In the last 20 years, we had three major pandemics from coronaviruses: SARS, MERS, and COVID-19. Now that COVID-19 is evolving and mutating, we are facing the threat that the world faces yearly coronavirus outbreaks, similar to influenza. We cannot afford that reality, so we are in urgent need of a vaccine now. The typical length of time it takes to develop a vaccine is 10-15 years, involving rigorous Phase I, II, III, and IV trials demonstrating safety and efficacy. However, we need something now.
Moderna, Inc was the first company to develop a potential mRNA-based vaccine and launch a Phase I human study in collaboration with the National Institute of Allergy and Infectious Diseases. In this post, I’ll describe what we know about Moderna, mRNA vaccination, and the Phase I study.
Moderna was founded in 2010, based off the laboratory research of Derrick Rossi. At that time, Rossi’s lab made synthetic mRNA in order to convert somatic cells (i.e. skin cells) into pluripotent stem cells and then muscle cells (Warren et al. Cell Stem Cell 2010). Tucked away in their supplementary figures is how they make synthetic RNA.
Moderna first partnered with Flagship Ventures to make mRNA to design any protein of interest. Using this technology, they have made synthetic mRNA solutions to treat infectious diseases, cancers, and rare diseases.
They have built prophylactic mRNA vaccines against a variety of infectious diseases such as Cytomegalovirus, Zika virus, and Ebstein-Barr virus.
A full list of their preclinical publications showing the efficacy of the mRNA vaccine in animals is listed here. For example, they showed that their mRNA vaccine can protect both a pregnant mouse and its newborn from the Zika virus (Jagger et al. Journal of Infectious Diseases 2019).
There are three broad categories of vaccine types: whole-pathogens, subunit, and nucleic acid derived. More detail here. Briefly, whole pathogen vaccines are killed or weakened viruses which are then delivered to people, such as the MMR vaccine. Subunit vaccines include only the components of the virus that activate the immune system (i.e. Pertussis vaccine). Nucleic acid vaccines introduce virus DNA or RNA into a cell, which then create viral proteins, and then lead to an immune response against the newly created viral proteins.
There are no current mRNA vaccines on the market used for prophylaxis against infectious disease. These vaccines have been challenging to make in the past because they have been difficult to deliver in vivo and they are prone to degradation from ribonucleases. However, there have been several technologies developed in the last decade to address these technologies. More detail is in the following review article by Pardi et al.
To improve delivery in vivo, scientists have tried a variety of approaches, summarized in the visual below:
To improve stability, scientists have added modifications to synthetic mRNA to make it resemble more like native mRNA, summarized below:
From my understanding of the research literature, a popular delivery mechanism is the liquid nanoparticle, which enhances antigen expression dramatically (Zhang et al. Front Immunol 2019).
Using liquid nanoparticles and mRNA vaccines, scientists have created robust immune responses against many viruses, such as the Zika virus and Ebola virus. These responses were all in animals, but a phase I trial using a liquid nanoparticle mRNA vaccine did show a significant immune response against the H10N8 and H7N9 influenza viruses in human volunteers. Figures showing the antibody persistence are below.
Moderna Clinical Trial
The Moderna mRNA vaccine is a synthetically stabilized mRNA sequence coding for the full-length, prefusion stabilized spike protein of SARS-CoV-2, which is responsible for viral entry into the cell. They deliver this vaccine in a lipid nanoparticle.
It seems like Moderna based their vaccine off Wu et al.‘s first genomic sequence of SARS-CoV-2 and Wrapp et al.‘s characterization of the spike protein in the prefusion conformation (both figures below).
Moderna then incorporated this sequence into their preexisting mRNA vaccine pipeline and was able to get a vaccine in a remarkable 42 days after the genetic sequence was published. Moderna press release here. It normally takes years to get to this step.
Moderna then launched a phase I open labeled study, enrolling 45 people into three cohorts, testing three different doses of the vaccine. Each person will get an IM injection of the mRNA vaccine on Day 1 and Day 29 of the study. The primary objective is to assess safety of the vaccine but Moderna will also assess how well this vaccine creates antibodies against SARS-CoV-2 at around the 3 month mark.
This means we are still months away from knowing how well this vaccine works. We are still at least 12 months out from getting this vaccine past phase II and III trials so that it can be used in humans. However, after reading the literature I am pretty optimistic.
We desperately need a vaccine against coronaviruses. We already had 3 pandemics in the last 20 years, and we will probably get another coronavirus pandemic. There is a real risk that we get yearly outbreaks just like influenza.
The Moderna mRNA vaccine is a new technology that has not been proven. However, it is fast to develop and the preclinical data of the mRNA vaccine technology is promising. I am hopeful that this will work.