COVID-19 Chapter 14: Virology, Take 2

She was admitted and began aggressive treatment with high low oxygen. Due to COVID precautions, we were not allowed into the hospital and had to communicate with her through the phone. As the days progressed, her condition worsened. When she would cough, she would gasp for air as if she was drowning. We kept our phone calls with her shorts so she could conserve her oxygen. Eventually we told her only to

use text messages. The hospital gave her convalescent plasma, but the treatment course was limited and it didn't seem to help. On July fourth, she was intubated with my mother on a ventilator. Any updates regarding her condition and prognosis were dependent upon the nurser doctor on the other end of the phone. The information regarding my mother's condition would change based on the person observing it. We closely watched her ventilator settings, and our hopes and emotions would rise and

fall with the daily reports. However, there was no true guidepost with which to evaluate her progress. We were frequently surprised by new conditions, such as her being septic, a persistent pneumothorax, and the development of APHEB. On August sixth, after thirty two days on a ventilator, the hospital transitioned her to compassionate care and removed her from the ventilator. Thirty four minutes later, my mother died. Before she died,

we saw the X rays of her lungs. Instead of the shadowy outline of two healthy lungs, it looked as if a family of spiders created an impenetrable web that showed as white lines criss crossed throughout the arc. My father was admitted to the hospital two days after my mother. My father has been disabled since two thousand and one after suffering a stroke which permanently compromised his balance and range of motion. He also suffers from heart disease and

has frequent bouts of APHEB. Despite his medical history, my father's only COVID symptoms were a fever, diarrhea, and extreme exhaustion. After five days in the hospital, he was discharged because he did not need oxygen. However, he was still testing positive for COVID. The convergence of his mobility issues and exhaustion meant that he could not even sit up in bed and could not care for himself. We struggled to take care of him while wearing PPE to avoid exposure

to ourselves. The same day my mother was intubated, we had to have my father readmitted to the hospital because the level of care he needed exceeded our capabilities. My father spent two more weeks in the hospital and survived. January twenty twenty one would have marked my parents' fiftieth way anniversary. Throughout this process, we struggled to obtain reliable and accurate information regarding my parents' conditions. Before my mother died, we were given the opportunity to come into the ICU

and see her. The images from that day in the ICU have stuck with me more than those of my mother herself. The entire ICU was COVID patients. Each patient was on a ventilator and confined to their room. Outside of the door to each room was the IV poll with no fewer than six IV bags and pumps. The atmosphere was eerily silent. The only sound we heard were a faint beeping in the distance and the stifled sniffling of nurses who took turns sitting at the nurses station,

quietly crying with their heads buried in their hands. It was clear to us that the doctors and nurses were trying to care for all of their patients, but they were continuously confronted by the dim, silent reality that most every person in the ICU would not go home.

result of people coming back into the country. We went into lockdown with the rest of the world in March and the lockdown Level four lasted for five weeks and during that time we have very strict conditions. Only hospitals, pharmacies, petrol stations and supermarkets were open, and we were only allowed out of our house for one local walker day or for our designated shopper to go get groceries from

the local supermarket. The idea was that we didn't put ourselves at risk anything that we did that might increase our chance of interacting with those outside our bubble. We just didn't go and then we went to level three. We are online. Shopping and takeaways were allowed for another fe few weeks and then by May, schools were open,

businesses were pretty much back to normal. Our Prime Minister took the scientific advice that she received really seriously and we were rallied as a team of five million to protect each other in the United against COVID nineteen. Ashley Bloomfield was a Director General of Health and he did a press conference at one pm every day to update everyone on new cases and which clusters had new cases. And even though everyone not everyone agreed with lockdown. We

had very few cases of people breaking it. People received government support and most people got paid at least eighty percent of their wage over lockdown, and our borders are still closed except for returning citizens in permanent residents and they have to undergo two weeks isolation in a government funded facility, which is a five star hotel until they give return three negative tests. So after that first lockdown, we had one hundred days with new cases, and to

be honest, it really felt like that was that. But then we had one relapse where just an Auckland, the Auckland region went back into lockdown for three weeks when one family tested positive in the community and they were able to find out that that was somebody from quarantine who had delayed incubation period, so they came up positive

once they were back in the community. And so contact tracing is a huge part of New Zealand's response and they now trace all cases genomically to help link the clusters. So COVID, is this a weird thing? Right now? We know it's out there, we did the work to eliminate it from the community, and there's this sort of peripheral

awareness of it. Because we wear masks on public transport in case another case comes through quarantine, and we hear stories from overseas and it's by no means completely rosy, like it's hard for people with loved ones overseas and you can't fly into the country unless you have a spacebook to the managed isolation, so there are people that are

missing out on coming home for Christmas. But we also go to concerts and have plans to travel with the New Zealand over summer and have big family Christmas celebrations, and we see what's going on, but we're not really part of that global narrative of quarantine and the ever present fear of in fiction or death for us here in New Zealand and instead because of how swiftly the government acts if there is a community case, we're sort

of on edge. But it's very easy to forget in the day to day that it's out there, because our lives are back to normal so to speak. Okaids are at school, where at work, and apart from not being able to travel overseas, there's not a huge difference to how we live now compared to in February, but we do have that feeling of how lucky we are to be in this situation. So basically all that to say,

there's a lot at the end of the title. New Zealand is proof that testing, contact, tracing, quarantine, and science and collective action can prevail, and hopefully we will and I've crossed the rest of the world as well.

for your first hand account. And once again, thank you so much to everyone who has submitted their first hand account so far.

last year, and so here she is. We are so thrilled to have back on virologist doctor Angie Rasmussen, affiliate at the Georgetown Center for Global Health, Science and Security, and she is going to answer all of our questions about SARS Kobe two, the virus that causes COVID nineteen. And we will let her introduce herself right after this break.

So it's most similar to SARS coronavirus classic. It's also related to MYRS coronavirus, which is another beta coronavirus, as well as to two of the common cold coronaviruses, which are also beta coronaviruses, and the other two common cold coronaviruses that circulate in humans are alpha coronaviruses. So it's

part of this larger family called coronaviruses. And what all coronaviruses have in common is they have a single stranded RNA genome, so their genome, their genetic material, is encoded on one single piece of RNA, a single strand, So unlike our genomes, which are double stranded, DNA is just one strand of RNA, and it's what we call positive sense, meaning that if it gets into a cell, it can be directly translated into protein by the ribosomes, which are

the organelles inside your cell that basically make proteins from RNA. And that's their normal function. So that's what coronaviruses have in common with each other. They all evolved at some point from a common ancestor coronavirus back in you know, ancient times, and now there's very diverse. They are very

diver family. We probably only know a handful of the coronaviruses that are out there, and only a subset of those actually infect people, so people should keep in mind not to scare anybody, but stars coronavirus two is a sarbco virus, as I mentioned, and there are quite a few of those that have been found circulating in wild bat species, and not all of them can probably infect humans,

but some of them may be able to. So there may be other coronaviruses out there floating around in the wild that may be potentially human pathogens, but we really don't know that much about that, and we I think really need to know more about that to prevent future pandemics from happening.

might mean in terms of disease outcomes. And lately, a we have a lot more information about just overall strains of SARS Kobe two in general, and then in particular, there's been a lot of coverage about the one UK strain as it has been called in the news, that seems to have now popped up in the US, for instance, and popped up all over different countries, and there's some

indication that it might be more contagious. Could you sort of just walk us through what this UK variant is, whether this appears to be a new strain, how different it is, and whether there are any you know, clinical outcomes that we are seeing in regards to the strain.

that it's genetically different. But we expect all these variants to be circulating around anyways, because the one thing about RNA viruses that you can count on is that they mutate every time that they replicate. So this is a normal and expected thing to have different variants with different

properties emerge. Whether there's strains or not is a matter of debate, just because sometimes when people say strain they mean something that's radically different, either genetically meaning that a much larger part of its genome is substantially different from the parent virus, or that it might be different immunologically meaning that you know your immune system will mount fundamentally different responses, make different antibodies to it. And we don't

have any evidence that that's happening for this. So the L and S trains that we talked about, which feels like a million years ago, didn't turn out to be L and S. I think that the L and S stod for I think low, low disease or lethal. I can't remember what they stood for, but one was mild and one was more severe, and that didn't turn out to be true. That was probably just an artifact of

the population sizes that they sampled. But this variant in the UK, which has the extremely catchy name of B one one seven is does appear to be more transmissible, and that's really based on a couple different lines of evidence.

One is that it became very prevalent, very very quickly in the southeastern United Kingdom, and I should note that it didn't really necessarily emerge in the UK, but that's where it was first detected because their genomic surveillance program, where they're actually sequencing about ten percent of the viruses that they identify, and in terms of new cases, that made it very easy for them to track the sort of rapid takeover, if you will, of this particular variance,

and it just became it out competed essentially all the other variants that were circulating in that population in about a couple of months, So that's really fast for a single variant to take over. So there was that evidence.

They also observed that people who were infected with this particular variant had higher viral loads at the time of diagnosis, and that's a little trickier because people aren't usually being sampled every day and tested, and you know, during the course of a viral infection, your viral load will change as the viral replicating and then as it starts to be cleared so it's hard to say if that's the mechanism by which it's more transmissible, meaning that people who

are infected with that are sheddy more virus, But that's what this preliminary data seems to suggest.

twenty five twenty six other countries so far. So this variant has been emerging and has been spreading globally for a while now. We just hadn't picked up on it until the week before Christmas.

to do with that. It could have something to do with increased fitness, which basically means that the virus is able to replicate to higher tighters. We don't know, but the good news is it doesn't appear to be associated, at least observationally with more severe clinical disease. And there is a mutation that inserts stop code on and to be ORF eight protein, and previously with both STARS coronavirus two and STARS, classic deletions in ORF eight have been

associated with attenuation or making the virus less virulent. So it may be that this stop codeon and ORF eight has something to do with that might not, but people are investigating this now.

in a preprint that showed that maybe not. So it's really hard to say, but to my knowledge, there haven't been any variants described that are more virulent than others apart from that L and S paper way back when that doesn't mean that they're not out there, but right now, at least in the US and in most countries besides the UK, we just aren't doing enough genomic surveillance overall.

So it's really difficult to associate particular variants with particular disease severities if you're not actually sequencing a big portion of the variance that you're seeing. I mean, in the US, if somebody goes in and gets a COVID test, you know, if they're very sick, they'll go to the hospital. But that doesn't necessarily mean that somebody's going to be doing the sequencing that's required to say, Okay, this person's infected

with this variant versus that one. So it's not to say that there aren't variants out there that are ass with more severe disease, but to my knowledge, we haven't found any yet. There are other variants that have been said to be more transmissible. There's one currently that was reported right around the same time as the UK variant

in South Africa that also may be more transmissible. They've said that it might also have some impact on virulence, but right now there's not a lot of data about that, or at least I haven't seen any to indicate whether or not that's the case. So the take home message for me with this is we would maybe have more information about this if we did more genomic surveillance, So we should really think about finding ways to do that.

good for us. They have a lower mutation rate than many other RNA viruses because even though they're rdrps are still very error prone. They have another enzyme that is an exonuclease that basically can do partial spell checking essentially, so it can correct some of the errors that the RDRP makes.

it's said to be under positive selection. So these new variants are the results of basically these mutations being acquired, providing some kind of advantage to the virus, and then getting passed on because they are under that positive evolutionary selection. People ask me a lot, how do we stop the virus from mutating? How do we prevent these variants from emerging.

The best way to do that is to keep the virus from replicating, and the best way to do that is to keep it from finding new hosts to replicate in. It all comes back basically to masks and social distancing and staying home and washing your hands and avoiding getting infected in the first place.

much do you think behavior could play a role in that. So, for instance, if that variant is less virulent than the other circulating more common variants, and that means that potentially more people who are infected with it are still walking around, maybe shedding virus asymptomatically and don't know, so could that be one of the major drivers of this apparently increased transmissibility.

it just as well as anything else. We already know that there's a lot of pre symptomatic transmission, and a lot of the literature doesn't really distinguish asymptomatic from pre symptomatic. So there are people who are asymptomatic completely through the entire course of their infection, and then there are people who are diagnosed while they're asymptomatic, but they later become symptomatic.

Those people already drive a fair amount of transmission. So if people are in a situation where they're more relaxed, they're not being as vigilant about these non pharmaceutical interventions intended to reduce exposure risk, and you have a more transmissible variant added into the equation, and whether they're more asymptomatics or not is probably not as relevant as just the fact that a situation in which you would have maybe had five people get infected now is resulting in

ten people getting infected.

or has recovered from being infected. We call that convalescent plasma convalescent serum, and you take that and you incubate it with the variants or with another virus that has the spike protein from the variants on top of it.

the surface of the virus particle. That protein is obviously pretty small to us, but it's pretty large to your immune system, and different antibodies will bind all over the surface of that spike protein. It's thought that the antibodies that bind to the specific part of the spike protein that binds the receptor, which is called the receptor binding domain, are the most neutralizing, meaning that they will be best able to render the virus non infectious. But not always virus.

Virus proteins can undergo conformational changes, changes in their shape and structure that occur when an antibody binds to a different part of the protein. So it's unlikely that you know, unless the mutations themselves are inducing sort of radical structural changes to the entire protein, that a few mutations are going to completely avoid the entire broad repertoire of antibodies that are going to be raised against it by your

immune system. However, ultimately we won't know until we do the experiments to actually find out.

these vaccine are synthetic and they're easy to change. You could make new mRNA vaccines very quickly, and I think that it would be very easy to adjust these to accommodate for new emergent variants. And over the long term, people have asked me, are we going to have to keep getting COVID shots over and over again because it's like the flu Well, stars coronavirus two is not like influenza, fortunately, and there are other reasons why we need to get

different flu shots every year. First and foremost, because there are a lot of different influenza viruses, including strains and multiple subtypes that are circulating and they can all reassort with each other, which makes things even more complicated. But we are aware that we need to make new flu

shots every year because of this exact issue. So if we can do that annually with an inactivated influenza vaccine, we can certainly do that, probably less than annually to accommodate for evolving stars coronavirus two.

viral protein. It's not spike, but it might suggest that maybe they're sort of developing different immune responses than people who are able to successfully control the infection, in which case, many of those antibodies are neutralizing antibodies that are specific for the spike protein. And it's not really clear why that is. I mean, it could be for a variety

of reasons. Be because the antibodies targeting end just aren't as effective at neutralizing the virus, and so people have more widespread infections, or it takes them longer to clear the infection. It could be because that's inducing immune responses that are associated with more disease severity rather than with virus clearance. So the T cells in your body can be polarized. They call it to act in a few different ways. Th one polarization is thought to be anti viral.

So that's basically your T cells saying all right, we're going to start telling the B cells to crank out a bunch of neutralizing antibodies. We're going to tell the CD eight T cells to go out and start killing infected cells. We're going to tell the CD four cells to start thinking about anti viral immunological memory.

But that's just one example of how sometimes the wrong type of immune response can lead to more disease severity rather than the immune system doing what it's supposed to

do and clear out the virus. So those anti n antibodies have been a hot topic of discussion for that reason, just because it's not clear if that's even important, but it is an observation that's been made, and it maybe explains why some people go on to develop ards or acute respiratory distress syndrome that's associated with severe COVID nineteen, and why some people have very mild infections that they that they can control and clear and and don't have

any problems with. And then there's the whole issue which we still really don't know very much about at all of long covid, which is not due to a persistent infection most likely, but due to sort of a reprogramming of inflammatory responses. We don't really know much about what causes that, why some people get that and not some people don't, why some people get that when they have pretty mild disease. So there's a there's a lot that we need to do here to look at, you know,

the types of immune responses. And I realized this doesn't have a lot to do with your original question, which was what do we know about antibodies to other viral proteins? But it may be that responses to other viral proteins by your immune system or interactions with the virus can determine outcome.

transmission by inhalation. I don't like calling it airborne though, just because a lot of people, I think hear that and they think like that seen and outbreak, where Dustin Hoffman is like it's gone airborne and like looks up at the vents in the hospital and it's not transmitted that way. There have been a couple reports of people in stacked apartment buildings that share plumbing lines having infections.

They can't rule out infection from congregating, for example, in shared spaces in those buildings, but I think that if that were happening all the time, we would have a lot more people infected, especially in New York. Having lived in New York in some terrible apartments, I can guarantee that we would have seen COVID spreading like wildfire in New York City. In apartment buildings that are sharing sewage lines and I'm sure are not perfectly sealed, we would

have been seen a lot more of that. So I think that this is opportunistic airborne in that in certain circumstances it's very easy to transmit this by inhalation. And that really is thinking about shared air. So anytime you're in an enclosed space with people who are breathing and putting out respiratory droplets and aerosols into the environment, and you can breathe them, particularly cumulatively over a period of time,

that's going to really increase that risk. And that risk, of course, can be mitigated by doing things like wearing masks to prevent you as source control, to prevent you from emitting particles yourself into the environment when you breathe or speak.

COVID is transmitted through shared air without a doubt, and that's a major mode of transmission, much more than fomites or contaminated surfaces.

than later. And that's what if you've heard people talking about the CT or the cycle threshold value, that's what that refers to. So a lower CT, meaning the sooner you got to identifying a positive signal with the PCR test, the more.

false negative. Essentially, if you just got over having COVID, you might be shedding viral RNA, which is what the PCR test detects for a long period of time, and that I think is what some people have referred to as a false positive. It's not actually a false positive, because you are detecting a real signal from viral RNA. It's just that the PCR test can't test for infectious virus.

And so it's really important in that regard to have an understanding of when you were actually infected, because a positive test in somebody who's recovered doesn't mean that you're actually still infectious over a long period of time, and that's been shown by multiple streams of experimental evidence and epidemiological evidence. So that's the PCR test. There are PCR tests that you get by the nasopharyngeal swab, which is

the big long Q tip. Some people are now doing those tests with the anteriornaries, which are the nostrils basically only, and some people have also developed PCR tests that use saliva, which are actually more sensitive than the nasopharyngeal swabs, and certainly I think probably a more pleasant experience to give us, like an example, than to.

molecular diagnostics or PCR testing. I think people should have the ability to test themselves, but they should also have clear guidance for what to do, and that is they should call their doctor, make sure that their case can be reported, and then make sure that they have all the information and support that they need to actually isolate themselves and put contact traces in contact with people that they have then and you know, in close physical proximity

with recently to make sure that those people can quarantine and get access to testing as well.

to learn. We live like in a world right now where people they want facts, they want them immediately, and if those facts aren't there, which in science is usually the case. You know, we are as scientists are trained to say this is very uncertain.

vacuum has been filled for me. It's certainly taught me that the way that I was trained to do virology through analyzing data, developing hypotheses and testing them and then if they're wrong, revising my hypotheses and testing those new ones is still the correct way to do that. But I've learned that I really have a long way to go, as do most of my colleagues in communicating that uncertainty to people. It's taken me a lot of experimentation, and I still haven't got it right in terms of how

I communicate. You know, like we don't know if antibodies are going to work against these new variants that are merging. For example, I can tell you how we'll go about looking into that. I can tell you, I can teach you all about the spike protein and antibody binding and how the immune system works. Although still the the immune system is like the most complicated thing in the world. So I think we've all learned that even though we

already knew it. But you know, it's really really hard for me to communicate to people that there's still probably going to be a lot of knowledge.

That maybe we should figure out a way to communicate to people like we should slow down, we should take our time with this because it's too important to get wrong. It kind of does matter if that answer is the

right one or if it's based in evidence. But for me, anyways, the most important thing I've learned, I think, is that we were not only unprepared, grossly unprepared to deal with the generational pandemic even though we knew what was coming, but we were also grossly unprepared to engage the public in fighting it. And that's something that absolutely has to change, and that's something that I'm probably going to be thinking about for the entire rest of my career, if not the rest of my life.

And in the case of coronaviruses like SARS Kobe two, the mutation rate actually isn't as high as we see in some other RNA viruses like influenza, and that's a good thing. It means that it doesn't change as quickly or as dramatically, and so while we have seen a number of different variants pop up and spread across the globe, these variants represent very small changes in the virus genome

and they aren't drastically different viruses. Many of these mutations, in fact, mean nothing at all really biologically, and have

no biological implications. We have, however, seen that at least one variant, the so called B one one seven, which is the one currently making headlines, does seem to be more transmissible than other variants, but we still don't know the precise mechanism for this apparent increased transmissibility, and at least some of its rise in prevalence could be due to the lowering of restrictions on things like public gathering and indoor dining and so on that led to just

a whole lot more transmission in general. Unfortunately, this B one one seven variant, and actually other variants so far observed don't appear to be associated with more severe disease. But the bottom line is that we also probably aren't doing enough surveillance overall to know for sure exactly how many variants there are, or whether some are more virulent than others, meaning more likely to cause severe disease. So the big question is how do we stop this process

of mutation of new variants emerging? I mean, and we can't stop it, but we can slow it down. We can slow it down by reducing transmission. Fewer new hosts for the virus means less replication and thus fewer opportunities for new variants to arise and spread.

all encode the entirety of that spike protein. That's the protein that SARS CoV two uses to actually enter our cells. So when you get vaccinated and your body starts producing this spike protein, you then start making antibodies against it, a whole bunch of them, which target multiple parts of that protein. And the spike protein, it turns out, is a pretty large protein. It's like over twelve hundred amino acids long. And the changes that we're seeing in these

viral variants are super small. In the case of B one one seven, we're talking twenty three nucleic acids out of their whole genome. Not all of those twenty three changes are in that particular spike protein. So while it is possible that small changes can affect vaccine effectiveness, it is overall unlikely. But that's probably not super reassuring to a lot of people. So we do have two other

better pieces of news that we learned. People are doing the research to answer this exact question of vaccine effectiveness as we speak. So that's awesome. And now that we have this vaccine technology, it's not going to be difficult in the future to make small changes as necessary to these vaccines going forward to make them effective against new variants.

In fact, in the case of mRNA vaccines, is actually a lot easier to produce new proteins or new mRNA than it would be to produce a new entire whole killed viral vaccine like we already do every year for influenza, for example.

I mean, we've covered them over and over again, but just to reiterate. That includes wearing a mask, increasing ventilation, being outside being further apart. But if you are in shared air, whether inside a building or inside a plastic tent outside at a restaurant, distance alone does not cut it because you are still sharing air. Overall, other forms of transmission, like from surfaces or fomites or fecal oral transmission don't seem to be big drivers of virus transmission,

which is great news. But that doesn't mean that if you rub your nose and then shake someone else's hand and then they touch their nose, that they can't get infected through that root. So that's why we still have to wash our hands and not touch our faces when we can help it. It's the Swiss cheese approach all over again. The more layers of protection you have, both literally and figuratively, the lower the risk of transmission.

We also learned that these at home tests that have recently been approved are these antigen based tests, and while they are excellent in a number of ways, we do need to make sure that there's really good communication and guidance around what to do with the information that these tests provide. Right now, that guidance is severely lacking, and without it, wide implementation of at home testing with rapid

tests could really backfire. False negatives and false positives are possible with any test, but a positive test really needs to be followed up in some way, and we need to have guidance or some sort of protocol as to exactly how to follow up if we're going to be using these tests at home.

healthcare workers, and communities. And one of the biggest challenges we've faced in this pandemic is how we communicate uncertainty. So much of this last year has been uncertain and the scientific process works to wade through uncertainty to find answers, but it takes time, and this pandemic is one of the first times that a lot of people have gotten a front row seat as to how slowly and incrementally knowledge can grow and how rarely things in science seem

black and white. We don't know all of the answers when we start the process, and jumping to conclusions either discarding or disseminating information early without evidence just makes everything more confusing in the long run. It's hopefully something we can learn from moving forward, how to better communicate this process and the uncertainty surrounding it to the wider public.