Corona Virus Update: tracking infections by App and do go outside (part 27)

Prof. Dr. Christian Drosten

This edition of the Corona Virus Update Podcast was about how effective an App could be that monitors with whom we have been in close contact lately and warns them if we develop symptoms or are tested positively.

Even if it is voluntary and only a part of the population uses the App, in addition to only a part heading its warning to stay inside it would have a drastic effect, which is comparable to a lockdown.

In addition informatics researchers think this tracking can be done in a way that respects the users privacy. Only who was close for a longer time is stored (this is determined by the short-range Bluetooth transmitter of your mobile phone). No locations are stored; if all data were on a national server, the contact information would allow very accurate estimates of ones position, but the contacts are stored on your own phone. Only when someone reports to be ill, this information would go to a national server and all other users could anonymously check this encrypted information. This seems to be a powerful way to fight the virus and would enable other restrictions to be release. If they can deliver on privacy claims, the software is open source, so we can check and the use of the App is voluntary, I would be in.

[EDIT: It possible to deliver the privacy promises, the CCC writes: "With the help of these technologies, it is possible to unfold the epidemilogical potential of contact tracing without creating a privacy disaster." The CCC are Germany's prime technology experts and privacy activists. I will follow their advice.

This contact tracing App should not be confused with the Corona Data Donation App ("Corona-Datenspende-App") of the Robert Koch-Institut, which was launched today for Android and iOS. This voluntary App uploads data from your fitness-tracker to estimate statistically how many people are ill from their temperature or pulse. This is a lot of private information, but these people already uploaded all this information to a corporation. It is only pseudonymous and only needs to be used by a much smaller part of the population to be useful for monitoring the situation and scientific research. As long as participants give informed consent and data can be deleted again this is fine.]

To make the computations on how effective the App would be, one needs estimates for how the virus in transmitted. This study computed that without intervention one person infects two others. (Other studies seem to be in the range of two to three.) About half of these infections are after symptoms appear and about half before. Because of this it is not enough to only isolate people with symptoms.

The other two factions are much smaller: On average one infected person infects 0.2 via contact infections (environmental transmission) and people who do not show any symptoms are responsible for 0.1 infections (asymptomatic transmission).

A part of the interview I skipped was about Trump's favorite drug, hydroxychloroquine and in particular about a new medRxiv, preprint on this drug. There is no clear evidence at the moment, so this only interesting in the light of Trump pushing it so hard, but less from a science point of view.

At the end is a question on what people can do themselves to strengthen their immune system: go out and do sports. Going out while keeping your distance is not an infection danger.

Prof. Dr. Christian Drosten specialises in emerging viruses and developed the WHO test; more on his background. This episode science journalist Anja Martini asks the questions.

The epidemiological model behind the App

Anja Martini:

93 percent of Germans are in favour of the restrictions, i.e. the social distancing rules and staying at home. This is the result of a [high quality] survey. When it comes to setting up a mobile phone App, Germans are divided.

Mr. Drosten, I remember at the beginning of the podcast [series] we talked briefly about apps in China and South Korea that analyse the movement data of mobile phone users in order to find possible infected persons. At that time you said that this was probably difficult in Germany, and I agreed with you.

The situation has now changed. In other words, we are now talking about apps that work anonymously via Bluetooth and that work on a voluntary basis. There is already a first study from Oxford, involving scientists across Europe. What do you make of it?

Christian Drosten:

Yes, this is a study from the group of Christophe Fraser, certainly one of the best epidemiological modelers. It's a very interesting study, I think. It's published in Science. It is about first of all calculating a much better, more accurate epidemiological model, which is simply much more fine-grained, where more information goes into it than was known until recently. The fact is that the scientific literature provides more and more data that can be evaluated and then fed into such models.

The beginning of this study is actually made from the observation that there are now actually more and more descriptions of transmission pairs in the literature and therefore the [[serial interval]] of this infection can actually be better determined. So how long does it take from symptom to symptom or from infection to infection. With symptom to symptom one speaks of "clinical onset serial interval", with the other - from infection to infection - of serial interval. And what you actually need is the serial interval itself. But it's all relatively difficult to quantify exactly determine. That is why one can at least make a good approximation over the "clinical onset serial interval".

This can then be derived again, also from literature reports, and that is how the study starts. 40 pairs of transmission from the literature are evaluated, they feed an already existing mathematical model to derive certain parameters and certain proportions of the overall transmission activity.

The [[basic reproduction number R0]], has been recalculated here as two. That is a relatively low value, if you look at what other analyses have found before. In some cases it was more like two and a half.

Anja Martini:

So [the study computes that] one person infects two others.

Christian Drosten:

Right. Now we have the option of decomposing these transfers into parts. ... The asymptomatic [part] means a carrier that never shows symptoms. And pre-symptomatic [part] of course means that it is transmitted before the carrier has symptoms. But you can find this carrier later, because he gets symptoms then. So of course you can still identify the contact patients later. This is a consideration that will be discussed later in the publication.

Let's first give the values that are derived: Pre-symptomatic 0.9, i.e. a part of 0.9 of of the R0 value two, symptomatic transmission has a part of 0.8 and then environmental transmission 0.2, asymptomatic transmission 0.1. If you add these four values together, you get two again.

If you now look at the figures, you will see that the overall pre-symptomatic transmission share is 46 percent of the total transmission activity. It is a similar figure from what we discussed a few days ago from another working group, from another paper.

The value R0 of two is apparently good news. Because when we get a R0 of two, [rather than higher other literature estimates] then we have less [transmissions] that must be reduced to reduce the R0 below one and thus also to bring the epidemic to get a standstill.

However, if you now realize that 46 percent of all this transmission activity takes place before the symptoms, it will of course then again be very difficult to reduce these transmissions. Because you can only isolate symptomatic patients. These considerations are now being fed into an interesting calculation that wants to find out: What can actually be done with certain interventions to detect an infected person?

How long does it take to detect it? And how many have been infected by the infected person in this time, because 46 percent of the transmission happens before the symptoms start? And because it also takes some time before a diagnosis is made after the onset of symptoms and then for the contacts to be identified.

A very important number plays a role in this, namely the serial interval of the infection, which has been recalculated here, which actually tells us: Even if one isolates immediately at the beginning of the symptoms, i.e. immediately removes a symptomatic person from the transmission situation, then not only has he already infected people, but these people who are subsequently infected are themselves also already contagious at the time when the first patients show the symptoms.

We have actually already observed something like this in the Munich case tracking study and were surprised by it. But now there is, in principle, quantitative evidence, which really backs up the whole thing with numbers and rates, that this is actually happening.

Difference between manual and automatic tracking

Christian Drosten:

The main outcome of the study is that you are too late with a simple [manual] identification of cases and contact tracing, because the whole thing depends on identifying symptomatic patients. So it really comes down to the last day. ...

In other words, here it is calculated in a formally very correct way and very robustly on the very latest figures, that from a certain point in time of the epidemic, targeted diagnostics plus case tracking plus isolation of contacts cannot stop this epidemic. This is no longer possible.

What you can do to stop such an epidemic is to simply do a lockdown. Then you don't have to track cases, everyone will be at home. You can of course do a combination of measures where you say there is a lockdown, which is a bit milder. Like the contact ban. ...

So here [the study] conceives a hypothetical App. This App can record the symptoms at the onset of the symptoms - so you just type it into your mobile phone: I have symptoms now. Then the App says: Okay, I've already sent the data you sent to the lab. That means the App can already do the registration for laboratory diagnostics. In principle, you can be diagnosed immediately - the App itself triggers the diagnostic process.

Then the information about this diagnosis, if it is positive, will be included. And at that moment, the App can start to trace back which other mobile phones were in your vicinity. Of course you can also tell how long the contact should be and so on. ... And these holders of the other mobile phones are then informed. "You were in contact with a patient during the infectious period of that patient".

And you can say in a nutshell, if the epidemics ran at the same speed as in the beginning in Wuhan and if 60 percent of the case identifications via the App were successful (which means, you have to realize, that if 60 percent of the population would install such an App and if then again about 60 percent of those who are informed that they should stay at home actually stay at home), then you could already lower R0 below one. This is amazing.

There are a few caveats on that. It is then said that in reality the speed of propagation in Europe is already faster than it was at the beginning in Wuhan. There are certainly several reasons for this. Population density, behaviour of the populations, but also how far the infection has already progressed. This of course makes it even more difficult again, so that a higher degree of cooperation among the population is actually needed. ...

But it is achievable, it is an achievable goal to use such apps to make these inevitable time delay in reporting activity to bridge the gap. To communicate the essential information "You have been in contact with an infected person, you should get tested now" and the time you gain there, that would actually do much more or almost the same as a real lockdown - under this mathematical model.

Then there are a few follow-up effects and a few possible opions. One possibility, for example, is that in a "high incidents situation" - a place where there's a very serious epidemic going on, or at a time when there's a wave of infections - you could bring even more speed into the whole system by saying we're going to leave out this testing stuff. We're reprogramming this App now. If I check this box now, I have symptoms, the App doesn't tell me: "Okay, I've already signed you up with the lab for testing," but the App says: "Okay, we see you as positive now.

Anja Martini:

Then I'll stay home.

Christian Drosten:

Right. Anything symptomatic is now defined as positive without testing. This is, of course, an intervention measure, that this criterion is aggravated.

Combining the App with other measures

Christian Drosten:

Of course you have to say that you could combine such an App, for example by other general factors that reduce the transmission of the infection, such as wearing masks. This is of course not included here, because we do not know exactly how much wearing masks could perhaps reduce the overall transmission activity if everyone wore a mask, and there are no estimates of the numbers. But it is conceivable that this combination of a mask, if everyone wears it in society, if it has an effect, that this effect will be added to such a finely controlled App.

And that is a real prospect. In this public discussion, which is of course already going on at the moment with some desperation: How do we exit these measures? And what do we do next?

I'm fascinated by the thought that such an App, especially if many would participate, would provide us with an instrument to achieve a completely different subtlety of control and to be able to say that normal life can go on.

There is no general lockdown. Companies can work, schools can teach, everything can work, but not for everyone at all times. There will come a time when you have this message on your mobile phone: "Please go into home quarantine. If you could then show this and your employer would say: Well, that's how it is, home quarantine this week. Then I find, that is at least a very interesting model one should not refuse thinking about.

At the end of the interview Drosten comes back to the App and emphasises another advantage:

And to think about such smarter measures that are really feasible and which, by the way, can even be implemented in poor countries, where lockdown does not work the same way, but where everyone still has a mobile phone in their pocket. Of course, we must think about this and set an example.

What can you do for your immune system?

Anja Martini:

Quite a lot of people also ask themselves again and again: Can we do more? For example, can we do something for our immune system and build it up? Maybe vitamin C, vitamin D. You got any ideas? Can you do that? Running?

Christian Drosten:

So of course it is always good to have a good immune system. And of course, it's always good to be fit as a fiddle. Surely it's not the case that you will immediately be infected by running in the park, just because you encounter other people. That's certainly not something to worried about, going outside and running. This, you can, I think, recommend.

But that's where it stops.

What you can say is to stay away from people who might be infected. Right now that would just be anybody you meet, for example when you go shopping or something.

There is this rule in the USA that says: Six feet, six seconds. So six feet apart and six seconds of contact, you should take that as a rule. So that you keep this minimum distance and don't stay so close to somebody for so long. That's probably such a good way of thinking when moving around in public places.

Other podcasts

Part 28: Corona Virus Update: exit strategy, masks, aerosols, loss of smell and taste.

Part 26: Corona Virus Update on Vaccines: clinical trials, various types, for whom and when.

Part 23: Corona Virus Update: need for speed in funding and publication, virus arrival, from pandemic to endemic

Part 22: Corona Virus Update: scientific studies on cures for COVID-19.

Part 21: Corona Virus Update: tests, tests, tests and how they work.

Part 20: Corona Virus Update: Case-tracking teams, slowdown in Germany, infectiousness.

Part 19: Corona Virus Update with Christian Drosten: going outside, face masks, children and media troubles.

Part 18: Leading German virologist Prof. Dr. Christian Drosten goes viral, topics: Air pollution, data quality, sequencing, immunity, seasonality & curfews.

Related reading

This Corona Virus Update podcast and its German transcript. Part 27.

All podcasts and German transcripts of the Corona Virus Update.

The study in Science Magazine on the impact an App could have: Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing

Corona Virus Update on Vaccines: clinical trials, various types, for whom and when (part 26)

Prof. Dr. Christian Drosten

This edition of the Corona Virus Update Podcast with leading German virologist Christian Drosten was all about vaccines. How can we speed up the development of a vaccine, how do the various types of vaccines work and how fast can they be produced, who would get the first doses available and when will vaccines be available?

The development of vaccines is a race against the time. In an interview with Trevor Noah Bill Gates explained that the USA is building 7 manufacturing plants for 7 possible vaccines, knowing that somewhere along the way they will focus on 2 of those 7 possible candidates and that thus 5 plants will never be used.

Large parts of this interview were about fundamentals. This was really interesting, I would almost go to the library to get a text book on vaccines, but I did not understand much of it well enough to translate it with confidence. So while probably still quite nerdy, this post is mostly about more practical matters.

Shortcut: use existing backbone vaccine system

Korinna Hennig:

Today we want to tackle the big issue of vaccines, which is a complicated and convoluted one. We actually have a strange situation. The development of vaccines has never been as fast as it is at present. The USA have already reported the first tests on volunteers. And yet all of this is still too slow - in terms of the virus - because several longer phases of clinical testing are prescribed.

Two weeks ago, you said here in the podcast that we need shortcuts for vaccine approval. Before we get into the big issue of "What is happening? What are the vaccine candidates aiming at?" I would still like to ask, in a very abstract way: At what point in the long process is such a shortcut even conceivable?

Christian Drosten:

This shortcut is not only conceivable, but has already been envisaged for some time. For example, what you can do is to use so-called vectors, vaccine vectors that we already know. ... We sometimes speak of the backbone of the vaccine. ... for example one that works well, which is MVA, which is [[Modified Vaccinia Ankara]]. This is a variant of the vaccinia virus, which was used for smallpox vaccination in the past, and is an extremely well tolerated vaccine carrier. And proteins or antigens from the new coronavirus can now be integrated into this system and can then be applied to humans and gets an immune response to these proteins of the new coronavirus.

But for this carrier system, and this also applies to some other carrier systems, a great deal of safety data is known from other diseases for whose vaccines these carrier systems have also been used. In other words, we know exactly and do not necessarily have to repeat everything in this emergency situation, such as how laboratory animals react to it. For example, how the basic solution of the vaccine is tolerated and so on. Many things, including pharmacokinetic issues. For example, how is this distributed in the muscle when the vaccine is injected into the muscle?

All these things have already been resolved. It is absolutely not to be expected that this marginal change of such a known carrier system will, due to the adaptation to this other virus, will lead to relevant differences in important places. Because one has both in this case now for the MERS virus experience with the MVA, as with other carrier vehicles, i.e. with other vectors, you also have experience for other vaccination targets, for other diseases. These are then only very minor adjustments.

How to infect human volunteers

As helpful background information, I have added the phases of the clinical trails for drugs in the table below, which I "borrowed" from our friends at Wikipedia. In case of vaccines you do not only need to test the drug, but also expose the volunteers to a potentially dangerous virus. How to do this in a realistic and safe way is not trivial.

(As a aside, interesting that Wikipedia used Roman numerals for the phases and then included a Arabic zero.)

Phase	Aim	Notes
0	Pharmacodynamics and pharmacokinetics in humans	Phase 0 trials are optional first-in-human trials. Single subtherapeutic doses of the study drug or treatment are given to a small number of subjects (typically 10 to 15) to gather preliminary data on the agent's pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs). For a test drug, the trial documents the absorption, distribution, metabolization, and removal (excretion) of the drug, and the drug's interactions within the body, to confirm that these appear to be as expected.
I	Screening for safety	Often are first-in-person trials. Testing within a small group of people (typically 20–80) to evaluate safety, determine safe dosage ranges, and identify side effects.
II	Establishing the preliminary efficacy of the drug, usually against a placebo	Testing with a larger group of people (typically 100–300) to determine efficacy and to further evaluate its safety.
III	Final confirmation of safety and efficacy	Testing with large groups of people (typically 1,000–3,000) to confirm its efficacy, evaluate its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely.
IV	Safety studies during sales	Postmarketing studies delineate risks, benefits, and optimal use. As such, they are ongoing during the drug's lifetime of active medical use.

Korinna Hennig:

We have already talked in this podcast about how important clinical testing is, that you first test for safety and intolerance, that you test it in animal experiments, that you then go to small groups and only in phase three do you do large cohort studies with many volunteers. Is it possible to run any of these processes in parallel?

Christian Drosten:

Yeah, it is already such that the preclinical evaluation can be shortened considerably because it is already known that these vaccines are very well tolerated. And that we will then carry out a safety study in a group of volunteers, in humans. If the vaccines are well tolerated, then it is possible to expand the vaccine relatively quickly, i.e. after an initial efficacy study, the trials can be expanded relatively quickly.

Then, of course, there is always the question - and this is also being discussed to some extent at the moment, as there are many commentaries on it in the medical literature - of how to deal with a situation where people would say, for example: "There is a crisis group of volunteers, they are all healthy and they would be willing to help. In principle, they would roll up their sleeves and say: "Vaccinate me and then give me the real virus in my throat so that I can get infected or something, so that the vaccine can then prove that it has protected me."

This simple consideration, the heroic volunteer - how to deal with it, it's not that simple. Such a person, who most of all means well and would like to have an approved vaccine quickly, is not in a position to judge for themselves, and so there is a person in charge of the experiment, a doctor and a scientist, who has many things to consider.

For example, you cannot simply put a laboratory virus in somebody's throat to make them get infected. The question is: how much virus is there in the natural infection? These exposure infections, which are known in animal experiments, where you give laboratory animals a defined dose of a laboratory virus and then see whether the vaccination you have previously given protects them, cannot simply be transferred to humans.

We do not know how the normal patient would naturally be exposed to the virus. This leads to the fact that in such studies, where one would like to shorten many things, one again needs a different kind of parallel exposure experiments in a good animal model. ...

Then, apart from that, there is a completely different line of reasoning. And that is that in this situation, which we have at the moment, with a lot of infection events taking place outside, you naturally have a situation where, in such broader studies of the effects of a vaccine in humans, you do not necessarily say, "You will infect the vaccinated persons after the vaccination", but rather simply say, "You vaccinate persons and you measure whether they get antibodies, for example". Or you can measure whether the immune cells of the person's body are activated and react against the virus. So you take blood from people after vaccination and then you extract immune cells from the blood and measure whether these immune cells have become sensitive to the virus in the test tube. ...

Here we get almost without wanting it and naturally also plan with it, information about the then actual protective effect. The virus will circulate until then, and of course we will also record among the inoculated patients who will later become infected. Of course, this will also be compared with the population in which the whole thing is taking place.

Most promising type of vaccine

I skipped a large part of the interview describing two part immune system (cellular and humoral response), how a vaccine triggers them and an example of why a vaccine can in the worst case backfire. Thus why one has to be careful before exposing volunteers. You better read an independent text, than my possibly inaccurate translation.

There are many ways to make a vaccine and Korinna Henning asked about the most promising route.

Christian Drosten:

The natural infection [response] is a mixture of cellular and humoral activity of the immune system. Humoral means antibody formation. Cellular means immune cell activation. Now we can say in one approach that we make particularly good antibodies. In another approach, however, we can also say that we make particularly good immune cell stimulation through a carrier vector of a vaccine, which stimulates the immune cells better than the natural virus would do. This means that we pick out the strengths of the immune system and stimulate them in a very special way. ...

It is not at the moment that it can be said that one way is already the more promising. One can certainly say that with the very simple way of the ordinary inactivated vaccine, you have to look very carefully and be very careful because of the dangers. And what I have just described, this antibody-mediated exacerbation, is only one of the dangers, the nasty surprises that can be experienced with such simple vaccines.

That's why it's right to focus on the more technically advanced vaccines. Here there is a sense where one can already say a little bit about the direction. And that is vaccines that aim to make particularly high neutralising antibodies that often only use a simple protein as a vaccine substance.

This protein is better produced in the biotechnological industry in a shorter time than very expensive modified live vaccines, i.e. vector vaccines that are mainly aimed at stimulating the cellular response in a particularly effective way. The production of this vector vaccine often simply quantitatively not so simple. Since you have to use a lot of production material in motion, i.e. many cell cultures in fermenters to achieve a high yield of these vaccines.

While the production of such proteins, simply biotechnologically, i.e. one can say: is more straightforward, you know exactly how that works. There are fewer parameters to optimize in the pharmaceutical industry, the purification processes are often simpler.

Who gets the vaccine first?

Christian Drosten:

Clinical staff, where we have people who are basically healthy and basically able to make a good immune response. ... This could be one of those preferred groups to be vaccinated.

And, of course, people will immediately think, no matter whether it's these vaccines or another ... of course we have to give it to the risk groups immediately. This consideration is perhaps a bit too simple in parts, because at the beginning, when the first vaccines are available, we may have to try to achieve a high impact in the population with a small amount of vaccine.

So, vaccinating medical staff has the greatest effect if you prevent all of them from dropping out. Clearly that is important, everyone understands that immediately. When vaccinating elderly people, for example, in many cases there is a big problem with vaccine dose. They need more vaccine for the same immune response.

And when the dose is limited, when the production of the vaccine is limited and you know that there is a group of patients who need five times more vaccine than the normal patient - then you will soon come to the point where you say that it is practically impossible to produce five times more vaccine. So you have to think, do you want to make five times more vaccine and vaccinate the people who are at risk? Or do we want to make five times more vaccine and thus vaccinate five times more normal patients, thereby significantly increasing the protection of the population with the vaccination and thus stopping the pandemic earlier? These are all considerations that have to be made individually for each specific vaccine.

When will we have a vaccine?

Korinna Hennig:

When we have talked about these biotechnological variants, biotechnologically produced protein: Does that include the 12 to 18 months it takes to get that far? Or is there still time to be gained through this very process?

Christian Drosten:

Right, you hear 12 to 18 months now. In this time range, which has always been said that if everything really goes well, if it goes very quickly, then, depending on the vaccine concept, you can expect to have an approved vaccine within one or one and a half years. In other words: next year at this time or next year in the summer. I can assure you that everyone is really trying extremely hard and that everyone is sitting down and talking to each other how we can still win time - because it is clear that the real relief of this situation comes from a vaccine. ...

We will certainly have a staggered process. We will certainly have a situation, where already small amounts of a very first vaccine are available. Where we also have grey areas, where we say that the vaccine has not yet been approved at all, that is still part of the approval procedure, that is still part of the clinical trial, in other words an efficacy study. But there are already so many patients involved that they will benefit from the vaccine. These things will naturally happen.

But if we think about it now, when we will probably have a vaccine for the general population, in other words: a vaccine is available, in sufficient quantity available, the whole logistics is also available, it is also filled in ampoules, it is already inoculated by doctors. Then we'll just have to say next year this time at the earliest this starts, and then by summer 2021 it starts for the broader public.

Other podcasts

Part 28: Corona Virus Update: exit strategy, masks, aerosols, loss of smell and taste.

Part 27: Corona Virus Update: tracking infections by App and do go outside.

Part 23: Corona Virus Update: need for speed in funding and publication, virus arrival, from pandemic to endemic

Part 22: Corona Virus Update: scientific studies on cures for COVID-19.

Part 21: Corona Virus Update: tests, tests, tests and how they work.

Part 20: Corona Virus Update: Case-tracking teams, slowdown in Germany, infectiousness.

Part 19: Corona Virus Update with Christian Drosten: going outside, face masks, children and media troubles.

Part 18: Leading German virologist Prof. Dr. Christian Drosten goes viral, topics: Air pollution, data quality, sequencing, immunity, seasonality & curfews.

Related reading

This Corona Virus Update podcast and its German transcript. Part 26.

All podcasts and German transcripts of the Corona Virus Update.

America is a somewhat weird country where comedians often produce better news coverage than the normal news on TV. Trevor Noah of the The Daily Show asks Bill Gates thoughtful questions: Bill Gates on Fighting Coronavirus.

Corona Virus Update: need for speed in funding and publication, virus arrival, from pandemic to endemic (part 23)

Prof. Dr. Christian Drosten

For me an interesting part of the Corona Virus Update Podcast was a critique of the scientific funding and scientific publishing system by Christian Drosten. Working on a better (and potentially faster) post-publication peer review system, this is of interest to me. The rest can skip to a discussion on the evidence for when the virus arrived in Europe, in the light of many anecdotal claims the virus arrived much earlier. And we finish off with why Drosten expects the SARS-CoV-2 virus to become endemic, that is stay forever.

A large part of the podcast was about a new research network of university hospitals to coordinate research on SOVID-19 in Germany. I presumed this was not too interesting for people outside of Germany, but readers interested in clinical research can try to read an automatic translation of the beginning of the German transcript.

In episode 23, science journalist Korinna Hennig of the German public radio station NDR Info interviews virologist Prof. Dr. Christian Drosten of Charite research hospital in Berlin. He was intimately involved in the research on the first SARS virus and produced the WHO test for the SARS-CoV-2 virus. The podcast has become one of the most listened to podcasts in Germany in just a few episodes and is my main source of nerdy info on Corona.

Question the whole system

From talking about the new German network for clinical COVID-19 research, Drosten moves to problems the normal funding system has given the speed that is necessary to fight the pandemic. In the past universities and research institutes had their own resources, but nowadays most of the funding flows via research projects (third party funding). This means that research proposals have to be written, reviewed and assessed. Only a small part of these proposals lead to funding and writing them thus binds much time that is nowadays no longer spend on science. Politicians like this system because they can feel that this looks like a free market, while in reality there is no market, science is a global public good.

Also the publishing system is not able to provide information fast enough. Normally one would write a solid manuscript, because only the best ones are accepted, they are reviewed, which takes a few months, updated, reviewed, etc. There is no time for that now. So the manuscripts are simply uploaded on manuscript server on the internet and can be downloaded by any scientist before they are reviewed by peers. These manuscripts are called preprints, as if they are to be printed in a journal (and as if most journals would still be printed on paper), but many will likely never pass review.

That was my take. Here is Christian Drosten:

Christian Drosten:

Our big problem in research, in the implementation of actual directly necessary scientific investigations - I am now not speaking about long-term basic research projects, I am talking about very specific questions: This new drug, is it helping or not? Will we know in a month? It would be good to know in a month.

In this situation, we can absolutely no longer afford to launch complicated applications, where we are competing fiercely for pots of money that may be wrongly dimensioned, and where it is no longer possible to organise the review of these applications. The reviewers are themselves scientists. But they are then themselves involved in these outbreaks.

In research funding, the more international and the more grandiose the whole thing becomes, the more this leads to a phenomenon that the qualification for obtaining such research funds is no longer necessarily the fact that one is really working on the problem, but that can lead to a situation where those who have specialised in obtaining research funds and not in treating these patients actually get the research funds. The qualification for obtaining such research funds is no longer necessarily the fact that one is really working on the problem, but that can lead to a situation where those who have specialised in obtaining research funds and not in treating these patients actually get the research funds.

Korinna Hennig:

That is anyway a big problem in scientific work, that it is said that this third-party funding has also become more and more important and eats away at an increasing proportion of the researchers in their actual everyday work.

Christian Drosten:

We see in the current scientific activity on the epidemic that the raising of third-party funds is no longer possible in its time frame. We urgently need other mechanisms for directing money to where it is really needed and where it can really be used. And where time is not stolen from those who treat and research patients.

We have exactly the same in the publishing market. There, too, we see that important information is difficult to communicate in the classic publication system. This entire information market is changing at the moment. We always discuss the preprints here in the podcast, and I always say they are preprints. We can do this here because I know my way around quite well, because I have been working on exactly this topic for many years and always understand immediately or frequently relatively quickly whether a study is really really solid and provides really new information. Or whether what is written in the headline or in the abstract sounds strong, but is in fact dead in the water.

This is something that is achieved in the normal publication process through an elaborate and drawn-out peer review process. But what we are seeing here at the moment is that the epidemic is moving much faster than the publication system is able to process the information. It is already difficult enough to collect the information while doing clinical research on patients. If, on top of that, the compilation of information is not sufficient because the results are submitted to a journal, but it is held up by reviewers who sometimes ask good questions, but sometimes ask these questions too late because they themselves are completely underwater and do not have time to review. And because they partly - let's say with a competitive idea - delay work, we know that everywhere. That is one of the weaknesses of the peer review system.

Then at some point we get into a situation where we have to question the whole system, where we really have to say: Can we actually afford such a system in such a situation? And we are currently seeing a huge flood of important publications appearing in these preprint servers, and they are coming from China. The colleagues there in China who have carried out clinical research and described their patients are only now able to subsequently evaluate what they have observed.

And the place where we see this first is in these preprint servers. You have to be very damn careful. Because in addition to many high-quality publications, which I also highlight from time to time in this podcast, there is a lot of dead wood.

When did the virus arrive in Germany and Europe?

Korinna Hennig:

More and more listeners are now emailing us with the question: Is it really impossible that the virus has not been around in Europe and Germany for some time?

Christian Drosten:

We've been getting a lot of requests lately from people saying, "I had this condition in December." ... I've had contacts where people have said: "I work for a large automotive supplier, and not the one that is known [in Starnberg]. ... "We had exactly the same thing. We also had visitors from China. And we also had a wave of infection afterwards and whole families got sick. Shouldn't we send samples?" So I always said: "Yeah, sure, send serum samples. We'll test it."

And in none of these cases have we ever found any evidence - with all these anecdotal investigations that we have conducted so far in Germany.

Also looking at the viral sequences it doesn't really look like it was there before mid-January in Europe. I remain open to this possibility, I'd like to add. I don't want to rule out this. But we, and others as well, from whom we know, have not found any evidence yet.

From pandemic to endemic

Korinna Hennig:

You said that you assume that SARS-CoV-2 will become endemic, i.e. that it will remain here permanently as a respiratory virus and not disappear completely at some point. Why are you so sure about that?

Christian Drosten:

Well, because it simply is spreading so far. Also because we can assume that a complete infection of the population will occur. In other words, we must assume that 60 or 70 percent of the population will be infected before the pandemic spread stops.

Then, of course, the rest will be subsequently infected, so that will continue to be the case after the infection. And then we will have the same starting conditions [for the new Corona virus] as for the other endemic corona viruses. And they also manage to keep population niches open and to develop them and then reinfect the children who are born after the infection in order to keep them in the population. Nobody can say for sure at the moment whether this virus will remain in the end or not. Everything looks very much like it.

Other podcasts

Part 28: Corona Virus Update: exit strategy, masks, aerosols, loss of smell and taste.

Part 27: Corona Virus Update: tracking infections by App and do go outside

Part 26: Corona Virus Update on Vaccines: clinical trials, various types, for whom and when.

Part 22: Corona Virus Update: scientific studies on cures for COVID-19.

Part 21: Corona Virus Update: tests, tests, tests and how they work.

Part 20: Corona Virus Update: Case-tracking teams, slowdown in Germany, infectiousness.

Part 19: Corona Virus Update with Christian Drosten: going outside, face masks, children and media troubles.

Part 18: Leading German virologist Prof. Dr. Christian Drosten goes viral, topics: Air pollution, data quality, sequencing, immunity, seasonality & curfews.

Related reading

The Corona Virus Update podcast and its German transcript. Part 23.

Corona Virus Update: scientific studies on cures for COVID-19 (part 22)

This edition of the Corona Virus Update Podcast focusses on the scientific work on cures for COVID-19. What are the various substances and drugs that are currently being tested, how do they work and how promising are they? But starts with a clarification of yesterday's podcast on lateral-flow antibody tests.

This is part 22 of the Podcast recorded on Wednesday the 26th of March 2020. Science reporter Anja Martini of Germany public radio (NDR Info) talks to Professor Christian Drosten, the head of virology at the at a top German research hospital, the Charité in Berlin. He developed the first test for the virus, which was send to 150 countries by the WHO.

Antibody tests for the public

Anja Martini comes back to yesterday's topic of antibody tests because she received many questions:

Offers are accumulating in doctor's offices: Namely 50 tests at a unit price of 22 euros, please pay one hundred percent in advance. What do you say? Should you be more careful with these things, or what kind of thought comes to mind?

Christian Drosten:

Well, yeah, sure. Careful, definitely. It has to be said, these are lateral flow tests that can be manufactured in large quantities. That's a good thing that it' s technically possible. It's just that the current lateral-flow tests available ... have not yet been validated. So we do not know whether these antibody tests work as well as a real laboratory-based test, i.e. an ELISA test for antibodies, for one thing.

And on the other hand, there is something we already know for sure, namely that antibody tests are too late for acute diagnostics. These antibody tests can only become positive after about ten days of the disease. There are a few patients who have antibodies after only seven days. But in today's situation, when you have a test for the new virus and wants to be tested, then you ask actually always: Did I get infected? Did my symptoms come from this virus maybe? In this situation an antibody test is not useful.

These tests are mostly produced by Chinese companies. Racists abuse this situation to attack China by accusing them of producing bad tests to attack the West. This is Trumpian ignorance of people who should be attacking Xi for being an authoritarian like Trump. They should be attacking China for their concentration camps, for their lack of political freedom. But you do not get to complain that you are a gullible uninformed fool.

Anja Martini:

This antibody test, which might become available for the general public, namely the self-test, how should I imagine it technically? ... You put a prick in your finger and then you can put it on a piece of paper and see if you have antibodies or not?

Christian Drosten:

Yeah, that's pretty much how these tests work. There are several devices that extract a drop of blood from a fingertip. Then they record it. And then it runs from one side to the other in a test strip as a front, just like for a pregnancy test the urine. And at the end there is one stripe or two stripes. And if you see two stripes, the test is positive ... But as I said, all this is not yet technically validated. It will work somehow, maybe better or worse. But of course the normal laboratory-based test will also be widely available.

Polymerase Chain Reaction test

Also Polymerase Chain Reaction (PCR) tests for the virus itself were discussed in yesterday's podcast. There are cases where the patient clearly had COVID-19, which you can see in a lung x-ray, but that the test does detect it. For example patients who stayed at home as long as possible and only arrive in the hospital the second week they are ill. In this case the virus has sometimes disappeared in the throat and is only present in the lungs. Either by sampling sputum the patient coughs up or with a suction catheter a doctor can take a sample from the lungs and detect the virus that way.

Christian Drosten:

This has also caused great concern in China, in Wuhan. So much so that, from a combined impression of this apparent unreliability of PCR from the throat, and also of the laboratories being overburdened, that practically no more PCR capacity was available, they switched to a diagnosis based on the CT image at the peak of the epidemic in Wuhan, because on average, patients were seen relatively late. They stayed at home for a long time, they did not want to go to the hospital. And then they changed the diagnosis.

Remdesivir

Anja Martini:

We want to look at drugs today, because there are now several drugs that are tested in hospitals. ... Remdesivir, for example, is a drug that was originally developed for Ebola and is now being tested in two studies on corona patients in Germany. What do you currently know about these studies and how they are going?

Christian Drosten:

In the case of Remdesivir, for the time being, we have here a substance with a plausible and known mechanism. It's an inhibitor of viral RNA polymerase, the virus' replication enzyme. And we have had this substance in the literature for quite some time, it is clear that it is effective against corona viruses in cell culture and also in animal models. That's good. So not for every substance that is currently undergoing clinical trials, we do not have this convincing initial evidence. But for remdesivir it is very good, this initial evidence. There's a real mechanism.

The above paragraph may be a bit too much in the weeds, but I included it to show how a scientist assesses a situation and the likelihood that something will work before the evidence is conclusive. Having two options where test tube tests show they work similarly against viruses, one would first go for the option where one understands why. Even if test tube showed somewhat less good results, I would still go for the one where we understand why. This is one way to protect yourself against problems with purely empirical evidence, which has produced reproducibility problems.

And now the company that distributes Remdesivir, Gilead, has been allowing [[compassionate use]] protocols for quite some time. This means that in certain constellations, the drug is released for a single patient. This is a phase of the disease where the patient already needs oxygen but does not yet need catecholamines, i.e. drugs that support the circulation. This is already a critical phase in the course of the disease. This is the transition where they say soon the patient may have to go into intensive care. It's a critical time when you want to influence [the condition of] the patient.

But the problem is that this is a direct antiviral substance, so we would like to administer it earlier. The virus attacks the respiratory tract in the first week of the disease. In the second week of the disease, when the virus deteriorates, we already have a combination of immune and viral effects that act in the lungs. This suggests that in this later phase you can't do as much if you specifically do something against the virus. You have to be careful that you might also do something against an excessive immune reaction. There are also clinical studies on this. And this is true for Remdesivir as well as for other substances where one could assume that there is a direct effect on the virus.

The rest of this section is background information on how RNA viruses work and how Remdesivir interferes, which you can skip if you just care about your health, but I find it fascinating.

Anja Martini:

How does Remdesivir work in this virus? What does it do?

Christian Drosten:

The virus is an RNA virus. And RNA viruses can't use the replication enzymes in the cell nucleus. Our cell nucleus has DNA. And when cells divide, the DNA has to be replicated.

And some viruses, DNA viruses often, they can use these multiplication enzymes for themselves. So they abuse the duplication enzymes of the cell nucleus for their own genetic material. But RNA viruses cannot do this because our cells do not need to duplicate RNA. Our cells do possess RNA. This RNA is only copied from DNA and is actually the template for proteins. This is the so-called messenger RNA, in the simplest approximation. There are of course other complicated subforms of RNA and so on. But let us now talk about the main case. This messenger RNA is not being replicated. It is simply copied once. But for viral replication, we need proper duplication. And in that process we need to have a step where RNA is copied from RNA. The viral genome consists of RNA, and the product consists again of RNA, we say the replicative intermediate, and from that again RNA has to be copied back again. After all, we have plus and minus and then again a positive sense of the genetic information in this multiplication.

All this leads us to the conclusion that the virus itself must bring along an RNA polymerase, an enzyme that carries out this multiplication, this transcription. There are different ways in which RNA viruses do this. Some RNA viruses have a functioning RNA polymerase in the virus particle. Polymerase is an enzyme that generates a polymer that transcribes. This takes a template, which is the genome of the virus, and makes a copy of it, a mirror image copy in the reading sense, and then takes this mirror image copy again and makes the next generation of genomes from it, which is then packaged. Some viruses bring this as a functioning enzyme, as a protein in the virus particle.

Other viruses simply encode this, they carry the enzyme as genetic information. This is then converted into protein in the cell by ribosomes. The protein that is produced there can then duplicate the viral RNA. Coronaviruses do it in the latter way. Corona viruses bring genetic information with them in order to create an RNA polymerase in the cell do-it-yourself, which is what the cell does, and this enzyme is inhibited with emdesivir. ...

We could also go back into detail here, because it is not quite so clear how things work exactly. We do not know whether the RNA polymerase itself is inhibited in its processivity, or whether the assembly of essential building blocks of the resulting RNA is inhibited, or whether the RNA polymerase continues to work, but makes so many copying errors that the viruses that come out of it are dead.

Chloroquin

Anja Martini:

Chloroquine, we still have to say, is an antimalarial drug that is not completely free of side effects, but also against the old SARS virus, at least in cell cultures, has been successful, right?

Christian Drosten:

Right, exactly. In cell cultures and against all kinds of viruses. ...

A lot of people who know about it, including myself, are very sceptical about chloroquine, whether it is really helpful in the end. But I also cannot say what it will look like in the end if a very large study is carried out with a large number of patients. And the up analyse the clinical fate of these patients, what would be the outcome for the patients? So there might be a very small effect.

This effect does not necessarily have to be directly related to the virus, because chloroquine also has a strong influence on inflammatory processes in general. These also play a role in lung damage, so that it is not possible to say exactly what to expect.However, one thing can be said: A resounding effect that really decides the fate of the clinical outcome can hardly be expected with chloroquine. ... Let's put it this way, then it would be very easy to observe it. Then there would be no such contradictory clinical studies. If the effects are quite clear, it is also quite easy to prove the clinical effect.

Favipiravir

Christian Drosten:

There is another substance called favipiravir. ... It is approved for use against influenza in several countries. So you can buy it in pharmacies against influenza, for example in Japan. ... This substance is also available in China against influenza. There is now a first study, which has been published, so perhaps we can clarify where we stand. So in case of Favipiravir, we know exactly what the mechanism is.

But I have to say that when it came up to give favipiravir against the new virus, I was surprised, because years ago, when this substance was still in the experimental phase, we did not call it favipiravir, but T-705, which was the short name for a chemical substance at that time. And it did not work well in cell culture. We didn't pursue it further. ...

Favipiravir is now being used in China after all. And a first study has just come out. ...

And in contrast to the French study, which we discussed for chloroquine last week, here it is the case that they really looked at a clinical starting criterion. They simply asked: How is the improvement of the clinical picture seven days after starting the administration of the drug? Clinical picture means for example respiratory rate, fever and other general symptoms of the disease. ...

Most of the cases here are quite normal initial cases, they are not intensive care cases. For example, there were only 18 severe cases here with pneumonia in a total of 116 people who were treated, so the overwhelming majority were not severe cases. And of course they have been included at an earlier stage accordingly.

So now we can say that the difference that can be obtained in this rather optimal situation is that clinical symptoms improve in 56 percent of the cases where no treatment is given, and in 72 percent of the cases where treatment is given. That is a significant difference, a significant difference statistically.

And that's amazing to me. I have to say that in view of the fact that we never actually saw a good effect of this substance in cell culture, I am still skeptical if this is real or if there's some kind of flaw in the clinical study. Now we have to see what other studies indicate. It's certainly not enough, to take one study and even more so one study that has not even been formally reviewed yet.

Camostat

Anja Martini:

I believe that you yourself are also working with Göttingen researchers on a drug at the moment. How does it work?

Christian Drosten:

That's right. There are studies that we have done together with Stefan Pöhlmann's group in Göttingen, a really absolute specialist in virus entry. Stefan has seen that it is possible to reduce virus entry with a substance called camostat. ...

So it is the case that this virus, this new SARS 2 virus, uses a certain transmembrane protease in a stronger way than the old known SARS virus. And that is, as the name suggests, a protein-cleaving enzyme, but this time it is not an enzyme from the virus but an enzyme from the cell. So the cell itself has this protein on its outer membrane. And with this protein, the cell involuntarily helps the virus enter the cell, by the passage through the membrane. This works in such a way that the surface protein of the virus is cut at one point, is clipped, and this clipping of the surface protein is the first step for the virus to pass through the cell membranes. This virus uses this cellular protein for this purpose.

There is a drug that inhibits this cellular protein and this drug is called camostat. I am deliberately saying drug and not substance, because this substance is approved as a drug for chronic pancreatitis. And it is only approved in Japan. So in Japan you can buy it in the pharmacy. This much we know. We know it works in cell culture, and we know the drug is available in Japan. That's all we know.

But on this basis we can now of course do something that cannot be done with other substances. Namely, we can say that we do not have time for large-scale animal experiments, but we have an approved substance here. In certain cases, we can now test this in clinical controlled trials to see whether patients benefit from it if they get this substance. This is a typical off-label use study. And we're going to do something like this start now.

That sounds promising. Do note that Drosten is here talking about his own research. It is always harder to be just as sceptical about your own work, any scientist will be able to attest.

Other podcasts

Part 28: Corona Virus Update: exit strategy, masks, aerosols, loss of smell and taste.

Part 27: Corona Virus Update: tracking infections by App and do go outside

Part 26: Corona Virus Update on Vaccines: clinical trials, various types, for whom and when.

Part 23: Corona Virus Update: need for speed in funding and publication, virus arrival, from pandemic to endemic

Part 21: Corona Virus Update: tests, tests, tests and how they work.

Part 20: Corona Virus Update: Case-tracking teams, slowdown in Germany, infectiousness.

Part 19: Corona Virus Update with Christian Drosten: going outside, face masks, children and media troubles.

Part 18: Leading German virologist Prof. Dr. Christian Drosten goes viral, topics: Air pollution, data quality, sequencing, immunity, seasonality & curfews.

Related reading

The Corona Virus Update podcast and its German transcript. Part 22.

Nature Magazine on the various possibilities where the virus comes from: The proximal origin of SARS-CoV-2. "This is strong evidence that SARS-CoV-2 is not the product of purposeful manipulation."

European Medicines Agency: COVID-19: chloroquine and hydroxychloroquine only to be used in clinical trials or emergency use programmes. "The European Medicines Agency (EMA) is a decentralised agency of the European Union (EU) responsible for the scientific evaluation, supervision and safety monitoring of medicines in the EU."

Corona Virus Update: tests, tests, tests and how they work (part 21)

The Corona Virus Update Podcast of Wednesday the 25th of March was mostly an interesting lecture about tests. With pain in my heart I cut out the part on the different types of antibodies and the different parts of the immune system. So if you know some German, do read the German transcript. It was a really interesting interview.

The interview with Prof. Dr. Christian Drosten, who studies emerging viruses, was performed by science journalist Korinna Henning. I presume colleagues now call her Corona Henning. Or maybe German public radio is more professional than a university.

The podcast is my main source of Corona science. It is great to listen to someone who knows what he is talking about and is honest about the current limits of our knowledge.

The podcast is about tests for the virus itself, which is what we currently mainly do, and about various antibody tests to detected whether people had the disease, that is had an immune response producing antibodies against the virus.

Polymerase Chain Reaction tests

The main work horse to determine whether people have COVID-19 is a Polymerase Chain Reaction test. This test detects the presence of virus DNA by multiplying it, if present.

Korinna Hennig:

We've already talked a couple of times in this podcast about antibody testing, which has high hopes because it can provide education about the many potentially very mild infections that go undetected. And about how much immunity is already in the population. But we have also repeatedly spoken about the need for large-scale testing for the virus itself. Perhaps we can clear up the large field a bit: The current test for the virus is a PCR test, which means Polymerase Chain Reaction. This is where the genetic information of the virus is multiplied and a colour reaction generated. In simple terms: what exactly is happening actually?

Christian Drosten:

This is a reaction in which the genetic material of the virus is copied and thereby multiplied. This is an invention from the late 1980s that has since then gained an increasing foothold in microbiological and virological diagnostics and in principle has increasingly replaced cultural methods - i.e. the cultivation [breeding] of such a bacterium or virus - in virology in particular; a lot is still being cultivated in microbiology.

This is due to the fact that PCR is both very sensitive and very fast, in terms of the method used, and also has a high specificity. This means that what you find there is really what you are looking for. That is because you have to add small DNA sections, really molecules, physical molecules, to this reaction in order to multiply what exactly matches these molecules.

This means that if, for example, I want to detect this new coronavirus in the polymerase chain reaction, then I have to produce small pieces of this new coronavirus in the laboratory, in the form of RNA, i.e. small snippets of RNA, which are only about 20 bases long, and they will then attach themselves to the genome. And they can only do this if they are really almost or completely identical, i.e. in the sequence of bases, with the genome of the virus you are looking for. And if there is another virus in there that is even a little bit similar, but is actually a different, we won't be able to detect it.

Korinna Hennig:

This means that other corona viruses are not incorrectly identified here?

Christian Drosten:

Right. So, the four cold viruses, human corona viruses, we can't detect them with that. That's not what we want. We only want the test to be positive if this new virus is actually present.

Where and when does the PCR test work?

The test by itself is highly reliable, but it is important that the sample of the patient is taken correctly.

Korinna Hennig:

But the test shows that presence of the virus, you just explained, not the immune response of the patient. In other words, if I do it too late, if I perhaps have symptoms, but the disease is already subsiding, then it is going nowhere, so to speak?

Christian Drosten:

With this disease, it is the case that in the first week of symptoms, the samples from the throat, i.e. the smears, are actually very reliably positive in the PCR. And then, in the second week, they are no longer reliably positive. Then the patient still has symptoms, but in the throat the test might not be able to detect this. This is not because the test is not good, but simply because the virus is no longer present in the throat, but it is present in the lungs.

We now know that even in patients who have very mild symptoms, i.e. who notice almost nothing of their illness, there is still quite a lot of virus in the lungs. And this remains there for about two weeks, or even three weeks, in the uncomplicated cases. That's how long we are able to detect the virus in the lungs with this polymerase chain reaction. However, many patients cannot simply cough up such a sample from the lungs, so throat swabs are actually the most common sample. What can be done, which is not yet well established systematically, is to take a stool sample. The virus is detectable there as well, and for quite a long time actually, as long, or almost as long, as in the lungs.

Korinna Hennig:

But no longer infectious, that was a realization that we also addressed at some point in the podcast: That this contact infection - as is the case with noro-viruses, for example - is not a transmission route for the coronavirus.

Christian Drosten:

Yeah, right. So in our tests, the virus is highly detectable in the stool. So that means it can be used as diagnostic information. But it doesn't look like an infectious virus. We can say this because we simply place the same sample in parallel on cell culture and then see whether a virus grows there and is alive. And it's not.

Random ELISA antibody tests

Sampling patients and people they may have infected makes it hard to interpret the data in terms of how the population is doing. This would require tests of random people. Such information would be very important for public policy.

Germany at the moment has about 50 thousand infections. With a population of about 80 million people, this means that in the order of one in a thousand are infected. Such random tests would thus need to be large to get reliable numbers. Germany already made about half a million tests. So such random tests would be possible, but would reduce capacity for potential patients. The current way of thinking is to wait doing random sampling until we have large scale antibody tests, which does not interfere with patient care.

Korinna Hennig:

You said before that we'll have to take a look around Easter, and then politicians will have to decide whether to take action. Then of course it would be good to know even more. Is it conceivable, as I just mentioned, that random tests could be carried out to detect even more really undetected infected persons?

Christian Drosten:

But what there will be in the very near future, and which is actually much more important and informative, are such random tests for antibodies. This is a completely different test procedure. If we get infected, it takes about ten days for us to produce antibodies in this disease. We have already looked at that; other studies agree. And those antibodies will then become even more apparent and even better in the next few days. So, at first, it's such a low level. And then, two or three weeks after infection, you have a very clear antibody in your blood.

And you can use a blood sample with a technically different kind of test - these are [[ELISA]] tests, enzyme-linked immunosorbent assay - to measure whether a patient has antibodies in his blood, regardless of whether he had a severe infection or a mild infection or a completely unnoticed infection. And that is what we are actually speculating on. If we knew that all infections were symptomatic, then you could actually say: well, we actually record quite precisely what we have in terms of PCR results, and now we do the calculations on that basis.

But what we do not know at the moment, and what unfortunately does not come out well from studies in other countries either - there are unfortunately no convincing data from China on this either - is the rate of those who are really completely unnoticed and infected in the population. So what is the incidental immune activity of this virus? How many people get infected without noticing it or without having taken it seriously because just a little bit of scratching of the throat? But they are still antibody-positive and, as we can assume, immune, and even then contribute to the 60 or 70 percent of the population that must have become immune or infected before the pandemic wave comes to a halt.

Validation of the ELISA antibody tests

Before introducing antibody tests on a large scale, one needs to study how accurate they are. Unreliable tests would be damage patients and help spread the disease.

Christian Drosten:

There is already the possibility of carrying out [a simpler] antibody tests on a smaller scale in the laboratory. ... We have been able to carry out antibody tests for this virus in our laboratory since mid-January - but only on a small scale because it is a lot of work. ...

For these large mass screenings, where we would like to test thousands of patients, we need an automated ELISA test, and they are all just being set up. ...

There is a German manufacturer, a large well-known manufacturer, whom we have helped from the beginning to both set up and, above all, evaluate these test procedures. So to ask: How does what they have set up there compare to our microscope test carried out at home? So when I say "at home", of course I mean in our own laboratory. ...

But [those validations] closed now, they look good. So we can attest to this manufacturer: Go ahead, start producing these so everyone can use them. Such studies are of course now taking place in many other countries. Other manufacturers are now asking us, too, whether we can help validate this. And of course we do that.

When will ELISA tests be available?

Christian Drosten:

We already have one machine here in the institute, and we will build a much larger machine in two weeks here in our laboratory. And other large laboratories elsewhere in Germany are also doing that these days, so it doesn't necessarily have to take another two or three months.

And these tests can then be sent in via a General Practitioner; a blood sample will be taken by the General Practitioner and the results will be available the next day or the day after next. ...

There are considerations on how to use such tests, which doesn't necessarily have to be the planned visit to grandma and grandpa, but also the question: Can this doctor or nurse actually treat patients with the disease again, maybe even with reduced self-protection, i.e. with reduced protective equipment, because there is immunity? That is a very important question, for example. Or outside in outpatient care, whether a nurse has survived the infection, yes or no, is extreme important for the operational capability.

Rapid antibody tests

Very new on the market are rapid tests, lateral-flow-tests, which look like pregnancy tests.

Christian Drosten:

Then, of course, such tests are now coming onto the market, antibody tests that you can buy yourself, perhaps soon in the pharmacy or even now already on Ebay. These tests have not yet been validated, they come mainly from Asia, especially from China. These are tests that also test for antibodies using a different test principle. At the moment, I simply have to say that this should be treated with caution because we do not yet have good validation studies. However, we are currently testing such tests from several manufacturers and are providing the manufacturers with feedback on how well they work. In the next few weeks we will certainly see publications and first publications about how well such rapid antibody tests work.

That these tests are not validated yet is used on social media to attack China for endangering the West with unreliable tests. I would say: if you are so careless to use such a test now, do not blame China for your Trumpian ignorance.

Other podcasts

Part 28: Corona Virus Update: exit strategy, masks, aerosols, loss of smell and taste.

Part 27: Corona Virus Update: tracking infections by App and do go outside

Part 26: Corona Virus Update on Vaccines: clinical trials, various types, for whom and when.

Part 23: Corona Virus Update: need for speed in funding and publication, virus arrival, from pandemic to endemic

Part 22: Corona Virus Update: scientific studies on cures for COVID-19.

Part 20: Corona Virus Update: Case-tracking teams, slowdown in Germany, infectiousness.

Part 19: Corona Virus Update with Christian Drosten: going outside, face masks, children and media troubles.

Part 18: Leading German virologist Prof. Dr. Christian Drosten goes viral, topics: Air pollution, data quality, sequencing, immunity, seasonality & curfews.

Related reading

The German podcast and German transcript of part 21.

All Corona Virus Update Podcasts and their transcripts in German.

Corona Virus Update: Case-tracking teams, slowdown in Germany, infectiousness (part 20)

The Corona Virus Update, part 20, of Tuesday the 26th of March was about whether the South Korean strategy of case-tracking teams is something for Germany as well, what the data on the number of confirmed infections tells us about the spread of the virus in Germany and about a new study on the infectiousness of the virus and what that tells us about how to contain it.

This podcast is produced by the German public radio broadcaster NDR. Science journalist Anja Martini interviews Professor Christian Drosten, just like every day. He is the head of the Virology Department at the Berlin Charité, which is one of the main research hospitals in Germany. As a scientist he can speak more freely than, for example, the director of the RKI, the German CDC. He specializes in emerging viruses and developed the WHO test for the new Corona virus.

Case-tracking teams in South Korea

Can we learn anything from how South Korea handled the situation? Too long, didn't read: South Korea is very strong in case tracking. They test a lot and have many people working to track contacts of known infected people. This produced good results for fighting one big outbreak, but there are still new infections and we will have to see how well this strategy works in future.

Christian Drosten:

There are case-tracking teams that can follow every infected person and look: Who has there been contact with? Where are the contacts now? The contacts are isolated and monitored and so on. I think that is simply not feasible here, if only for personnel reasons. That's why the question of whether you can learn anything from it is a bit futile.

But it's also true that one shouldn't be fooled. For a very long time, there was the impression in Korea that the outbreak is now actually under control. But what's often forgotten to say is that a big part of the initial outbreak in Korea was a single event. ... And of course you could follow that very well. Of course, you have a list of participants and can say: Okay, they were all there, and we're really going after them now.

But this effect is now over in Korea. This transmission event is now so far in the past that it has been captured. And that has done a lot to bring down the curve in Korea right now. But what I am now hearing from Korea is that individual transmission chains are now starting up all over the country, because of course there have been other cases registered in parallel via multiple channels (let's consider the proximity to China). And that just now in Korea the new infections are clearly increasing, because it's not this very focused measure any more, but suddenly you have to be everywhere. And I could do that I imagine that this will also no longer manageable in Korea, to be everywhere at the same time. But in general, they do case tracking very carefully. And I have a feeling can do this better simply by staffing levels than we in Germany.

Spread in Italy and Germany

Anja Martini:

Italy is now going into the third week of quarantine. The first experts are now breathing a sigh of relief because the number of deaths has not increased any further. How much can we already tell from these figures and this development? How much can one learn from this, and what can we trust?

Christian Drosten:

So the number of cases [infections], which in Italy are apparently not so easy to count because probably not so much diagnosis is made, are the absolute numbers of infections. But of course what has to be counted are the deceased. And it takes on average about three weeks between the onset of symptoms and their passing away. Or between the infection, you have to say correctly, and death. And that's why that's the effect that happens in the statistics. A curfew and other quarantine and isolation measures were put in place three weeks ago. And now you can see the effect, even on the deceased. And that is unfortunately almost a natural constant that can be observed. It just takes three weeks.

And you see it more quickly with [infection] cases in countries that can detect the cases very reliably. ... But in this short period of maybe ten days at the most, we want to see that the increase in new infections is already decreasing, at least in a system, a country where we are already close to reality with diagnostics - which we hope we are in Germany. ... I would be very pleased if this were to be confirmed in the next few days. But one must also say that we will have to wait a little longer. It has to last a few days, this effect, before you can see: So you can see something.

The next paragraph required quite some explanations to interpret the science-speak of Drosten. I hope I did it right. He seems to be saying that already in this early phase the number of cases is decreasing compared to model computations based on the past. That means that the spread of the virus has become less efficient, likely due to all the policy measures taken. Even more summarized: the policies seem to work.

"[The number of infections are] perhaps already now in this early phase, the expected values [from models] are changing compared to the observed values. So there seems to be a difference, which is good. [Because this suggests the model parameters about how the virus spreads are improving] And if it stays like that for the next few days, then you will look at it for a while. And then, for example, in this difference you have a new basis for readjusting models. [Estimating how the policies have affected the spread of the virus] And then mathematicians and modelers in Germany will actually be called upon to take and evaluate this data and then to prepare it for policymakers, for example."

This will also affect the number of deaths, but the coming weeks it will still rise.

We will of course see changes in the deceased with a two or three week delay. Incidentally, we also have to remind ourselves, and I would perhaps like to say this again now, that despite the measures that we already have at the moment, the number of deaths will of course continue to rise, because this effect will continue. And this, too, will be reflected in model calculations. That will of course also be important, because it will give an insight into the seriousness of the cases. And this severity of cases must be taken into account in terms of hospital capacity.

So this kind of epidemiological modelling that is needed here at the moment is not just a pure description of the situation of the cases, but must also take into account when we reach the capacity limit of the medical system. So completely different figures have to be included, such as the number of beds or the number of ventilation places.

And in the very near future, the question will be posed to the scientific community: Where do we stand now? How can we now readjust? Must we leave the current measures as they are? Or can we relax the brakes a little in some places, because it is not just a pure, naked scientific consideration, but also because scientists are well aware that the current measures are of course causing great social and economic damage. And these things have to be weighed against each other.

Around Eastern we should have a better assessment of the situation.

Infectiousness study

Anja Martini asks Drosten about a new study from Hong Kong. He first explains how scientific publishing has changed due to the time pressures of the epidemic. If you are not interested in that you can skip the next long quote.

(The quote provides anecdotal evidence that without peer review scientists would focus much more on studies from well-known groups and that peer review thus helps outsiders gain the credibility they need to have people invest time in their work. I have a blog post on that.)

Christian Drosten:

This is a study that has been published on a preprint server. At the moment we have this very fast situation in scientific publication activity. Normally the review process of a scientific contribution takes weeks or even months. So sometimes it goes from a scientist to a journal. They don't send it to the journal for review. Then you send it to another journal and they send it out. The reviewers need two months, then the comments come back. And then the magazine says: "Fix it, please. And then another month goes by.

And you can't afford that right now with epidemiological research. And that's why at the moment, scientific articles are actually placed in online resources, the so-called preprint servers, as they are written. There are two very big ones, called bio-archives and med-archives.

I always go through them like this. I have to sort a lot of things, because they are not peer-reviewed scientific articles. That means there's also a lot of dead wood. There are a lot of things that you won't see officially appear in this form later on, because they won't survive the review process. That means, what I always do in my free minutes is that I look at the things that appear in a new way. And things that I think are of such a high quality, that will survive any review process, that's really well done, I discuss these things here sometimes. So then I say: this is interesting data. And so it is with this study here.

It comes from Hong Kong from a very well-known epidemiological modeling group, Gabriel Leung.

It is important when a patient is infectious.

[The study was about] when does this disease actually become infectious? Already before the symptoms or with the symptoms or after the symptoms? And this is very important, because with the old SARS corona virus we can briefly sum up: It was so easy to contain because it only becomes truly infectious long after the symptoms start, in the average patient.

Drosten himself also had a small study on this topic. Currently still a preprint (not peer reviewed).

This study has also already shown that the virus replicates in the throat in the early phase of infection and that the virus is clearly detectable in swabs even in the very earliest swabs to such an extent that it is already on the descending branch even on day one and two in swabs. So the further one waits - and if one takes smears from a patient every day - the fewer and fewer, right from the beginning.

The new study found the same result, but with many more patients.

These authors found exactly the same thing in a group of 94 cases in Guangdong, i.e. in southern China near Hong Kong. ... And they saw that from day one the virus was on the decline. That means the peak of the virus must be before the first day.

The new study also quantified how long it takes to be infected.

Then they did something very interesting, something purely epidemiological: they also looked at transmission cases in the same context, namely 77 couples, 77 patients, where it is known that one person infected the other, and they looked closely: How long did it actually take?

I did not understand the explanation of how this works, but the key word is "[[Serial Interval]]". The result was:

The median is 5.2 days, the mean is 5.8, so this is a somewhat skewed distribution, but still with very close averages, so 5.2 to 5.8, you can say is the series inteval.

So the time to infect someone is about the same as the incubation time.

They also calculated the incubation time from their own earlier, very well done study: 5.2 days mean incubation time. This is of course interesting, because we have here a phenomenon where practically the serial interval is almost as long as the incubation time. This tells us that the average patient waits for the symptoms after infection for as long as it takes to transmit the infection between two patients. And if you look at it that way, it means that not only do we have a mean onset of transmission on the day the symptoms start, but probably before that as well. So the average patient is basically transferred [infected] on the day the symptoms start, but this is just the average patient. Some patients are not transferred until after the start of their symptoms and unfortunately some are transferred before the start of their symptoms. ...

it can be said that infectivity starts two and a half days before the onset of symptoms, on average. And the so-called area under the curve, i.e. the area covered by this probability curve, before the onset of symptoms, is 44 percent. In other words, it can be assumed that 44 percent of all infectious events occurred before the infective person was even ill. ...

This also means, of course, that if you lock yourself up at home as soon as the symptoms begin, you have already infected people if you allow a normal social life to continue. So this means that with normal rules of infection protection in case of a noticed illness you cannot contain this disease. There has to be social distancing in a targeted way, where the aim is to change behaviour - and not to identify symptoms and isolate the sufferers. That simply will not work with this disease.

Other podcasts

Part 28: Corona Virus Update: exit strategy, masks, aerosols, loss of smell and taste.

Part 27: Corona Virus Update: tracking infections by App and do go outside

Part 26: Corona Virus Update on Vaccines: clinical trials, various types, for whom and when.

Part 23: Corona Virus Update: need for speed in funding and publication, virus arrival, from pandemic to endemic

Part 22: Corona Virus Update: scientific studies on cures for COVID-19.

Part 21: Corona Virus Update: tests, tests, tests and how they work.

Part 19: Corona Virus Update with Christian Drosten: going outside, face masks, children and media troubles.

Part 18: Leading German virologist Prof. Dr. Christian Drosten goes viral, topics: Air pollution, data quality, sequencing, immunity, seasonality & curfews.

Related reading

Corona Virus Update with Christian Drosten podcasts and transcripts (one day later).