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.

Related reading

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

All podcasts and German transcripts of the Corona Virus Update.

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

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