Yazmin I. Rovira Gonzalez, PhD, Johns Hopkins UniversityAlumna
On May 18th 2020, Moderna, Inc. – a clinical-stage biotechnology company focused on mRNA technologies, including messenger RNA-based vaccines and therapies – announced their Interim Phase 1 results for their messenger RNA vaccine (mRNA-1273) against novel coronavirus SARS-CoV-2.
But first, what is an mRNA vaccine and how does it work?
Traditional vaccines, such as the smallpox vaccine, work by mimicking infectious agents – pathogens – and, by doing so, train our bodies to better respond against them and in a more effective manner. These conventional vaccines contain inactivated disease-causing organisms or proteins made by the infectious agent. These infectious agents, also known as antigens, are inactivated by heat or chemical treatment so that they will not cause disease. Exposing the body to antigens leads to the production of antibodies, which are molecules directed against specific pathogens, and “prime” it to respond more rapidly and effectively if exposed to an active pathogen in the future. Vaccination has been key in diminishing or eradicating infectious diseases, but producing certain vaccines can be long and difficult depending on the pathogen.
RNA vaccines on the other hand, use a different approach. Normally, cells use DNA as the template to make mRNA molecules, which are then translated to build proteins. An mRNA vaccine is made of an mRNA strand that codes for a disease-specific antigen. This antigen-coding mRNA strand enters the body’s cells and the mRNA, along with the cells’ protein-making machinery, is used to produce the pathogen’s antigen. This antigen is then displayed on the surface of cells so that the body’s immune system can recognize it and trigger an immune response directed against that pathogen.
As you can see, in a traditional vaccine, the antigen is introduced in the body to produce an immune response. However, no antigen is introduced in the case of RNA-based vaccines, only the RNA containing the genetic information that have the instructions for the body to produce the antigen itself. The RNA-based vaccines can be injected in various ways (e.g. under the skin, in the vein, lymph nodes, etc.) so that they can enter cells and use the RNA sequence of the antigen to produce antigen protein.
The Phase 1 study of Moderna’s mRNA-1273 was led by the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH), and it involved looking at immunogenicity across three dosages – 25 ug, 100 ug and 250 ug. Each dose level cohort consisted of 15 participants, of ages 18-55 (n = 15 per cohort). After 15 days and a single dose, all participants across all three dose levels were able to develop antibodies that became detectable in the blood (seroconvert). Two weeks after the second dose of the 25 ug dose level (day 43, n = 15), the levels of binding antibodies were comparable to the levels seen in the blood samples from patients who have recovered from COVID-19. At day 43 in the 100 ug dose cohort (n = 10), the levels of binding antibodies exceeded the levels seen in the blood samples from patients who have recovered from COVID-19. Samples are not yet available for the remaining participants.
It is important to know, however, that not all antibodies that bind an infectious particle are neutralizing. Neutralizing antibodies defend a cell from a pathogen or infectious particle by neutralizing any biological effects, rendering the pathogen or particle noninfectious. Non-neutralizing antibodies, or binding antibodies, bind specifically to the pathogen, but do not interfere with their infectivity. Currently, neutralizing antibody data are only available to the first four participants in each of the 25 ug and 100 ug dose level cohorts. The mRNA-1273 vaccination triggered an immune response where neutralizing antibodies were produced in all eight participants, and the levels of neutralizing antibodies at day 43 were at or above the levels seen in blood samples from patients who have recovered from COVID-19. Although Moderna’s May 18th press release suggested that the vaccine was well-tolerated, one of the participants in the 100 ug cohort developed a Grade 3 adverse event, and three participants in the 250 ug cohort (highest dose) developed Grade 3 systemic reactions after the second of two doses.
On May 6th, the U.S. Food and Drug Administration (FDA) completed its review of the Moderna’s Investigational New Drug (IND) application for mRNA-1273, allowing it to proceed to a Phase 2 study that will include two dose levels – 50 ug and 100 ug – with the aim of selecting a dose for pivotal studies. On May 12th, the FDA granted mRNA-1273 Fast Track designation, which would expedite the review process for this drug. Moderna is finalizing the clinical trial protocol for a Phase 3 study, expected to begin in July 2020. If successful, the next step after the completion of Phase 3 trials would be for the company to file for a Biologics License Application (BLA) to request permission from the FDA to manufacture and introduce the vaccine into the market. More information of the company’s work to date on SARS-CoV-2 and mRNA-1273 can be found here.
Although mRNA vaccines are not made with pathogen particles or inactivated pathogens, there are some important challenges that have to be overcome to ensure that these products work.
- Unexpected effects: the antigen-coding mRNA sequence or strand may trigger an unintended immune response. Therefore, the mRNA vaccine sequences should be designed to mimic those produced by mammalian cells.
- Degradation: RNA is prone to rapid degradation, which is why some scientists have found ways to combat this RNA degradation. For example, molecules can be added to bind the RNA and protect it from degradation, or the RNA strand can be incorporated into a larger molecule to help stabilize it.
- Transport and Storage: Current vaccines can lose their efficiency when exposed to different temperatures. Therefore, the RNA sequence can be changed to make it easier to store at different temperatures.
You might wonder, if this vaccine works, how will it be manufactured? On May 1st, Moderna announced an agreement with Lonza to establish manufacturing suites for Moderna at Lonza’s facilities in the US and in Switzerland for the production of COVID-19 vaccine candidate mRNA-1273 and additional future products through a 10-year agreement between the companies. Technology transfer is expected to begin in June 2020, with the first batches of the vaccine to be manufactured at Lonza’s US site in July, if successful. Taking advantage of Lonza’s worldwide facilities would ultimately allow for the manufacture of the material equivalent of up to 1 billion doses of mRNA-1273 per year for use worldwide, based on an expected dose of 50 ug.
Challenges aside, this new and exciting technology could be applied to many diseases. Indeed, the field of RNA therapeutics in general has attracted significant investment, focus, and interest from both academic research institutes and pharmaceutical companies. Notably, Moderna set a record for the biggest biotech Initial Public Offering (IPO) – the process by which a private company goes public by selling its stocks to the general public – with its value at about US $7.8 billion in 2018. Moderna along with BioNtech and CureVac attracted $2.8 billion of private investment since 2015. While the field of RNA vaccines is still growing and the clinical potential of RNA vaccines in humans remains to be firmly established, RNA vaccines appear to be a promising technology, and the current spike of investment in RNA therapeutics is likely to result in further clinical studies. The upcoming clinical trial data will let us know if an mRNA vaccine is the silver bullet everyone is looking forward to.