Coronavirus: some of the science behind it (level C1)

• Interview conducted 30/03/2020 as our knowledge of coronavirus is evolving some of the information may change. The treatment options tested and our knowledge about how the virus acts on the body are the things most likely to change through the course of the pandemic.*
• Most of interview is in the original format, changes made so it better suits interview format.

The interview was an audio interview: Questions, transcription and editing by Rachel Melinek

I’d like to thank Ben Johnson for agreeing to be interviewed. A copy of the interview is shown below:

Square bracketed and bold numbers are terms which are explained further in the notes.

Me: Could you tell me a little bit about your background?

Ben Johnson: At the moment, I work in science communication for the publisher Springer Nature managing blogs and social media. But my background is as a virologist, and I used to work in the main respiratory virus diagnostic lab, what is now Public Health England, that’s where I did my PhD. I then worked for several years at Imperial College London, doing vaccine research. I’ve also studied basic virology and viral diagnostics.

Me: What family of viruses is the coronavirus, and is it like the flu? What makes the coronavirus worse than the cold and the flu?

Ben Johnson: The coronavirus has an RNA [1] genome; this is where it stores its genetic information. If you take the common cold and the flu separately, the common cold is caused by about 200 different viruses, some of which are coronaviruses. There are many different coronaviruses; there are a small number of them that infect humans. As well as the common cold, there are much more severe viruses that include SARS (Severe Acute Respiratory Syndrome) and MERS (Middle Eastern Respiratory Syndrome). If you look at influenza, it’s a different type of virus. It has a very different life cycle, to the coronavirus, it’s in a different family. If you look at severity, this is something which is an evolving situation, understanding how severe COVID 19 is because in some people it is like having a bad cold. Some people just have a cough, and that seems to be quite a large proportion of people. Indeed, if you look at the outbreak on the cruise ship Diamond Princess, which was one of the large sources of infection early on, it looks like about 18% of people had no symptoms at all. Then you have a small proportion which develop a severe disease like pneumonia and an even smaller proportion which have a fatal disease. In some ways, it is both milder and more severe than the flu. In many people, it is mild; it looks like most people, possibly more than half just have a cough. In a small proportion of people, it’s much more dangerous.

Me: What do we know about how COVID-19 acts on the body at a cellular level and a general level?

Ben Johnson: We don’t know a lot about how COVID-19 acts at this stage. If you look at other coronaviruses, they generally infect the upper respiratory tract, that’s why they cause a cough. Sometimes they affect the lower respiratory tract, which is how they cause pneumonia, and they don’t tend to spread beyond that. They don’t tend to leave the respiratory tract, but they can, in some rare cases. If you look at SARS it looked like the disease there was due to the body over reacting to the virus, so you get an overactive immune response, and that is true of several viruses, so influenza is the same where you get very severe influenza you get something called a cytokine [2] storm, it’s your immune system over-responding and it’s that which makes you ill. Even in normal influenza, what makes you ill is your body’s response to infection. At the moment, it doesn’t particularly look like you get this cytokine storm or this over-reactive immune response. The very small number of studies we have so far suggest that the virus is suppressing the immune response, so it looks like your T lymphocytes [3] are suppressed. We will learn a lot more as the weeks go on in terms of how the virus interacts with the body.

Me: How is it passed from person to person?

Ben Johnson: It seems to be mostly droplets, so through coughs, it doesn’t seem to be aerosolized like influenza. So, influenza, you create these huge aerosols when you sneeze, and you get a spread of influenza travelling in your area. As it’s mainly spread through coughing, washing your hands is very important. A major source of transmission is what’s called fomites which means its spread via objects. So, you cough on your hand, you touch a door handle, someone else touches the door handle, and they eat a sandwich, and they catch the virus that way. Again, that is true of most respiratory diseases; they can be spread through objects, so cleaning things such as door handles and washing your hands are effective. If you tried to do social distancing [4] during an influenza outbreak, it would be much less effective. Social distancing works in this context, however, because of its spread through these droplets, which requires close contact. Social distancing doesn’t work for influenza because you create an aerosol. If you imagine spraying some deodorant, those droplets hang in the air and spread through the air as coronavirus does not spread through aerosols; that’s why this 2-meter rule really should be effective.

Me: The virus is an envelope virus, and this is related to the effectiveness of handwashing. How do measures such as hand washing help to combat infection?

Ben Johnson: Soap and water is the most effective thing you can do. Alcohol works as well, but the challenge with alcohol is that you need to make sure that you are covering every cm of your hands with the alcohol as you don’t get a foam-like you do with soap. As it’s an envelope virus, it has a layer of fat around. Imagine when you are doing the washing-up. When you add some washing up liquid to some oil, you see all the oil disperse the washing up liquid. With the virus, the lipid layer is dispersed so it will burst open the virus, and the virus then becomes non-infectious. It’s essentially dead, so soap and water are incredibly effective. I heard a doctor say that he had never seen someone wash their hands properly without proper training; you do need to cover every inch of your hands wash them thoroughly for 20 seconds. There is good epidemiological evidence for influenza, which also has a lipid envelope (a layer of fat around it) that during an influenza outbreak, the people who wash their hands the most often are the least likely to get sick.

Me: Could you talk me through the treatment contenders? I hear there are antivirals, mRNA vaccines that are all possible contenders for treating COVID-19.

Ben Johnson: There are three arms to how we can tackle the disease, one is antivirals, one is vaccines, and the last is expanding hospitals. One of the reasons that the fatality rate is so high is because in severely affected countries, for example, China and Italy hospitals are overwhelmed, so somebody who may have survived through ventilation will not survive because there aren’t enough ventilators. Thus, it is a significant arm of any country’s response, increasing the number of intensive care unit beds and the number of people who can have oxygen. In terms of scientific aspect what is being tested is existing drugs, ones which are already licenced against other diseases. There are four main ones being trialled at the moment. One of them is the malaria drug hydroxychloroquine. Another drug is an experimental antiviral by Gilead which is Remdesivir, and that seems to have some effect. Also being tested are two HIV drugs, so again there was one study that said it did have an effect, then there was another study of 199 people that said it didn’t have an effect, and people are also looking into interferon beta. Interferon beta is produced naturally by your body, and it’s an antiviral, and its actually what makes you ill when you have the flu, so it’s not a very pleasant treatment. It’s very effective against hepatitis C which is a kind of related virus. The WHO is trying to coordinate testing of these drugs as what we want to know is whether these drugs are more effective than the standard treatment at the hospital; after we know that the treatments are truly effective they can be rolled out, but extensive testing is done in all cases before treatment is given. There are a number of vaccines already in human trials. As you’ve mentioned, some of these are mRNA-based vaccines. Vaccines take time and the reason for that is that an antiviral is given to people who are sick whereas a vaccine is given to healthy people, so it has to be safer than antivirals. If you’re very sick in hospital, you are willing to accept a certain measure of risk-taking for a drug; if you’re healthy that risk becomes unacceptable. It is generally thought that a vaccine is a year or more away just because of the safety tests that have to be done.

Me: The government has bought out a new test? What is the acceptable level of false positive and false negatives?

Ben Johnson: There are several types of tests. Some tests detect the virus, and the gold standard here is a PCR (polymerase chain reaction) [5] based test. It only works if you have an infection at that moment, and it won’t tell you whether you have had an infection in the past. It is very sensitive, and you have to run the test only in special settings because it’s very easy to get false positives, which makes it quite hard to roll this test out, and that’s why not enough people are being tested. That’s partly why not all health care workers are being tested because it’s quite hard to scale it up, and you need people who are specially trained, so you don’t get false positives. The other test that is being rolled out is an antigen [6] test that also only works if you are currently infected with the virus, but it’s much easier to do. In general, an antigen-based test is more likely to give you a false negative because it’s less sensitive, so it may not be able to detect the virus when the PCR test would be able to detect the virus. It is similar to a pregnancy test in that its rapid and can be administered by those with very little training. The third type of test, which is important, is an antibody-based test. This test can determine whether anyone has had an infection in the past. These tests are quite hard to do, for several reasons, one being that the common cold has infected most of us if not all of us and that’s another coronavirus. Hence, you need to make sure that the antibody [7] test can tell the difference between an antibody against the common cold virus and an antibody against the COVID-19 coronavirus. Not such an issue, but there is some cross-reactivity [8] between SARS and COVID-19. So, if you have been infected with SARS, which is a small number of people, you may show up positive for this test even though you’ve not been infected. This test is so important because it will allow you to say quite convincingly who has been infected. If you’ve been infected in the past, you should have some immunity even if it’s not lifelong, so in theory people who have been infected can start to go about their daily lives again.

Me: So, measures such as testing could affect the time needed to keep social distancing in place? What other factors would affect this? What factors, for example, are people considering when they give different time estimates for things such as social distancing? What can you say about the current models?

Ben Johnson: Models are only as good as the data that go into them, so models can be really informative but they rely on some assumptions. One of those assumptions is around social contacts, so they build a model of the UK population, for example, and how often people interact with each other. It’s a very complex model, and it factors in things such as where people travel, how they get to work, whom they interact with, and how many people they interact with. Another aspect is what’s called the Ro, so this is how many people on average you give the virus to when you are infectious. For COVID 19 its thought to be between 2 and 3. Between 2 and 3 is a very broad range, if you say we infect 2 people that gives a very different model than if you say we infect 3. Another thing that is a real challenge is that the range of disease symptoms is something we’re learning more about that each week. If you consider social distancing, I think the key thing to remember is that some social distancing will have to be in place; until enough people in the population are immune, which means they’ve caught the virus or they’re immune through a vaccine or you treat them with a drug when they’re infected. There is no solution where you have social distancing and then the outbreak goes and then life goes back to normal. What you either need to do maintain social distancing as we have now or you introduce a model where everybody who is infected gets tested, and all their contacts get tested, and the reason for that is the role of the asymptomatic carriers. If you consider a strategy where only people with symptoms stay at home, the disease will continue to spread, because those that have no symptoms will continue to go about their daily lives spreading the infection. China has tackled the virus with intense social isolation. This is why, in the UK, the strategy whereby you reduce contacts is important, everybody’s staying at home more often; going out once a day to the supermarket, once a day for exercise and essential journeys (frontline workers or certain medical appointments). Once cases drop, which hopefully, they will if that is effective, you then introduce a policy where as soon as anybody has a cough or a fever, they are tested for the virus. Critically you will also test everybody they’ve been in contact [9] with, so this is a strategy that allows you to find the asymptomatic people. This strategy is being carried out in several locations, for example, Singapore, Taiwan, South Korea, and Hong Kong. So, the policy we have in the UK at the moment where we have social distance for everybody has to continue until we have either:

· a vaccine or effective drugs

· potentially enough capacity in hospitals that we think we can withstand an outbreak

· have a policy of testing and contact tracing.

Me: Are there different estimates of how soon people can go back to life as normal?

Ben Johnson: There are certain factors to consider, and these aren’t just to do with features of the virus. It’s in part dictated by how society responds to the virus; for example, if we were to do nothing, the model predicts that the outbreak would peak in 3 months. So, any intervention that we do will mean that the outbreak will take longer than that. The reason that were not letting the outbreak happen is because in the UK, the estimates from Imperial College London are that that would lead to half a million deaths. A minimal reaction model might have minor social distancing; schools remain open, and social isolation is only for those that have symptoms, then the Imperial model said that that would lead to 250,000 deaths. Both these solutions were obviously deemed unacceptable. So, all the measures that we actually have to stop the spread of the virus prolong the outbreak. The more effective the social distancing and social isolation, the more prolonged the outbreak will be. If these measures are effectively put in place it will mean that fewer members of the population will have immunity and so once you have this policy you need to maintain social distancing indefinitely or the virus comes back, until you have some effective drug or vaccine. Thus, the length of the outbreak depends on the availability of treatment. The other option is that you do what the government is doing e.g., in the UK, you implement very strict social distancing, and as cases reduce, you implement a policy of mass testing. That is more difficult to do because of contact tracing and the need to have forced isolation for those individuals who are perfectly well but have been identified as carriers.

Me: What are other countries which have different rates from the UK doing differently, for example, Germany? Is Germany more compliant, or is it just different strategies that are the reason for these differences?

Ben Johnson: The case fatality [10] rate is different in different countries. I think there are several factors there. I think one factor is the age of the population. For example, Italy does have quite an elderly population; I think 23% are over 60 or over 65. A particular influencer in terms of case fatality is the testing strategy. So, Germany and Italy are good comparisons. Germany is testing people who have an illness however mild, and Italy is only testing people who have severe disease. That’s the case in the UK too; we are now only testing those with severe disease, with the hope that we’re soon able to test more people, for example, frontline healthcare workers. As soon as you stop testing people with mild disease it makes the virus look more dangerous than it is. If you compare that to South Korea, who are testing all people with the disease, however mild and their contacts, then you start to include the asymptomatic people. I would expect that the actual case fatality rate of the virus is whatever the current lowest estimate is or lower because I don’t think any country is managing to catch all of those asymptomatic people. We’ll only find out about those people missed in testing when the serology test goes live, so that’s the one looking at antibodies it looks at whether you’ve had a past infection. A great place to start with these tests would be Wuhan in China. You could test the whole city, and see how many people were infected, then you could do the same in all affected countries. This would be the only method that would show you an accurate measure of how dangerous the virus is in terms of the proportion of people with severe illness.

Me: Any nice stories about people researching the coronavirus for the readers?

Ben Johnson: Quite a lot of my former colleagues, as I used to work in influenza are now working on COVID-19, and I do know that one of them who is based in the Rocky Mountains in Colorado. She had a cake left on her doorstep by somebody and she doesn’t know who. It had a thank you note. It was evident that they knew she worked on the virus. It was from a neighbour, and she still has no clue.

There are a number of labs around the world that are working on coronaviruses .Those that have been working on similar viruses have also started to work on coronavirus. Many labs that work on quite unrelated areas are now starting to work on different aspects of the coronavirus. It is heartening to see the research community turn their attention to this.

Me: How likely is another pandemic given the global connectedness, climate change, factory farming, and excursions into nature? What lessons can we learn from this one?

Ben Johnson: I started my degree in virology 21 years ago, and during that degree, I remember being told that we are overdue the next pandemic. That was the case then and in that time we have had avian influenza and we have had the swine flu pandemic, both of which were less severe than this. Now we have the COVID-19 coronavirus outbreak. I think if you asked 10 years ago particularly after SARS and MERS, I think any virologist would tell you it may not be influenza but; it will probably be a coronavirus. This outbreak is not a surprise to anyone working on infectious diseases. If you look at countries that were affected by avian influenza and SARS, places in Asia, they have dealt with the outbreak very well e.g., Taiwan, Singapore, Hong Kong, and to some extent South Korea. South Korea was very unlucky as it had a lot of spread very early on, but the number of cases in South Korea is growing very, very slowly now and that is because they knew this was coming and they were prepared. I think Europe and the US have been quite complacent as we thought this is something that happens elsewhere. You can prepare for this; the key is lots of testing and understanding how isolation works, but it is difficult as it does require a measure of losing your freedom. It’s something we’re not very keen to do for very good reasons. It also needs proper monitoring of cases. There will be another outbreak it could be in 5, 10, 20 years, but another outbreak is inevitable because if you look at bats, they have 100s of coronaviruses which then go into an intermediate host. There was a study in Nature on Thursday showing this with pangolins, which are trafficked illegally for some traditional medicines. So other viruses have an intermediate host examples are camels with MERS and civet cats with SARS. These intermediate hosts spread it to humans. There are ways you can reduce the likelihood of this happening; for example, you can look at improving hygiene in wet markets or find other ways of trading animals. I think being prepared and assuming that there will be another outbreak and putting in measures to monitor cases works, and that’s something that all countries should be looking to do in the future.

Notes on terminology and additional points

1 RNA and DNA both carry genetic information. The genetic information encodes proteins which make up the virus particle.

2 Cytokines are proteins which are important in cell signalling. They signal immune cells such as T cells and macrophages so that they can target the site of the infection. A cytokine storm is when the signal produced results in too many immune cells aggregating at one site. Cytokine storms can result in significant damage to body tissues and organs.

3 T lymphocytes are a type of immune cell

4 Social distancing is a measure that reduces the number of times people come into contact with eachother. The distance that you keep between people who are not members of your household is 2 metres or as my sister would say imagine a tall person lying down between yourself and the other person.

5 PCR is a technique which amplifies genetic material within a sample in order to be better able to study it. In this case the amplification means that you can detect the viral genes and determine whether someone has the virus.

6 An Antigen is a substance which is foreign to the body and produces an immune response

7 An Antibody attaches to a pathogen such as a virus or bacteria enabling the body’s immune system to attack it.

8 Cross reactivity-this occurs when an antibody raised against a specific antigen has a high affinity towards a different antigen

9 Contact tracing-finding out who someone with a virus in this case COVID 19 has been in contact with during the time that they were likely to be infectious

10 Case fatality rate-Proportion of deaths compared to the total number of people diagnosed