Source/Disclosures
Disclosures: Corash is a co-founder and employee of Cerus Corp. Guarner, Liu and Roback report no relevant financial disclosures. Healio could not confirm Yang’s relevant financial disclosures at the time of reporting.
April 01, 2020
7 min read
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Convalescent plasma transfusion shows promise for severely ill patients with COVID-19

Source/Disclosures
Disclosures: Corash is a co-founder and employee of Cerus Corp. Guarner, Liu and Roback report no relevant financial disclosures. Healio could not confirm Yang’s relevant financial disclosures at the time of reporting.
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Laurence Corash, MD
Laurence Corash

Preliminary research has shown the potential of convalescent plasma therapy to improve clinical outcomes of patients with severe disease related to COVID-19.

Results of an uncontrolled case series, conducted in China and published in JAMA, showed five patients critically ill with COVID-19 and acute respiratory distress syndrome demonstrated improvement in clinical status after receiving convalescent plasma that contained neutralizing antibodies.

In a separate feasibility pilot study — also conducted in China — 10 patients with severe COVID-19 all showed significant improvement in clinical condition within 3 days of receiving convalescent plasma, which is derived from donors who recently recovered from the infection.

“The situation is so acute and so serious that we have to try many different things,” Laurence Corash, MD, chief scientific officer and co-founder of Cerus Corp., told Healio. “But, of all the different things that have been tried thus far, convalescent plasma has shown the most consistent and best responses. Based on previous experiences with convalescent plasma in other viral diseases with high death rates, I am optimistic that this will work here.”

Convalescent plasma has “an old history,” Corash said. It showed some benefit for a small number of patients during the Spanish influenza epidemic in 1918. It reduced mortality from 16% to about 1% among individuals with Argentine hemorrhagic fever, it decreased time to hospital discharge among people in Hong Kong with severe acute respiratory syndrome, and it also has been used to treat Ebola, Corash said.

Cerus Corp. has formed a collaborative research group designed to optimize convalescent plasma therapy for patients with COVID-19.

Donating plasma is different than donating blood. Plasma is extracted from the donor using a specific machine, with red blood cells and platelets returned to the donor. Donors can give about 850 mL of plasma per session, and based on the preliminary data from China, this can treat up to four patients with severe symptoms related to COVID-19, Corash said.

“The people to go after immediately are those who had documented COVID-19 disease and have recovered to see if they are willing to donate plasma,” Corash said. “The idea is to create a huge inventory of this plasma that can be readily available. We already collect and transfuse plasma for other diseases, such as auto-immune and immune-deficiency diseases.”

Case series results

The five patients with COVID-19 in the case series (age range, 36-73 years; women, n = 2) all had severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment, had received mechanical ventilation, and had a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO/FiO) of less than 300 mm Hg. Only one had a preexisting medical condition (hypertension and mitral valve insufficiency).

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Patients underwent transfusion with convalescent plasma with a SARS-CoV-2-specific antibody binding titer greater than 1:1,000 and a neutralization titer exceeding 1:40. The plasma was donated by five patients aged 18 to 60 years who recovered from COVID-19, and was administered 10 to 22 days following hospital admission.

Body temperature changes, sequential organ failure assessment scores, PaO/FiO, viral load, serum antibody titer, routine blood biochemical index, acute respiratory distress syndrome, and ventilator use before and after transfusion all served as study endpoints.

Final follow-up was March 25.

Results showed that, within 3 days of plasma transfusion, four patients experienced normalization of body temperature. Sequential organ failure assessment scores decreased among all five patients, and PaO/FiO increased within 12 days after treatment (range, 172-276 before treatment vs. 284-366 after treatment). A PaO/FiO ratio less than 200 indicates severe disease, and less than 300 indicates less severe acute respiratory distress syndrome.

Moreover, viral loads decreased and became negative within 12 days after transfusion, and SARS-CoV-2-specific enzyme-linked immunosorbent assay and neutralizing antibody titers increased (range, 40-60 before treatment to 80-320 on day 7 after treatment).

“The neutralizing antibody titers, vital for the restriction of viral infection of the five recipients, significantly increased after plasma transfusion,” Lei Liu, MD, of Shenzhen Third People’s Hospital in China, and colleagues wrote. “The results highlight the possibility that antibodies from convalescent plasma may have contributed to the clearance of the virus and also the improvement of symptoms.”

Acute respiratory distress syndrome resolved by day 12 for four patients.

Within 2 weeks of treatment, three patients were weaned off mechanical ventilation.

Three of the five patients have been released from the hospital after stays of 51, 53 and 55 days. The other two patients remained in stable condition at 37 days after transfusion.

“It took the patients a while to recover, but it ultimately got them off the ventilator, which is very important,” Corash, who was not involved with the study, told Healio. "COVID-19, in some cases, causes acute lung injury, which is a very specific syndrome. When you have that injury, your mortality rate is about 40%.”

“What’s more important is treating patients before they need mechanical ventilation to see if you can stop them from progressing” Corash added. “Considering we don’t have enough ventilators in the United States, I think this is going to be our best immediate strategy.”

Pilot study results

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The 10 adults with severe COVID-19 in the pilot study (median age, 52.5 years; men, n = 6) received a single dose of 200 mL convalescent plasma with neutralizing antibody titers above 1:640, along with maximal supportive care and antiviral agents.

Median time from onset of symptoms to hospital admission was 6 days (interquartile range [IQR], 2.5-8.5). Median time to convalescent plasma transfusion was 16.5 days (IQR, 11-19.3).

Common symptoms at disease onset included fever (n = 7), cough (n = 8) and shortness of breath (n = 8). Less common symptoms included sputum production (n = 5), chest pain (n = 2), diarrhea (n = 2), nausea and vomiting (n = 2), headache (n = 1), and sore throat (n = 1). Four patients had underlying chronic conditions, such as hypertension and cardiovascular and/or cerebrovascular diseases.

Three patients required a ventilator, three received high-flow nasal cannula oxygenation and two received conventional low-flow nasal cannula oxygenation.

Safety of convalescent plasma transfusion served as the primary endpoint. Secondary endpoints included improvement of clinical symptoms and laboratory parameters within 3 days after transfusion.

Results showed all symptoms among the 10 patients — especially fever, cough, shortness of breath and chest pain — disappeared or improved within 1 to 3 days of transfusion.

Two of three patients weaned off medical ventilation to high-flow nasal cannula; One of two patients discontinued high-flow nasal cannula. Moreover, seven patients who had previous viremia had undetectable viral loads after transfusion.

“This pilot study on convalescent plasma therapy showed a potential therapeutic effect and low risk in the treatment of [patients with severe COVID-19],” Xiaoming Yang, MD, researcher at China National Biotec Group Co. Ltd. and National Engineering Technology Research Center for Combined Vaccines in Wuhan, China, and colleagues wrote. “One dose of convalescent plasma with high concentration of neutralizing antibodies can rapidly reduce the viral load and tends to improve clinical outcomes. The optimal dose and treatment time point, as well as the definite clinical benefits of convalescent therapy, need to be further investigated in randomized clinical studies.”

‘Accelerate the effort’

Both academic and industry groups are beginning to investigate the efficacy of passive antibody therapies for COVID-19 infection.

If substantial, robust evidence from rigorously conducted clinical trials clearly establishes effectiveness, and if tests could identify patients who may benefit from passive immunity, the U.S. and other countries could consider a national campaign to provide such treatment, John D. Roback, MD, PhD, professor in the department of pathology and laboratory medicine and director of the Center for Transfusion and Cellular Therapy at Emory University School of Medicine, and Jeannette Guarner, MD, professor in the department of medicine at Emory University School of Medicine, wrote in an editorial accompanying the JAMA study.

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“Although a logistical challenge, this may be one approach to protect high-risk populations and could synergize with parallel efforts to develop vaccines and antiviral drugs,” Roback and Guarner wrote. “However, just as executive direction was critical for rapid implementation of COVID-19 tests, so it will be important to accelerate this effort.”

Cerus Corp. has already begun a program to collect plasma from donors who recovered from COVID-19, Corash said.

Beyond collecting plasma and treating patients with COVID-19, Corash and colleagues developed the INTERCEPT Blood System to ensure that blood-borne infectious diseases are not transmitted from the donor to the patient.

“What we do with this technology is take the plasma and measure the levels of neutralizing antibodies to see if it will be effective for treating the virus in the patients,” Corash said. “We then treat the plasma with our pathogen and activation technology — which is licensed for plasma and platelets by the FDA — to reduce the risk for infectious pathogens in the donor plasma so that we don’t transmit it back into the sick patient. ... In short, we are essentially sterilizing the plasma.”

The INTERCEPT system deploys proprietary small molecules that, when activated, bind to and block the replication of infectious pathogen DNA and RNA in the blood. To treat platelets and plasma, a molecule called amotosalen HCl is activated using ultraviolet A light.

A different molecule and approach are used in red blood cells because light cannot pass through hemoglobin in these cells. Instead, a proprietary S-303 molecule is activated with a change in pH. In both cases, potentially dangerous infectious pathogens — such as viruses, bacteria and parasites — and T cells that can cause graft-versus-host disease are rendered inactive.

“This process of treating the plasma takes anywhere between 5 and 10 minutes,” Corash said. “With the kits that will initially be used in the U.S., you then have to incubate the plasma for 12 hours to reduce the level of residual compound, and then you can transfuse it. Following FDA approval for a new plasma set, that incubation time will be reduced to less than 15 minutes. We are in the process of setting up a national network with Vitalant Research Institute and Vitalant Blood Services to screen large numbers of potential donors and collect plasma.” – by John DeRosier

Disclosures: Corash is a co-founder and employee of Cerus Corp. Guarner, Liu and Roback report no relevant financial disclosures. Healio could not confirm Yang’s relevant financial disclosures at the time of reporting.

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