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Vaccine Timeline
Before Jenner and After COVID-19

Numerous events across the centuries have shaped the history of vaccines so far.

The history of vaccines did not begin with Jenner's smallpox vaccine. It will not end with the recent vaccines against the novel coronavirus, which caused the COVID-19 pandemic. The history of vaccines begins before the first vaccine, with an immunizing procedure called "inoculation" by some and "variolation" by others. According to researchers, inoculation with materials from smallpox lesions to trigger immunity against smallpox dates back to antiquity in China. And the first written account of the procedure was written in 1549.

Variolation

Versions of an earlier time of practicing inoculation were more oral histories than written records. , "In this version [of inoculation in China before it was written] (inoculation) was invented by a Taoist or Buddhist monk, or possibly a nun, about 1000 AD and practiced by Taoists as a mixture of medicine, technique, magic, and spells which were transmitted orally and which were covered by a taboo so that they were never written down. Needham can give no firmer evidence for this version than the fact that it was a widely accepted tradition. An editorial commentator wonders whether it is realistic to believe that something with the importance of inoculation would have remained completely secret for over 500 years."

Secret or not, the practice of inoculation traveled west toward the Ottoman Empire in the 1500s, reaching Constantinople (modern day Istanbul, Turkey) in the mid-1600s. From there, inoculation traveled to Europe and Northern Africa. From Northern Africa, . He told Reverend Cotton Mather -- -- about being inoculated by enslavers to resist smallpox and get better pay for his enslavement. Cotton Mather, together with a local doctor in Boston, adopted and promoted inoculation as .

Around the same time, , a British socialite living in Constantinople with her diplomat husband, had her son inoculated by a local physician. She then asked her daughter -- back home in Scotland -- to be inoculated. By 1723, the evidence was clear that inoculation in a controlled setting and under the supervision of a physician was preferable to catching smallpox "the natural way." 

After his son died from smallpox in 1736, . He wrote several introductions to written works of the time about the procedure. In one such document written in 1759, Benjamin Franklin even included some numbers on the death rates of those who were inoculated (also known as "variolated"). The numbers gave even more proof that the risk of death was lower in those who were inoculated, cementing the practice in Europe and North America. Such was the adoption of variolation that .

Vaccination

By the late 1700s, observed that milkmaids and others previously infected with cowpox were immune to smallpox. Cowpox caused lesions similar to smallpox, but the lesions were localized, and the disease was much milder and not considered deadly. Building on the world and observations of other physicians at the time, . The gambit paid off. The subjects of these experiments showed a mild reaction to cowpox, and no reaction nor disease to smallpox inoculation. The first vaccine was born.

For almost eighty years, cowpox vaccination against smallpox remained the only vaccine in use around the world. Science and technology were not yet there to create vaccines against other disease-causing organisms, though many tried. One such person was , a French biochemist who enjoyed experimenting with microorganisms and kept detailed records of all his laboratory procedures. In Pasteur's time, . Rabid animals from the forest would bite and infect street dogs or cattle. People who would then be bitten by the dogs or exposed through their cattle would succumb to rabies.

Attenuation

Pasteur theorized that something in the saliva of the rabid animals was causing rabies. Though he could not see the rabies virus, Pasteur proved the disease was communicable, and he got to work on a vaccine. The work involved exposing animals to small doses of rabies, much like the variolation had been done in the past. This did not work, however. The rabies virus was too infectious, too virulent. As a result, Pasteur approached the problem differently: weaken the infectious agent somehow before giving it to a person.

One version of smallpox variolation involved drying the material extracted from smallpox lesions before giving it to someone. It was believed the drying caused the material to be less virulent, so . By this time, it was understood that the virus attacked the central nervous system of infected animals. Even if the virus could not be seen, the damage was visible. Pasteur took the dried brain and spinal cord from one rabbit, and gave it to another. He would wait for that rabbit to develop rabies, euthanize it, and repeat the process with a third, then a fourth, etc. Late down the chain, rabbits exposed to the dried brain and spinal cord were not getting sick. Furthermore, they were resisting any attempts at infection through fresh specimens of saliva from rabid animals.

Before going public with his findings, Louis Pasteur -- like Edward Jenner -- took a gamble and exposed human subjects to the dried material in reverse. He started with dried brain and spinal cord from the last rabbit to be inoculated, and worked toward the material from the first rabbit, delivering stronger and stronger doses of the rabies virus. The most well-known human subject was , a young man bitten by a rabid animal. To save Joseph's life, physicians allowed Pasteur to practice his procedure on Joseph. After all, without a cure, Joseph would likely suffer a painful death from rabies. Attempting something was better than nothing.

After the expected incubation period of rabies of about 21 days, Joseph did not develop any signs or symptoms of the disease. Pasteur's vaccine was a success. The next leap in vaccination technology had occurred. Scientists used an analogue to the infectious agent -- cowpox for smallpox -- to use the infectious agent in a less virulent ("attenuated") way. Other vaccines developed at, or in collaboration with, the Pasteur Institute in Paris, France, were based on the same principle of weakening the pathogen before giving it as an inoculation.

Toxoid Vaccines

Later in the 1800s, scientists studying the immune response of humans and other animals discovered antibodies. These proteins were created some time after infection, and they would bind to the pathogen and inactivate it. That "some time after infection" was critical, however. Without antibodies, the person could develop the disease and perish. Scientists then worked on safe ways to create those antibodies in large batches and give them to people as a sort of immune patch, while people developed their own antibodies. Thus was born the era of anti-toxins.

While not true vaccinations, anti-toxins were created when a toxin from tetanus or was given to a large mammal, like a horse. The mammal would develop antibodies against the toxin, and the antibodies were harvested, purified, and given to people showing signs of the disease. In 1902, contamination of one such anti-toxin with actual tetanus toxin led to several injuries. . It was the first step toward regulation of medicines and therapies, something we still see today.

Later, in the 1920s, scientists discovered that an antitoxin combined with a toxin would inactivate the toxin, but leave it intact enough for the human immune system to react against it. Antitoxin-toxin vaccines for diphtheria and tetanus were developed. However, a problem persists in a large segment of the population receiving antitoxin (alone or in combination with a toxin). They were developing an allergic reaction to the proteins from the animals used to create the antitoxin. To solve this problem, scientists found a way to inactivate the toxin before giving it as a vaccine. The age of toxoid vaccines was born, giving us such vaccines as the diphtheria and tetanus vaccines. Protection against those diseases became safer after not having to rely on large mammals to produce them.

Electron Microscopy

In the 1930s, scientists developed the electron microscope. Unlike traditional light microscopes, electrons were used as the "probe" to visualize structures smaller than those seen under light microscopes. This brought about a revolution in virology, as individual viral particles were first seen and classified according to their shapes and sizes. It was no longer necessary to wait and see what kind of infection would be caused by inoculating cell cultures or laboratory animals. Now, a specimen could be placed under an electron microscope, and the causative agent identified.

Electron microscopy led to an explosion in viral research. Samples from the 1918 Spanish Flu pandemic were analyzed, and the influenza virus was observed and classified. Samples from nerve tissue of polio victims showed the poliovirus. Based on their size and shape, where they were isolated from in a body, and what type of infection and disease they were producing, viruses were being catalogued quickly. Vaccines against them arrived almost as fast.

In the 1940s, scientists worked on vaccines against influenza, polio, measles, and other viruses deemed critical national security importance. That decade brought vaccines against influenza, which was then understood to be not just one virus, but several types of influenza virus for which different vaccines would be needed. Similarly, polio was understood to be three types of virus in the same group, so a vaccine against one type did not protect against the others.

Polio

Armed with the knowledge of different virus types of the same virus group, scientists worked on vaccines against all types to prevent all disease. By 1954, after decades of well-funded research, . It was a vaccine against polio, and it went against the dogmas established at the time: the vaccine had to contain live/attenuated virus, and that a dead virus could not cause an immune response. The work of , and other women helped lead the way to a vaccine that saved thousands of children's lives.

The 1960s brought the oral polio vaccine as a replacement to Salk's vaccine, after the eroded the public's trust in vaccines. The oral vaccine, developed by Albert Sabin, was tested in the Soviet Union and Latin America, and then brought to the United States with much success. By the 1990s, polio was eliminated from the United States and much of Europe. By the early 2000s, polio was eliminated from the Americas, Europe, and most of Asia. By the 2010s, polio had receded to local outbreaks in Africa and Central Asia. By the 2020s, types 2 and 3 of polio are eradicated, and type 1 is only present in Central Asia.

Eradication

The 1950s and 60s also brought great cooperation among the nations in eliminating and then . That old adversary, the one that got the whole science of vaccination started, was on the retreat through programs in developed nations to vaccinate every individual starting at a young age, not allowing for any exceptions except medical ones. Those who did not want to be vaccinated , or even in certain jobs. Through a worldwide effort to vaccinate every person alive, smallpox became the first human virus to be eradicated when the . Since its eradication, the smallpox vaccine is only used in personnel working with the smallpox virus and in military members as part of readiness against an intentional release of the virus.

Scientific Leaps

More advances in scientific understanding of microorganisms and immunity brought leaps in vaccine technology. When it was understood that the pathogen could be killed and still elicit an immune response, the question was asked whether the whole pathogen was needed or just a protein on its surface. The answer was that some pathogens' surface proteins were enough to trigger an immune response against future infection. The era of subunit vaccines was born.

Later, scientists discovered that the genetic material of pathogens could be used in the laboratory to create the proteins. This did away with the need to grow pathogens in hazardous settings, reducing the risk of accidental exposures for laboratorians working on vaccines. The proteins created could then be "glued" onto another material and delivered to the body via a vaccine, triggering an immune response. The era of recombinant vaccines was born.

COVID-19

In late 2019, . By early 2020, the cluster had grown into the COVID-19 pandemic that continues into mid-2022. The novel coronavirus causing COVID-19 was a relative of the coronavirus that caused an outbreak in several countries in 2003-2004, and another that caused another multinational outbreak in 2013-2014. Because of the urgency of the COVID-19 pandemic, governments around the world invested heavily in vaccine development.

China announced the in June 2020. Sinovac used killed virus to trigger an immune response. Russia announced its in August 2020, after only two months of clinical trials. Sputnik V used a "hollowed out" adenovirus to deliver the messenger RNA of the coronavirus into the recipient's immune cells. That same month, two companies in the United States, Pfizer and Moderna, , which used lipid nanoparticles instead of a viral vector to deliver the genetic material to immune cells. By December 2020, the FDA approved the two mRNA vaccines for emergency use in the United States in people at risk for infection and complications.

Once in the immune cells, the messenger RNA tells the cells' protein-producing machinery to create proteins similar to those on the coronavirus' surface. The immune cells then present these proteins to other cells: T cells and B cells. The T cells then destroy any virus or virus-infected cells, while the B cells produce antibodies to deactivate viruses and give long-term immunity.

The History So Far

That is where we are as of mid-2022. We now have several types of vaccines: inactivated; live-attenuated; subunit, recombinant, polysaccharide, and conjugate; toxoid; viral vector; and mRNA. However, there is much more to the history of vaccines than what was covered in this overview. There are stories from outside the United States (and "The West" in general) that need to be told. The well-known "pioneers" in vaccination were not alone in their work and discoveries. Most vaccine advancements were a group effort.

So, please look at the timeline and all the events we have researched and posted there for you. We will continue to update the timeline as needed, expanding it to include events in other parts of the world where advances in vaccine science happened but were overlooked. We will also add accomplishments from people you may have never hard from. If you have any questions, please contact us. We would be happy to discuss the science and history of vaccines with you.