INTRODUCTION

By February 26, 2022, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic had affected over 430 million people and caused nearly 6 million deaths [1]. Several risk factors for poor outcomes of coronavirus disease-2019 (COVID-19) have been established, largely measures of age, comorbidities, and immunocompromising conditions [2–5]. Solid organ transplant recipients (SOTR) have been particularly susceptible to poor outcomes, with an early multicenter cohort study reporting an intubation rate of 31% and 28-day mortality rate of 20.5% among hospitalized SOTRs [6▪▪]. Although much of these poor outcomes can be attributed to a high burden of comorbidities [6▪▪,7▪,8], COVID-19 in SOTRs has been associated with cardiac events (odds ratio [OR] 1.23), acute kidney injury (OR 2.35), allograft rejection (OR 31.79), and graft loss (OR 79.67) in the subsequent 90 days [9▪].

Several interventions have lessened the risk for poor outcomes of COVID-19 in SOTRs, including vaccination and early administration of therapeutics. Here, we aim to review the use of antispike monoclonal antibodies for the prevention and treatment of COVID-19 in SOTRs. 

Box 1:

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ANTI-SPIKE MONOCLONAL ANTIBODIES

The SARS-CoV-2 spike protein is an essential component of viral entry into human cells through virus-host cell membrane fusion [10]. This critical role in viral pathogenesis has made the spike protein a prime target for therapeutics. Monoclonal antibodies against the spike protein were initially detected in the blood of a patient who recovered from COVID-19. These immunoglobulin-G molecules were subsequently manufactured in laboratories to develop immunotherapies that aimed to impede the process of virus entry and limit host infection with SARS-CoV-2.

The two initial antispike monoclonal antibody preparations, bamlanivimab and casirivimab-imdevimab, were studied in randomized, placebo-controlled clinical trials (RCT) of outpatients with mild-to-moderate COVID-19. These drugs reduced the risk of hospitalization and emergency department (ED) visits (bamlanivimab, 1.6% versus 6.3%) or medically attended visits (casirivimab-imdevimab, 3% versus 6%) [11▪▪,12▪▪]. On the basis of these trials, bamlanivimab and casirivimab-imdevimab were each granted emergency use authorization (EUA) by the United States (US) Food and Drug Administration (FDA) for treatment of mild-to-moderate COVID-19 in patients with comorbidities associated with higher risk of progression to severe disease, such as SOTRs [13].

Since then, EUAs have been issued for other antispike monoclonal antibodies including bamlanivimab-etesevimab, sotrovimab, bebtelovimab, and tixagevimab–cilgavimab (Table 1) [14–17]. As the SARS-CoV-2 pandemic progressed, variants of concern (VOC) have developed that affected the clinical utility of these antispike monoclonal antibodies. The emergence of SARS-COV-2 B.1351 (Beta) and P.1 (Gamma) led to the revocation of bamlanivimab EUA, whereas B.1.1.529 (Omicron) made bamlanivimab-etesevimab and casirivimab-imdevimab ineffective for postexposure prophylaxis (PEP) and treatment. Sotrovimab and bebtelovimab maintain activity and are authorized for treatment of SARS-CoV-2 B.1.1.529 (Omicron) [18,19], whereas the tixagevimab–cilgavimab combination is also believed to retain efficacy as preexposure prophylaxis (PrEP) at double the initial dose recommendation, owing to reduced activity against the Omicron VOC [20].

Table 1 - Current or previously authorized antispike monoclonal antibodies for coronavirus disease-2019 Indication Administration RCT efficacy SOTR data Resistant variants of concern Bamlanivimab Treatment Intravenous 0.25a[11▪▪] Yes B.1.351 (Beta)P.1 (Gamma)B.1.617.2 (Delta)B.1.1.519 (Omicron) Bamlanivimab-etesevimab Treatment Intravenous 0.30a[22▪] Yes B.1.351 (Beta)P.1 (Gamma)B.1.1.519 (Omicron) PEP 0.56b,c[70] No Casirivimab-imdevimab Treatment Intravenous (preferred), subcutaneous 0.28a[71] Yes B.1.1.519 (Omicron) PEP Intravenous, subcutaneous 0.19b[69] No Sotrovimab Treatment Intravenous 0.14a[51▪▪] No BA.2 (Omicron sublineage) Bebtelovimab Treatment Intravenous 1.7%d[19] No None Tixagevimab-cilgavimab PrEP Intramuscular 0.23b[20] No None

PEP, postexposure prophylaxis; PrEP, preexposure prophylaxis; RCT, randomized clinical trial; SOTR, solid organ transplant recipient.

aRelative risk of progression to severe disease (defined as hospitalization or death within 28 days).

bRelative risk of symptomatic COVID-19.

cBased on an RCT of bamlanivimab monotherapy for PEP. Based on this trial, bamlanivimab-etesevimab was authorized for PEP due to then-currently circulating variants resistant to bamlanivimab monotherapy.

dRate of hospitalization in an uncontrolled, open-label trial of high-risk adults with mild-to-moderate COVID-19.

TREATMENT OF MILD-TO-MODERATE CORONAVIRUS DISEASE-2019 IN SOLID ORGAN TRANSPLANT RECIPIENTS

Antispike monoclonal antibodies are recommended for early treatment of laboratory-confirmed mild-to-moderate COVID-19 in SOTRs. Patients should be treated within the first 7–10 days of symptom onset. Patients with severe disease, those hospitalized for COVID-19 or requiring oxygen supplementation, are excluded based on EUA criteria.

The authorization of antispike monoclonal antibodies in SOTRs is based on the original RCTs that included standard-risk and high-risk patients [11▪▪,21▪▪,22▪]. Subsequent observational, retrospective studies of antispike monoclonal antibodies in high-risk patients, including SOTRs, have shown reductions in hospitalizations [23–30], ED visits [24–27], intensive care unit (ICU) admission [23], and mortality [23,27]. A higher burden of comorbid medical conditions and immunocompromised status (OR 2.78) have been associated with higher chance of hospitalization [30,31].

There are no RCTs that specifically assessed the efficacy and safety of antispike monoclonal antibodies in SOTRs. However, after authorization for use, there have been increasing numbers of reports suggesting their efficacy and safety in SOTRs. These data are largely limited to small case series and larger treatment cohorts that compared the outcomes to historical cohorts. All these retrospective studies have assessed bamlanivimab monotherapy, bamlanivimab-etesevimab, and casirivimab-imdevimab treatments. In contrast, there are currently no studies examining sotrovimab or bebtelovimab in SOTRs.

Based on these observational retrospective studies, SOTRs who received antispike monoclonal antibodies have rates of hospitalization ranging from 0% to 16.7% [32▪,33–38,39▪▪,40,41▪], ICU admission 0% to 8.3% [32▪,36,39▪▪], and mortality 0% to 4.2% [32▪,33,36,37,41▪]. These rates are comparably lower than previous historical cohorts. From studies with a comparator group, there were lower rates of progression to severe disease [33], ED visits [38], hospitalization [38,39▪▪,41▪], and mortality [33,41▪] among those who received antispike monoclonal antibodies. One study found receipt of an antispike monoclonal antibody to be protective from hospitalization or ED visit (hazard ratio 0.216) after adjustment for age, chronic kidney disease, race, and ethnicity [38]. Furthermore, these therapies appear to confer more benefit when given earlier in the disease course [30,32▪]. Despite the limitations of these retrospective studies, their collective findings support the conclusion that antispike monoclonal antibodies appear to be associated with improved outcomes in SOTRs.

Antispike monoclonal antibody therapy appears beneficial among high-risk patients, including SOTRs, who develop breakthrough COVID-19 after completion of primary vaccination series. One study of all high-risk patients, including SOTRs, found casirivimab-imdevimab treatment was associated with lower risk of hospitalization regardless of vaccination status [42]. Another large cohort of fully vaccinated high-risk patients, including SOTRs, also found antispike monoclonal antibody therapy to reduce the odds of hospitalization. This effect was greater among patients with more comorbid conditions [43]. It is believed that antispike monoclonal antibodies may provide benefit among vaccinated SOTRs as they have a suboptimal response to COVID-19 vaccination. An observational study of fully vaccinated SOTRs with breakthrough COVID-19 found 14.3% presented with severe disease [44▪]. However, among those who presented with mild-to-moderate disease and were treated early with monoclonal antibody therapy, only 3.4% progressed to severe disease requiring hospital admission. Smaller cohorts have also been reported and showed similar outcomes [45,46]. These data suggest a role for antispike monoclonal antibody therapy in treatment of vaccinated SOTRs with breakthrough COVID-19.

Recent data suggest antispike monoclonal antibodies may have greater efficacy among seronegative patients, even those with severe or protracted disease [47,48]. SOTRs, especially those who have also received B-cell-depleting agents, often do not mount a sufficient humoral immune response [49,50] and may benefit from passive immunotherapy. Accordingly, there has been interest in serologic testing to assess humoral immune response to vaccination and natural infection, which could then guide the use of monoclonal antibodies. However, serologic assessment of antibody status has not been standardized, and clinical validation has been lacking. Indeed, this is a limitation common to most studies of antispike monoclonal antibodies.

OTHER OPTIONS FOR OUTPATIENT THERAPY FOR CORONAVIRUS DISEASE-2019

In addition to antispike monoclonal antibodies, the four other therapies authorized or approved for treatment of mild-to-moderate COVID-19 in high-risk individuals in the US include remdesivir, nirmatrelvir-ritonavir, molnupiravir, and high-titer convalescent plasma. Although none of these therapies have been compared directly, they have individually been shown to reduce risk of hospitalization in high-risk patients with mild-to-moderate COVID-19 [51▪▪,52▪,53▪,54,55]. Outside of the lower efficacy of molnupiravir and high-titer convalescent plasma, the clinical effectiveness of sotrovimab, nirmatrelvir-ritonavir, and remdesivir appear to be comparable when given early during mild-to-moderate COVID-19 (Table 2). Combination therapy with these agents with different mechanisms of action has been suggested, but this has not been systemically evaluated. The current scarcity in drug supply is preventing the use of dual therapy for a single patient.

Table 2 - Comparison of currently authorized outpatient therapies for mild-to-moderate COVID-19 in all high-risk patients, including solid organ transplant recipientsa Administrationb Relative risk of hospitalization or death within 28 days Number needed to treat to prevent 1 hospitalization Advantages Disadvantages Sotrovimabc[51▪▪] Single IV dose over 15 min, within 7 days 0.15 17 Single infusion Requires IV administration and one hour of observation Remdesivir [52▪] 3 daily IV doses, within 7 days 0.13 22 FDA approved; most widely available Multiple daily IV infusions Nirmatrelvir-ritonavir [53▪] 5 days PO, within 5 days 0.11 18 Orally administered Numerous drug–drug interactions with ritonavir, including calcineurin inhibitors Molnupiravir [54] 5 days PO, within 5 days 0.70 35 Orally administered Lower efficacy, concerns for mutagenicity Convalescent plasma [55] Single IV infusion, within 9 days 0.46 30 Single infusion IV administration, lower efficacy

FDA, Food and Drug Administration; IV, intravenous; PO, per os.

aSpecific data for solid organ transplantation does not yet exist. All drugs are under emergency use authorization, except for the FDA-approved remdesivir

bTiming is relative to date of symptom onset.

cClinical data for bebtelovimab have not been published at the time of writing. Bebtelovimab is given as an IV push over 30 s, within 7 days of symptom onset.

Each medication has its own advantages and drawbacks that should be considered when prescribing these therapies. Antispike monoclonal antibodies, high-titer convalescent plasma, and remdesivir are administered intravenously, necessitating 1 or 3 daily appointments in an outpatient infusion center. Nirmatrelvir is administered orally and obviates the need for an infusion center, but its use may result in significant drug–drug interactions on account of its pharmacologic booster, ritonavir. In SOTRs specifically, nirmatrelvir-ritonavir may lead to supratherapeutic levels of common immunosuppressant medications such as calcineurin inhibitors and mammalian target of rapamycin inhibitors. As such, use of nirmatrelvir-ritonavir in SOTRs requires a protocolized approach to management. Even close monitoring, such as therapeutic drug monitoring, may be difficult logistically since patients with COVID-19 are advised to isolate at home to prevent SARS-CoV-2 transmission. The other oral antiviral drug, molnupiravir, is not preferred by most providers due to its low efficacy and the potential for teratogenicity and mutagenesis. High-titer convalescent plasma likewise has lower efficacy than most current agents, although it is felt to be a safe option for SOTR [55–59]. Given the conflicting findings on efficacy, both the Infectious Diseases Society of American (IDSA) and National Institutes of Health recommend against the use of convalescent plasma for hospitalized patients, whereas the IDSA only recommends its use in ambulatory patients without access to other treatment options [60,61].

In our view, a programmatic approach that addresses logistical challenges should be implemented so antispike monoclonal antibodies such as sotrovimab are provided as the preferred agents for the treatment of mild-to-moderate COVID-19 in SOTRs. It provides passive immunotherapy to SOTRs who have impaired immune response to SARS-CoV-2, and who may have suboptimal response to COVID-19 vaccination. Its single dose offers convenience over three daily doses of intravenous remdesivir, avoids the problematic interactions with immunosuppressants from nirmatrelvir-ritonavir, and provides higher efficacy than molnupiravir. In addition to addressing the logistical challenges of parenteral therapeutics, it is important to ensure equity among the highest risk groups and under-represented populations. Recent studies have shown disparities in antispike monoclonal antibody use among those with disproportionately more high-risk comorbidities [62] and among racial and ethnic groups, even among SOTRs [38,63,64].

PRE-EXPOSURE PROPHYLAXIS

Vaccination remains the mainstay of COVID-19 prevention for all eligible patients, including SOTRs. However, SOTRs have suboptimal response to primary series and booster doses of COVID-19 vaccines. Accordingly, PrEP with antispike monoclonal antibodies has been suggested to provide additional protection in those whom vaccination is not anticipated to provide maximal benefit owing to immunosuppression, such as SOTRs.

In the US, the FDA has granted EUA for the monoclonal antibody combination tixagevimab–cilgavimab as PrEP for patients with moderate-to-severe immunocompromised status [17]. Authorization was based on data from two RCTs of over 5000 largely immunocompetent, unvaccinated adults. These studies found a single dose of tixagevimab–cilgivimab reduced the risk of symptomatic infection by 77% compared with placebo over a median of 3 months [65].

The RCTs did not specifically assess the efficacy of PrEP in SOTRs, but it is presumed individuals with a decreased response to vaccination would similarly benefit. In addition to SOTRs, there are many other patients considered moderately to severely immunocompromised, such as those with hematologic malignancies, bone marrow transplant recipients, primary immunodeficiencies, and receipt of CD20-depleting agents [17]. Due to the initial imbalance of high demand for a limited drug supply, healthcare institutions have been developed clinical prioritization tiers to preferentially provide PrEP to those at highest risk [66]. In our institution, SOTRs that are considered at the highest risk and are prioritized for PrEP include lung transplant recipients, small bowel transplant recipients, multiorgan transplant recipients, those who received T-cell depleting therapies for induction immunosuppression or treatment of rejection during the past 12 months, and those who received CD20-depleting agents for treatment of posttransplant lymphoproliferative disorder or antibody-mediated rejection. Eventually, once the drug supply is sufficient, all SOTRs will be eligible for PrEP with tixagevimab–cilgavimab. Real-world clinical experience on the efficacy and safety of tixagevimab–cilgavimab PrEP has yet to be evaluated in SOTRs and other immunocompromised populations.

POST-EXPOSURE PROPHYLAXIS

Despite an overall decreased immunologic response, SARS-CoV-2 vaccination among SOTRs provides significant reduction in the risk of severe disease [67]. In SOTRs with known exposure to SARS-CoV-2, guidance from the Centers for Disease Control and Prevention encourages individuals to remain vigilant for symptoms and, should they develop, to quarantine and undergo testing to reduce the risk of exposing others.

In the US, the FDA had previously issued EUA for casirivimab-imdevimab and bamlanivimab-etesevimab as PEP in high-risk patients, such as SOTRs, with close contact to an individual infected with SARS-CoV-2, defined as being within six feet for 15 min or more in a 24-h period [14,68]. The primary data supporting this practice were from RCTs demonstrating the safety and overall efficacy of these interventions in high-risk patient groups [69,70]. These clinical trials were not specific to SOTRs, and there are no transplant-specific data to assess the effectiveness of this approach. However, casirivimab-imdevimab and bamlanivimab-etesevimab are ineffective against the SARS-CoV-2 B.1.1.529 (Omicron) VOC and are no longer in use. The antispike monoclonal antibodies retaining activity against the Omicron variant, sotrovimab, bebtelovimab, and tixagevimab–cilgavimab, are not currently authorized for PEP, though further studies are underway.

SAFETY

Safety-related outcomes were favorable in the initial RCTs of antispike monoclonal antibodies [11▪▪,12▪▪,51▪▪,71]. Adverse events were uncommon, and rates of serious and mild adverse events were similar between the treatment and placebo groups. Rates of infusion reaction ranged from 1.0% to 2.3%. Subsequent observational studies showed similar results, ranging from 0.8% to 13.7% depending on study definitions and population [23–25,29,32▪,72,73]. Anaphylactic reactions are rare, though have also been reported [39▪▪]. For tixagevimab–cilgivimab, the rates of severe cardiac events, including myocardial infarction and congestive heart failure, were higher in the treatment group than placebo (0.6% versus 0.2%) [65]. These occurred in patients with preexisting cardiovascular risk factors without a clear temporal association to the administration of tixagevimab—cilgivimab.

Though there were initially theoretical concerns for these monoclonal antibody therapies precipitating acute rejection, most studies found few or no episodes of rejection within 30 days, noting that COVID-19 itself has been associated with rejection [9▪,32▪,37,39▪▪]. Additionally, the initial trials excluded pregnant patients, and little was known about the effect of these antibodies on pregnancy outcomes. However, initial reports have shown encouraging outcomes for mothers and newborns [74–76], though data is much more limited for SOTRs [77].

INFECTION PREVENTION AND CONTROL ISSUES

The maximal clinical benefit of antispike monoclonal antibody treatment is most evident early in the course of infection. The EUA recommend their use within 7–10 days of symptom onset, although real-world experience suggests SOTRs who receive earlier treatment had better outcomes [32▪]. However, this early time coincides with the period when patients have high viral loads and are likely in the highly infectious stage of illness. Accordingly, healthcare systems should be equipped to administer these treatments with infection prevention and control (IPAC) measures, to prevent SARS-CoV-2 transmission to healthcare personnel, patients, and other individuals [78]. Ideally, an infusion facility should be physically separated from traditional infusion facilities that serve non-COVID-19 patients. Medical personnel with direct contact with patients should be properly trained in IPAC protocols and practices, including use of personal protective equipment such as gowns, gloves, eye wear, and procedural masks. Patients should be advised to avoid public transportation when traveling to and from the infusion facilities and avoid lingering in common areas and waiting rooms. Patients should wear a mask at all times. SOTRs should be advised to remain in isolation for 20 days after the onset of clinical symptoms, regardless of treatment with antispike monoclonal antibody [79].

In contrast to the monoclonal antibodies used for treatment of mild-to-moderate COVID-19, tixagevimab–cilgavimab is provided as PrEP and may be given in traditional infusion facilities since eligible SOTRs should be uninfected and without SARS-CoV-2 exposure.

CONCLUSION

Antispike monoclonal antibodies are useful as treatment that limits the severity of COVID-19 in SOTRs, a population that is high-risk for poor outcomes. When given early in the course of infection, these therapies have been consistently shown to be safe and effective in this immunocompromised population, even among vaccinated patients. A multidisciplinary, programmatic approach is essential to identify and treat these patients early in their disease course. PrEP with tixagevimab–cilgavimab is recommended, although real-world efficacy in SOTRs remains to be seen. Continued surveillance of circulating variants and further study into novel methods to provide these therapies to high-risk patients is crucial to limit severity of COVID-19.

Acknowledgements

None.

Financial support and sponsorship

This work was supported by Mayo Clinic, Rochester, Minnesota, USA (R.R.R).

Conflicts of interest

R.R.R is the principal investigator of research funded by Regeneron, Roche, Gilead (all funds provided to his institution), and is a member of the Data Safety Monitoring Board of Novartis, on projects not directly related to this submission. All other authors have no potential conflicts of interest to report.

Funding: Intramural grant from Mayo Clinic (R.R.R)

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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