Monday, April 19

Study assesses impact of anti-SARS-CoV-2 convalescent plasma in COVID-19 disease

The current COVID-19 pandemic is still very much active in most parts of the world. In the absence of effective antiviral drugs or vaccines, scientists are studying the use of blood plasma from convalescent COVID-19 patients, banking on its neutralizing antibody content.

A new study published in June 2020 on the preprint server medRxiv* describes the first attempt to correlate the clinical characteristics of the convalescent plasma (CP) donor with the antibody levels and types in the plasma. The University of Chicago researchers also try to identify predictors of the rise in recipient antibody levels following plasma donation.

Vial containing blood plasma from a COVID-19 patient. Image Credit: JHDT Productions

Convalescent Plasma in COVID-19

The use of CP is based on the transfer of neutralizing antibodies, as well as non-neutralizing antibodies and immunomodulatory compounds. Patients with severe COVID-19 have been observed to show significant improvement following the use of CP. This has led to the setting up of a supply chain for CP using a large number of recovered patients.

However, CP is effective only if the antibody titer is high. Earlier antibody studies show that most patients develop IgM and IgG within two weeks of the earliest symptoms, directed against the receptor-binding domain (RBD) and spike protein viral epitopes, and capable of neutralizing the virus. However, a small percentage of patients do not develop any demonstrable antibodies to spike or RBD antigens.

The Study: Antibody Titers in COVID-19

The study includes 103 donors, all of whom had CP collected 28 days or more after their symptoms resolved. The average duration of symptoms was 12 days, and less than 10% had other illnesses or had previously been hospitalized with the illness.

The antibody titers among donors on the day of CP collection has a wide range, from 0 to almost 1:4,000 for anti-RBD antibodies, and 0 to about 1:3,200 for anti-spike antibodies. Adjusting for multiple factors like age, sex, ABO blood type, and symptoms like cough, fatigue, and myalgia, they found that the following factors were predictive of a higher anti-RBD titer: age, fever, history of hospitalization, absence of myalgia, and fatigue.

Anti-spike antibody levels were predicted by the same factors, except fatigue. O blood type was linked to lower anti-RBD levels but not anti-spike.

Effect of CP in COVID-19

The second part of the study looked at 10 patients with severe or critical COVID-19, with an average age of 62 years. The average symptom duration was 12 days, and most of them were on supplemental oxygen. Among the 10 patients, 8 patients were discharged and 1 critically ill patient who had been on extracorporeal membrane oxygenation (ECMO) died, while one remained on ECMO.

Three recipients had no anti-RBD antibodies on the day of transfusion, day 0, and three had anti-spike titers. However, the antibody titer was very high in both ECMO patients on day 0, and this fell after CP transfusion. The other eight recipients had a rise in antibody titer after receiving CP, mostly within 3 days, but one showed a rise only on day 7 and day 14 for anti-spike and anti-RBD, respectively.

The average increase in anti-RBD was 31% per day, while it was 40% for the anti-spike antibody. The rate of fall in the ECMO patients was 9% and 8%  for anti-RBD and anti-spike, respectively.

Safety of and Neutralizing Antibodies in CP in COVID-19

There were no adverse effects of CP transfusion, and no direct worsening of the clinical condition linked to this therapy, including in patients on immunosuppressant drugs following stem cell therapy, and one patient with end-stage renal disease who was on dialysis.

The researchers conclude that there were higher neutralizing antibody titers among older, hospitalized patients with a history of fever but no myalgia. At the same time, anti-RBD was higher in patients with a history of fatigue.

The variable clinical characteristics of convalescent patients and the differences in their immune response underlie the failure of recovery to correlate with seroconversion in some patients. One remarkable finding was the increased neutralizing antibody titer in AB donors compared to O donors, who are less vulnerable to COVID-19. Earlier studies have shown that the presence of anti-A antibodies inhibits S protein-ACE2 binding in vitro.

Despite the wide range of antibody titer in CP, 80% showed a significant rise in both ant-spike and anti-RBD antibodies within 3 days after transfusion. The antibody titer continued to show an increase up to 14 days in four of the recipients, but the illest patients showed a fall in antibody titer.

Implications and Future Directions

The safety of CP is well demonstrated in this trial, with no evidence of antibody-dependent enhancement of disease. The possibility of obtaining plasma with higher antibody titers may increase if the plasma is collected soon after natural infection and not long after recovery. The antibody response may be stimulated by other antibody effects that modulate the immune response, such as Fc receptor-mediated stimulation of viral uptake to increase antigen presentation to effector cells.

The investigators also suggest the importance of setting up local blood collection facilities to make use of local strain-specific antibodies in plasma that will be optimally effective. Moreover, the technique of CP preparation is a rather simple and rapidly scalable technique, which lends itself to in-hospital blood bank facilities.

The study concludes, “Development of a convalescent plasma program is feasible, rapidly deployable and economical when existing resources of equipment, space, and personnel are used.”

Further work to validate the clinical predictors of high antibody titer in CP and the antibody response following transfusion will help improve the efficacy of this therapy, and to understand how CP works as well as to establish the best viral epitopes for this treatment.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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