COVID Transmissions for 8-13-2020

The mistakes we make

John Skylar, PhD

Aug 13, 2020

Greetings from an undisclosed location in my apartment.

It has been 270 days since the first documented human case of COVID-19.

Housekeeping note:

In-depth about mistakes, today.

Glossary terms are bolded words with links to the running newsletter glossary.

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Now, let’s talk COVID.

Russian Roulette, another shot:

Additional reporting that I found today indicates that not only has the Russian vaccine not been tested, but it also isn’t actually approved to the degree that the Russian government claimed. It won’t be widely available until January 2021 in Russia, around the time that companies like Moderna and Pfizer expect to be able to make their vaccines available. The Russians were just grabbing headlines, it seems. Putin has called this vaccine “Sputnik 5,” and I think that says a lot about what the purpose of the announcement actually was.

Mouse experiments question role of interferon in controlling COVID-19

A group at Yale has performed some experiments infecting SARS-adapted mice with SARS-CoV-2, examining both mice that have a competent interferon response vs mice that are incapable of mounting such a response: https://rupress.org/jem/article/217/12/e20201241/151999/Mouse-model-of-SARS-CoV-2-reveals-inflammatory

Interferons are master controllers of immune responses. Type I interferons, specifically, are at the center of antiviral immunity, kicking off the initial response to virus infection and inducing hundreds of genes that make cells a more hostile environment for viruses. They are also inflammatory and can cause a lot of irritation and tissue damage.

For this reason, it is expected that interferons, given at the right time during infection, could potentially help control COVID-19. Given at the wrong time, it is expected that they could do a lot of harm.

These researchers—the first author of the paper being Dr. Ben Israelow, MD, PhD, someone I was in grad school with—wanted to see if an interferon response had any impact on the level of disease markers or on the viral load in the mice that they were working with. There are a number of technical accomplishments in the work, but the main upshot is this:

There was no difference between viral loads in mice with competent interferon responses vs mice without competent interferon responses. This suggests, at least, that the natural interferon response is not highly limiting to this virus.

I don’t know that this means that supplemental interferon isn’t an option for treatment. First, “mice lie, monkeys exaggerate.” Second, SARS-CoV-2 originated in bats, and bats are known to have a low level, constant immune activation that is probably related to their nature as flying mammals—there are metabolic changes that have caused their immune systems to evolve differently than those of other mammals. So, bat viruses may need to evolve to overcome a constant background interferon response. SARS-CoV-2 may have retained a certain amount of protection against the normal level of interferon response. It’s possible that as a therapeutic, additional interferon will help to overcome this, despite this result.

Another aspect of the result, though, was that inflammatory damage and markers of inflammation in the interferon-competent mice were much higher than in the interferon-incompetent mice. So, that suggests that interferon responses to SARS-CoV-2 can be damaging to mice without limiting the virus. That may speak to the mechanism of disease in humans, since it’s well-established that interferon begins the inflammatory response that makes us begin to feel sick.

All in all, there are not a lot of surprises here, but this does make me wonder just how effective interferon may actually be against SARS-CoV-2.

What am I doing to cope with the pandemic? This:

Exercise

Those of you who know me personally or follow my twitter will know that I’ve been working on getting back in shape this year, after a long period without having any time for exercise. During vacation I let that schedule go a little and so I’m doubling my efforts now that I’m back to keep things going. It’s possible to stay healthy during the pandemic!

COVID testing

As part of my annual physical this week, and in light of my having gone on a trip, I went ahead and got a SARS-CoV-2 PCR test and antibody test. Both negative!

The mistakes we make

A big part of science is being wrong. One of the most interesting virologists alive, Dr. John Yewdell, once gave a talk for the students at Mount Sinai. It’s an early career talk that he has well-honed and gives all the time. It’s a great talk. One of the key things he says is to consider what we are doing right now—whatever our project is—and realize that we are probably wrong. Whatever we discover, our interpretations and discoveries are almost certainly incorrect because we are working in imperfect conditions on topics that no one has studied before. The only way to be right is to repeat things that are well-established, and that isn’t scientific discovery.

Instead, Dr. Yewdell told us, what’s more important than being right is to carry the torch of the scientific method through all that we do. Do our experiments, report our findings, and continue the traditions of a self-correcting, self-evaluating process that tries to improve human knowledge and understanding. We need to be wrong in a certain way now so that others can correct us in the future.

In that spirit, I wanted to visit a topic that has been on my mind a lot: the things that we got wrong early in the COVID-19 pandemic because of preconceptions from past experience. I’ve been listening to the This Week in Virology podcast from early in the pandemic, and surprised to hear the same misconceptions I had coming from the hosts. Like me, they thought that the virus would self-limit and likely not cause a pandemic. Like me, they thought that masks were unlikely to be helpful. Like me, they advocated for a model of transmission that considered close contact and surfaces to be the most likely modes of spread. Also like me, they were skeptical of reports of asymptomatic transmission. I shouldn’t single out the TWiV hosts, though—we got our ideas from the CDC, the WHO, and our knowledge as virologists. We made the mistakes that anyone with imperfect knowledge would have made. And, true to their nature as scientists, the TWiV hosts corrected themselves as new information became aware. I’ve done the same, as appropriate, with my own preconceptions.

I recognize where these preconceptions came from, and I think it’s worth revisiting why we had these ideas.

Why did we think the virus would self-limit?

The initial outbreak in Wuhan was in a city of 11 million people, and as far as the Chinese and the WHO were able to determine, only about 80,000 people there got infected. We know now that it’s likely that this number was not accurate. I am not making some kind of accusation against Chinese authorities, but rather pointing out that very few countries have managed good surveillance for this virus. US numbers are also likely inaccurate. This virus is hard to accurately detect given its ability to cause minimal or nonexistent symptoms in many patients, and its being a new pathogen without an existing surveillance network.

Seeing 80,000 infections in a city so large, it wasn’t clearly just how contagious the virus really was, and it wasn’t clear how many people were actually susceptible. I was incredulous when Dr. Mark Lipsitch of Harvard suggested that 40 to 70% of people might get infected with SARS-CoV-2, because there didn’t appear to be evidence to support such a high attack rate. I still think there wasn’t evidence to support that, even though ultimately I concede that it has become apparent that this virus is indeed extremely contagious and a large percentage of the population is susceptible.

Based on the data available, this looked like a milder SARS strain that spread at an alarming rate but that might ultimately be contained through good social interventions. I had a preconception from SARS-CoV-1 that this species of virus was not very effective at spreading between people, and that in general it was ill-adapted to spread in human populations. I thought that it would self-limit like SARS had, because SARS was the experience that I could compare to.

Based on the data available now, clearly that’s not correct. This virus is able to slip past such social interventions because it is hard to detect. That’s one way I’ve had to change my mind during the pandemic.

Masks don’t work?

Years of studies of respiratory viruses had convinced me that unless you were appropriately trained and wearing an N95 respirator that was fit-tested, masks were pointless in respiratory infections because the gaps in those masks were fantastically larger than small aerosols and droplets. Numerous studies in the 2009 H1N1 influenza virus pandemic had demonstrated that wearing a mask that wasn’t an N95 did little to prevent infection in mask-wearers.

I told people that I didn’t think masks would help. I was wrong, but I wasn’t just wrong about facts: I was asking the wrong question entirely.

The studies that I was familiar with, and the work that had been done, was all to ask: does a mask protect you?

Instead, what we should have been asking was, “does a mask protect others?”

Now, that alone isn’t the full problem. I was totally aware that if you’re sick, a mask can help protect people around you. An article I wrote back then even mentions that masks should be worn by sick people to protect their contacts. But, because I did not know the degree to which the virus had spread through my local population, I was not thinking about the need for asymptomatic people to protect others from the infections they might not know they had.

So, two problems combined: due to preconceptions from my knowledge of influenza viruses, I thought that masks would do little to protect people, and I also thought that most people who didn’t feel sick weren’t infected in a way that could spread to others. That turns out to also have been a preconception from knowledge of other viruses, but we’ll come to that later.

Since then, it has become apparent that it is possible to be so unaware of an infection with SARS-CoV-2 that you are not able to adequately gauge the risk you pose to others. In that circumstance, you should assume you are infected. Even if you tested negative yesterday. Or even today. And since you are assuming you are infected, you should wear a mask to prevent transmission to others.

The close-contact, surface-based transmission model

Another thing that was in vogue early in the pandemic was an obsession with handwashing and hygiene theater. The thought was that infection was transmitted similarly to human coronaviruses and influenza viruses, through large respiratory droplets and “fomites,” which is a fancy word for virus-contaminated objects. This was a preconception based on other viruses and also based upon the apparently low amount of spread in Wuhan, at least in my case.

Since that time, it has become apparent that while surfaces are capable of transmitting SARS-CoV-2, they are not the primary means of transmission. It has also become apparent that the virus is able to spread through the air, and potentially not through large droplets alone. This substantially impacts the disease control measures needed to contain the virus.

It doesn’t do much to send your team of NFL players through a sterilizing spray before they come into contact with each other, for example, if one of them is infected. That player will bring the virus through the sterilizer and shed new virus when afterwards. That player is a much bigger threat, with or without the sterilization step, than any virus that might be on the other players’ clothes or hands. Social distance is far more important than hand sanitizer.

That’s not to say that hand sanitizer isn’t useful. If you’re infected, hand sanitizer and a mask might help you reduce the amount of virus you put out into the world in a meaningful way. If you’re not, it might clean contamination off your hands before you infect yourself. However, we know at this point that hand sanitizer is not enough. Masks, social distancing, and minimizing high-risk activities are all essential disease control measures beyond just hygiene.

Asymptomatic people spread virus

Again, based on our understanding of other viruses like influenza, most virologists thought that SARS-CoV-2 would not be easily transmitted by people who were not actively symptomatic. This applied as much to “presymptomatic” patients still in the incubation period as it did to infected people who never showed any symptoms at all.

In an influenza virus infection, contagion is at its highest from 24 hours before symptoms begin until about 5 to 7 days after symptoms start. Transmission of virus outside of this window is rather rare. Other viruses also show this pattern, and many thought that SARS-CoV-2 would also behave in this fashion.

Not only were people’s perspectives colored by these preconceptions, there were also officials with major health organizations like the WHO who maintained that evidence did not support transmission of the virus by people without symptoms.

This was wrong. People who do not have symptoms are clearly able to spread SARS-CoV-2; this became apparent when the virus spread globally with ease following the initial outbreak in Wuhan. It came to other countries and spread extensively before it was picked up by local surveillance; this seemed to suggest that it must be able to spread either during the incubation period or from patients who were not showing symptoms.

Today, we know that asymptomatic patients can shed infectious virus. We don’t know it from extensively large studies, but we know it’s possible and we know that it is a good explanation of the rapid global spread of this virus. It also is consistent with the fact that universal mask-wearing, even by those who are asymptomatic, can help to contain outbreaks.

As you may have noticed, a lot of the preconceptions that led to these missteps were based off of past experience with influenza virus. Influenza, as a disease, is one that has essentially neverending pandemics. While we do declare each new pandemic over at one point or another, the reality is that pandemic influenza viruses continue to spread through the population on an annual basis after they first appear. Each year, strains of the virus move through the human population globally. On top of that, influenza pandemics are regular enough that nearly every generation has been alive for one, if not more, so the influenza viruses are also a source of information on how novel viruses spread through the population. As such, influenza virus is a key data point in scientific understanding of how respiratory viruses spread through human populations.

So, a lot of our early approach to SARS-CoV-2 was based on experience from influenza control, as well as our experience with SARS and other human coronaviruses.

As we’ve learned, SARS-CoV-2 is not influenza virus. It is more deadly, it is more contagious, it is more amenable to aerosolization, and it spreads in a stealthier fashion through human populations. Learning that adequately was a key step in being able to locally contain the virus in those areas where it has been brought under control.

So does this mean scientists are idiots?

This piece isn’t about how terribly stupid we were in our preconceptions. Instead, the point is to highlight that science, and the scientific process, are effective ways of correcting ourselves and our errors.

SARS-CoV-2 is a virus that no one anywhere had known a single thing about before December 2019. Not a single fact that we know today was known then. An intensive process of laboratory and clinical investigation has been conducted at an unprecedented pace to understand this virus.

For centuries, people believed that swamp gas caused plague. It took hundreds of years and millions upon millions of deaths across those centuries for people to figure out that a germ causes plague. Even after that, it took additional decades to develop antibiotics to be able to cure people of plague.

Here we are in August, just 9 months after SARS-CoV-2 entered humans. By early January, we had sequenced the virus. As that month developed, we had a sense of its structure, how it infects human cells, and also its origins. By March, we were beginning to understand the best ways to treat an infection with this virus. In May, a real picture of potential treatments and vaccines began to emerge. By July, we had our first data in humans with those vaccines.

We had preconceptions. We tested those assumptions. We learned. We advanced the science. In generations past, we would have been powerless to do all of these things at the pace we managed in 2020. While in the US, we should have been able to do even better, as a species, humanity has performed at unbelievable levels of scientific achievement through the course of this pandemic. We have done it by learning from our mistakes, and improving our understanding while carrying the torch of scientific inquiry.

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