Coming out of lockdown, ready, steady… gone already!?

So we have been let loose and lockdown is being de-escalated slowly but have we gone too soon? We don’t have a vaccine, treatments give only modest benefits and we’re not so good at social distancing on a beach! “Experts” are a little alarmed at the pace of release and I think we’re going to be stuck with Covid-19 for a while yet, so what shall I blog about this week?

One of the stories that keeps grumbling along in the background of Covid-19 is the potential to use antibodies from patients who have survived the infection to treat patients with active infection. It’s known as plasma therapy and it’s not as crazy it might at first sound.

This is NOT Plasma Therapy!

​In fact using antibodies to treat infections is nothing new. Back in about 1900 Emil von Behring and Paul Ehrlich discovered a treatment for diphtheria by infecting a horse with the bacterium (Corynebacterium diphtheriae), taking that serum from the horse and then giving it to their patients with diphtheria (Note: do not do this! Ethical approval has changed radically since this time!). Although at the time Behring and Ehrlich were pleased with the results, they didn’t actually know why their new treatment worked; the serum contained antibodies which killed the bacterium and neutralised the toxin. It was brilliant!
 
Prior to this time diphtheria was a common cause of death and killed most of the children it infected; it must have been terrifying. This “new treatment” was revolutionary and quite rightly resulted in the award of the first Nobel prize for medicine (although it was only given to von Behring!). Today, we actually use antibody therapy in the management of infections on a regular basis, including still using antibodies to neutralise diphtheria toxin.
 
There are three types of preparations available to us…
 
Note: in medicine we use the term immunoglobulin (Ig) when we are talking about antibody… why? Just to be confusing I think….
 
Types of antibody preparation
There are 3 different types of antibody preparation used in the management of infection:

• Intravenous immunoglobulin (IVIg) – this is immunoglobulin collected from multiple blood donors which is concentrated for use in other people. This type of Ig contains low concentrations of antibodies from multitudes of bacteria, viruses, etc. to which the donors had previously been exposed. It is not specific to any particular microorganism.
• Pooled immunoglobulin – this is also immunoglobulin from multiple blood donors but it has been screened and concentrated to give high levels of Ig to a specific microorganism e.g. Varicella Zoster Ig, Hepatitis B Ig or Ebola Ig
• Monoclonal antibodies – this Ig is made in a laboratory in genetically modified cells (usually myeloma cancer cells or even sometimes bacteria) that have been specifically chosen to target a particular molecule or microorganism e.g. RSV or Ebola. In fact Paul Ehrlich postulated this type of treatment and did finally get a Nobel Prize in 1908!

 
There are two ways we use antibody therapy: prevention and treatment…
 
Prevention of infection using antibodies
During the later stages of the immune response to infection the human body starts to produce antibodies. These antibodies eventually clear the infection, or at least suppress it so it no longer causes disease. Some of these antibodies become part of our long term immunity to future exposures to the disease.
 
So artificially giving protective antibodies to someone who has been exposed to an infectious microorganism can prevent the infection from occurring… just as if they had natural immunity from having had a previous infection or vaccination. This is sometimes called “passive immunity” as compared to “active immunity” which occurs as a result of vaccination or infection.
 
Passive immunity works if you have the antibodies before you are exposed or if the antibodies can be given within the incubation period of the disease to prevent infection from occurring (this can sometimes be a bit of a race, and the Microbiologist will have probably said something unhelpful like… “You’ll need to get this urgently from Pharmacy”… knowing full well its Sunday evening!).
 
All of our different types of antibody preparations can be used in these circumstances:

• IVIg – this can be used to prevent measles in those who have been exposed to measles but who have not been vaccinated or might not respond to vaccine e.g. very young infants, pregnancy and immunocompromised patients. This relies on the fact that many blood donors have been immunised and therefore there are lots of relevant antibodies in the IVIg.
• Pooled Ig – this can be used to prevent infection in non-immune patients who have been exposed to a certain microorganism e.g. exposure to chicken pox in pregnancy, the neonatal period or who are immunocompromised, or similarly given for exposure to hepatitis B in unvaccinated people, those who have received a high-risk exposure or those that have previously not responded to the vaccine.
• Monoclonal antibody – this can be used to prevent infection in infants who are particularly at risk of severe bronchiolitis with Respiratory Syncytial Virus (RSV), the product is called Palivizumab.

 
Treating infection using antibodies
Antibodies can be used in the treatment of infections in order to help the patient’s immune system remove the infecting microorganism or neutralise toxins in order to prevent damage being done. In this situation the disease has already occurred, but the antibody is being used to stop it getting worse. This is what is being proposed for Covid-19 patients using pooled Ig; however this is still at an experimental stage.
 
All of our different types of antibody preparation can be used to treat infections:

• IVIg – this type of preparation is often used to try and clear the patient’s blood stream of circulating toxins; it relies on either previous vaccination in blood donors e.g. tetanus, or donors having been previously exposed to a particularly common toxin mediated diseases which they have naturally controlled with their own immune response e.g. Panton Valentine Leukocidin Staphylococcus aureus, invasive Group A Beta-haemolytic Streptococcus, Clostridium perfringens gas gangrene and severe Clostridium difficile associated disease
• Pooled Ig – this method has been used to treat severe infections using plasma taken from patients who have recovered from certain infections e.g. Ebola, SARS (classical)
• Monoclonal antibody – during the West Africa outbreak of Ebola in 2014 a monoclonal antibody preparation called ZMapp was created by the Canadians and Americans to treat patients with Ebola. It is now produced by a company called LeafBio but it is still experimental.

 
So what about Covid-19?
So we are still in the experimental phase of the treatment of Covid-19. However Scientists are looking at all sorts of ways of trying to treat the infection. One of these ways is to develop antibody treatments in the same way as was used for SARS and Ebola. The 2 options are to use plasma from patients who have recovered from Covid-19; the other is to produce a monoclonal antibody.
 
Producing monoclonal antibodies is very difficult so plasma therapy is the main treatment being looked at. Essentially this would involve collecting blood from patients who have recovered from Covid-19, separating off the plasma, and then giving it by infusion to patients with active infection.
 
This sounds relatively straight forward as we have systems in place for donating blood and separating plasma already (great!!) BUT it isn’t actually that easy (Boo!!). In order for this to work you have to identify patients who have had Covid-19 and who ALSO have high levels of protective antibody.
 
It appears that ONLY those that have had severe infections actually produce a lot of antibody, so you’re donor has to have been a patient who was really unwell with Covid-19 AND survived. You also have to have a good test to detect antibodies in the plasma of the donors (which are only just becoming available now) AND only then can it be used to see if this new antibody treatment is effective at controlling the infection… and this is also currently a big unknown. Just how good are these antibodies?! And do they make people better or could they make people worse?
 
So we’re back to the clinical trials, again! Some patients with severe Covid-19 are now being given plasma therapy and we’ll have to wait and see whether this works. I think it might. The science is good, and it has been successfully done before with other diseases so hopefully it will work again. We’ll see.
 
P.S. Thank you Emil von Behring and Paul Ehrlich for your “dodgy ethical trials” in the 1900s, without you medicine might be at a loss.