Investigational Convalescent Plasma Therapy to Combat Deadly COVID-19: Desperate search for an effective therapy
Written by Amin Islam
Basics and Background
COVID-19 is a serious and deadly RNA virus, hundreds of thousands of people already died globally; millions affected. There are no proven effective therapies found so far. Different antivirals and steroid in combinations are being used with variable results so far. We need to identify effective treatments for COVID-19. One possible treatment is giving hospital admitted patients a transfusion of plasma – the liquid part of blood – that contains antibodies against COVID-19 from donors who have already recovered from the infection. Antibodies in plasma of people who have recovered from infection can reduce the growth of the virus and also reduce the amount of the virus in the lungs. We need to identify people who have had COVID-19 infection and have high levels of these antibodies. We are able to collect plasma – called convalescent plasma CP – from these patients. Plasma collected from patients who have recovered from an infectious disease has been used over many decades for a variety of different infectious agents, although evidence of its effectiveness and safety is mostly limited to empirical reports. Convalescent plasma can be transfused to patients fighting an infection or can be used to manufacture immune globulin concentrates (plasma derived medicinal products). During a rapidly expanding outbreak of a viral infection, large populations of susceptible persons may become ill early in the event, prior to availability of effective vaccines and antiviral therapies. As highlighted by the WHO Blood Regulators Network, an organised programme to collect convalescent plasma or serum from disease survivors could provide a potentially valuable empirical intervention while data on effectiveness and safety of its use are being gathered through structured clinical trials.
The COVID-19 pandemic is a clear situation where plasma from recovered patients might be a valuable resource to support the disease treatment within randomised or case-control clinical trials or observational studies of plasma transfusion and in the development of plasma-derived medicinal products. The use of convalescent plasma for prophylactic treatment of ‘at-risk’ population groups is also a possibility in the future. Data from the SARS outbreak and preliminary data from China for COVID-19 suggest that the treatment has promise, particularly while effective medicinal products or vaccines are still under development and testing, although robust scientific evidence and solid haemovigilance data are still lacking. The safety and effectiveness of convalescent plasma transfusion should be tested ideally in randomised case controlled clinical trials and enrolment of patients in those trials should be favoured when they meet eligibility criteria. However, in the current COVID-19 crisis, and given that these will take significant time to produce results and will not be available for participation to all hospitals, it is proposed that monitored use in observational studies should proceed in parallel after getting robust protocols and ethical approval.
What is convalescent plasma (CP)?
CP is plasma donated by people who have recovered from a particular virus (in this case COVID-19) and whose plasma contains antibodies to that virus. The antibodies present in the donor plasma may, in theory, support the patient’s immune response to recover from the virus.
How effective is CP in general and COVID-19 specifically?
CP has been used as experimental treatment for coronaviruses in small numbers of patients with COVID-19 and Middle East Respiratory Syndrome (MERS). It has similarly been used for other infections such as Ebola and influenza. While results have been promising it has not been proven to be beneficial in large scale trials. The safety and effectiveness of CP needs to be confirmed by robust clinical trials. COVID-19 CP treatment is therefore being managed under the auspices of clinical trials in the United Kingdom. All clinical trials have to follow a rigorous approval process to protect patients and ensure robust results are generated. We are working closely with the government and all relevant bodies to ensure these procedures are completed as quickly as possible.
There are 2 clinical trials managing the provision of COVID-19 CP in the UK-
1. REMAP-CAP – this clinical trial is looking at treatments including CP for patients with COVID-19 infection who have been admitted to the intensive care unit (ICU).
2. RECOVERY– this clinical trial is comparing treatments including CP for patients with COVID-19 infection who have been admitted to hospital.
Professor David Roberts, a Haematologist from University of Oxford who is the principle investigator of UK- CP trial says- there has never been a randomised controlled trial to show the effect of convalescent plasma. We will test the effect of convalescent plasma to treat patients in intensive care. As yet, there are no proven treatments for COVID-19. We are leading a programme on behalf of the Department of Health and Social Care to gather reliable evidence through clinical trials and provide samples to support external research and development. Using international evidence and UK expertise, the most promising potential treatments have been identified and the UK is running national clinical trials to gather evidence across the whole disease spectrum.
From which donors is COVID-19 CP being collected?
We can only collect plasma from people who have recovered from COVID-19 for more than 28 days. This is either 28 days from hospital discharge (for people who went into hospital) or 35 days since diagnosis (for people who were not admitted to hospital). Until recently, only a small number of people were eligible to donate. NHSBT has started to collect plasma from the first recovered donors now and, at the same time, is also working to rapidly increase future capacity. As above, the clinical trials will be looking at the effectiveness of CP across a range of neutralising antibody titre levels.
The Science and measurement of antibodies specific to COVID-19
The development of immunity to a pathogen through natural infection is a multi-step process that typically takes place over 1-2 weeks. The body responds to a viral infection immediately with a non-specific innate response in which macrophages, neutrophils, and dendritic cells slow the progress of virus and may even prevent it from causing symptoms. This non-specific response is followed by an adaptive response where the body makes antibodies that specifically bind to the virus. These antibodies are proteins called immunoglobulin. The body also makes T-cells that recognize and eliminate other cells infected with the virus. This is called cellular immunity. This combined adaptive response may clear the virus from the body, and if the response is strong enough, may prevent progression to severe illness or re-infection by the same virus. This process is often measured by the presence of antibodies in blood. WHO continues to review the evidence on antibody responses to SARS-CoV-2 infection? Most of these studies show that people who have recovered from infection have antibodies to the virus. However, some of these people have very low levels of neutralizing antibodies in their blood, suggesting that cellular immunity may also be critical for recovery. As of 30th April 2020, no study has evaluated whether the presence of antibodies to SARS-CoV-2 confers immunity to subsequent infection by this virus in humans. Laboratory tests that detect antibodies to SARS-CoV-2 in people, including rapid immunodiagnostic tests, need further validation to determine their accuracy and reliability. Inaccurate immunodiagnostic tests may falsely categorize people in two ways. The first is that they may falsely label people who have been infected as negative, and the second is that people who have not been infected are falsely labelled as positive. Both errors have serious consequences and will affect control efforts. These tests also need to accurately distinguish between past infections from SARS-CoV-2 and those caused by the known set of six human coronaviruses. Four of these viruses cause the common cold and circulate widely. The remaining two are the viruses that cause Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome. People infected by any one of these viruses may produce antibodies that cross-react with antibodies produced in response to infection with SARS-CoV-2. Many countries are now testing for SARS-CoV-2 antibodies at the population level or in specific groups, such as health workers, close contacts of known cases, or within households. WHO supports these studies, as they are critical for understanding the extent of – and risk factors associated with – infection? These studies will provide data on the percentage of people with detectable COVID-19 antibodies, but most are not designed to determine whether those people are immune to secondary infections.
Convalescent plasma donors should be recruited directly by the use of national registries of patients that were infected with COVID-19 and recovered, wherever such registries are in place. Alternatively, potential donors should be identified through collaboration with treating hospitals. Personal data sharing strategies must comply with national rules. The following criteria for donor eligibility should be applied:
Donor should be eligible to donate blood and blood component as per the country’s national guidelines and regulations and in addition.
- A prior diagnosis of COVID-19 documented by a laboratory test or a clear history of COVID-19 symptoms when testing was not available.
- At least 14 days should have passed since full recovery or at least 14 days after laboratory evidence for viral RNA clearance from the upper respiratory tract. Asymptomatic, COVID-19 laboratory confirmed, persons may also donate convalescent plasma at least 14 days after the end of their preventive isolation or quarantine period (which is 14 days after testing positive). Blood establishments might delay the timing of plasma collection when findings regarding the timing of optimal and maximal antibody production in those who have recovered from COVID-19 become available.
- Donors without a history of blood transfusion and female donors who have never been pregnant or are tested and found negative for anti-HLA/HPA/HNA antibodies using a validated assay. Standard donor criteria for blood or plasma donation must be met.
- Non-reactivity of blood samples for transfusion transmitted infections including HIV, HBV, HCV, syphilis and locally transmitted infections, such as malaria and Chagas disease, using in vitro diagnostic systems locally licensed for the testing of blood components for transfusion.
- Informed consent.
Collection, processing and storage and transfusion
Donors will ideally donate plasma by plasmapheresis, but where that is not possible, whole blood can also be collected, with plasma separation in the blood establishment. The normal donation procedure should be followed including normal donation intervals for those donating by plasmapheresis more than once. Plasma obtained by plasmapheresis should be split before freezing into 2-3 separate units (e.g. 3×200 ml). Final products should be specifically labelled as COVID-19 Convalescent Plasma/Blood and stored in a dedicated location. The processing that is routinely applied in the country or blood establishment for the preparation of plasma for transfusion should be applied. Thus, pathogen reduction should be applied if it has been the normal practice in the blood establishment and should not be introduced for this particular blood component if not normally applied for plasma for transfusion. Convalescent Plasma will be the same as that used for FFP so the same storage, same defrosting technique and administration and expiry 24 hours post thaw. Any serious adverse reactions in the donor should be notified to the competent authority without delay.
Testing of donated plasma
It is strongly recommended that defined SARS-CoV-2 neutralizing antibody titres (NAbs) be measured in the donated plasma. It is suggested that neutralising antibody titres should optimally be greater than 1:320, but lower thresholds might also be effective. Where such testing is not yet available, plasma can be collected and frozen until release for use once the test has been performed on an archived sample and the result is available. When the measured neutralizing activity in the collected plasma is considered to be too low, the plasma should be made available for other use (ideally fractionation). In the absence of neutralizing antibody testing, a test for the presence of anti-SARS- CoV-2 antibody should ideally be performed prior to release. In emergency cases, where plasma is released for transfusion without any antibody testing, archived samples should be tested at a later date once testing is available. If an adequate correlation between neutralizing activity and Elisa antibody testing were to be demonstrated, this could replace the test for neutralising antibodies. It is advised that additional archive samples of the donated plasma are saved for reference studies, e.g. 10 x 0.5ml frozen aliquots from plasma samples taken at the time of donation. For repeat plasmapheresis donations, services should collect plasma from donors with higher rather than lower titres, as collection capacity permits. Fortunately, people with these high levels of antibodies can give plasma every two weeks while antibody levels stay high.
Post-donation treatment of blood or plasma
- Where feasible, pathogen inactivation of plasma using a licensed technology in place in the blood establishment is desirable to control residual risks of transfusion transmitted infectious diseases and to allay concern about possible superinfections with SARS-CoV-2.
- Whole blood should be stored between 2°C and 6°C for a duration depending upon the anticoagulant and preservative used.
- Liquid plasma may be stored between 1°C and 6°C for up to 40 days.
- Plasma frozen at -18°C or colder within 24 hours after blood collection can be stored for up to 12 months.
- Convalescent plasma collected from donors who do not fulfil post-COVID-19 suitability
- criteria for routine blood donation should be stored separately from other blood products in inventory.
- Convalescent plasma should bear special labelling as an investigational product for treatment of COVID-19.
- Donor blood/serum/plasma samples obtained at the time of donation should be saved frozen at -20°C or colder for retrospective testing of the total and neutralizing titres of anti-SARS- CoV-2 antibodies and further scientific investigations.
Recommendations for plasma transfusion
- Follow standard hospital procedures and recommendations for thawing and transfusion of plasma.
- It is crucial to ensure ABO compatibility of plasma between the donor and the recipient and avoidance of RhD sensitization in cases where whole blood is transfused.
- Transfusion of plasma from at least two donors may be therapeutically beneficial to achieve more effective immune protection from delivery of diverse antibodies.
- In the absence of published peer-reviewed reports of transfusion of convalescent COVID-19 plasma, patients could receive an initial dose of 200 mL, followed by one or two additional doses of 200 mL according to disease severity and tolerance of the infusions.
- Blood/serum/plasma samples of the recipient prior to and after transfusion should be taken for future potential scientific investigations.
Human plasma transfusion is a routine, daily event in modern hospitals. Human Anti-SARS-CoV-2 plasma differs from standard plasma only by virtue of the presence of antibodies against SARS-CoV-2. Donors will satisfy all criteria for blood donation based upon federal and state regulations for volunteer donor eligibility and will be collected in FDA licensed blood centres. Therefore, the risks to transfusion recipients are likely to be no different from those of standard plasma. Risk of transfusion- transmissible infection is very low in the US and other high-income countries. Typically cited estimates are less than one infection per two million donations for HIV, hepatitis B and hepatitis C viruses. There are also non-infectious hazards of transfusion such as allergic transfusion reactions, transfusion associated circulatory overload (TACO), and transfusion related acute injury (TRALI).While the risk of TRALI is generally less than one for every 5,000 transfused units, TRALI is of particular concern in severe COVID-19 given potential priming of the pulmonary endothelium. However, routine donor screening includes HLA antibody screening of female donors with a history of pregnancy to mitigate risk of TRALI .Of note, risk factors for TACO (e.g. cardiorespiratory disease, advanced age, renal impairment etc.) are shared by those at risk of COVID-19, underscoring the need for careful attention to fluid volume management.
Specific risks pertaining to Human Anti-SARS-CoV-2 plasma include transfusion-transmitted SARS-CoV-2. This is largely theoretical since the recipient is already infected and there has never been a report of transmission of a respiratory virus by blood transfusion. There is no donor screening in effect for common respiratory viruses such as influenza, respiratory syncytial virus and parainfluenza. SARS-CoV-2 is not considered to be a relevant transfusion-transmitted infection and only 1% of symptomatic patients have been reported to have detectable SARS-CoV-2 RNA in their blood. In Wuhan, 2430 blood donations were screened in real-time (January 25 to March 4, 2020): a single (0.04%) — asymptomatic—donor was found to be positive for SARS-CoV-2 RNA. A second (0.02%), asymptomatic, SARSCoV-2 RNA positive donor was identified on retrospective screening of 4995 donations (December 21 to January 22, 2020), an additional two donors were identified as being RNA- emic through follow-up of donors who had developed fever subsequent to their donations. Nevertheless, donors will still need to wait 14 days following resolution of their symptoms to be eligible to donate; they will also need to be negative for SARS-CoV-2 as determined by molecular testing (e.g. of an NP swab). There is also the theoretical possibility of antibody-dependent enhancement (ADE) following transfusion of human anti-SARS-CoV-2 plasma. ADE refers to a process whereby antibodies that developed during a prior infection exacerbate clinical severity as a consequence of infection with a different viral serotype. This phenomenon is well-known for some viruses, notably Dengue virus. The largely theoretical risk of ADE in COVID-19 would be attributable to antibodies potentiating infection upon exposure to other strains of coronavirus; this mechanism has been offered as a possible reason for the geographic variation in disease severity. Concerns about coronavirus-ADE stem primarily from in vitro studies using monoclonal antibodies (mAbs), whose relevance is uncertain to the polyclonal antibody composition found in convalescent plasma. In this regard, mAbs have been shown to have very different properties when acting as single molecules rather than in combination with other mAbs. Nonetheless, although ADE is unlikely to be relevant to the proposed use of convalescent plasma in prevention and treatment of a disease with the same virus, caution is warranted. Somewhat reassuring is the apparent absence of ADE reports with the use of convalescent plasma for SARS, MERS or COVID-19. For completion, it is unknown to what extent convalescent plasma might blunt the development of a natural immune response, especially when administered for prophylaxis.
Some Question and Answer section to NHSBT panel on 29th April 2020 presented nationally by webinar: Dr Gail Mifflin, Medical and Research Director NHSBT chaired by Dr Shubha Allard, Secretary NBTC
1) Is antibody enhancement a concern when giving Convalescent Plasma?
There is a risk as with any virus and could make the patient’s condition worse, however no evidence at the moment with COVID-19 if giving a high titre of neutralising antibody don’t see this occurring but do with lower titres. Any adverse reactions report to SHOT.
2) Why Convalescent plasma and not an Immunoglobulin being made?
So, both they are good potential line of treatment for patients but basically due to time, plasma fractionated Immunoglobulin will occur but needs more manufacturing and will also need to be trialled.
3) UK plasma can we use due to previous restrictions due to CJD?
Yes, just last year the tight restrictions were lifted due to current processes and leucodepletion and were risk assessed with assistance from MHRA.
4) Viral inactivation plasma has this been considered i.e. with Methylene blue as we do for patients born after 1996 to prevent CJD?
During the Ebola trials they did virally inactivate the plasma products, however little data regarding viraemia in patients that recovered. No rationale to do this for Convalescent plasma as we don’t currently do this on current FFP and platelets products. The NHSBT did consider but it would slow the process down further. With the strict donor selection there is no advantage to do this. No more dangerous than other products with viral load, with Ebola they did this as they had more time.
5) How will the trial process start?
100 patients will receive the products and then in conjunction with SHOT if they are happy with the figures coming through of a low level of adverse effects to patients the recovery trial can then start. They’ve had 147 donors to date so far that they are validating and then stock will be considered so as many hospitals can be included as possible in this early part of the trial.
6) Will there be a prophylaxis trial?
America Blood service are looking into this aspect of treatment as well as Ireland and if their trials are found to be successful it will be rolled out in the UK, for patients such as those on chemotherapy it will be most beneficial.
7) Is there a higher risk of other complications if such high levels of Clotting factors are transfused over a long period of time?
It is something to consider as COVID patients are already at risk of thrombosis and this will have to be considered as part of the trial. For arterial / MI’s just don’t know. The Australian Blood service is looking into this element so it is literally an International effort. There is a risk of fluid overload that’s why they are recommending staggering the transfusion of 1 UNIT 1 day and the second the next. In ITU patients less of a risk due to fluid balances. It is more of a risk in the recovery trial and again it is a criterion to report to SHOT.
8) Is there going to be a project to collect antibodies from vaccinated patients?
Not at the moment but will be considered in the future, it will be the same process as FFP and administration.
9) Children dose of Convalescent Plasma:
There is no lower age limit and the dose 8mls/kg.
10) Is the NHSBT working with other organisations?
Yes, and also looking at distribution so it’s equal across the country and there is a teleconference once a week with all the different UK NHSBT sites
11) Will there be donor recruitment leaflets being issued so hospitals can give to patients on discharge that have recovered from COVID -19?
None at the moment but doesn’t mean to say they won’t all areas and suggestions being considered.
COVID-19 pandemic is a global threat, hundreds of thousands of people already died and millions affected yet we do not have any effective treatment strategy. There is intense search for a rapid vaccine discovery and antiviral launched worldwide. The on-going clinical trials will explore the best possible way how to combat this deadly disease. The convalescent plasma therapy has shown some rapid response and clinical improvements from smaller case control studies and also from the past experiences. Convalescent plasma-CP Together with other combinations of antiviral are showing some glimmer of hope and light at the end of the tunnel.
- International society blood and transplant guidelines on CP during COVID-19 pandemic, April 2020.
- National Health Service Blood and Transplant, NHSBT with NHS England, convalescent plasma therapy for COVID-19 in corporation with REMAP-CAP and RECOVERY-CP clinical trials, United Kingdom.
- Dr Gail Miflin, Medical and Research Director NHSBT chaired by Dr Shubha Allard, Secretary NBTC, 27th and 29th April 2020, National webinar, United Kingdom.
- C. Shen, Z. Wang, F. Zhao, et al. Treatment of 5 Critically Ill Patients with COVID-19 Convalescent Plasma. JAMA/Preliminary Communication. doi:10.1001/jama.2020.4783
- Roback JD, Guarner J. Convalescent Plasma to Treat COVID-19: Possibilities and Challenges. JAMA 2020.
- Guidelines on good manufacturing practices for blood establishments, TRS 961 (2011), Annex 4 https://www.who.int/bloodproducts/publications/GMP_Bloodestablishments.pdf?ua=1
- Working Party of Global Blood Safety, International Society of Blood Transfusion. Points to consider in the preparation and transfusion of COVID-19 convalescent plasma. https://isbtweb.org/fileadmin/user_upload/Points_to_consider_in_the_preparation_of_COVID_convalescent_plasma_-_200331_ISBT_WP_GBS_Final.pdf
- WHO Blood Regulators Network (BRN). Position Paper on use of Convalescent Plasma, Serum or Immune Globulin Concentrates as an Element in Response to an Emerging Virus, September 2017. https://www.who.int/bloodproducts/brn/2017_BRN_PositionPaper_ConvalescentPlasma.pdf?ua=1
- Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications Fan Wu, Aojie Wang, Mei Liu, Qimin Wang, Jun Chen, Shuai Xia, Yun Ling, Yuling Zhang, Jingna Xun, Lu, Shibo Jiang, Hongzhou Lu, Yumei Wen, Jinghe Huang doi: https://doi.org/10.1101/2020.03.30.20047365
- Deployment of convalescent plasma for the prevention and treatment of COVID-19 Evan M. Bloch , Jeffrey A. Bailey, Aaron A.R. Tobian J Clin Invest. 2020. https://doi.org/10.1172/JCI138745.
Pooled plasma might be tested for minimum effective titre of antibody and for a maximum effective outcome as a side line procedure.