From Smallpox Scabs to mRNA Shots
Inside the evolving toolbox that’s kept humanity alive
Remember last week’s story about those four guys at the bar who thought mRNA vaccines appeared out of nowhere? They left that night knowing the technology was 40 years old. But there was a question I couldn't fully answer with a beer in my hand: "If we already had vaccines that worked, why didn’t we just stick to those older types of vaccines for COVID-19?”
It's a fair question. And answering it requires opening up the entire vaccine toolbox, from the methods our ancestors used (yes, we're talking smallpox scabs) to the genetic blueprints we're writing today.
My brilliant colleagues, Dr. Nancy Haigwood, Izzy Brandstetter Figueroa, and Dr. Elana Pearl Ben-Joseph, helped me dig deeper into these questions. Because understanding our vaccine options isn't just academic. It's practical knowledge you need when your uncle starts talking about being a guinea pig at Thanksgiving dinner. Let’s discuss…
A Success Story Written in Survival
Vaccines are undoubtedly one of the greatest successes to emerge from the field of public health. The development and widespread use of vaccines in the 20th century have reduced childhood mortality from diseases like diphtheria, mumps, pertussis, and tetanus by almost 100%. Diseases that once killed children, like measles (which we still vaccinate against) and smallpox (which vaccines completely eradicated by 1980), no longer pose the same threat. Some vaccines, like those for measles and polio, provide long-lasting protection, while others require boosters. When was the last time you saw someone with paralytic poliomyelitis? If your answer is "never," or even better, "huh? What's that?", you have the polio vaccine to thank for that.
This astonishing reduction in infectious diseases did not happen overnight, nor did the development of the vaccines used to achieve these results. They are the product of years of trial and error. Each vaccine has the same ultimate goal: to stimulate an immune response that is both strong enough and specific enough to recognize and fight off a pathogen before it has the chance to make us really sick.
When someone says, "Why not use traditional vaccines instead of mRNA?" they're assuming all vaccines work the same way. They don't. Each technology was developed to solve specific problems that earlier vaccines couldn't handle.
From Stone Tools to Genetic Blueprints
Vaccines as we know them today are a reflection of scientific, technological, and manufacturing advances driven by medical need and safety over the past two centuries.
Early "vaccines" were very basic. Take smallpox, for example. Written accounts from as early as the 16th century show that healthy individuals were intentionally exposed to the smallpox virus by means such as inserting a cotton plug soaked with pus from an infected person's pustule into the nose, inhaling dry fragments of a smallpox scab, or wearing an infected person's clothing.
Not only was it pretty gross, but it was quite risky. People sometimes were exposed to too much live virus and contracted full-blown smallpox anyway. Despite these significant risks, the practice persisted because it still offered better odds than facing smallpox naturally. This understanding that a small amount of live virus could trigger an immune response without causing severe disease became one of the first tools in our immunization toolbox.
The Evolution of Vaccine Technology
In 1796, Edward Jenner revolutionized the field by using cowpox virus to protect against smallpox, the first true 'vaccine.' Building on this principle, 19th-century scientists Louis Pasteur and Emile Roux discovered they could deliberately weaken (or 'attenuate') dangerous pathogens. They extracted the rabies virus from infected rabbits and weakened it enough that the immune system could recognize the virus without it being strong enough to cause rabies.
The Old Guard: Vaccines That Use Actual Viruses and Bacteria
Live-attenuated vaccines are vaccines made from a weakened form of a virus or bacteria. They have the advantage of generating long-lasting immunity, often lifelong with just one or two doses. The experimentation required to attenuate viruses took extensive time in the lab. With testing in animals and humans over the years, this technology led to the development of safe and effective vaccines against measles, mumps, rubella (MMR), varicella (chicken pox), and many more diseases.
These vaccines work incredibly well, which is why your MMR shot from childhood still protects you. But because they contain live weakened viruses, there's a small risk these viruses can mutate back to a more harmful form. This risk becomes greater in people with compromised immune systems, which is why vaccines like MMR aren't recommended for this population.
Inactivated vaccines began in the late 1800s and early 1900s, where a virus or bacterium was killed (inactivated) such that it could no longer cause disease but retained its complex outer structure enough to trigger strong immunity. Initial inactivated vaccines included vaccines against plague, cholera, salmonella, and pertussis.
The first polio vaccine, developed and licensed in 1955, used an inactivated virus to safely induce immunity when given as a shot. Around the same time, a live-attenuated oral polio vaccine (given as a liquid by mouth) was also developed and introduced in the early 1960s, providing protection against all three polio strains and offering the advantage of easy oral administration. Today in the US, children receive only the inactivated polio vaccine (IPV), as the live vaccine was discontinued in 2000 due to rare cases of vaccine-derived polio. However, many countries still use the oral live-attenuated vaccine for its ease of administration and ability to provide community immunity.
Note: Another early advance led to toxoid vaccines for diseases like diphtheria and tetanus (developed in the 1920s-1940s). These vaccines use inactivated bacterial toxins to trigger protective antibodies.
The Middle Generation: Just the Important Parts
With refinements to purification processes over the years, a virus or bacterium could be broken apart to isolate very specific parts ('split' or subunit vaccines), and just these parts would be used for the vaccine. These are considered very safe because they only use a small piece of the pathogen and therefore cannot cause disease. They also have fewer side effects. These are usually known as subunit vaccines.
Conjugate vaccines used for pneumonia and meningitis built on this technology. In this type of vaccine, a weak antigen from the pathogen (usually a sugar molecule) is connected to a protein molecule. This combination helps the immune system recognize and respond more effectively to the weaker antigen. This was first deployed in the 1980s, with several additional vaccines becoming available in the 1990s and 2000s.
Recombinant DNA technology emerged around this time, and with it came the ability to create even safer vaccines without any actual virus present. This technology allowed vaccine developers to use laboratory strains of yeast or bacteria as factories to produce just the proteins they needed. The protein is purified and then used as the active ingredient in the vaccine. In 1986, the first recombinant vaccine was approved for hepatitis B. In this vaccine, the only part of the virus present was a replica of its surface protein. The vaccine against human papillomavirus (HPV), introduced in 2006, was engineered similarly.
When someone worries about "live virus" in vaccines, you can explain that many modern vaccines (like those for hepatitis B and HPV) don't contain any virus at all, just proteins. And even the flu shot most people get is made from killed virus that can't cause infection.
The New Frontier: Instructions Instead of Ingredients
The vaccines described so far are produced in vitro, meaning they're manufactured outside of a living organism in a laboratory. The last few decades have focused on ways to deliver genetic instructions that allow vaccines to be produced in vivo (within the human body) to generate an immune response without risking infection. Instead of using cells in culture to make the antigen in a lab, the human body becomes the vaccine factory.
Scientists have tried using harmless viruses as delivery vehicles (viral vectors) to carry genes encoding pathogen antigens into human cells, but our immune system learns to recognize these delivery viruses too, limiting their effectiveness for booster doses. DNA-based vaccines have a similar goal, but haven't worked well in human trials.
This is where mRNA comes in. Unlike DNA, which would need to enter the cell's nucleus, mRNA stays in the cellular cytoplasm, makes its protein, then naturally breaks down within days. (That's not a flaw; it's actually a safety feature.)
Don't Shoot the Messenger(RNA)!
It's been over five years since the COVID-19 pandemic started, and just under five years since the FDA issued an Emergency Use Authorization for the first mRNA vaccine for COVID-19. Throughout this time, there's been a barrage of questions about the technology and skepticism around the speed at which these vaccines were developed. We've addressed these topics in a recent Unbiased Science post.
When SARS-CoV-2 was identified as the pathogen responsible for COVID-19, genomic sequencing revealed that it was a coronavirus, very closely related to viruses that had previously caused outbreaks of SARS-CoV and MERS (Middle East Respiratory Syndrome). The vaccine effort soon focused on the Spike protein, aiming to produce a stable form that would generate antibodies that blocked the virus from entering cells.
Why mRNA for COVID?
Let’s think back to January 2020: Scientists posted the genetic code of a new virus online. Within 48 hours, U.S. scientists at the Vaccine Research Center at the National Institutes of Health had designed the vaccine. Not manufactured, not tested, just designed. On a computer.
How? Because with mRNA, you don't need the actual virus. You just need its genetic sequence.
Public health leaders looked inside their vaccine toolbox:
Live-attenuated vaccines were ruled out quickly for both safety and practical reasons.
Traditional recombinant protein vaccines had potential, but require large-scale production that takes too long.
While some companies (like Novavax) did pursue a recombinant protein vaccine, the virus was mutating and spreading so rapidly that it would be nearly impossible to keep up.
The development of mRNA as a platform had been ongoing for over 40 years. There were promising results in animals based on mRNA delivery in mouse models. An mRNA vaccine could overcome the laborious process of scaling up for a recombinant protein vaccine. Once inside the body, the mRNA could produce the Spike protein immediately and initiate the desired immune response. The mRNA is temporary, and it does nothing to the host DNA.
Operation Warp Speed: What Actually Happened
Resources (money and expertise) were poured into the effort, called "Operation Warp Speed." It cost billions of dollars to make vaccines, and the plan was to offer them for free. The first mRNA-based COVID-19 vaccines were scaled up to millions of doses, called "at-risk" manufacturing because there was no guarantee that the vaccines would be approved.
Instead of doing Phase 1, waiting a year, doing Phase 2, waiting another year, then Phase 3, they ran them back-to-back with overlap. Simultaneously, tests were performed in animal models to show that the vaccine induced strong, specific immunity and that when challenged with SARS-CoV-2, only vaccinated animals were protected from disease. Clinical trials confirmed the vaccines’ safety and efficacy, leading to FDA approval first for adults and later for children.
The key takeaway here is that COVID-19 vaccine development followed the same rigorous safety protocols and monitoring as other vaccines, but the timeline was greatly accelerated. No safety studies were skipped. Efficacy trials were placebo-controlled and included over 30,000 participants to test the Moderna vaccine and over 44,000 for the BioNTech vaccine.
When someone says we were "guinea pigs," remind them that the same number of people were tested as with any vaccine. The only difference was that instead of waiting years between trial phases, safety and efficacy data were analyzed and published as soon as possible. Results were available quickly because the virus was everywhere, and the trials showed protection from severe disease in those who received mRNA vaccines, but not in those who received the placebo. The financial risk was taken by the government, and no safety risks were taken by the people.
The Reality Check: Current Limitations
Like any tool, mRNA vaccines have their limitations.
All vaccines require cold storage and specialized distribution systems to maintain stability, potency, and efficacy, but mRNA vaccines require even colder temperatures to maintain the integrity of the RNA. This means mRNA vaccine access is limited to countries with infrastructure that can support extreme cold chain delivery, further entrenching issues of vaccine equity.
Here's the brutal irony: The communities hit hardest by COVID-19 often couldn't access mRNA vaccines because they require storage at -70°C (-94°F). That's colder than Antarctica! Most vaccines are stored at much warmer (cold) temperatures (5-46°F). While wealthy nations debated vaccine preferences, much of the world couldn't even maintain the freezers needed to store them.
Because mRNA naturally breaks down in the body, these vaccines may need more frequent boosters than other technologies. The lipid coating required to deliver the mRNA has required changes to formulation and manufacturing that may not yet be available worldwide. Finally, mRNA vaccines aren't a universal solution. Their success relies on identifying the right proteins and antigens for a given disease; for many pathogens, we haven't even identified the right targets yet.
More Than Just a Glimmer of Hope
We're just scratching the surface of what mRNA technology can do.
Beyond infectious diseases, mRNA technology is being programmed to help our immune system recognize and attack cancer cells by producing tumor-specific proteins unique to each patient's cancer. Right now, there are people enrolled in trials for personalized cancer therapeutics, their tumors' genetic code uploaded, vaccines designed specifically for them.
We're talking about treatments for rare genetic diseases that would have been science fiction five years ago. Vaccines that could prevent allergies. Therapies that could reverse autoimmune conditions. The same platform that saved millions from COVID-19 is now being adapted to fight diseases we thought were untouchable.
The technology gives us the speed and flexibility to respond to the next pandemic in ways we never could have before. What took us 63 days for COVID-19 could be even faster next time. And unlike traditional vaccine development, which requires different approaches for different pathogens, mRNA provides a consistent platform where we just need to change the genetic instructions.
The Bottom Line for Your Conversations
If someone asks why we needed mRNA when other vaccines worked fine, here’s what you can say: We didn't need it for diseases we'd already conquered. We needed it for the battles we couldn't win with our old tools.
The old vaccines in our toolbox aren't going anywhere. Your kids will still get their MMR shots, their polio vaccines, and their tetanus shots. But for the diseases that have haunted us, for the next pandemic, for cancers that kill, we finally have a power tool in our toolbox.
And it only took us 40 years to build it!
Today, we continue the fight for mRNA vaccines. We do this not only because they're a scientific milestone, but because they've saved millions of lives...and they're just getting started.
Stay Curious,
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Thanks! Love collaborating with everyone at Unbiased Science.
Brilliant summary!