Plasma Therapies: Effective COVID-19 Treatments?

The race is on to find remedies to prevent and treat the COVID-19 virus that has infected more than 38 million and killed more than one million people worldwide. While much focus has been on a preventive vaccine, numerous other treatments to reduce the severity of infection and reverse the course of disease are being studied. Plasma therapies have taken a seat among these investigational treatments as pre-existing therapeutic options, including high-dose intravenous immune globulin (IVIG), convalescent plasma and hyperimmune globulin. And, although there is a great deal of hope for the promise of plasma therapies to treat COVID-19 patients, their effectiveness is still unknown, and other challenges remain, most notably the availability of plasma to manufacture them.

IVIG, Convalescent Plasma and Hyperimmune Globulin: The Difference?

IVIG, derived from the plasma of thousands of donors from the general population, provides passive immune protection against a broad range of pathogens. It is used to treat primary and secondary immunodeficiencies, autoimmune/inflammatory conditions, neuroimmunologic disorders and infection-related sequelae. Currently, seven manufacturers commercially market nine different IVIG products. And, while it may provide immunomodulatory effect in a hyperinflammation state such as can occur with COVID-19, it is absent any specific neutralizing antibody titers against novel pathogens such as the SARS-CoV-2 virus that causes COVID-19.¹

Convalescent plasma, collected from recovered patients, can be transfused directly into people experiencing serious complications from COVID-19. It is an individualized therapy, which means the plasma comes from one or several donors and is transfused directly to one patient, which makes it difficult to scale to the levels needed globally. However, since there is limited processing and faster availability, it can be ready for use the same day plasma is collected, but it must be infused or frozen within 24 hours. To ensure its safety, donated plasma must be evaluated to ensure it does not contain other viruses, and the blood needs to be tested to ensure it is compatible with the recipient’s blood. However, its effectiveness varies since the amount and range of antibodies in a unit of plasma varies by donor. In addition, because plasma is 90 percent water and convalescent plasma is minimally processed, it contains fewer virus-specific antibodies per unit of volume.²

Hyperimmune globulin is derived from convalescent plasma that has been pooled, processed and purified to concentrate antibodies with the potential to treat people at high risk for serious complications from COVID-19. A mass-produced therapy from donors who have recovered from COVID-19, it is sent to manufacturing facilities where it is pooled together, processed to remove or inactive viruses and toxins, and purified to concentrate antibodies. Requiring more processing and clinical trials, it takes longer to become available; however, it has a longer shelf-life (24 months to 36 months), making it easier to distribute and store for use in future outbreaks. Unlike convalescent plasma, blood-type matching is not required.  Because hyperimmune globulin is pooled from convalescent plasma donors and then purified and concentrated, it can be standardized to have a minimum level of antibodies in each unit, which means the effectiveness of different batches should not vary therapeutically. And, because it is highly concentrated, it contains more virus-specific antibodies per unit of volume.²

High-Dose IVIG Studies

To date, one randomized placebo‐controlled, double‐blind clinical trial, as well as data from retrospective, case series and open‐label randomized controlled trials have indicated IVIG immunotherapy could benefit severe and critically ill COVID‐19 patients.

Results from the first randomized placebo-controlled double-blind clinical trial were published at the end of October in the journal BMC Infectious Diseases. In the study, 59 patients with severe COVID-19 infection who did not respond to initial treatments were randomly assigned to two groups: 30 patients who received four vials of IVIG daily for three days (in addition to initial treatment), and 29 patients who received a placebo. Patients’ demographic, clinical and select laboratory test results were recorded and deemed to not be statistically different between the two groups. In addition, the occurrence of in-hospital mortality was recorded, which found the mortality rate was significantly lower in the IVIG group compared to the control group (6 [20.0 percent] vs. 14 [48.3 percent], respectively). Multivariate regression analysis demonstrated administration of IVIG did indeed have a significant impact on mortality rate.³

In an article published in Clinical & Translational Immunology, researchers presented a multicenter retrospective cohort study that evaluated the efficacy of IVIG in 325 severe and critically ill COVID‐19 patients admitted to hospitals in southern China between December 2019 and March 2020. In the study, 174 patients (64 percent male, median age 61 years) received a dose of 0.1 g/kg to 0.5 g/kg of IVIG per day for between five and 15 days, while 151 patients (51 percent male, median age 56 years) did not receive this therapy. Additional therapies included antibiotics, antiviral drugs and steroids per guidelines in China. Results showed early administration (less than or equal to seven days postadmission) of high‐dose (greater than 15 g per day) IVIG improves the prognosis of critical‐type patients with COVID‐19. However, the researchers cautioned the study had limitations since it was a retrospective study, there was a wide range of IVIG dose and varying duration of treatment, and there was a lack of analyses of various inflammatory cytokines and immune cells. There are also data from six other studies that were mostly case series or retrospective, with an exception of one study that was a randomized open‐label trial. Most of these studies combined corticosteroids with IVIG, making it difficult to evaluate the therapeutic benefits of IVIG. However, all did show some therapeutic benefit.⁴

Perhaps one of the most promising of the other six studies that evaluated high-dose IVIG for treating COVID-19 patients in the U.S. is Octapharma’s first study of its Octagam 10% (immune globulin intravenous [human]) plus standard of care (SOC) compared to SOC alone to prevent mechanical ventilation in COVID-19 patients requiring high-flow oxygen. That study enrolled 33 COVID-19 patients experiencing hypoxia who were at risk of requiring mechanical ventilation. Sixteen patients with a median age of 51 years received 0.5 g/kg/day for three days with 40 mg of methylpredisolone 30 minutes prior to infusion, and 17 patients with a median age of 58 years received SOC alone. Findings revealed the use of IVIG reduced the rate of progression of respiratory failure requiring mechanical ventilation (13 percent with IVIG versus 41 percent without IVIG). According to lead investigator George Sakoulas, MD, of Sharp Memorial Hospital and the Sharp Rees-Stealy Medical Group in San Diego, Calif., “While this [study] did not achieve statistical significance among the collective subject cohorts, the reduced rate of progression to mechanical ventilation with IVIG achieved statistical significance among the subset with a calculated or estimated Alveolar-arterial gradient of greater than 200 mm Hg (14 percent with IVIG versus 58 percent without IVIG).”⁵

Dr. Sakoulas is also leading a larger multicenter, randomized, double-blind placebo-controlled study to determine if high-dose Octagam 10% therapy will slow or stop respiratory deterioration in patients with severe COVID-19. Secondary objectives of this study are to measure the effects of the treatment on slowing or stopping the clinical progression of COVID-19 by improving pulmonary function, quality of life and correlated impact on metabolic factors. The study is estimated to enroll more than 200 patients and is currently enrolling.⁶

Grifols Therapeutics is conducting a study to determine if a high dose of IVIG plus standard medical treatment (SMT) can reduce all-cause mortality versus SMT alone in hospitalized participants with COVID-19 requiring admission to the intensive care unit (ICU) through day 29. Participants receiving IVIG plus SMT will receive the first IVIG infusion of Gamunex-C on day one up to a total net dose of 2 g/kg, based on participant’s body weight (maximum dose = 160 g for participants over 80 kg), administered in divided doses as infusions of 500 mg/kg, based upon participant’s body weight, over four days, or 400 mg/kg, based upon participant’s body weight, over five days. Participants will also receive all SOC interventions while hospitalized from day one to day 29. The primary outcome measure is all-cause mortality rate at day 29. The study is currently recruiting, and there is no scheduled end date.⁷

Grifols is also conducting a study to determine if high-dose IVIG plus SMT can reduce the proportion of participants dying or requiring ICU admission on or before day 29 or who are dependent on high-flow oxygen devices or invasive mechanical ventilation on day 29 versus SMT alone in hospitalized patients with COVID-19. This study will enroll an estimated 100 patients who will receive Flebogamma (immune globulin [human] liquid) at the same dosing as its Octagam study.⁸

 Although why IVIG seems to have beneficial effect is not yet precisely understood, it is believed to be due to a reduction in the inflammatory mediators following IVIG therapy, which suggests IVIG might target cytokine storm in severe and critically ill COVID‐19 patients by complement scavenging, inhibition of innate immune cells and effector T‐cell activation, and expansion of Tregs.⁴

Convalescent Plasma Studies

Because studies suggest convalescent plasma is effective in treating other coronaviruses, researchers are studying its use for treating COVID-19. For instance, a study conducted in 2004 in Hong Kong showed patients with SARS who were given convalescent plasma earlier in the infection process were discharged from the hospital sooner and were less likely to die than patients who were given it later. And, in 2014, the World Health Organization published guidance on convalescent plasma donor selection and treatment after research showed positive results for Ebola.⁹

Unfortunately, most current research does not show convalescent plasma is effective in treating SARS-CoV-2. One study in China that was reported in JAMA in June found convalescent plasma in addition to standard treatment didn’t significantly improve patients with severe or life-threatening COVID-19.8 In June, a meta-analysis was conducted of 20 studies (one randomized controlled trial, three controlled nonrandomized studies of interventions [NRSIs], and 16 noncontrolled NRSIs) with 5,443 participants, 5,211 of whom received convalescent plasma. Results were very uncertain whether convalescent plasma has any effect on 1) all-cause mortality at hospital charge, 2) prolonged time to death and 3) improvement of clinical symptoms at seven days.¹⁰

Some research does show convalescent plasma seems to reduce the risk of dying from COVID-19. An analysis of 35,000 hospitalized patients who received convalescent plasma to treat severe COVID-19 within three days of diagnosis were less likely to die than patients who received convalescent plasma later in their illness. But, that study had no control group.¹¹ In another safety study of convalescent plasma, there was a trend toward fewer deaths in 145 patients who received plasma versus 435 patients who did not. However, the researchers reported the results were not statistically meaningful. But, when they broke the data down to look at people who received plasma treatment with high levels of antibodies within 72 hours of being admitted to the hospital, they did see a statistically meaningful difference: About 7 percent of those who didn’t get plasma died within 28 days of hospitalization, compared with 1.2 percent of patients who were treated with plasma with high levels of antibodies within a couple of days of hospitalization. The researchers stressed, though, that only results from randomized, controlled trials will be able to determine how well the treatment works.¹²

While convalescent plasma is generally considered safe, it is not without some risks. In a Johns Hopkins University study of more than 16,000 Americans with COVID-19 who were infused with plasma from recovered patients, no major safety issues were reported.7 In another study of 5,000 patients published in the Journal of Clinical Investigation, researchers found serious adverse events such as allergic reactions or transfusion-related lung injury occurred less than 1 percent of the time.¹² And, in the meta-analysis discussed previously, the researchers concluded they are very uncertain whether convalescent plasma affects the number of serious adverse events. Other studies have reported on possible grade 3 or grade 4 adverse events, the majority of which were allergic or respiratory events. However, those researchers were unsure whether convalescent plasma affects the risk of moderate to severe adverse events. Lastly, one study reported 15 deaths, four of which they classified as potentially, probably or definitely related to transfusion of convalescent plasma.⁹

What’s important to note is there are no randomized controlled trials yet that have shown convalescent plasma works against the SARS-CoV-2 virus. Nevertheless, on Aug. 23, as part of the U.S. Food and Drug Administration’s ongoing efforts to fight this pandemic, the agency issued an emergency use authorization (EUA) for the use of investigational convalescent plasma to treat hospitalized patients with serious or life-threatening COVID-19 infection.¹³ Indeed, it’s important to understand that while outcomes were tracked of the some 70,000 COVID-19 patients who were treated with convalescent plasma prior to the EUA, those outcomes were not intended to be a formal clinical trial since there was no control arm.¹⁴

Even so, EUA gives physicians permission to use an experimental therapy in certain circumstances. And, while it’s not the same as FDA approval (there are no approved therapies for COVID-19), researchers can test convalescent plasma in clinical trials of COVID-19. And, use of survivors’ plasma can also be extended to people with serious or immediately life-threatening COVID-19 who aren’t eligible for clinical trials.¹²

Hyperimmune Globulin Studies

Hyperimmune globulin, which provides passive immunity to COVID-19, could be used for both prevention and treatment. As part of a collaboration with FDA, the National Institutes of Health and the Biomedical Advanced Research Development Authority, among others, hyperimmune globulin products are being developed to undergo clinical trials to evaluate their safety and efficacy:

• Since April, Grifols has been collecting COVID-19 convalescent plasma for its anti-SARS-CoV-2 hyperimmune globulin in more than 245 Grifols U.S. donation centers. The donors’ plasma has high levels of anti-SARS-CoV-2 neutralizing antibodies. In July, Grifols delivered the first manufactured batches of its anti-SARS-CoV-2 hyperimmune globulin for clinical trials. Its hyperimmune globulin, which is derived from blood plasma of healthy donors recovered from COVID-19, has the potential to be a highly specific, pure and safe medicine that delivers a high and consistent concentration of protective antibodies against the novel coronavirus. As of this writing, FDA had approved the protocol to start the clinical trial that will evaluate its safety and efficacy.¹⁵

• Patients are now being enrolled in the Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) Phase III clinical trial that will evaluate the safety, tolerability and efficacy of an investigational anti-coronavirus hyperimmune intravenous immune globulin (H-Ig) medicine for treating hospitalized adults at risk for serious complications of COVID-19 disease. If successful, the CoVIg-19 Plasma Alliance’s H-Ig may become one of the earliest treatment options for hospitalized COVID-19 patients. The investigational H-Ig materials for the trial will be provided by CSL Behring and Takeda on behalf of the Alliance, as well as by two other companies.¹⁶

Another trial listed on the clinicaltrials.gov website is being sponsored by Green Cross Corp., which began recruiting in September. The company’s study will evaluate the efficacy and safety of its 5131A hyperimmune globulin for hospitalized patients of COVID-19.¹⁷

Interestingly, while the aforementioned trials are all testing hyperimmune globulin products manufactured from donated human plasma, there have been published news reports about investigational treatments for COVID-19 using hyperimmune serum developed with antibodies from horses. For example, Immunova developed its hyperimmune globulin product by injecting a SARS-CoV-2 protein into horses to generate a large amount of neutralizing antibodies. Plasma is then extracted from the horses, purified and processed. After positive results in laboratory tests, its clinical trial will be tested in 242 people diagnosed with moderate to severe COVID-19 symptoms.¹⁸ The Indian Council of Medical Research (ICMR) is also developing horse sera containing antibodies against COVID-19 as a potential alternative to plasma therapy after a study conducted in India showed the latter does not prevent deaths in moderate and severe COVID-19 patients. According to ICMR, plasma recovered from patients experiencing COVID-19 has a varying profile of antibodies, efficacy and concentrations, which makes it unreliable as a clinical tool for patient management. But, it says, the standardization of antibody-rich plasma can be achieved using animals. After completing animal trials, ICMR received clearance to begin a clinical trial in humans.¹⁹

For more information on hyperimmune globulin, see “The Promise of COVID-19 Hyperimmune Globulin Products” on p.46.

The Uncertainty of Plasma Supply

Perhaps one of the greatest obstacles for plasma therapies is supply. Inherently, since IVIG is manufactured from human plasma donated by the general population, there is potentially ample supply. However, that assumes people will donate. And, during this pandemic, plasma donations have significantly declined due to impacts of social distancing measures and other mobility restrictions. According to the Plasma Protein Therapeutics Association (PPTA), considering the complex manufacturing of plasma-derived therapies can take seven to 12 months, any decline in plasma donations could impact patients’ ability to access this therapy. In response, PPTA and other organizations such as the Immune Deficiency Foundation and the Immunoglobulin National Society have launched campaigns to raise awareness of source plasma collection, recognize the contributions of plasma donors in saving and improving lives, and increase understanding about lifesaving plasma therapies.²⁰ 

But, even more of a challenge is obtaining enough donated plasma from people who have recovered from COVID-19. The American Red Cross announced in July that it’s facing an emergency shortage of convalescent plasma since it is being distributed faster than donations are coming in. When COVID-19 cases spiked, the American Red Cross saw hospital demand for convalescent plasma more than double, reducing the supply by more than 70 percent. Currently, the agency is collecting convalescent plasma at more than 170 locations throughout the U.S. to help meet patient needs. But more donations are needed to keep up with immediate and future patient needs.²¹

Clinicians and hospitals can help with convalescent plasma collection. In partnership with FDA, the American Red Cross has developed a process to identify and qualify individuals who have recovered from COVID-19 and collect their COVID-19 convalescent plasma. The program is working with clinicians to enable rapid access to a new experimental plasma treatment for the most seriously ill patients. However, because this is still an investigational new drug (IND) program, requesting and receiving convalescent plasma occurs outside the routine product ordering processes. FDA has allowed for three pathways through which hospitals can acquire convalescent plasma: the Expanded Access Protocol (EAP), a Single Patient Emergency Investigational New Drug (eIND) application or another Investigator-Initiated Research IND. Specific information can be found at Recommendations for Investigational COVID-19 Convalescent Plasma (www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma). Clinicians participating via the EAP and eIND pathways to receive COVID-19 convalescent plasma for their currently ill patients can register them at www.redcrossblood.org/donate-blood/dlp/plasma-donations-from-recovered-covid-19-patients/clinician-registration.html.²²

Interventions Are Needed Now

Until a preventive vaccine is developed to protect against the SARS-CoV-2 virus, the urgent need for other effective interventions such as plasma therapies remains. While there is no clear indication plasma is effective, studies of the use of high-dose IVIG have shown it may be helpful in severe COVID-19 cases. It is also believed convalescent plasma could be a highly effective treatment since it has shown promise in other diseases. Practically speaking, it is unknown whether hyperimmune globulin will be effective since no clinical trials have yet been completed. Nevertheless, even if plasma therapies show promise for treating COVID-19 patients, plasma collection and processing remain a challenge.