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.

2018
Self-Amplifying RNA vaccines give equivalent protection against influenza to mRNA vaccines but at much lower doses in mice (Link)

2017
CureVac CLINICAL VACCINE TRIAL
Safety and immunogenicity of mRNA rabies vaccine in humans, 2013 – 2016 (Link)

Image source: Wikimedia Commons

2017
MODERNA CLINICAL VACCINE TRIAL
Immune response against H10N8 and H7N9 influenza virus after mRNA vaccine in mice, ferrets, non-human primates, and humans (Link)

Image source: Wikimedia Commons

2017
Injected non-replicating mRNA encoding monoclonal antibody protects humanized mice from HIV-1 challenge (Link)

Image souce: humanized mouse, Princeton University

2017
VACCINE FOR CANCER IN HUMANS
Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer in human patients, 2007 – 2012 (Link)

Img source: Melanoma, Wikimedia Commons

2017
Protection from Zika virus with single low-dose mRNA vaccination in mice and monkeys (Link)

Img source: Wikimedia Commons

2017
High magnitude and high quality antibodies induced by mRNA influenza vaccine in non-human primates (Link)

Img source: Wikimedia Commons

2016
mRNA vaccine generates protective immunity in mice against Ebola, H1N1, and Toxoplasma gondii from single dose (Link)

Image source: Ebola virus, Wikimedia Commons

2012
Protective immunity from mRNA vaccine against influenza A infection in young and old mice, ferrets, and pigs (Link)

Image source: University of Georgia

2012
Using lipid nanoparticles to deliver mRNA vaccine in mice and rats (Link)

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.

2008
Development of adjuvant cocktail for mRNA therapies for tumor immunity in human and mouse cells (Link)

Image source: A vaccine vial, CDC

2005
Modifying mRNA decreases inflammatory responses in human and mouse cells (Link)

Image source: Myocardial inflammation, Cardiosecur Magazine

2001
mRNA vaccine has protective effects against influenza A, respiratory syncytial virus, and tick-borne encephalitis virus in mice (Link)

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.

1999
Intramuscular injection of a self-replicating RNA vaccine protects mice from an injection of colon tumor cells (Link)

Image source: Wikimedia Commons

1996
Pulsing dendritic cells with tumor-derived RNA is effective to induce tumor immunity in mice (Link)

Image source: A dendritic cell, Wikimedia Commons

1994
Intramuscular injection of RNA encoding a protein from the Semliki Forest Virus induces an immune response in mice (Link)

Image source: Semliki Forest Virus, Wikimedia Commons

1993
RNA encoding a protein from the influenza virus induces an immune response in mice (Link)

Image source: Influenza Virus, Wikimedia Commons

1990
Injecting RNA into a mouse leads to the production of a protein encoded by that RNA in the mouse (Link)

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.

1978
Injecting mouse cells with rabbit RNA leads to the production of rabbit proteins in mouse cells (Link)

Image source: Mouse lymphocytes, Wikimedia Commons

1971
Injecting frog eggs with rabbit RNA leads to the production of rabbit proteins in frog eggs (Link)

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

animal testing, animal research, vivisection, animal experiment
CC-BY: Speakingofresearch.com

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