This is the next post in our Corona Hope series. If you have missed the previous articles you may want read them before continuing. The goal here is to give us all insight into the science behind the efforts that are ongoing to find us all a route out of the coronacrunch we are all experiencing. And by doing so to give us all just a bit more hope to sustain us.

It is also part of a series of questions on vaccines for blood cancer patients

As we have been explaining the immune system we have used a  hypothetical World War 2 example. We explained that when a human body encounters an infection that it has never seen before it is as though we had to create a design for a weapon to fight back from scratch.  We imagined if the Spitfire had not been designed before the Nazis started to attack the UK. It seems clear that  no matter how fast ten thousand designers worked to try and figure out a whole new weapon to fight back with they would not have been able to do so quickly enough. Britain would not have stood a chance. When you think of it that way it is remarkable that the body can ever fight back and win against a new enemy. Of course it doesn’t always succeed as the daily globl death toll from COVID-19 demonstrates.

How could disaster have theoretically been averted in our hypothetical scenario? How can we improve our own chances of fighting off infection? One approach would have been to import Spitfires from other countries that had successfully fought off the Nazis. Leaving aside the fact that there were no such countries available, this is the idea behind what is  called “passive vaccination” or the use of convalescent plasma or IVIG.

But what of active vaccination, how does that work? What we do here is we look into the future and anticipate a potential threat. We trick the body into thinking it is already in the middle of an infection, triggering the lymphocytes to search for the perfect counter-weapon in exactly the same way they would when the invaders arrived.

During any new infection, or following a vaccination, hundreds of millions of lymphocytes are screened until we find one that can make an antibody that successfully defeats the invader. That then leads to a huge multiplication of that lymphocyte creating thousands of copies in a very short time.  The copies produce the same antibody.  Some of these daughter cells then turn into plasma memory cells which can last decades. Each plasma cell is effectively a mature lymphocyte who has an antibody plan prepared and ready to go if needed again.

Stimulating this process is the idea behind active vaccination. How can we get the body to work on finding the right design before it has had to deal with the threat? In our Spitfire analogy the UK would have earlier presented the designers with an indication of what the enemy planes were like to help them create their ideas.

Traditional vaccinations aim to present the immune system with a blueprint for a crucial part of the virus or bacteria which are unique to it. This is the lock for which we are asking the body to try and find a key. This can  be a weakened forms of the illness itself, often a live virus vaccine that has been somehow engineered to be less dangerous. Alternatively the vaccine can be a piece of protein from the virus or bacteria that has been isolated and synthesised. People with blood cancer cannot have a live vaccine because they are not able to fight back and the vaccine might therefore cause disease. Sometimes in some diseases a live vaccine can even mutate back to the wild form and cause an outbreak.

The process of designing and testing a vaccine usually takes years or even decades. As COVID19 is a new disease we do not yet have any proven vaccines but there are many being tested at various stages. None is further on than one plucky paradigm changing vaccine from Oxford. We will focus in on that later on in  the next post.  It does represent an entirely new approach which is effectively a “plug and play” vaccine platform. This platform allowed the team to generate a working potential vaccine as early as January 2020. And if all goes to plan it may be ready to be given to millions of people in September this year! This would be by far the quickest development of a vaccine for any sickness in the history of man.

It is good for us to keep the hope of a COVID19 vaccine alive. Sadly, however  so far no vaccine has yet been fully developed and deployed  broadly for any of the most recent new illnesses that have emerged. Ebola, SARS, MERS, AIDS. We have worked on vaccines for all of these with some success but none have been fully tested, licensed and fully deployed. So it is remarkable that we may be just a couple of months away from completing the work on a vaccine for a disease that only emerged towards the end of 2019.  It may feel like this vaccine is taking a long time, but it could be by far the fastest vaccine development in human history.

One remarkable thing about lymphocytes is that they are the only cells in the human body that  are actively encouraged to mutate. The active end of the  antibodies lymphocytes produce are shuffled millions of times over like a deck of cards.

The number of possible variations in the antibodies is surely almost unlimited.  Like looking for a needle in the haystack the body is searching for the one in a billion antibodies that do the job we want them to. The job of an antibody is simply to act as a label. The antibody binds to the antigen and either neutralises it directly, or if the antigen is attached to a cell the antibody binds to it and acts like a huge beacon summoning the other parts of the body’s immune system to go to work hunting down and destroying the alien invader.

When a matching lymphocyte is found it will then be signalled to multiply very rapidly indeed growing into a clone of thousands. And as it grows antibodies are released not just locally where the injection was given but throughout the body. Suddenly the body is making the antibody in  vast quantities. The idea is that these antibodies will neutralise the invader if it attacks at a later stage.

Through antigens (the lock) and the antibodies that match them (the key) we identify friend and foe. It is when we produce antibodies to proteins on our own cells that autoimmune reactions occur as our body tries to destroy itself. Identifying harmless things like pollen and dust mites as alien invaders and producing antibodies to them is also what causes allergy.  Although interestingly one type of antibodies actually neutralise the antigen and mean that we don’t get such severe allergies.  Thus when those antibodies drop during certain blood cancers, allergies can become more severe. Unfortunately people with blood cancer have dysfunctional immune systems and we can therefore be at increased risk of both auto-immune problems and allergies.

The not so humble lymphocyte is really an arms factory producing specific targeted weapons that if they work properly will hunt and destroy only the enemy.

During the second World War the Swiss Army gave all the adult males a gun to keep in their house.  This continued until quite recently. The idea was simple. It meant the whole country was the army. If invaded one gun would not acheive much against the raging might of the enemies massed against them. But if that one gun could kill two or three beige its owner was taken out perhaps millions of those guns would be the secret to victory?

Was there a theoretical risk that in the panic the population would turn their guns on each other and cause damage? Yes but like the government relied on the sense of civic duty of the population not to do that. In the early stage of an infection having loads of antibodies around is a great thing. Later on, however there can sometimes be an over -reaction of the immune system. One of the challenges in COVID-19 is the body in attempting to fight off the virus can begin to destroy its own lungs. Thus it has been shown that dexamethasone, a steroid which suppresses the immune system actually helps save lives of those experiencing this form of severe over reaction which leads to a particularly sort of pneumonia.

As I write this I do have a lot of hope for society that this new vaccine could be the key to unlocking our victory over this disease. We are a relentless and innovative people. And not for the first time this plucky island race of which I am a part might just save the world as it stands facing an enemy that threatens us all.

75 years on from the end of World War two the celebrations have been muted due to the current outbreak.  There are parallels with the current situation. The UK were the last hope standing against the Nazi threat in Europe whilst the USA was still sleeping. The Brits produced 22,000 Spitfires to act like antibodies and lock onto enemy aircraft and bring them down. And our plucky stand sent out a large signal to our American cousins that beckoned to them, pleaded with them, cajoled them to come and help us. And help they did. But just maybe a geek in the city of Oxford May turn out to be the saviour of the world in 2020. The story of one man or woman against an enemy and coming up with a solution is a compelling one. It’s why captain Tom is now Sir Tom as his plucky stand galvanised and offered hoe to a nation to keep faith and dig into their own depleted pockets and give.

Our problem is that as a cancer of the lymphocytes many of us may find this vaccine just doesn’t work. We may possibly get given pooled antibodies, but one little understood fact about vaccination is that it doesn’t depend on the individual’s response to actually work.  Rather vaccination works alongside people who go down with a disease and recover (giving them natural immunity) in causing  the group to become immune as a whole. This means that ultimately there is not enough people vulnerable to the disease in the population to allow it to spread.  This may be enough to vanquish a disease ultimately leading to its eradication.   This is called herd immunity.

For every disease there is a percentage of the population who must be immune in order to stop a new outbreak from taking off if someone comes into the population carrying the disease. This immunity can be caused either by a vaccine or by having developed immunity during a prior infection.

For some diseases which are especially contagious (i.e. they spread very rapidly) the  proportion of the population you need to be immune to prevent a new outbreak is around 99%. Anyway it turns out from a bit of education that I gave myself (see the links below) that there is a simple way to calculate this percentage, which is to look at Ro.  Most people know by now that Ro is the number of people on average that a person with the disease infects.  The higher it is the more quickly a disease spreads. And by containment measures like social distancing, lockdown, and shielding we have shown that you can influence the Ro. So presumably, given that we want to be able to lift all restrictions at some point, then the natural Ro is what we should be considering when it comes to what proportion of our population we need to become immune in order to protect all of us. Actually herd immunity really is shielding. It is where your housemates, your friends, your family, the people you work with, everyone you meet at the shops all protect you because enough of them are immune that the disease will not spread in the population.  Thus you would be protected even if you are not yourself immune.  Getting to this herd immunity is our passport to not worrying about COVID19 any more.  Though of course ideally we will need such herd immunity to be global. That is a whole lot of vaccine!

The formula for the proportion of the population which must be immune to stop the spread is 1 – (1/Ro). This is expressed as a decimal and you can use the result to transform it into a percentage.

One figure sometimes mentioned in newspaper articles about herd immunity is 60%.  Plug in that into the equation corresponds with an Ro of 2.5. This is calculated from 1/0.4.  We do not know for sure that is the correct “natural” Ro, and I have seen higher figures published elsewhere.

So for example if the Ro is 5 then the herd immunity level would need to be 80%. Since 1/0.2 = 5. It turns out this was a value for Ro being mentioned earlier on in some publications, although it seems scientists now believe this estimate is too high. But perhaps populations have been more cautious even where there is not a formal lock down in place.

I mentioned earlier some diseases need a herd immunity of 99%.  For it to need to be that high you’d be looking at an Ro of 100, which must show just how infectious some diseases can be.  Imagine a disease which could infect 100 people on average from each infected individual.  That really is a scary thought.

Of course the seriousness of a disease is assessed by how easy it is to catch multiplied by how likely it is to kill. So for example a couple of months back in New York they reached the point that 1/1000 average New Yorkers had died. At that point 1/100 New Yorkers over 75 had died making them ten times as likely as the average person to die.  If you then start adding other independent risk factors as estimated in a paper I explained in my post on why blood cancer patients are at high risk then the risk would go up even higher.

But clearly no matter how high your risk of serious complications is from COVID19 if nobody has the disease in your population you cannot catch it. Clearly we do not ideally just want to let the disease spread throughout the population even if that would eventually mean we are immune. Because if we did that then, given that the proportion of New Yorkers who had caught the disease at that point in the outbreak was only 10%, we would be looking at perhaps between six and eight times the number of deaths.  Obviously that doesn’t factor in the fact that doctors are getting better at treating this condition and finding certain medications do actually lower mortality of people in hospital.

Right now in the UK the government tells us based on weekly random population screening that only 1 in 1700 British people have the disease.  This is down from a peak of 1 in 40.   It’s super clear to see that the proportion of people around you catching the disease is a crucial predictor of your own ultimate risk and so once the chance of us encountering an infected person starts to go down it becomes safer for us to venture out.

This graphic shows the way the wave of excess mortality which has spread across the UK now seems to be receding.

It seems unlikely that the proportion of our population with the disease will drop to zero until we either reach herd immunity naturally or a vaccine is developed. But that doesn’t necessarily mean we must remain strictly shielding with no exceptions until a vaccine is found. The government has relaxed it’s advice to us telling us that it is safe for us to go on carefully social distanced walks and has this week spoken about relaxing and then even pausing shielding altogether. 

Each of us will have to consider what level of risk we are prepared to tolerate.  Generally we do not think about risk. Nobody considers when they get in a car that there is a theoretical risk of crashing that car and being seriously injured or dying.  It is not quite clear to me at what background level of infection in a population we will feel safe to go out as much as we previously did.  I suppose that will vary from individual to individual.   And whilst there is any virus circulating of course crowded indoor environments will always pose a greater risk than spread out socially distanced outdoor environments.  But we do also need to live a little.  Being stuck inside a bubble for ever doesn’t seem like a realistic option.

Lockdowns drive down the Ro but don’t change the biology of the virus so when they are fully released the Ro goes up to whatever it is biologically for the virus. Although presumably the fact that some members of the population are now immune must act as a brake on the spread even if it is not high enough to eliminate the disease altogether.  Ro is always based on the average number of people a single case goes on to effect, so this will be hugely effected by the population density and behaviour. So you can see why in a city like New York or London with crowded commuter trains and clubs and bars the risk is that a single person could infect tens of people in reality. You would predict that just like the flu the disease would eventually reach rural areas, but get there much more slowly. Perhaps the biggest influence on the risk is population density.

Most Western countries are too crowded to ever completely irradiate it, and it is not possible for us to successfully quarantine a whole country as New Zealand has done since we are so dependent on deliveries from mainland Europe which arrive in lorries driven by people who could potentially import the disease even if we managed to get the rates down. At the moment it seems like the warmer weather will not abolish it, but it is possible that colder weather in the winter might be associated with a second spike.

So to conclude our personal risk is not only dependent on our immune function but on the chance we have of encountering an infected individual and if we do encounter them how close we are when we meet them.  With the current slowing of the rate in some countries this does reduce our risk, although it will be hard for us to be confident that there might not be local outbreaks or second peaks until there is a broad population immunity caused either by a lot more people catching the disease or a successful vaccine. In the next post I will talk about the nature of the Oxford vaccine and some of the others also being tested.

Read More

Entry level

• BBC science article

Intermediate

• Article on lymphocytes
• New York data (updated)

Advanced

• Epidemiological article
• Early estimate of Ro