SIMPLIFYING DISCUSSION ON Convalescent Plasma transfusion for corona cases:
To date, there are no proven options for prophylaxis for those who have been exposed to SARS–CoV-2, nor therapy for those who develop COVID-19. Immune (i.e., “convalescent”) plasma refers to plasma that is collected from individuals following resolution of infection and development of antibodies. Passive antibody administration through transfusion of convalescent plasma may offer the only short-term strategy for conferring immediate immunity to susceptible individuals. There are numerous examples in which convalescent plasma has been used successfully as postexposure prophylaxis and/or treatment of infectious diseases, including other outbreaks of coronaviruses (e.g., SARS-1, Middle East respiratory syndrome [MERS]). Convalescent plasma has also been used in the COVID-19 pandemic; limited data from China suggest clinical benefit, including radiological resolution, reduction in viral loads, and improved survival. Globally, blood centers have robust infrastructure for undertaking collections and constructing inventories of convalescent plasma to meet the growing demand.
What is the evidence that convalescent plasma might be beneficial in COVID-19?
The use of convalescent plasma collected from previously infected individuals to passively-transfer antibodies in order to protect or treat humans dates back almost 100 years, with some evidence for benefit against rabies, hepatitis B, polio, measles, influenza, Ebola and other pathogens.1,2 Results from small case series during the prior MERS and SARS coronavirus outbreaks documented safety and faster viral clearance following convalescent plasma administration, particularly when given early in the disease course.
The vast majority of patients who recover from COVID-19 illness develop some level of circulating neutralizing antibodies to various SARS-CoV-2 proteins 2-3 weeks following infection, detectable by ELISA or other quantitative assays. This has been demonstrated in at least two cohorts of rhesus macaques infected with SARS-CoV-2 who generated antibody responses and could not be re-infected with the virus weeks to months later.
Multiple published and unpublished studies have now reported on the use of convalescent plasma to treat severely or critically ill COVID-19 patients, without unexpected or serious adverse events. Many patients improved clinically and cleared the virus, however the role of the convalescent plasma treatment in these patients is unclear, because all patients received at least one additional therapy, including antivirals, antibiotics or antifungals, and corticosteroids. In the sole randomized controlled trial reported to date, patients with severe disease, but not intubated patients with critical disease, receiving convalescent plasma showed more frequent and faster clinical improvement compared to controls, however the trials was terminated early due to lack of eligible patients at the study sites in China, with waning of the pandemic there3. The results from this RCT support the concept that convalescent plasma should be used prior to life-threatening disease in order to more rapidly clear virus and avoid further tissue damage, rather than using this approach to treat patients with inflammatory end organ failure.
Multiple ongoing clinical trials are investigating the use of convalescent plasma in patients with less severe infection, or prophylactically in highly susceptible individuals, such as exposed health care workers or family caregivers of COVID-19 patients, situations predicted to result in more potential benefit from passive antibody transfer.
What are the potential risks of convalescent plasma for COVID-19?
Convalescent plasma transfusion appears safe as over 7000 units have been transfused to over 5000 patients to date in the US (uscovidplasma.org). Known risks of plasma transfusion include allergic reactions, transfusion-associated circulatory overload (TACO), and transfusion-associated acute lung injury (TRALI) as with any plasma or blood transfusion. Additional concerns include potential worsening of immune-mediated tissue damage via the poorly understood phenomenon of antibody-dependent enhancement (ADE), and blunting of endogenous immunity to the virus. However, ADE has not been documented to date, so likely is not a major issue for COVID-19 convalescent plasma infusions. Importantly, blood product transmission of the SARS-CoV-2 virus has not been documented and is extremely unlikely via transfusion from a recovered donor with a documented antibody response, even if viral spread to tissues outside the lung may have occurred earlier in the donor’s illness.
-Authorisation of convalescent plasma collection, testing, processing, storage and distribution Blood establishments complying with the criteria described below for donation, collection, processing and testing should be authorised by their competent authority to proceed, unless the Member State has put more stringent requirements in place or their existing authorisation already covers these activities for any plasma for transfusion, including convalescent plasma. This will allow the rapid creation of national and EU inventories of convalescent COVID-19 plasma. Blood establishments that have put in place systems for gathering outcome data to demonstrate safety and quality, as defined below, should be authorised for convalescent plasma distribution, unless the Member State has put more stringent requirements in place or their existing authorisation already covers this activity for any plasma for transfusion, including convalescent plasma.
Donor eligibility 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 and EU data protection rules. The following criteria for donor eligibility should be applied: 1. A prior diagnosis of COVID-19 documented by a laboratory test or a clear history of COVID19 symptoms when testing was not available.
2. 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.
3. 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. 4. Informed consent. Collection, processing and storage 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. 3x200 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 . 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 titers be measured in the donated plasma. It is suggested that neutralising antibody titers 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. Distribution of COVID-19 convalescent plasma Convalescent plasma should be distributed by blood establishments on the request of a hospital in the following circumstances: • the specific patient has laboratory confirmed COVID-19; • has been hospitalised due to acute illness or a risk of acute illness; • has given informed consent. The uncertainty about the efficacy of convalescent plasma in treating people with COVID-19 should be communicated to potential recipients, whether they are part of a clinical trial or of monitored use, to avoid fostering unfounded expectations and to ensure that prospective recipients make informed decisions regarding treatment. Blood services should aim to issue the components with the highest antibody titres available. The transfused dose of plasma should be adjusted to its neutralizing antibody titer and the plasma volume of the recipient.
The use of convalescent plasma is an interim approach to treatment until availability of hyperimmune globulin, drug therapies, and vaccines. While the concept of plasma treatment is simple, numerous steps are involved, requiring cooperation between multiple entities including recovered patients who serve as donors, blood centers or other plasma collection centers, treating physicians and their patients, and health care administrators and regulators overseeing the safety of each step. Use of plasmapheresis to collect large volumes of plasma is desirable. Current estimates suggest a single donor collection can be used to treat 2-3 recipients. We now have antibody assays available to ensure plasma units contain antibodies. However, we have yet to correlate these antibody assays with neutralizing antibody titers, or most importantly with patient outcomes.
FINALLY;What other passive immunity therapies are being developed for COVID-19?
Companies are developing purification procedures to produce potent concentrated neutralizing antibodies from convalescent sera and immunizing large animals such as horses and cows with SARS-CoV-2 proteins in order to create antiserum. Biotechnology companies are racing to develop cocktails of monoclonal antibodies active against the SARS-CoV-2 virus, and clinical trials are in active development..