Since the COVID-19 outbreak started, vaccines have become a major talking-point world wide. For some, vaccines against the virus are a source of immense hope and seen as the golden ticket out of this global pandemic. To others, these new vaccines are source of deep concern and distrust. While this may seem like a novel problem for our modern world, inoculations against deadly, widespread diseases and their opponents have been around for centuries.
Life Before Vaccines
To start, we'll need go back to the less high-tech predecessors of vaccines, inoculations. Inoculation is "the introduction of a pathogen or antigen into a living organism to stimulate the production of antibodies." Inoculation against smallpox was so popular it got its own name, "variolation." Early examples of inoculations/variolations used in China as early as 200 BCE included taking smallpox scabs from a sick person and scratching them into the skin of a healthy person, or grinding up smallpox scabs and blowing them up the nose of a healthy person. The healthy person would contract smallpox, but since the scab materials were often held onto for a few days before being used for inoculations, this infection was generally more mild than catching it naturally and, afterward, they would be immune to the disease.
Immunity was desperately needed as smallpox was a deadly virus that killed roughly 30% of those infected and left its survivors scarred, possibly blind, and possibly sterile. Deaths were significantly higher in babies and young children, with estimates closer to 80%-90%. Evidence of smallpox was present across Africa, Asia, and Europe since at least 400 BCE, meaning the disease wrecked havoc on humans across millennia. In regions with smallpox, new outbreaks sprang up in densely populated areas nearly once every decade. This meant most people along the trade routes the connected Africa, Asia, and Europe were exposed to smallpox several times in their lives, starting in childhood. Smallpox was then introduced to the Americas by Europeans in the 1500s, with devastating effects. Those living in the Americas had never been exposed to the lethal disease before and as a result an estimated 90% of Native Americans died of smallpox. Areas like Australia and New Zealand were similarly decimated by smallpox after contact with European colonizers.
To prevent against the disastrous consequences of smallpox, areas across Africa, India, and the Ottoman Empire took up variolation similar to that used in China by the 1700s with great success. The rest of the world, however, still struggled to combat the disease. In 1684, doctors in England only treated those who could afford to pay for treatments. However, instead of healing these patients, expensive medical care ended up hurting a patients chances of surviving the infection. Mainly because contemporary treatments included blood letting, avoiding any form of heat, and drinking a dozen beers, all things known to worsen an illness today.
In 1718, the wife of the British Ambassador to Turkey, Lady Mary Wortley Montagu, had her son variolated in Constantinople. While she saw this procedure to be a lifesaving necessity, those around her were skeptical. To prove the safety and efficacy of variolation, and at the request of Montagu, prisoners and abandoned children were inoculated by having smallpox inserted under the skin then deliberately exposed to smallpox a few months later. When none of those in the experiment contracted the disease, the procedure was deemed a success and variolation began to take off across Europe.
In what would become the United States, a minister, Cotton Mather, learned of variolation from Libyan-born Onesimus, who Mather enslaved. Mather went on to promote the practice in Boston during a smallpox outbreak in 1721, where vaccination saved countless lives. A few decades later, English physician, William Heberden wrote a pamphlet that described how parents could inoculate their children against smallpox, which was distributed across the country for free. When this pamphlet was met with suspicion, US founding father, Benjamin Franklin wrote an introduction that went into detail on the safety and efficacy of variolation in Boston's 1721 outbreak. Having lost his son to the disease, Franklin's preface was meant to convince those who were fearful of variolation to inoculate their children.
The World's First Vaccine
Variolation was not without risk and had three major drawbacks since worked by purposefully infecting patients with a milder form of smallpox. First, the disease was still deadly and killed roughly 1% of those who contracted it through variolation. Second, variolation patients were contagious and the procedure had to potential to trigger an outbreak if patients came into contact with people who had never contracted the virus. Third, when matter was taken from one person's smallpox sore and placed into another person's body, other diseases, such as hepatitis, tuberculosis, or syphilis, could also spread.
Additionally, bringing variolation to new places was challenging logistically since it required matter from an active smallpox infection. Traveling overseas could take several months, but smallpox infections generally lasted only a couple of weeks. This meant that children who had never been exposed to the virus would be taken on long voyages to act as a human chain of infection. The first child would be variolated, then the scabs from their infection would be used to variolate the next child and so on and so forth until the ship made it to its destination and matter from the last child's infection could be used to inoculate the new population.
In 1796, British doctor Edward Jenner took the fight against smallpox one step farther. He had noticed that milkmaids, who had gotten cowpox from the cows they milked, did not get smallpox later on. Jenner then infected a boy, James Phipps, with matter from a cowpox sore on the hand of a milkmaid, Sarah Nelmes. James was later exposed to smallpox and did not catch the disease. This discovery led to an understanding that cowpox virus could protect against human smallpox and is considered the first vaccine. While variolations worked by purposefully exposing people to the disease, this new technique was purposefully exposing people to a less deadly form of the virus, in this case a less dangerous relative of smallpox.
Vaccination against smallpox began to spread, slowing becoming popular worldwide. Based on the success of these vaccines, countries began to implement the first vaccine mandates. In 1807, Bavaria required vaccinations for all military personal, since an outbreak on the battlefield could cost Bavaria the war and the movement of soldiers was often tied to outbreaks. In 1853, England created a broad vaccine mandate, which was then followed by several other countries. Each of these edicts were met with resistance. Some saw it as the rich taking away the freedom of the poor, others as a violation of their religious freedom, and still others as part of colonial control.
Despite the opposition, smallpox vaccination rates skyrocketed. As technology advanced, the vaccine went from being something collected from human cowpox victims, to something collected directly from the cows themselves. Thanks to these advances, the deadly disease was eradicated from North America in 1952 and Europe the following year.
However, smallpox continued to caused death and disfigurement throughout the early 1900's in Africa, Asia, and South America. In response, the World Heath Organization initially campaigned to end smallpox in 1959, and renewed their efforts in 1967 with more funding, vaccines, and support from each country involved in the program. The program was successful, so much so that smallpox became the first, and currently only, human disease successfully eradicated from Earth in 1977. This extraordinary feat meant that people born after the 1970's would never know the pain of contracting smallpox, heartbreak of losing a loved one to the disease, or scarring of a smallpox vaccine.
The Golden Age of Vaccines
Having found a world-changing way to prevent smallpox, scientists turned to hundreds of other diseases. Over the next 150 years, vaccines were developed for rabies, cholera, tuberculosis, diphtheria, tetanus, and pertussis, with the last three being combined into one vaccine most Americans receive today. These saves countless lives, but took teams of researchers decades to make. Given the insurmountable number of diseases, this pace seemed far too slow to provide all the vaccines needed for modern life.
Luckily, vaccines found their next superstar in Marice Hilliman. Hilliman was an American scientist who created his first vaccine for the US government in 1944 for Japanese encephalitis. From there, he went on to create more than 40 human and animal vaccines, including those currently used to protect against measles, mumps, chickenpox, rubella, hepatitis A, hepatitis B, pneumococcal pneumonia, meningitis, pandemic influenza, and chlamydia. For context, prior to Hilleman, no scientist had ever created more than two or three vaccines in their career.
It wasn't just the shear number of new vaccines that made Hilleman one of the most important scientists in modern medicine, it was also the number of people who would take his vaccines. The 1918 flu pandemic had killed tens of millions of people worldwide and returned year after year to wreck more damage. While the virus mutated a bit each year, it wasn't until 1957 that a new devastating strain emerged, the H2N2 virus. This strain of the flu was first noticed in Asia, with the US government receiving reports of 20,000 cases in Hong Kong, cause deep concerns about what would happen when the virus reached America. Hilleman took a sample of the virus from an American who had been serving overseas to create a vaccine, which he then urged manufactured to produce at a large enough scale to prevent mass casualties in the US. The flu killed over a million people worldwide that year, but deaths in the US were significantly lower than initial estimates thanks to Hilleman's vaccine. Based on the research needed to create and the success of the 1957 flu vaccine, a new flu vaccine is created each year to combat the prevailing strain of the disease.
Hilleman discovered how viruses transform when they switch from infecting one species to another, like the flu did in 1957. He was able to use this knowledge to then create vaccines faster than ever before. Hilleman would take a sample of a live human virus, then grow it in a chicken embryo, taken from an egg. As the virus evolved in the lab to better infect chickens, it would become less infectious to humans. This process of making a virus less infectious to humans is known as "attenuation." He needed to find the right balance between making a strain of virus that was too weak to make people sick, but still strong enough to cause an immune reaction. This process could take decades, but Hilleman and his team were able to break records and create a mumps vaccine in only 2 years after he took a sample of the disease from his daughter.
Hilleman and his team created 8 of 14 vaccines most Americans receive. Additionally, attenuated vaccines became the gold-standard of protection and are the basis for most vaccines used today.
Future of Vaccines
While attenuated vaccines are the standard, research for a new ways to generate vaccines has been going on since the late 1980's with a focus on mRNA.
For context, our genes are encoded in DNA, a molecule made up of two interlocking strands that tells our cells everything they need to make and keep life going, including the receipt for how to make proteins. DNA is stored in the nucleus of the cell, where it can be kept safe from outside forces that want to alter it. Think of DNA as a hard copy of a Latin dictionary; it tells you everything you need to know to build that language, but can easily be damaged or lost and is not going to let you speak to anyone. The machinery needed to create proteins is called the ribosome and it lives outside the nucleus, where it is free to move around and interact with other parts of the cell. In order to get the protein receipt out of the nucleus to a ribosome, a portion of your DNA is copied onto a single stranded molecule called messenger RNA (mRNA) in a process called transcription. mRNA works like a handwritten copy of one word and it's definition from your Latin dictionary; it is small, easy to move around, and a lot less risky than carrying the entire book everywhere you go. This mRNA is taken out of the nucleus and brought over to the ribosome. The ribosome then reads the mRNA and based on that message, creates a specific protein in a process called translation. If DNA and mRNA are in Latin, then proteins would be in whatever language you speak. Proteins are what do most of the work in the cell and are needed to create and maintain tissue and organs. They are the language being spoken everyday, what allows you to make sentences and communicate ideas.
Scientists began making mRNA as a research tool for studying gene function. However, as they learned more about the molecule, researchers found more and more ways mRNA could be used. As labs went down their own research avenues, they shared their findings with the world. By sharing their breakthroughs, scientists helped propel researchers working on very different projects forward at new speeds.
Some researchers looked into ways mRNA could help treat diseases. Genetic diseases are caused by a mutation in someone's DNA that prevents their body from being able to create a protein correctly. Theoretically, mRNA therapies could bring in a handwritten note with the right message to get the body to make the correct protein, treating the genetic disease. This led to a lot of interest and research from both pharmaceutical companies and universities, with a number of potential therapies currently being tested in labs and humans.
Other scientists focused on cancer. Cancer is caused by to damage in the DNA that lets cells grow out of control. Today, doctors can determine the specific protein and gene that has gone awry in your cells. Using mRNA, you could, give someone the code to make the right protein, and therefore stop their tumors from growing. Alternatively, you could give someone a note that targets cancer cells and makes them more responsive to cancer treatments. Research is ongoing into mRNA therapies and vaccines against cancer.
Using mRNA for vaccines is not a new idea. In the early 1990's multiple companies started to look into manufacturing mRNA vaccines, but found the price of making this novel type of vaccine to be far too high to be worth further investigation. However, decades of research finally advanced mRNA vaccines to the point where they were no longer considered too expensive to be worth making. In 2020, companies began running small-scale clinical trials in humans using mRNA vaccines to treat infectious diseases. However, with the outbreak of COVID-19, focus quickly shifted to making a vaccine against this novel disease. Both Pfizer-BioNTech and Moderna were able to swiftly test and manufacture a mRNA vaccine against COVID-19, which were the first of such a vaccine approved in the US. While this approval is currently for emergency use only, both vaccines are expected to be granted full approval once they are able to conduct the kind of long-term testing required by the FDA.
Based on the success of mRNA vaccines against COVID-19, mRNA vaccines are back in the spotlight and being researched for their potential to protect against a number of diseases including HIV/AIDs, the flu, Zika, and cancer. With ongoing trials in humans for each of these diseases, and more, it looks like vaccines are far from the end of their story. While this means the debate around vaccines will also continue in the upcoming years, it also means the world may soon have access to protection against diseases once thought impossible to defeat.
When inoculation was first discovered, thousands of years ago, it seemed impossible to imagine a world without smallpox. From smallpox's first vaccines to when it was finally eradicated, vaccines had advanced to cover dozens of diseases and become standard for most children worldwide. Vaccines have saved an uncountable number of lives globally, with new lifesaving possibilities expected in the upcoming years and limitless potential in our lifetimes. As we've seen with the COVID vaccine, new technology allows for quicker, easier, and cheaper ways to manufacture these indispensable injections, making them more accessible to the world. Additionally, record numbers of people are taking COVID-19 vaccines and seeing how safe and helpful their are against this deadly disease. With increased access and fewer reasons to be fearful, the history of vaccine skepticism may finally see its final chapter, opening up a new age in the story of vaccines.