7th April 2020 – Is Vaccination or something else the solution to COVID-19?
A Blog by Dr David J Flavell PhD FRCPath
Charity & Scientific Director of Leukaemia Busters
7th April 2020
Vaccinating the Herd
In the first part of March near the beginning of the COVID-19 crisis in the UK, the government were actually suggesting that the infection be allowed to run its natural course and rip through the population unhindered. The idea behind this concept was to build up immunity against the coronavirus that causes the COVID-19 illness in at least 70% of the UK population. This is the estimated minimum magic figure that would ensure “herd immunity” meaning that so many people would have become immune that there would be insufficient numbers of individuals for the virus to infect thus breaking the person to person transmission cycle in the community. Then someone advising the government ran the figures and realised that such a strategy would lead to the loss of maybe half million lives and very possibly even more than this horrendous figure. It was an epiphany moment for our leaders that brought a complete change of strategy and little by little we were led into the almost complete lockdown that we are now in.
It is an absolute truth that the only way at present to slow down the SARS-CoV-2 virus transmission rate is to practice an isolation strategy but ultimately this will not cure the problem, even when the number of new infections has dropped to a very low level the virus will probably still be out there waiting to pounce when we all try to return to a normal way of life. In this regard all eyes are on Wuhan to see if COVID-19 re-emerges now that isolation restrictions are being eased there. It’s probably too early to say yet but early indications are that some new cases are now appearing in Wuhan, the big question is will COVID-19 take off at the same pace as before? If it does then this could mean that a see saw of lockdowns and partial freedoms may become the norm disrupting our normal lives for months, perhaps even years ahead. Don’t be too alarmed though because I believe, along with the majority of my colleagues in the biomedical research community, that our own scientific ingenuity will win the day. With this in mind let’s consider the various options and strategies that are available right now and how long these might take to bring into good effect to prevent a succession of lockdowns from reoccurring time after time.
Firstly it has to be said that the entire global biomedical research community, whether non-profit/academic or commercial are as one to tackle this serious global health problem with the aim of returning us all back to normality. As labs worldwide come together cooperatively, utilising the amazing new technologies that we now have at our fingertips means that we can move the research needed to defeat the COVID-19 problem ahead at a rapid pace. The aim would be to ease us all back into a normal way of life without the disease bouncing back and putting us back to square one or worse.
So what is the answer to prevent that nightmare scenario from happening?
The answer undoubtedly lies with science combined with public health measures and the ability of our biomedical research scientists to bring this epidemic (and potentially future epidemics due to other pathogens) firmly under control through our own scientific ingenuity by devising novel vaccines and treatments that will do this virus down. So I’m going to use today’s blog to talk about the just two of the options we have and the likely success that each will bring to solving the problem and crucially how long each is likely to take to have an impact. We can’t and we won’t stay locked down forever and I can clearly see a way out of the current circumstances through a combination of approaches that will result in a staged easing of restrictions over a several month period. However, a cautionary warning, this will only work if we methodically follow public health recommendations of social distancing and other related measures.
The final solution to the COVID-19 problem will come from within ourselves; our own immune system will ultimately be our saving grace. But with the COVID-19 infection our immune systems are a double edged sword; on the one hand around 80% of people do mount an effective immune response against the virus get better and are probably immune to further re-infection at least for a period of time. It’s the other 20% of people who fail to mount an effective immune response who then progress further to develop serious life-threatening symptoms and ironically it’s their own immune system that is largely to blame as it overreacts to the virus and in so doing damages the persons own lungs and sometimes other organs. Immunologists are well on the way to understanding precisely how the damage caused by COVID-19 in seriously ill or dying patients occurs and already there are a number of potential medicines ranging from antibodies to small molecule such as those used against the AIDS virus or malaria that are showing some promise but not yet fully proven. But as important as it is, before we consider treatments for patients with pre-existing serious infection let’s look at what must be achieved to make this problem go away in the long term, not just a short term temporary fix.
What are the “Exit Strategies” that would allow a return to normal?
The obvious answer to the COVID-19 problem is to render everyone immune to the virus either through option one, natural exposure to other infected individuals in the community or the alternative option two through the use of an effective vaccine. It sounds easy doesn’t it but in practical reality there are numerous hurdles to overcome to achieve this goal. A minimum 70% (and ideally more) of the population would need to be rendered immune by either method to ensure that herd immunity had been achieved in the general population just as was successfully achieved in the past for polio and diphtheria through global vaccination programmes.
Option 1 – The Herd Immunity Through Natural Community Infection Solution
The big problem with the natural infection approach is of course that 20% or so of individuals exposed naturally to COVID-19 infection in the community would develop serious symptoms due to the activity of their own over-zealous immune response against the virus leading to perhaps as many as half of these dying, most of them elderly but as we are seeing many who are not. The approach of letting the infection rip through the general population would therefore not be ethically acceptable, too many lives would be lost.
A way out of this, as I briefly discussed in my blog on the 5th April (Biomarkers and You) would be to develop a screening test for one or more biomarkers to reliably identify those individuals who were at risk of developing serious complications from COVID-19. This would then release individuals who lacked the biomarker(s) out of lockdown to return to normal life whilst the 20% or so who possessed the biomarker(s) would remain in isolation to avoid infection. Of course this would mean that a proportion of those individuals who returned to normal life would become infected but having been identified as low risk in not possessing the biomarker(s), they would not become seriously ill. Once a sufficient number of low risk individuals had been infected in this way then adequate herd immunity would have been built up in the community to allow for the high risk individuals to be released from lockdown to return to normal life. For this strategy to work acceptably the biomarker(s) would have to be highly reliable at identifying those individuals who would not go on to develop life threatening symptoms. Of course the success of this strategy would rest entirely on scientists being able to identify one or more biomarkers that would reliably separate the high from low risk individuals. There are already candidate biomarkers under consideration and I know for sure that there is a great deal of work going on in laboratories around the world to seek out new ones. If the natural community infection strategy were to fail because we were not able to identify a reliable biomarker(s) then we would be left with the option of a vaccine to give herd immunity through the tried and tested immunisation route. Biomarkers will come I’m pretty sure but there is always the possibility that they may not in which case vaccination would have to be the alternative plan.
Option 2 – The Vaccine Solution
The vaccine solution aims to achieve exactly the same thing as the natural community infection scenario. Vaccination is aimed at artificially conferring immunity on sufficient numbers of vaccinated individuals to result in herd immunity but without causing the illness in those vaccinated. The thing is that vaccine development is not a quick process if it’s to be done properly. Rushing into it and getting it wrong could actually make the situation a whole lot worse for reasons I’ll explain later. There are already several commercial pharmaceutical and biotech companies together with at least three (and likely more) academic groups in the race to develop various types of vaccine. There are now at least four different forms (or platforms as they’re called in the trade) that vaccines can be based on which I’ll now explain.
- Whole “killed” or inactivated virus vaccine as the platform that simply sits at the site of injection stimulating an immune response without replicating itself.
- Whole “living” but attenuated virus vaccine that actively infects and replicates itself in the cells of the vaccinated individual but doesn’t cause illness. This can be comprised of the coronavirus itself or another virus known as a vector into which the genetic material of the coronavirus has been inserted. Johnson & Johnson have developed a vaccine using this platform with a viral vector known as an adenovirus.
- Subunit vaccine platform is one where one or more of the proteins that coat the outside of the virus are produced artificially by genetic engineering and these are then used to immunise the individual.
- Nucleic acid vaccines (DNA or RNA vaccine) platform that uses a genetically engineered strand of DNA or RNA synthetically produced that codes for one or more of the surface proteins of the virus. When this is injected into the muscle of the individual being vaccinated, the DNA or RNA enters the muscle cell which then instructs the muscle cell of that individual to produce the viral protein according to the instructions encoded in the strand of DNA/RNA. The synthesised viral protein is then released from the muscle cell where it stimulates an immune response against that protein in the vaccinated individual and hence the virus.
All four types of vaccine for COVID-19 are either in development or undergoing clinical trials as I write but no one knows yet which of the above platforms will deliver the most effective vaccine, see http://www.ncbi.nlm.nih.gov/pubmed/32219057. In all cases the aim is to present to the immune system of the vaccinated individual viral proteins that are seen as foreign which will therefore stimulate an effective protective immune response through the generation of antibodies that neutralise the virus and prevent it from entering the cell together with the generation of killer white blood cells termed cytotoxic T-cells that seek out and eliminate cells that are already infected with the virus. This might sound straightforward enough but it’s not, it can represent 2 – 5 years’ worth of work. Each vaccine requires testing extensively firstly in animal models of COVID-19 infection to show that it actually works in protecting animals from the virus, then it has to undergo safety evaluation in a limited number of human volunteers then finally a much larger scale clinical trial, usually hundreds of volunteers who are then monitored to see if any develop infection after mixing in the community.
And here lies the first problem with the development of a COVID-19 vaccine, with lockdown the way it is, vaccinated individuals would not generally encounter any naturally infected people in the outside world. That then leaves us with what are termed challenge studies where a vaccinated individual some weeks after vaccination is deliberately exposed to the virus under clinical conditions and then observed over a period of time to see if they develop the infection. The problem with that approach with COVID-19 is that we know that in maybe as many as 10% of infected individuals it is a fatal disease making challenge studies ethically unacceptable – unless that is we had a reliable biomarker to single out those volunteers at low risk. Yet this is exactly the way that the original smallpox vaccine was developed by Edward Jenner back in 1796 when he challenged his gardeners 12 year son with smallpox virus after vaccinating him six weeks previously with cowpox virus. Today that challenge study would not be allowed for ethical reasons and a smallpox vaccine may never have been developed in the way to save the millions of lives it has through history thereafter. Maybe in the times we are in, this historical perspective provides a strong argument that we need to set aside the concerns we might have in normal times and practice a more aggressive less concerned approach in order to save many more lives than would otherwise be lost.
That brings me to another problem with vaccine development for COVID-19 and it’s this. Previous studies from the original SARS outbreak in 2002/03 due to a very similar coronavirus where a number of vaccines were developed and tested showed that some vaccines stimulated an immune response that instead of being beneficial actually made the disease worse when animals were challenged with the virus. In other words vaccination increased the degree and extent of pneumonia and other multiple problems probably because the immune system responded inappropriately in much the same way it does in patients who develop severe life threatening symptoms from COVID-19 infections. This is why vaccine development for COVID-19 needs to proceed with great caution, there is the danger that by taking short cuts things might be missed and we end up with a vaccine that instead of protecting the individual actually increases the severity of infection when they encounters the real virus. I hope that you can see now why vaccine development should not be rushed and why if done properly it takes years and not months to reach the final goal. That said you may be aware that an early phase trial in healthy individuals of an RNA vaccine from the company Moderna is already underway in Seattle https://www.nih.gov/news-events/news-releases/nih-clinical-trial-investigational-vaccine-covid-19-begins whilst others are in the pipeline. And finally, once we do have a vaccine that’s shown to be effective and safe the next enormous logistical challenge would be producing sufficient to vaccinate the vast majority of world’s population together with a distribution and administration system of doses to where needed; this alone is a gargantuan task that will take time and money, lots of it.
I sincerely hope that we will be able to overcome the problems and challenges outlined above and above all else I hope that the very early trials currently underway have successful outcomes. But lurking in the back of my mind and in the minds of many others is that because of insufficient animal testing beforehand they may turn out to be ineffective or worse still cause more severe disease in those vaccinated when eventually they encounter the real coronavirus in the outside world. Let us hope that these fears are unfounded and success powers through with a sprinkle of good fortune much as it did for Edward Jenner for smallpox in the eighteenth century.