Since 11 March 2020, the world is officially in the grip of the COVID-19 pandemic. COVID-19 convalescent plasma (CCP) has shown positive results as a supportive therapy. As pathogen inactivation (PI) has been encouraged by some authorities (18, 21-23), the INTERCEPT™ Blood System for plasma provides several unique benefits.

COVID-19 convalescent plasma

Caused by a newly-identified member of the beta coronavirus family, SARS-CoV-2, COVID-19 poses a major global health challenge. By 12 May 2020 the virus had affected more than 4,139,794 people worldwide, and had caused more than 285,328 deaths (1). In the absence of any preventive or curative treatment approved for use, treatment of COVID-19 patients is limited to supportive therapy. One of the tracks being followed is convalescent plasma (CP), a well-known therapeutic approach that has been applied, with varying levels of success, in other viral outbreaks in the past (2-12).

Data from China and South Korea indicate that antibodies collected from recovered COVID-19 patients can reduce viral load and improve clinical conditions. Reports have shown that administration of COVID-19 convalescent plasma (CCP) is safe, and was not associated with major adverse events. Thus, due to tolerability and potential efficacy, CCP is a good candidate to be evaluated in further trials as a therapeutic option to control the COVID-19 pandemic (13-17).

Pathogen inactivation

Pathogen inactivation of CCP is proposed by authorities and specialist societies to mitigate the risk of transfusion-transmitted infections (TTI) during the window period and the risk of potential SARS-CoV-2 superinfection (18-25). Transfusing additional viral load is not recommended for sick recipients, and the risk is unacceptable in the case of prophylactic use for healthy recipients. PI would make it possible to relax donor deferral (26) and bypass the quarantine period of 3 to 4 months applied to donors with an unknown risk profile, ensuring fast CCP availability and additional safety by reducing risks of TTI for patients in urgent need (21,24,25). Finally, if the SARS-CoV-2 antibody test is not readily available, CCP pooling might theoretically increase the chances that neutralising antibodies are present in a high enough titer, and may improve the diversity of the polyclonal immunoglobulin (39). The increased viral risk associated with pooling might be mitigated by PI.

INTERCEPT Blood System for plasma

As an FDA-approved and CE Mark certified Class III medical device, the INTERCEPT Blood System for plasma offers multiple benefits when it comes to PI. Whereas INTERCEPT treatment has shown a negligible impact on immunoglobulins and their neutralising activity in ebola CP (27,28), it has demonstrated effective inactivation of a large number of pathogens (29,30), SARS-CoV and MERS-CoV (30-34), which are genetically very similar to SARS-CoV-2, among others.

In addition, INTERCEPT treatment offers the opportunity to keep plasma liquid at the ready, preserving it from bacterial contamination as it is kept refrigerated for 5 days (35,36) after thawing. Operationally suited for apheresis plasma (37), with an overall throughput of about 36 units per hour, the system allows for fast implementation (only one week may suffice) (38).
  1. World Health Organization COVID-19 dashboard. https://covid19.who.int/
  2. Enria DA, Briggiler AM, Sanchez Z. Treatment of Argentine hemorrhagic fever. Antiviral Res. 2008;78(1):132-9.
  3. Enria DA, Briggiler AM, Fernandez NJ, Levis SC, Maiztegui JI. Importance of dose of neutralising antibodies in treatment of Argentine haemorrhagic fever with immune plasma. Lancet. 1984;2(8397):255-6.
  4. Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52(4):447-56.
  5. Hung IFN, To KKW, Lee CK, Lee KL, Yan WW, Chan K, et al. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest. 2013;144(2):464-73.
  6. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015;211(1):80-90.
  7. Soo YO, Cheng Y, Wong R, Hui DS, Lee CK, Tsang KK, et al. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2004;10(7):676-8.
  8. Lai ST. Treatment of severe acute respiratory syndrome. Eur J Clin Microbiol Infect Dis. 2005;24(9):583-91.
  9. Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44-6.
  10. Arabi Y, Balkhy H, Hajeer AH, Bouchama A, Hayden FG, Al-Omari A, et al. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus. 2015;4:709.
  11. Organization WH. Use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease for transfusion, as an empirical treatment during outbreaks. 2014 [Available from: http://apps.who.int/iris/rest/bitstreams/604045/retrieve.
  12. Dean CL, Hooper JW, Dye JM, Zak SE, Koepsell SA, Corash L, et al. Characterization of Ebola convalescent plasma donor immune response and psoralen treated plasma in the United States. Transfusion. 2020.
  13. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically ill patients with Covid-19 with convalescent plasma. JAMA 2020;323(16):1582–9. https://doi.org/10.1001/jama.2020.4783.
  14. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A 2020. https://doi.org/10.1073/pnas.2004168117.
  15. Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F, et al. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol 2020. https://doi. org/10.1002/jmv.25882
  16. Ahn JY, Sohn Y, Lee SH, Cho Y, Hyun JH, Baek YJ, et al. Use of convalescent plasmatherapyintwoCOVID-19 patientswithacuterespiratory distresssyndrome in Korea. J Korean Med Sci 2020;35:e149https://doi.org/10.3346/jkms.2020.35. e149.
  17. Zhang Bin, Liu Shuyi, Tan Tan, Huang Wenhui, Dong Yuhao, Chen Luyan, et al. Treatment With Convalescent Plasma for Critically Ill Patients With SARS-CoV-2 Infection. Chest 2020. https://doi.org/10.1016/j.chest.2020.03.039. In press.
  18. Points to consider in the preparation and transfusion of COVID-19 convalescent plasma. Jay Epstein & Thierry Burnouf on behalf of the ISBT Working Party on Global Blood Safety
  19. WHO Blood Regulators Network (BRN). Interim Position Paper on blood regulatory response to the evolving outbreak of the 2019 novel coronavirus SARS-CoV-2*
  20. COVID-19 Convalescent Plasma Collection: Donor Eligibility, Processing, Labeling, and Distribution. AABB’s CCP collection protocol – 03 31 2020
  21. Centro Nazionale Sangue. Protocollo operativo per la selezione dei pazienti-donatori (convalescenti con diagnosi virologicamente documentata di COVID-19), per la qualificazione biologica del plasma da aferesi eventualmente prodotto nonché per le successive correlate procedure di riduzione dei patogeni e di stoccaggio controllato.
  22. "Position paper - SIMTI and SIdEM " on the production of hyperimmune plasma to be used in the therapy of SARS-CoV2 disease.
  23. Producción de plasma hiperinmune de donantes convalecientes COVID-19 (ConPlas-19). Multi-center, Randomized, Clinical Trial of Convalescent Plasma Therapy Versus Standard of Care for the Treatment of COVID-19 in Hospitalized Patients. Producción de plasma hiperinmune de donantes convalecientes covid-19, sometidos a un proceso de reducción de patógenos (inactivación).
  24. Protocole d’utilisation thérapeutique 24 avril 2020 Plasma convalescent COVID-19 Infection par le coronavirus SARS-CoV-2 (maladie COVID-19)
  25. COVID-19 : L’ANSM encadre le recours possible à l’utilisation de plasma de personnes convalescentes pour des patients ne pouvant être inclus dans les essais cliniques - 30/04/2020
  26. Einfürung risikominimierender Massnahmem zur Prävention der Übertragungen des neuartigen Coronavirus (2019nCoV) durch Blutkomponenten zu Transfusion Empfehlung des Paul-Ehrlich-Instituts (PEI) vom (10.02.2020)
  27. Geisen et al., Pathogen-reduced Ebola virus convalescent plasma first steps towards standardization of manufacturing and quality control including assessment of Ebola-specific neutralizing antibodies, Vox Sanguinis, 2016
  28. Dean et al., Characterization of Ebola convalescent plasma donor immune response and psoralen treated plasma in the United States. Transfusion. 2020.
  29. INTERCEPT Blood System for Plasma, Technical Data Sheet
  30. Lanteri et al., Inactivation of a broad spectrum of viruses and parasites by photochemical treatment of plasma and platelets using amotosalen and ultraviolet A light, Transfusion 2020
  31. Singh et al., 2006. Photochemical treatment of plasma with amotosalen and longwavelength ultraviolet light inactivates pathogens while retaining coagulation function. Transfusion 46: 1168-1177
  32. Pinna et al., 2005. Amotosalen photochemical inactivation of severe acute respiratory syndrome coronavirus in human platelet concentrates. Transfus Med 15: 269-276
  33. Hindawi et al., 2018. Inactivation of Middle East respiratory syndrome-coronavirus in human plasma using amotosalen and ultraviolet A light. Transfusion 58: 52-59
  34. Hashem et al., 2019. Amotosalen and ultraviolet A light efficiently inactivate MERS-coronavirus in human platelet concentrates. Transfus Med 29: 434-441
  35. TUV approval
  36. Erickson A. et al., Plasma treated with amotosalen and ultraviolet A light retains activity for hemostasis after 5 days post-thaw storage at 1 to 6C, Transfusion, 2017
  37. INTERCEPT Blood System for Plasma, Instructions for Use
  38. Cerus data on file
  39. Theusinger O. et al., Quarantine versus pathogen-reduced plasma-coagulation factor content and rotational thromboelastometry coagulation, Transfusion, 2017

How the INTERCEPT™ Blood System for plasma supports treatment of COVID-19.

A free ebook from Cerus

COVID-19 convalescent plasma (CCP) has shown positive results as a supportive therapy that can reduce viral load and improve clinical conditions. Pathogen inactivation is an important step in providing CCP to help patients in need, quickly and safely.

Download your copy of the ebook and learn about these topics and others: 

  • Does COVID-19 convalescent plasma offer a valid treatment solution for COVID-19 patients?
  • Does the INTERCEPT PI process interfere with the neutralising activity of immunoglobulins?
  • How does the INTERCEPT Blood System for plasma perform on viral inactivation?

This free 13-pager ebook explores the implications and importance of pathogen inactivation for COVID-19 convalescent plasma.

cover ebook

 

 


Q&A

Why is convalescent plasma (CP) being explored as a treatment option for COVID-19?

Does COVID-19 convalescent plasma (CCP) offer a valid treatment solution for COVID-19 patients?

How important is pathogen inactivation (PI) of CCP?

What is the added value the INTERCEPT Blood System for plasma offers when it comes to PI?

How does the INTERCEPT Blood System for plasma perform on viral inactivation?

Does the INTERCEPT PI process interfere with the neutralising activity of immunoglobulins?

How does INTERCEPT fit into CCP collection and transfusion protocols?

How does the INTERCEPT Blood System help ensure continuity of blood supply, even during pandemics?

 

Why is convalescent plasma (CP) being explored as a treatment option for COVID-19?

The novel emerging respiratory pathogen SARS-CoV-2 is the causative agent for the very contagious and highly morbid respiratory illness COVID-19. First detected in China, the pathogen has now spread in more than 200 countries, and is responsible for a pandemic COVID-19 outbreak. By 12 May 2020, the disease had affected more than 4,139,794 people worldwide, and had caused more than 285,328 deaths (1). Scientists worldwide are exploring every conceivable option to curb COVID-19’s impact as quickly as possible.

CP is a well-known therapeutic approach. The transfusion of plasma collected from recovered patients, and thus containing immunoglobulins:

  • Could improve clinical outcomes of patients (2-6).
  • Might serve as a prophylactic option for healthy recipients (7).
  • In addition to providing passive immune therapy, CP might be superior to hyperimmune globulin preparations in patients with organ damage, such as acute lung injury, because it has the potential to improve endothelial cell barrier dysfunction caused by viral infection, as was shown in vitro and in animal models (8). 

CP has been applied, with varying levels of success, to viral outbreaks in the past such as SARS, MERS, Ebola, influenza A H1N1, and Argentine hemorrhagic fever (9-19).

Being a newly identified member of the beta coronavirus family, SARS-CoV-2 shows close similarity to MERS-CoV (same family) and SARS-CoV (same strain), the causative agents of Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), respectively (20,21). Therefore, CP is being tested as a supportive treatment option in more than 50 countries worldwide.

2020_CERUS_COVID19_treatment_1

 

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  1. World Health Organization COVID-19 dashboard. https://covid19.who.int/
  2. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically ill patients with Covid-19 with convalescent plasma. JAMA 2020;323(16):1582–9. https://doi.org/10.1001/jama.2020.4783.
  3. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A 2020. https://doi.org/10.1073/pnas.2004168117.
  4. Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F, et al. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol 2020. https://doi. org/10.1002/jmv.25882
  5. Ahn JY, Sohn Y, Lee SH, Cho Y, Hyun JH, Baek YJ, et al. Use of convalescent plasmatherapyintwoCOVID-19 patientswithacuterespiratory distresssyndrome in Korea. J Korean Med Sci 2020;35:e149https://doi.org/10.3346/jkms.2020.35. e149.
  6. Zhang Bin, Liu Shuyi, Tan Tan, Huang Wenhui, Dong Yuhao, Chen Luyan, et al. Treatment With Convalescent Plasma for Critically Ill Patients With SARS-CoV-2 Infection. Chest 2020. https://doi.org/10.1016/j.chest.2020.03.039. In press.
  7. Bloch et al., Deployment of convalescent plasma for the prevention and treatment of COVID-19, J Clin Invest_2020
  8. Wu F. et al., Resuscitative strategies to modulate the endotheliopathy of trauma: from cell to patient, Shock 2020
  9. Enria DA, Briggiler AM, Sanchez Z. Treatment of Argentine hemorrhagic fever. Antiviral Res. 2008;78(1):132-9.
  10. Enria DA, Briggiler AM, Fernandez NJ, Levis SC, Maiztegui JI. Importance of dose of neutralising antibodies in treatment of Argentine haemorrhagic fever with immune plasma. Lancet. 1984;2(8397):255-6.
  11. Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52(4):447-56.
  12. Hung IFN, To KKW, Lee CK, Lee KL, Yan WW, Chan K, et al. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest. 2013;144(2):464-73.
  13. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015;211(1):80-90.
  14. Soo YO, Cheng Y, Wong R, Hui DS, Lee CK, Tsang KK, et al. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2004;10(7):676-8.
  15. Lai ST. Treatment of severe acute respiratory syndrome. Eur J Clin Microbiol Infect Dis. 2005;24(9):583-91.
  16. Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44-6.
  17. Arabi Y, Balkhy H, Hajeer AH, Bouchama A, Hayden FG, Al-Omari A, et al. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus. 2015;4:709.
  18. Organization WH. Use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease for transfusion, as an empirical treatment during outbreaks. 2014 [Available from: http://apps.who.int/iris/rest/bitstreams/604045/retrieve.
  19. Dean CL, Hooper JW, Dye JM, Zak SE, Koepsell SA, Corash L, et al. Characterization of Ebola convalescent plasma donor immune response and psoralen treated plasma in the United States. Transfusion. 2020.
  20. Hui DS et al., 2020. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health — The latest 2019 novel coronavirus outbreak in Wuhan, China. Int. J Infect Dis 91: 264-266
  21. Kandeel M, 2014. Bioinformatics analysis of the recent MERS-CoV with special reference to the virus-encoded spike protein. Mol Enzymology and Drug Targets (iMedPub) 1: 1-10

Does COVID-19 convalescent plasma (CCP) offer a valid treatment solution for COVID-19 patients?

Currently, no pharmacologic agents effective against SARS-CoV-2, the causative agent of COVID-19, have been approved for treatment of the disease. COVID-19 patient treatment is thus limited to supportive therapy. Transfusion of plasma containing neutralising antibodies (NAb) to SARS-CoV-2 from asymptomatic or convalescent COVID-19 donors is a potential near-term solution. Data from China and South Korea indicate that plasma containing antibodies collected from recovered COVID-19 patients can reduce viral load, improve clinical conditions, and is not associated with major adverse events, making CCP a good potential therapeutic candidate to control the COVID-19 pandemic (1-5).

COVID-19 convalescent plasma (CCP) has been regulated under investigational or compassionate use in several countries and by various regulatory institutions, such as the FDA, and clinical trials have been initiated to test its efficacy and safety (6).

  • As the number of convalescent or asymptomatic COVID-19 individuals increases, convalescent plasma sources become more abundant.
  • International scientific organisations such as WHO, ISBT, and AABB have issued position papers providing guidelines for the collection and treatment of CCP (7-9).
  • CCP is now being collected in numerous countries in order to treat COVID-19 patients in the frame of clinical trials or for compassionate use.

Worldwide, more than 50 countries have started the production of CCP. In at least half of those countries (27 countries as of 12 May 2020) one or more sites have adopted pathogen inactivation for their CCP units.

  • The INTERCEPT Blood System technology is applied, or is about to be applied, to the production of safer and effective CCP units in the vast majority (more than 22) of countries producing pathogen inactivated CCP (27 as of 12 May 2020).
    The map indicates the countries and the number of sites producing CCP with INTERCEPT in the EMEA region, as of 12 May 2020.
  • Overall, more than 80 organisations worldwide are producing CCP using the INTERCEPT Blood System, and more are about to join (10).  

Map CCP

 

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  1. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically ill patients with Covid-19 with convalescent plasma. JAMA 2020;323(16):1582–9. https://doi.org/10.1001/jama.2020.4783.
  2. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A 2020. https://doi.org/10.1073/pnas.2004168117.
  3. Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F, et al. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol 2020. https://doi. org/10.1002/jmv.25882
  4. Ahn JY, Sohn Y, Lee SH, Cho Y, Hyun JH, Baek YJ, et al. Use of convalescent plasmatherapyintwoCOVID-19 patientswithacuterespiratory distresssyndrome in Korea. J Korean Med Sci 2020;35:e149https://doi.org/10.3346/jkms.2020.35. e149.
  5. Zhang Bin, Liu Shuyi, Tan Tan, Huang Wenhui, Dong Yuhao, Chen Luyan, et al. Treatment With Convalescent Plasma for Critically Ill Patients With SARS-CoV-2 Infection. Chest 2020. https://doi.org/10.1016/j.chest.2020.03.039. In press.
  6. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds March 24,2020
  7. Points to consider in the preparation and transfusion of COVID-19 convalescent plasma. Jay Epstein & Thierry Burnouf on behalf of the ISBT Working Party on Global Blood Safety
  8. WHO Blood Regulators Network (BRN). Interim Position Paper on blood regulatory response to the evolving outbreak of the 2019 novel coronavirus SARS-CoV-2*
  9. COVID-19 Convalescent Plasma Collection: Donor Eligibility, Processing, Labeling, and Distribution. AABB’s CCP collection protocol – 03 31 2020
  10. Cerus data on file

How important is pathogen inactivation (PI) of CCP?

Leading scientific associations, such as ISBT and SIMTI/SIDEM, encourage pathogen inactivation (PI) of convalescent plasma (CP) (1,2). The Italian national blood association (CNS), as well as the national CCP clinical trial protocol (CONPLAS-19) in Spain, consider it mandatory (3,4). The French regulatory agency (ANSM) includes amotosalen and UVA light PI treatment in the preparation of CCP for compassionate use (5,6).

Pathogen inactivation of CP offers the following benefits:

Fast availability, providing additional safety 
Many convalescent plasma donors will be non-habitual donors with an unknown risk profile. They would have to pass the usual deferral criteria, and their plasma donation would be quarantined for 3 to 4 months, despite testing negative for most common viruses. PI makes it possible to relax donor deferral, and by minimising the residual risk associated to the window period, allows immediate CCP transfusion, ensuring fast CCP availability and reduced risks of TTI for patients in urgent need. 

  • The Paul-Ehrlich-Institut (PEI)’s advisory board to German blood centres issued specific preventive measures for blood donations. Blood components treated with PI are excluded from these measures (7):
    • 4 week deferral of travellers from China
    • 4 week deferral of donors in contact with COVID-19 patients
    • 8 week deferral of donors with confirmed prior COVID-19 infection

This advice greatly facilitates the collection and transfusion of CP to treat COVID-19 patients. It minimises the risks of plasma transfusion, and allows for earlier collection of CP, containing optimal levels of antibodies against SARS-CoV-2.

Plasma safety from SARS-CoV-2

Despite the selection criteria for recovered donors, convalescent plasma may harbour residual SARS-CoV-2.

Publications indicate that SARS-CoV-2 RNA can be found in COVID-19 symptomatic and asymptomatic patients (8).

  • Exposing a COVID-19 patient to the risk of superinfection is not advisable, especially as this might be a different strain of the virus (9). If CCP is prophylactically transfused to healthy recipients, the residual SARS-CoV-2 risk is unacceptable.

CERUS_CCP_treatment-COVID-19_linkedin_posts_1200x675px_3 Site

 

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  1. Points to consider in the preparation and transfusion of COVID-19 convalescent plasma. Jay Epstein & Thierry Burnouf on behalf of the ISBT Working Party on Global Blood Safety
  2. "Position paper - SIMTI and SIdEM " on the production of hyperimmune plasma to be used in the therapy of SARS-CoV2 disease.
  3. Centro Nazionale Sangue. Protocollo operativo per la selezione dei pazienti-donatori (convalescenti con diagnosi virologicamente documentata di COVID-19), per la qualificazione biologica del plasma da aferesi eventualmente prodotto nonché per le successive correlate procedure di riduzione dei patogeni e di stoccaggio controllato.
  4. Producción de plasma hiperinmune de donantes convalecientes COVID-19 (ConPlas-19). Multi-center, Randomized, Clinical Trial of Convalescent Plasma Therapy Versus Standard of Care for the Treatment of COVID-19 in Hospitalized Patients. Producción de plasma hiperinmune de donantes convalecientes covid-19, sometidos a un proceso de reducción de patógenos (inactivación).
  5. Protocole d’utilisation thérapeutique 24 avril 2020 Plasma convalescent COVID-19 Infection par le coronavirus SARS-CoV-2 (maladie COVID-19)
  6. COVID-19 : L’ANSM encadre le recours possible à l’utilisation de plasma de personnes convalescentes pour des patients ne pouvant être inclus dans les essais cliniques - 30/04/2020
  7. Einfürung risikominimierender Massnahmem zur Prävention der Übertragungen des neuartigen Coronavirus (2019nCoV) durch Blutkomponenten zu Transfusion Empfehlung des Paul-Ehrlich-Instituts (PEI) vom (10.02.2020)
  8. Chang L, Zhao L, Gong H, Wang Lunan, Wang L. Severe acute respiratory syndrome coronavirus 2 RNA detected in blood donations. Emerg Infect Dis. 2020 Jul [May 12, 2020]. https://doi.org/10.3201/eid2607.200839
  9. Tang X, Wu C, Li X, Song Y, Yao X, Wu X, et al. On the origin and continuing evolution of SARS- CoV-2. National Science Review. 2020.

What is the added value the INTERCEPT Blood System for plasma offers when it comes to PI?

The INTERCEPT Blood System for plasma is an FDA approved and CE Mark certified Class III medical device intended for the ex vivo preparation of pathogen reduced plasma, derived from whole blood or apheresis plasma, through an active molecule (amotosalen) that is activated by UVA light. As such, this solution offers multiple benefits when it comes to PI.

  • Viral inactivation performance
    The INTERCEPT Blood System for plasma has demonstrated effective inactivation of a broad spectrum of pathogens (viruses, bacteria and parasites) and contaminating donor leukocytes (1,2).
  • Preservation of immunoglobulins
    The impact of the amotosalen and UVA light pathogen inactivation process on antibodies and their neutralising activity has shown to be negligible, based on experience with Ebola convalescent plasma (3,4).
  • Fast availability of CCP
    INTERCEPT’s robust inactivation makes it possible to relax donor deferral during the COVID-19 pandemic (5) and bypass the quarantine time of 3 to 4 months applied to donors with an unknown risk profile in some countries (9-12), ensuring fast and safer CCP availability for patients in urgent need.
  • Operationally suited for apheresis plasma
    Up to 650 mL of plasma can be processed to produce up to 3 units of 200 mL plasma each, with a single disposable set and one illumination cycle (6). The overall throughput is calculated at 36 final units per hour.
  • Fast implementation
    One week may suffice to complete implementation, training and validation of the INTERCEPT Blood System for plasma (7).
  • Pooling option
    If the SARS-CoV-2 antibody test is not readily available, CCP pooling increases chances that neutralising antibodies are present in a high enough titer.
    Pooling may also improve the diversity of the polyclonal immunoglobulin, an advantage against pathogens with high mutation rates such as SARS-CoV- 2 (8). The increased viral risk associated with pooling might be mitigated by PI.

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  1. INTERCEPT Blood System for Plasma, Technical Data Sheet
  2. Lanteri et al., Inactivation of a broad spectrum of viruses and parasites by photochemical treatment of plasma and platelets using amotosalen and ultraviolet A light, Transfusion 2020
  3. Geisen et al., Pathogen-reduced Ebola virus convalescent plasma first steps towards standardization of manufacturing and quality control including assessment of Ebola-specific neutralizing antibodies, Vox Sanguinis, 2016
  4. Dean et al., Characterization of Ebola convalescent plasma donor immune response and psoralen treated plasma in the United States. Transfusion. 2020.
  5. Einfürung risikominimierender Massnamem zur Pravantion der Ubertragungen des neuartigen Coronavirus (2019nCoV) durch Blutkomponenten zu Transfusion Empfehlung des Paul-Ehrlich-Instituts (PEI) vom (10.02.2020)
  6. INTERCEPT Blood System for Plasma, Instructions for Use
  7. Cerus data on file
  8. Tang X, Wu C, Li X, Song Y, Yao X, Wu X, et al. On the origin and continuing evolution of SARS- CoV-2. National Science Review. 2020.
  9. Centro Nazionale Sangue. Protocollo operativo per la selezione dei pazienti-donatori (convalescenti con diagnosi virologicamente documentata di COVID-19), per la qualificazione biologica del plasma da aferesi eventualmente prodotto nonché per le successive correlate procedure di riduzione dei patogeni e di stoccaggio controllato.
  10. Producción de plasma hiperinmune de donantes convalecientes COVID-19 (ConPlas-19). Multi-center, Randomized, Clinical Trial of Convalescent Plasma Therapy Versus Standard of Care for the Treatment of COVID-19 in Hospitalized Patients. Producción de plasma hiperinmune de donantes convalecientes covid-19, sometidos a un proceso de reducción de patógenos (inactivación)
  11. Protocole d’utilisation thérapeutique 24 avril 2020 Plasma convalescent COVID-19 Infection par le coronavirus SARS-CoV-2 (maladie COVID-19)
  12. COVID-19 : L’ANSM encadre le recours possible à l’utilisation de plasma de personnes convalescentes pour des patients ne pouvant être inclus dans les essais cliniques - 30/04/2020

How does the INTERCEPT Blood System for plasma perform on viral inactivation?

The INTERCEPT Blood System for plasma employs the unique properties of amotosalen, a photoactive compound that, upon illumination with UVA light, irreversibly blocks the replication of DNA and RNA. The mechanism has proven to be effective on a broad spectrum of pathogens as well as on contaminating donor leukocytes (1,2).

In light of the current COVID-19 threat and the use of COVID-19 convalescent plasma to treat patients, the high efficacy of INTERCEPT against several viruses is worth consideration.

Nineteen viruses (15 enveloped viruses and 4 non-enveloped viruses) were evaluated for sensitivity to amotosalen/UVA pathogen inactivation treatment, and the results were summarised in a recent review publication. Log reduction factors (LRFs), defined as the difference in infectious titres before and after amotosalen/UVA treatment, ranged from 4 to 7.6 for 16 out of the 19 viruses tested (2).

This table, extracted from the INTERCEPT for plasma technical data sheet, shows an extent of inactivation between 4 and 7 logs for the majority of the viruses tested (1). LRFs of ≥4.0 log are generally considered the minimum requirement based on the regulatory standards outlined by the Committee for Human Medicinal Products (3).

tabel 5 20200625

Inactivation data showing log reduction of >5.5 for SARS-CoV (4) and 4.67 for MERS-CoV (5), both viruses that show genetic similarity to SARS-CoV-2, may suggest that INTERCEPT PI would offer a similar potency against the causative agent of COVID-19.

The table below indicates the LRF obtained by INTERCEPT treatment for coronaviruses in plasma and platelets.
Post 5 table 2

Two ongoing studies, conducted with external collaborators, are evaluating the SARS-CoV-2 inactivation efficacy of INTERCEPT, and results will soon be available.

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  1. INTERCEPT Blood System for Plasma, Technical Data Sheet
  2. Lanteri et al., Inactivation of a broad spectrum of viruses and parasites by photochemical treatment of plasma and platelets using amotosalen and ultraviolet A light, Transfusion 2020
  3. Nahler G. Committee for Proprietary Medicinal Products (CPMP). In: Dictionary of pharmaceutical medicine. Vienna: Springer; 2009.
  4. Singh et al., 2006. Photochemical treatment of plasma with amotosalen and long-wavelength ultraviolet light inactivates pathogens while retaining coagulation function. Transfusion 46: 1168-1177
  5. Hindawi et al., 2018. Inactivation of Middle East respiratory syndrome-coronavirus in human plasma using amotosalen and ultraviolet A light. Transfusion 58: 52-59
  6. Pinna et al., 2005. Amotosalen photochemical inactivation of severe acute respiratory syndrome coronavirus in human platelet concentrates. Transfus Med 15: 269-276
  7. Hashem et al., 2019. Amotosalen and ultraviolet A light efficiently inactivate MERS-coronavirus in human platelet concentrates. Transfus Med 29: 434-441

Does the INTERCEPT PI process interfere with the neutralising activity of immunoglobulins?

Key to the value of CCP as a supportive therapy for COVID-19 patients is the presence of a sufficient number of active antibodies in the plasma that is transfused. Hence the importance for PI treatment to interfere as little as possible with the titre or neutralising activity of immunoglobulins.

INTERCEPT effect on Ebola antibodies

In 2016, a study on pathogen-reduced Ebola virus convalescent plasma (ECP) showed that the INTERCEPT process had an impact of 2% to 4% on total IgG (1) – an impact which turned out to be considerably lower than the effect on total IgG and IgG1 that other PI methods had shown in previous studies (2-4).

An even more recent study tested the impact of amotosalen/UVA PI technology on anti-Ebola virus antibody in six patients (5). The antibody titres, assessed by multiple assays, were conserved after INTERCEPT treatment and the antibodies’ neutralising activity remained essentially similar compared to untreated ECP.

Post 6 table 1 23 06

The table summarizes the impact of pathogen inactivation (PI) on the immunoglobulin content
or activity for the INTERCEPT technology in comparison with other PI methods. EBOV=Ebola virus.

INTERCEPT effect on SARS-CoV-2 antibodies

No data on the effect of PI and cryopreservation on SARS-CoV-2 specific IgG titre and neutralising activity was available until the recent publication of a letter to the editor of The Lancet Microbe (6).

CCP samples were collected before and after PI treatment with INTERCEPT and subsequently after CCP storage at 2 to 6 °C or shock freezing at –30 °C (Figure 1). The authors conclude that PI of CCP with the INTERCEPT system, and either shock-frozen storage at –30 °C or liquid storage at 2 to 6 °C for up to 9 days after PI treatment, does not alter the potential therapeutic potency of CCP.

The authors recommend PI to mitigate the risk for transfusion-associated viral transmission.

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Figure 1. Impact of INTERCEPT PI and cryopreservation on anti-SARS-CoV-2 IgG content and neutralising antibody titre on 5 plasmapheresis CCP products.

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  1. Geisen et al., Pathogen-reduced Ebola virus convalescent plasma first steps towards standardization of manufacturing and quality control including assessment of Ebola-specific neutralizing antibodies, Vox Sanguinis, 2016
  2. Balint et al. Plasma Constituent Integrity in Pre-Storage vs. Post-Storage Riboflavin and UV-light Treatment – A Comparative Study, Transfus Apher Sci, 2013 
  3. Bihm et al., Characterization of plasma protein activity in riboflavin and UV light-treated fresh frozen plasma during 2 years of storage at -30 degrees C, Vox Sanguinis, 2010
  4. Cap et al., Treatment of blood with a pathogen reduction technology using ultraviolet light and riboflavin inactivates Ebola virus in vitro. Transfusion, 2016
  5. Dean et al., Characterization of Ebola convalescent plasma donor immune response and psoralen treated plasma in the United States. Transfusion. 2020
  6. Tonn T. et al., Stability and neutralising capacity of SARS-CoV-2-specific antibodies in convalescent plasma, The Lancet Microbe, 2020

How does INTERCEPT fit into CCP collection and transfusion protocols?

Protocols for the collection of CCP, as well as for CCP transfusion, are not the same everywhere. Based on CCP protocol analysis from a selection of countries (1-4), the general criteria for eligible donors includes patients:

  • Who were previously diagnosed as COVID-19 positive
  • Who recovered and have been without any symptoms for at least 14 days
  • Whose PCR test results came back negative for SARS-CoV-2 at least once, or repeatedly

In some countries, however, only male or nulliparous female donors are selected or the absence of anti-HLA antibodies is checked. If the proper tests are available and validated, the anti-SARS-CoV-2 antibody levels are usually measured, and most protocols suggest a minimum potency threshold for eligibility.

Plasma collection is performed via apheresis, for a volume of about 600 mL. Depending on the protocol and on the country, the CCP is stored in units of 200 to 300 mL. The INTERCEPT system fits smoothly into the procedure. With a single disposable set and one illumination cycle, it can process up to 650 mL of plasma and produce up to 3 units of 200 mL pathogen-inactivated plasma per unit. Both freshly collected and previously frozen plasma can be treated to maintain a steady CCP production in case of intermittent CCP donations.

One of the main differences in the protocols is target patient selection for CCP treatment. Some protocols, such as the one applied first in Italy (2), favour severely ill patients for selection, for example intubated patients who are under mechanical ventilation or continuous positive airway pressure (CPAP). Other protocols, like the one applied in France (3), include only patients in the early onset of symptoms, up to 6 days. According to the ConPlas-19 Spanish protocol patients under mechanical ventilation, in the late stage of the disease, are excluded. CCP treatment regimen also varies, from single CCP unit administration (1,2) to multiple CCP units over multiple days (3).

With an illumination throughput calculated at 36 final units per hour*, by combining the multi-dose inactivation with the fast illumination turnaround time, INTERCEPT enables the efficient preparation of pathogen inactivated CCP that can be made available to support hospitalised patients in need or stored frozen to create a therapeutic option in case of a potential second wave of the pandemic.

*= the equivalent of 6 final plasma units (2x INTERCEPT Plasma sets) can be processed in one illumination cycle. Illumination time, including loading and unloading, is etimated in 10 min (5)

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  1. Producción de plasma hiperinmune de donantes convalecientes COVID-19 (ConPlas-19). Multi-center, Randomized, Clinical Trial of Convalescent Plasma Therapy Versus Standard of Care for the Treatment of COVID-19 in Hospitalized Patients. Producción de plasma hiperinmune de donantes convalecientes covid-19, sometidos a un proceso de reducción de patógenos (inactivación).
  2. Hyperimmune Plasma for Critical Patients With COVID-19 (COV19-PLASMA). Plasma From Donors Recovered From New Coronavirus 2019 As Therapy For Critical Patients With Covid-Foundation IRCCS San Matteo Hospital and OSPEDALE CARLO POMA ASST MANTOVA. https://clinicaltrials.gov/ct2/show/NCT04321421#studydesign
  3. Efficacy of Convalescent Plasma to Treat COVID-19 Patients, a Nested Trial in the CORIMUNO-19 Cohort (CORIPLASM). Assistance Publique - Hôpitaux de Paris, Etablissement Français du Sang. https://clinicaltrials.gov/ct2/show/study/NCT04345991?cond=convalescent+plasma&cntry=FR&draw=2&rank=1
  4. Recommendations for Investigational COVID-19 Convalescent Plasma. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma
  5. INTERCEPT Blood System for Plasma, Instructions for Use

How does the INTERCEPT Blood System help ensure continuity of blood supply, even during pandemics?

Global outbreaks like the one we are experiencing with COVID-19 can serve to underscore potential problems with our health systems. The coronavirus pandemic is shining a light on continuity of blood supply, which, in terms of safety and availability, can be affected by regional/national outbreaks of emerging or re-emerging pathogens.

 

In outbreak conditions, restricted access to blood donations and quarantine are often applied to avoid potential risks of transfusion-transmitted infections, which can negatively impact availability and can put the supply of blood components at risk.
An effective way to avoid any potential shortages is to have a pathogen inactivation strategy in place, that can be scaled up if and when it is required.

For institutions without a pathogen inactivation strategy, faced with a sudden, unexpected outbreak, the INTERCEPT Blood System can still be implemented quickly, ensuring that blood supply remains safe and available, minimising delays or interruptions.

When Ile de La Reunion, for example, was hit by a Chikungunya outbreak in 2005 that infected 30% of inhabitants, a complete conversion to pathogen inactivation of platelet components with the INTERCEPT Blood System was achieved in two weeks (1), with no additional personnel required.

During the current COVID-19 pandemic, convalescent plasma (CCP) pathogen inactivation with the INTERCEPT Blood System was introduced in emergency at the Carlo Poma Hospital (Mantova, Italy) and Basel University Hospital (Basel, Switzerland). With the help of the Cerus deployment team, all installation, training, and validation of the INTERCEPT Blood System for plasma was carried out in one week (2).

Providing a rapid and effective response in the emergency of a pandemic with travel and other logistical restrictions can be challenging. For this purpose, the Cerus deployment team has added virtual tools to support training and installations remotely, ensuring smooth service and support.

Some countries have demonstrated that a proactive safety strategy against emerging pathogens via nationwide INTERCEPT Blood System adoption can be achieved. Smooth implementation for all platelet components in all blood transfusion services was accomplished in 12 months in Switzerland (3). Regional successful implementation experiences were reported in Belgium (4) and France (5) paving the way to subsequent nationwide adoption.

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  1. Rasonglès et al., Transfusion of platelet components prepared with photochemical pathogen inactivation treatment during a Chikungunya virus epidemic in Ile de La Réunion. Transfusion, 2009
  2. Cerus data on file.
  3. Jutzi M, et al., Nationwide Implementation of Pathogen Inactivation for All Platelet Concentrates in Switzerland. Transfus Med Hemother. 2018
  4. Osselaer JC et al., Universal adoption of pathogen inactivation of platelet components: impact on platelet and red blood cell component use. Transfusion, 2009
  5. Cazenave JP et al., Use of additive solutions and pathogen inactivation treatment of platelet components in a regional blood center: impact on patient outcomes and component utilization during a 3-year period. Transfusion, 2011

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Contact

If you have any questions about Covid-19 Convalescent Plasma or pathogen inactivation, please contact: 

Cerus Europe B.V. 
T: +31 33 496 0612
contact@cerus.com

Copyright 2020, CERUS. All rights reserved. MKT-EN 00443-01, v2.0
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