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So. How do pandemics end? A new brain dump covering that and everything else I think you need to know about Covid-19 going forward. By me. Over an unspecified time. A sequel to this thread (1): https://twitter.com/gnomeicide/status/1225797543797436417?s=19
I'm a microbiologist who's dabbled in lots of other areas of science and technology, but I'm also coming at this as a history nerd. Like, how man and microbe have interacted through history has always fascinated me. (2)
Now the question isn't really as simple as 'where do pandemics go', you've got to understand why and how they propagate before you can answer that. One explains the other. So, why do pandemics happen? (3)
A pandemic happens when a microbe causing a disease can spread worldwide, typically from person to person, and sustain itself within populations. So for a disease to spread like this there has to be infection and spread. (4)
...an epidemic can be far more localised, there has to be spread of a pathogen within a locality but it doesn't for whatever reason spread outside of that area. And yes, there are a whole load of scenarios between 'epidemic' and 'pandemic'... (5)
...a disease can rip through a continent but no further. And this has happened in the past - nature doesn't respect our arbitrary definitions of 'pandemic' and 'epidemic'! (6)
To spread and become a pandemic a disease has to be able to sustain itself in a population. Or people (or plants, or animals...) have to be able to catch it and spread it on. And that seems obvious, but it does mean that some surprising pathogens tend -not- to become pandemic (7)
To go a bit dark for a moment, if a disease kills too many then its spread is limited. When myxomatosis was introduced into Australia to kill off rabbits, a strain that was over 99% fatal failed. There weren't enough survivors... (8)
...it was when less lethal strains evolved that the disease spread. And this is something we see all of the time. It is a terrifying fact of life that the only thing preventing some of the most heinous diseases wiping out millions is the lethality of those diseases themselves (9)
...another thing a pathogen needs to cause a chunky pandemic is not to be too unpleasant all the way through its course of infection. If before or as soon as you're infectious you're on your back then yes, the disease can spread, but its unlikely to spread far and fast (10)
Ebola, for example, takes a few days to take hold. And then you're going nowhere fast - symptoms start like an influenza, but its not one of those 'I've got a bit of a bug' things, its an 'I've fallen down and I'm not getting up' feelings (11)
...and it also needs to be something that can spread relatively easily. Sexually transmitted diseases have ripped communities apart, of course, but they rarely spread all that quickly through communities (except when that community has a distinctive sense of fun perhaps) (12)
So if its spread from person to person by sneezing, touuch, or a common animal vector, thats a big factor in whether it can cause a pandemic. And there's one other really big influence... (13)
...is the disease new to the populations it reaching? Have they any immunity? A new pathogen can spread faster because few have any immunity. And perhaps as importantly few may understand how to stop it. (14)
...when you've assimilated all of these factors, how a pandemic (or widespread epidemic) comes to an end is simple. Either everyone who can die is dead, everyone remaining is now immune, or we have interrupted the transmission of the infection and it isn't spreading (15)
...and we have example of all three of those. Of the three, everyone being killed off is obviously the worst solution. Immunity can either be a great answer (by vaccination), a terrible answer (spreading the disease widely) or a lucky one (a less dangerous mutant spreads) (16)
...whereas interrupting the diseases spread is a great solution but one which requires future vigilance, in case it re-emerges. (17)
In the previous thread I described what happens when a deadly pathogen (or more correctly a lot of different pathogens) hit a new population that isn't immune. It can be horrific. Its no way to end a pandemic if it can be avoided! See (18): https://twitter.com/gnomeicide/status/1225805120522375168?s=20
But thats not the only example of a disease outbreak ending when everyone who is likely to die is dead. In fact we see these repeatedly in history - the Antonine Plague (2nd century) killed 5 million people. The Cyprian Plague (3rd century) killed around 5000 a day in Rome (19)
...those plagues were probably measles and smallpox saying "HI EUROPE! WE HAVEN'T MET!". But we don't entirely know - some say that the Antonine plague was more likely something close to Ebola. I don't agree, I side with measles and smallpox here (20)
...one could even see the Cyprian Plague as the beginning of a slow, messy end for the Roman empire - other than the odd, isolated success it marks the end of the high point of Roman splendour. Yes. Its that important (21)
..anyway, another way you can be left with a resistant population is if there's a mutation in the pathogen that kills fewer. Why would that help? Well its all about competition, and immunity... (22)
...if a pathogen can spread without killing, it can probably infect more people. If you live and spread a pathogen then it does better out of you than if you keep over dead in a couple of days. (23)
...and this is how many -think- that the global flu pandemic of 1918-1920 ended. Spanish flu (which was a flu, but not Spanish!) deaths slowed to a trickle by 1921, as we think less lethal strains evolved, and once you'd caught one of those and got better you were immune (24)
...now the other way that we can get mass (herd) immunity, the proper way that doesn't involve making millions of children orphans and killing off a civilisation changing number of people is to develop a vaccine. Obviously the best example is smallpox, now eradicated (25)
...I don't think a pandemic has ever been stopped in its tracks with a vaccine, and that if we manage to stop Covid-19 with a vaccine while its still causing a pandemic that will be an unprecedented scientific and technical feat of greater importance than the moon landing (26)
...I covered vaccines in the previous thread and I'll come back to them (and where we are now) in good time. But the words 'wow', 'awe inspiring' and 'unprecedented' apply even to the less optimistic predictions. (27)
The best example of a pandemic defeated by quarantine and control was SARS. In 2003 SARS killed about 1 in 10 of those it infected. Nasty little bugger SARS. But through breaking the chain of infection it was defeated. Hard work by scientists and doctors, backed by the WHO (28)
...lets not under-state how important that was. Efforts to stop SARS saved MILLIONS of lives. Break the chain of infection and the disease is beaten. (29)
So... They're your options for stopping a pandemic. You either don't, and hope a less lethal or damaging mutation out competes it (and if it doesn't many, many millions die), you break its chain of infection through quarantine and contact tracing, or you make a vaccine (30)
Yes, clever cloggs, there is another theoretical route out. But no, I don't believe anyone has ever really thought about engineering a less lethal form of a deadly pathogen and releasing it to spread in a population (31)
...at present, at least to the best of my knowledge, the idea of an infectious vaccine is mostly within the realms of sci-fi. I know. It sounds like a great idea. it probably isn't though (32)
...anyway, enough of this for now. Maybe quarantining and what that has to achieve (and why its harder with the new coronavirus than it was with SARS) next. Later, folks. (33)
So. Examples of how these measures have ended pandemics. Breaking the cycle of infection. I have mentioned SARS, and how the efforts of clinicians and scientists saved millions of lives. Wikipedia has a great, well referenced primer (34): https://en.wikipedia.org/wiki/2002%E2%80%932004_SARS_outbreak
...by tracking spread, tracing those who were in contact with those carrying it, and testing and isolating, SARS was stopped in its tracks. SARS is of course a close cousin of the Covid-19 virus - although its nastier, and consequencly less infectious (35) https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome
...although a better example is the unimaginatively named third cholera pandemic of 1846-1860. I know, ancient history, but hear me out - this one is important (36)
...cholera had spread and killed many, many people before but we didn't really know how. May still referred to poisonous 'miasma', the idea that the smell of rot and sewage was somehow the cause and not merely another symptom of the same problem (37)
...and at this stage (1856) along comes a man called John Snow. No, not this John Snow. This John Snow knows nothing.
I'm referring to this John Snow. And if you don't know who he is you should, bevcause he's a goddamn hero. (39) https://en.wikipedia.org/wiki/John_Snow
Snow proved it wasn't some poisonous miasma that caused cholera, he proved it was germ contaminated water that spread cholera and in so doing changed the face of public health forever. By identifying the source of infection, the cycle of infecting more people could be broken (40)
...and led ultimately to cities around the world changing water and sewage management system. If you've never heard of the 1854 Broad Street Cholera outbreak, read this. I don't understate things when I call Snows study of this world changing (41) https://en.wikipedia.org/wiki/1854_Broad_Street_cholera_outbreak
...and ultimately thats what all this isolation we're going through is for. Its like not taking water from the Broad Street pump - we're trying to break the cycle of infection. And when we get to a point where the numbers are containable things change again (42)
We are, if you like, John Snowing it now, and when we get to numbers controllable via. contact tracing and containment then we can take the SARS approach. Do you follow me? There are too many in most countries to monitor closely now. We need to get numbers down to that. (43)
Shouldn't we have caught this when numbers were still low and on the way up, implemented lockdowns then and managed it with contact tracing and quarantining then? Yes. That would have saved lives. Could that have happened politically? That part is outside my area of knowedge (44)
...but I can say that those who try to tell you that they organised a lockdown to coincide with the peak of infection, or that contact tracing is only workable later in an epidemic, thats nonsense. Look at SARS. Thats not how things work (45)
...and I would advise that you should be wary of political types making such statements and always, always come back to the science instead (46)
So, how else can we end a pandemic? Ahh, yes, immunity. Gained by one of three ways - masses of people catching the disease, the disease mutating into a less serious form that out-competes it and we get immunity to it more 'cheaply', and vaccines (47)
...well thats a topic for later, because its a big topic. More soon. (48)
Back again. Is it going to mutate an become less dangerous, we all catch it because then people are just going to get on with their lives? Maybe. Is it instead going to mutate into a worse, dangerous mass killer? Also maybe. The former is more likely than the latter (49)
...a mutation that kills more easily can happen. But if it kills more it isn't likely to spread faster, because except where the body itself is the agent of spreading a disease a dead vector isn't spreading it. Killing is a competitive disadvantage for a pathogen (50)
...now it -can- get more infectious. And there is a legitimate concern that's happening. But it isn't likely that it will get more lethal. (51) https://www.bbc.com/news/health-52557955
...there are not as yet, however, different strains. (52) https://www.standard.co.uk/news/uk/coronavirus-covid19-no-evidence-mutated-deadlier-strain-uk-scientists-a4433606.html
...the thing about mutation that people rarely get is that it just sort of happens. All the time. A very small proportion of mutations are bad for an organism, an even smaller number are advantageous. Most are just sort of there (53)
...remember there's a thing in molecular biology called the Central Dogma. A bit of nucleic acid makes one protein, and we call that bit of nucleic acid a gene. Each gene is hundreds and hundreds of bases (A,T, G and C in us and A, U, G and C in this virus... (54)
...because we use DNA and the virus uses RNA (yes, I know, I'm skipping over things, sorry molecular biologists) so in its nucleic acid it uses uracil instead of the guanine we have in our DNA (55)
...yes, our RNA uses uracil too. But anyway, that code of many, many hundreds or thousands of bases in sequence breaks down into three base triplets. Each three base code means something. There are three base codes for each of the amino acids, there are start and stop codes (56)
...but with 4 bases and 3 nucleotides for each amino acid there's a lot of redundancy when mutations happen. Mutations, incidentally, are literally this nucleic acid sequence being changed in some way... (57)
...so most point mutations, as they're called, where one base is swapped for another, won't do anything to the proteins made by that nucleic acid. Those changes fall into that redundancy area (58)
...and even if they do impact on the protein, even if they mutation changes one amino acid for another, changing the protein sequence at one location, the 20 amino acids used all fall into different families and not all such changes make any real difference (59)
...so to a huge extent the news stories you see about there being 30, 60 or however many mutants of Covid-19 come from a position of not really getting it. Those mutations are usually completely irrelevant to how the virus spreads or kills (60)
...but they -are- passed on. So while or not that much interest from a strict medical perspective they're fascinating from the point of view of a molecular biologist or epidemiologist studying how an organism spreads around the world. (61)
...as the disease moves and picks up these mutations you can follow it's progress this way. (62)
...so is it going to mutate and get less dangerous like we think Spanish Flu did? Maybe. Possibly. Sad truth is that the more people get it, the more people who die, the more likely this is to happen (63)
Bluntly the more copies of the virus there are, the more of it there is, the more mutants there are. Will it happen? Well it happens. But the cost is high. It would be a bad thing to pin our hopes on this (64)
Right, enough for now, got a cup of tea and things to do. I should probably go back to vaccines next. Talked a lot about vaccine development in the last big thread, and there have been a lot of developments since then. I have a question for you all though... (65)
...do you need me to cover the basic types of vaccine first? (66)
Ok. Vaccines. Obviously I went in to why vaccines are epic iny last thread. And they are, they really, really are. But I asked yesterday whether people need an intro to different types of vaccine and the answer is yes. So, here goes. (67)
There are always lots of ways of classifying things. And how you choose to sub-categorise things comes down in part to taste, as well as why you're doing it. Sorry vaccinologists, this is both beneath your level of knowledge and may irritate you... (68)
There are sort of four kinds of vaccines. They exist for different reasons, and I'll explain why for each kind. Firstly, there are live attenuated vaccines. Basically you've got live viruses that are weakened or less active. The advantage is they're really effective... (69)
...like with one dose and a second booster they last for a lifetime. MMR is a great example of an enormously wonderful, successful live attenuated vaccine. The disadvantages are because they're love they need to be chilled, and a tiny minority can't take them... (70)
...which is why herd immunity is very important with MMR. If we go below a certain level of vaccination in any area, the tiny minority who can't take it are endangered needlessly. Just as well MMR has an amazing success and safety record. Shame about the conspiracy theorists (71)
The next kind is inactivated vaccines. A killed virus, with the same antigens creating a similar immune response. Rabies, influenza etc. are done this way. Shelf life is much better, but you don't get such a long immunity, and you therefore need boosters, maybe annually (72)
The third kind doesn't have a good name, and it's not one kind anyway. But I'm going to call it a 'subunit vaccine'. It's part of the coat or outer part of the pathogen, sometimes perhaps stuck to a helper molecule to make it antigenic enough (73)
...now historically they're a big ask. Harder to make, or at least they were. Longer shelf life and strong immune responses are typical. And usually they also work for people who can't take other vaccines. But often booster shots are needed later... (74)
...in a way they're really clever, far more clever than the whole microbe ones because they require such intimate understanding of how antigens are presented. HPV and Whooping Cough vaccines are this kind. (75)
Then you've got toxin vaccines. You have a microbe that itself won't kill you but makes something that will, so you make a vaccine that targets that. You've all had tetanus shots and you keep that up to date with boosters, right? That's the kind of thing we're talking about (76)
"but you haven't talked about DNA vaccines and that's The Future, Cab, get with the 21st Century". Yeah, ok, that is amazing but there aren't any for people yet. If you're interested see (77): https://en.m.wikipedia.org/wiki/DNA_vaccination?wprov=sfla1
...and there are other sort of R&D stage vaccine types like live recombinants. Someone correct me if I'm wrong but they're not a thing for people yet either? (78)
Right that's it for now. Deep breath before delving in to some of the vaccines in development for Covid-19. To say that both the scale and rate of development is amazing here would be an understatement, and I feel like I'm over using the word 'unprecedented'. But more later. (79)
So you know how the existing vaccines used in human medicine work now. And you know they aren't the same, and that some kinds of vaccines work for a year or two and some more or less for a lifetime. And you'll understand that making a vaccine usually takes many years... (80)
...so, take a deep breath. Vaccines for Covid 19. Deep dive time. At last count we were up to 115 different vaccines in development around the world. A staggering number working by some of those traditional means and a bewildering range of next generation technologies (81)
...big pharma, small pharma, biotech companies, academic labs, governments, the WHO and other international bodies have thrown the kitchen sink at this problem with the goal of compressing the time taken to develop a vaccine from years to months...(82)
There are around 10 vaccines in clinical trials. Traditionally Phase I rials are to make sure something is safe, and Phase II are to make sure it works. In the first stage you make sure no one is made desperately sick, then you test to see if antibodies are being made (83)
...but there is also something called a Phase I-II trail where both are done together. About 5 of the trials so far are in Phase II or Phase I-II, meaning that we will start getting clinical data on their efficacy between May and November. (84)
Now it sounds like this is a crazy number. But remember we have never had a vaccine against a human coronavirus before. And a lot of vaccines fail in development - only 10-20% of vaccines researched work (85)
And they can fail for all sorts of reasons. Not effective enough, create too many adverse reactions in patients, have problems with allergenicity, don't create immunity that lasts long enough, etc. And it takes years and can cost hundreds of millions to find this out (86)
...so when I say that many billions are being raised to compress research and development into months rather than years and that this is unprecedented, that regulators are doing whatever they can to safely shorten the pathway to a new drug, I'm not overstating this (87)
...so is this the way out? Well I initially predicted that November would be the earliest this might be possible but that a vaccine delivered next year would still be a miraculous innovation in the time. (88)
And I stand by that. But, still, wow. (89) https://www.bbc.co.uk/news/amp/health-52329659
But what you need to know? This isn't the way out of lockdown in the short term, but it's a way to return to full normality in the longer run. And while we may get -a- vaccine soon it may but be -the- vaccine... (90)
...if we get a vaccine that's 60-80% effective in the short term that works for a year or two, that would be an enormous win here. If one of the 114 other vaccines in development comes later and vanquishes this virus, that's fine. We can in that scenario wait (91)
Ok. Enough for tonight. Wondering about a deeper delve into other research next. Sound good? (92)
Ok. More research hilights that I think you need to know about. Firstly, way back I talked in the other thread about some reports of people getting reinfected. You may recall my take was "maybe, probably not, wait and see". (93)
...I might also have mentioned (because in some ways I'm an old fashioned microbiologist) that one of the problems with modern PCR based diagnostics is they don't readily differentiate between live and dead pathogens... (94)
...so if you've got a load of dead virus particles hanging around, and a stupendously sensitive diagnostic test that detects them, you'll detect the dead ones and get a false positive (95)
...but if that rest is a bit fiddly to do and human error can mess it up (and rtPCR is certainly that) you'll also get a lot of false negatives. Meaning the diagnostic test, while amazing, has drawbacks. Like all diagnostics do (96)
...well here you go. Not to brag or anything (because any microbiologist could have told you that), but I was right. (97) https://www.livescience.com/coronavirus-reinfections-were-false-positives.html?utm_source=Selligent&utm_medium=email&utm_campaign=9161&utm_content=LST_Newsletter+&utm_term=3481463&m_i=G3e6Fdxk5hAKyhgR7s2GNgsUlRpfbCg8mAB3oMd_PN4KKnVLnfyEqaYGr0dzqCXNcR1H%2BjTyjJZzkY8VoxmlvTb55fTBgGwVvUR2JPOGGt
...we don't know what this will look like a year from now. But Covid-19 virus is mutating slowly, it isn't forming news strains (at least not yet) but reinfection remains unlikely. This is of course excellent news, for two reasons. (98)
...firstly, it means outbreaks eventually end, the same virus doesn't keep going round and round. Secondly, it means that at least for a period of time there is immunity - so a vaccine of some sort should work. (99)
Another thing that we touched on before was how many people have had it, and we need serological testing of representative populations to know that. Long words, brief explanation (100)
...you take a proportion of the population, test to see how many have antibodies against the virus, multiply that up and from that you know how many have been exposed. And we are starting to see that now (101)
...and it is as we expected. Far more people get it than are tested positive. But -nowhere near enough- for this to be a route to herd immunity. For example here 2.7% of those in Kobe had antibodies to it. Statistically irrelevant for herd immunity (102) https://www.medrxiv.org/content/10.1101/2020.04.26.20079822v2
...that's your lot for now. More later. Maybe either looking at the state of research in drug therapy, or something else. Will see what looks most interesting. (103)
Ok, so I've been pitching these threads as 'what you need to know about Covid-19 today, and in this second thread I've been talking mostly about how pandemics end and how the routes out of this may emerge. I'm broadening this out a little (104)
...because it occurs to me, now I think about it, that there are things that we need to consider coming out of this. And one that I've just been talking to someone about is Legionnaires disease. It could very well bite us in the ass here... (105)
...Legionella bacteria are weird, with truly odd ecologies I won't explain in detail - but they survive and grow in the cool, near still water of buildings where no one is going in and running the taps and air conditioning (106)
Don't just take my word for it - building managers across the world are going to have to take note or A LOT of people will die (107) https://www.reuters.com/article/us-health-coronavirus-legionnaires/buildings-closed-by-coronavirus-face-another-risk-legionnaires-disease-idUSKCN2261AO
...this is especially true when a lot of people who have suffered from Covid-19 go back to work in buildings that might be swamped with legionella. The numbers might be genuinely frightening. (108) https://www.escmid.org/research_projects/study_groups/legionella_infections/
Also in the 'what you need to know about Covid-19' category, news from Wuhan is that yes, the disease can re-emerge when it seemed to have gone. And the scale of the response necessary to be absolutely on top of this is staggering (109) https://edition.cnn.com/2020/05/12/asia/wuhan-coronavirus-testing-china-intl-hnk/index.html
In this and the preceding thread the word 'unprecedented' keeps coming back, but the intention to do full rtPCR testing followed by serology where necessary in 11 million people in 10 days is, again, unprecedented (110)
...and one has to wonder at the impact of both false negative and false positive tests, even if normally rare (which anecdotally they are not), might have in such massively parallel data analysis. (111)
...in other news, because life just isn't fair and Yemen clearly hasn't suffered enough already, Covid-19 is compounding what is already a humanitatian disaster (112): https://www.mercurynews.com/2020/05/11/coronavirus-yemen-declares-aden-an-infested-city/
...and sadly in 'that was predictable but its still tragic' news, Brazil has become a hot spot for infection... (113): https://www.saude.gov.br/noticias/agencia-saude/46872-brasil-registra-177-589-casos-de-coronavirus-e-72-597-pessoas-recuperadas
...Chile has gone to the World Bank for assistance as healthcare reaches a state of near collapse... (114): https://bajio.telediario.mx/internacional/sistema-de-salud-llega-casi-al-limite-en-chile-por-coronavirus
...and if we needed another reminder, we are once again forced to see that stigmatising people for their sexuality will come back and haunt a society, no matter what your beliefs are it isn't the right answer to any question, at any time (115): https://www.forbes.com/sites/alexandrasternlicht/2020/05/12/with-new-covid-19-outbreak-linked-to-gay-man-homophobia-on-rise-in-south-korea/#32305ecf4909
...meanwhile the hunt for drug treatments continues. No, this doesn't mean taking chlorquinine (covered with suitable and it turns out correct skepticism in my previous thread). It means that trials are being conducted across the world. Such as (116): https://pharmafield.co.uk/pharma_news/covid-19-drugs-trial-rolled-out-across-uk-homes-and-communities/
...and you may also recall that I've been covering the adaptation of existing drugs based initially on in silico analysis since the outset, and where this has taken us is to several drugs now being trialled. Such as (117): https://uk.reuters.com/article/us-health-coronavirus-japan-medicine/a-tale-of-two-japanese-drugs-in-tests-to-fight-covid-19-idUKKBN22O3DC
Oh, as its an infectious disease and you can catch it, it would serve you better if everyone who gets it can afford drugs they need. Drug development is incredibly expensive, and that (among other things) can lead to expensive drugs. Thats a problem. (118) https://www.theguardian.com/world/2020/may/11/soaring-drug-prices-could-bar-access-to-future-coronavirus-treatments
