Johns Hopkins University researchers propose using antibodies from the plasma or serum of those who have recovered from COVID-19 to help boost the immunity of newly infected patients and for those at risk of contracting the disease.
Researchers say the antibodies may bind to and neutralize SARS-CoV-2.
The technique has been proven successful in prior outbreaks, including the SARS epidemic and the 1918 flu pandemic.
With a vaccine for COVID-19 still a long way from being realized, Johns Hopkins immunologist Arturo Casadevall is working to revive a century-old blood-derived treatment for use in the United States in hopes of slowing the spread of the disease.
With the right pieces in place, the treatment could be set up at Johns Hopkins University in Baltimore within a matter of weeks, Casadevall says.
The technique uses antibodies from the blood plasma or serum of people who have recovered from COVID-19 infection to boost the immunity of newly infected patients and those at risk of contracting the disease.
These antibodies contained in the blood’s serum have the ability to bind to and neutralize SARS-CoV-2, the virus that causes COVID-19.
Casadevall-a Bloomberg Distinguished Professor of molecular microbiology and immunology and infectious diseases at the Johns Hopkins Bloomberg School of Public Health and School of Medicine-published a paper on the proposal today in The Journal of Clinical Investigation.
“Deployment of this option requires no research or development,” he says. “It could be deployed within a couple of weeks since it relies on standard blood-banking practices.”
In this case, physicians would ask patients who recover from COVID-19 to donate their blood, from which sera would be isolated.
After processing the serum and removing other toxins or trace illnesses, it can be injected into sick patients and those at risk of contracting the disease.
The procedure for isolating serum or plasma is a long-established technology that can be performed using equipment normally found in hospitals and blood-banking facilities, and recent advances make it as safe as a blood transfusion, Casadevall says.
Experts around the U.S. are rushing to implement the treatment in several different areas, including New York City, Casadevall says. Doctors in Shanghai have already used the plasma therapy with newly infected coronavirus patients in China and have reported promising early results.
Japan’s largest drugmaker, Takeda Pharmaceuticals, has also begun testing the therapy.
The Johns Hopkins Research Team has put initial funding toward Casadevall’s project, to purchase equipment and set up an operation in Baltimore.
Casadevall and his team are working now with state and federal officials to try to secure more resources.
The medical concept-known as “convalescent plasma” or “convalescent sera”-dates back to the early 20th century, and was used successfully in the past to counter epidemics including mumps and the measles.
In a recent Wall Street Journal op-ed, Casadevall points to a notable case preventing a measles outbreak at a U.S. prep school in 1934.
Infusions of antibody-laden blood have been used with reported success in prior outbreaks, including the SARS epidemic and the 1918 flu pandemic.
Experts say a challenge of the technique is that precise timing is important in order to maximize the boost to a patient’s immunity.
The treatment is not envisioned as a panacea to treating coronavirus, but a temporary measure that could help until stronger options such as vaccines are available.
“It’s all doable-but to get it done it requires effort organization, resources… and people who have recovered from the disease who can donate the blood,” Casadevall says.
He adds that many people have stepped up to the plate at Hopkins and are already working to put this system in place.
Casadevall says he believes the solution “could do a lot locally” in the Baltimore region. He also noted that Johns Hopkins could become the Investigational New Drug (IND) center in the U.S. for this treatment, helping to administer it across states.
Learning more about how to use the sera most effectively will require further clinical studies. “We will learn new science from this calamity,” Casadevall says.
Passive antibody therapy involves the administration of antibodies against a given agent to a susceptible individual for the purpose of preventing or treating an infectious disease due to that agent.
In contrast, active vaccination requires the induction of an immune response that takes time to develop and varies depending on the vaccine recipient.
Thus, passive antibody administration is the only means of providing immediate immunity to susceptible persons. Passive antibody therapy has a storied history going back to the 1890s and was the only means of treating certain infectious diseases prior to the development of antimicrobial therapy in the 1940s (1, 2).
Experience from prior outbreaks with other coronaviruses, such as SARS-CoV-1, shows that such convalescent sera contain neutralizing antibodies to the relevant virus (3).
In the case of SARS-CoV-2, the anticipated mechanism of action by which passive antibody therapy would mediate protection is viral neutralization.
However, other mechanisms may be possible, such as antibody-dependent cellular cytotoxicity and/or phagocytosis.
Possible sources of antibody for SARS-CoV-2 are human convalescent sera from individuals who have recovered from COVID-19, mAbs, or preparations generated in certain animal hosts, such as genetically engineered cows that produce human antibody (4).
Although many types of preparations are or will soon be under development, the only antibody type that is currently available for immediate use is that found in human convalescent sera (Figure 1).
As more individuals contract COVID-19 and recover, the number of potential donors will continue to increase.
A general principle of passive antibody therapy is that it is more effective when used for prophylaxis than for treatment of disease.
When used for therapy, antibody is most effective when administered shortly after the onset of symptoms.
The reason for temporal variation in efficacy is not well understood but could reflect that passive antibody works by neutralizing the initial inoculum, which is likely to be much smaller than that of established disease (5).
Another explanation is that antibody works by modifying the inflammatory response, which is also more easily achieved during the initial immune response, a stage that may be asymptomatic (6).
As an example, passive antibody therapy for pneumococcal pneumonia was most effective when administered shortly after the onset of symptoms, and there was no benefit if antibody administration was delayed past the third day of disease (7).
For passive antibody therapy to be effective, a sufficient amount of antibody must be administered.
When given to a susceptible person, this antibody will circulate in the blood, reach tissues, and provide protection against infection. Depending on the antibody amount and composition, the protection conferred by the transferred immunoglobulin can last from weeks to months.
Risks and benefits
COVID-19 convalescent sera can be used for either prophylaxis of infection or treatment of disease. In a prophylactic mode, the benefit of convalescent serum administration is that it can prevent infection and subsequent disease in those who are at high risk for disease, such as vulnerable individuals with underlying medical conditions, health care providers, and those with exposure to confirmed cases of COVID-19.
Passive antibody administration to prevent disease is already used in clinical practice.
For example, patients exposed to hepatitis B and rabies viruses are treated with hepatitis B immune globulin (HBIG) and human rabies immune globulin (HRIG), respectively.
In addition, passive antibody is used for the prevention of severe respiratory syncytial virus (RSV) disease in high-risk infants. Until recently, a polyclonal hyperimmune globulin (RSV-IG) prepared from samples of donors with high serum titers of RSV neutralizing antibody was used, but these preparations have now been replaced by palivizumab, a humanized murine mAb.
Used therapeutically, convalescent serum would be administered to those with clinical disease in an effort to reduce their symptoms and mortality.
The efficacy of these approaches cannot be inferred without carrying out a controlled clinical trial.
Based on the historical experience with antibody administration, it can be anticipated that antibody administration would be more effective in preventing disease than in the treatment of established disease (12).
Risks of passive administration of convalescent sera fall into two categories, known and theoretical. Known risks are those associated with transfer of blood substances, which include inadvertent infection with another infectious disease agent and reactions to serum constituents, including immunological reactions such as serum sickness.
With modern blood banking techniques that screen for blood-borne pathogens and match the blood type of donors and recipients, the risks of inadvertently transferring known infectious agents or triggering transfusion reactions are low.
However, convalescent sera used in a therapeutic mode would likely be administered to individuals with pulmonary disease, in whom plasma infusion carries some risk for transfusion-related acute lung injury (TRALI) (28), and this should be a consideration in the risk-benefit assessment.
The theoretical risk involves the phenomenon of antibody-dependent enhancement of infection (ADE). ADE can occur in several viral diseases and involves an enhancement of disease in the presence of certain antibodies.
For coronaviruses, several mechanisms for ADE have been described, and there is the theoretical concern that antibodies to one type of coronavirus could enhance infection to another viral strain (29).
It may be possible to predict the risk of ADE of SARS-CoV-2 experimentally, as proposed for MERS (29).
Since the proposed use of convalescent sera in the COVID-19 epidemic would rely on preparations with high titers of neutralizing antibody against the same virus, SARS2-CoV-2, ADE may be unlikely.
The available evidence from the use of convalescent sera in patients with SARS1 and MERS (30), and anecdotal evidence from its use in 245 patients with COVID-19 (27), suggest it is safe. Nevertheless, in convalescent serum trials, caution and vigilance to identify any evidence of enhanced infection will be required.
Another theoretical risk is that antibody administration to those exposed to SARS-CoV-2 may prevent disease in a manner that attenuates the immune response, leaving such individuals vulnerable to subsequent reinfection.
In this regard, passive antibody administration before vaccination with respiratory syncytial virus was reported to attenuate humoral but not cellular immunity (31). This concern could be investigated as part of a clinical trial by measuring immune responses in those exposed and treated with convalescent sera to prevent disease.
If the risk proved real, these individuals could be vaccinated against COVID-19 when a vaccine becomes available.
Given that historical and current anecdotal data on use of convalescent serum suggest it is safe in coronavirus infection, the high mortality of COVID-19, particularly in elderly and vulnerable persons, suggests that the benefits of its use in those at high risk for or with early disease outweigh the risks.
However, for all cases where convalescent serum administration is considered, a risk-benefit assessment must be conducted to assess individual variables.
These considerations were invoked recently with the decision to use mAbs in the treatment of Ebola virus disease (32).
Deployment and proposed use
To deploy convalescent serum administration for COVID-19 the following six conditions must be met:
(i) availability of a population of donors who have recovered from the disease and can donate convalescent serum;
(ii) blood banking facilities to process the serum donations;
(iii) availability of assays, including serological assays, to detect SARS-CoV-2 in serum and virological assays to measure viral neutralization;
(iv) virology laboratory support to perform these assays;
(v) prophylaxis and therapeutic protocols, which should ideally include randomized clinical trials to assess the efficacy of any intervention and measure immune responses; and
(vi) regulatory compliance, including institutional review board approval, which may vary depending on location.
Ideally, the use of convalescent serum would involve multiple centers, follow randomized control protocols, and have a single center as a governing body.
Each of these conditions should be available in developed areas affected by COVID-19. At least one pharmaceutical company, Takeda, is gearing up to generate antibody preparations against SARS2-CoV-2 from COVID-19 convalescent sera (33).
Producing highly purified preparations containing a high titer of neutralizing antibodies against SARS2-CoV-2 is preferable to convalescent sera given that these are safer and have higher activity.
Unfortunately, such preparations will not be available for many months, whereas locally produced convalescent sera could be available much sooner.
We anticipate that once the necessary regulatory permissions are in place, individuals who recover from COVID-19 can be approached to donate blood for serum preparation or antibody isolation through apheresis.
Recovery from COVID-19 will be assessed clinically, and such individuals must be shown to free of SARS-CoV-2, including in their blood by appropriate viral nucleic acid screening.
Donated blood products will be screened for infectious agents according to current blood banking practices, and individual sera will be studied for specific antibody content and neutralizing activity to SARS-CoV-2.
Depending on the volumes needed and the neutralizing activity of donated convalescent sera, these could be pooled or used individually, and preparations for clinical use would be treated for pathogen attenuation.
At this time, we do not know what an effective neutralizing titer would be in a susceptible individual given passive antibody therapy for prophylaxis, and determining this parameter would be part of the study design.
Similarly, we do not know what doses would be effective therapeutically. We do know that when convalescent serum was used to prevent measles or mumps the amounts used were in the order of 10–40 cc (10, 11).
In contrast, when convalescent serum was used to treat severe disease in soldiers with 1918 influenza, the amounts given were in the hundreds of milliliters (34).
These older studies claimed efficacy even though convalescent serum was given without any knowledge of neutralizing titers. Those experiences suggest that even small amounts of antibody may prevent and/or treat infection.
Hence, we can anticipate that effective prophylactic doses would be much smaller than therapeutic doses.
This makes sense, since the infecting inoculum is likely to be much smaller than the viral burden during severe disease.
COVID-19 convalescent sera could be used to treat individuals with early symptoms and prevent disease in those exposed. Today, nurses, physicians, and first responders exposed to known cases of COVID-19, some of whom have developed disease, are being quarantined, which threatens to collapse the health care system.
It is anticipated that convalescent serum will prevent SARS-CoV-2 infection in those to whom it is administered. If this is established, individuals who receive convalescent sera may be able to avoid a period of quarantine.
This could allow them to continue their critical function as health care providers. Convalescent sera could also be used to prevent disease among family members caring for COVID-19 patients at home.
Clearly, the use of convalescent serum would be a stopgap measure that could be used in the midst of the current epidemic. However, even local deployment will entail considerable coordination between different entities, such as infectious disease specialists, hematologists, blood banking specialists, and hospital administrators.
Hence, as we are in the midst of a worldwide pandemic, we recommend that institutions consider the emergency use of convalescent sera and begin preparations as soon as possible. Time is of the essence.
- J Clin Invest. https://doi.org/10.1172/JCI138003.
- Johns Hopkins University