The rapid development of messenger RNA (mRNA) vaccines for SARS-CoV-2 was based on years of research and has given real hope to scientists developing new vaccines for other viruses and pathogens.
Many clinical trials are underway to test mRNA vaccines to treat and prevent infections and diseases, such as cancer, cytomegalovirus (CMV), Ebola, hepatitis C virus (HCV), human immunodeficiency virus 1 (HIV-1), influenza, malaria, rabies, and Zika. mRNA vaccines can be delivered repeatedly, are inexpensive to produce, and can be rapidly manufactured. This new technology has the potential to improve human health and positively impact mortality around the world.
Historically, vaccines were created using inactivated viruses or other microorganisms (e.g., inactivated polio vaccine), live attenuated viruses (e.g., yellow fever vaccine), or protein sub-units. In the past, vaccinology has been slow to respond to viral outbreaks with new development, and no vaccines have been able to prevent chronic infections, such as HIV-1 and herpes simplex virus, or recurrent infections, such as seasonal influenza. However, studies to date have shown that mRNA vaccines have successfully produced immune responses against CMV, HCV, and rabies virus in mice, HIV-1 in rabbits, and HIV-1 and human CMV in rhesus macaques. By September 2020, in response to the COVID-19 pandemic, 64 vaccine candidates for SARS-CoV-2 were in clinical trials and another 173 in pre-clinical development. A number of those were based on mRNA technology.1
What is messenger RNA (mRNA)?2, 3
During normal cellular function, the DNA genetic code contained in a cell’s nucleus is transcribed (copied) into an intermediary form called mRNA. mRNA is then transported to the cytoplasm of the cell, where it serves as the template for protein production. This production requires the presence of small, cytoplasmic organelles called ribosomes. The ribosomes “read” the instructions provided by the mRNA and create the protein, step by step, in a process known as translation.4 Proteins serve multiple functions and provide other structural elements to a cell.
What is the basis of mRNA vaccine technology?5
Synthetic mRNA is a man-made variation on the natural production of mRNA and provides the basis for this new vaccine technology. There are two major types of mRNA vaccines: self-amplifying RNA (saRNA) and non-replicating RNA vaccines. When injected into a recipient, both encode for specific proteins, called antigens, which when produced by the recipient’s cells, are recognized by the body as “foreign” and result in an immune response. Non-replicating vaccines only encode the targeted antigen via their mRNA, but self-amplifying (self-replicating) vaccines encode the targeted antigen as well as the viral replication machinery that allows for intracellular RNA replication and protein expression. They replicate their RNAs after entering the cell’s cytoplasm, enhancing the production of the encoded antigen. saRNA vaccine is advantageous over non-replicating RNA vaccine because it requires a lower dose of mRNA. These vaccines have shown increased immunogenicity and effectiveness, even at a lower dose of mRNA.6
Successful vaccine development requires the right combination of antigen mRNA design, a delivery system for the mRNA to reach its target tissue, and an effective manufacturing process. mRNA is produced in a bioreactor, and the initial DNA fragments, transcription enzymes, reagents, and by-products are removed using chromatographic purification, critical to the potency of the final product. mRNA production does not carry the same risks as other vaccine platforms, such as live virus, viral vectors, inactivated virus, or subunit protein vaccines.2
Advantages of mRNA vaccines
- Do not contain a live virus
- Efficacy not dependent on recipient cell division
- Do not interfere with the recipient DNA or genome in any way: mRNA has a short half-life (approximately seven hours) and results in controlled expression of the encoded antigen. The cell breaks down mRNA shortly after it has finished using the instructions, reducing the risk of metabolic toxicity.
- High potency, capacity for rapid development and adaptation to viral mutations
- Low-cost manufacture and safe administration
- Do not require cell culture for production, increasing speed and safety of manufacture
Disadvantages of mRNA vaccines
- mRNA is sensitive to oxidation making it relatively unstable, and as a result, must be stored at low temperatures
- Rare anaphylactic reactions to mRNA-lipid nanoparticle (LNP) vaccines occur (see below)
Vaccine delivery methods7
The delivery method to recipient cells must protect mRNA against degradation, increase the half-life (time before degradation), and ensure the mRNA is able to get through the protective lipid membrane of the cell. This requires the use of injected carriers, such as small fat capsules called lipid nanoparticles (LNPs) and adjuvants, which are pharmaceuticals that help increase the efficacy and strength of an immune response. The safety of the LNP delivery system has been illustrated by two SARS-CoV-2 vaccines, mRNA-1273 (Moderna) and BNT162b2 (Pfizer/BioNTech). Recent advances include attaching saRNA to the surface of the LNP, improving antibody response.8,9
Moderna’s mRNA-1273 vaccine is an LNP-encapsulated mRNA-based vaccine. The 94.1% efficacy of this vaccine is far higher than that observed for respiratory viruses, such as the inactivated influenza vaccine, which has an efficacy of 59%.10 Moderna’s next generation COVID-19 vaccine mRNA-1283 is in Phase 1 clinical trial and is being developed as a potentially refrigerator-stable mRNA vaccine with either a single- or two-dose regimen. 11
The Pfizer/BioNTech vaccine BNT162b1 is also an LNP mRNA vaccine; however, it differs from the Moderna vaccine in chemical structure, manufacturing process, and manner of final delivery of mRNA into the target cells.
The SARS-CoV-2 virus is known to mutate, and a big advantage of mRNA vaccines is that the programmed vaccine sequence can be modified and adapted to new strains of the virus. 5
Prophylactic and therapeutic vaccines under development
In 2006, Gardasil, the first prophylactic cancer vaccine, was approved to use against the human papilloma virus (HPV), which is responsible for many cervical cancers. However, conventional vaccine approaches are generally not suited for use in cancer therapy. mRNA vaccines, on the other hand, can be designed to target tumor-associated antigens that are expressed in cancer cells to cause destruction or reduction of the tumor burden. While saRNA and non-replicating mRNA are both used for prophylactic vaccination, only non-replicating mRNA can be used for therapeutic cancer vaccines. Synthetic mRNA therapeutic vaccines are also different in that they target specific tissue and may require repeated doses to resupply a protein-antigen over a person’s lifetime.5
Vaccines are currently in development to target metastatic prostate cancer, metastatic lung cancer, renal cell carcinoma, brain cancers, acute myeloid leukemia, and pancreatic cancer. At the time of this writing, 46 mRNA cancer vaccine studies were either active or in the process of recruiting patients into trials. Combining mRNA vaccinations with traditional chemotherapy, radiotherapy, and immune checkpoint inhibitors increases the potential for better survival outcomes.2, 12
HIV mutates to create different strains of the virus, and so developing an HIV vaccine against multiple strains has proved elusive to date. In February 2021, the International AIDS Vaccine Initiative (IAVI) announced that an HIV vaccine in Phase I clinical trial, IAVI G001, had successfully generated antibodies in 97% of the adult volunteers who received the vaccine. In conjunction with Scripps Research, the IAVI is now partnering with Moderna to develop and test an mRNA-based HIV vaccine.13 A separate study by Pardi et al showed that a single modified mRNA vaccine encoding the anti-HIV-1 neutralizing antibody VRC01 produced high levels of functional antibody and protected humanized mice from HIV-1 infection.2
Prophylactic and therapeutic vaccines for other diseases
Trials of mRNA vaccines against bacterial and parasitic disease are limited. It is extremely difficult to find antigens that can be considered for vaccines against bacteria becausethey are a hundred times larger than viruses and their structure includes cell walls, cell membranes, capsules, proteins, and nucleic acids. Although low-cost antibiotics exist to treat many bacterial diseases, anti-microbial resistance is a growing problem. Parasitic vaccines are equally problematic because it is difficult to produce live attenuated vaccines in vitro, and because parasites’ reproduction cycle and antigen make-up are much more complex. However, a recent study evaluating saRNA vaccine efficacy against malaria showed that the vaccine delayed symptoms of infection, increased the number of T-cells, and protected mice from reinfection. A proportion of parasites also are able to evade the immune system. As with bacteria, some effective anti-parasitic treatments are already available.5
To date, there are still no treatments or vaccines available for the Zika virus. Zika was originally identified in 1947 but came to prominence in 2014 when multiple cases of microcephaly were reported in newborn babies as a result of Zika infection in pregnant women. Advances have now been made in the development of a saRNA vaccine for the Zika virus. A 2020 study reported that two lead saRNA vaccines trialed in mice and non-human primates elicited potent neutralizing antibody responses, with one providing complete protection against the virus. 14
mRNA is a safe and effective method of vaccination and offers a solution to meet the threat of emerging infectious diseases and the need for swift vaccination. It does not interfere with a person’s DNA and is only transient in its effect. In principle, any protein-antigen can be encoded and expressed by mRNA, making it highly useful in the development of prophylactic and therapeutic vaccines. mRNA vaccines have promise to be a game-changer in disease prevention and treatment, combining cutting-edge modern technology with conventional approaches.
For the insurance industry, this vaccine technology has the potential to improve rates of morbidity and mortality, ultimately affecting insurance pricing, underwriting, and claims outcomes. The global effort to develop mRNA-based vaccines for COVID-19 has greatly advanced mRNA technology and increased the speed of mRNA vaccine development, and it is likely that new mRNA vaccines for other diseases will soon emerge.