The main question, they say, is which vaccine to prioritize first.
The Pfizer / BioNTech coronavirus vaccine was the first mRNA vaccine ever approved for the market. Has the past year fundamentally changed the way vaccines will develop in the future?
Uğur Şahin: The case of Covid-19 really shows the advantages of mRNA vaccines in different ways. The first is that it was the fastest time of vaccine development in the history of the disease. This is one of the key benefits of mRNA vaccines – which can be produced in short production cycles, and the time to clinical studies could be only a few weeks.
The second is that the data clearly show that this is not only the fastest approach, but also a very effective approach in inducing not only immune responses – antibody and T cell responses – but also in the prevention of symptomatic diseases. New (actual) data that appear also (show that it is effective in) prevent infection, which is important for pandemic control.
And the third is that we just see that the technology, which has never been delivered for global use before, has enabled the delivery of vaccines to many, millions of people. We plan to produce two billion doses by the end of this year.
And this is just the beginning. This is mRNA 1.0. This is proof of concept for a new class of pharmaceutical drugs.
Now that you have successfully developed one mRNA vaccine, is it just a case of attaching other sequences of RNA viruses or pathogens and creating new vaccines? What other infectious diseases do you have in sight?
Özlem Türeci: This is now one of the important questions, namely how to give priority to all possibilities. Going all the way to conditional market approval for Covid-19 has allowed us to establish technology for all stages of clinical development and regulatory compliance.
In principle, there are many other infectious diseases and pathogens in which we should simply cut out the Sars-CoV-2 spike protein sequence and insert genetic information for the antigen from another virus or pathogen into the same backbone of the mRNA vector, and then basically repeat what we did. And the flu is most pronounced because we are already working on it. But we have several other indications for infectious diseases (like tuberculosis) where we have already started preclinical work and are currently in the process of putting together the next shortlist.
You mentioned that you had already started working on the flu vaccine before last year. Why was the Covid-19 vaccine developed so quickly in comparison?
OT: We only worked with Pfizer for the flu vaccine in 2018 and were in the phase of doing basic preclinical work (when the pandemic hit). So I wouldn’t say the flu is that slower.
The fact is that we were in a global pandemic with Covid-19, which meant that global attention and resources were being invested in it – all stakeholders, including regulators and clinical networks, had a personal interest. Processes have been accelerated to launch the first human studies or to conduct large trials that usually take months due to long waiting periods.
When we try to work with the flu again, we will be able to take full advantage of mRNA in terms of short production cycles to adapt to seasonal variants and all other aspects.
You originally viewed mRNA vaccines as a way to treat cancer. Why?
OT: Uğur and I are doctors and we have treated cancer patients. We are also immunologists and we are fascinated by the immune system. Then we asked the question: how can we serve medical needs as physicians, and what the current standard of care cannot? We immediately thought about using immune therapies and activating the immune system.
USA: We have been working on mRNA for over 20 years. The reason we started was our vision of individualized cancer therapy, based on the observation that tumor antigens, antigens on cancer cells that recognize T cells (in the immune system), are unique in every cancer patient.
We realized that future therapy could (be based) on analyzing the patient’s tumor and discovering which antigens would be appropriate, and then producing a vaccine based on that data. And this idea requires the right technology – technology that would allow (us) to powerfully induce an immune response against any type of tumor antigen and that can be produced within a few weeks – because cancer, of course, could grow.
When we started, we evaluated DNA, vector-based vaccines, peptides, recombinant proteins – all of which had previously been tested as a potential vaccine technology. But then we evaluated the mRNA and realized that this could be really powerful. We were able to see that mRNA can be expressed in dendritic cells, which are key cells for inducing an immune response. And that was one crucial factor, and the ability to produce vaccines quickly was another. And that’s why we started developing mRNA vaccines.
What a leap it was to focus this work on infectious diseases?
OT: When we started (our work) many years ago, it was very clear that we needed to study the immune system in order to be able to redirect it against cancer.
The immune system has developed mechanisms to protect and defend against pathogens such as viruses. RNA viruses are the oldest, which means that although we have been working on cancer (immunotherapy) for so many years, we have had to thoroughly understand the mechanisms (immune system) that were originally against the virus, and also develop methods to mobilize various immune system effectors. immune response) against antigen. We had to deeply improve the strength of mRNA vaccines, because it is very difficult to achieve strong immune reactions against our own antigens on cancer cells.
Therefore, it was actually a small step from taking all this and using it (knowledge of the immune system) for what it was originally intended for, namely protection against viruses.
USA: The basic principle is the same – it is about engineering and delivering antigen to dendritic cells to elicit an immune response.
When you saw in clinical trials that your vaccine was 95% effective against Covid-19, were you surprised?
OT: When we started (in January 2020), we didn’t know too much about the biology of the virus. Our goal was to get an ideal immune response and we knew how to adjust our vaccine to get that immune response. So when we got the data from our phase 1 trial, we clearly saw that we had achieved our goal.
However, what we did not know was how effective this immune response could be. The traditional efficacies of vaccines are generally, and usually for influenza vaccines, between 50% and 70%. 95% was a very positive surprise.
‘We clearly see the era of the mRNA vaccine.’
Dr. Özlem Türeci, co-founder, BioNTech
How is vaccination accelerated and how do we get more data in terms of efficacy, transmission effect, safety and so on, what are you specifically looking for in that data?
OZ: Understanding the effectiveness of the general population is very important. Data (from real-world studies) appear to confirm the high efficiency of the general population and subgroups of the population.
We have already shown in our clinical trial that (our vaccine works) regardless of gender and age. But you can’t include all subpopulations – such as immunocompromised patients or patients with kidney disease who regularly undergo hemodialysis – in a sample-size clinical trial that allows you to draw conclusions. This will come with data from real-world studies and will help us understand (which) levels and subgroups of the population that the vaccine protects.
The goal is to achieve herd immunity.
USA: At the moment, one of the challenges is people who say, “This is new, and because it’s new, I’m suspicious, I’d like to get a traditional vaccine.” But this is likely to change as we continue to share data. We will continue to explain how these mRNA vaccines work. For the Covid-19 vaccine, we had eight publications in less than twelve months. And there is more.
Do you think that one day all our vaccines will be mRNA vaccines?
OZ: I think we can say that we believe that mRNA will be transformational. We clearly see the era of mRNA vaccines. (However) there are limits at which mRNA is not the right format due to the biology of a particular pathogen.
USA: So far, mRNA vaccines cannot supply bacterial carbohydrate antigens. Thus, all pneumococcal vaccines (which help protect against bacteria that cause pneumonitis or meningitis, for example) where you really need these carbohydrates cannot synthesize mRNA. The mRNA vaccine cannot deal with any type of antigen design in which mRNA cannot be encoded so that a human cell translates it into a protein. So we believe there will be room for other vaccines as well.
Early in your work, you received basic research funding from the EU – how did that help?
USA: EU funding, as well as funding from the German government, has allowed us to create a deep scientific understanding of immune recognition of cancer. Funding also supported the early stages of our mRNA vaccine research. It helped us improve our vaccines and generate preclinical and early clinical data for our individualized approach to the mRNA vaccine. The results obtained by these projects helped us to identify investors who believe in our vision. The pharmaceutical development of new drugs is very expensive and compared to the amount we have raised, mainly as venture capital, the amount we have received from the EU is negligible. However, it is important to understand that the development of innovation is an iterative process. The clinical findings we have created with these mRNA vaccines raise new questions and will open up new areas of research.
This interview is edited for clarity and length.
BioNTech received EU funding for MERIT project and EUR 100 million in funding from the European Investment Bank for the development of the Covid-19 vaccine. Uğur Şahin received funding from the European Research Council of the EU. If you liked this article, consider sharing it on social media.