Safety and efficacy of convalescent plasma for COVID-19: the preliminary results of a clinical trial

Abstract

Background. The lack of effective etiotropic therapy for COVID-19 has prompted researchers around the globe to seekr various methods of SARS-CoV-2 elimination, including the use of convalescent plasma.

Aim. The aim of this work was to study the safety and efficacy of the convalescence plasma treatment of severe COVID-19 using the plasma containing specific antibodies to the receptor binding domain (RBD) of SARS-CoV-2 S protein in a titer of at least 1:1000.

Methods. A single-center, randomized, prospective clinical study was performed at the FRCC FMBA of Russia with the participation of 86 patients who were stratified in two groups. The first group included 20 critically ill patients who were on mechanical ventilation the second group included 66 patients with moderate to severe COVID-19 and with spontaneous respiration. The patients in the second group were randomized into two cohorts in a ratio of 2:1. In the first cohort (46 patients), pathogen-reduced convalescent plasma was transfused (twice, 320 ml each), in the second cohort (20 patients) a similar amount of non-immune freshly frozen plasma was transfused to the patients.

Results. The use of plasma of convalescents in patients with severe COVID-19 being on mechanical ventilation does not affect the disease outcome in these patients. The mortality rate in this group was 60%, which corresponds to the average mortality of COVID patients on mechanical ventilation in our hospital. In the second group, clinical improvement was detected in 75% and 51%, for convalescent and non-immune plasma, respectively. Of the 46 people who received convalescent plasma, three patients (6.5%) were transferred to mechanical ventilation, two of them died. In the group receiving non-immune plasma, the need for mechanical ventilation also arose in three patients (15%), of which two died. The hospital mortality in the group of convalescent plasma was 4.3%, which is significantly lower than the average COVID-19 hospital mortality at our Center (6.73%) and more than two times lower than the hospital mortality in the control group (n=150), matched by age and by the disease severity.

Conclusions. Thus, we demonstrated a relative safety of convalescent plasma transfusion and the effectiveness of such therapy for COVID-19 at least in terms of the survival of hospitalized patients with severe respiratory failure without mechanical ventilation. In the absence of bioengineered neutralizing antibodies and effective etiotropic therapy, the use of hyperimmune convalescent plasma is the simplest and most effective method of specific etiopathogenetic therapy of severe forms of COVID-19.

Keywords

SARS-CoV-2 / COVID-19 / plasma of convalescents / antibodies to RBD S-protein / ARDS / mechanical ventilation

References

[1] Баклаушев В.П., Кулемзин С.В., Горчаков А.А., и др. COVID-19. Этиология, патогенез, диагностика и лечение // Клиническая практика. 2020;11(1):7–20. [Baklaushev VP, Kulemzin SV, Gorchakov АА, et al. COVID-19. Etiology, pathogenesis, diagnosis and treatment. Journal of Clinical Practice. 2020;11(1):7–20. (In Russ).] doi: 10.17816/clinpract26339.

[2] Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med. 2006;145(8):599–609. doi: 10.7326/0003-4819-145-8-200610170-00139.

[3] Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52(4):447–456. doi: 10.1093/cid/ciq106.

[4] Cheng Y, Wong R, Soo Y, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44–46. doi: 10.1007/s10096-004-1271-9.

[5] Ko JH, Seok H, Cho S, et al. Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience. Antivir Ther (Lond). 2018;23(7):617–622. doi: 10.3851/IMP3243.

[6] Bin Ju, Qi Zhang, Jiwan Ge, Ruoke Wang , Jing Sun, Xiangyang Ge et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection. 2020. doi: 10.1038/s41586-020-2380-z.

[7] Sridhar S, Luedtke A, Langevin E Effect of dengue serostatus on dengue vaccine safety and efficacy. N Engl J Med. 2018;379(4):327–340. doi: 10.1056/NEJMoa1800820.

[8] Wan Y, Shang J, Sun S, et al. Molecular mechanism for antibody-dependent enhancement of coronavirus entry. J Virol. 2020;94(5):e02015-19. doi: 10.1128/JVI.02015-19.

[9] Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis. 2020;ciaa344. doi: 10.1093/cid/ciaa344.

[10] Zhang B, Liu S, Tan T, et al. Treatment with convalescent plasma for critically ill patients with SARS-CoV-2 infection. Chest. 2020. pii: S0012-3692(20)30571-7. doi: 10.1016/j.chest.2020.03.039.

[11] Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020. pii: 202004168. doi: 10.1073/pnas.2004168117.

[12] Shen C, Wang Z, Zhao F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020. doi: 10.1001/jama.2020.4783.

[13] Dzik S. COVID-19 convalescent plasma: now is the time for better science. Transfus Med Rev. 2020. doi: 10.1016/j.tmrv.2020.04.002.

[14] Hyperimmune plasma for critical patients with COVID-19 (COV19-PLASMA). ClinicalTrials.gov; 2020. NCT04321421.

[15] Convalescent plasma to limit coronavirus associated complications. ClinicalTrials.gov; 2020. NCT04325672.

[16] Anti-SARS-CoV-2 inactivated convalescent plasma in the treatment of COVID-19. ClinicalTrials.gov; 2020. NCT04292340.

[17] Safety in convalescent plasma transfusion to COVID-19. ClinicalTrials.gov; 2020. NCT04333355.

[18] Временные методические рекомендации «Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19)». Версия 7 (утв. Министерством здравоохранения РФ 3 июня 2020 г.). [Vremennyye metodicheskiye rekomendatsii «Profilaktika, diagnostika i lecheniye novoy koronavirusnoy infektsii (COVID-19)”. Version 7 (utv. Ministerstvom zdravookhraneniya RF 3 iyunya 2020 g.). (In Russ).] Доступно по: https://base.garant.ru/74212510/. Ссылка активна на 12.06.2020.

[19] Аверьянов А.В., Перкина А.С., Сотникова А.Г., и др. Исследование безопасности плазмы реконвалесцентов в терапии COVID-19 // Медицина экстремальных ситуаций. — 2020 (принято в печать). [Aver’yanov AV, Perkina AS, Sotnikova AG, et al. Issledovaniye bezopasnosti plazmy rekonvalestsentov v terapii COVID-19. Meditsina ekstremal’nykh situatsiy. 2020. (In Russ).]

[20] Клыпа Т.В., Бычинин М.В., Мандель И.А., и др. Клиническая характеристика пациентов с COVID-19, поступающих в отделение интенсивной терапии. предикторы тяжелого течения // Клиническая практика. — 2020. — Т.11. — №2. [Klypa TV, Bychinin MV, Mandel IA, et al. Clinical characteristics of patients admitted to an ICU with COVID-19. Predictors of the severe disease. Journal of Clinical Practice. 2020;11(2). (In Russ).] doi.org/10.17816/clinpract34182.

[21] Food and Drug Administration. Recommendations for Investigational COVID-19 Convalescent Plasma. [cited 2020 May 1]. Available from: https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma.

[22] Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020;e2010044. doi: 10.1001/jama.2020.10044.

[23] Sean TH Liu, Hung-Mo Lin, Ian Baine, et al. Convalescent plasma treatment of severe COVID-19: A matched control study. medRxiv. 2020. Available from: https://www.medrxiv.org/content/10.1101/2020.05.20.20102236v1.

Funding

Федеральный научно-клинический центр специализированных видов медицинской помощи и медицинских технологий Федерального медико-биологического агентства РоссииFederal Scientific and Clinical Center of Specialized Types of Medical Care and Medical Technologies of the Federal Medical and Biological Agency of Russia

RIGHTS & PERMISSIONS

Baklaushev V.P., Averyanov A.V., Sotnikova A.G., Perkina A.S., Ivanov A.V., Yusubalieva G.M., Novikova O.N., Shikina V.E., Dupik N.V., Kedrova A.G., Sanzharov A.E., Shirshova E.V., Balionis O.I., Valuev-Elliston V.T., Zakirova N.F., Glazov Y.N., Panukhina I.A., Soloviev N.A., Vinokurov A.G., Ivanov Y.V., Vasilev V.N., Klypa T.V., Troitsky A.V.