The versatile value of mRNA vaccines

With the high demand for mRNA-based vaccines for COVID-19, mRNA went from a scientific term to a household name. As the template for translation, mRNA serves as an adaptable and efficient platform for vaccine development. By plugging in mRNA sequences that encode viral proteins or antigens that arise from cancerous mutations, scientists can craft vaccines that train the immune system to respond to a variety of diseases. 

Robert Georgantas, the president and chief technology officer at the biotechnology company Providence Therapeutics, leads a team of researchers leveraging the unique advantages of mRNA to develop next-generation vaccines. He and his team are working on mRNA vaccines with broad spectrum protection against multiple COVID-19 variants and general coronaviruses and others that provide precise and personalized attacks on aggressive cancers. 

What are the advantages of mRNA-based vaccines? 

As we saw during the COVID-19 pandemic, mRNA vaccines can be very quickly tested and brought to market. They’re nimble in that we can easily change the sequence for the protein that the vaccine produces. Additionally, mRNA formulated in lipid nanoparticles can trigger the body’s natural immune response without artificial adjuvants, which are often required to boost a vaccine’s activity. The RNA itself causes an immune response because dendritic cells, macrophages, and monocytes have evolved over millions of years to react to viruses, particularly single-stranded RNA viruses. The lipids in the nanoparticle can also cause an immune response because the immune system recognizes things like bacteria that have lipid components in their cell walls. We have this nice little package that looks somewhat like a virus and a bacterium to act as a self-adjuvant, eliminating formulation challenges and potential side effects due to external adjuvants that can lengthen the vaccine development timeline.

Compared to protein-based vaccines, which don't show the same glycosylation patterns and other modifications to the protein that are hugely important for the immune response, mRNA-encoded proteins much more effectively capture the natural biology of the antigen. Additionally, with a protein-based vaccine, the amount of protein administered is the only amount that the body has to react to. With an mRNA vaccine, that RNA is translated over and over until it eventually degrades, effectively producing more protein and enhancing the immune response against it. 

What is your approach to an mRNA-based vaccine for COVID-19? 

With mRNA, we can encode the full-length SARS-CoV-2 spike protein. This allows us to generate antibodies and T cell responses to different regions of the protein, so if part of it mutates, we still get a reaction against other parts. We also add in the D614G mutation that is seen in all of the variants of concern to date, meaning that the vaccine could initiate an immune response to that specific mutation. In a phase 2 trial, this vaccine showed equivalent activity to the Pfizer vaccine and a high safety and tolerability profile. 

I hope that for ovarian, lung, pancreatic, and other deadly cancers, these vaccines will treat a much larger proportion of patients and not only extend their lives, but cure their diseases.
- Robert Georgantas, Providence Therapeutics 

We are also developing more of a pancoronavirus vaccine. Instead of just the SARS-CoV-2 spike protein, it incorporates several different proteins across various coronaviruses. By going after multiple highly conserved proteins within that family, the vaccine will provide more universal protection against coronaviruses. Limited only by the length of the RNA that we can deliver, we can easily combine three large coronavirus proteins.  

How do your research teams develop mRNA-based vaccines for cancer? 

We have a program in precision vaccines that involves testing a patient for a well established oncogenic mutation using a diagnostic tool such as a biopsy and using an RNA construct specific for that mutation as the vaccine. We also have a program in personalized vaccines that entails performing whole genome sequencing on a patient’s tumor to identify multiple mutations. We can then develop an RNA construct that targets 10 to 50 unique mutations. The advantage of a vaccine that goes after this many mutations is that it's very hard for the cancer to mutate away from it and escape the immune system. From the time of patient diagnosis and tumor sequencing, we can produce a personalized mRNA cancer vaccine in less than 90 days. Our lead indication is advanced ovarian cancer, which has a high mutation burden and mortality rate. We are developing precision vaccines that are specific for mutations commonly seen in subsets of ovarian cancer and are working toward personalized ovarian cancer vaccines. 

What do you hope to accomplish as a company in the future? 

Now that we have our mRNA vaccine development and manufacturing pipelines in place, we can move fast to be right at the forefront of protecting the public if there’s another pandemic. We are also expanding our work in infectious disease to create new vaccines for diseases such as rabies and shingles. Personally, I'm extraordinarily excited about the possibilities for the cancer vaccines. I hope that for ovarian, lung, pancreatic, and other deadly cancers, these vaccines will treat a much larger proportion of patients and not only extend their lives, but cure their diseases. 

This interview has been condensed and edited for clarity.