Like nearly everyone on the planet I am worried about COVID-19. SARS-CoV-2 (the virus that causes COVID-19) appears to be killing between 1% to 3.5% of the people it infects and has a R0 (i.e. how many new people each person infected goes onto infect) of between 2.5 to 3.9. Left to run wild, the virus will likely kill tens of millions of people worldwide.
The governments of the world have implemented strict population isolation protocols to try and limit the spread of the virus, but the economic cost of this is extremely high. A vaccine for COVID-19 is 12 to 18 months away (at best).
We are stuck in a diabolic situation where the only way to prevent the economy sliding into a slump deeper than the Great Depression is to consign many tens of millions of people to an early grave. Is there a way out?
SARS-Cov-2 Viral Diversity
SARS-CoV-2 like all viruses mutates (changes) overtime. Many of these genetic changes are small (single nucleotides) that are not important to the replications or transmission of the virus from person to person, but they can be used to identify the origin of the virus. DeCODE genetics has been testing Icelanders for COVID-19 and genome sequencing the SARS-CoV-2 strains isolated. They have found two very important pieces of information:
- More than 50% of the people infected with SARS-CoV-19 are asymptomatic (i.e. they have no illness).
- They can identify the geographical origin of the strains by the genetic differences (mutations) between the different strains.
Furthermore, researchers in China have identified a mutant strain of SARS-CoV-2 which appears to be less pathogenic than most strains infecting people. This strain (ZJ01) had single nucleotide mutations in a key functional gene that made it less able to spread through the body.
This data suggests a simple and testable hypothesis – there are natural strains of SARS-CoV-2 in the world that have mutated to be non-pathogenic (asymptomatic), but are still infective and will provide immunity to the more pathogenic (deadly) strains.
If we can find one of these non-pathogenic viral strains out in the wild we could give it to everyone in the world and solve our diabolic problem. This non-pathogenic strain would act much like the live attenuated (oral) polio vaccine.
How do we find the attenuated SARS-CoV-2 strains?
This hypothesis is worthless if we have no way of finding any of these non-pathogenic SARS-CoV-2 viral strains. Luckily there is a quick and cheap way to find these strains if they exist – test asymptomatic people for COVID-19 and then genome sequence the SARS-CoV-2 strain that has infected them with the aim of identifying a virus with mutation(s) in an essential viral gene(s). This is what the Chinese researched did to find their less pathogenic strain
This approach is cheap (a couple of hundreds of dollars a virus strain) and quick (a week or less). With almost no effort or cost we could sequence a few thousand viral strains from asymptomatic people until we find a virus strain with the right mutations to make it harmless and which is in effect an attenuated vaccine. We would know that this strain can still reproduce in people and lead to immunity, but not make people seriously ill.
What viral mutations are we looking for in a good non-pathogenic viral strain?
We would ideally be looking for a virus strain with a large(ish) deletion in an essential viral gene. This sort of mutation is easy to spot in the SARS-CoV-2 genome data, and because the genetic information has been removed, it makes the virus very unlikely to be able to mutate back into a dangerous strain. Ideally, the strain identified will have infected a number of other people in the local area too so we can know it is safe.
Has this ever been done before?
Yes. The polio, measles, rubella, mumps, and chicken pox vaccines are all live attenuated viruses. Even something as dangerous as smallpox was controlled in the 18th century using a variation of this idea called Variolation. The idea was the doctor would deliberately infect you with a less harmful strain of smallpox to make you immune to the more deadly strains of smallpox. Of course, they didn’t know how this approach worked in the 18th century, but it was still very effective and millions of people were saved from dying from smallpox by it.
Some people have been calling dosing with a low dose of the virus variolation, this is not what variolation is. While such a low-dose approach might make the COVID-19 less dangerous to the person being infected, it doesn’t make the virus any less dangerous for those around you that you might infect. Such an approach could also not be used on the vulnerable leaving them exposed to the illness.
What are the risks?
The major risk is the virus we think is safe is not 100% safe. While we can use community spread of the identified strain to estimate how safe it will be (i.e. if it has infected 1000 people and none have got seriously ill then we should have a pretty good idea that it is safe), but our knowledge will be incomplete. We can of course spend the next few years testing and trialling, but if we do this by the time any strain is shown to be 99.999% safe (not even the polio vaccine is 100% safe) we will have all got COVID-19 and the world’s economy will be a smoking ruin.
We have a choice of taking some small risk now, or face the certainty of a much worse problem later. Time to accept some risk and do something.
Update. Q & A
I have been getting a few questions on this post so I thought I would address them here.
How do you know there is an attenuated viral strain out there?
Because such strains have already been found. I am hypothesising that there is more than one based on the known mutation rate of coronaviruses and the number of cases. Coronaviruses like SARS-COV-2 mutate continuously (this is why companies like deCODE can tell the geographical origin of different strains) as the molecular machinery for replicating their RNA genome is not very accurate. When you combine this with the millions of mild cases out in the world, the odds are on our side that there is at least one person infected with a strain that has a mutation that makes the virus less dangerous (attenuated). We just need to look for this strain – luckily the tools we need to use (genome sequencing) are now cheap and quick. What would have been impossible 20 years ago can now be done in a week.
Aren’t most people who have mild/asymptomatic cases infected with a dangerous strain?
Yes. Almost all (>99.9%) of people who are infected (and have a mild case) are infected with a dangerous strain of the virus, they just happen to have an immune system that can control the virus well. With COVID-19 a mild case does not mean you are infected with an attenuated strain – for most people with a mild case if they happen to infect a person with preexisting conditions or who is old, that person will be at a high risk of dying. A mild case does not equal a harmless strain.
My argument is coming from the other direction. While almost all mild cases of COVID-19 are caused by a dangerous strain of SARS-CoV-2, an attenuated strain of SARS-CoV-2 will only cause mild disease. If you want to find an attenuated strain you need to look at mild cases even though >99.9% of the people you check will be infected with a dangerous strain. What we want to find is one of the rare natural viral mutants that is attenuated. Where you will find such a viral mutant is in people with a mild/asymptomatic form of the disease.
Can’t we just wait for the vaccine?
No. Apart from the time it will take to develop, trial, and mass produce a vaccine (12-18 months), it is unlikely that any vaccine will be practicable. The reason why is immunity to respiratory viruses (like corona) doesn’t last long – 6 months to 2 years. We would have to keep vaccinating everyone in the world every year (or maybe every 6 months if we are unlucky). This just isn’t going to work in the real world (especially poor countries) and is one of the reasons we don’t have a vaccine for the coronavirus strains that cause the common cold. Unless we can drive the current dangerous SARS-CoV-2 strains to extinction we are going to have a problem with this disease indefinitely.
Isn’t social distancing and quarantining solving the problem?
Yes and no. Yes countries like South Korea and Australia have shown that through mass screening and social distancing you can keep a lid on the disease, but this leaves the population susceptible to a new outbreak. Singapore and Japan have recently seen this in action where they eased restrictions and found the disease came back and they had to reintroduce restrictions. I don’t think many people want to live for years with cycles of restrictions, easings and further outbreaks.
Wouldn’t the use of such an attenuated strain just be a vaccine?
Yes in one way, but it is a little more subtle. Assuming we can find an attenuated strain, then how to best use it a separate question. The most important thing to note is that such a virus would not be a vaccine from a regulatory perspective. It is just a natural virus that you can catch in a natural way. Hang out someone infected with the attenuated virus and you will catch it without doing anything, go home and those around you will catch it from you and so on. While I wouldn’t suggest this is the best way to get the attenuated virus out into the community (it would be much better to just post a sample of the virus to everyone), such spread is outside the regulatory framework for vaccines.
Giving it deliberately to lots of people would change the ecosystem for the dangerous strains of the virus. The dangerous strains would find it difficult to spread through the community as many (most) people would have already been infected (and hence immune) with the attenuated strain. Overtime the dangerous strains would become rarer, and the attenuated strains more common, until eventually the dangerous strains would go extinct and we would just be left with the mild version. While we would not be able to get rid of this mild strain, it would just be another of the hundreds of viruses out there causing common colds. The idea is at its base is really to replace the dangerous strains with a less dangerous strain that we can live with.
Why can’t we just use the less pathogenic SARS-CoV-2 strain already identified in China?
While the ZJ01 SARS-CoV-2 strain identified in China appears to be less pathogenic, the mutations that make it so are single base changes. These can easily mutate back to the more dangerous version of the virus. The viral strain we want to find will have a deletion mutation where a section of the viral genome is removed. Deletion mutations are much more difficult to mutate back to the dangerous type since rather than just a change from one nucleotide to another (e.g. C > T), the deleted region is missing and can’t easily be recreated by mutation. Put simply, deletion mutations are more stable to back reversion.