Introduction

This article is made available for historical review, monoclonal antibody use is not currently indicated for this condition.

COVID-19 illness is a clinical syndrome caused by a SARS-CoV-2 infection. It was first reported in Wuhan, China, in December 2019 and quickly spread to a pandemic level in 2020. A meta-analysis report stated that an estimated 18.2 million people died globally because of the COVID-19 pandemic between Jan 1, 2020, and the end of December 2021.[1] 

SARS-CoV-2 or severe acute respiratory syndrome coronavirus 2, is a single-stranded RNA virus with a close resemblance to the virus causing the 2003 SARS outbreak.[2] SARS-CoV-2 differs from MERS (middle east respiratory syndrome) and SARS (severe acute respiratory syndrome) coronaviruses in that it has a higher transmissibility and a lower fatality rate.[3] SARS-CoV-2 is transmitted by inhalation of contaminated droplets or direct fluid contact. It starts after an incubation period of around 5 days but could range from 2 to 14 days.

The clinical presentation varies from asymptomatic cases to severe disease with hypoxia and respiratory compromise. The United States National Institutes of Health (NIH) classifies the clinical manifestations of SARS-CoV-2 as follows:[NIH COVID GUIDELINES]

• Asymptomatic or Presymptomatic Infection: positive testing for SARS-CoV-2 but no symptoms consistent with COVID-19.
• Mild Illness: Individuals who have any of the various signs and symptoms of COVID-19 but do not have shortness of breath, dyspnea, or abnormal chest imaging.
• Moderate Illness: The presence of lower respiratory disease without hypoxia (oxygen saturation (SpO) ≥94% on room air).
• Severe Illness: Hypoxia, Spo <94% on room air, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO/FiO) <300 mm Hg, respiratory frequency >30 breaths/min, or lung infiltrates >50% to lung volume.
• Critical Illness: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction.

Mild to moderate cases of COVID-19 are usually managed on an outpatient basis. Patients requiring oxygen therapy to maintain their oxygenation are usually hospitalized and may require intensive care management for assisted ventilation, organ support, and treatment of secondary infections.

Management of non-hospitalized patients with COVID-19 in the outpatient setting involves triaging the severity of symptoms and the potential for clinical progression. Identifying patients who are at high risk for severe disease is of prime importance, so patients may be offered therapies that can deter their progression to severe disease. 

Monoclonal antibodies have been identified as a potential therapy to prevent COVID-19 disease progression in patients at risk for severe disease. Most antibodies made by the human body are polyclonal, meaning that they are derived from multiple B lymphocyte lineages and have slightly different specificities for target antigens. Monoclonal antibodies, however, are produced by a single B-lymphocyte clone and are highly specific for their target antigen.[4][5] Monoclonal antibodies have been in use since 1985 and have been used as therapies for malignancy, autoimmune disease, infectious organisms, and drug reversal.[6][7][8] 

In the race to decrease the global burden of COVID-19, several monoclonal antibodies were developed and granted emergency use authorizations (EUAs). However, as COVID-19 variants emerged, most of the monoclonal antibodies had their EUAs revoked due to limited efficacy against dominant circulating variants and subvariants. This activity reviews the pathophysiology and function of these monoclonal antibodies and the risks and benefits of these agents. However, it must be noted that according to the National Institutes of Health (NIH), none of these monoclonal antibodies are recommended in 2023 for the treatment of COVID-19. The only monoclonal antibody with an active EUA is tixagevimab co-packaged with cilgavimab, which is authorized for preexposure prophylaxis of COVID-19.[9] According to United States Food and Drug Administration (FDA) update on 1/6/2023, a SARS-CoV-2 Omicron subvariant is not anticipated to be neutralized by this monoclonal antibody combination; however, they are waiting for additional data to make their final decision.

Function

Monoclonal antibodies (mAbs) are derived from select B-lymphocytes from convalescent plasmas of recovered patients.[10] Most of the current therapeutic mAbs are IgGs (immunoglobulins subtype G) due to ease of production and prolonged circulating half-life.[11] Neutralizing antiviral monoclonal antibodies have been used clinically against Ebola virus disease (EVD), e.g., ZMapp[12], and respiratory syncytial virus (RSV), e.g., palivizumab. Neutralizing antibodies can directly neutralize the virus without the aid of other immune factors or cells.

Monoclonal antibodies against COVID-19 disrupt host cell entry by binding the angiotensin-converting enzyme 2 (AE2) receptor binding domain (RBD) of the virus. SARS-CoV-2 engages the host cell ACE2 receptor via the spike (S) glycoprotein to cause infection. This makes spike S glycoprotein on the coronavirus surface a common target for antiviral therapy, most notable of which are monoclonal antibodies.[13]

According to one study, single-cell sorting identified 4277 SARS-CoV-2 spike protein-specific memory B cells from just 14 COVID-19 survivors.[14] They were able to identify 453 neutralizing antibodies, the most potent of which recognized the spike protein RBD. The "extremely potent" monoclonal antibodies (mAb) allowed for lower quantities of antibodies to reach target efficacy with decreased cost and sustainable manufacturability.[14] 

Consequently, many different monoclonal antibodies (mAb) were developed and granted emergency use authorizations for the treatment of acute COVID-19 illness in patients with mild to moderate disease who were at high risk for progression to severe disease. Clinical data revealed that the use of mAbs in these patients reduced viral load and improved symptoms.[15][16] They were also shown to decrease hospitalizations in these patients.[16][17]

Like other RNA viruses, there is a high potential for mutation, and several variants of SARS-CoV-2 have been identified. Thus far, several variants of concern have been identified, such as the alpha variant (B1.1.7 lineage, United Kingdon (UK) origin), beta variant (B.1351 lineage, South African origin), gamma variant (P.1/B.1.1.28.1 lineage, Brazilian origin), and delta variant (B1.617.2 lineage, Indian origin).[18] These variants have key mutations in the spike protein of the virus, and in some cases, such as the UK variant, make the virus 43 to 82% more transmissible.[19]

On November 26, 2021, the World Health Organization (WHO) identified the Omicron variant (B.1.1.529) as a variant of concern (VOC). This variant carries a high number of mutations, especially in the main antigenic target of mAbs.[20] As of January 2023, all previously authorized monoclonal antibodies have lost their EUAs for the treatment of COVID-19 due to the resistance demonstrated by this variant.

Issues of Concern

A potential complication of human mAbs use against viral pathogens is that it may promote selection for escape mutants.[14] Many mAbs addressed this issue by using a combination of antibodies directed against non-overlapping epitopes.[14] However, as new variants and subvariants emerged, their efficacy against the SARS-CoV-2 virus dwindled to the point that they are no longer authorized for use. 

Since late 2020, the SARS-CoV-2 virus has mutated drastically, with the accumulation of several mutations and deletions in the binding domains of various mAbs.[21] These mutations have been found to reduce the neutralizing activity of several mAbs. 

Therefore, monoclonal antibody therapy is currently not indicated for the treatment of acute COVID-19, even if they meet the criteria on their EUAs. This is because, as of January 2023, the dominant circulating variants and subvariants are not effectively neutralized by any of the previously authorized mAbs. The FDA and the NIH advise against their use until further notice.

Clinical Significance

Analysis by Stokes et al. of confirmed cases reported to the CDC found that older individuals (≥65 years old) with underlying comorbidities have a much higher risk of hospitalizations than those without (45.4% vs. 7.6%). In the same patient population, mortality was also greatly increased compared to younger healthy individuals (19.5% vs. 1.6%).[22] Monoclonal antibody therapies were thus developed to be used in patients at risk for developing severe disease with the goal of decreasing hospitalizations and mortality. 

Individuals were identified as high risk if they had advanced age and/or underlying medical conditions that increase the risk of severe disease. According to the United States Centers for Disease Control and Prevention (CDC), conditions that have conclusive evidence demonstrating a higher risk of severe COVID-19 illness when acutely infected include:CDC: Risk Factors for Severe COVID-19 Illness

• Asthma
• Cancer
• Cerebrovascular disease
• Chronic kidney disease
• Bronchiectasis
• COPD (Chronic obstructive pulmonary disease)
• Interstitial lung disease
• Pulmonary embolism
• Pulmonary hypertension
• Cirrhosis
• Non-alcoholic fatty liver disease
• Alcoholic liver disease
• Autoimmune hepatitis
• Cystic fibrosis
• Diabetes mellitus, type 1 and 2
• Heart conditions (such as heart failure, coronary artery disease, or cardiomyopathies)
• HIV (Human immunodeficiency virus)
• Mental health conditions such as mood disorders and Schizophrenia spectrum disorders
• Obesity (defined as body mass index (BMI) of greater than 30 kg/m2 or greater than 95th percentile in children)
• Pregnancy and recent pregnancy
• Smoking, current and former
• Solid organ or blood stem cell transplantation
• Tuberculosis
• Use of corticosteroids or other immunosuppressive medications

However, as stated above, the most recent NIH treatment guidelines for the management of COVID-19 illness (accessed on January 3rd, 2023) do not recommend any monoclonal antibodies for the treatment of acute COVID-19 illness due to the dominant circulating variants and subvariants that are resistant to these agents.[NIH COVID-19 Treatment Guidelines] The only monoclonal antibody with an active EUA is tixagevimab co-packaged with cilgavimab, which is authorized for preexposure prophylaxis of COVID-19.[9] According to United States Food and Drug Administration (FDA) update on 1/6/2023, a SARS-CoV-2 Omicron subvariant is not anticipated to be neutralized by this monoclonal antibody combination; however, they are waiting for additional data to make their final decision.

In the absence of mAb options for nonhospitalized adults with mild to moderate COVID-19 illness (who are not on supplemental oxygen), the following therapeutic options are advised by the United States National Institutes of Health (NIH):[NIH COVID-19 Treatment Guidelines]

• Ritonavir-boosted nirmatrelvir. This is an oral medication that consists of protease inhibitors. It has been shown to reduce hospitalization and death when given to high-risk, unvaccinated, non-hospitalized patients. It must be given within 5 days of symptoms onset. Of note, this medication has strong cytochrome P450 inhibition and therefore has many drug-drug interactions that need to be carefully assessed.
• Remdesivir. This is a nucleotide analog that inhibits the SARS-CoV-2 RNA polymerase. The recommended duration of therapy in this setting is 3 days. 
• Molnupiravir. This is a mutagenic ribonucleoside antiviral agent. Due to the risk of genotoxicity with this agent, it is not recommended in pregnant patients. This agent should only be used if both of the above therapies are unavailable or cannot be given.

Enhancing Healthcare Team Outcomes

Monoclonal antibodies are intended for the treatment of outpatient mild-moderate COVID-19 infections in patients with risk factors for progression to severe disease. Effective use of mAbs requires the coordinated efforts of an interprofessional healthcare team, including clinicians, pharmacists, nurses, and medical assistants.

Healthcare providers must be able to recognize patients at risk for progression to severe disease who would benefit from monoclonal antibody infusion and recognize which patients must be hospitalized for severe infection. When administering monoclonal antibodies, the interprofessional team must be prepared for adverse events such as transfusion reactions and anaphylaxis. This requires equipment and medications used for the immediate treatment of allergic reactions. Patients must be observed for at least one hour after receiving a monoclonal antibody infusion to ensure patient safety. 

The interprofessional healthcare team is also responsible for educating the patient on infection control measures. After receiving monoclonal antibody therapy, the patient must continue self-isolating and use infection control measures such as social distancing, frequent handwashing, and wearing personal protective equipment. 

Healthcare providers should also be aware of the resistance patterns of SARS-CoV-2 variants. They should review the information found in section 15 on the fact sheets issued for each of the monoclonal antibodies. Providers should also review the CDC website, which provides information from state and local health authorities that report viral variants in the region, which will help guide treatment decisions. Up-to-date information regarding the use of authorized medications is essential to optimize clinical outcomes. A well-coordinated interprofessional team can minimize the use of ineffective therapies and optimize clinical outcomes for patients affected by this disease.[Level 5]