How is the population controlled in India

(86) Coronavirus update: The example of India

Status: 04/28/2021 4:24 p.m.

In the new episode of the NDR Info Podcast Coronavirus Update, virologist Christian Drosten speaks, among other things, about dwindling antibodies, the pandemic dynamics and the vaccination strategy.

"Canceling vaccination priorities", "Relaxing requirements for vaccinated and convalescent people", "Implementing uniform federal measures" - these are important issues that are currently being politically negotiated in Germany around the pandemic. A look at India, however, makes you meek. What is happening in India right now, NDR Info science editor Korinna Henning talks about in episode 86 with Christian Drosten, the head of virology at the Berlin Charité. Dwindling antibodies and the risk of vaccination for pregnant women are also discussed.

The main topics of the episode at a glance - jump directly to the text passage with a click

Immune Escape in the Indian variant B.1.617

Role of IgA antibodies in the spread of the virus

Importance of the age structure in India

IgA antibodies on the mucous membrane disappear

IgA antibodies in vaccinated persons

"Non-responders": No antibodies rarely after infection

The compatibility of vaccination in pregnant women

Risks for pregnant women with Covid-19

Pros and cons of child vaccination

Decoupling of incidence and ICU bed development

Role of rapid tests and B.1.1.7

Federal emergency brake and the example of Hamburg

Socio-economic inequality

Korinna Hennig: We have to talk about India, the reasons for this violent second or third wave there. But we also have to look at how long which antibodies remain after an infection, maybe also after the vaccination. And what that means for the view of autumn and winter. And it's about the latest findings on vaccination for pregnant women. And the debate about which key figures are actually still suitable for recording the infection rate in this phase of the pandemic.

Let's start with India: the numbers are dramatic. Around 350,000 new infections in a single day were reported over the weekend. That was more than a third of the global incidence. There are harrowing reports from the hospitals that lack oxygen and from the crematoria too. Now the headlines are talking about the Indian double mutant who is blamed for it. This is a bit misleading because it is not two dangerous variants that come together, but because you are looking at mutations in two places in the spike protein. It is normal that there are always multiple mutations in variants. Nevertheless, let's take a quick look at B.1.617, as it is called. Is this variant overestimated in terms of its importance for the current situation in India?

Christian Drosten: At the moment I would think that the media rating is overrated. It's a bit of a woodcut, as is always reported. Today I listened to the radio again - and in principle it is always the same story: The incidence is reported, which of course is now certainly colored by testing. You don't really know what the number of cases is, what the real number of infections is. But of course it is very high. So you just see what is there in the public image, in the street, in the hospitals. Then it is always associated with this B.1.617 variant. Exactly this term "double mutant" that always resonates. It sounds like this is the big change that is causing this situation in India. I don't think that's the case. You have to look soberly at the epidemiological data, the study data that are now available. You have to be clear about something beforehand: The situation, the structure in India is very different from that in many other countries. We already had control measures in India in the first wave. I think they were relaxed relatively soon.

And in September there was a first clear wave of dissemination, which did not have such a big impact because the people in India, the population, have already remembered the control measures, what one has to do. And now we have a naturally occurring, one could say second wave. It's actually a third wave. But the first wave was strictly controlled by intervention measures. Then we have a supply that is completely different in India. So, the number of hospital beds per inhabitant - that is in a completely different relationship. That's why we get pictures in the media that are very frightening. But there is of course a different supply capacity there, much less. Then we will have a population that is difficult to protect itself and is difficult to withdraw. So these are completely different basic requirements. Then you just have to look at the data. And the big question that naturally arises is: If a virus variant is to be held responsible for suddenly changing the whole picture, then one would expect that there was basically something like population immunity beforehand, that herd immunity has been achieved in India. This also resonates in some media reports. And that doesn't really seem to be the case.

India far from herd immunity

Hennig: That is what we discussed in Brazil before. You have already said that, there have already been high numbers in India. But now you have taken a closer look at the seroprevalence there. There are sero surveys that were already carried out in the third round, i.e. to look for antibodies in the population. What kind of knowledge do we have from this? How contaminated was the country at the start of this second or even third wave?

Drosten: Yes, we now have a preprint available that summarizes a sero survey. Household examinations were made there. A huge network of epidemiologists has organized itself in such a way that households have been selected, structured geographically and demographically. Then you visited these households and said: Everyone who lives here can get a serological test if they want. Of course, many agreed. There have been three such rounds of research across India. So this is an amazing organizational effort. That was done once before summer, around May and June, then after summer, August, September. That was in the first wave of contamination, which is really clearly visible in India.

Then there was another check-up: In December and January, so in principle before the start of this new wave of infection. The numbers are like this: You have 0.7 percent seroprevalence before summer, so that's very little. As I said, there were control measures in place when the virus was introduced. Then 7.1 percent after the summer. And then in December, January, we're in the 24.1 percent range. That is far from herd immunity that would be put anywhere in the 70 percent range. Then of course the question is: the antibodies that have now been measured, are they synonymous with immunity? You have to add that, of course, they are never quite. Antibodies also have their weaknesses in interpreting the situation. I want to mention two very special considerations, two corrective considerations.

That is one. Antibodies generally go down a bit over time. This means that the assumed prevalence has to be corrected a little upwards, but not very much. There are data that suggest that after one year with IgG antibodies, i.e. the main antibody in the serum, one can assume that 90 percent of all infected people should still have IgG antibodies after one year. Therefore you have to correct that slightly. But certainly not now from 24 to 30 percent, so that would perhaps be the absolute upper limit of where one would have to make corrections for one's idea. We had discussed this at the time, at the only major seroprevalence test for Manaus, and it was probably corrected far too much upwards.

Hennig: In Brasil.

Drosten: Exactly. This December, January wave in Manaus, which was certainly not in spite of herd immunity, but also there the idea of ​​herd immunity was probably simply exaggerated and premature. It just didn't exist yet. And here we are now in December, January in the range of maybe 25 or 30 percent.

Hennig: Can the same be said for the urban slums that exist in Brazil and India and that are even more difficult to protect?

Drosten: Exactly. The fact is that you naturally have effects of population density - that is inevitable. In the country you don't meet as often as in a very densely populated area in a big city with poor hygiene conditions. The authors also divided it into rural areas, then normal urban areas and then actually poor areas, slum areas. This is how they find a gradient in seroprevalence. So in rural areas 21.4 percent, in urban areas 29.4 percent. And in the poor areas 34.6 percent. So there is an increase in it. But that is not the case now that in the poor areas, in the very, very densely populated areas with poor hygiene conditions, one could say that one would already be close to herd immunity there. That's just not the case yet.

Hennig: India also sent teams to the slums in the first wave or at the very beginning, when there was also a lockdown. So he took measures back then, but they may no longer take place today.

Immune Escape in the Indian variant B.1.617

Drosten: In the first wave, India was very scared of the effects of this virus after seeing it spread in Wuhan. And of course then took relatively drastic measures at the time, which, however, simply could no longer be maintained economically and which could not even be supported in parts of the country. But we remember pictures in the media of migrant workers who then had to return to their home villages without any protection or help, some of whom then walked for days just to go home. Because where they work, in the big cities, they could no longer stay and were no longer tolerated.

There were bad social conditions. That's why I couldn't go through it anymore. I would like to say again: It is of course not the case that all of this is completely wrong with the reports about the effects of variants. The 617 variant, for example, which has Immunescape characteristics. Its obvious. If this is meant: a double mutant. Then what it means is: there is an exchange at position 484, which is one of the main receptor binding domains. There is a glutamine built in instead of a lysine. And we know this glutamate-lysine exchange with the mutant from South Africa. And also with the P1 variant from Brazil.

Hennig: E484K it's there.

Drosten: Exactly. And here it is E484Q. We don't really know what this difference means. But that's an Immunescape site of this virus, it's here. And then we have another one. That's leucine at 452 exchanged for arginine. We know that, there is a variant that also clearly shows a slight Immunescape, this is a variant that occurred in California. Now it is like that again, one cannot deny that there is probably an Immunescape. But still, this combination is certainly not that unique. So, we have other variants that show even more Immunescape characteristics. You wouldn't say: This is something very special about this virus here in India.

And then we have another position, i.e. P6181R exchange, again exchange to arginine, i.e. from proline to arginine. There is another exchange at the same point in the variant B.1.1.7 described for the first time in England. This is a proline-to-histidine exchange at the same point, and probably has the same functional effect. This is an additional basic amino acid at the furin cleavage site, which we have already discussed in previous episodes, that tropism or fitness effects may also be expected there. So that perhaps an increase in the ability to transmit without any immune effect, any Immunescape effect is conceivable here. The laboratory studies are pending. There are first superficial investigations that suggest this as I have just outlined. There is a slight immune cape against neutralizing antibodies. It's not strong, it's around a factor of two. That has just appeared as a preprint, just very fresh.

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So that's not something that really worries you. In effect, this is less than the South African mutant. I think one has to be clear about what happens when such an Immunescape mutant appears in a naturally infected population. As we have now seen in South Africa, as we have seen in Brazil, as we are now seeing in India. These are populations in which the virus has already immunized the population to a greater extent. A partial protection has already been set up in each case. In India it is perhaps in the range of 30 percent of the population before the wave of infections that has now emerged. Now comes an Immunescape variant that makes part of this 30 percent receptive again. But that's only a very small part. These are the edges of the distribution.

The role of IgA antibodies in the spread of the virus

These are all mathematical distributions that you have to imagine. And not just individual numerical values. These edges will be cut off. That is, just from an idea that with this virus there are suddenly no longer 30 percent who are completely immune to it, but maybe only 26 percent or something, so small cuts. Then, over time, the effects of immune loss also appear. One effect is: Overall, the antibodies go down slowly. But you can imagine, according to the data that are now available overall, maybe ten percent loss per year in IgG. But there are other antibodies, such as IgA. This is what you should bear in mind here. This is an antibody that is also produced in the body, but which has the task of specifically protecting the mucous membranes. We already discussed this in detail in a previous podcast episode about what IgA is. We can measure this in the serum and it is transported from the serum to the mucous membranes, this IgA. So we actually find that in the fluids of the mucous membranes, in saliva, in secretions, in the nose and so on.

Hennig: Where to not find IgGs.

Drosten: Exactly or only to a very small extent. It is also produced by plasma cells locally on the mucous membrane, IgA, to an increased extent. So we have a direct production of the mucous membrane and a filtering through, a secretion from the serum, from the blood serum. And these IgA antibodies, which are specially designed to nip incidents of infection in the bud on the mucous membranes. Because these IgA antibodies also have neutralizing properties, they are also neutralizing antibodies. Part of the total neutralization activity that we measure in the serum is therefore made up of IgA. There have recently been study data for this. There is a work from China that is interesting, from Wuhan. But you can also see it when you run your own laboratory and monitor studies, vaccination studies, immunity studies. You can see that this IgA goes away faster than the IgG. We see in some of the cohorts that we accompany here with us, especially with mildly infected, naturally infected patients - that will have been the majority of patients in India - the majority had a mild course and were naturally infected. They lose their IgA after two or three months. So they no longer have any measurable IgA. Especially not if you were to measure in saliva. And in people who had a more severe course, the IgA remains for a significantly longer time, for many months. We don't yet know exactly when it will end, but it will certainly last for a few months.

And the entirety of such a population in a country like India, for example, then has just after the first wave of infection in this case began in August, September in large numbers and then in autumn many mild courses have set in and then until winter 30 Percent immunity, the first are so far that the IgA is lost. And those are people who then contribute to the spread of the infection in the sense that they no longer have any protection on the mucous membrane or only have reduced protection. There are no black and white effects, they are always grayscale. And here we simply have reduced protection over the mucous membrane. That means, these are patients who get a second infection.Many of them will not get a severe second infection because they have also built up T-cell immunity in the background. And the T cells are very robust against Immunescape. They prevent it from spreading to the lungs or at least from developing pneumonia, a severe course.

Hennig: So they protect the individual.

Drosten: Correct. Exactly. That is the individual protection, the individual protection. These are people who, from the point of view of the virus - who are only interested in infecting someone, whether they get seriously ill or not - are again a member of the population available for infection. That means that you have to subtract that from the 30 percent immune, so that in the end we are in the net, i.e. with those who are really no longer infectable, maybe only ten percent or so. Of course, there is so little immune protection in the population that the combination of IgA loss and this emergence of a slight Immunescape mutation make it look like a completely susceptible population to the virus.

Now there is a raging wave of infection. This is what we are seeing in India right now. And the insight into the data on what proportion of the circulating virus population actually makes up the 617 mutant, which actually does not necessarily suggest that this is a pure 617 virus wave. Rather, it is more of a colorfully mixed virus population. For example, B.1.1.7 is also strongly represented, which is now simply infecting a population that is beginning to lose the initial immunity from the first two or one and a half waves in India. And at the same time the virus is a little more spreadable, a little more robust against immunity. And these effects just come together.

Hennig: Can you somehow estimate from the data, there is not as much sequencing in India as, for example, in England, how proportionally the variants are on the way? So what role does B.1.1.7 play, for example? The variant that dominates the action for us.

Drosten: I don't want to put this into numbers here because the database is so small. We are talking about a few hundred PCR tests that were carried out in one region. But we are having a mad riot raid in this region. So it's almost like throwing the dice. So there are numbers that suggest that maybe 60 percent in the severely affected areas are 617 mutants. But, as I said, these numbers are so small that nothing can be made of them. So the population that was examined there.

Hennig: But asked the other way around, you know that B.1.1.7 also plays a major role?

Drosten: Yes, B.1.1.7 occurs to a large extent in India, and has been for a few months.

Circulating virus populations are normal

Hennig: Just to explain again, because you explained the amino acid exchange in detail earlier: The mutation N501Y, which is held responsible for higher transferability in the B.1.1.7, the English, not only English variant, which comes in the Indian variant not before, as far as we know.

Drosten: No, it doesn't appear here. This occurs again in other such mutants. The phenomenon that we are seeing here in general worldwide in the circulating virus population of SARS-CoV-2 is convergence. So we see that in this ever-growing family tree of viruses on very different branches that are no longer directly related to one another, the same mutations repeatedly arise independently of one another. They do not arise in isolation, but sometimes several arise at the same time. And therefore it is relatively obvious that the same combinations will be seen again and that new combinations of previously known mutation features will also be seen. The fact that all of this is so highly convergent is actually something of encouragement to me. That actually tells me that the reactivity of the human immune system is very uniform around the world.

There are also immunological features that confirm this, that underline that it is likely that people all over the world react roughly in the same way to this virus and therefore the virus also shapes its immune landscape roughly the same. This gives hope that after two or three years of this virus' ability to spread, we will end up with a virus population that is on the one hand very, very different and mosaic-like around the world - so the genomes are then probably also recombined with one another. That is a very colorful background, but the main properties in terms of receptor binding and neutralization will probably come down to a common denominator and then probably stabilize in this state.

So that we can hope that we do not get into a situation like with influenza, where we see big leaps in antigenicity every two, three, four years and then we lose some of the effectiveness of the vaccine again. Because when we choose the SARS-2 vaccination, we want to get into a state where we only have to make an indication vaccination, i.e. with comparatively weak vaccines only in the population where the risk is greatest for a severe course , re-vaccinate. And other large sections of the population do not need to vaccinate because there is a basic immunity so that the normal, not at risk, something like a severe cold or even maybe a mild cold, when in reality it is the SARS-2 virus.

The importance of the age structure in India

Hennig: We had already talked about this hopeful finding in an earlier podcast episode. Nevertheless, I would like to bring up one aspect of India again. Compared to Germany, India is a really very young population. And now we see these dramatic pictures that there are a lot of younger people in the hospitals. Associated with this is of course the fear, if you look at these pictures, that the variant and also all the variants that are on the way may make them sicker than you know so far, regardless of the Immunescape? What is the reason for the young people? Can you explain that?

Drosten: At the moment we have no evidence that this virus increases the severity of the disease. And based on the other findings about the other mutants that have similar properties, it is not to be expected that there will be any great increases. We really have to realize what the basic situation is. We have in the Indian population, I can say that now, because that is what is written in this study for the Sero-Survey, which we just briefly discussed, there is the proportion of the population in it. And we have between the ages of ten and 17 years - the study only examined from ten years, so younger children were not examined there - from ten to 17 years, that's only eight percent of the population.

And then from 18 to 44 we're at 57.1 percent of the population. So if we add that up, 65 percent of the population is up to 44 years old. It's a completely different picture than ours. And now you have to imagine: What would it be like if that were the case with us? So let's imagine we infect a lot of young people. In principle, we would ignore the older part of the population, because here in India these are smaller proportions. Let's ignore them now and imagine what it would look like if we in Germany had very poor equipment with intensive care beds and hospital beds in general. Such a virus would then run largely freely. If we were to do a few rough calculations, we would come to the conclusion: It would look the same for us. It's just like this: if many people are infected at the same time, then in absolute terms, even in the younger age groups, you suddenly have a lot of sick people in a short time frame. This is what is happening here.

No more young people infected in India

We can of course also add other effects. For example, the basic health of the population in India is not the same as ours. For example, many people in India still have hepatitis B. This is a serious general disease that has long-term effects on their basic health. Also on the ability to ward off infectious diseases, which also have serious sequelae of an internal nature that predispose us to more severe Covid-19 courses. That's only an example. We don't have a very well cared for, very healthy population in this country. And that compensates for this effect on the young population a little. We also see something very interesting here, which once again supports all the basic assumptions that we have always made here in previous podcast episodes: the seroprevalence, i.e. the contamination of the virus - how common is the virus, in which age group the same everywhere.

We even have an emphasis on the children examined here. They have the highest seroprevalence. But these are not significant differences. Overall, we are in the same range in all age groups. These age groups have different risks for severe disease. The younger, the lower the risk. But then the high number of absolutely infected people compensate for that. So if we have ten times less risk with the younger ones, but we have ten times as many infected people, then we have the same problem as before.

Hennig: That is, it is about absolute numbers. It is not that the proportion of seriously ill among the younger ones is greater here, but simply that the proportion is generally so large due to the force of the wave.

Drosten: Yes. I just want to say I can't rule all of this out. It may be that in two months it will turn out that something is wrong with this virus. Just now, there is no scientific evidence to support it, no reason to believe it, based on past scientific information about other virus variants. That's why I'm having a hard time at the moment, this perception that you sometimes hear, this nasty new virus, and now the boys are getting sick to a great extent, I don't connect with them.

Hennig: One last time about this new virus about this mutant. You have just mentioned the neutralization effect briefly. So what kind of Immunescape is there if there is a small one? India is an important production location for vaccines and has since stopped exporting so that it can now also supply its own country. The progress of vaccination in India is extremely slow. I looked again: With the first dose, i.e. first vaccinations, India is now only 8.5 percent of the population. That is only a little more than a third of what we have in Germany. And for the fully vaccinated, it looks very bleak, the rate is only 1.6 percent. A version of the AstraZeneca vaccine and a dead vaccine are used in India. That is very important for India, an inactivated virus, Covaxin, which is produced in India. What clues are there for how well the vaccination works against this variant that is now in focus?

Dead vaccine also effective against variant?

Drosten: There is a small preprint that was made with the strong participation of the company that makes this dead vaccine. So dead vaccine means: Virus is grown in cell culture, is then usually killed by a chemical substance so that it can no longer replicate. Then an irritant is added, a vaccine booster, an adjuvant and this is then injected into the muscle. Then a kind of inflammation occurs in the muscle and this inflammation then simultaneously stimulates the immune cells.

This leads to an immunity, which is where antibodies come about. One can measure the neutralizing antibody response in the form of serum neutralization activity. That was done in this study. By comparing a previously circulating B clade virus, then interestingly, I'll say the British B.1.1.7 virus - we will probably never know whether this really comes from the UK. And then the 617 virus, this Indian virus that is in focus. What you first see: The normal, the wild-type virus and the B.1.1.7 variant neutralize equally well. So no loss of neutralization for B.1.1.7, as previous studies on Biontech and Astra have already shown. So it's the same with this dead vaccine. The protection is equally good. So another confirmation. B.1.1.7 is not an Immunescape variant, but still a fitness variant.

Hennig: Transferable.

Drosten: Right, easily transferable, but not because of Immunescape. With this new virus, the neutralization activity is almost twice as bad. That is not much. So now for someone who is laboratory savvy, this is something not to worry about when it comes to immune protection. Well, that doesn't bother me at all.

IgA antibodies on the mucous membrane disappear

Hennig: Let us conclude the subject of India now. Mr Drosten, you have already mentioned this big issue of antibody persistence, i.e. how long do the antibodies stay and how long which antibodies stay and what does it do with population immunity and protection against the transmission of the virus? You have just said there is a paper from Wuhan where you can look very well, because it all started there, how the antibodies behave over time. What do we know about this, about this special effect of IgA antibodies, also with a view to how things could go on with us, with those who have recovered, for example?

Antibody study in Wuhan

Drosten: Yes, this study, which by the way is published in the "Lancet", has already been formally appraised, and examined the population in Wuhan. This is a large-scale household survey study. There are almost 3,600 households here - families are said in the paper, which is perhaps even more in line with the concept of a household in China - and a total of over 9,500 people were examined. Here really all ages, from the newborn to the old, depending on who lived in the household. That was tested for antibodies and again three times, as in the Indian study. This was done once in April, after the great wave of infections in Wuhan, after the great lockdown, when the impression arose that the worst of the worst for the city was over in Wuhan. Then a follow-up check in June, then in October and December.

What was initially found was very interesting: In April, after the great wave of infections, a 5.6 percent seroprevalence. That's the starting point, that's quite a number if you think about it. So it was discovered, in such a very modern city, that a completely new disease is in progress. Epidemiologists make this decision to impose the lockdown and it comes under control. Now you look in retrospect: How many were actually infected here? That is actually 5.6 percent of the population. That is a lot for such a first wave that was then checked. You can check that again, for example according to certain districts that are represented in different ways in this sampling.

You can use small representative correction factors, then in April after this first wave of contamination you get a corrected rate of infection of almost seven percent. First of all, that was very interesting for me, for my idea of ​​how sweeping this infection was. Now these patients can be re-examined. You can now say: Now we have defined our sample to be examined. Now we ask them again whether they will draw blood again in June and again in the period from October to December. You can now see something interesting here, broken down into IgG, IgM and IgA antibodies: It is the case with IgG, those who are one hundred percent IgG-positive in April will still have 97.5 percent in June, i.e. 97 , 5 percent of them still have a positive IgG status and still have detectable IgG antibodies.

And 91 percent in the months of October to December. So it's been almost a year, nine months have passed, and only nine percent no longer have IgG antibodies. This is for a respiratory disease that the respective people have contact with for the first time in their lives and which most report in retrospect - i.e. 80 percent report that they actually didn't notice much about it, so here it says asymptomatic - only in memory cannot be remembered of symptoms. But that could mean that you had a sore throat three months ago.

Hennig: So weakly symptomatic is also included.

Drosten: I would think that means everything, that was not a noticeable course. Only nine percent lost their IgG antibodies in the first nine months. With IgM, it's normal for them to go away. And with IgM, it is also normal that the test is not as sensitive. In this test, which was used here, only 13 percent had IgM antibodies detectable at the beginning.In June and through November it was 3.9 and 1.5 percent. This is due to the fact that the IgM is the immediate antibody, which then disappears again on average after six weeks, in all possible infectious diseases. But what is interesting now is the IgA, the mucous membrane antibody, the protective antibody for the contamination, here too these first generations of laboratory tests are not very sensitive. That is why it is so here, while we detect IgG antibodies to one hundred percent, we have only detected IgA antibodies in 15.8 percent. However, that does not mean that there are no IgA antibodies in one hundred percent. We can't see those in this lab test because the lab test isn't sensitive enough. There are now better laboratory tests. If you wanted to test this in the laboratory over the long term, i.e. that would be relevant for routine medical care, then companies would of course also go there and develop even better tests. But at the moment these tests are not very sensitive.

Hennig: In other words, the antibody tests that we are now also using here are often not sensitive enough to reliably detect the IgAs?

Drosten: So the IgA antibody tests have two problems. Firstly, they are not very sensitive, so the detection rate is lower than then tested for IgG in the same patient. Then you have another problem: around five to ten percent of all patients have IgA antibodies even though they have never had contact with SARS coronavirus-2. So that's not very specific either. In other words, this antibody test is done in addition. This is an antibody test that says nothing for individual diagnostics in a patient about whom we know nothing. But if we know that the patient has already had a PCR-positive infection or that he has IgG-positive antibodies, then we can gain valuable additional information. In this case, the additional information: Okay, immune protection is there. But what is the mucous membrane protection like now? If we ask that, then in the first study in April we see almost 16 percent. In the June survey, just under ten percent. In the follow-up examination in November only 3.5 percent. So, roughly speaking, there are only 20 percent of the antibodies left.

Hennig: IgGs remain stable and the IgAs, which provide protection against infection, fade away over time.

Antibody protection diminishes over time

Drosten: Exactly. So after nine months, just a quarter of the then IgA-positive patients can still detect IgA. At the same time, the level of IgA drops. We don't see that with IgG. We said we were still at 91 percent. It is so that the level, the concentration of these antibodies has hardly dropped. By the way, it is actually the affinity that we are testing. And that is not the case with IgA. In the case of IgA, the titer, the affinity, also falls. The antibodies are no longer as reactive. All this together is a very strong indication that the mucosal protection is being lost at the population level. A considerable proportion is lost within a year.

I could also translate this into the epidemiological idea of ​​thinking into the future from season to season, if I want to put it that way: With a seasonal cold, which has a typical winter seasonality, one would think: Aha, lose from winter to winter 75 percent of the population already have their mucous membrane protection here and can become infected again next winter. Now you have to know that these are all people who have only been infected once. But if I've already had three or four or five such infections in my life, then the IgA protection will last longer, several years and not just a few months. With increasing post-infection, post-infection with the natural infection, everything gets even better. So this is now nothing where you have to throw up any doomsday scenarios, according to the motto: The virus will always be pandemic, will never stop and so on. This is nonsense. Everything we see here are perfectly normal observations that we would expect while such a virus has settled in and is on its way to an endemic situation.

IgA antibodies in vaccinated persons

Hennig: That gives us a positive long-term view of it. But in the short and medium term it is still not entirely meaningless, because so far we have based our view of the summer on the idea: More and more people will have protection that, above all, also protects others. But we can't say anything from these Wuhan findings about how it behaves after a vaccination, can we? With the IgAs.

Drosten: Well, we have just discussed the mucous membrane protection, the IgA protection, it goes away with time. We have now discussed that for natural infection. And now, unfortunately, I have to say something that will worry many again. But that's the way it is. I'm just saying how it is. Even after a vaccination, it is of course the case that the IgA antibodies that arise initially are lost again after a while. Unfortunately it is that we do not know how long it will take with the vaccinations that are now being studied. We don't know about Astra. We don't know that at Biontech. We don't know that at Moderna. And we don't know for any other vaccine either. We only know this for natural virus infections, for example based on this study in Wuhan. But I can also say that, I can completely confirm this on the basis of our own laboratory observations, most of which have not yet been published because they are accompanying examinations to studies that we are carrying out, and this study is still ongoing. And it is the same with vaccinations. We also do such accompanying examinations there. We look at vaccinated groups of people. And I can say: yes, the IgA is also lost here.

Hennig: So that's more than an analogy. That is an observation.

Drosten: That is already an observation of experiences from my institute. I deliberately do not want to give any numbers, because these are simply ongoing and sometimes very small examinations. I just want to say, purely qualitative, everything else would also be a surprise if the mucosal protection via the IgA remained lifelong after a double vaccination. That is not to be expected. So that goes away again. This will likely go away in months, not years. Possibly at a time when it is possible to say who will be fully vaccinated in the spring, could already have significantly reduced IgA antibody levels in the next winter. To the extent that the mucous membrane protection is already reduced again. I don't want to say that it's gone. It's never completely gone. As I said, these are not black and white effects that we are describing here. But the mucous membrane protection is then probably already reduced again. Of course, this does not mean absolute within limits.

But within limits, these people will then again belong to the transmitted population despite being vaccinated, i.e. the population that can also pass the virus on again. But what we don't know is whether this transfer is completely efficient or whether it is only very partially efficient. So it may well be that the rest of the IgA immunity, and incidentally also the T-cell immunity, which also does its good on the mucous membrane by shortening virus replication - these two effects together could actually continue the transmission capacity in a low percentage range bring up. However, it can also be that these people are clearly communicable again many months, but less than a year after the vaccination. Here, too, it is the same again, nothing that stays that way forever. People will then have their first natural infection after the first vaccination. This will be a very strong boost to immune protection. And after a season or two of Covid-19 infections in the population, this immunity will remain much more robust and stable, so that IgA protection will certainly last a year or two. This is exactly what we have with the cold coronaviruses, with the normal human coronaviruses.

Vaccines are quick to adapt

In addition, it has to be said, of course, there will also be re-vaccinations. We can plan that from autumn and winter, as with the flu vaccination, the risk groups will be re-vaccinated anyway with a one-time booster vaccination in the sense of an indication vaccination. These are then probably vaccines that already have an update with regard to the escape variants. It is relatively easy to make an update for the mutations at the level of an approved vaccine. These are well-practiced processes. We know that from the influenza vaccination. We always have to update the vaccine antigen. These are all very well-established processes in terms of regulation, and that happens quickly. We then have the option of doing an immune protection update at the same time. And then the question is: How big must the population be in the coming season that we have to re-vaccinate? So at most, that would mean that we all who are vaccinated now have to re-vaccinate in the winter.

Hennig: To maintain civil protection.

Drosten: If it turns out that these IgA antibodies and also the mucous membrane-relevant T cells are lost again relatively quickly in people who have now been vaccinated. We do not know that. We have no data on this.

Hennig: That you just mentioned it yourself, the question: How big does the share have to be? Can you say something like that? How large should the proportion of people in the population who still have IgAs, i.e. mucosal antibodies, be in order to protect others?

Drosten: As I said, these are not black and white effects. It's not about having or not having IgA. It is also about the titer height. So it's impossible for me to quantify that now. Except with relatively simple statements like: 70 percent based on the R-value. Or now with the new, with the 1.1.7 mutant maybe 80 percent. Using a naive conversion factor that you can easily do. But that's actually a kind of black and white thinking. And that's why I don't want to do this quantitatively at all. I would like to say something qualitative that is perhaps not even known to the public and that is completely lost in the entire media and political discussion, namely: We know: The vaccinations are effective and efficient against the disease. The phase 3 studies have shown us that. The effectiveness studies that follow have also confirmed this to us. We achieve values ​​of 90 percent and higher. And then we also have this perception: In addition, the vaccination also protects 70, 80, 90 percent against PCR positivity, i.e. against the infection in general, even against the unnoticed infection. In other words, it protects against the spread of the virus. So this is the population effect of vaccination.

But we have to make it clear that these values ​​are measured values ​​in studies that were recorded. People were tested with the PCR after they were vaccinated. They weren't tested after a long wait, but the study has to be finished at some point and it has to be published. That means, after a short waiting period, the vaccinated people were tested. And after this short time, the immune protection is best built up through the vaccination. So the few weeks after the second dose of vaccination - it doesn't get any better in terms of immunity. During this time it is measured who is still PCR-positive and, by the way, also how positive one is in the PCR. Because it is not about PCR positive or negative, but also about seeing in the studies that if positive, then only weakly positive.

Hennig: So with a lower viral load.

Follow-up vaccinations will be necessary

Drosten: Exactly, we can measure the viral load. It all looks great. These vaccines really look like they are practically imparting sterile immunity. Mind you, practically, so almost, approximately. There are always gaps. I just want one thing to be said. Namely, that this picture will change after a few months. Then these vaccines will probably no longer look so resilient when it comes to passing the virus on. That is something that simply has to be taken into account in public. It shouldn't be scandalized either. It's completely normal, it's an infectious disease here. And not the first we know as medical professionals. Everything we see here is like most similar infectious diseases. So none of this is a surprise.

It's also not as if that would be a reason for sensational headlines if someone thinks about writing: "Drosten says the vaccination doesn't last long," or things like that. That is trivial. We know that and we expect it. These days we are simply getting the first data packets that also confirm that this will be the case. And you have to plan with it. Because why else would we start up vaccine factories now and place orders for vaccines for the next season, when on the other hand we can work out that we probably vaccinated most of the adult population through July and August? If this vaccination protection stayed that way forever, then you would never have to re-vaccinate. And you don't have to do that because some mutants are coming around the corner, but primarily because immunity against such mucosal viruses is not a lifelong, sterile thing. So we're not talking about a measles vaccination here.

Hennig: But you have already outlined the long-term perspective. So when the virus becomes endemic, when you have contact with it from time to time and thus build up such long-term protection again, also with the IgAs. One could also say heretically: Well, if all the difficult courses are prevented, we cannot simply say that in autumn, winter, when there should be a fourth wave, then we all only have easier courses. Then why do you possibly need a booster vaccination?

Drosten: Yes, that is correct within limits. The question is simple: where are the assessment limits? How do you have to get out? The great difficulty with this disease is that the risk groups - apart from age - are relatively broadly distributed in the population, including the younger population. So the basic predispositions that convey a risk here are also present in 35- and 45-year-olds. There are still unclear risk dispositions where one says there is someone who is a good athlete, who has been intubated to full health within a few days. There are also such courses. We just don't really know about the correlations yet. That's why a certain security consideration has to play a role at the moment. I think especially countries like Germany with an old population age profile have to be careful. And rather assume in winter that more than just very narrowly defined risk groups will have to be re-vaccinated.

"Non-responders": No antibodies rarely after infection

Hennig: I would like to come back to the subject of vaccination of special groups in a moment. But one last short question about antibodies, because we often get questions about that. There are also people who do not develop antibodies at all after infection or vaccination. How common is such a phenomenon?

Drosten: That is relatively rare. You can see that it's true. You see non-responders, i.e. people who are vaccinated and who then have no antibodies at all. But the question is: how long does it take? Often, non-responders are simply late responders. In elderly people in particular, IgG antibodies sometimes only develop after a month or sometimes even later. It's normal. My impression is - even if this has not yet been confirmed, there is no comprehensive literature on it - that this is in the low single-digit percentage range for very old people who have been vaccinated. This phenomenon is not something that is common among the younger population. We have other vaccinations, for example hepatitis B vaccination is known for it. There is also a certain rate of non-responders among younger people. They don't get a proper immune response. This is apparently not the case with this disease. These vaccines are very, very active. And we actually see this absence or this severe delay in the immune reaction, especially in very old people.

Hennig: And after infection, but also tends to be very weak, that little happens.

Drosten: Correct. It's a completely different situation. Of course, there are also young people who have a PCR-positive infection without any symptoms, sometimes with a very short duration of virus replication, if you really measure it. Sometimes there is actually no immune reaction in the form of IgG antibodies. There are indications that they still have T cells. We took that apart a long time ago in a podcast episode, this phenomenon.

Hennig: That means, however, that these are also the cases in which a single vaccination might then be sufficient.

Drosten: These are the classic candidates for a very good response to the primary vaccination, exactly.

The tolerance of the vaccination in pregnant women

Hennig: Now we are on the subject of vaccination. I just hinted that today we want to take a look at what is actually happening with vaccinations for groups that are not planned for vaccination at the moment because they do not yet have enough data. In Germany, for example, vaccination has not yet been recommended for pregnant women. But that's different in other countries. Understandably, we repeatedly receive questions about this, because all parents-to-be are very concerned about this phase of the pandemic. In the UK, for example, the Joint Committee on Vaccination and Immunization - roughly what the Standing Committee on Vaccination does here - recommends vaccinating pregnant women. In France, too, vaccination takes place in the middle third of pregnancy, and in the USA too, for example. There is now data from the USA on the compatibility of the vaccination. They looked at more than 35,000 pregnant women, if I saw it correctly, and published it in the "New England Journal of Medicine". In summary, can we say that looks pretty good?

Drosten: Yes exactly. This is actually a study that can be discussed in such a way that one says that vaccination does not in principle pose any risk. You can of course delve a little deeper into this whole thing. So it is actually the case that in the USA, of course on a voluntary basis, pregnant women could be vaccinated at any time, even at any gestational age, i.e. also in the first trimester, in the first third of pregnancy, where there are always higher concerns.

Hennig: Because the miscarriage rate is already high. Regardless of the vaccination.

Drosten: Yes, let's put it this way, the vaccine damage and also the overall miscarriage rate in this phase of pregnancy are higher because the organ development is not complete at that time. That is the real reason in the first trimester of pregnancy. The embryo is then much more sensitive. It is now the case that vaccination has taken place here. And then surveys were done. There are basically three different data sources. Two of these work via a cell phone survey that the women who identified themselves as pregnant at the time of the vaccination. They were advised that they should register, they were re-analyzed in two different databases, but ultimately based on the same system, the same principle.

This is an SMS-based dialogue, where you are linked to Internet pages, where you can provide your information, an ongoing questioning and follow-up examination. The other is a passive reporting system, especially for doctors, of vaccine side effects. In principle, this is a reporting point for vaccination side effects. All of the information was collected there. Pregnant women were compared with non-pregnant women who were also vaccinated as a control group. The whole thing was done from mid-December to the end of February. Then it was evaluated. Pregnant women who are in the perception phase and who are pregnant have been vaccinated. The perception phase means: 30 days before the last rule up to 14 days afterwards, i.e. in the time when, in theory, implantation could take place and in which time vaccine protection is already building up. That could also influence early miscarriage, for example, which would also have been recorded in this survey.

No vaccination risk for pregnant women

Now that this has been described, one can perhaps better say again - long story short - all the complications that go hand in hand with a pregnancy are just as common in terms of their frequency as with non-vaccinated people in the same population, with not - vaccinated pregnant women. In this case, that's what you take from databases. Of course, a comparison was made between pregnant and non-pregnant people who were vaccinated. Again, the vaccine side effects are roughly the same whether you're pregnant or not, with a slight trend. And this trend can be described as follows: Pregnant women tend to have local vaccine reactions more often, so the arm hurts and these acute things. But they have a little less systemic vaccination reactions, for example fever. So this is a little more common in non-pregnant women in the same age group.

Hennig: That's what sounds almost a bit comforting even. Is it still possible to read out a bit that what is practiced in France, i.e. vaccinating in the second trimester of pregnancy, is perhaps a little more reliable to assess?

Drosten: Exactly. It is good that you are asking that, because this study already has a loophole. In fact: The decisive factor here is actually with the women in whom the pregnancy was completed by a live birth, with whom you can really say that everything went well, despite the vaccination, in the end, without any ifs and buts , of whom 98.3 percent were vaccinated in the third trimester. It couldn't be otherwise, because the study ran from mid-December to the end of February. It's now published. That is, the pregnant women who were then in the first trimester are still pregnant now. The study is ongoing, this is an interim report from the study. We can hardly deduce anything from this study for the most vulnerable phase of pregnancy, for the first trimester. So the little we can say, i.e. the spontaneous abortion rate, is unchanged. This is just like the non-vaccinated pregnant population in the United States. But there are few who fall for this. We don't have a single pregnancy, as we can actually tell, in the study, which was fully followed up with an initial vaccination. So that's still to come.

Hennig: From a practical point of view, however, it is probably also something that feels better for parents-to-be. Because if you then have a miscarriage and then doubt whether it was the vaccination after all, that is a difficult situation that you have to deal with. And it's only about three months that you can protect yourself and then say: Now maybe a vaccination would be possible.

Drosten: Correct. This approach in France is certainly a good, cautious compromise that is being made. That's right.

Hennig: Without going into depth, can we briefly put that in relation to what we know about the general risks of Covid 19 disease for pregnant women and the children-to-be? There are also studies there, but they are transnational. And then you always have to look again to see what role the health system is playing. But in general terms?

Risks for pregnant women with Covid-19

Drosten: Yes, there is a big one that has now been published in "JAMA Pediatrics". This is such a pregnancy outcome study. Starting last March, pregnant women were included in the study for eight months in 18 countries. And what you did is, you were mainly interested in the births. The focus here is less on the pregnant women themselves, although there is now risk data on this. But the period that is really looked at here is more the last period of pregnancy and then also the birth and the question of what about the newborn? As I said, 18 countries - many of them from the global south are represented.

So we do not have a study with a focus on industrialized countries, even if industrialized countries do occur. So this is more of a possibly representative study worldwide. What you looked at here are 706 infected pregnant women and roughly double the number of non-infected pregnant women. Here, too, of course, we just have to simply name the key findings from the study, otherwise it all just takes too long and becomes too complicated. But the relative risk, we have always introduced this term here ... You can well imagine the term eclampsia and preeclampsia, which is also popularly referred to as pregnancy poisoning - strange word - you sometimes hear that. Many are familiar with this. This problem that arises more in later pregnancy, where the high blood pressure is there and so on.

These symptoms, also in the direction of acute type 2 diabetes, are similar symptoms that occur there. This syndrome presents itself with a relative risk of 1.76. So there infected people have a 76 percent increased risk, so you can perhaps translate it, summarized for eclampsia and preeclampsia. Then you can go further here in a list. Serious infections around the time of birth and at the end of pregnancy that require antibiotic treatment have a relative risk of 3.38. So that's really significant. Then intensive care unit admission relative risk of over five. And a three-day longer course. Maternal mortality relative risk of 22.3, so enormous.

Hennig: But that has to be viewed differently all over the world.

Drosten: Correct. We have to say that again in a moment. But I'm just going to read the list aloud for a moment. Premature birth 1.59, so one would say almost 60 percent increase. Then medically indicated termination of pregnancy. So if you have to say, for medical reasons, it has to be now, 1.97. Then severe neonatal disease, i.e. around the birth of a direct newborn, relative risk of 2.14, i.e. a doubling. But these are not industrialized countries, there are many countries from tropical areas with very poor basic health care, where the term "maternal health" is used differently than ours. Where we really have complication rates around childbirth that are significant. Where we then have very strong social selection, you just have to say that too. If you are then, for example, in a maternity hospital in a country in the geographical south, you will almost inevitably see very strong social differences if you compare the group of coronavirus infected with the non-infected group. Of course, these are again very strongly correlated with complications around the time of birth.

Hennig: Nevertheless, things like eclampsia, preeclampsia, that is, pregnancy poisoning, are phenomena that also exist in industrialized countries. Which are also here and which give a clear indication in one direction. Nevertheless, to summarize, there are good data here for vaccinating pregnant women. But vaccination of pregnant women is not yet recommended in Germany, but of course it is not prohibited either. So individually, depending on the risk, the doctor can decide together with a pregnant woman to vaccinate her now.

Drosten: Yes. I think there will always be a further development of the recommendations; by the way, that is already possible in Germany. It is not at all as if, for example, the STIKO would strictly oppose this. But we will continue to develop there in Germany. And I think that the approach in France, for example, should be supported on the basis of the data that are now available.

Pros and cons of child vaccination

Hennig: We will continue to develop in terms of vaccination. Of course, this also applies to the large area of ​​child vaccination. Although it's not that easy to look at. We have already touched it briefly a few times here in the podcast. There are studies that are already running. In episode 83 we looked at these studies with Sandra Ciesek. Biontech / Pfizer, for example, has already published an interim report from clinical phase III for the use of their vaccine for children from the age of twelve, which is not yet the final one. But these are such rudimentary data that give a very good picture.

Nevertheless, vaccination for children is a matter of weighing up. Also seen from an ethical point of view, because you can still see that children are affected less often by the disease, which is more severe. This is also reported by the intensive care units. Apparently - as of now - the variants have not changed anything. Now one could also say: do we actually need children for civil protection, for herd immunity? I checked that in Germany there are twelve million children under the age of 16, that's about 14 percent. Wouldn't that be possible without the children?

Drosten: So first of all you have to say that the Pfizer / Biontech vaccine could now also vaccinate 16- or 17-year-olds. And they certainly contribute to the spread, they are very mobile and active after puberty. We all know the subject. So that is certainly the right approach to extend that with vaccination to that effect. The topic is very complex. I think it is very clear that you cannot calculate that bluntly. So that's a compartment in society where you can't say, then you just vaccinate everyone else and in the end you get an 80 percent vaccination rate and thus herd immunity. It won't work that way.

This compartment is conclusive, at least at certain times. So the school, for example, where all the children are together. Then you will possibly have an infection in the school. We do not yet know how it will look like, this is an interesting and in part a bit alarming observation that we can make now in the near future, for example in England. We have a situation that now, after the very active vaccination, 60, 65 percent of the total population is vaccinated. That is, a little more with the adults. The children are not vaccinated in England either. And school has now started again. We can now actually observe in England in the next few weeks whether the incidence is rising again in the school age groups or whether it is staying down. That is a very interesting prognosis, also for us, of course, as a first approximation.

High vaccination coverage probably protects children and adolescents

At the moment it looks like the numbers from the Office for National Statistics, where infection surveys are still being made, that the children are not yet rising in the number of infections. So it is to be hoped that the high vaccination rate among adults shields children. That would be very good. And of course, after everything we've just said, you have to ask the next question: How is it six months later? Towards autumn, when it gets colder again, you are more inside again. And the adults have been vaccinated for more than six months and the mucous membrane vaccination protection is slowly becoming less, are the children still so well shielded? Or there is then a surge in infection activity in the schools, out of the schools. Then hit back on the adults again before they were re-vaccinated there?