So it’s the burning question… political parties are demanding answers and the Government are saying “not yet”… but what is it all about and how do we come out of lockdown due to Covid-19.
On the face of it this might seem simple. All the Government has to do is say “right, that’s it, everyone back to work, school, gym, parks, beach…wherever!” But it’s really NOT as simple OR safe as that.
In order to safely come out of lockdown we need to be sure that there will be no rebound in the number of cases, and at the risk of sounding alarmist there is a real possibility of this happening before we realise it’s too late.
Remember, it takes about a week to develop symptoms after exposure to SARS Cov2, and another week before all of your contacts become unwell. Although most people are fine it still doesn’t account for those who are not and those who end up in hospital during the second week of illness. This means that it takes at least 4 weeks (1 week incubation, 1 week contacts, 2 weeks illness) before we “see” the effects of any change in policy about the lockdown. AND it will take a further 4 weeks for things to settle down again if we go back into lockdown! That’s 2 months… that’s up to end of July! We do not want to get this wrong so a careful cautious approach is what is required. I know I don’t like it either but…
On the face of it this might seem simple. All the Government has to do is say “right, that’s it, everyone back to work, school, gym, parks, beach…wherever!” But it’s really NOT as simple OR safe as that.
In order to safely come out of lockdown we need to be sure that there will be no rebound in the number of cases, and at the risk of sounding alarmist there is a real possibility of this happening before we realise it’s too late.
Remember, it takes about a week to develop symptoms after exposure to SARS Cov2, and another week before all of your contacts become unwell. Although most people are fine it still doesn’t account for those who are not and those who end up in hospital during the second week of illness. This means that it takes at least 4 weeks (1 week incubation, 1 week contacts, 2 weeks illness) before we “see” the effects of any change in policy about the lockdown. AND it will take a further 4 weeks for things to settle down again if we go back into lockdown! That’s 2 months… that’s up to end of July! We do not want to get this wrong so a careful cautious approach is what is required. I know I don’t like it either but…
The only sure-fire way to end this is for SARS Cov2 to be no longer able to spread in the community so no one will become sick (that means the reproductive rate <1, e.g. an infected person infects less than 1 other person), and there are only 3 theoretical strategies I can think of how this might happen:
Vaccination
Okay, this is the miracle solution everyone is waiting for; and to be fair it is the only realistic solution (which I will go onto explain)… but don’t hold your breath there is no vaccine coming quickly. Even if this week’s vaccine trial in Oxford is successful!!!
It is actually pretty simple to come up with the basis for a vaccine. Heck, even I could probably rustle one up in our hospital lab (obviously with the help of my talented biomedical scientists to keep this Frankenstein Doctor in check!)… you take a live attenuated virus, plus a piece of protein combined with a booster molecule, plus bits of RNA associated with proteins to boost the immune response.... See getting some form of attenuated virus to inject in someone’s bum is relatively simple!
But before you start queuing outside my office (or reporting me to the GMC for experimenting on people!) let’s just give this some more thought. Spoiler alert!
It’s not enough to have a vaccine; yep sorry! You see the vaccine has to be safe AND effective AND distributed/delivered SO that is a whole new heap of difficult.
How do you develop a vaccine?
Once you have your idea for a vaccine you have to make sure it works in animals, I know experimenting on animals is a difficult subject but let’s accept this is how it’s done. To do this you have to have a “good animal model” and guess what? There are few good animal models for Covid-19 (e.g. the virus seems to favour humans as a host and not infect or survive in other animal hosts).
In order to study an infection in an animal the animal has to be able to catch the infection. Most studies are done on mice but mice cannot “catch” SARS Cov2, weird huh? It turns out that mice don’t have the same ACE2 receptor as humans and it is the ACE2 receptor that allows the virus to bind to cells and insert the viral RNA.
The same problem occurred with classical SARS back in 2002-3. In order to study these viruses, scientists had to genetically modify (GM) mouse embryos so that their ACE2 receptor allowed the virus to bind, then bring these embryos to birth and then create a colony of breeding mice so that they had an on-going supply of GM mice to study. This all lengthens the timeline to the vaccine. The science community did eventually do this and they started studying classical SARS. However as classical SARS didn’t ever become “the” big problem first thought their funding was slowly but significantly cut and so these GM mice were allowed to “die out” with only their genetic material was preserved.
- We have a vaccine capable of protecting people
- We develop sufficient herd-immunity through natural infection
- The virus mutates to be non-infectious
Vaccination
Okay, this is the miracle solution everyone is waiting for; and to be fair it is the only realistic solution (which I will go onto explain)… but don’t hold your breath there is no vaccine coming quickly. Even if this week’s vaccine trial in Oxford is successful!!!
It is actually pretty simple to come up with the basis for a vaccine. Heck, even I could probably rustle one up in our hospital lab (obviously with the help of my talented biomedical scientists to keep this Frankenstein Doctor in check!)… you take a live attenuated virus, plus a piece of protein combined with a booster molecule, plus bits of RNA associated with proteins to boost the immune response.... See getting some form of attenuated virus to inject in someone’s bum is relatively simple!
But before you start queuing outside my office (or reporting me to the GMC for experimenting on people!) let’s just give this some more thought. Spoiler alert!
It’s not enough to have a vaccine; yep sorry! You see the vaccine has to be safe AND effective AND distributed/delivered SO that is a whole new heap of difficult.
How do you develop a vaccine?
Once you have your idea for a vaccine you have to make sure it works in animals, I know experimenting on animals is a difficult subject but let’s accept this is how it’s done. To do this you have to have a “good animal model” and guess what? There are few good animal models for Covid-19 (e.g. the virus seems to favour humans as a host and not infect or survive in other animal hosts).
In order to study an infection in an animal the animal has to be able to catch the infection. Most studies are done on mice but mice cannot “catch” SARS Cov2, weird huh? It turns out that mice don’t have the same ACE2 receptor as humans and it is the ACE2 receptor that allows the virus to bind to cells and insert the viral RNA.
The same problem occurred with classical SARS back in 2002-3. In order to study these viruses, scientists had to genetically modify (GM) mouse embryos so that their ACE2 receptor allowed the virus to bind, then bring these embryos to birth and then create a colony of breeding mice so that they had an on-going supply of GM mice to study. This all lengthens the timeline to the vaccine. The science community did eventually do this and they started studying classical SARS. However as classical SARS didn’t ever become “the” big problem first thought their funding was slowly but significantly cut and so these GM mice were allowed to “die out” with only their genetic material was preserved.
So when Covid-19 took off, the science community mobilised to re-establish these GM mouse colonies so SARS Cov2 could be studied and a vaccine worked on. There’s another “BUT” coming… but this all took time (in case you’re wondering the gestation period of a mouse is about 21 days, good to know huh!).
Once you have your mice you can then vaccinate some and not vaccinate others, then you can try and infect the lot (remember SARS Cov2 doesn’t “like” to infect most other things, just us humans) to see if the vaccine protects the vaccinated… simple… or maybe not.
Not all antibodies are equal
Some more bad new! Not every vaccine is effective at preventing infection. Sounds weird but… The vaccine may trigger an antibody response (antibodies bind proteins from an infectious source, identifying them as harmful) BUT these antibodies also need to be able to “neutralise” the virus in order for them to be effective (e.g. stop the virus implanting its RNA).
Guess what? Coronaviruses are poor inducers of neutralising antibodies… bummer! In fact studies of classical SARS showed that some patients with mild infections didn’t produce detectable neutralising antibodies and even those who had severe infections and did produce neutralising antibodies had lost these protecting antibodies within a few years, as the virus didn’t trigger long-term immunity from memory B cells. All very complex but basic upshot is that SARS Cov2 is a poor inducer of immunity!
But, let’s assume we do have a good vaccine in the animals, what comes next.
After the animals
Once the vaccine has been shown to be effective in animals it has to be tested to see if it is safe to give to humans in a Phase 1 study or as it is sometimes called “a first in man study”. This is what is occurring in Oxford at the moment…
A small number of volunteers, usually 20 or more, are given the vaccine and then observed to look for serious side-effects. … What could go wrong…? Most of the time there are few serious side-effects (as this has been cautiously determined in animal models, this [safety!] is one of the time extending elements of vaccine production…) but occasionally these effects are dramatic and life-threatening, do you remember the “When A Drug Trial Goes Wrong” from March 2006?
Phase 2 studies
Assuming the vaccine is shown to be safe then Phase 2 studies can begin in order to confirm efficacy as well as safety in much larger numbers of volunteers, several hundreds. Now this is where it gets tricky for something like Covid-19.
In order to assess efficacy then you need to have large numbers of people exposed to the infection that have either been vaccinated or not vaccinated. This becomes a bit of an ethical quagmire. On the one hand you have an infection that could potentially kill someone, so you can’t deliberately expose people to infection, and on the other hand you have a vaccine that could protect people and so it’s difficult to withhold it from people who could catch the infection and die… not easy.
But these types of study can be done after careful consideration of the ethics and clear consent from the participants. These types of study are often open studies of limited numbers of patients and are really there to assess safety in a bit more detail.
What next?
After the Phase 2 study comes the Phase 3 study, where you get to give vaccine to equally large numbers of people, or even into thousands, in order to properly assess how well the vaccine prevents infection. In order to assess this properly and ethically you need a large placebo controlled double-blinded randomised trial… but what does that mean (I know… I know… its … “two orthopaedic surgeons looking at an ECG!” thanks ECIC the “former” orthopaedic physio).
Patients in the trial need to be randomly chosen to receive either the vaccine or a placebo that is indistinguishable from the vaccine. The double-blinded bit means that everyone involved in delivering the placebo or vaccine doesn’t know which is being given; this information is kept secret until the trial is over and the results are being looked at. This is a large logistical exercise and very expensive and time-consuming to perform.
Short cuts! Are they possible?
It is possible to short cut this process slightly with vaccines by conducting Phase 2 and 3 at the same time, enrolling large numbers of patients into the phase 2 study. It still takes a very long time though… many months at least even with a very common infection like Covid-19. And it is no guarantee that the vaccine will prove to be safe or effective. If the vaccine is not safe or effective, then it’s back to square one…
Yes but let’s assume we have our vaccine, what next?
Okay let’s assume that the Phase 3 trial was a success and our vaccine can prevent Covid-19, what happens next?
Firstly we need a large supply of vaccine…
and I mean a LARGE supply of vaccine!
Pretty much everyone in the world is at risk of Covid-19 and without knowing who has had it and who might be immune it is likely that everyone (the World’s population is expected to reach the 8 billion milestone in 2023) would need the vaccine, or at least enough to give adequate herd-immunity.
The current expert opinion is that 70% of the population need to be immune in order to stop SARS Cov2 circulating. If a vaccine is 100% effective then 70% of the population need immunising (that’s only about 47 million people in the UK alone!).
However if the vaccine is only 70% effective then everyone needs it… and that’s 67.8 million people in the UK! Drug companies like Pfizer have apparently already started to scale up manufacture of their experimental vaccine in order to try and get sufficient quantities of vaccine as quickly as possible BUT if their vaccine doesn’t work then they will lose a lot of money. The sceptic in me makes me question if this financial risk might adversely impact the interpretation of any clinical study?! I’d want to see the raw data made publicly or widely available for peer scrutiny but I don’t know if they will do this as a “gesture of global goodwill”.
Added to this, it will still take ages to get millions (UK) and even billions (Worldwide) of doses made.
That’s a massive logistical issue which will take months or years to do. To make billions of doses of vaccine, keep them in whatever careful conditions they need to be kept in (e.g. keeping them cool or refrigerated) and then distribute them to everyone in the World who needs them. In reality this is unlikely to be done. The cost will be high and poorer countries are likely to get a crappy deal, as usual.
Then the Phase 4 study starts! What more trials?
In Phase 4 careful records of EVERYONE who has been given the vaccine are kept in order to ensure it remains safe and effective. This is another logistical nightmare but if the vaccine is shown to be unsafe or ineffective after all then guess what? …yep, back to square one again.
We’ll have a vaccine by next…
So getting a vaccine is not as simple as the vaccine companies or the media would have us believe. It is a major undertaking and will likely take many months or even years to get sufficient immunity to protect us from further Covid-19 infections; my prediction is that a vaccine is probably not going to be available until towards the end of next year at he earliest.
BUT what about strategies 2 and 3? You said we had 3 options!!
Okay, before you start panicking (ECIC aka wife was at “hysterical laughter/crying” stage by this point of the blog… but then she was also in our garden drinking a gin & tonic in our “cacoon” at the time!) or thinking this sounds like too much of a headache so we should just wait for either 2) sufficient people to have had the infection to give herd-immunity or 3) for SARS Cov2 to mutate to become non-infectious… let me rain on that parade as well.
Once you have your mice you can then vaccinate some and not vaccinate others, then you can try and infect the lot (remember SARS Cov2 doesn’t “like” to infect most other things, just us humans) to see if the vaccine protects the vaccinated… simple… or maybe not.
Not all antibodies are equal
Some more bad new! Not every vaccine is effective at preventing infection. Sounds weird but… The vaccine may trigger an antibody response (antibodies bind proteins from an infectious source, identifying them as harmful) BUT these antibodies also need to be able to “neutralise” the virus in order for them to be effective (e.g. stop the virus implanting its RNA).
Guess what? Coronaviruses are poor inducers of neutralising antibodies… bummer! In fact studies of classical SARS showed that some patients with mild infections didn’t produce detectable neutralising antibodies and even those who had severe infections and did produce neutralising antibodies had lost these protecting antibodies within a few years, as the virus didn’t trigger long-term immunity from memory B cells. All very complex but basic upshot is that SARS Cov2 is a poor inducer of immunity!
But, let’s assume we do have a good vaccine in the animals, what comes next.
After the animals
Once the vaccine has been shown to be effective in animals it has to be tested to see if it is safe to give to humans in a Phase 1 study or as it is sometimes called “a first in man study”. This is what is occurring in Oxford at the moment…
A small number of volunteers, usually 20 or more, are given the vaccine and then observed to look for serious side-effects. … What could go wrong…? Most of the time there are few serious side-effects (as this has been cautiously determined in animal models, this [safety!] is one of the time extending elements of vaccine production…) but occasionally these effects are dramatic and life-threatening, do you remember the “When A Drug Trial Goes Wrong” from March 2006?
Phase 2 studies
Assuming the vaccine is shown to be safe then Phase 2 studies can begin in order to confirm efficacy as well as safety in much larger numbers of volunteers, several hundreds. Now this is where it gets tricky for something like Covid-19.
In order to assess efficacy then you need to have large numbers of people exposed to the infection that have either been vaccinated or not vaccinated. This becomes a bit of an ethical quagmire. On the one hand you have an infection that could potentially kill someone, so you can’t deliberately expose people to infection, and on the other hand you have a vaccine that could protect people and so it’s difficult to withhold it from people who could catch the infection and die… not easy.
But these types of study can be done after careful consideration of the ethics and clear consent from the participants. These types of study are often open studies of limited numbers of patients and are really there to assess safety in a bit more detail.
What next?
After the Phase 2 study comes the Phase 3 study, where you get to give vaccine to equally large numbers of people, or even into thousands, in order to properly assess how well the vaccine prevents infection. In order to assess this properly and ethically you need a large placebo controlled double-blinded randomised trial… but what does that mean (I know… I know… its … “two orthopaedic surgeons looking at an ECG!” thanks ECIC the “former” orthopaedic physio).
Patients in the trial need to be randomly chosen to receive either the vaccine or a placebo that is indistinguishable from the vaccine. The double-blinded bit means that everyone involved in delivering the placebo or vaccine doesn’t know which is being given; this information is kept secret until the trial is over and the results are being looked at. This is a large logistical exercise and very expensive and time-consuming to perform.
Short cuts! Are they possible?
It is possible to short cut this process slightly with vaccines by conducting Phase 2 and 3 at the same time, enrolling large numbers of patients into the phase 2 study. It still takes a very long time though… many months at least even with a very common infection like Covid-19. And it is no guarantee that the vaccine will prove to be safe or effective. If the vaccine is not safe or effective, then it’s back to square one…
Yes but let’s assume we have our vaccine, what next?
Okay let’s assume that the Phase 3 trial was a success and our vaccine can prevent Covid-19, what happens next?
Firstly we need a large supply of vaccine…
and I mean a LARGE supply of vaccine!
Pretty much everyone in the world is at risk of Covid-19 and without knowing who has had it and who might be immune it is likely that everyone (the World’s population is expected to reach the 8 billion milestone in 2023) would need the vaccine, or at least enough to give adequate herd-immunity.
The current expert opinion is that 70% of the population need to be immune in order to stop SARS Cov2 circulating. If a vaccine is 100% effective then 70% of the population need immunising (that’s only about 47 million people in the UK alone!).
However if the vaccine is only 70% effective then everyone needs it… and that’s 67.8 million people in the UK! Drug companies like Pfizer have apparently already started to scale up manufacture of their experimental vaccine in order to try and get sufficient quantities of vaccine as quickly as possible BUT if their vaccine doesn’t work then they will lose a lot of money. The sceptic in me makes me question if this financial risk might adversely impact the interpretation of any clinical study?! I’d want to see the raw data made publicly or widely available for peer scrutiny but I don’t know if they will do this as a “gesture of global goodwill”.
Added to this, it will still take ages to get millions (UK) and even billions (Worldwide) of doses made.
That’s a massive logistical issue which will take months or years to do. To make billions of doses of vaccine, keep them in whatever careful conditions they need to be kept in (e.g. keeping them cool or refrigerated) and then distribute them to everyone in the World who needs them. In reality this is unlikely to be done. The cost will be high and poorer countries are likely to get a crappy deal, as usual.
Then the Phase 4 study starts! What more trials?
In Phase 4 careful records of EVERYONE who has been given the vaccine are kept in order to ensure it remains safe and effective. This is another logistical nightmare but if the vaccine is shown to be unsafe or ineffective after all then guess what? …yep, back to square one again.
We’ll have a vaccine by next…
So getting a vaccine is not as simple as the vaccine companies or the media would have us believe. It is a major undertaking and will likely take many months or even years to get sufficient immunity to protect us from further Covid-19 infections; my prediction is that a vaccine is probably not going to be available until towards the end of next year at he earliest.
BUT what about strategies 2 and 3? You said we had 3 options!!
Okay, before you start panicking (ECIC aka wife was at “hysterical laughter/crying” stage by this point of the blog… but then she was also in our garden drinking a gin & tonic in our “cacoon” at the time!) or thinking this sounds like too much of a headache so we should just wait for either 2) sufficient people to have had the infection to give herd-immunity or 3) for SARS Cov2 to mutate to become non-infectious… let me rain on that parade as well.
Strategy 2 - Allow sufficient people to have had the infection to give herd-immunity
It is tricky to determine who is immune to Covid-19, as accurate figures are not available (back to ability to test, see “Testing Times” blog). However it is likely that severe disease occurs in 1.5%, which maybe 10 fold lower than currently thought, as the “real mortality” for Covid-19 when factoring in mild and untested patients is around 0.2% (NB the currents statistics we have available to us do not show mild and untested patients). Even with this low figure, if you apply it to the population of 67 million in the UK then you would see about 1 million severe cases and 134,000 deaths… any volunteers?! It’s just unacceptably high by anyone’s standard. So herd immunity is not our saviour.
Strategy 3 - What about virus mutation?
The good news is that this virus is very stable; it is mutating at incredibly slow rates. It has built-in processes that help protect it from mutation e.g. an effective enzyme called RNA polymerase, and added to this there is no selective pressure to force it to mutate. BUT is this good news?!? Not really because it is already very effective at transmitting between people. It has no requirement to change or to adapt or get less (or more) virulent; it’s happily reproducing effectively in us! Mutation is just not likely to happen… not for many, many years.
So we have to wait for a vaccine, that’s the only real way we can get out of this situation. Now that doesn’t mean we’ll be locked up for the foreseeable future (after all we can’t test a vaccine without people being exposed!) but we are going to have to get used to living differently until that vaccine does come along… but I’ll get to that in Lockdown Part 2…
PS ECIC says having peanuts with her second gin & tonic helped relieve her symptoms of panic! Please note there is no medical science behind this…
It is tricky to determine who is immune to Covid-19, as accurate figures are not available (back to ability to test, see “Testing Times” blog). However it is likely that severe disease occurs in 1.5%, which maybe 10 fold lower than currently thought, as the “real mortality” for Covid-19 when factoring in mild and untested patients is around 0.2% (NB the currents statistics we have available to us do not show mild and untested patients). Even with this low figure, if you apply it to the population of 67 million in the UK then you would see about 1 million severe cases and 134,000 deaths… any volunteers?! It’s just unacceptably high by anyone’s standard. So herd immunity is not our saviour.
Strategy 3 - What about virus mutation?
The good news is that this virus is very stable; it is mutating at incredibly slow rates. It has built-in processes that help protect it from mutation e.g. an effective enzyme called RNA polymerase, and added to this there is no selective pressure to force it to mutate. BUT is this good news?!? Not really because it is already very effective at transmitting between people. It has no requirement to change or to adapt or get less (or more) virulent; it’s happily reproducing effectively in us! Mutation is just not likely to happen… not for many, many years.
So we have to wait for a vaccine, that’s the only real way we can get out of this situation. Now that doesn’t mean we’ll be locked up for the foreseeable future (after all we can’t test a vaccine without people being exposed!) but we are going to have to get used to living differently until that vaccine does come along… but I’ll get to that in Lockdown Part 2…
PS ECIC says having peanuts with her second gin & tonic helped relieve her symptoms of panic! Please note there is no medical science behind this…
RSS Feed
