The successful development of mRNA vaccines for COVID-19 is ‘transformational’ and opens the doors to new types of vaccines for other infectious diseases as well as cancer, according to Dr Özlem Türeci and Dr Uğur Şahin, the co-founders of Germany’s BioNTech.

The main question, they say, is which vaccine to prioritise first. 

The mRNA vaccine era is just starting, according to Dr Özlem Türeci and Dr Uğur Şahin, the co-founders of Germany’s BioNTech. Image: BioNTech SE 2020, all rights reserved

The Pfizer/BioNTech coronavirus vaccine was the first mRNA vaccine ever to be approved for the market. Has the past year fundamentally changed how vaccines will be developed in the future?

Uğur Şahin: The COVID-19 case really shows in different ways the advantages of mRNA vaccines. The first one is that it was the fastest (vaccine) development time ever in medical history. This is one of the key advantages of mRNA vaccines – that they can be manufactured in short production cycles and the time to clinical studies could be as low as a few weeks.

The second is that the data clearly shows that it's not only the fastest approach, it is also a very effective approach in inducing not only immune responses – antibody and T cell responses – but also in preventing symptomatic disease. New (real world) data emerging also (shows that it is effective at) preventing infection, which is important for controlling the pandemic.

And the third is that we are just seeing that the technology, which was never supplied for global use before, has enabled the delivery of vaccines to many, many millions of people. By the end of this year, we plan to manufacture two billion doses.

And this is just the very beginning. This is mRNA 1.0. It’s the proof of concept for a very new pharmaceutical drug class.

Now that you’ve successfully developed one mRNA vaccine, is it just a case of plugging in other virus or pathogen RNA sequences and creating new vaccines? What other infectious diseases do you have in sight?

Özlem Türeci: That's one of the important questions now, namely how to prioritise all the opportunities. Having gone all the way to conditional market authorisation for COVID-19 has allowed us to establish the technology for all the stages of clinical development and regulatory submission.

In principle, there are many other infectious diseases and pathogens where we would just need to cut out the Sars-CoV-2 spike protein sequence and insert the genetic information for an antigen from some other virus or pathogen into the same mRNA vector backbone and then basically repeat what we have done.

And flu is the most imminent one because we are already working on that. But we have a couple of other infectious disease indications (such as tuberculosis) where we have already started preclinical work and are in the process of assembling the next shortlist.

You mentioned you had already begun working on a flu vaccine prior to last year. Why was the COVID-19 vaccine developed so fast in comparison?

OT: We started our co-operation with Pfizer for the influenza vaccine only in 2018, and we were at the stage of doing the foundational preclinical work (when the pandemic hit). So I would not say that influenza is so much slower.

The fact is, that with COVID-19, we were in a global pandemic, which meant the world’s attention and resources were going into it – all stakeholders, including regulatory authorities and clinical networks had a vested interest. Processes to initiate first-in-human studies or conducting large trials which normally take months due to long waiting periods have been accelerated.

When we now pick up again our flu work, we will be able to leverage all the advantages of mRNA in terms of short manufacturing cycles to adapting to seasonal variants and all the other aspects.

You originally started looking at mRNA vaccines as a way to treat cancer. Why?

OT: Uğur and I are both physicians and we have treated cancer patients. We are also immunologists and fascinated by the immune system. So then we asked the question: how can we serve the medical need as physicians, which the current standard of care cannot? We immediately thought about using immune therapies and activating the immune system.

US: We have been working on mRNA for more than 20 years. The reason why we started was our vision of individualised cancer therapy, based on the observation that the tumour antigens, the antigens on cancer cells, which are recognised by T cells (in the immune system), are unique in every cancer patient.

We understood that a future therapy could be (based on) analysing the patient tumour and finding out which antigens would be suitable and then producing a vaccine based on this information.

And this idea requires the right technology – a technology which would allow (us) to induce an immune response against any type of tumour antigen in a potent way and which can be manufactured within a few weeks – because the cancer, of course, might be growing.

When we started, we evaluated DNA, vector-based vaccines, peptides, recombinant proteins – everything that has been tested before as a potential vaccine technology. But then we evaluated mRNA and we understood this could be really powerful.

We could see that mRNA could be expressed in dendritic cells, which are the key cells for inducing an immune response. And that was one decisive factor and the ability to manufacture the vaccine fast was another. And that's why we started to develop mRNA vaccines.

How big a leap was it to refocus this work on infectious diseases?

OT: When we started (our work) many years ago, it was very clear that we had 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 most ancient ones, which meant even though we worked on cancer (immunotherapy) for so many years, we had to thoroughly understand those (immune system) mechanisms which were originally against viruses, and also develop methods to mobilise different effectors of the immune system (cells that carry out immune responses) against an antigen.

We had to profoundly improve the potency of mRNA vaccines because it is very difficult to mount strong immune responses against self-antigens on cancer cells.

And therefore, it was actually a small step from taking all this and using it (knowledge about the immune system) for what it originally by nature was meant for, namely virus protection.

US: The fundamental principle is the same - it is about engineering and delivering an antigen to dendritic cells to induce an immune response.

'We clearly see an era of mRNA vaccines.' Dr Özlem Türeci, co-founder, BioNTech

When you saw in the clinical trials that your vaccine was 95% effective against COVID-19, were you surprised?

OT: We did not know too much about the biology of the virus when we started (in January 2020). Our objective was to get an ideal immune response, and we knew how to tweak our vaccine to get this immune response. So when we got the data from our phase 1 trial, we clearly saw that we had achieved our objective.

However, what we did not know was how much can this immune response achieve in terms of efficacy. Traditional vaccine efficacies are in general, and typically for influenza vaccines, between 50% and 70%. The 95% was a very positive surprise.

As the vaccination roll-outs accelerate and as we get more data in terms of the effectiveness, the effect on transmission, safety and so on, what in particular are you looking out for in that data?

OZ: Understanding efficacy in the broader population is very important. Data (from real world studies) seems to confirm a high efficacy across the broader population and population subsets.  

We have already shown in our clinical trial that (our vaccine works) irrespective of gender or age. But you cannot include all subpopulations – like immunocompromised patients, or patients with renal disease who get haemodialysis on a regular basis – in a clinical trial at sample sizes which allows you to draw conclusions. This will come with the data from the real world studies and will help us to understand (which) levels and subsets of the population the vaccine protects.

The goal is to achieve herd immunity.

US: At the moment, one of the challenges is people saying: ‘This is new and because this is new I am sceptical, I would like to get the traditional vaccine.’ But this will most likely change fast 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 12 months. And there's more to come.

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 an era of mRNA vaccines. (However) there are borders where, due to the biology of the respective pathogen, mRNA is not the right format.

US: mRNA vaccines so far cannot supply bacterial carbohydrate antigens. So all the pneumococcal vaccines (that help protect against bacteria that cause pneumonitis or meningitis, for example) where you really need these carbohydrates cannot be synthesised by mRNA.

Any type of antigen design which is not possible to be encoded by mRNA to be translated to protein by the human cell, can't be addressed by an mRNA vaccine. So, we believe there will be room for other vaccines.

You received basic research funding from the EU early on in your work – how did that help?

US: The EU funding, and also the funding of the German government allowed us to generate deep scientific understanding of the immune recognition of cancer. The funding has also supported the early stages of our mRNA vaccine research.

It helped us to improve our vaccines and generate preclinical and early clinical data for our individualised mRNA cancer vaccine approach. The results obtained from these projects helped us to identify investors who believed in our vision.

Pharmaceutical development of new medicines is very costly and compared to the amount we raised, mostly as venture capital, the amount we got from the EU is negligible.

However, it is important to understand that innovation development is an iterative process. The clinical findings that we have generated with these mRNA vaccines provoke novel questions and will open up new research areas.