The role of convalescent antibodies in managing COVID-19
- There is historical validity to the use of passive antibody therapy for treatment of viral infections (Ebola, H1N1 influenza, SARS and MERS) that can inform the use in the current COVID-19 epidemic.
- Convalescent plasma therapy is positioned to be a rapidly available therapy and is likely to be most beneficial early in disease course to prevent disease progression
- Potential adverse effects include antibody-dependent enhancement (ADE)
- There are currently multiple trials underway across the globe, across the country, locally in San Diego (Scripps and UCSD) as well as those sponsored by pharmaceutical companies to assess the efficacy of convalescent plasma in the treatment of COVID-19
Summary of Information
In light of the COVID-19 pandemic, many have asked about the potential prophylactic or therapeutic role of convalescent antibodies. Currently there are no vaccines. Although there are many treatments in rapid development, as of now there are no FDA-approved treatments for COVID-19. While therapeutics remain in development, the idea of convalescent antibodies has been proposed in many recent articles as an option when there are sufficient numbers of recovered patients who are able to donate serum. Furthermore, convalescent antibody therapy has been brought to the forefront of discussion after the FDA announced its status as an emergency investigational drug on March 24, 2020.
Pathophysiology of Passive Antibody Therapy
Convalescent antibody therapy uses the principle of passive immunity and involves the administration of antibodies against a given pathogen to a patient to prevent or treat an infection by that pathogen. This therapy differs from vaccines, which induce active immunity over time in the recipient patient. It is generally thought that passive antibody therapy has better efficacy in the form of prophylaxis than as treatment. Although the mechanism for this is not clear, it has been proposed that the passive antibodies work primarily by neutralizing the initial inoculum and suppressing viremia or perhaps by modifying the initial immune response.
Historical Precedents in using Passive Antibody Therapy
Passive antibody therapy has a long history of use dating back to the late 19th century, before the time of antibiotics or antivirals.1 In the early 20th century, it was used in the 1918 H1N1 influenza virus epidemic. A meta-analysis of looking at 8 studies using convalescent sera in the 1918 H1N1 pandemic involving a total of 1703 patients found that in 6 of the studies, patients treated with convalescent plasma had a reduction in mortality (absolute risk differences ranged from 8-26% and pooled risk difference of 21%; C.I. of 95%; p< 0.001). In the 21st century, convalescent serum has also been used during the 2009 H1N1 influenza pandemic and 2013 West African Ebola pandemic. In the case of the 2009 H1N1 pandemic, Hung et al studied 93 patients with severe H1N1 infection requiring ICU level care, 20 of whom received apheresis plasma treatment. Hung et al found that in the treatment arm, mortality was significantly lower (20% vs 54.8%, P=0.01) and patients had reduced viral load and cytokine response. In the case of Ebola, Sahr et al investigated 69 patients with Ebola virus infection, of which 44 were given convalescent serum, and found that case fatality rate and viral load were reduced in the treatment arm. In 2013, Hung et al reported a multicenter randomized controlled clinical trial in critically ill 2009 influenza A (H1N1pmd09) patients and found reduced mortality when hyperimmune globulin was administered within 5 days of symptom onset (OR, 0.14; 95% CI, 0.02-0.92; P = .04).
Notably, convalescent serum has also been used in the two recent coronavirus epidemics, SARS in 2003 and MERS in 2012. Cheng et al reported that when 80 patients with SARS refractory to methylprednisone were given convalescent plasma, the patients who had received the plasma earlier than day 14 after symptom onset had a better clinical outcome, defined as discharge prior to 22 days of symptom onset (58% vs 16%; P< 0.001). Sixty-one percent of the patients with a good outcome were PCR positive and seronegative for coronavirus compared to 21% of the group with a poor outcome, further suggesting that administration of the convalescent serum early on in the infection was beneficial. In the case of MERS, there have been anecdotal reports of the use of convalescent serum use however others have reported challenges. Three patients in South Korea were with MERS treated with convalescent serum but only two of the patients were found to have neutralizing antibodies in their serum. Arabi et al reported testing 443 potential donor samples (196 patients with suspected or confirmed MERS, 230 exposed healthcare workers, and 17 exposed household contacts) and found only 2.7% had a reactive ELISA result, highlighting the challenge of finding enough donors with sufficiently high antibody titers.
Proposed Uses, Risks and Ethical Considerations
Based on historical and anecdotal data, the use of convalescent plasma is a potentially feasible option to treat the novel coronavirus infection. Recovered COVID-19 patients are a valuable source of convalescent plasma. Based on experience with convalescent plasma in other infections, COVID-19 convalescent plasma would likely be most useful to treat early symptoms of the disease. While data are lacking, convalescent plasma could also be used to prevent SARS-CoV-2 infections, helping individuals who are exposed, such as healthcare providers, first responders, and family members who care for COVID-19 patients at home.
The known risks for passive administration of convalescent plasma are those associated with the transfer of blood substances. This includes inadvertent infection with other infectious diseases and immunological reactions to the serum constituents. However modern blood banking techniques that match donors and recipients and screen for blood-borne pathogens can help keep these risks low. It should also be noted that the infusion of plasma in individuals with pulmonary disease will have some risk for transfusion-related acute lung injury (TRALI). There is also a potential for increased same-day thrombotic event risk (0.04 to 14.9%) which is associated with treatment using human immunoglobulin. One possible theoretical risk is the antibody-dependent enhancement of infection (ADE), a phenomenon in which the presence of certain antibodies to one serotype could enhance the infection of another serotype. Several mechanisms for ADE have been reported in coronaviruses, however, ADE may be unlikely in the proposed use of convalescent plasma for COVID-19 because preparation of the convalescent plasma would have high titers of neutralizing antibody against the same virus, SARS2-CoV-2. Another theoretical risk is antibody administration might attenuate the immune response to prevent disease, which could leave those individuals vulnerable to subsequent reinfection. Other issues to be considered include the lack of high-quality studies and the need for donors with high neutralizing antibody titers. Also, it would be important to follow precise ethical and controlled conditions in the production and use of COVID-19 convalescent plasma. A careful risk-benefits assessment prior to administration is recommended.
New Recommendations from the FDA and Current Investigations in COVID-19
On March 24, 2020 the FDA approved investigational COVID-19 convalescent plasma to be used as an emergency investigational drug in “serious or immediately life-threatening COVID-19 infections” after a licensed physician obtains authorization through an emergency IND Application (eIND). The FDA specifies that plasma can only be collected from those that are eligible to donate blood and should only be collected from those who have had 14 days of symptomatic recovery from a laboratory documented COVID-19 infection and now test negative for the virus. Patients are eligible to receive this donor plasma if they have laboratory confirmed COVID-19, give informed consent, and have severe or immediately life-threatening disease; defined as dyspnea, respiratory rate ≥30, oxygen saturation ≤93%, a PaO2/FiO2 ratio ≤ 300, lung infiltrates >50% within 24-48 hours, respiratory failure, septic shock, or multiple organ dysfunction or failure. The FDA responds to standard eIND requests in 4-8 hours, with a verbal authorization option if a response is required in less than 4 hours.
Multiple trials of convalescent plasma have been initiated in China, but no official results have been released yet. According to news reports on the trials, one trial of 245 patients showed improvement in 91 that were treated. In another, 13 critically ill patients that were treated all showed reduction in viral load but no reduction in disease severity. Neither reported complications with treatment.
Locally, Scripps Research and UC San Diego are collecting donated plasma from recovered COVID-19 patients and planning to isolate antibodies and determine their effectiveness in inhibiting the virus (Robbins, 2020). Although these first steps may only take days to weeks, it would likely take months to produce enough to allow for large scale treatments.
Across the country universities such as Washington University in St. Louis and Johns Hopkins University are investigating convalescent plasma treatments, identifying it as a favorable treatment option given that it will be available faster than novel drugs or vaccines. According to researchers at Johns Hopkins, this treatment could be available within weeks since it does not require development and relies only on standard blood banking techniques.23 After the FDA’s approval of convalescent plasma for eIND status, Mount Sinai and Albert Einstein College of Medicine plan to start treatments as early as next week. Vanderbilt Vaccine Center and Mount Sinai have also announced that they are working on identifying neutralizing antibodies in recovered patients’ serum that could be reproduced as treatment, with Vanderbilt hoping to start human clinical trials in early summer.
Additionally the pharmaceutical companies Regeneron and Takeda are working on developing antibody based COVID-19 treatments. Regeneron says they have already “identified hundreds of virus-neutralizing antibodies” and plan to start large-scale manufacturing of a “novel multi-antibody cocktail” by mid-April.27 In early March Takeda began developing an “Anti-SARS-CoV-2 polyclonal hyperimmune globulin” that will be intended for high-risk infected patients.
Authors: Ritika Prasad, MS4, Thanh Tran, Natalie Oberhauser-Lim, MS3 -- UC San Diego
Completed on: March 26, 2020
Last updated on: April 13, 2020
Reviewed by: Marsha-Gail Davis MD
Reviewed on: April 9, 2020
This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego. For more information about the project, please visit http://earth2-covid.ucsd.edu
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