Christian Drosten

Showing posts with label Christian Drosten. Show all posts

Monday, 20 April 2020

Corona Virus Update: the German situation improved, but if we relax measures so much that the virus comes back it will not be just local outbreaks (part 32)

The state of the epidemic has improved in Germany and we now have about half number of people getting ill compared to the peak we had a month ago. This has resulted in calls to relax the social distancing measures. The German states have decided that mostly nothing will happen the next two weeks, but small shops will open again (and some other shops) and in some states some school classes may open again (although I am curious whether that will actually happen, German Twitter is not amused).

An estimate of the number of new cases by the date these people got ill. Similar graphs tend to show the new cases for the date they were known with the health departments, by looking at the date people became ill, which is often much earlier, you can see a faster response to changes in social distancing. In dark blue you see the cases where the date someone got ill is known. In grey were it was estimated because only the case is know, but not when someone became ill. In light blue is an estimate for how many cases will still come in.

So in the last episode of the Corona Virus Update science journalist Korinna Henning tried to get the opinion of Christian Drosten on these political measures. He does not like giving political advice, but he did venture that some politicians seem to wrongly think measures can be relaxed without the virus coming back. The two weeks that the lockdown continues should be used to prepared other measures that can replace the lockdown-type measures, such a track and trace CoronaApp and the public wearing everyday masks.

Another reason it may be possible to relax measures somewhat would be that the virus may spread less efficiently in summer. It is not expected to go away, but the number of people who are infected by one infected person may go down a bit.

When the virus comes back, either because we relaxed social distancing too much too early or because of the winter, it will look differently from this first wave. This first wave was characterized by local outbreaks. A second wave would be everywhere as the virus (and it various mutations) are spreading evenly geographically.

Korinna Henning asks Drosten to explain why it is easier for him to call COVID-19 a pandemic than for the World Health Organization. This question was inspired by Trump complaining that the WHO called the pandemic too late. Drosten notes that it has political consequences when the WHO calls the situation a pandemic, but that does not influence the situation in your country and what Trump could have done.

Really interesting was the part at the end on some possible (not guaranteed) positive surprises.

Prof. Dr. Christian Drosten, expert for emerging viruses and developer of the WHO SARS-CoV-2 virus test, which was used in 150 countries.

The situation and measures in Germany

Korinna Hennig:

What's your assessment, how long would [the reproductive rate] have to stay below one for it to have a really long-term effect and we're not going to say that at some point we have to close all the schools again.

Christian Drosten:

I believe there is talk of months [in a report by the Helmholtz Association]. I can well believe that this is the case. However, this is not the path that has been chosen in essence [by the German government], but rather - I believe - the idea has arisen that the intention is to keep it within the current range, perhaps by taking additional measures to reduce the pressure a little more.

That is an important point of view, and one that needs to be understood. It is not primarily a question of saying that we have now achieved a great deal, that the measures have already had a considerable impact. And now we are simply letting them go a tad, because we no longer want to. Then at some point we will have to take a look and then we will have to consider how to proceed, that is one view.

The other is that everything will work out fine. Sometimes you can hear that between the lines. I have the feeling, particularly among the general public, that many people, even in politics, are speculating that it will not come back at all, that it will not pick up any momentum. Unfortunately, that is not what the epidemiological modelers are saying, but it is generally assumed that, if nothing is offered as a counter-offer to this relaxation of measures, it will really get out of hand.

And the idea is, of course - and this is a very real idea in Germany - that people say that they are now relaxing these measures to a small extent, but to a really small extent. It is rather the case that corrections are being made in places where we think we can perhaps get away with it without the efficient reduction of transmission suffering in the first place. And now, in the time that has been gained by the decision, it is preparing to allow other measures to come into force. And this of course includes the great promise of automated case tracking.

The cell phone tracking ... doesn't have to do the job completely, but you can combine it. You could say that there is a human manual case tracking system, but it gets help from such electronic measures, while you introduce these electronic measures. After all, this is not something that is introduced overnight; there must be some transition. I believe that the few weeks of time that have now been gained once again can be used to introduce such measures, and that is where a great deal of faith comes from at the moment.

Of course, there are other things to hope for as additional effects, such as, for example, a recommendation on the wearing of masks by the public. That could have an additional effect. Of course there will also be a small additional effect on seasonality. We have already discussed this, and there are studies which say that, unfortunately, there is probably not a large effect on seasonality, but there is a small effect on seasonality.

That is where things are coming together, so that we hope that the speed of propagation will perhaps slow down again overall and that we will at least be able to enter an region over the summer and into the autumn, where we will unfortunately see the effect of winter coming again, a possible winter wave, but where we will then have the first pharmaceutical interventions. Perhaps a first drug, with which certain risk patients could be treated in an early stage. Maybe first use studies, so efficacy studies of first vaccines. This is the overall concept, which one hopes will work.

Currently one infected person infects 0.7 or 0.8 other persons (RO, the reproduction number). That is behind the decline in the number of new cases. Theoretically you could thus allow for 25% more contacts while still being in a stable situation. I would be surprised if the small relaxations decided for the next two weeks would do that. I do worry that these relaxations make people take to problem less seriously and that can quickly lead to 25% more contacts.

I would personally prefer this decline to continue until we get to a level where containment by manual tracking infected people and their contacts becomes an effective way to fight the epidemic; Mailab explains it well in German.

If we get the tracking of infected people with a CoronaApp working, it would matter much less at which level of contagion we start, but I do not expect that the CoronaApp will be able to do all the work, it will likely need to be complemented by manual tracking. With the current plans, according to rumours in the media, placing less emphasis on privacy of the users, I worry that too few will participate to make any kind of dent. An app were we can only hope and need to trust that the government keeps its side of the bargain and does not abuse the data would also be less useful in large parts of the world where you can definitely not trust the government.

That some states are already starting with opening up some classes is in principle a good thing. But it goes too fast, the schools are not prepared yet and I see quite some backlash coming. If done well, by opening a few school classes we could have learned how to do this before we do more and we could study how much this contributes to a higher reproduction number R0. If we are lucky maybe hardly; see the last section on possible positive surprises.

Summertime

The flu normally goes away in summer, this is not expected for SARS-2, but the reproduction number could be 0.5 lower, that is that one infected person would infect half a person less. Without measures it is expected to be between 2 and 3 and we have to keep this reproduction number below 1 to avoid that the situation gets out of hand again. The summer may thus help a bit, which could mean less stringent restrictions.

It is not well understood what exactly makes the summer harder for the flu and even less for SARS-2. One aspect is likely that people are outside more and ventilate buildings more, which dilutes and dries the virus. Also when it comes to schools, it may be an option to do the classes outside, where the distancing rules could be less strict than indoors.

Museum could create large sculpture gardens outside for the summer. As the conference centres are empty and unused they could be used as social distancing museums. The empty hotels could be used to quarantine people who might otherwise infect other people in their households. We have to support the hotels anyway to survive until the pandemic is over.

I have often dreamed of conferences while walking outside in nature. You could transmit the voice of the speaker with a headset. The power points slides with Comic Sans would be missing. This may be the year to start this as alternative to video conferences. (Although there would still be transport.)

World Health Organization and Trump

Korinna Hennig:

Could you briefly explain again what the difference is when you say here in the podcast for example: Yes, we have a pandemic in an early phase. And the WHO is still hesitating for a very long time. What is the crucial difference when the WHO makes such an assessment?

Christian Drosten:

So I am only an individual and can give my opinion, which you can follow or not. You can take me for someone who knows what he's doing. Or you can say: He's just a fool and he says things here.

Of course, this has different consequence with the WHO. In the case of a UN organisation, this has certain consequences, not only when it comes to saying that this is a pandemic, but also, and especially, when it comes to saying that this is PHEIC, i.e. Public Health Emergency of International Concern. That is a term used in the context of international health regulations. This then also has consequences for intergovernmental organisations. This scope has certainly also led to delays in all these decisions by the WHO.

Of course there are advisory bodies. After all, the WHO is not a person, but an opinion-forming and opinion-collecting organisation. Experts are called together, committees that have to vote at some point and where there is sometimes disagreement. And then they say that we will meet again next week and until then we will observe the situation again. This then leads to decisions that are perceived as a delay by some countries. This is an ex post evaluation of the WHO's behaviour.

At the moment this is again all about politics. And it is about a decision by Donald Trump, who has now said that he is suspending the WHO payments, the contributions, because the WHO did not say certain things early on.

It was, of course, known relatively early on from individual case reports that cases had already been introduced in the USA. And now to say that it is a pandemic that is taking place in all other countries ... So the statement that this is a pandemic is to acknowledge the situation, that this is far is widespread. This has nothing to do with the assessment for your own country. Since you know, it is in your own country, you have to ask yourself: Will do I act or not?

Korinna Hennig:

And there are of course financial liabilities between countries that are linked to the WHO.

Local outbreaks in wave 1, everywhere in wave 2

If there is a second wave, it will not look like this first wave.
Christian Drosten:

What happened in the case of the Spanish flu was this: We also had a first wave there in some major US cities - that is very, very well documented - that caught our attention. However, it did not occur in all places, but was distributed extremely unevenly locally. It was conspicuous here and there, and elsewhere people did not even notice that this disease existed at all.

Even there, even at that time, people were already working with curfews and similar things. This was also happening in spring, by the way. Then it went into the summer and apparently there was a strong seasonal effect. And you didn't even notice the disease anymore. And under the cover of this seasonal effect - we can perhaps now envisage this as, under the cover of the social distancing measures that are currently in force - this illness has, however, unnoticed, spread much more evenly geographically.

And then, when the Spanish flu hit a winter wave, the situation was suddenly quite different. Then chains of infection started at the same time in all places because the virus had spread unnoticed everywhere and no one had paid any attention to it. This is of course an effect that will also occur in Germany, because we do not have a complete ban on leaving and travelling here, and of course we do not have zero transmission either, but we have an R, i.e. a reproduction number that is around or sometimes perhaps even slightly below one. But that does not mean that no more is being transmitted.
So you can look at our homepage, for example, at the Institute of Virology at the Charité - we have now published a whole set of [virus] sequences from Germany. You can see that the viruses in Germany are already very much intermixed, that the local clustering is slowly disintegrating and that all viruses can be found in all places. So let me put it very simply.It is slowly but surely becoming very intermixed. ...

We'll be in a different situation when winter sets in. ... Suddenly you'd be surprised that the virus starts everywhere at once. Of course it is a completely different impact that such a wave of infection would have.

What I find interesting to see it that there is nearly no difference in virus activity between cities and rural regions in Germany anymore. If anything, just looking at the map below, I have the impression that rural regions have more virus activity. On the other hand, in the beginning, I feel there was more activity in the cities.

Yesterday's map of the RKI, the German CDC, of the number of new cases over the last week per 100,000 inhabitants. The larger cities are denoted by a small red dot, the location of the smaller cities can sometimes be seen as a smaller region in a different colour. The darkest region is an outbreak, which was likely due to a strong beer feast.

Positive surprises

Christian Drosten:

It is also quite possible that there will be positive surprises. For example, we still know nothing about children. It is even the case that in studies that are very systematically designed, this effect is often still left out. We know from other coronavirus diseases, especially MERS, that not only are children hardly affected, but they are hardly ever infected. Now the question is, of course, whether this is also the case with this disease, that not only they do not get any symptoms and are therefore not so conspicuous in the statistics, but that they are somehow resistant in a certain way and that they do not even have to be counted in the population to be infected. So what is 70% of the population? Is it possible to consider the 20 percent of children as finished, because they do not get infected at all? In reality, only 50 percent of the population need to be infected? This is a big gap, which can also be interpreted as a great hope.

And there is something else - we are anticipating that, epidemiological modellers are doing that, and they are taking that into account: That there may be an unnoticed background immunity from the common cold corona viruses, because they are already related in some way to the SARS-2 virus. It could happen, however, that certain people, because they have had a cold from such a corona virus in the last year or two, are protected in a previously unnoticed way.

All I want to say is that we are currently observing more and more - and a major study has just come out of China in the preprint realm - that in well-observed household situations, the secondary attack rate, that is to say the rate of infected persons who become infected when there is an index case in the household, an infected person, is quite low. It is in the range of 12, 13, 14 percent. Depending on the correction, you can also say that it is perhaps 15, 16, 17 percent. But it does not lie at 50 or 60 percent or higher, where you would then say that these are probably just random effects. The one who didn't get infected wasn't at home during the infectious period or something.

How is it possible that so many people who were supposed to be in the household are not infected? Is there some sort of background immunity involved?

And there are these residual uncertainties. But at this stage, even if you include all these residual uncertainties in these models, you still get the picture that the medical system and the intensive care unit capacity would be overloaded. That is why it is certainly right at the moment to have taken these measures. We must now carry out intensive research work as quickly as possible, as we clarify issues such as: What is really wrong with the children? Do they not get seriously ill, but are they in fact infected and are giving off the virus and carrying it into the family? Or are they resistant in some way? The other question that we absolutely must also answer is: why do relatively few, perhaps even cautiously put, unexpectedly few get infected in the household? This is a realisation that is now maturing so slowly.

As I said, a new preprint has just appeared from China, and a few other studies suggest that this is the case. The Munich case tracking study, for example, has already hinted at this a bit. You have to take a closer look at that. Is there perhaps a hitherto unnoticed backgroundimmunity, even if only partial immunity?

That wouldn't mean that we were wrong at this point in time, and what we have done now was wrong. At the moment, even if you factor in these effects, you get the impression that it's right to stop this, that we're not getting into such a rampage that we can no longer control. But for the estimation of how long the whole thing will last, new information could arise from this. It could then be - and I would like to say this now, perhaps as a message of hope - that in a few weeks or months, new information will come out of science that says that the infection activity will probably stop earlier than we thought because of this special effect.

But I don't want to say that I can announce something now. These are not hints from me, or data that have been available for a long time, but that I wouldn't want to say in public or anything. Rather, they are simply fundamental considerations that we simply know too little about this disease at the moment. And that the knowledge, which is actually growing from week to week, will also influence the current projections.

Other podcasts

Part 31: Corona Virus Update: Don't take stories about reinfected cured patients too seriously.

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.

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.

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.

Pages

Monday, 20 April 2020

Corona Virus Update: the German situation improved, but if we relax measures so much that the virus comes back it will not be just local outbreaks (part 32)

The situation and measures in Germany

Summertime

World Health Organization and Trump

Local outbreaks in wave 1, everywhere in wave 2

Positive surprises

Other podcasts

Related reading

Thursday, 16 April 2020

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

The basic problem determining whether someone is ill

Reporting of the results

Study one

Study two

Other podcasts

Related reading

Friday, 10 April 2020

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

An exit strategy

Types of masks

Droplets and aerosols

How long is someone contagious

Infection via surfaces

Loss of smell and taste

Other podcasts

Related reading

Tuesday, 7 April 2020

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

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?

Other podcasts

Related reading

Monday, 6 April 2020

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

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?

Other podcasts

Related reading

Most read posts

Search this blog

Blog archive

Follow blog feed