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June 15, 2020

Monoclonal Antibodies for Prevention and Treatment of COVID-19

Author Affiliations
  • 1Vaccine Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
  • 2Institute for Global Health and Infectious Diseases, University of North Carolina, Chapel Hill
JAMA. Published online June 15, 2020. doi:10.1001/jama.2020.10245

The coronavirus disease 2019 (COVID-19) pandemic has created a worldwide crisis and inspired an urgent search for prevention and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Attention has focused on the development of vaccines, new antiviral agents, and convalescent plasma infusions. Monoclonal antibodies have received less attention even though neutralizing antibodies are a key component of protective immunity for most viral diseases. Neutralizing monoclonal antibodies to SARS-CoV-2 have the potential for both therapeutic and prophylactic applications, and can help to guide vaccine design and development.1

Since the identification of SARS-CoV-2 as the causative agent of COVID-19, numerous research groups have isolated monoclonal antibodies (most often from the B cells of patients who have recently recovered from SARS-CoV-2, and in some cases from individuals who were infected with the severe acute respiratory syndrome coronavirus [SARS-CoV] in 2003). It is also possible to generate effective monoclonal antibodies by immunization of humanized mice. Modern methods allow the rapid identification of pathogen-specific B cells and recovery of immunoglobulin heavy chain and light chain genes that can be expressed to produce monoclonal antibodies, usually in the form of IgG.

The main target of SARS-CoV-2 neutralizing monoclonal antibodies is the surface spike glycoprotein that mediates viral entry into host cells. Essentially all monoclonal antibodies of interest target this protein. Viral infection is mediated by the interaction between the viral spike and the angiotensin-converting enzyme 2 (ACE 2) receptor found on numerous cell types, but neutralizing monoclonal antibodies block this event. Although current knowledge is increasing about the epitopes present on the SARS-CoV-2 spike protein, prior knowledge of other human coronaviruses has facilitated rapid advances in understanding the atomic level structure of the spike protein.2 The majority of monoclonal antibodies isolated to date specifically target the receptor-binding domain on the spike protein that allows SARS-CoV-2 to make contact with the ACE 2 receptor.3,4 However, based on current knowledge of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), it is likely that neutralizing antibodies can target other regions of the spike protein as well.5 Neutralizing monoclonal antibodies are often characterized by their potency in vitro in a variety of cell culture assays, which is an important attribute used to help select monoclonal antibodies with potential for clinical use.

The Clinical Utility of Monoclonal Antibodies

SARS-CoV-2 monoclonal antibodies have the potential to be used for both prevention and treatment of infection. Benefits have been demonstrated in animal models for both SARS-CoV and MERS-CoV monoclonal antibodies. Most people recovering from SARS-CoV-2 infection will generate a cellular and humoral immune response against SARS-CoV-2. Given the lack of effective therapies for patients with advanced COVID-19, several groups have collected convalescent plasma and measured SARS-CoV-2 neutralization titers. In the largest study to date, Joyner et al6 administered 1 to 2 units of convalescent plasma to 5000 patients with severe or life-threatening SARS-CoV-2 infection. The investigators reported an incidence of less than 1% for severe adverse events and a 7-day mortality rate of 14.9%, which is consistent with the natural history of severe infection.6

Liu et al7 reported a benefit from convalescent plasma with a neutralizing titer dilution of greater than 1:320 when provided to hospitalized patients who did not require intubation. Further assessment of the potential clinical benefits of convalescent plasma is anticipated. The limitations of convalescent plasma include the difficulty in collection, variability of binding and neutralizing antibody titers, potential contamination with infectious agents, risk of transfusion reactions, and circulatory overload associated with administration. However, success in convalescent plasma research serves to inspire development and deployment of monoclonal antibodies.

Treatment With Monoclonal Antibodies

Even though more than 75 monoclonal antibodies have been licensed for use by the US Food and Drug Administration, only 3 are used to treat or prevent infectious diseases—respiratory syncytial virus, anthrax, and Clostridioides difficile. Two different monoclonal antibody products have been shown to be effective in reducing mortality from Ebola virus disease,8 especially if used during early onset of infection. One of these was a combination of 3 monoclonal antibodies, while the other was a single monoclonal antibody. The successful treatment of an aggressive fatal virus supports the potential of monoclonal antibodies for the treatment of COVID-19.

Several SARS-CoV-2 monoclonal antibodies are poised to enter clinical trials during the summer of 2020. Therapeutic trials will include treatment of patients with SARS-CoV-2 infection, with varying degrees of illness, to block disease progression. Given the long half-life of most monoclonal antibodies (approximately 3 weeks for IgG1), a single infusion should be sufficient. Most patients with SARS-CoV-2 infection (in the absence of advanced age or comorbidities) will recover without treatment, albeit at variable rates, emphasizing the need to study monoclonal antibodies in patients most likely to benefit from early monoclonal antibody therapy. A potential limitation of monoclonal antibodies for treatment of COVID-19 is the unknown bioavailability of passively infused IgG in tissues affected by the disease, especially the lungs, which serve as a key target of SARS-CoV-2 infection. Another consideration is the effect of viral diversity, so it will be important to monitor for the emergence of resistant viral mutations under selective pressure of monoclonal antibody treatment. Accordingly, monoclonal antibodies have been chosen to target conserved regions of the viral spike and some products will include of a combination of 2 monoclonal antibodies targeting different sites on the spike protein.

Prevention

An effective vaccine is a necessary solution to the COVID-19 pandemic. Although the vaccine development process generally takes years or even decades, aggressive efforts to evaluate several COVID-19 vaccine candidates concomitantly are planned to shorten the development process to 12 to 18 months.9 Monoclonal antibodies provide an alternative avenue for the prevention of COVID-19. Passive infusion of monoclonal antibodies as preexposure or postexposure prophylaxis might offer immediate protection from infection that could last weeks or months. Newer technologies that modify the Fc region of the antibody to extend the half-life of monoclonal antibodies can provide potentially protective levels for months, depending on the monoclonal antibody concentrations required.

Even if a vaccine is available, the weeks of time required to generate an effective immune response emphasizes the benefits of passive immunity in a variety of circumstances including health care settings, households, and facilities where outbreaks have been common and devastating. Nursing homes and meat-packing plants have experienced large SARS-CoV-2 outbreaks. Monoclonal antibodies administered to nursing home residents during an outbreak might also serve to limit the progression of disease during undetected early infection. In addition, older individuals and those with underlying comorbid conditions might not mount a robust protective response after vaccination, and so monoclonal antibodies may be required to provide protection.

Challenges

There are substantial challenges to demonstrating the benefits of monoclonal antibodies in clinical trials. Because most people with early infection recover, the clinical end points needed to demonstrate a benefit relative to placebo are not easily achieved. Likewise, it may be difficult to demonstrate benefit in patients with more severe disease, in whom inflammation and coagulopathy may be more important than viral replication. For monoclonal antibody prevention trials, the difficulty is finding individuals at sufficient risk (ie, a high enough attack rate) to demonstrate prevention of symptomatic infection. As the COVID-19 pandemic evolves across the US and the world, the clinical research infrastructure will require the flexibility to provide monoclonal antibodies on short order to populations or facilities at high risk of infection. Another potential challenge is the ability to produce enough monoclonal antibody product. Although this will be influenced by the dose required and may differ for prevention and treatment, current commercial manufacturing capacity can likely produce millions of doses annually.

There is also some concern for immune enhancement of COVID-19 because vaccine-associated enhanced disease has been observed in animal models of SARS-CoV and for other animal coronaviruses. Categories of possible disease enhancement include antibody-mediated enhancement of viral entry and replication in target cells (Fc-bearing monocytes or macrophages) and virus-antibody immune complexes and the associated cytokine release. For the former, antibody-mediated enhancement is classically defined as Fcγ-receptor–mediated enhanced disease in the presence of subneutralizing concentrations of antibodies or nonneutralizing antibodies.10

Conclusions

Neutralizing antibodies have an important role in the protection or recovery from many viral infections. Several monoclonal antibody products will enter clinical trials over the next few months and be assessed for their ability to limit or modify SARS-CoV-2 infection. In addition, a drug that reliably prevented progression of COVID-19 would greatly reduce the concerns and uncertainty associated with SARS-CoV-2 infection and give physicians a therapeutic tool they must have for their patients. Establishing the therapeutic or prophylactic efficacy of monoclonal antibodies would be a major advance in the control of the COVID-19 pandemic.

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Article Information

Corresponding Author: Mary Marovich, MD, Vaccine Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr, Bethesda, MD 20814 (mary.marovich@nih.gov).

Published Online: June 15, 2020. doi:10.1001/jama.2020.10245

Conflict of Interest Disclosures: Dr Mascola reported having a patent pending related to coronavirus antibodies and the methods of use. Dr Cohen reported serving as a consultant to Gilead and Merck. No other disclosures were reported.

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Ju  B, Zhang  Q, Ge  X,  et al. Potent human neutralizing antibodies elicited by SARS-CoV-2 infection. bioRxiv. Preprint posted online March 26, 2020. doi:10.1101/2020.03.21.990770
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Pinto  D, Park  YJ, Beltramello  M,  et al.  Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody.   Nature. Published May 18, 2020. doi:10.1038/s41586-020-2349-y PubMedGoogle Scholar
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Wang  L, Shi  W, Chappell  JD,  et al.  Importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on the Middle East respiratory syndrome coronavirus spike glycoprotein to avoid neutralization escape.   J Virol. 2018;92(10):e02002-e02017. doi:10.1128/JVI.02002-17 PubMedGoogle ScholarCrossref
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Joyner  M, Wright  S, Fairweather  D,  et al. Early safety indicators of COVID-19 convalescent plasma in 5,000 patients. medRxiv. Preprint posted online May 14, 2020. doi:10.1101/2020.05.12.20099879
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    2 Comments for this article
    EXPAND ALL
    Plasma vs Potentially Less Toxic IV IgG or Monoclonals
    Neil Blumberg, MD | University of Rochester
    The safety data on plasma is, I believe, not complete, because only acute reactions have been considered (a few hours). There are extensive observational data and in vitro data suggesting human allogeneic plasma may be immunomodulatory, interfering with NK and T cell function, and associated with serious adverse events that occur days after infusion. These include nosocomial infection, inflammation, organ injury and thrombosis. Such adverse events are even more clearly associated with the common practice of infusing non-ABO identical plasma, which generates immune complexes of soluble ABO antigen and antibody in vivo. ABO non-identical plasma transfusions have associations with bleeding, ARDS, organ injury and sepsis.

    Currently there are no data implicating IVIgG preparations with these adverse effects (excepting hemolysis), and most monoclonal therapeutics do not seem to have such unfavorable benefit:risk ratios. ABO matching is still a problem with IV IgG, which contains anti-A and anti-B. Newer preparations in development have the potential to reduce the risk of hemolysis and immune complex formation by removing much of the anti-A and anti-B. Monoclonals do not usually cross react with A and B antigens on red cells (and all the rest of the body's cells) and probably carry much less risk of hemolysis than plasma and IVIgG. The main advantage of convalescent plasma is, of course, that it does not require months to years of processing and development for new viral infections. But it probably carries the most serious safety concerns.
    CONFLICT OF INTEREST: None Reported
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    Results May Disappoint
    Giuliano Ramadori, Professor of Medicine | University Clinic, Internal Medicine ,Göttingen, Germany
    Mary Marovich and her coauthors (1) convincingly report about the hopes attributed to vaccines and/or monoclonal neutralizing antibodies for prevention or treatment of a COVID-19 infection. The authors also draw attention to possible problems in demonstrating efficacy of such antibodies in clinical trials.

    In fact, neutralizing antibodies may prevent cellular invasion in vitro but may not have any efficacy in vivo. It is known that viral hepatitis C-RNA may be detected together with neutralizing antibodies in the blood of infected persons.We also still do not have a vaccine against HCV nor against HIV, both RNA-viruses.
    The efficacy of the influenza vaccine also seems to be doubtful according to recently published work (2); the number of patients hospitalized with influenza-induced pneumonia was similar, independently of the vaccination status (2).

    On the other hand, authors also suggest that supportive measures in symptomatic COVID-19-infected patients may even be more effective than many more expensive therapeutic options (3). 

    REFERENCES
    1. Marovich M,Mascola JR,Cohen MS:Monoclonal antibodies for prevention and treatment of COVID-19.JAMA 2020,June 15
    2. Chow EJ,Rolfes MA, O´Halloran M et al.Respiratory and Nonrespiratory diagnoses associated with influenza in hospitalized adults. JAMA Network Open 2020;3(3):e201323
    3. Sun Q,Qiu H, Huang M,Yang Yi. Lower mortality of COVID-19 by early recognition and intervention: experience from Jiangsu Province. Ann Intensive Care2020;10:33 doi.org/10.1186/s13613-020-00650-2
    CONFLICT OF INTEREST: None Reported
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