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Florian Krammer Sep 27
1) SARS-CoV-2 Vaccines - I promised a Tweetorial and here we go. This is going to be long and nerdy. But I'll make sure it is easy to understand. If you want more details, please just read this:
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Florian Krammer Sep 27
Replying to @florian_krammer
2) I'll try to give an overview of the process, the technologies, correlates of protection, the candidates, how they perform in non-human primates and what we know about their performance in humans so far.
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Florian Krammer Sep 27
Replying to @florian_krammer
3) Let's start with the process. Developing vaccines usually takes a long time. Usually there is a medical need and some idea of how to design the vaccine, often in an academic lab. Versions of the vaccine are tested in iterative processes, the constructs are optimized....
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Florian Krammer Sep 27
Replying to @florian_krammer
4)....and this can take a few years. Then funding needs to be secured/a commercial partner needs to be found to advance this further into clinical trials. This can also take time. Once funding is in, a process is developed, GMP (good manufacturing practice aka high quality)....
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Florian Krammer Sep 27
Replying to @florian_krammer
5)...material needs to be produced, more formal animal experiments and toxicology studies are performed and then an IND (investigational new drug) application is filed. This process might take another 2-4 years. Then you go into Phase I trials (2 years), Phase II trials.....
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Florian Krammer
6)...(2 years) and if everything looks great, the market is still there and the developer is sure the risk is low, they embarke on Phase III (which takes also about 2 years and is very very expensive). Just to explain the Phases: Phase 1 (<100 individuals) to check initial safety
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Florian Krammer Sep 27
Replying to @florian_krammer
7) and some immunogenicity, Phase II (a few 100 individuals) explores safety, immunogenicity and optimizes doses/regimens and Phase III (often thousands of individuals) looks at how well the vaccine works (efficacy) and safety in a large number of people.
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Florian Krammer Sep 27
Replying to @florian_krammer
8) Now, if Phase III looks good you file a biologics license application (BLA) to the FDA to bring the vaccine to the market. They may ask for more data, it is a process. You end up with about 15 years of development. Only then you start to produce the vaccine, which is expensive
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Florian Krammer Sep 27
Replying to @florian_krammer
9) Here is an overview of the process.
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Florian Krammer Sep 27
Replying to @florian_krammer
10) Now, for SARS-CoV-2 this looks very different. A lot of preclinical work was done on coronavirus vaccines. The target, the spike protein was known. So, the fiddling around for years was skipped. This antigen was then just plugged into existing technology.....
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Florian Krammer Sep 27
Replying to @florian_krammer
11) ...and existing processes. In some cases, preclinical/toxicology data from similar vaccines was used for the initial IND. Clinical phases were staggered - which speeds thing up a lot.
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Florian Krammer Sep 27
Replying to @florian_krammer
12) Now, the question is, doesn't this compromise safety? Not really. Vaccine development is slow because it needs to be de-risked. You only go to the next step if you think the risk of failure - which will costs lots of money - is low. For SARS-CoV-2 money doesn't matter.
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Florian Krammer Sep 27
Replying to @florian_krammer
13) Everything is done at economic risk - and that speeds things up. No sane vaccine developer would do this in 'peace time'. So, we are already in Phase III trials, what happens next? Now, vaccines can be licensed the regular way or via an 'emergency use authorization'.
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Florian Krammer Sep 27
Replying to @florian_krammer
14) The 'emergency use authorization' allows the vaccine to be used before it is fully licensed based on available data that suggests a risk benefit. It is unclear if this will happen with SARS-CoV-2 vaccines, but it is possible. We will see.
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Florian Krammer Sep 27
Replying to @florian_krammer
15) The FDA published a guidance document for SARS-CoV-2 vaccine developers if you are interested. It can be found here.
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Florian Krammer Sep 27
Replying to @florian_krammer
16) So, with considering all this, we end up with a vaccine development timeline of about 10 months to 1.5 years - depending on the licensing pathway.
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Florian Krammer Sep 27
Replying to @florian_krammer
17) We will get back at what will happen once we have a licensed vaccine. But let me now go into the different types of vaccines that are around. We talk about 'vaccine platforms' when we talk about different kinds of vaccines. Currently, more than 180 vaccines are...
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Florian Krammer Sep 27
Replying to @florian_krammer
18) ....globally in development for SARS-CoV-2. Forty (40!!!!) are in clinical trials, ten (!!!!) are already in Phase III. The WHO keeps a living document with these which can be found here:
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Florian Krammer Sep 27
Replying to @florian_krammer
19) I made a graph to visualize this (slightly outdated). It is just amazing. And these candidates, even the advanced ones are very much globally distributed. I'll explain in the end why this distribution and diversity is so important.
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Florian Krammer Sep 27
Replying to @florian_krammer
20) But let's go through the platforms first. I feel people are a little afraid of different types of vaccines often because they don't understand how they work. So, let's change that.
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Florian Krammer Sep 27
Replying to @florian_krammer
21) We can divide the candidates into classic platforms (which are used for many viral vaccines), modern platforms (which are used for some newer licensed vaccines) and new platforms (which have never used for a licensed vaccine).
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Florian Krammer Sep 27
Replying to @florian_krammer
22) Let's start with classic: Inactivated vaccines are a typical example. You isolate the virus, grow it in cell culture (e.g. Vero cells) and then you harvest and concentrate it (usually by ultracentrifugation). Following that, you physically or chemically kill the virus....
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Florian Krammer Sep 27
Replying to @florian_krammer
23)....and you have your vaccine. This has been in use for a very long time and works for many vaccines (e.g. hepatitis A, influenza virus etc.). The virus can't infect your cells anymore but your immune system responds to it, mostly by making antibodies.
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Florian Krammer Sep 27
Replying to @florian_krammer
24) This can be done with SARS-CoV-2 but you need to have a biosafety level 3 production facility. Several vaccines in China, India and Kazakhstan made this way are being developed with some already far in Phase III. But since they are not developed in the US or Europe, it is ...
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Florian Krammer Sep 27
Replying to @florian_krammer
25) ...unlikely that they will be on the market here.
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Florian Krammer Sep 27
Replying to @florian_krammer
26) Another classic platform are live attenuated vaccines. Here, the virus is genetically weakened. In the old days a virus was just passaged under unfavorable conditions until it liked these conditions better than humans. Then you would inoculate humans and the virus...
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Florian Krammer Sep 27
Replying to @florian_krammer
27)....would just grow a little. Not making you sick but mimicking natural infection that triggers an immune response similar as to the pathogenic virus. Nowadays, there are more ways to do that, e.g. by altering the genetic code so that it doesn't translate well anymore...
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Florian Krammer Sep 27
Replying to @florian_krammer
28)....a technology called codon deoptimization, or by just taking away a gene of the virus that it needs to make us sick. However, coronaviruses are hard to manipulate genetically and there might still risk from these vaccines for people with compromised immune systems....
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Florian Krammer Sep 27
Replying to @florian_krammer
29) Historic examples for live attenuated vaccines are e.g. the measles or yellow fever vaccines, or FluMist, which is the flu vaccine that kids get as nasal spray. They work well. Unfortunately, only three live attenuated vaccines are in development for SARS-CoV-2....
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Florian Krammer Sep 27
Replying to @florian_krammer
30) ...and they are far behind.
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Florian Krammer Sep 27
Replying to @florian_krammer
31) OK, now modern vaccine platforms. Let's start with recombinant protein vaccines. For these you basically take the gene of a viral antigen and you express that antigen in a suitable system (e.g. bacteria, mammalian cells, insect cells, yeast or even plants).
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Florian Krammer Sep 27
Replying to @florian_krammer
32) No infectious virus is involved anywhere, making this very safe. For SARS-CoV-2 you can express the whole spike protein (like Novavax) or just the receptor binding domain (RBD) which it the part of the spike that docks to your cells or you can make virus-like particles.
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Florian Krammer Sep 27
Replying to @florian_krammer
33) Vaccines based on this technology work well and are on the market for influenza (FluBlok), hepatitis B and human papilloma virus (HPV). The technology works well and is safe. The frontrunner here is currently Novavax (just entered Phase III in the UK) and Sanofi.
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Florian Krammer Sep 27
Replying to @florian_krammer
34) Another modern technology are replication incompetent viral vectors. You basically take another virus, you gut its own genome and paste the gene for your desired antigen into it. Then you produce these vectors in a suitable cell line. Once they get injected into the vaccinee
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Florian Krammer Sep 27
Replying to @florian_krammer
35) they force some of the cells of the vaccinee to make the antigen. Again, in this case the antigen is the spike protein of SARS-CoV-2. Now, this is nothing that is concerning, in fact, SARS-CoV-2 does the same. The difference is, that the viral vectors do not replicate....
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Florian Krammer Sep 27
Replying to @florian_krammer
36)....but just deliver the genetic information for you cell to make the antigen which is then recognized by your immune cells. These types of vaccines are licensed for Ebola in the EU and have been considered safe for that purpose. For SARS-CoV-2 some of the vaccines in...
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