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26 September 2017

Shedding light on our prophylactic vaccines’ mechanism of action

Giuseppe Ciaramella
Ph.D., Chief Scientific Officer, Infectious Diseases, Moderna

When I describe leading infectious disease research efforts at Moderna, I often say it’s a bit like being a kid in a candy shop. We have this amazing, versatile tool in our hands. And we’re pushing the boundaries of this platform technology’s capabilities by exploring a range of options simultaneously – both across therapeutic areas and within therapeutic areas.     

On the infectious diseases front, our development pipeline currently comprises nine prophylactic vaccines – including monovalent, multivalent and multi-pathogen vaccines. There are Phase 1 studies underway for five of these vaccines. We are advancing several additional prophylactic vaccines as well as antibody programs at the research stage.

Collaborations are an integral part of how we conduct research. Our many academic collaborators and our partners are a critical part of our ecosystem. One of the things we enjoy most is sharing the results of those collaborations with the broader scientific community.

Understanding how our vaccines elicit a robust immune response

I’m quite excited about a paper that we announced today that’s been published in Molecular Therapy in collaboration with Dr. Karin Loré and her team at the Karolinska Institutet. The paper describes the results from a collaboration we undertook with Dr. Loré to gain a firmer understanding of the kinetics of our vaccines – how they’re absorbed and distributed – as well as how they interact with specific cells of the immune system.   

We embarked on this collaboration a couple of years ago, compelled by a growing body of strong preclinical data. In animal models, our vaccines were eliciting a robust immune response, and we wanted to understand mechanistically how they were working.

This study was conducted in non-human primates (NHPs) to closely reflect what happens in humans.  For one part of this study, we selected a research version of our influenza H10N8 vaccine, which we were already planning to take to the clinic.

(Read here about the human data we published for our H10 vaccine in April 2017.)

Our vaccines, including H10N8, are composed of lipid nanoparticle (LNP)-encapsulated mRNAs. For this study, we also made another vaccine where we labeled the LNP with a fluorescent molecule. And then the mRNA we used coded for a reporter protein, which would create a fluorescent signal different from the fluorescent molecule we used on the LNP.

Once we injected the vaccine, we could then follow both where the LNP went and where the mRNA went, as a consequence of the protein being expressed. 

What we found

  • The H10N8 vaccine elicited a robust immune response, and we confirmed both antibody and T cell responses. We were also able to characterize the antibody response in terms of quality and timing.

  • Following administration of the vaccine in the muscle, we saw antigenic expression in macrophages (a type of white blood cell) at the injection site.

  • The vaccine then drained to the lymph nodes closest to the injection site, as would be expected for any vaccine.  Importantly, though, the vaccine was also taken up by dendritic cells in the lymph nodes, and we saw antigenic protein expression in these cells as well. 

  • We also were able to characterize the various subsets of immune cells that were actually interacting with the vaccine – taking it up and expressing it.

Moderna mRNA vaccine approach

Key takeaways … and significance of findings at the platform level

With these findings, we now have preclinical data demonstrating that our H10N8 vaccine is draining into the lymph nodes, and we also know exactly where in the lymph nodes. And we’ve confirmed that the vaccine is expressing antigenic proteins both at the injection site as well as in antigen-presenting cells (dendritic cells) in the lymph nodes. We believe it is the combination of these two that is responsible for the robust immune response we’re seeing from our vaccines.

Importantly, given the software-like nature of our medicines, these results should be, in the main, consistent across our other vaccines.

We’re grateful that we had the opportunity to work with Dr. Loré and her colleagues to help us better characterize the immune response to our vaccines.

And we’re excited to share more about our progress in development in the months ahead.