27th April 2020 – It’s not good enough to just to produce any old antibodies against the virus, they have to be of the right type.

A Blog by Dr David J Flavell PhD FRCPath & Dr Sopsamorn (Bee) Flavell BSc PhD
Scientific Directors of Leukaemia Busters

27th April 2020

Not All Antibodies Are Equal

As immunologists we can tell you one simple fact and it’s this. If it wasn’t possible to develop effective immunity to the COVID-19  virus then nobody would recover from it. The fact is that the vast majority do recover means in reality that our immune response is indeed highly effective at protecting most people. The big question that needs to be answered is..

which is the really critical part of the immune response that allows people to recover and once we’ve identified this how can we put that knowledge to work in making an effective vaccine?

We’ve heard in recent days cautionary messages from politicians, their advisers and from some of the scientists themselves that a vaccine may or may not work and that the majority or possibly all of the 80 or more vaccines now in development globally may all fail to give protective immunity.

In our opinion this is far too pessimistic, to the contrary we believe that an effective vaccine is much more likely than not, an opinion we base on some understanding of how our immune system works and the already  known characteristics of the virus. As we said at the beginning of this article if immunity was not achievable then nobody would actually recover, it would be a one hundred percent mortality rate but clearly that is not the case so effective immunity must exist. The big question therefore is how long does immunity persist for, is it a month, a year, ten years or for life?

We would therefore like to use today’s blog to explain just how our immune response works in protecting us against COVID-19 (and of course many other microorganisms that attempt to invade us) and why it is that the type of antibody that is produced is vital in providing long lasting protection. We need to start our grand tour of the immune system with a type of white blood cell called a lymphocyte that is constantly circulating in our blood and our various organs and tissues, always on the lookout for invading organisms such as viruses or bacteria. They do this via sensors on their surface called antigen receptors that “patrol” continuously for foreign invaders which they recognise through the shape of the molecules, usually proteins, on the surface of the invading organism.


Once they detect something foreign they swing into action by producing antibodies that mimic the exact opposite or anti-shape of the invaders protein molecule so that the two fit together like a hand fits in a glove. This is called the primary immune response and usually takes around two to three weeks, the same length of time it often takes to recover from influenza or indeed COVID-19 for this very reason.

But the antibody response doesn’t end there as the antibody producing lymphocytes increase in number (and we’re talking of by billions of cells here) and as they do so they undergo some very clever internal genetic rearrangements that changes the shape of their antigen receptors to improve their fit to the antigen making the antibodies they secrete grip on more tightly to the invading organism. In the jargon this is called antibody affinity maturation and this process increases the potency of the antibodies. This process continues and eventually after 3 – 6 weeks the lymphocytes switch from making an antibody called Immunoglobulin M (IgM) in the primary response to one called Immunoglobulin G (IgG) in a secondary response all which then have a tighter grip or affinity for the viruses antigen.

What happens next is another bit of biological magic, the creation of lymphocytes that retain a memory of the invader which then remain in the circulation as memory lymphocytes, sentinels that are long lived for years or even a lifetime ready to spring into action immediately if we encounter that same microorganism at some point in the future through what’s termed a tertiary immune response. These so called memory lymphocytes are what give us long term immunity and are the basis for the highly successful vaccines of the past against smallpox, diphtheria, polio and so on. It is the longevity of survival of memory lymphocytes in our circulation that determines how long immunity lasts for, a figure that is not currently known yet for the COVID-19 virus though continued research over the coming years will eventually determine this.

Not All Antibodies are Created Equal

Now let us explain one of the complications behind both the development of a reliable antibody test to tell if someone has had COVID-19 and how the same problem goes hand in hand with vaccine development. It’s all down to “not all antibodies are created equal”. As we said earlier, lymphocytes produce antibodies against the protein antigens on the surface of invading microorganisms in order to neutralise their infectivity. Proteins however are very big molecules and there are usually many different parts of the molecule (called epitopes in the jargon) that antibodies recognise and attach to.

Some of these antibodies that attach to certain parts of the molecule may not neutralise the invading virus. Take the SARS-CoV-2 virus that causes COVID-19, the major protein that the virus uses to enter the cell is large and is called the Spike or “S” protein which the virus uses to enter the cell to infect it where it can  start its cycle of aggressive viral replication. The virus enters the cell by using a specific part of its S protein to attach to a molecule called ACE-2 on the surface of the cells resident inside the victim’s nose, throat and lungs. Antibodies that are produced against the part of the S protein that attaches to ACE-2 on the victim’s cells will block this attachment thus preventing the virus from entering and infecting the cell. That then is the basis for immunity to the virus, a physical blockade by antibody that prevents the virus from infecting the cell.

This type of antibody thus confers true protective immunity and the victim will recover from the infection and be protected from future infection with the same virus. Imagine now that there are people who make antibodies against different parts of the S protein but not against the part that blocks the entry of the virus into the victims cells. They will have no protective immunity. Ongoing research will tell us if perhaps these are the 20% or so of patients with COVID-19 who progress to develop serious life-threatening symptoms simply because their immune response has failed to produce the right type of antibody to neutralise the virus and prevent it from entering the cell via the ACE-2 receptor. This is an over-simplification of the situation and there may also be other factors but we hope that it gives you a clear mind image of how important the particular type of antibody produced actually is.

No Test is Better than a Misleading Inaccurate Test

This leads us to the other related issue of an antibody test that is able to detect whether or not somebody has had COVID-19 already and whether or not the tested individual is genuinely immune from reinfection. Such a test must be highly specific and precise, that is, it must give very low false positive and false negative results that would give a completely wrong impression of the true position for an individual. High false negative or positive results would be dangerously misleading and lead to a worse situation; as has been often said, no test is better than an inaccurate test.

As alluded to in the blog “Testing Times” a reliable antibody test will be one of the keys to help us unlock the lock down because it will tell us who can safely return to normal life feeling secure in the knowledge that they are immune from re-infection. But there is yet another problem and it’s this. Many other coronaviruses that cause minor illnesses such as the the common cold, just like the COVID-19 virus also possess a spike protein that share common epitopes against which many people when exposed will have produced antibodies against in the past.

Specificity and Sensitivity are the Key for a Successful Antibody Test

If any particular antibody test detects antibodies against these common shared epitopes there will be no way to discriminate which are due to another coronavirus that the individual had been exposed to previously or to the COVID-19 coronavirus. Such a test would therefore lack specificity and would give highly misleading results. The answer to this would be to identify which parts of the S protein were unique to only the COVID-19 virus, which we know do exist, and use this part of the molecule in any test to detect only antibodies against this. There are tests now under development that aim to achieve just this but many of those that have already flooded the market recently have proven dangerously inaccurate giving false results and therefore have introduced a further level of difficulty. This is the chief reason why the UK government have appeared to be slow on rolling out an antibody test, many of those that have been examined have just not been good enough but we can tell you that there is one such test on the horizon that should be ready for general use quite soon.

A Question of Immunity

Then there’s the question of immunity, how can we know whether the particular type of antibody that any individual produces actually confers true long term immunity? For this to be the case, as we explained previously, the antibody must interfere with and block the virus from infecting the cell. Not all antibodies will be capable of achieving this, it will be only those antibodies that block the viruses entry into the cell.

Any antibody test should therefore be capable of specifically detecting this type of antibody, a positive result for which would give confidence that the person who tests positive for this would have truly effective immunity against re-infection. Such a serological test would also be vital to monitor the types of antibody produced by individuals receiving experimental vaccines in order to determine which ones stimulate the right type of antibody for immunity. There is of course more work needed to confirm these things generating the necessary knowledge and understanding that will eventually extricate the whole human race from the current COVID-19 situation. Fear not, because as we write we know that there are laboratories throughout various parts of the world working frantically to do just this.

For all the same reasons it follows  that any vaccine for COVID-19 must also generate the right kind of antibodies against the correct part of the spike protein for it to generate effective immunity.  All these things take time and we will just have to be patient and adapt our lives to circumstances for the time being until the solutions finally begin to emerge which, as sure as night becomes day, they surely will.

Our next blog “A Cure for COVID-19” will be coming in a few days’ time.

To read our other blogs click here.