This is the first of two posts on the potential use of antibodies in the treatment of COVID-19.
Viruses and Antibodies
The fact that viruses reproduce using the host cells’ metabolic processes makes it more difficult to design drugs to target them after they have entered the cells. There is always the possibility that any drug developed might damage the host as well. It is far better to prevent the virus entering the cells using a chemical entity specifically targeted at the virus in question: this is where antibodies come in.
Antibodies are glycoproteins (protein molecules with sugar molecules attached) which are mainly produced by cells called plasma cells. They are produced as a major part of the body’s immune response to bacteria and viruses. They are highly specific, binding to a particular molecule of the attacking organism, called the antigen. The part of the molecule to which the antibody binds is called an epitope.
SARS-CoV-2 Binding to Host Cells, and How Antibodies Might Prevent It
See also: “COVID: Know Thine Enemy—Preamble”.
The SARS-CoV-2 spike (S) protein is responsible for binding of the virus particle to angiotensin converting enzyme 2 (ACE2) in the host cell membranes: the viral receptor. The S protein is the target for natural antiviral antibodies. It has two subunits: S1 and S2. The S1 subunit has a receptor-binding domain that binds to ACE2. S2 contains a section which crosses the viral membrane and mediates fusion of viral and host cell membranes after particles are internalized into structures called endosomes, although fusion at the cell surface can also occur in certain situations.
Antibodies could block viral entry by: (1) preventing the S protein from binding to host cell receptors; (2) preventing the conformational changes the S protein undergoes in order to produce membrane fusion; or (3) mimicking receptor binding, and prematurely triggering fusion-producing conformational changes in the S protein before it encounters ACE2.
Treatment of Viral Infections with Convalescent Plasma
The first examples of passive antibody therapy for viral infections involved the transfusion of plasma from patients who have recovered from an illness (convalescent plasma) into those who were infected, or were at risk of, the same infection. The immunity that results from this is short-term, but it can be effective if it is conferred at a critical point in the infection.
There is convincing evidence of benefit from transfusion of convalescent plasma in the treatment of a viral illness called Argentine haemorrhagic fever, which has a mortality rate around 15-30% (compared to around 1% for COVID). The treatment is now used routinely for the disease. A trial of the use of convalescent plasma in the treatment of Ebola in 2016 was not successful, but the neutralising antibody level of the infused plasma was later found to be low. A retrospective study of the use of convalescent plasma in the treatment of SARS in 2004 was published. Forty SARS patients with progressive disease after ribavirin (antiviral) treatment and 1.5 g of pulsed methylprednisolone (a steroid) were given either convalescent plasma (n = 19) or further pulsed methylprednisolone (n = 21) in a retrospective non-randomised study. Patients in the plasma group had a shorter hospital stay, and lower mortality. However, the neutralising antibody levels of the infused plasma were non-standardised, and the comparator group remained on steroids, which could have affected the result.
Use of Convalescent Plasma in COVID Patients
Some studies have already been carried out using convalescent plasma in COVID patients. Duan et al (2020) performed a prospective, non-controlled trial involving patients with severe COVID. These patients were transfused with plasma containing high levels of neutralising antibody. This produced a rapid increase in antibody levels in the patients, with no detectable SARS-CoV-2 RNA in the blood at the time of sampling, as well as clinical improvement. There was, however, no control group for comparison. Another study showed that convalescent plasma given with a median time of over 20 days from viral shedding being first detected seemed to affect viral clearance, but had no effect on mortality. This result may have been affected by the timing of transfusion.
Hopefully, further studies of the use of convalescent plasma in the COVID pandemic will include a treatment group given plasma with predetermined high levels of antibody, and a control group given non-immune plasma. The best time at which the plasma should be transfused remains to be worked out.
Limitations of Convalescent Plasma and Newer Approaches
There are several limitations to the use of convalescent plasma in treatment. These include: (1) batch-to-batch variation; (2) the need for blood type matching; (3) the need for screening of the plasma for blood-borne diseases eg HIV, hepatitis. The more modern approach is to use monoclonal antibodies. These are antibodies that are made by identical immune cells which are all clones belonging to an unique parent cell. Monoclonal antibodies can have monovalent affinity, IE they bind to the same epitope. There are many techniques which allow the production of antiviral monoclonal antibodies, and they can be rapidly scaled up for testing during outbreaks.
There are now several reports of monoclonal antibodies that potently neutralise SARS-CoV-2. Some of these were isolated from convalescent plasma. A number of them have been shown in animal models to decrease viral RNA.
See also the Science Rules! Podcast episode called Coronavirus: Can A Stranger’s Blood Save Your Life?
See also my next post: “Anti-COVID Antibodies 2: Monoclonal Antibodies and Why the Llama could be Man’s New Best Friend”.