The Promise of COVID-19 Convalescent Plasma Therapy
This article was originally published on asm.org July 25, 2019, but has since been updated by the authors.
As the number of cases of SARS-CoV-2 in the United States continues to rise into the millions, with the death toll now topping an almost unimaginable 180,000 and no end in sight, there is rising anxiety about when, and if, a vaccine will be available. The most optimistic estimates predict one or more vaccines will become available in the year 2021, but these estimates must be viewed with caution because questions about the safety, efficacy, production, supply and distribution of said vaccines remain to be answered.
Without a current vaccine to immunize against SARS-CoV-2, and the pathway to a cure still relatively unknown, it is clear that COVID-19 will be with us for the foreseeable future. Therefore, other COVID-19 treatment and prevention modalities are urgently needed. One such promising treatment, the use of convalescent serum from COVID-19 patients, was advocated by Casadevall and Pirofski shortly after the pandemic arrived in the United States. The guiding principle behind this therapy is the idea that convalescent serum, collected from patients who have recovered from COVID-19, will contain antibodies against SARS-CoV-2 that can be transfused to prevent or treat infection in others. The use of antibodies to treat or prevent a variety of viral infections, such as hepatitis A, poliomyelitis, measles, mumps, rabies and influenza was first described in the 20th century. More recently, studies during the 2009 H1N1 influenza outbreak and the 2013 African Ebola epidemic, as well as a systematic review of convalescent plasma use in severe acute respiratory infections, all showed survival benefit with convalescent plasma therapy.
Understanding why this type of therapy has been so historically successful, requires a deeper dive into immunity. There are 2 basic forms of immunity, active immunity and passive immunity.
Vaccination is an example of active immunity. Injection with a foreign substance, such as viral protein, produces an active immune response from the host that results in the production of antibodies (as well as other proteins which can aid in defending the body against the viral pathogen). Upon secondary exposure to the virus, those antibodies will bind to the foreign proteins (antigens) associated with that virus and prevent viral infection or reproduction in host cells
Passive immunity results when antibodies are “passed” from one host to another. It is an essential form of immunity for the fetus developing in utero, and in the infant and young child who is breast-fed. Antibodies that the mother has produced against a wide variety of microbial pathogens are “passed” to the child and offer protection at their most vulnerable stage of immunological development.
The use of convalescent plasma from patients who have recovered from SARS-CoV-2 is another example of passive immunity. Antibodies from recovered patients are transfused to a new host with the goal of mediating protection via suspected viral neutralization. However, all viruses are different, and thus behave differently. Therefore, we cannot assume or expect that convalescent plasma will work for SARS-CoV-2 just because it worked for other viruses.
So, what do we know about the use of convalescent plasma to treat COVID-19 patients? A few recently published papers and preprints are worth highlighting. The first, published by Joyner et al., is a safety report from the Mayo Clinic Expanded Access Program (EAP). This EAP was developed in response to the COVID-19 outbreak in the U.S. It was a collaboration between the U.S. Food and Drug Administration (FDA), the Mayo Clinic and the national blood banking community to collect and distribute investigational convalescent plasma to patients infected with SARS-CoV-2 who had, or were judged to be at high risk of progressing to, severe or life-threatening disease, and were hospitalized in acute care facilities. This report evaluated the first 5,000 hospitalized participants with severe or life threatening COVID-19 to receive COVID-19 convalescent plasma (CCP) and found that <1% of study participants had serious reactions to the treatment. In a recent publication, Joyner et al. provided a safety update in 20,000 hospitalized patients that were treated with CCP under the Mayo Clinic EAP. Incidence of serious adverse events remained low, and CCP was thus judged to be safe in hospitalized patients with COVID-19.
Despite a large number of hospitalized patients treated with CCP for severe COVID-19, randomized control trials (RCTs) have been sparse. Li et al. published an open-label, multicenter study of CCP treatment of COVID-19 in China. This study included 103 patients with severe or life-threatening COVID-19 from 7 medical centers in Wuhan, China, who were randomized to receive either CCP + standard treatment (n = 52) or standard treatment alone (n = 51). The study was underpowered, in large part because it was terminated early due to containment of SARS-CoV-2 in China (they had planned to enroll 200 patients), but trends toward accelerated clinical improvement were observed by day 28 in patients who presented with symptoms around 2 weeks into their illness. Furthermore, in an analysis stratified by disease severity, patients with less severe disease experienced about 5 days faster recovery and overall greater likelihood of clinical improvement by day 28. Investigators stopped a second RCT early after finding that patients had already developed antibodies against the virus prior to receiving CCP.
Two newly published preprints by Joyner et al. are worth noting. The first one aggregated patient outcome data from a total of 21 studies (4,173 COVID-19 patient outcomes), of which 12 were controlled studies (including 2 RCTs) and 9 were case series and case reports, to determine the effect of CCP on mortality. This analysis method showed that the aggregate mortality rate for CCP recipients was substantially lower than non-CCP recipients – namely, when aggregating data from the 12 controlled studies, CCP recipients had a mortality rate of 10% compared to 22% in non-CCP recipients. The second preprint explored potential signals of efficacy in 35,322 patients from 2,807 acute care facilities across the U.S. and territories that received CCP under the EAP. Patients who received CCP within 3 days of COVID-19 diagnosis, compared to those who received CCP 4 or more days after COVID-19 diagnosis, showed a reduction in 7-day (8.7% (8.3%, 9.2%) vs 11.9% (11.4%, 12.3%)) and 30-day (21.6% (21.0%, 22.3%) vs 26.7% (26.1%, 27.3%)) crude mortality rates, suggesting that earlier use of CCP was associated with lower observed rates of mortality. Additional analyses were performed in a subset of 3,082 patients who received 1 unit of CCP, of which the anti-SARS-CoV-2 IgG antibody titers were known. Lower 7-day and 30-day mortality rates were seen in those patients who received high antibody titered plasma within 3 days of COVID-19 diagnosis compared to those who received lower antibody titered plasma 4 or more days after COVID-19 diagnosis. While these findings offer encouraging support for the notion that CCP is a potential efficacious treatment when transfused early and with high antibody levels, it is extremely important to note that these are observational studies – not RCTs – and thus must be interpreted as such.
Although current knowledge about COVID-19 therapies, including CCP, is increasing rapidly due to the record number of research studies being globally implemented, there are still many challenges to be addressed. As Casadevall and Pirofski very nicely point out, there are a number of requirements that must be met before convalescent plasma can be deployed as a treatment or prevention option for COVID-19. First, there must be a population of available donors who have recovered from COVID-19 and can donate convalescent plasma. Second, we must have blood banking facilities that are equipped to initially process the donations and then later issue the correct plasma. The rapid uptake of convalescent plasma therapy in hospitalized patients between April and August 2020 demonstrates how the existing infrastructure of blood donations allowed for rapid mobilization of this therapy. A third, but more challenging aspect of evaluating the efficacy of CCP and distributing it broadly, involves understanding the individual components of this polyclonal antibody therapy. We must have the necessary SARS-CoV-2 serological, virological and neutralization assays, as well as the adequate laboratory support to perform these assays. Lastly, we need prophylaxis and therapeutic protocols to assess the efficacy and measure the immune response of CCP, while still maintaining good regulatory oversight. In order to meet the above requirements, we need to continue to build upon the rapidly growing CCP data in order to answer some critical questions.
Further, there are many donor variables that we currently don’t understand. The growing body of literature on SARS-CoV-2 antibodies, including an oral abstract by Markmann et al., suggests that not all CCP from various donors will be the same. We suspect that only some CCP contains the right amount of the right antibodies to be an effective therapy. In short, we still need to identify who, if anyone, has developed enough protective antibodies to be clinically valuable against SARS-CoV-2.
Because of the growing COVID-19 epidemic in the United States, I (HR) was abruptly recalled to the US from South Africa where I was doing HIV/AIDS research as part of my Infectious Diseases Fellowship at UNC. Unsure of what would be required of me, I was surprised to see, on my first day of the COVID-19 infectious diseases service, that we were able to offer CCP as a potential treatment for very scared and ill patients with COVID-19.
But this leads us to our final point. One of the most compelling things about CCP, if it proves to be a beneficial therapeutic or preventative for COVID-19, is the potential availability and scalability of this treatment. In our current global pandemic, low, middle and high-income countries are all being affected by this virus. As a result, health disparities and inequities are being magnified. The race for new, experimental therapies requires significant financial investment and scientific infrastructure, which puts many of these therapies out of reach for much of the world’s population during the early stages of development and production. CCP, on the other hand, comes from patients who have recovered from SARS-CoV-2 infection. Currently we have 2 of the 3 things that may allow this to be globally scalable– a global infrastructure for plasma transfusion, and a ready supply of potential donors. Now, if we want to make this promising therapy a global reality, we need a better understanding of the immune response both in individuals who have recovered from and those who are currently suffering from SARS-CoV-2 infection.
As the number of cases of SARS-CoV-2 in the United States continues to rise into the millions, with the death toll now topping an almost unimaginable 180,000 and no end in sight, there is rising anxiety about when, and if, a vaccine will be available. The most optimistic estimates predict one or more vaccines will become available in the year 2021, but these estimates must be viewed with caution because questions about the safety, efficacy, production, supply and distribution of said vaccines remain to be answered.
Without a current vaccine to immunize against SARS-CoV-2, and the pathway to a cure still relatively unknown, it is clear that COVID-19 will be with us for the foreseeable future. Therefore, other COVID-19 treatment and prevention modalities are urgently needed. One such promising treatment, the use of convalescent serum from COVID-19 patients, was advocated by Casadevall and Pirofski shortly after the pandemic arrived in the United States. The guiding principle behind this therapy is the idea that convalescent serum, collected from patients who have recovered from COVID-19, will contain antibodies against SARS-CoV-2 that can be transfused to prevent or treat infection in others. The use of antibodies to treat or prevent a variety of viral infections, such as hepatitis A, poliomyelitis, measles, mumps, rabies and influenza was first described in the 20th century. More recently, studies during the 2009 H1N1 influenza outbreak and the 2013 African Ebola epidemic, as well as a systematic review of convalescent plasma use in severe acute respiratory infections, all showed survival benefit with convalescent plasma therapy.
Understanding why this type of therapy has been so historically successful, requires a deeper dive into immunity. There are 2 basic forms of immunity, active immunity and passive immunity.
Vaccination is an example of active immunity. Injection with a foreign substance, such as viral protein, produces an active immune response from the host that results in the production of antibodies (as well as other proteins which can aid in defending the body against the viral pathogen). Upon secondary exposure to the virus, those antibodies will bind to the foreign proteins (antigens) associated with that virus and prevent viral infection or reproduction in host cells
Passive immunity results when antibodies are “passed” from one host to another. It is an essential form of immunity for the fetus developing in utero, and in the infant and young child who is breast-fed. Antibodies that the mother has produced against a wide variety of microbial pathogens are “passed” to the child and offer protection at their most vulnerable stage of immunological development.
The use of convalescent plasma from patients who have recovered from SARS-CoV-2 is another example of passive immunity. Antibodies from recovered patients are transfused to a new host with the goal of mediating protection via suspected viral neutralization. However, all viruses are different, and thus behave differently. Therefore, we cannot assume or expect that convalescent plasma will work for SARS-CoV-2 just because it worked for other viruses.
So, what do we know about the use of convalescent plasma to treat COVID-19 patients? A few recently published papers and preprints are worth highlighting. The first, published by Joyner et al., is a safety report from the Mayo Clinic Expanded Access Program (EAP). This EAP was developed in response to the COVID-19 outbreak in the U.S. It was a collaboration between the U.S. Food and Drug Administration (FDA), the Mayo Clinic and the national blood banking community to collect and distribute investigational convalescent plasma to patients infected with SARS-CoV-2 who had, or were judged to be at high risk of progressing to, severe or life-threatening disease, and were hospitalized in acute care facilities. This report evaluated the first 5,000 hospitalized participants with severe or life threatening COVID-19 to receive COVID-19 convalescent plasma (CCP) and found that <1% of study participants had serious reactions to the treatment. In a recent publication, Joyner et al. provided a safety update in 20,000 hospitalized patients that were treated with CCP under the Mayo Clinic EAP. Incidence of serious adverse events remained low, and CCP was thus judged to be safe in hospitalized patients with COVID-19.
Despite a large number of hospitalized patients treated with CCP for severe COVID-19, randomized control trials (RCTs) have been sparse. Li et al. published an open-label, multicenter study of CCP treatment of COVID-19 in China. This study included 103 patients with severe or life-threatening COVID-19 from 7 medical centers in Wuhan, China, who were randomized to receive either CCP + standard treatment (n = 52) or standard treatment alone (n = 51). The study was underpowered, in large part because it was terminated early due to containment of SARS-CoV-2 in China (they had planned to enroll 200 patients), but trends toward accelerated clinical improvement were observed by day 28 in patients who presented with symptoms around 2 weeks into their illness. Furthermore, in an analysis stratified by disease severity, patients with less severe disease experienced about 5 days faster recovery and overall greater likelihood of clinical improvement by day 28. Investigators stopped a second RCT early after finding that patients had already developed antibodies against the virus prior to receiving CCP.
Two newly published preprints by Joyner et al. are worth noting. The first one aggregated patient outcome data from a total of 21 studies (4,173 COVID-19 patient outcomes), of which 12 were controlled studies (including 2 RCTs) and 9 were case series and case reports, to determine the effect of CCP on mortality. This analysis method showed that the aggregate mortality rate for CCP recipients was substantially lower than non-CCP recipients – namely, when aggregating data from the 12 controlled studies, CCP recipients had a mortality rate of 10% compared to 22% in non-CCP recipients. The second preprint explored potential signals of efficacy in 35,322 patients from 2,807 acute care facilities across the U.S. and territories that received CCP under the EAP. Patients who received CCP within 3 days of COVID-19 diagnosis, compared to those who received CCP 4 or more days after COVID-19 diagnosis, showed a reduction in 7-day (8.7% (8.3%, 9.2%) vs 11.9% (11.4%, 12.3%)) and 30-day (21.6% (21.0%, 22.3%) vs 26.7% (26.1%, 27.3%)) crude mortality rates, suggesting that earlier use of CCP was associated with lower observed rates of mortality. Additional analyses were performed in a subset of 3,082 patients who received 1 unit of CCP, of which the anti-SARS-CoV-2 IgG antibody titers were known. Lower 7-day and 30-day mortality rates were seen in those patients who received high antibody titered plasma within 3 days of COVID-19 diagnosis compared to those who received lower antibody titered plasma 4 or more days after COVID-19 diagnosis. While these findings offer encouraging support for the notion that CCP is a potential efficacious treatment when transfused early and with high antibody levels, it is extremely important to note that these are observational studies – not RCTs – and thus must be interpreted as such.
Although current knowledge about COVID-19 therapies, including CCP, is increasing rapidly due to the record number of research studies being globally implemented, there are still many challenges to be addressed. As Casadevall and Pirofski very nicely point out, there are a number of requirements that must be met before convalescent plasma can be deployed as a treatment or prevention option for COVID-19. First, there must be a population of available donors who have recovered from COVID-19 and can donate convalescent plasma. Second, we must have blood banking facilities that are equipped to initially process the donations and then later issue the correct plasma. The rapid uptake of convalescent plasma therapy in hospitalized patients between April and August 2020 demonstrates how the existing infrastructure of blood donations allowed for rapid mobilization of this therapy. A third, but more challenging aspect of evaluating the efficacy of CCP and distributing it broadly, involves understanding the individual components of this polyclonal antibody therapy. We must have the necessary SARS-CoV-2 serological, virological and neutralization assays, as well as the adequate laboratory support to perform these assays. Lastly, we need prophylaxis and therapeutic protocols to assess the efficacy and measure the immune response of CCP, while still maintaining good regulatory oversight. In order to meet the above requirements, we need to continue to build upon the rapidly growing CCP data in order to answer some critical questions.
Who is a good candidate for CCP donation?
Growing evidence is emerging about whether SARS-CoV-2 antibodies are capable of potent neutralizing activity. In particular, Robbiani et al., as well as multiple other studies, have shown that the receptor binding domain (RBD) of SARS-CoV-2 is a major target of neutralizing antibodies. However, the quantity and specificity of SARS-CoV-2 antibodies necessary to have a therapeutic or preventative effect is currently unknown, and it is therefore crucial to define the therapeutic range of antibody titers for CCP. Excitingly, through close collaboration with our colleagues in the lab, UNC just opened the coronavirus-inactivating plasma (CoVIP) therapy trial. CoVIP is an RCT led by Dr. Luther Bartelt that will compare patients receiving plasma with validated neutralizing antibodies to SARS-CoV-2 with patients receiving plasma with very high neutralizing antibodies to help answer this question.Further, there are many donor variables that we currently don’t understand. The growing body of literature on SARS-CoV-2 antibodies, including an oral abstract by Markmann et al., suggests that not all CCP from various donors will be the same. We suspect that only some CCP contains the right amount of the right antibodies to be an effective therapy. In short, we still need to identify who, if anyone, has developed enough protective antibodies to be clinically valuable against SARS-CoV-2.
What are the logistical barriers to collecting and processing of CCP?
Plasma is a component of whole blood. The other main components of whole blood include red blood cells, white blood cells and platelets. While a single unit of plasma can be processed after whole blood collection, most patients are currently treated with at least two units of plasma. The demand for CCP as therapy would far exceed donor supply if relying on whole blood preparation. A more efficient method to collect at least 2, and up to 3 or 4, units of plasma from a single donor collection is plasmapheresis. Plasmapheresis is the process of separating plasma from the other whole blood components. A plasmapheresis machine is used to draw blood, then separate and return blood cells and platelets to the donor. This whole process takes about 45 minutes, and what is left over for donation is the plasma. After collection, plasma must be quickly frozen so it can be safely stored until use.
Barriers to donor recruitment should also be taken into consideration. CCP donation centers will only be effective if the public has knowledge of and accessibility to the facilities. Information has to be disseminated to the public in ways that the lay person can understand – both from a content perspective and a language perspective. We were fortunate to rapidly establish a COVID-19 plasma donation center at UNC. A major challenge we faced was disseminating information in Spanish during a time when we are seeing disproportionally high infection rates in the Latinx population in North Carolina.
Furthermore, donors need to be able to get to a plasma donation center in order for the program to be effective. For donors that live hours away, simply getting to the door can be a huge barrier – both from a time and cost perspective – something we are currently witnessing. Next, the facilities, equipment (plasmapheresis machine, freezers to store the plasma, supplies) and staff must be available. Lastly, effective leadership and coordination of these processes is essential.
How is the safety of CCP assured?
We rely on many years of experience with donated blood products to develop and ensure that safety measures are in place and adhered to. Donated blood products must always be tested and meet certain, stringent requirements (which include screening for bloodborne pathogens) outlined by the FDA before they can be used. Furthermore, the blood type of the donated plasma must match the blood type of the recipient. Finding CCP donors who are AB blood types, which is the least common ABO blood type, present in only ~5% of the US population, has been particularly challenging. In addition, there are infrequent risks associated with receiving plasma ie. allergic reactions, lung damage and difficulty breathing. All recipients must therefore be monitored for these uncommon adverse reactions.Who should receive CCP therapy, and when should they receive it?
We, and many other researchers across the globe, are furiously in the process of trying to answer these questions. Does this therapy only work at certain stages in the disease process – i.e., earlier vs later? Does the severity of one’s illness at a given time dictate whether they will benefit from treatment? Does the make-up of the recipient’s SARS-CoV-2 antibodies affect whether they will benefit from CCP or not? Are there certain biomarkers that can help predict whether a recipient will benefit from CCP? Although we have begun to answer some of these questions through the studies mentioned above as well as multiple others, these essential questions need to be further addressed through well-designed and well-powered (large) randomized controlled trials (RCTs).How will we measure the efficacy of CCP therapy?
You may start to see a theme here – one critical way to assess efficacy of CCP is through RCTs comparing people who get CCP and those who do not. Another important thing to note here, as stated nicely by Bloch et al. is that the antibodies’ duration of efficacy is unknown, but it is postulated to last weeks to a few months. Not only does this further emphasize the need to study durability of efficacy of CCP– i.e., after one receives CCP, how long do those antibodies remain at high enough levels to continue providing therapeutic effect, but also raises the question of whether multiple transfusions are necessary during the patients’ disease course and recovery.Because of the growing COVID-19 epidemic in the United States, I (HR) was abruptly recalled to the US from South Africa where I was doing HIV/AIDS research as part of my Infectious Diseases Fellowship at UNC. Unsure of what would be required of me, I was surprised to see, on my first day of the COVID-19 infectious diseases service, that we were able to offer CCP as a potential treatment for very scared and ill patients with COVID-19.
But this leads us to our final point. One of the most compelling things about CCP, if it proves to be a beneficial therapeutic or preventative for COVID-19, is the potential availability and scalability of this treatment. In our current global pandemic, low, middle and high-income countries are all being affected by this virus. As a result, health disparities and inequities are being magnified. The race for new, experimental therapies requires significant financial investment and scientific infrastructure, which puts many of these therapies out of reach for much of the world’s population during the early stages of development and production. CCP, on the other hand, comes from patients who have recovered from SARS-CoV-2 infection. Currently we have 2 of the 3 things that may allow this to be globally scalable– a global infrastructure for plasma transfusion, and a ready supply of potential donors. Now, if we want to make this promising therapy a global reality, we need a better understanding of the immune response both in individuals who have recovered from and those who are currently suffering from SARS-CoV-2 infection.
