Variable Variability

Thursday, 16 April 2020

Corona Virus Update: Don't take stories about reinfected cured patients too seriously (part 31)

Prof. Dr. Christian Drosten

The last Corona Virus Update Podacast with specialist for emerging viruses Prof. Dr. Christian Drosten had two main topics. The internationally most important one is about press reports that cured patients would be reinfected or even that people may not become immune after recovering from the disease. ThEN WHat AbOuT hErD iMmUNiTy?

I have seen people who are normally careful and well informed talk about these "reinfections". However, it is very likely just a problem with measurement accuracy when in the final stages of the disease the amount of virus becomes very low and hard to detect, especially in samples taken from the throat.

The other half of the podcast was about a study on the spread of SARS-CoV-2 in the German municipality Heinsberg. A region not too far from Bonn were there was a big early outbreak after a Carnival party. At a press conference some preliminary results were presented without any detail on the methods, on how these results were computed. The numbers suggested less people may die and more may be infected without knowing it.

There was first a wave of publicity praising the results and discussing the political implications. Then after consulting scientists there was a wave of publicity claiming the study was rubbish, while all the scientists had said was that they did not have information on the methods and thus could not comment. Sometimes they explained the kind of information they would need to have and that was spun into the study doing this this wrong, which was not claimed. On social media people started attacking the Heinsberg scientists or those asking for more information, which can only be based on whether they liked the numbers (politically) because they knew about the methods even less. For a day Germany looked like the US culture war. Social media has a mob problem that needs addressing.

It was not a glorious hour for science reporting by (probably mostly) political journalists. Anyway because this is much ado about nothing until we have a manuscript describing the methods and purely German I have skipped this part. I was nodding a lot, yes those are the kinds of problems you have interpreting measurements, yes you really need to know the measurement process well to assess the results. There are so many similarities between sciences.

It may still be fun for the real virology science nerd to learn the kind of details that matter to interpret a study. They can read the German transcript.

The basic problem determining whether someone is ill

Korinna Hennig:

Over the weekend there have been several reports from China and South Korea about patients who were considered to have recovered or were discharged from hospital and have now tested positive again. So this is not about antibodies, but about the actual virus detection in the throat swab, for example, or from the lungs. Is it conceivable that the virus is reactivated? You also examined the course of the PCR tests on the Munich patients.

Christian Drosten:

This phenomenon can be described as follows: A patient is discharged from the hospital, verified as corona negative and as cured. And a moment later - it could be days, three or four days, or even up to seven or eight days - the patient is tested again. And suddenly he is positive for the virus in the PCR. It is said that the patient may have become newly infected, or in reality he was not immune at all, although he survived the disease. Or the virus has come back again, and you know certain infectious diseases, herpes viruses are the prime example, which can always come back.

One asks the question: is this perhaps the case with this new virus? Unfortunately, there are still very few precise descriptions in the scientific literature of how the virus is excreted in patients in different types of samples, for example in swabs taken from the throat or in lung secretion, also known as sputum, or in stool samples - these are all the types of samples we know that the virus is detectable. Only a few studies have so far described how this behaves over time in relation to excretion.

We have made and published one of them. We have made an overview picture of this excretion over time in nine patients from Munich. ... This shows the detection limit of the polymerase chain reaction. And you can see clearly, especially towards the end of the disease process, when the patients recover, that there is still virus present. It is sometimes detectable, sometimes for a few days in a row, then again for a few days in a row it is not detectable. This always jumps above and below the detection limit.

These are simply statistical phenomena that occur. A PCR can only test a certain sample, a certain sample volume for virus. There are statistical distribution phenomena which mean that the virus has in principle been there the whole time, but the test cannot always detect it. You have to picture it like this, I often explain it to students like this: you have a swimming pool full of water and goldfish are swimming in it. And there is no doubt that they are there. But now you take a sample from this paddling pool with a bucket, blindfolded. And then you may have a goldfish in your bucket and sometimes not. Still, one would not deny that there are goldfish in the swimming pool. ...

Reporting of the results

And now the question is simply how to deal with it. I can tell you that here in Germany something like this would not happen, because we have a culture here, where results like this are questioned relatively quickly and rules are always seen with the possibility of an exception. In other words, a German health authority would practically say: well, okay, that's obvious, that's what happened now.

But in the Asian culture of public health there is a much greater strictness in dealing with such rules. That is not so bad. I don't want to criticize it now. It is simply a cultural difference that when such a rule is established, it is adhered to.And when it is then said that we now agree that a patient who has been PCR negative twice in a row, we define him as cured and discharge him. ...

It is a thoroughness to say: No, this rule will not be questioned now, this is no exception, but we just enter it into the table. The patient was tested negative twice and now he is positive again. And now we test a few hundred of such discharge courses and enter all this in the table and discuss it only after we have the table completely. Then we write this together and write a scientific publication about it. This is exactly what happened, several times.

These scientific publications are now in a public resource and readable, but now this discussion process is starting. So, now it's starting with people reading such publications, who perhaps do not know the details and say: What is this? It looks like a reinfection. What is going on with this virus? And it's being spread again through even more discussion channels. This creates excitement and uncertainty.

As a scientist, I would prefer the "Asian" process, that is the cleaner data, where you know exactly what happened. You have to understand the measurement process, but the scientific literature is for scientists.

I like the movement to open science, which makes it easier for people to participate in science and also for scientists to do science, but the scientific literature is not written for normal people and it will lead to problems when people with half-knowledge start reading the scientific literature. In this case it was probably innocent, in many cases bad actors abuse this to mislead the people.

Study one

How the samples were take for one of the studies was not fully clear, as can happen with preprints.

So it may well be that at one point when the patient was discharged, they simply took swabs from the throat, and at another time they may have looked in the lung secretion that someone coughed up. Such things can happen, these are two different types of samples.

And we know well, that the lung secretion stays positive much longer after discharge. And we also believe that it is not infectious for others. Using cell culture virus isolation studies, which we also did in our publication we tried this. We already believe it's no longer infectious. We've never been able to isolate an infectious virus. ...

Study two

In the other study it is actually more interesting, it is a bit more explicit. They examined 172 patients beyond the point of discharge. In 25 of them, the test was positive again, on average after 5.23 days after discharge. There it is also clearly stated, the discharge criterion was two negative throat swabs in a row.

So: The patient had to have a negative throat-swab twice, then he was discharged as cured. But we know exactly that the throat-swab is the sample that becomes negative earliest in patients. So in the second week of illness, many patients no longer have a positive throat-swab on most of the days that one tests, while stool and sputum are still reliably almost always positive.

And then it is said that of these 25 patients, 24 patients had severe histories. For me, this indicates that if someone has a severe history, he will of course be discharged later. Then he will be treated in hospital for a longer time. And especially with these patients we know that the virus in their throat is almost always completely gone. So the virus in the throat has had time to be eliminated. So in severe cases, the throat swab is no longer positive after this long time.

Let me set a break here to let this sink in. If it were really a problem of people being re-infected because they did not acquire immunity, it would be the patients who got most ill, who did not acquire immunity. If it really were a matter of immunity, the opposite would be more logical.

Then it is said that 25 patients have been diagnosed as positive. But in 14 of them, the laboratory test was positive again after they had been discharged from the stool, i.e. not from the throat-swab, and this tells me that we have exactly this mix-up here. For we know that the stool samples in particular remain positive for the virus for a long time, and I have to say that here too, by the way, we have not found any infectious virus in them. This is probably again only dead, excreted virus.

And with others it was throat swabs, which then tested positive again. But then we have to say again, a throat swab can also contain naturally coughed up lung mucus. You cough up the stuff and it sticks to the back of your throat.

You can see from the way in which it was done methodically and from the samples in which it was found, and also from the type of patients, that people say that these are patients who have been seriously ill for a long time, that there is a risk of falling into this trap, into this confusion. I would even suspect that the authors themselves simply know that this "mistake" could be present here. ...

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.

Tuesday, 14 April 2020

Opening up Germany in a Randomized Controlled Trial

It is now clear that for now Germany has managed to avoid spiralling into a situation where the new Coronavirus overburdens the healthcare system. In fact, I think we can say that the number of cases is declining.

So in Germany the discussion has started about slowly opening up society again. On Wednesday the 15th of April the government wants to decide what to do next week. While the number of confirmed infections is going down, I feel it would be good to basically keep the current measures in place for two more weeks. This would lower the numbers to where the tracking and tracing of infected people becomes an effective way to keep infections down, which means less restrictions long-term.

But we could use this two weeks for an experiment, which will help us make better decisions. The best experiments are [[randomized controlled trials]], where you have two conditions and randomly one of them. This is typically how new medicines are tested. Here one would randomly assign a pill or a placebo to patients.

In case of COVID-19 measures the two conditions could be a relaxation of measures or not. Because this is about the spread of a virus in a community, you cannot randomly select people, you will have to randomly select regions. As Germany is a federal state, a logical selection would be randomly assigning states, but you could also do it for municipalities. That would be better scientifically, but harder to implement.

Without mitigation measures one infected person infects 2 or 3 others. We have to bring this number below 1 to stop the epidemic. About half of the infections are transmitted by people with symptoms and half by people before they have symptoms. Some are transmitted by people who will never get symptoms and some via the environment, without direct contact. So quarantining people (with symptoms) is important, but not enough, we also need to reduce the number of physical contacts between people without symptoms, that means basically all of us. But it does not have to go to zero, which is why essential people are still working and supermarkets are open.

So we have to decide which physical contacts to allow until we have a cure or a vaccine and which ones we do not. This is a compromise between how important the contact is and how dangerous it is. Keeping supermarkets open is clearly important, people have to eat. Most dangerous are close contacts, with many people, over a longer time, inside buildings. Parties with thousands of people are clearly dangerous and, while nice, less important.

Those two decisions are easy, supermarkets open, parties closed.

The most difficult decision I see is about whether to open or close school.

On the one hand, this would be important. We cannot have our kids locked in at home, children need to move. We cannot have them miss school for one and a half year, the more so as this sacrifice does not help them as school children do not get ill. Children not going to school also prevents many parents doing essential work from going to work or working from home efficiently.

On the other hand, going to school would be dangerous. With many children, this means an enormous number of contacts. And it will be hard to change the behaviour of kids at school to reduce the contacts. (Within one class I am not even sure whether we should try.)

What makes the decision even harder is the uncertainty in how infectious children are. We know they can be infected, but as they do not have many symptoms, they may be less efficient in spreading it than adults.

So studying the influence of opening schools would be a good use of a randomized controlled trial. You could do this carefully by only having one or two years go back to school. Rather than switching from compulsory schooling, to closings schools, back to compulsory schooling, we could also make it voluntary. Parents who are in a health risk group could then opt keeping their children at home. While parents who most urgently need to work could opt to send their children to school.

Whatever we decide, I think it would be a good use of our time to use it for an experiment that helps us make better decisions about a disease we do not know much about yet.

Monday, 13 April 2020

A privacy respecting track and trace app to fight Corona is possible and effective

An app to track and trace infections seems to be a promising way out of the lockdowns. Tracking the contacts of infected people is a main strategy to fight this epidemic as long as we do not have a cure or vaccine. It is the main strategy used in South Korea and they are able to keep the number of new infections below 100 per day with it.

When the virus spreads more widely, like in many countries who did not take the virus serious enough soon enough, it becomes difficult for the health departments to track and trace so many people. In addition, a part of the contacts will not be known to the infected person and will thus not be tracked; for example, someone sitting next to you on public transport or in a restaurant.

How the app works

For the last case South Korea uses GPS information from mobile phones. I am not comfortable with the state having all that location data, but fortunately there is a better alternative. This is a great cartoon explaining how contact tracing can be done fully respecting privacy. The short version of this is below.

The Chaos Computer Club (CCC), German's most reliable technology activists, explain the conditions to make this work and have promised to warn about bad apps. I am happy use such an app and will listen to the CCC for advice. The CCC is comparable to America's [[Electronic Frontier Foundation]].

Let's hope data brokers Google and Apple getting involved does not mess this up. At least one group of scientists who started this approach are hopeful Google and Apple will help. We need many people participating, so we need something everyone can embrace.

How effective it is

A recently published study published in Science claims that such fast contact tracing could be as effective as a lockdown if 60% participate & 60% heeds its warnings.

To compute this they first estimate how the virus spreads; this paragraph can be skipped if you are not interested in the scientific basis. They estimated how long the incubation time is (5.5 days). On average it takes 5.0 days between one infected person and the next to show symptoms. So the moment someone gets ill, the people they have infected have started infecting other people. They estimate that on average 1 person infects 2 others. (This is a low value, other studies tend to find between 2 and 3.) The direct transmission from a symptomatic individual to someone else ("symptomatic transmission") explains 0.8 infections of those 2 infections. So even if if we theoretically would remove this fully the number of infections would still grow exponentially. Infected people infect 0.9 people before they show symptoms ("Pre-symptomatic transmission"). People without symptoms infect 0.1 people ("asymptomatic transmission"), while "environmental transmission", infections where people did not meet, account for 0.2 infections.

So it is important to be fast. This is the advantage of the app over a health departments trying to reach people by phone and email. Still it is worthwhile to both do manual and app tracing. A person from the health department calling you telling you your friend or colleague is ill and explaining how quarantine works is likely more effective than a notification by your phone. For this manual work to be effective we need to get the number of new infections down.

The speed of the testing is an important part of this strategy. It will thus work better in countries like Germany with a strong testing program than in America where much less testing is done, which in the short term makes the numbers look better, but does not make the situation better. The paper also studies how effective it would be if people with symptoms can warn people before being tested. This is naturally faster, but false warnings triggered by hostile actors can abuse the system. To avoid this one can tie the app to test results, where the health care providers can give the app user a code in case of a positive test.

When the app warns someone that they have been in contact with an infected person, this person will have to go into quarantine. This will work better in a country with paid sick leave and when the government gives the warning of the app the same status as "sick certificates" from the doctor.

The proximity detection by Bluetooth is far from perfect, so there will be false positives, but I would argue that that is still better assuming everyone had contact with an infected person and putting all of society on lockdown.

Enough people will have to participate. Fortunately it does not have to be all, apparently 60% is already enough. The privacy invading app of Singapore only has a take up of 10 to 15%. I would personally not use such an app, I'd rather take a small risk dying than giving a government really dangerous powers, while I would be happy to use the above described one. So I would expect the adoption of a decent app to be higher.

One would install the app to help others, so this may work less well on countries where the ruling class has pitted groups against each other to solidify their power. Ross Anderson from the UK is pessimistic about the adoption of such an app. I am quite optimistic. But we will have to do the experiment. Do note that when reading the second opinion of Anderson that I feel he does not accurately describe how the app would work; part of my text above is based on such misunderstandings others may have.

Prof. Dr. Christian Drosten, one of the main virologists in Germany who specializes in emerging viruses, thinks the app could work to reduce infections. In a recent podcast of the public radio channel NDR Info he talked about the app:

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. ...

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. ...

And you can say in a nutshell, if the epidemics ran at the same speed as in the beginning in Wuhan ... 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. ...

You could combine such an App, for example by other general factors that reduce the transmission of the infection, such as wearing masks. ...

[The study models a situation where] 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.

Drosten can naturally only judge the effectiveness. The Chaos Computer Club (CCC), German's most reliable technology activists support the technical concept. It naturally depends on implementation details and while they will not recommend an app, they have promised to warn about bad apps. I will listen to the advice of the CCC.

Electronic Frontier Foundation makes clear that a trace and track app can only be part of a package of measures and rightly emphasise the importance of consent.

Informed, voluntary, and opt-in consent is the fundamental requirement for any application that tracks a user’s interactions with others in the physical world. Moreover, people who choose to use the app and then learn they are ill must also have the choice of whether to share a log of their contacts. Governments must not require the use of any proximity application. Nor should there be informal pressure to use the app in exchange for access to government services. Similarly, private parties must not require the app’s use in order to access physical spaces or obtain other benefits.

Individuals should also have the opportunity to turn off the proximity tracing app. Users who consent to some proximity tracking might not consent to other proximity tracking, for example, when they engage in particularly sensitive activities like visiting a medical provider, or engaging in political organizing.

A German conservative politician wanted to force people to use the app. He did not have a good day on social media. Well deserved. That is the most effective way to destroy trust and in times of Corona we need high compliance and thus solutions that have broad support.

The German National Academy of Sciences, Leopoldina, recommends three measures to replace the lockdowns. 1) Such an app. 2) Massive testing. 3) Everyone wearing simple masks in public. (In German.)

In the Netherlands, Arjen Lubach asks many questions on how such an app would be used. (video in Dutch.) Would your boss be allowed to force you to use such an app? Would this be a condition to use public transport? Would a restaurant be allowed to require customers to use an app? Would you be forced to share your random numbers when you find out that you are infected? Could you turn off the app? Could you ignore the warning of the app?

I had not considered many of these questions because I considered it natural to each time opt for the most free option and expect that that leads to much more people participating and thus to the largest effect. Any force to use the app would only make sense on a societal level. A boss or a restaurant has no advantages from such a measure, just like the users themselves only help society, not themselves.

My impression is that a main reason Germany got through this pandemic with only a blue eye is that the population was well informed, understood the danger, knew what to do and was very cooperative. It is relatively easy in science, but I have seen a huge part of people working from home well before there were any rules to do so. Meetings were cancelled well before the limits for the maximum number of participants went down to that level.

The alternative to so much compliance would be quite draconian rules and a lot surveillance and enforcement, leading to much more violations of freedom and economic damage. Thus I would expect that the best way to make the app a success is to respect the privacy of the citizens and respect their autonomy to make the right decisions. In countries were this is not possible, I am sceptical of the app helping much, except if they go full China and most countries do not have the enormous repressive system that would necessitate.

Where I do agree with Arjen Lubach is that we have to have this discussion now. It is not a matter of using the app or not, but how do we want to use it. We should have that discussion before we introduce it. Just like we should discuss all other measures and whether and when they can be relaxed. Even if we do not know exactly when yet, we can already discuss what has priority, opening school, shops, restaurants or car factories?

Disclaimer. In am just a simple climate scientist, not a virologist, nor an epidemiologist or encryption specialist. I had wanted to stay out of this topic and not pretend to be an instant Corona specialist, but the dumb people do not show such restraint and only few actual experts speak up. Those that do, report that they find it unpleasant. As a climate scientist I am unfortunately used to the well-funded hate mobs trying to bully others into silence and will not let myself be intimidated. Plus a large part of this post is about societal issues, where everyone should participate, not just experts.

Friday, 10 April 2020

Corona Virus Update: exit strategy, masks, aerosols, loss of smell and taste (part 28)

Prof. Dr. Christian Drosten

Today's podcast had a wide range of topics, from the proposal for an exit from the lockdown by the German National Science Academy, to face masks (which is one of their proposals), to transfer of the SARS-CoV-2 virus by droplets and by tiny airborne particles (aerosols), how long a patient is contagious and a new study on the loss of smell and taste as a symptom of COVID-19.

The Corona Virus Update Podcast is an initiative of the German public radio channel NDR Info. Today science journalist Anja Martini does the interview with Prof. Dr. Christian Drosten. He is an expert for emerging viruses at the [[research hospital Charité]]. Fittingly the hospital was founded outside the city walls of Berlin three centuries ago to help fight an outbreak of the bubonic plague, which had already depopulated large parts of East Prussia.

An exit strategy

In the previous podcast Drosten talked about a study, which suggested that a mobile phone app, which can help trace back contacts of infected people, would be quite effective in reducing the spread of the virus. About as powerful as a lockdown.

Three day later the German National Academy of Science, Leopoldina, recommended three measures, which could become an alternative for a lockdown. 1) This app, 2) more testing, 3) wearing simple masks in public.

[EDIT: It goes viral in America that Apple and Google will somehow help with such apps. That most of the work is already done by governments is not something that gets much millimetres, while it is not that clear to me what Apple and Google will contribute. They say first an API. Maybe that helps to make different apps interoperable? In a second phase they want to integrate it in the OS. If that means that the data (also) goes to Apple and Google, that would be an efficient way to kill the project.]

Leopoldina presents a model, which suggests this would be enough to keep new infections per day close to zero in May, although they also show data from South Korea, which has a similar strategy, were there is still a decent amount of new infections going on. So the model does not capture reality fully.

Anja Martini:

The Leopoldina, the National Academy of Science, issued a second statement from its working group on the virus at the end of last week. You are also part of this working group. ... It recommends - over and above the measures that we have already taken so far, in other words keeping our distance - hygiene and quarantine in the event of suspicion, isolation: Consistent wearing of masks, including in local public transport and at school, more tests, including random tests, and the use of cell phone data, which we have already discussed here. If this is done, the number of people infected by an infected person could, according to the calculations, be reduced to less than one by the middle or end of May. Even if, after Eastern, more public life were to be gradually allowed again. That is cause for optimism for the time being, isn't it? Please explain this prognosis to us!

Christian Drosten:

Of course, one looks for ways to get out of the current measures. And an organisation like the Leopoldina, which is made up of scientists, also looks at the latest scientific data. Just last week we discussed a study published in "Science" about the effects that can be expected from such mobile apps, i.e. mobile phone apps that allow much more detailed and faster case tracking.

We can simply track a certain number of infected people at the local health departments. At some point, the capacity runs out. You can't make an infinite number of phone calls and contact an infinite number of contacts and tell them to stay home and so on. It just runs out at some point. A mobile app is not exhausted that quickly and it also gets behind it much faster. That's the one provision there.

If the modelling study on the impact of this app is right, this should do most of the work.

So one can wonder why masks are additionally proposed by Leopoldina. My impression from previous podcasts is that Drosten is quite sceptical of masks. While there is evidence that they reduce the amount of viral material an infected person produces, there is not much evidence on how much they would contain the spread of the virus.

Maybe that lack of strong evidence is why Drosten wonders whether people would be persuaded to wear the masks. I do not see much of a problem, but maybe I am too optimistic. Wearing a mask is a much smaller limitation than staying at home. And I recently came by this beautiful photo of California during the Spanish flu, where people are wearing masks at an outdoor barber shop. Another culture not used to masks that were willing to wear them when needed.

You can achieve considerable increases if you add some general effects [additional measures] to this very special tracking via mobile apps. A general effect can be the wearing of masks if everyone does it. In our society, we certainly do not have the best starting conditions to let everyone wear masks. There will quickly be people who say they don't want to, they don't see the point or they can't do it.

We have currently, of course, an additional argument in public, namely: you cannot buy any masks at all, because there are none. That is why it is of course not very promising at first to consider what would happen if a general obligation to wear masks were to be imposed ad hoc?

This is a relatively complicated phenomenon, ... to impose such a thing in a society where the whole thing is not culturally anchored and not trained. That is the one difficulty. It is of course taken into consideration in a forum like the Leopoldina, where social scientists, psychologists and so on are also represented. This is precisely why the totality of the expertise is represented, not only life scientists are in it, but also sociologist.

Types of masks

Christian Drosten:

We have hardly any scientific evidence that says that self-protection through simple masks works. Of course, there are much more complicated, elaborate masks for special wearers, i.e. for certain occupational groups, who also provide self-protection.

But these masks have actually never been available in large numbers. They are not so easy to produce so fast, as far as I know. By the way, they are also not easy to wear for everyone. You have to imagine that here in medicine there are preliminary occupational medical examinations for employees who have to wear these very safe self-protection masks in their professional life. Not everyone is able to do this, for example, if there is any doubt, the medical profession must carry out lung function tests. And something like that cannot be recommended for the normal population.

I am not sure I understand his claim on the simple masks:

With these [simple] masks it is the case, there is no scientific evidence of a benefit for self-protection. There is, however, starting evidence, which has not been very virus-specific so far, for the protection of others. But this of course presupposes that really everyone, everyone, everyone in society, in public life, must wear these masks.

I would expect that when half of all people do it you get half of the effect. But maybe Drosten means that for this to help for your own protection everyone would have to do it. Also if only half would do it, to help the others, one could expect that the participation drops. That is a kind of [[public goods game]] It could also be that he does not expect much of an effect and that half would thus really not be worth it.

Droplets and aerosols

A large part of the podcast was about the difference between droplets with virus and aerosols. Droplets would be defined as being large enough to drop to the ground by gravity within a minute, while aerosols can stay in the air for hours. It was a long and nuanced discussion about evidence on how these particles are produced and removed, how infectious they are and how important they are.

People are worried about the aerosols, about "airborne virus" because it means that you could be infected without having noticed someone coughing. But in the end the droplets are most important: "we are pretty sure that the vast majority of the viruses that are released in these diseases of the upper respiratory tract ... are these larger droplets - and they fall to the ground". So to focus on what is important, I only translated a small part:

Christian Drosten:

These large droplets over five microns (and they can can be much bigger, they can also be 100 micrometers, i.e. a tenth of a millimeter, so that you can really see them with the naked eye) - these are the droplets that we are talking about in a droplet infection. In other words, what you give off - which is part of a moist speech [when people spatter when they talk], for example, but also comes out when you cough or sneeze - and which falls to the ground within a radius of one and a half to two meters.

In this research into the common cold, we are pretty sure that the vast majority of the viruses that are released in these diseases of the upper respiratory tract (i.e. the diseases that mainly occur in the throat and nose) are these larger droplets - and they fall to the ground. Much of our precautions and infection prevention considerations are based on this insight.

Then there is something else, namely aerosols, whose particle size is less than five micrometers. For the experts, it must be said that this is of course not a sharply defined size, and an aerosol that really floats in the air and stays in the air longer, the actual droplets are even much smaller, they are less than one micrometer in size. ...

If I release such a droplet and it floats in the air in front of me, then it starts to dry and then it becomes smaller. The smaller it gets, the more likely it is that it will remain in the air for a long time. But at the same time there is another effect, namely when this droplet gets smaller and smaller, it will eventually be too small for the virus, and the virus will dry out and will no longer be infectious.

So on the one hand aerosols are potentially more problematic by staying in the air longer, on the other hand they are likely less contagious, while many studies only analyse whether virus is present, not whether the material is infectious. Reading such studies one should pay attention to this difference.

How long is someone contagious

An interesting preprint studied how much virus could be found in hospital rooms of COVID-19 patients.

Christian Drosten:

Wipe samples were taken - in 30 different hospital rooms, from 30 different patients, all of whom had the disease, in a hospital in Singapore, from all kinds of surfaces, and tested them for virus again.

By the way, I have to add here, in all these studies, especially the last study that we discussed first, and this one too, it is always only a viral detection of RNA and not of infectivity in the cell culture.

Anja Martini:

In other words, a virus that can be detected, but which possibly no longer infects anyone.

Christian Drosten:

Right, exactly. A desiccated virus, it still has the same amount of RNA and you can still detect it. None of this means anything directly about infectivity right now, it just means that virus has got there.

And here it is the case that a lot of deposited RNA has already been found in these samples. In the floor samples, for example, more than half of the wipe samples were virus-positive, i.e. viral RNA could be detected - which suggests that the virus is deposited to a considerable extent, which is a sign of the fact that the virus is in fact deposits considerably, which favours the concept of a coarser drops.

But then, something else and very important, I think: With these 30 patients were these virus swab samples always positive only in the first week of symptoms. In the the second week, when the patients were still definitely sick the wipe samples were no longer positive. So no more virus settles on the surfaces, was accordingly also no significant virus concentration more in the room air.

Note, this is just one study. Decisions should be based on all available evidence and an uncertainty estimate.

Infection via surfaces

If I understand it right, when someone coughs in their hands and then shakes hands, that is seen as droplet transmission and not as transmission via a surface. This route is important and a reason for the advice not to cough in your hands and to wash them regularly.

Anja Martini:

The insight we have from this is that we are infected via the air we breathe, via coughing, via aerosols, and not, as is a question much asked by listeners here, what is actually the case with infection via surfaces?

Christian Drosten:

Infection via surfaces themselves has been modelled, for example, in the study by Christophe Fraser that we discussed last week. He comes to the conclusion that perhaps ten percent of all transmissions could function via surfaces at all.

Many people I talk to don't really believe in the relevance of surface transmission. ...

We do not currently assume that this virus is significantly transmitted via surfaces. The current measures to prevent transmission are aimed at preventing both droplet and airborne transmission, especially - to say it again - droplet transmission. And the studies that have now been discussed here, that have now been published, do not suggest - even if small-droplet aerosols have been detected - that this mechanism would be the main focus.

Anja Martini:

This means, once again asking from the consumer's point of view, ... can we actually neglect surface disinfectants in our private lives?

Christian Drosten:

I am almost sure that it is not worthwhile to pay a lot of attention in the household to treat all kinds of surfaces with disinfectant. In a hospital, of course, this may be different. ...

My impression is that this was scientific "may", which mostly means "will". We sometimes talk in a somewhat weird way.

Images from television, for example, in China, where tanker lorries are driving through the streets with disinfectants, I think that has more of a psychological effect on the population than a real effect in curbing the transmission of infection.

I love those videos of teams with disinfectant sprayers walking through the streets as if they could be eye to eye with a terrorist any second.

Loss of smell and taste

Anja Martini:

What does a possible disease or even an infection with the virus actually do to the sense of taste and smell? This was already something of an observation in the press. There was also a Belgian study. Now there is one from Iran based on an online questionnaire.

Christian Drosten:

Yes, I think it's a very interesting study. There are already clear indications. In the Munich patient observation we have already seen a loss of the sense of taste and smell in almost half of the cases. So this has already been published.

There is now even a functional study that has just been published - and it says that it is a very specific type of cells in the olfactory system, in the nose, in the olfactory bulb, that is actually infected and affected by this virus.

But that is not what we want to discuss here. Interestingly, it is a study from Iran. I think it is simply great to see that this kind of useful research also comes from a country that is highly affected and where we all know that the data situation is unclear. The science there has to work in a difficult system, has also difficulties, for example, to get certain reagents. But but here comes a very interesting study, from the preprint realm, to the public.

Iranian scientists conducted a survey - also supported by apps and the Internet - and reached 15,000 people with this survey. Of these, 10,000 actually had a loss or impairment of the sense of smell. In fact, 76 percent of these 10,000 patients - an impressively large number - had a sudden loss.

You can tell the difference between saying that suddenly I couldn't smell anything anymore. Or whether you say, well, I just had a cold. And 75 percent, a similarly high rate, actually had influenza-like symptoms. So now that not only a runny nose is part of it, but also a noticeable fever and so on. This was clarified by questionnaires.

83 percent also had a loss of taste, which was also described, also in the Munich patients, so that a loss of taste is also involved. They could no longer taste or smell anything. ...

And if I suddenly couldn't smell anything anymore in my everyday life, I would stay at home and try to clarify what is going on with me at the moment, in the current situation.

Other podcasts

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.

Tuesday, 7 April 2020

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.

Monday, 6 April 2020

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.

Wednesday, 1 April 2020

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.

Pages

Thursday, 16 April 2020

The basic problem determining whether someone is ill

Reporting of the results

Study one

Study two

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Tuesday, 14 April 2020

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Monday, 13 April 2020

How the app works

How effective it is

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Friday, 10 April 2020

An exit strategy

Types of masks

Droplets and aerosols

How long is someone contagious

Infection via surfaces

Loss of smell and taste

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Tuesday, 7 April 2020

The epidemiological model behind the App

Difference between manual and automatic tracking

Combining the App with other measures

What can you do for your immune system?

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Monday, 6 April 2020

Shortcut: use existing backbone vaccine system

How to infect human volunteers

Most promising type of vaccine

Who gets the vaccine first?

When will we have a vaccine?

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Wednesday, 1 April 2020

Question the whole system

When did the virus arrive in Germany and Europe?

From pandemic to endemic

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