Hi John, thank you for producing this newsletter. I have found it to be invaluable- most especially given the hyper-politicization of everything these days.
I’m curious to know how much the virus itself, especially in comparison to other endemic coronaviruses in the area of origin?
If the wet market isn’t the likely point of origin, where else might be an area species overlap that would produce a spillover event?
I’m also curious to get your thoughts on variants and vaccine ‘break-through’. I imagine that in the design phase of vaccine development, a highly conserved protein/epitope/antigen would be the target.
are these true break-through events by these variants or is more likely just an issue of variability of vaccine efficacy among individuals?
How much do we know about how these emerging variants differ from the OG SARS-CoV-2?
And lastly, how are viruses speciated? I know offspring viability tends to be the litmus test for organisms, but when does a variant get its own Wikipedia page?
If you’ve answered any of the above before, apologies! And thank you again for your work.
Hi there! I’ve wanted to reply to this for quite some time, but with many developments last week I am only getting to it now.
First, I want to thank you for your kind words. I think there has been quite enough sensationalism throughout this pandemic, with some people trying to capitalize on fear of the emergency, and others trying to capitalize on denying it. I would much rather be led by data. I’m glad that that comes through.
Now to your questions. Your first question, I think, has a missing word. I believe you’re asking how much variation there is in SARS-CoV-2 relative to other sarbecoviruses in Asia. It has a pretty high identity with viruses that have been isolated from bats in Asia, particularly in Southeast Asia. However, it has some unusual variations that were somewhat unexpected. These may have come from recombination with another unknown sarbecovirus in bats, or they may have originated during a passage through some other intermediate animal host. The exact way that these variations arose will be a subject of scientific inquiry for many years, I expect.
For your next question, I have to point something out about your terminology. “Wet market” does not mean what most people think it means. In Asia, there are wet markets and dry markets. Dry markets sell dry goods, in other words, things that are not fresh produce and meats. Things like electronics, fabrics, etc. Wet markets sell fresh food. In the West, we would call them food markets. There is an impression that has arisen that live animal markets and wet markets are the same thing, but they are not. Live animal markets, on the other hand, are tightly restricted in China. The Huanan Wholesale Seafood Market in Wuhan happens to trade in both wet foods and live animals, however. I just think it’s important to demystify the terms here.
Anyway, to really answer your question, species spillover events happen a lot more than you’d think. Humans are constantly encroaching on the habitats of other animals in our search for resources. There are a lot of places where human expansion has put people at an interface with wild animals, and the effects generally do not go in a way that favors the health of the local ecology. Sometimes, however, there is blowback on human ecology as well. In many cases, when diseases transfer from wild animals to humans, it is because of humans hunting those animals directly. And indeed, someone may have been hunting bats. People in the US catch diseases hunting squirrels and other small game, and the same may happen in China too.
People also interact with animals incidentally to other activities. For example, Nipah virus, an incredibly deadly virus that I studied during my PhD, passes into humans from bats during the collection of date palm sap. Date palm sap is harvested much in the same way that maple tree sap is collected; it is then fermented and consumed as a kind of wine. Fruit bats like to eat it too, though, and frequently interact with the harvesting vessels. Fruit bats, particularly the Flying Foxes that carry Nipah virus, are often very large, and have a very careful balance of metabolism, food intake, and flight weight. This means that they tend to extract as much nutrient value from their food as they can as quickly as possible, and then spit out or otherwise excrete what is left, also as quickly as possible. The result is a lot of contaminated stuff that is spat out or otherwise discarded right next to something intended for human consumption. Viruses can transfer to humans by this mechanism. Perhaps something similar took place with SARS-CoV-2, either directly from bats or via an intermediate host.
Yet another option is transfer through an intermediate host in an agricultural setting. After the SARS outbreaks of the early 2000s, China put restrictions in place on interactions with wild animals, particularly for consumption purposes. To satisfy demand for wild animals, a project to raise these animals on farms was started. It is possible that in these wild animal farms, there were opportunities for interactions between bats and the animals being raised there. This is also reminiscent of something that happened with Nipah virus.
When Nipah virus first emerged in Malaysia, it was on a pig farm. The pigs were separated into three different buildings based on their age, and in order to make additional money off of the farm’s land, the owners planted mango orchards nearby to the pig enclosures. The mangos were for sale at market. Fruit bats love mangos, and they would chew the fruit and then spit out the pulp (again, maintaining the all-important flight weight). This led to pulp entering one of the pig enclosures, and bringing Nipah virus with it, where it infected the pigs. There, because of the age-related movement of pigs, the virus was supplied with a steady stream of new susceptible hosts. This allowed it to adapt somewhat to the pigs, and eventually facilitated its transfer into humans. It killed almost 40% of those infected.
I could envision something similar happening in a wild animal farm. Perhaps contact with local bats transferred a proto-SARS-CoV-2 into the wild animal population. There, it may have accumulated mutations that made it better-suited to infect a wider group of mammals, and eventually it may have transferred into humans.
Any of these scenarios is plausible. We will need to learn more in order to assess what happened exactly.
Now to your next question, which is a little easier to answer: No, I don’t think we are seeing genuine break-through events, because real-world data, even in the presence of variants, is showing vaccine efficacy that is aligned with the efficacy seen in clinical trials. While I am somewhat concerned about evidence that B.1.351 may be able to cause mild disease at greater rates in vaccinated people (with the AstraZeneca vaccine, specifically) than other variants, I don’t think that these events represent true defeat of the vaccine. The vaccine in question did not have incredibly high efficacy against overall disease to start with, at least not compared to the mRNA vaccines, and the drop was based on a pretty restricted population. Meanwhile, its stellar efficacy against serious disease and death from COVID-19 was not compromised. So I don’t know if I would call this “breakthrough” per se. Instead, I think we are seeing a vaccine that generates slightly incomplete immunity in many patients, and a variant that can also evade immunity slightly. Put that together and you will see some more cases of mild disease.
I’m not very concerned about this because I believe that infection of a vaccinated person with a new variant is quite likely to make them immune to that variant in short order. Human immune systems are extremely adaptable, and can update their memory of a pathogen to reflect changes that have happened in its antigens since the last time the person was exposed to those antigens.
So far, the variants are not wildly different from SARS-CoV-2 as it first emerged in Wuhan. The mutations that are observed are few in number, though some have clear functional consequences. Several are clearly antibody-evasion mutations, but this handful of changes is not likely to compromise an immune response that is composed of antibody and T-cell responses that target varied and disparate parts of the virus. It may allow the virus to survive a little longer in a vaccinated host, perhaps enough to pass on to an unvaccinated person if they should meet one (making it a good idea to keep wearing masks even when vaccinated), but I don’t expect them to break through immunity enough to give a person serious disease as they currently stand.
For what it is worth, I think this is what happens with many human coronaviruses. We are exposed to them as children and develop decent immunity against them, but over time they mutate. Instead of getting seriously ill when exposed to these new variants, we just get a mild cold and our immunity is updated, until the next new variant is seen. If everything goes right with our vaccine-induced immunity, I anticipate that new variants of SARS-CoV-2 will be like common cold viruses, causing disease to a mild extent in some people, no disease in others, and perhaps severe disease in people who have severe levels of immunosuppression.
Now to the next question...”how are viruses speciated?” As it turns out, viruses are speciated by committee. There is a group called the International Committee on the Taxonomy of Viruses, and they convene groups of experts to examine new sequences and new phenomena in order to decide if viruses have made the leap to becoming separate species. Typically this requires quite a dramatic change, and a lot of the work to decide on a new species is done when some strange isolate is found out in the wild and a debate is needed over whether it is part of an existing species or something new.
For variants, the ICTV decides usually whether they are new strains, or just variants of an existing strain. Strain definition is not as stark as species definition. Viral species are rarely very similar to one another. Strains may have a very high level of similarity, but with key differences. Specifically, there are two sorts of differences that can make a strain: first, it may be immunologically distinct. This means if I am immune to variant X, and I am exposed to variant Y, my immunity to variant X doesn’t prevent me from experiencing full-blown disease. If that is the case, then variant X and variant Y will probably be called strain X and strain Y by the ICTV. Another option may be geographic dominance. If variant X is found to dominate on a specific continent, but is unable to overcome variant Y on another continent, and vice versa, ICTV is likely to declare these to be different strains.
It’s not a very hard and fast distinction; the committee has to make a call in each case.
I'm not a virologist, but my understanding is that we don't speak of viral "species," what with their not being alive and all. (Of course, geologists have been known to speak of mineral "species.")
About that frozen food hypothesis ... transmission by eating doesn't exist. You, IIRC, agreed with that a few days ago. So that's only possible if Wuhan citizens are in the habit of powdering frozen meat and snorting it up their noses. I am confused.
We could make the same points about influenza, but it seems to be happily transmitted from all sorts of surfaces into people.
While COVID-19 has much lower risk of fomite transmission, it is not zero, particularly if the contamination is especially severe. As frozen meat (or other foods) thaw, their properties change.
I don't think it's possible to rule out this mode of spillover. I agree with the report's statement that it is a possible route of origin for the virus entering into humans. I do not think it is the most likely route; the report also indicates that the investigators did not believe it is the most likely route.
Hi John, thank you for producing this newsletter. I have found it to be invaluable- most especially given the hyper-politicization of everything these days.
I’m curious to know how much the virus itself, especially in comparison to other endemic coronaviruses in the area of origin?
If the wet market isn’t the likely point of origin, where else might be an area species overlap that would produce a spillover event?
I’m also curious to get your thoughts on variants and vaccine ‘break-through’. I imagine that in the design phase of vaccine development, a highly conserved protein/epitope/antigen would be the target.
are these true break-through events by these variants or is more likely just an issue of variability of vaccine efficacy among individuals?
How much do we know about how these emerging variants differ from the OG SARS-CoV-2?
And lastly, how are viruses speciated? I know offspring viability tends to be the litmus test for organisms, but when does a variant get its own Wikipedia page?
If you’ve answered any of the above before, apologies! And thank you again for your work.
Kind regards.
Hi there! I’ve wanted to reply to this for quite some time, but with many developments last week I am only getting to it now.
First, I want to thank you for your kind words. I think there has been quite enough sensationalism throughout this pandemic, with some people trying to capitalize on fear of the emergency, and others trying to capitalize on denying it. I would much rather be led by data. I’m glad that that comes through.
Now to your questions. Your first question, I think, has a missing word. I believe you’re asking how much variation there is in SARS-CoV-2 relative to other sarbecoviruses in Asia. It has a pretty high identity with viruses that have been isolated from bats in Asia, particularly in Southeast Asia. However, it has some unusual variations that were somewhat unexpected. These may have come from recombination with another unknown sarbecovirus in bats, or they may have originated during a passage through some other intermediate animal host. The exact way that these variations arose will be a subject of scientific inquiry for many years, I expect.
For your next question, I have to point something out about your terminology. “Wet market” does not mean what most people think it means. In Asia, there are wet markets and dry markets. Dry markets sell dry goods, in other words, things that are not fresh produce and meats. Things like electronics, fabrics, etc. Wet markets sell fresh food. In the West, we would call them food markets. There is an impression that has arisen that live animal markets and wet markets are the same thing, but they are not. Live animal markets, on the other hand, are tightly restricted in China. The Huanan Wholesale Seafood Market in Wuhan happens to trade in both wet foods and live animals, however. I just think it’s important to demystify the terms here.
Anyway, to really answer your question, species spillover events happen a lot more than you’d think. Humans are constantly encroaching on the habitats of other animals in our search for resources. There are a lot of places where human expansion has put people at an interface with wild animals, and the effects generally do not go in a way that favors the health of the local ecology. Sometimes, however, there is blowback on human ecology as well. In many cases, when diseases transfer from wild animals to humans, it is because of humans hunting those animals directly. And indeed, someone may have been hunting bats. People in the US catch diseases hunting squirrels and other small game, and the same may happen in China too.
People also interact with animals incidentally to other activities. For example, Nipah virus, an incredibly deadly virus that I studied during my PhD, passes into humans from bats during the collection of date palm sap. Date palm sap is harvested much in the same way that maple tree sap is collected; it is then fermented and consumed as a kind of wine. Fruit bats like to eat it too, though, and frequently interact with the harvesting vessels. Fruit bats, particularly the Flying Foxes that carry Nipah virus, are often very large, and have a very careful balance of metabolism, food intake, and flight weight. This means that they tend to extract as much nutrient value from their food as they can as quickly as possible, and then spit out or otherwise excrete what is left, also as quickly as possible. The result is a lot of contaminated stuff that is spat out or otherwise discarded right next to something intended for human consumption. Viruses can transfer to humans by this mechanism. Perhaps something similar took place with SARS-CoV-2, either directly from bats or via an intermediate host.
Yet another option is transfer through an intermediate host in an agricultural setting. After the SARS outbreaks of the early 2000s, China put restrictions in place on interactions with wild animals, particularly for consumption purposes. To satisfy demand for wild animals, a project to raise these animals on farms was started. It is possible that in these wild animal farms, there were opportunities for interactions between bats and the animals being raised there. This is also reminiscent of something that happened with Nipah virus.
When Nipah virus first emerged in Malaysia, it was on a pig farm. The pigs were separated into three different buildings based on their age, and in order to make additional money off of the farm’s land, the owners planted mango orchards nearby to the pig enclosures. The mangos were for sale at market. Fruit bats love mangos, and they would chew the fruit and then spit out the pulp (again, maintaining the all-important flight weight). This led to pulp entering one of the pig enclosures, and bringing Nipah virus with it, where it infected the pigs. There, because of the age-related movement of pigs, the virus was supplied with a steady stream of new susceptible hosts. This allowed it to adapt somewhat to the pigs, and eventually facilitated its transfer into humans. It killed almost 40% of those infected.
I could envision something similar happening in a wild animal farm. Perhaps contact with local bats transferred a proto-SARS-CoV-2 into the wild animal population. There, it may have accumulated mutations that made it better-suited to infect a wider group of mammals, and eventually it may have transferred into humans.
Any of these scenarios is plausible. We will need to learn more in order to assess what happened exactly.
Now to your next question, which is a little easier to answer: No, I don’t think we are seeing genuine break-through events, because real-world data, even in the presence of variants, is showing vaccine efficacy that is aligned with the efficacy seen in clinical trials. While I am somewhat concerned about evidence that B.1.351 may be able to cause mild disease at greater rates in vaccinated people (with the AstraZeneca vaccine, specifically) than other variants, I don’t think that these events represent true defeat of the vaccine. The vaccine in question did not have incredibly high efficacy against overall disease to start with, at least not compared to the mRNA vaccines, and the drop was based on a pretty restricted population. Meanwhile, its stellar efficacy against serious disease and death from COVID-19 was not compromised. So I don’t know if I would call this “breakthrough” per se. Instead, I think we are seeing a vaccine that generates slightly incomplete immunity in many patients, and a variant that can also evade immunity slightly. Put that together and you will see some more cases of mild disease.
I’m not very concerned about this because I believe that infection of a vaccinated person with a new variant is quite likely to make them immune to that variant in short order. Human immune systems are extremely adaptable, and can update their memory of a pathogen to reflect changes that have happened in its antigens since the last time the person was exposed to those antigens.
So far, the variants are not wildly different from SARS-CoV-2 as it first emerged in Wuhan. The mutations that are observed are few in number, though some have clear functional consequences. Several are clearly antibody-evasion mutations, but this handful of changes is not likely to compromise an immune response that is composed of antibody and T-cell responses that target varied and disparate parts of the virus. It may allow the virus to survive a little longer in a vaccinated host, perhaps enough to pass on to an unvaccinated person if they should meet one (making it a good idea to keep wearing masks even when vaccinated), but I don’t expect them to break through immunity enough to give a person serious disease as they currently stand.
For what it is worth, I think this is what happens with many human coronaviruses. We are exposed to them as children and develop decent immunity against them, but over time they mutate. Instead of getting seriously ill when exposed to these new variants, we just get a mild cold and our immunity is updated, until the next new variant is seen. If everything goes right with our vaccine-induced immunity, I anticipate that new variants of SARS-CoV-2 will be like common cold viruses, causing disease to a mild extent in some people, no disease in others, and perhaps severe disease in people who have severe levels of immunosuppression.
Now to the next question...”how are viruses speciated?” As it turns out, viruses are speciated by committee. There is a group called the International Committee on the Taxonomy of Viruses, and they convene groups of experts to examine new sequences and new phenomena in order to decide if viruses have made the leap to becoming separate species. Typically this requires quite a dramatic change, and a lot of the work to decide on a new species is done when some strange isolate is found out in the wild and a debate is needed over whether it is part of an existing species or something new.
For variants, the ICTV decides usually whether they are new strains, or just variants of an existing strain. Strain definition is not as stark as species definition. Viral species are rarely very similar to one another. Strains may have a very high level of similarity, but with key differences. Specifically, there are two sorts of differences that can make a strain: first, it may be immunologically distinct. This means if I am immune to variant X, and I am exposed to variant Y, my immunity to variant X doesn’t prevent me from experiencing full-blown disease. If that is the case, then variant X and variant Y will probably be called strain X and strain Y by the ICTV. Another option may be geographic dominance. If variant X is found to dominate on a specific continent, but is unable to overcome variant Y on another continent, and vice versa, ICTV is likely to declare these to be different strains.
It’s not a very hard and fast distinction; the committee has to make a call in each case.
I hope this helps answer your questions!
I'm not a virologist, but my understanding is that we don't speak of viral "species," what with their not being alive and all. (Of course, geologists have been known to speak of mineral "species.")
We do use the term "species" to refer to viruses. Please see here: https://en.wikipedia.org/wiki/Virus_classification
I'll provide a longer reply to the OP in a little bit, just haven't had enough time just yet.
I took microbiology before the classification system changed. Stupid progress!
About that frozen food hypothesis ... transmission by eating doesn't exist. You, IIRC, agreed with that a few days ago. So that's only possible if Wuhan citizens are in the habit of powdering frozen meat and snorting it up their noses. I am confused.
My suspicion is that this would have been fomite transmission from handling contaminated frozen meats.
Frozen meat is sticky. For that matter, raw meat is sticky. I still find it hard to figure out how the fomites get into someone's nose.
We could make the same points about influenza, but it seems to be happily transmitted from all sorts of surfaces into people.
While COVID-19 has much lower risk of fomite transmission, it is not zero, particularly if the contamination is especially severe. As frozen meat (or other foods) thaw, their properties change.
I don't think it's possible to rule out this mode of spillover. I agree with the report's statement that it is a possible route of origin for the virus entering into humans. I do not think it is the most likely route; the report also indicates that the investigators did not believe it is the most likely route.