Human mRNA vaccine trials in the 2010s? A history lesson in animal research

The recent mRNA vaccines for COVID-19 are the first of their kind, but they weren’t created overnight. RNA itself was discovered in the 1960s. Then, basic research in the 1970s paved the way for vaccine development in the 90s, optimization in the 2000s, clinical trials for influenza and rabies in the late 2010s, and the development of SARS-CoV-2 vaccines in early 2020. Along the way, scientists discovered that mRNA technology could also fight cancer. 

Here we give a quick list of just some of the animal research crucial for the development of mRNA vaccines, in reverse chronological order.

How do mRNA vaccines work?

First, a brief primer on mRNA technology is necessary. The main idea behind an mRNA vaccine starts with antibodies and proteins. Antibodies are created by the immune system to quickly identify and neutralize viruses. Viruses are encased in proteins, and the antibodies use these proteins to identify the virus.

The goal of mRNA vaccine technology is to make proteins unique to the virus without injecting the body with the virus itself. To do this, scientists design mRNA that will provide instructions for the protein-making-machinery in our bodies to make a protein unique to the specific virus. The immune system sees this foreign protein, makes an antibody to quickly identify it, and then you are protected if the actual virus ever enters your body. This is because the antibodies can quickly identify the virus with the unique proteins.

The unique proteins degrade within a few weeks, or are attacked by our immune systems. Thus, the mRNA vaccine can signal an immune response and make antibodies specific to the virus without ever injecting the body with a virus. Also, the mRNA itself quickly degrades in the body within a few days. Once degraded, the protein-making-machinery in our bodies will no longer receive the instructions to ever make that protein again, unless given a booster vaccination.

Now, a history lesson…

The 2010s: Vaccine optimization and human clinical trials

This is the decade when mRNA vaccinations really started making progress. Most recently there were a number of mRNA vaccines tested in mice, rats, ferrets, non-human primates, and humans. Some treated common influenza A, while others treated Ebola, Zika, or Rabies. Much of this advancement in technology was due to an earlier finding in 2012, when scientists determined that lipid nanoparticles could be used to protect the mRNA from more quickly degrading while being transported to the machinery making the proteins.

Image source: Wikimedia Commons

Image source: Wikimedia Commons

Image souce: humanized mouse, Princeton University

Img source: Melanoma, Wikimedia Commons

Img source: Wikimedia Commons

Img source: Wikimedia Commons

Image source: Ebola virus, Wikimedia Commons

Image source: University of Georgia

Image source: Wikimedia Commons

The 2000s: Optimizing mRNA vaccines

The finding, in 2012, that lipid nanoparticles could prevent degradation of the mRNA wasn’t the only optimization necessary to get mRNA vaccines off the ground. First, scientists needed to make sure the immune response to the unique protein from the mRNA wasn’t problematic. That is, the body could still produce an immune response with inflammation, fever, coughing, an overproduction of mucus, etc. when given an mRNA vaccine. Ideally, you want to limit the immune response. But, you also want to make sure that there is enough of an immune response to produce enough antibodies to protect the body if the virus ever enters it. Thus, in the 2000s, scientists developed ways to decrease inflammation by modifying the RNA and enhance the immune response with an adjuvant–an ingredient added to the vaccine to create a stronger immune response.

Image source: A vaccine vial, CDC

Image source: Myocardial inflammation, Cardiosecur Magazine

Image source: Tick-borne encephalitis virus, Wikimedia Commons

The 1990s: RNA and Vaccines

These were the early days of RNA and vaccines. Most research was done on mice to determine that mRNA could be injected into the animals to make the unique proteins we discussed earlier. This technology was also modified to create tumor immunity to fight cancer. This work was supported by a finding at the start of the decade that injecting a foreign RNA into a mouse leads to the production of a foreign protein encoded by that RNA.

Image source: Wikimedia Commons

Image source: A dendritic cell, Wikimedia Commons

Image source: Semliki Forest Virus, Wikimedia Commons

Image source: Influenza Virus, Wikimedia Commons

The 1970s: Injecting RNA produces new proteins

Here scientists started to understand the power of RNA, that injecting mRNA from animal A into animal B leads to animal B producing animal A proteins. This is because mRNA holds instructions that tell the machinery in charge of making proteins what proteins to make. So, in the 1970s, scientists discovered that when the RNA holds instructions to make rabbit proteins, and that RNA is injected into frog eggs or mouse cells, the frog eggs and mouse cells make the rabbit proteins.

Image source: Mouse lymphocytes, Wikimedia Commons

Image source: Frog eggs, Wikimedia Commons

Take away

Without the basic research in the 1970s, 90s, 2000s, and 10s we would not have been able to make the mRNA vaccines to fight the COVID-19 pandemic. It has taken 50 years to develop this technology, utilizing the power of animal research and the scientific method. And the studies I have highlighted just scratch the surface. See the reviews provided in the sources for more information.

– Justin A. Varholick, Ph.D. 

Sources:
Understanding mRNA COVID-19 Vaccines
https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/mRNA.html

mRNA vaccines — a new era in vaccinology
https://www.nature.com/articles/nrd.2017.243 

Lipid nanoparticles for mRNA delivery
https://www.nature.com/articles/s41578-021-00358-0

Who discovered messenger RNA?
https://www.sciencedirect.com/science/article/pii/S0960982215006065

Moderna Vaccine Trials in US before 2020 (*Studies with a biological intervention with mRNA refer to mRNA vaccines)
https://clinicaltrials.gov/ct2/results?cond=&term=&spons=ModernaTX&strd_s=&strd_e=01%2F01%2F2020&cntry=&state=&city=&dist=&Search=Search&sort=nwst