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Can plasma from convalescent COVID-19 patients help others to recover from the disease?

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When a new dangerous infection emerges, drugs and vaccines are usually not available straight away. But because the human immune system responds rapidly to new infections, antibodies from recovered patients can help other patients still exposed to the virus. Although antibody treatments are not widely employed, this form of blood transfusion treatment has a long history and might work for COVID-19 too.

What is the science behind convalescent plasma?

In response to a virus infection, every patient produces a different set of antibodies; individuals who recover from the disease are more likely to have produced antibodies that have bound to the virus effectively and stopped it infecting cells. Using a small blood transfusion taken after a patient recovers – when they are in ‘convalescence’ – these antibodies can be shared with other patients who cannot make effective antibodies themselves or who are making them too slowly to get better. This is ‘passive immunity’ because the patient controls their infection using immunity borrowed from another person.

Antibodies are found in plasma – the yellowish liquid that remains when red and white blood cells and platelets have been removed from blood. If the factors in the liquid blood that allow clotting are also removed it is called serum. To treat infections with antibodies, we only need to transfuse the plasma or serum, not the whole blood.

What is the evidence that it works?

Convalescent serum was first used to treat patients in the Influenza pandemic of 1918.[1] More recently, convalescent plasma has been used to treat patients with ‘Swine Flu’ (cause of the 2009 influenza pandemic), with viral haemorrhagic fevers including Lassa fever and Ebola virus Disease, and with the two other emergent coronavirus diseases, SARS and MERS. In general, studies of the effects of convalescent plasma have not involved formal randomised controlled trials and are difficult to interpret. Nevertheless, a comparative analysis of eight studies involving SARS and influenza patients concluded, despite the limitations of each study, that plasma therapy improved the chance of survival.[2]

For COVID-19, convalescent plasma has been used to treat 15 seriously ill hospitalised patients in Wuhan and Shenzhen, China.[3][4] The patients were given convalescent plasma around 2-3 weeks after they became unwell. The transfusions were safe and all of the patients survived but these small non-randomised studies cannot tell us how effective the therapy will be for other COVID-19 patients in other settings.

Concentrated and purified antibodies

Convalescent plasma can be purified to make what is called hyperimmune immunoglobulin, which has a higher concentration of antibodies (antibodies are protein molecules with attached sugars that are formally called immunoglobulins). Hyperimmune immunoglobulin was tested in a previous pandemic of influenza (‘Swine flu’) in 2009. Although the treated patients did not recover any more frequently than those given control infusions, patients who were treated early in the illness did show some benefits.[5]

Hyperimmune immunoglobulin is used routinely in the UK’s National Health Service (NHS) to protect patients who have been exposed to hepatitis B or rabies; it has also been used effectively for many years to treat infants with immunodeficiency or chronic lung disease, providing protection against respiratory syncytial virus (RSV), a common respiratory virus that causes wheeze and pneumonia.

Monoclonal antibodies are derived from clones of blood cells that produce a single type of antibody, for example one that binds to a particular virus protein. These cells are cultured in the laboratory to generate a purified form of antibody treatment. Monoclonal antibodies are usually safer and more effective than human serum. For example, they have largely replaced hyperimmune immunoglobulin in protecting vulnerable infants against RSV. They were also used successfully to treat Ebola virus disease [6] whilst convalescent plasma taken from single donors was not successful.[7]

Are there any risks?

Convalescent plasma is a form of blood transfusion and carries many of the same risks. These include infection with another pathogen or negative reactions by the patient to a substance in the transfusion. The risks can be minimised by the routine safety procedures of blood transfusion laboratories that screen for known infections and test the compatibility of blood samples from the donor and the recipient. In rare circumstances blood products given to critically ill patients with pneumonia can worsen the lung disease (transfusion-related acute lung injury). As with any medical intervention, convalescent plasma is only administered after an individual risk assessment.

How could convalescent plasma be used against COVID-19?

Early in an epidemic, sick people would be treated with convalescent plasma taken directly from recovered patients. For very serious diseases such as Ebola virus disease, where the total number of patients is relatively small and a large fraction die, there are few convalescent donors. For COVID-19, the pool of potential donors is very large. By screening donor-blood to see how effective it is at neutralising the virus in laboratory tests, and by combining blood from multiple donors, companies are aiming to produce a commercial hyperimmune immunoglobulin that can be used more widely to treat COVID-19. Because hyperimmune immunoglobulin is already in use for other diseases, and is safe, the development and regulatory approval of such products for COVID-19 is likely to happen quickly.

New monoclonal antibodies would need to be tested more thoroughly, involving human trials, and this will take a few months longer.

The effectiveness of convalescent plasma products will only be known after clinical trials have been undertaken to define the volume and the concentration of antibody required and when it should be given in the illness. Neutralising the virus after it has already stimulated an overwhelming inflammatory response in the most ill patients is not likely to be effective, so convalescent plasma may work better early in the illness, or even as a preventive therapy.[8] For example, it could protect those who are at high risk, such as older people, patients on chemotherapy, or vulnerable people who have known exposure to the coronavirus but are not yet sick.

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References

  1. McGuire LW, Redden WR. THE USE OF CONVALESCENT HUMAN SERUM IN INFLUENZA PNEUMONIA-A PRELIMINARY REPORT. American Journal of Public Health. 1918 Oct;8(10):741-744. DOI: 10.2105/ajph.8.10.741.

  2. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, 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. The Journal of Infectious Diseases. 2015 Jan;211(1):80-90. DOI: 10.1093/infdis/jiu396.

  3. Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. PNAS. 2020 Apr. DOI: 10.1073/pnas.2004168117.

  4. Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 Mar. DOI: 10.1001/jama.2020.4783.

  5. Hung IFN, To KKW, Lee CK, et al. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest. 2013 Aug;144(2):464-473. DOI: 10.1378/chest.12-2907.

  6. van Griensven J, Edwards T, de Lamballerie X, et al. Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea. The New England Journal of Medicine. 2016 Jan;374(1):33-42. DOI: 10.1056/NEJMoa1511812.

  7. Mulangu S, Dodd LE, Davey RT Jr, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. The New England Journal of Medicine. 2019 Dec;381(24):2293-2303. DOI: 10.1056/nejmoa1910993.

  8. Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. The Journal of Clinical Investigation. 2020 Apr;130(4):1545-1548. DOI: 10.1172/jci138003.

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