Blog Posts - Mridul K. Thomas

ecology - statistics - phytoplankton

23/04/2021

24/4/2021

The situation in India: 300k cases and 2000 deaths recorded per day and rising rapidly. Perhaps 10 times that number in reality, maybe more. The deceased being burnt in parking lots because there is no space for cremations. People dying in waiting lines outside hospitals, and inside crowded emergency rooms/ICUs because supplies have run out. Families desperately begging on social media for help in finding a hospital bed, an oxygen cylinder, or a drug that somebody has told them will cure their dying kin.

This is why so many of us were yowling since early last summer that every damned vaccine needed to have accelerated review and approval if it was even moderately protective. That we needed to plough mountains of money into creating manufacturing capacity even though many of the vaccines would not work out. That the months wasted on following standard review protocols were prioritising arse-covering over saving lives - possibly millions of lives. That slowing the whole vaccination process over every possible rare side-effect in the hope of maintaining faith in the system was dooming many to a horrible death while simultaneously wrecking confidence in vaccines globally, even in places without much prior antivax sentiment.

There's plenty of blame to go around for this present crisis. Pride of place certainly goes to the utterly incompetent and vile Indian government. But the US has made things worse by stopping the export of basic material needed for vaccine manufacturing. This has slowed down the rest of the world's ability to produce vaccines even as the US imports materials for its own vaccination program. If you can make your voice heard in the US about this, please urge your government to fix this!

06/04/2021

7/4/2021

It's all still quite uncertain, but more evidence has been accumulating that there is a very rare link between the Oxford/AstraZeneca vaccine and a combination of blood clots throughout the body + low platelets (the cells involved in clotting, so this seems contradictory and is quite weird).

By rare, I mean something like 1 per 100,000 vaccinated people seem to develop this reaction. That proportion is also quite uncertain; it could be closer to 1 in 20,000 or 1 in 1,000,000. A high proportion of the small number of cases studied have died. This may be in part because the blood thinners sometimes used to treat symptoms such as these could actually make this particularly rare condition worse. So understanding this means that we may be able to save many more people who develop this reaction by treating more appropriately.

Even if this reaction turns out to be caused by the vaccine, the risk of dying of Covid is way, way higher - maybe thousands of times higher for the elderly. And vaccinating people also prevents Covid spread. So giving the Oxford/AstraZeneca vaccine to people (especially old people) definitely saves many lives, and I still think Europe should not have stopped using it while we figured this out. And that we should keep using it in much of the world where better options are not available.

But there are places (New Zealand, Australia, etc) where case loads are so low that it's reasonable to pass on this vaccine and wait for better ones, assuming this risk is real. For young people in other places, the risk of dying from Covid is so low that it's also somewhat reasonable to skip this vaccine in favour of others. But if other vaccines are not available right now and skipping this means they have to wait, it will likely lead to more infection spread and more deaths overall; a tough choice.

^This is all heavily hedged because we still don't know this stuff with much confidence.

15/03/2021

16/3/2021

You probably know that many European countries have suspended the use of the Oxford/AstraZeneca vaccine. This seems to be a panicky, unjustified reaction based on incredibly limited evidence. About 40 people have experienced some clotting out of >10 million doses administered. The numbers are very similar for the Pfizer vaccine, which remains unquestioned. And these numbers appear to be about what you'd expect if you monitored 10 million random mostly elderly people for a few weeks. If you apply extreme scrutiny to big numbers of people without a reference or control group, you will see all kinds of patterns that don't really mean anything. Even if the vaccine does increase the risk of clotting, it does so by a minuscule amount while protecting you from a still-burning pandemic.

European governments continue to screw this up badly. I assume they think that suspending vaccinations because of 'concerns' while they 'review the situation' makes them seem responsible and makes people trust the system more. I suspect they are wrong and that they are fatally undermining the painfully limited trust that their citizens already have. Incidentally, this has happened before; we lost the first ever vaccine for Lyme disease in the 90s because of a loss of trust:

"The clinical trials for the vaccine showed that arthritis occurred at similar rates in both the vaccine and placebo groups. But media reports and suits by plaintiff’s lawyers led to fears among members of the public. Even after a panel of outside advisers to the FDA voted that the vaccine’s benefits outweighed its risks, sales fell so low that the company withdrew the vaccine from the market" (Story from here: https://www.statnews.com/2021/03/15/the-curious-case-of-astrazenecas-covid-19-vaccine/ )

The Oxford/AstraZeneca vaccine isn't the best available. But it is effective (I'd take it if I could), Europe is short of vaccines, and it is seeing a variant-driven surge. This is not helping.

I'd also like to remind you that the US and Europe are sitting on tens of millions of Oxford/AstraZeneca vaccine doses that they are not using while abusing intellectual property law to prevent poor countries from manufacturing vaccines for their citizens.

11/02/2021

16/3/2021

The UK variant B117 was first noticed in early December. It became major news by mid-December and several countries shut down travel links by the 20th.

By that date, it was already in at least 33 countries (now in 81). We desperately need more sequencing and better monitoring.

02/02/2021

2/2/2021

Re-upping this weekend Covid post explaining variants, mutations and how the virus' evolution is likely to play out. The past couple of days have brought bad news that unfortunately bear out predictions from some recent posts.

New cases of the UK variant B117 show it has evolved further and has mutation E484K (see post). This mutation probably makes our antibodies (from existing vaccines & earlier infection) somewhat less effective against the virus. E484K is a major reason why the South Africa variant B1351 is such a threat, and we need to worry about this new mutated B117 for the same reason. It appears to be very rare right now (known only from a few cases in the UK) and I hope we can eradicate it. But we sequence very little, so similar evolution may be happening in other places and we wouldn't know.

Also, more evidence accumulates that the UK variant is more lethal than earlier ones, with about a 65% increase being most likely.

Vaccines ARE still effective, especially in protecting against severe disease and death. Get vaccinated as soon as you can.

31/01/2021

31/1/2021

Here's the second of two back-to-back Covid posts focussed on vaccines and evolution. The first part can be read at https://www.mridulkthomas.com/covid/30012021-part-1.

Some parts of this post are moderately speculative and based on a general understanding of evolution and not a deep understanding of viruses. Take with a pinch of salt, and I welcome criticism of these thoughts.

Terminology:
I will refer to three mutations: N501Y, E484K and K417N.
And to three variants of the virus: the UK variant (B.1.1.7), the South Africa variant (B.1351) and the Brazil variant (P.1). I'll skip the dots and say B117, for example.

1) Mutations happen spontaneously when nucleic acids like DNA and RNA are copied, because the process is imperfect and some of those copies have errors (to oversimplify a bit). Most mutations tend to be very bad for the organism (I mean the virus) because they stop some part of it from working and many parts are necessary. These mutations are immediately 'lost' because the organism (the virus) cannot reproduce itself, so we never get to see these mutations that are damaging to the virus even though they are the majority. A small number of mutations will tend to be only slightly bad; they will arise and then slowly die out over a few generations because they are less good than their relatives without the mutation. Some mutations have no real effect and just get passed on without changing anything. A very tiny proportion can make the organism better (for the virus that is, it would be worse for us).

2) This is a bit more complicated with a new virus like this one. An organism that has been around for a long time has evolved and adapted to its environment. Evolution never stops, but the easy adaptations - the simple changes that cause big improvements - have already happened, and so it's extremely rare for a mutation to help much. But a new virus has not had the time to do that. It's suddenly experiencing a totally new and different environment after many generations of adapting to life in bats. So there are many more possible ways for it to get better at growing and spreading in humans (that is, make it worse for us), and the number of possible mutations that can help it get better is likely to be much larger. We are very lucky that this virus mutates quite slowly. We've had hundreds of millions of infections so far and perhaps trillions of virus particles generated, but only a tiny handful of mutations have arisen that have clearly helped the virus i.e. made it worse for us.

3) We cannot rely on evolution to make this virus safer for us. A common but incorrect idea is that the virus will necessarily evolve to become less deadly over time. There is some evolutionary logic to this notion. A dead host cannot transmit the virus, the thinking goes, so variants that are less likely to kill their hosts should be more successful at being transmitted. These variants should therefore take over from more lethal ones. It's a nice story but there's little evidence that this happens in other viral diseases. And even the logic fails completely with Covid. The reason is that people infected with Covid pass on the virus mostly within the first week of their infection. If they die, it happens about 2-3 weeks after that. So whether the infected person lives or dies does not affect transmission of the virus. Evolution will not necessarily push the virus to become less lethal because it does not even 'see' whether the infection was lethal or not. It might become less lethal. But the opposite is perhaps equally possible: the virus could evolve to become more lethal. There's a small amount of evidence from the UK that this has happened. People infected with the UK variant there are thought to have a death rate that was 30% higher than previous strains (more evidence needed to be confident in this). I should note that a possible 30% increase in the probability of dying from Covid is very bad news, but it's not as terrifying as it sounds at an individual level. It's about how much worse your risk of dying from Covid would be if you were ~2 to 3 years older.

4) Of the many mutations we have seen in the viruses we have sequenced from around the world, the most noteworthy right now are mutations N501Y, E484K and K417N. You'll probably hear more about them in the next few weeks. The names denote the position and nature of the change in a protein. For example, N501Y means that a mutation changed the amino acid at the 501st position on a protein from asparagine (symbol N) to tyrosine (symbol Y). All three of these mutations alter a specific part of the 'spike' protein that the virus uses to attach itself to our cells. Some of our vaccines are designed specifically to elicit antibodies from us that will attack this protein in the virus. This is because it's a distinctive target (different from other viruses and antigens), the virus needs it to have a particular shape to attach to our cells, and because of this it probably evolves more slowly than other parts of the virus. But this protein has evolved in several virus variants, and the changes have had a variety of effects.

5) To simplify some terminology: a variant / lineage / strain is a group of viruses that have descended from a common ancestor and share similar sets of mutations. If new mutations arise in a variant that make it seem different enough, then we deem the viruses with those new mutations a new variant. We give the variant a new name, just like we name strains of wheat or rice. But the way we name virus variants is dizzyingly complicated and unintuitive. There are multiple scientific names, and some of them are named after important mutations (which can occur in multiple variants, remember). So the 'UK variant' is also called B117 by some scientists and 501Y.V1 by others. Geographical names are considered bad because they can lead to negative publicity for the associated place. But the alphanumeric gibberish of B117, B1351 and B11248 (renamed P1) is incomprehensible at a time when we desperately need clarity. In the future I think we should name these like hurricanes or after random objects (apple/banana/cantaloupe). For now I would stick with the geographical names for simplicity.

6) From some fantastic lab studies, we have a pretty good understanding how some mutations have caused a few variants to spread more quickly. The mutation N501Y evolved independently in all three variants we are most alarmed about - the UK variant B117, the South Africa variant B1351, and the Brazil variant P1. Remember that mutations arise at random, so the fact that this one arose independently in 3 variants that all spread more rapidly is strong evidence that it matters a lot. We know even more: N501Y probably increases transmission rates because it makes the virus better at attaching to our cells. Another mutation E484K is present in the South Africa and Brazil variants and is the most concerning of the mutations we understand. Among other properties, E484K appears to give the virus more protection against antibodies (our own or manufactured monoclonal antibodies). This makes our vaccines less effective against variants with this mutation and probably also makes reinfection with these variants more likely. This may be true of another mutation K417N as well, which is also present in both the South Africa and Brazil variants. It's possible that E484K spread quickly because it allowed variants with this mutation to reinfect people who had already had Covid from earlier variants (quite uncertain, under investigation). There are many more mutations that we don't understand quite as well as these three. They likely modify how the main mutations mentioned earlier work. For example, N501Y has arisen in some other variants that don't seem to spread faster - so it's possible that it needs to be combined with some other mutations to help the virus, or that the combination helps them a lot more than N501Y by itself. The opposite is also possible; some mutations may make N501Y less helpful to the virus. We still don't understand these combinations well, and they will matter in the near future.

7) I want to highlight the distinction between mutations and variants, and explain why we are worried about both. The same mutations can occur in multiple variants, either because it arose independently or because they inherited it from a common ancestor. The mutations I talked about above evolved independently in the UK, South Africa, and Brazil variants. Each of these variants also have other mutations that make them distinctive. The South Africa variant B1351 has the mutations N501Y, E484K, K417N and several more that we do not understand well. We keep track of which geographic regions some specific mutations are found because we know that they make the virus more dangerous to us. It is useful to know, for example, that E484K is found in most of the viruses in a country - people there may have less protection against the viruses they face. But because we don't understand many of the mutations well, we also need to track variants that are more dangerous; they may possess a particularly potent combination of mutations. For example, we know that the South Africa variant B1351 spreads faster and that we have less protection against it from vaccines, even if we don't fully understand all the mutations that cause that to happen (E484K is part of the story but probably not all of it). The next few months are going to involve plenty of discussion both of new mutations and new variants. There will be new variants that arise that have some of these same mutations as well as new ones. We will have to worry about these new variants, but we don't know how much to worry because we don't know about how the other mutations they will carry affect the virus. And there will also be new mutations that arise in some of these existing variants, which may lead to them being designated new variants - just like a single species of mammal can over time split into multiple species that we will give separate names.

8) Now that large numbers of people have been infected in many places, and we are ramping up vaccinations, many more people will have some immunity against the virus. This is a tremendous change in the evolutionary landscape. I expect to see the rise of a broader range of mutations & variants as a consequence. Why? Mutations that earlier may not have increased the spread of the virus much could now make them more successful (i.e. worse for us). Many mutations probably exist which earlier may not have conferred much benefit to the virus and may even have made the virus worse (which would be good for us, and would lead the mutation to die out). But if these mutations allow the virus to get around our antibodies (whether from a vaccine or previous infection) even partially, they now confer a huge advantage for the virus. Imagine a change to shape of the protein that the virus uses to attach to our cells. You could imagine a change that makes it slightly worse at attaching to our cells. Normally this would make it less infectious than background Covid strains and so viruses with this different protein would die out. But if the new protein shape is different enough that it is not 'recognised' by our antibodies, this mutation will now confer a huge advantage to the virus and will spread. It's possible that E484K spread because of this. It is not likely to be the only such mutation - we should expect to see many more in the coming months.

9) I want to reiterate that vaccination is going to massively improve our situation, and fast. Despite the spread of these variants, we should be able to get deaths down to negligible numbers in developed countries in months by doing this, and life will start to return to normal there. But developing countries will wait much longer for vaccination because of terrible planning: we have failed to build the manufacturing or distribution capacity needed to vaccinate a large chunk of the world's population quickly, and we should have. This is not even a moral argument. It is in the interest of rich countries to speed up vaccination in poor ones because large, partially-vaccinated populations will be a reservoir for evolution of variants that can return to rich countries and possibly evade their immunity then (again, this is fixable with updated vaccines, which can be designed quickly).

10) What can you do? Get vaccinated as soon as you can. Wear good masks (N95/KN95/FFP2) from now till at least a couple of weeks after your vaccination. Once you're vaccinated, you still might want to be a bit careful for a while. I will probably wear some mask in crowded or indoor spaces till cases are very low. But I think people who argue you should continue isolating as before even after vaccination are out of their minds. Go hug your friends and family once you've got some immunity. I sure as hell will.

30/01/2021

30/1/2021

I've been busy working on tracking Covid variants with Brooks Miner (www.covidvarianttracking.com & @CovidVariants on Twitter) so haven't written a Covid update in a while. Here's the first of two back-to-back posts focussed on vaccines and evolution. I would strongly advise you to get any vaccine you have access to, with strong caveats for the Bharat Biotech Covaxin vaccine in India (zero data, shady govt. practices), and weaker ones for the Chinese & Russian vaccines I discussed a few weeks ago (some data available, seems okay if it is reliable):

1) What you probably already know: the UK variant and the South Africa variant spread substantially faster than background strains - somewhere between 30% & 70%. A Brazil variant with some of the same mutations probably spreads at a similar speed. The UK variant has increased rapidly in Denmark, Ireland, Portugal, and now Switzerland - the picture has been pretty bad in these countries in recent weeks. Check our maps at the link above and you see cases of it have been detected in most parts of the world. Though many are from travellers, it's too late for many/most countries to avoid outbreaks. But where it is still at low frequency, there is probably a 2-4 month window before this variant (or one of the others) forms the majority of cases. The South African variant is also being detected much more widely now, with many more cases from African countries (which generally have poorer genetic surveillance systems in place) and clear signs of community transmission in the US. The Brazilian variant P1 seems to be wreaking havoc there but has not really spread outside it yet - as far as we know.

2) What you can do: distance yourself even more strictly for now, and get better masks. Buy yourself N95/KN95/FFP2 masks without valves and wear them. If you don't have access to these, wear multiple layers of masks. Before we got our FFP2s, we were wearing cloth masks on top of surgical masks for some additional protection.

3) These variants and similar ones will likely cause an increase in case loads in many countries that are lagging on vaccinations (most of them). This is NOT inevitable! The UK & Ireland were the countries worst hit by these faster-spreading strains - and they have seen cases decline rapidly since they put in place additional protection measures. It's still possible to control this, and we must do everything we can to. The vaccinations give us an additional edge in this race, but the same old measures - masks, distancing, quarantines - are sufficient if done well.

4) We have data on 2 new effective vaccines (Novavax, Johnson & Johnson) but there are good reasons for concern in the medium to long term. These new vaccines have been tested recently and we can evaluate their performance against the new variants. Both are very effective against most Covid strains but Novavax is slightly less so against the UK variant B117 (~85% efficacy vs. 95% for older variants). Both also considerably less effective against the South African variant B1351: approximately 60% instead of 90% for Novavax, 60% vs.70% for Johnson & Johnson (the values may be more similar for serious infections). We've had good reason for some weeks to think that antibody responses against the South African & Brazil variants are less effective, and this shows that those reductions matter in the real world. It also probably means that all the other vaccines will also offer less protection against at least these two variants, as well as others that are not yet on our radar. Yet again, there's been misleading public health messaging around this, I'm afraid.

5) 60% effectiveness is very good and you should definitely get vaccinated! And the protection against serious infections seems even better (if you fall ill, it appears to be milder). If the virus could not evolve any more, a 60% reduction in infection rates everywhere would end the pandemic. But they will continue to evolve (see next post about this). If 60% reflects vaccine effectiveness now, additional evolution should reduce that number as more mutations arise in these variants. At least some of those mutations will make the virus even better at getting around our antibodies. Vaccine makers are creating new forms of the vaccine that will specifically target the mutations in the new variants. The mRNA vaccines from moderna and Pfizer/BioNTech are particularly good for this - they can be retooled in weeks. But it's a moving target and our vaccine manufacturing and distribution capacity (not to mention our political and administrative capabilities) lag well behind the viral spread.

6) [Warning: speculation] If antibodies from the vaccines are less effective against these variants, it also seems likely that antibodies from an earlier Covid infection will be less effective. Immunity is about more than antibodies and reinfections are rare now. But I would expect that getting infected a second time will be more likely with the new variants.

7) I want to underscore that we can get ahead of this and avert much loss of life from these variants in developed countries at least. Remember that an infected 80-year-old is 100 times more likely to die than a 40-year-old, and about 1000 times more likely to die than a 20-year-old. If countries prioritise the most vulnerable populations (basically the elderly) for vaccination, then they should avoid most deaths even if the variants continue to spread. This would be a massive success and is actually quite likely. Israel has given nearly 60% of its population at least one dose! The UAE is at about 30%. The UK about 12%. The US is at 8% despite its very public failures on many counts. The EU is lagging badly at 2.5% and has been hit by a string of bad news, with many expected vaccine deliveries being delayed. All these numbers are way lower than they would have been if governments had reacted competently, but they still represent real and important progress. I expect to see rapid declines in deaths in the next few weeks starting with Israel and the UAE, but also the US and the UK, partly driven by vaccination and partly because the deaths caused by the Christmas travel will fade out soon. We might see flare-ups again because of these variants, but I would expect deaths in most of these places to remain low even if infections rise again because the elderly will be vaccinated.

8) The medium-term outlook (~few months) is more scary in the developing world, which is at the back of the queue for vaccines. Most African countries have not started vaccination because they could not pay as much as developed countries. They are not expected to make major progress on vaccination till 2022, and some might take till 2023 to complete. There has probably been large-scale underreporting of cases and deaths from many of these countries, and the rise of fast-spreading variants could quickly drive new outbreaks even in countries that have controlled their spread (and many developing countries have done so, which should shame the developed ones).

9) The long-term outlook is complicated because a pandemic that is still out-of-control in some parts of the world threatens even those parts that have been vaccinated. Every outbreak offers more opportunities for evolution, which you cannot stop. The best way to avoid this mess was to not give the virus trillions of opportunities to mutate and therefore 'find' some of the rare mutations that help it. In other words, stopping the pandemic early on. That ship has sailed. The next best is to reduce community transmission now so that in addition to vaccination, we deny the virus opportunities to accumulate new mutations that will help it spread in the face of antibody defences. It will be impossible to sustain this effort for another 2 years while we get every developing country vaccinated. In that time, additional mutations will quite likely arise that will lead to variants with a stronger ability to evade our antibodies re-entering developed countries (see next post).

10) It therefore continues to be overwhelmingly valuable even for developed countries to invest in production facilities for vaccines. And in optimising the entire supply chain. The reason why some places got 6 doses instead of 5 from their Pfizer vials is that they were using special syringes that wasted less liquid - how many lives can we save by producing more 'low dead space syringes'? We are not in the endgame yet and the benefits of these investments outweigh the costs by several orders of magnitude. One estimate is that moderna & Pfizer will earn about $10 billion from the vaccine; the economic losses due to Covid are so far in the region of $5 trillion. Just give them all more money to make more and faster. I'm astounded that the EU delayed vaccines by - among other things - negotiating strongly for lower prices and for manufacturers to be held liable for problems.

21/01/2021

30/1/2021

The new Covid variants are alarming. Brooks Miner and I build a dashboard to track the spread of the major ones: http://covidvarianttracking.com. We plan to update this daily.

I don't think there's a similar tool out there, so please do share this with anyone interested.

Features to be added soon: the proportion of new cases in a country caused by each variant, percentage of the population vaccinated, and how long it should take for the fast-spreading variants to dominate in new cases.

11/01/2021

12/1/2021

Daily cases were going down in most Swiss cantons in December. If variant B117 takes over, every canton would likely see daily cases start to rise again. This might hit us hard in 1-2 months if we don't do a lot more to control spread now.

From Brooks Miner & me: https://public.tableau.com/profile/brooks.miner#!/vizhome/Coronavirus_effective_R_Switzerland/SwissMaps

09/01/2021

12/1/2021

If the UK strain B117 spreads internationally, it probably means large increases in Covid case numbers worldwide in 1-3 months, including in many countries that have the pandemic under control now.

Brooks Miner and I put together a simple visualisation of what the global situation would look like if B117 replaced existing strains (already happening in England, Denmark & Ireland): https://public.tableau.com/profile/brooks.miner#!/vizhome/Coronavirus_Effective_R/WorldMaps

So now we're in a race to vaccinate as many people as we can before this gets out of control. Talk to people you know about how safe the major vaccines are and how important it is that they get vaccinated ASAP. Spread the message (feel free to share the maps linked above) that we need to vaccinate as quickly as the vaccines can be produced.

Why I did this

I am not an expert on Covid, viruses, or vaccines, but I am a scientist with relevant training. I believe we have a responsibility to clearly communicate science to the public, especially in emergencies. So I started to write summaries of Covid developments on facebook in March 2020 to help friends and family understand the situation as it unfolded. This is an archive of those posts (created much later).

I also tracked the spread of alarming Covid variants for a few months at http://covidvarianttracking.com/ and mapped the consequences of faster variant spreading at https://tabsoft.co/2YwHCmZ.