There is currently no specific treatment for SARS-CoV-2. However, a number of treatments have been explored in patients with life-threatening COVID-19 (such as antimalarial drugs, antivirals, immunomodulatory agents, and glucocorticoids) with varying results. Convalescent plasma collected from recovered COVID-19 patients, containing antibodies against SARS-CoV-2, could potentially be an effective therapeutic tool. In addition, preclinical studies with neutralising monoclonal antibodies (mAbs) for SARS-CoV-2 have shown promising results. The use of convalescent plasma and mAbs is defined as ‘passive immunisation’ or ‘artificially-acquired passive immunity’.
Convalescent plasma and hyperimmune immunoglobulin
Convalescent plasma and hyperimmune immunoglobulin prepared from convalescent plasma have been used in the past to treat conditions when no vaccine or pharmacological interventions were available. They provide passive immunisation, which can help the immune system to control the disease until an immune response is triggered in the infected person. Diphtheria, hepatitis A and B, polio, measles, and rabies are examples of diseases where convalescent plasma has been effective.
Convalescent plasma contains pathogen-specific neutralising antibodies, which are able to neutralise a virus. The duration of conferred protection after administration differs depending on a number of factors, and ranges from weeks to months. Convalescent plasma and hyperimmune immunoglobulin are prepared by hospitals and blood banks when enough potential donors have recovered from the infection. Compared to convalescent plasma, hyperimmune immunoglobulin has the advantage that the antibody amount and concentration can be more accurately dosed. Evidence shows that in people with COVID-19, the severity of infection has an impact on antibody titres, with less severe disease leading to a lower neutralising antibody response.
Dr Lise Estcourt, Consultant Haematologist, NHS Blood and Transplant (NHSBT), Oxford, UK : “Convalescent plasma is plasma derived from a single donor. The amount of antibodies varies significantly between donors. Hyperimmune globulin is a standardised product that is produced by pooling plasma from many different donors.” – Read the full interview
Although vaccine development programmes are being fast-tracked, large-scale manufacturing and administration to a large population to achieve community protection will likely take many months. Prophylactic and therapeutic convalescent plasma could bridge the gap before safe and efficient vaccines become widely available. Additionally, some populations (e.g. the elderly or people who are immunocompromised) might not respond well to vaccines.
However, so far there is conflicting evidence about the effectiveness of convalescent plasma and hyperimmune immunoglobulin at treating severe acute respiratory infections and people affected by COVID-19. A multitude of clinical trials investigating the safety and effectiveness of convalescent plasma and hyperimmune immunoglobulins are ongoing. The results of these trials will help to clarify the still unanswered issues related to these forms of treatment.
Dr Lise Estcourt, Consultant Haematologist, NHS Blood and Transplant (NHSBT), Oxford, UK : “We used evidence from randomised controlled trials (the highest quality evidence) to assess whether convalescent plasma improves outcomes for people hospitalised with COVID‐19. Currently there is not enough evidence to determine whether convalescent plasma affects the risk of dying in hospital or decreases the need for breathing support.”
Using convalescent plasma to treat COVID-19 must follow high standards for plasma donation. For a donation to be accepted, the following criteria must be applied:
- the donor must have recovered completely and have no residual SARS-CoV-2 in the body;
- the donor must have produced high titres of protective antibodies (SARS-CoV-2–specific IgG antibodies);
- the donor’s physical condition must meet basic blood donation standards, and tests for other infectious diseases must be negative;
- the donor must provide informed consent for donation.
Although convalescent plasma and hyperimmune immunoglobulin are generally deemed safe and well-tolerated, adverse events can occur. Reported side effects are similar to those for other types of plasma blood components, including fever, allergic reactions, and transfusion-related acute lung injury.
Neutralising monoclonal antibodies
Antibodies are proteins that attack a specific protein called an ‘antigen’. Once attached, antibodies can force other parts of the immune system to destroy the cells containing the antigen. Researchers can design antibodies that specifically target a certain antigen. These antibodies can be produced in the lab and are known as monoclonal antibodies (mAbs). Monoclonal antibodies have become an effective new biologic class with a wide range of clinical indications such as inflammatory diseases, autoimmune diseases, cancer, and infectious diseases.
SARS-CoV-2 is the causative agent for COVID-19 infection. The infection is initiated upon attachment of the viral transmembrane spike (S) antigen, leading to membrane fusion and entry into host cells. SARS-CoV-2 S is the main target of neutralising antibodies.
Dr M. Alejandra Tortorici, Virologist at the Department of Virology, Institut Pasteur, Paris, France : “In the laboratory, it is possible to isolate individual neutralising antibodies, each of them is reactive against one specific region (or epitope) in S and each of them has a specific potency (or neutralisation capability). These antibodies can be recombinantly produced in the lab and are called neutralising monoclonal antibodies.” – Read the full interview
Neutralising mAbs isolated from people infected with SARS-CoV-2 are the most rapid manufactural intervention for passive administration that might be developed to either prevent or treat COVID-19.
Preclinical studies carried out in different animal models suggest that pre-exposure use of SARS-Cov-2 neutralising mAbs might prevent or at least reduce disease severity in people at high risk of acquiring infection, such as health professionals. In addition, SARS-CoV-2 neutralising mAbs could be administered early during COVID-19 infection in patients at high risk of developing severe disease. By reducing acute virus replication, an early mAbs intervention could induce a better outcome.
Several clinical trials have started to test the safety, tolerability, and efficacy of neutralising mAbs using either a prophylactic or therapeutic approach. Neutralising mAbs targeting different sites on SARS-Cov-2 are currently being tested.
Dr M. Alejandra Tortorici, Virologist at the Department of Virology, Institut Pasteur, Paris, France : “Prophylactic and therapeutic use of neutralising mAbs could help during a pandemic before safe and efficient vaccines are available worldwide. In addition, they are a useful alternative for people who respond poorly to vaccination.”
As seen with SARS-CoV-1 and HIV, viruses resistant to a particular antibody can emerge among the circulating virus variants. SARS-CoV-2 is also known to develop and accumulate mutations over time. In these cases, combinations of two of more neutralising mAbs targeting different sites on SARS-Cov-2 will be important to respond the mutational capacity of the virus and prevent the emergence of resistant viral variants.
Expanding the number of potent neutralising mAbs with different specificities against SARS-Cov-2 will allow the formulation of more effective cocktails of antibodies, which may provide a powerful way to minimise mutations, and confer a synergistic neutralising effect.
A final but important limitation that should be mentioned is that the use of neutralising mAbs in clinical settings is dependent upon the manufacture of large amounts of them, at high cost.