mRNA Technology: Four Decades in the Making

mRNA technology took 40 years to perfect. Here's the story, briefly. So if you’re sitting around the holiday table and someone tells you the mRNA technology is “too new” to trust, you now have the “receipts” to explain why that’s not accurate.

Jess Steier Unbiased Science
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Crystal structure of the histone mRNA stem-loop, Tan Dazhi (GNU Free Documentation License)

When mRNA vaccines emerged as heroes during the COVID-19 pandemic, headlines heralded them as a revolutionary new technology. Many people wondered: How could a new technology be safe enough to give to millions of people? The answer reveals a surprising truth: mRNA technology isn't new at all. Scientists have been developing and testing it since 1978 systematically proving its safety through decades of careful research.

Few people realize that mRNA vaccines existed long before COVID-19, but they hadn't gained widespread use for a simple reason: while they consistently proved safe in trials spanning decades, they often fell short of the high efficacy standards required for regulatory approval. In other words, the vaccines were safe but not effective enough at preventing disease to justify widespread use. Then came COVID-19, and something extraordinary happened.

The Scientific Journey: 1978-1990

The story of mRNA technology began in 1978 when scientists made a groundbreaking discovery that would lay the foundation for future vaccine development. They found that they could successfully deliver mRNA into cells using liposomes—tiny spherical droplets of fat that could carry genetic material. This wasn't just a theoretical breakthrough; researchers demonstrated practical success by introducing rabbit mRNA into mouse spleen lymphocytes and observing protein production.

By 1990, the field had advanced significantly. Scientists successfully demonstrated that liposome-delivered mRNA could work in living organisms, not just in laboratory cell cultures. Using mice as test subjects, they showed that the delivered mRNA could produce proteins for up to 60 days after injection—a finding that hinted at the technology's potential for therapeutic applications. Importantly, these early studies helped establish that cells could process external mRNA safely, without disrupting their normal functions.

Understanding the Technology

To understand why mRNA vaccines have proven so safe, it helps to understand how they work. Unlike traditional vaccines that introduce inactivated pathogens or protein fragments, mRNA vaccines work more like an instruction manual for your cells:

  1. The mRNA molecule carries temporary instructions for making a specific protein

  2. The instructions stay in the cell's cytoplasm (outer area) and never enter the nucleus where DNA is kept

  3. The cell reads these instructions and produces the protein

  4. The cell's natural processes break down the mRNA within days

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  5. The immune system recognizes the protein and builds defenses against it

This process mimics natural viral infection but with a key difference: the mRNA only provides instructions for making a single, harmless protein—not the whole virus. This makes it impossible for mRNA vaccines to cause the disease they protect against.

Key Innovations: 1995-2005

The path to viable mRNA vaccines required solving two major challenges, each teaching valuable lessons about vaccine safety:

  1. The Inflammation Challenge (1997): During HIV vaccine research, scientists discovered that synthetic mRNA could trigger unwanted inflammatory responses. This might sound alarming, but it led to a critical breakthrough: researchers developed modified nucleosides, including a compound called pseudouridine, that allowed mRNA to deliver its message without triggering inflammation. This modification is now used in COVID-19 vaccines, which is why they don't cause the inflammatory problems seen in early research. It's a perfect example of how identifying a safety concern led to making the technology even safer.

  2. The Delivery Challenge (Early 2000s): Scientists needed a way to protect the mRNA and deliver it safely to cells. The development of Lipid Nanoparticles (LNPs) solved this problem. Think of LNPs as tiny protective bubbles made of fats similar to those in our cell membranes. These particles:

  • Shield the mRNA from breaking down too quickly

  • Help cells absorb the mRNA efficiently

  • Break down naturally in the body

  • Have been extensively tested for safety

Pre-COVID Clinical Trials: Building the Safety Record

First Cancer Vaccine Trials (1995)

  • Goal: Test mRNA vaccines against tumors

  • Results: Successfully demonstrated immune response against cancer markers

  • Safety Profile: Well-tolerated with no significant adverse events

  • Why It Didn't Go Mainstream: While safe, the immune response wasn't strong enough to effectively fight tumors. This trial exemplified a pattern we'd see repeatedly: the technology was safe but needed refinement to be effective enough for approval.

First Human Infectious Disease Trial: Rabies (2012)

  • Participants: 101 healthy volunteers

  • Goal: Prevent rabies infection

  • Safety Results: Mostly mild reactions, no serious safety concerns

  • Efficacy Results: Only 71% achieved protective antibody levels

  • Key Takeaway: While the vaccine proved remarkably safe, it didn't consistently reach the high protection levels needed to replace existing rabies vaccines. The safety record was excellent, but efficacy wasn't competitive with traditional vaccines.

Moderna's Influenza Trials (2015)

  1. H10N8 Study (201 participants)

  • Safety Profile: Excellent, with mostly mild reactions

  • Efficacy: Variable immune responses

  • Conclusion: Another example where safety was confirmed but effectiveness couldn't match existing flu vaccines

  1. H7N9 Study (156 participants)

  • Safety Record: Well-tolerated, no serious concerns

  • Efficacy: Stronger immune response but still not consistent enough

  • Outcome: While safety was again confirmed, the vaccines didn't offer clear advantages over traditional flu shots

In each of these trials, safety was consistently demonstrated. The technology didn't go mainstream not because of safety concerns, but because it hadn't yet found a disease target where it could demonstrate superior effectiveness compared to existing vaccines.

The COVID-19 "Lucky Break"

What made COVID-19 different? The SARS-CoV-2 virus proved to be an ideal target for mRNA vaccination, primarily because of its spike protein. Unlike previous targets, this protein had three characteristics that aligned perfectly with mRNA technology:

  1. Accessibility: The spike protein sits exposed on the virus surface, making it an easy target

  2. Stability: It maintains its shape consistently, allowing antibodies to recognize it reliably

  3. Vulnerability: Antibodies targeting this protein effectively neutralize the virus

This combination of factors created the perfect scenario for mRNA vaccines to demonstrate their full potential. The technology didn't suddenly become safe—it had been safe for years. Instead, it finally found a target where it could also be remarkably effective.

Looking Forward

The success of mRNA vaccines against COVID-19 has opened new possibilities, all building on decades of safety data:

Each new application benefits from over 40 years of safety research and understanding.

Conclusion

The story of mRNA technology teaches us an important lesson about medical innovation: true breakthroughs often come not from sudden discoveries but from decades of careful research and refinement. While COVID-19 may have introduced the world to mRNA vaccines, their safety was established through years of rigorous testing long before the pandemic.

Understanding this history helps explain why scientists were so confident in the safety of COVID-19 mRNA vaccines: they weren't working with a new, untested technology, but rather with one whose safety profile had been repeatedly demonstrated over decades. What changed with COVID-19 wasn't the safety of the technology—that was already well established. What changed was finding the right target to demonstrate its effectiveness.

This long view of mRNA technology's development should reassure those with concerns about its safety. The technology didn't rush to market; it waited decades until it could prove both safe AND effective. This patient, methodical approach to development is exactly what we want to see in medical innovation.

So when you’re sitting around the holiday table and your uncle tells you the mRNA technology is “too new”— you now have the “receipts” to explain why that’s not accurate.

Stay curious,

Unbiased Science

Unbiased Science is a science communication hub. We create and deploy weekly podcast episodes, daily infographics via social media, and bi-weekly newsletters here with the occasional added content. Our goal is to provide science-based and objective appraisal of the available evidence on science and health-related topics relevant to listeners’ daily lives.

Dr. Jessica Steier is a public health scientist with expertise in public health policy, biostatistics, and advanced analytics. Dr. Sarah Scheinman is a Chicago-based neurobiologist with expertise in basic science, preclinical, and translational biomedical research. Her primary focus is on the molecular mechanisms of aging and neurodegenerative diseases, but she also has subject-matter expertise in cell biology, genetics, epigenetics, and psychology.

Subscribe. Contact the Unbiased Science team at jsteier@unbiasedscipod.com.