soon as they meet high-risk criteria, and to stress the importance of patients reporting symptoms and/or a positive SARS-CoV-2 test or high-risk exposure to their health care provider immediately. Antibodies are only effective when given early after viral infection, and during surges in infection rates, availability of antibodies is limited and administration can be logistically challenging. Oral antivirals are available via EUAs for early treatment of at-risk patients; however, availability is limited. These medications would be highly relevant for immunocompromised patients in addition to or as an alternative to monoclonal antibodies, particularly for strains resistant to available antibodies.
Monoclonal antibody therapies have not yet been tested, nor have they been shown to be protective in large cohorts of immunocompromised or other at-risk hematology patients. Thus, such patients should be counseled to receive all recommended vaccinations, wear masks, and avoid high-risk activities as much as possible, even following antibody infusions.
What are relevant considerations regarding SARS-CoV-2 antiviral medications in hematology patient populations?
Two oral antivirals recently became available via EUAs for early treatment of patients at high risk of severe COVID-19 disease outcomes: PAXLOVID (co-packaged nirmatrelvir and ritonavir) or molnupiravir. Both are approved for initiation within five days of symptom onset and consist of five days of oral treatment. Hematology patients falling into the at-risk categories listed as appropriate for monoclonal antibodies would also be considered eligible and appropriate for either of these oral antivirals.
Both drugs would be predicted to be active against all currently circulating strains including the various Omicron variants, in contrast to several of the monoclonal antibodies, as detailed above. PAXLOVID reduced the risk of hospitalization or death by 88 percent compared to placebo, and molnupiravir reduced hospitalization and death by 30 percent. Currently, availability of these oral antivirals remains limited, although a new “Test to Treat” program has recently been initiated in the US to simplify and speed access to these medications for patients and physicians. It is important to inform patients of the importance of contacting their health care provider immediately upon symptom onset or a positive SARS-CoV-2 test in order to start the process of obtaining either medication or an appropriate monoclonal antibody..
Rivaroxaban and apixaban have significant drug interaction with ritonavir, a component of PAXLOVID. Co-administration will increase the concentration of apixaban or rivaroxaban and may increase the risk for bleeding. As PAXLOVID treatment lasts only five days, the clinical significance of the interaction with DOACs remains unclear. Alternatives to PAXLOVID in high-risk nonhospitalized patients with COVID-19 include Molnupiravir, Sotrovimab, or Remdesivir. The potential risks and benefits of using PAXLOVID in an individual patient on rivaroxaban/apixaban must be weighed in the context of whether alternatives are available and the individual patient’s susceptibility to severe COVID-19 disease. For hospitalized patients, dexamethasone and remdesivir are not believed to have effects on anticoagulant metabolism. Monoclonal antibodies should also not affect drug levels.
What is the current status of COVID-19 convalescent plasma (CCP) for prevention or treatment of COVID-19 disease?
Particularly before monoclonal antibodies were available, multiple studies focused on the use of CCP to deliver antibodies to patients with COVID-19 without unexpected or serious adverse events. Many of the early studies were observational and nonrandomized in patients with severe or critical disease, complicated by the evolution of additional treatment interventions over time, such as steroids, antivirals, and other drugs; by patient heterogeneity; and by a lack of detailed analyses of neutralizing antibody content of infused units. More than 90,000 patients were enrolled in an FDA-sponsored expanded access program coordinated by Mayo Clinic. In addition, an EUA was issued by the FDA allowing CCP administration to hospitalized COVID-19 patients outside clinical trials. While many patients improved clinically, the specific role of CCP was unclear, given treatment with other therapies including antivirals and/or corticosteroids. Multiple randomized controlled trials (RCTs) enrolling severely ill hospitalized patients failed to show benefit, which is not surprising based on theoretical considerations and experience with convalescent plasma for other infections, and all support administering CCP early relative to symptom onset.
The data regarding administration of CCP prior to hospitalization and early after symptom onset are less clear and still evolving. While at least one small RCT reported that infusion of high-titer CCP within three days of symptom onset in at-risk patients yielded less progression to severe respiratory disease, NIH halted accrual to the C3PO trial for futility, after enrolling 511 of 900 planned patients presenting to the emergency department within one week of onset. A large double-blinded RCT of high-titer CCP in outpatients was recently published and showed a relative risk reduction of 54 percent in the CCP group. Of note, all patients hospitalized were unvaccinated or partially vaccinated, and the enrollees were not selected to be high risk; thus, applicability to the immunocompromised is unclear. It is possible that the NIH C3PO trial cohort represented more advanced patients presenting to the emergency department versus outpatients earlier in their disease trajectory enrolled in the RCTs. It is important to stress that all these trials were carried out pre-Omicron.
The World Health Organization, Infectious Diseases Society of America (IDSA), and NIH do not currently recommend use of CCP in COVID-19 infected or exposed patients, including immunocompromised patients, outside clinical trials. The initial EUA issued by the FDA remains active, but was revised earlier in 2021 to limit CCP administration to hospitalized patients early after admission with high-titer units. Currently, CCP cannot be administered to outpatients, but given the more promising recent results for outpatient administration of high-titer CCP, a request to modify the EUA is being considered.
The evolution of mutant strains such as Delta and Omicron, resistant to the most widely available anti-spike monoclonal antibodies (see above), and the lack of availability of monoclonal antibodies in many countries worldwide have the potential to rekindle use of CCP. On one hand, evidence that patients who were previously infected with earlier strains of SARS-CoV-2 can develop disease from new strains such as Omicron suggests that CCP units collected following recovery from strains prevalent earlier in the pandemic may have little activity. Conversely, polyclonal antibody responses theoretically have advantages over monoclonal antibodies in terms of retaining activity against evolving mutants. Units of CCP collected from fully vaccinated individuals who have had a recent Omicron or other variant infection likely contain extremely high titers of antibodies and deserve further study.
ASH Comment on EUA for Convalescent Plasma
In response to the EUA, ASH has published additional commentary and recommendations regarding convalescent plasma.