The History of the mRNA Vaccines

We have received numerous requests to document the history of mRNA vaccine technology, and we’re working on a dedicated article to be hosted on the main History of Vaccines site along with edits to the pertinent articles already there. Meanwhile, here is a rundown of the history of mRNA vaccine technology.

Different Viruses, Different Vaccines

The first thing we need to understand is that viruses comes in different classes. The main ones are DNA and RNA viruses. DNA viruses include, among others, the herpes viruses that cause genital herpes, chickenpox and other infections. As their name implies, DNA viruses contain DNA that integrates with the host DNA in certain cells and uses the host cells’ replication mechanism to multiply. These viruses can be dangerous because that DNA integration could trigger an activation of cancer genes in the cell. For example, the Human Papillomavirus (HPV) is known to cause cervical cancer in women and genital/rectal cancer in men and women.

On the other hand, RNA viruses carry RNA and they do not integrate that RNA into a host DNA. Instead, the RNA from the virus goes straight to the host ribosomes in cells (not the nucleus, where DNA is kept), and the ribosomes do the work of replicating the virus. Examples of these viruses include rabies, influenza and the Human Immunodeficiency Virus (HIV). HIV is special because it carries with it an enzyme called “reverse transcriptase” that transcribes the RNA into DNA, and then that DNA integrates into the host cells to continue the replication process. This complexity in HIV replication is why an HIV vaccine is difficult to create while vaccines for rabies and for influenza are old.

Researchers need to consider how a virus replicates when creating a vaccine. If the virus replicates in only some cells and tissues of the body, and the immune system cannot get there easily, then the vaccination strategy has to be done one way. It is made a different way if the immune system can reach the infected cells and tissues differently. And then it is made a whole other way if you need the immune response to be primarily antibodies versus a whole immune system response. Just as the immune system is complex, the development of vaccines is complex.

HIV infection and replication process

mRNA Function

The next thing we need to understand is how mRNA functions. For this part, a video is worth a thousand words:

As you saw in that video, the messenger RNA (mRNA) takes the code to the ribosome where the protein is put together. That final protein is what then leaves the cell. In the case of an mRNA vaccine, the vaccine delivers the mRNA to the ribosome (not the nucleus, where DNA is housed) and a protein that looks just like the virus protein is created. When that protein leaves the cell, the immune system recognizes is as a viral protein and goes to work creating antibodies against it.

The First Steps Toward an mRNA Vaccine

In 1990, scientists discovered that they could inject mice with mRNA and DNA to make the mouse cells create a protein. That protein production lasted for a few weeks. In 1992, mRNA coding for vasopressin (anti-diuretic hormone) was injected into rats, resolving their diabetes insipidus symptoms. From these findings, it was theorized that a viral or bacterial protein could be created by a living animal’s cells, and that the immune system of the animal would then react against it. The only thing standing in the way was the inherent instability of mRNA. It just doesn’t like to be outside of cells.

The Next Steps and Operation Warp Speed

From the 1990s to the 2010s, the race was on to develop a way to deliver mRNA without it becoming unstable. There were advances in development of cancer vaccines, allergy vaccines, and parasite vaccines in that time. By the time the Coronavirus Pandemic came, several companies were working on mRNA vaccines with relatively stable delivery systems. The extra boost from the urgency of the pandemic and the government funding they received allowed them to conduct large-scale clinical trials at almost the same time that they were tweaking their formulations. By the time Moderna and Pfizer submitted their data to the Food and Drug Administration for Emergency Use Authorization, about 30,000 people in the Moderna trial (including my wife) and over 43,000 in the Pfizer trial had received the vaccine.

Two very long and very public hearings were held where experts in different fields of science reviewed the data from the clinical trails and voted on recommending approval of the vaccines. The videos are below in their entirety (about 8 hours each).

Pfizer Hearing

Putting It All Together

No one woke up on a morning in December and decided that an mRNA vaccine was the way to go without any prior knowledge of the science and technology of mRNA vaccines. That knowledge goes back decades, and there have been many people working on this technology with many companies and governments spending large amounts of money on it. There have been clinical trials on mRNA vaccines not just for the coronavirus but for cancer and other ailments. Little by little, advances were made that brought us to the current vaccine.

Even Edward Jenner relied on knowledge gained throughout the centuries of the practice of inoculation. And those who used inoculation before there was vaccination relied on the observations and experiences of those before them to reach the conclusion that inoculation was needed. This is how human understanding of the complex world around us evolves, through knowing what has been and dreaming of what could be.

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Author: René F. Najera, DrPH

I am the editor of the History of Vaccines site, an online project by the College of Physicians of Philadelphia. All opinions expressed on these blog posts are not necessarily those of the College or any of my employers. Check out my professional profile on LinkedIn: https://www.linkedin.com/in/renenajera Feel free to follow me on Twitter: @EpiRen