From Smallpox to Today: The Science of Vaccination


Few subjects can spark a more heartfelt debate among parents of young children than vaccines. It is easy to find very scary information online about the danger of vaccines, and yet it is hard to find a pediatrician who would not agree that vaccines are one of the most effective public health tools we have. They save millions of lives each year, one at a time, and have been doing so for decades all around the world.

Perhaps these heated arguments partially arise out of a general lack of understanding of science and biology that is very common in modern society. We enjoy the benefits of science, but don’t often know, or even care, to learn about the “magic” behind our electronic devices, the clean water that flows into our homes, and the electricity that is available at the flick of a switch. Many think that an understanding of science is too hard to grasp, when in fact, scientific literacy is not beyond the grasp of any educated person. The widespread lack of scientific literacy, together with our human biases that lead us to errors in risk assessment, often combine to produce confusion and angst on the issues of vaccines, as well as other topics.

How Vaccines Work: A Look at Smallpox

Most people have an idea that vaccines are something we need, and they do good. Yet those same people often don’t have much of an idea about how they actually work. Science often follows technology, and this case is no exception—a detailed understanding of how vaccines work continues to develop decades after the first successful vaccination program. The first vaccine was instituted against one of man’s great viral enemies of the past: smallpox. Fortunately, the ingredients for successful eradication of this scourge did not require a detailed scientific understanding of how it worked.

For eradication of smallpox, two main things were required: First, the fact that smallpox was a human-only virus; there was no animal reservoir of disease. Therefore, if all humans can be virus-free at one moment in time, then at that moment the virus will literally be extinct, gone, quite unlikely to appear again. Think about it. Amazingly, the same is true of any human-specific disease: if all people harboring it are somehow able to stop spreading it all at once, it would be gone. Note the qualifier above that it is “quite unlikely” to reappear. Certainly, the scenario that led to COVID-19 could happen again, should it jump once more from the wild animal population and become easily spread among humans. This is why we need to invest in good surveillance and detection. Even smallpox could in theory escape from deep-freeze, but if it did, heaven forbid, at least we know how to fight it.

The second ingredient that resulted in the eradication of smallpox was, of course, a vaccine. In the case of smallpox, nature provided the vaccine in the form of a similar, but usually non-lethal virus found in our four-legged farm friends, most notably the humble cow. In fact, the word “vaccine” is derived from the Latin word for cow, vacca, the source of the original smallpox vaccine. Even now that we know many of the cellular details of how a vaccine works, a live vaccine that causes a small infection remains one of the most effective vaccine types. Edward Jenner’s contribution in 1796 was demonstrating the ability of cowpox virus to protect against smallpox.

a wood engraving depicting men standing around an overturned cow, extracting cowpox for the purpose of making it into a smallpox vaccine

When cowpox material was scratched onto the skin, the resulting small infection, usually accompanied by a small blister, provided protection from smallpox. Seemingly miraculously, the immunity that the body develops against the cowpox is retained as a cellular memory that persists for years, and prevents reinfection from the same, or in this case similar, viruses. Over time, newer strains of the original vaccine virus, known as vaccinia have been developed that provide milder symptoms, yet still provide protection, and the vaccine is still being developed, should it ever be needed.

Starting as early as the fifteenth century, the earliest records of anything resembling vaccination was the process of variolation, which was indeed dangerous, and involved use of actual smallpox virus, inhaled nasally or introduced into the skin with a small incision. So it was no surprise that Jenner’s vaccination, even though safer than variolation, was viewed with great suspicion: the insertion of an infected animal’s body fluids into your own body is undoubtedly quite disgusting. But we must try to imagine the driving force that led people to this was the far greater horror of the disease itself. Smallpox, polio, and measles—these three diseases which are now either completely or nearly fully eradicated—caused unimaginable human misery, so it would only take a little success for variolation and later vaccination to overcome the “ick” and “ow” factor with respect to the vaccine and the needle. And vaccines today are more than a little successful at preventing a wide range of diseases.

How Vaccines Work Today

Today vaccine development has progressed to a quite mature technology, and vaccines have been developed against the most prevalent and dangerous human and animal diseases. There are exceptions where vaccines have not succeeded, most notably against HIV, the cause of AIDS, and malaria. Although efforts continue and incremental progress has been made, the particular features of these pathogens, one a retrovirus, the other a single-celled parasite, renders them much more challenging to vaccinate against. Here is another lesson: the vaccine strategy must be matched to the disease, and some vaccines are better than others!

Types of vaccines are nearly as diverse as the diseases they prevent. Vaccine types include inactivated (killed) pathogens, as well as some that remain active but are genetically unable to cause disease. Polio vaccines have included both types, the inactivated polio vaccine is currently in use, originally championed by Jonas Salk, yet the oral vaccine developed by Albert Sabin, containing live-but-weakened virus was instrumental in the fight against polio due to its ease of use and effectiveness in mimicking disease, leading to an effective immune response.

Other vaccines may contain purified proteins or components derived from the pathogen, or a toxoid (resembling a toxin, but non-toxic) from a bacteria. One example is for hepatitis B, where a single protein that forms the virus “shell” is manufactured in the lab and purified, and when placed in a buffer solution, the purified proteins form tiny virus-like particles, which of course are very safe, and yet they induce immune protection. Vaccines taken by older adults that target pneumococcus include multiple distinct sugar chains that are unique to the dozens of types of the pneumococcus bacteria. The most commonly used pneumococcal vaccine contains 23 polysaccharide antigens of the more prevalent strains in its formulation. Interestingly, young children respond poorly to this sugar-only vaccine, and to make it more effective, the immune system can be tricked by joining the bacterial sugars to an immunogenic protein, called conjugation. A similar conjugation trick is used for two other vaccines designed to prevent meningitis caused by H. influenzae and N. meningitidis.

The annual influenza vaccine is a collection of flu proteins produced by an engineered (non-flu) virus in millions and millions of hen eggs. I was surprised to learn from a vaccine company executive that the flu vaccine apparently uses one egg per vaccine dose. That is a lot of eggs. The search for a more efficient way to deliver antigens to the body in a way that is still safe and provides effective immune stimulation has more recently included the introduction of nucleic acids, either DNA or RNA, and encoding the proteins of interest into the body. While such nucleic acid vaccines are still being developed, the theory behind them suggests it is likely to work, eventually.

a vaccine is bring drawn from a vial into a syringe

There are many types of vaccine, but they all have in common the fact that a foreign material is being introduced into your body. This is the essential idea of how all vaccines work: not only must a foreign substance be present, but it must be recognized as foreign, which requires it to be delivered in a way that tricks the body into seeing it as something to counteract. Immunizing humans is made more challenging than animals by the fact that we desire to have very few adverse responses, so this aspect of vaccine formulation—including immune stimulators known as adjuvants—is limited to the mildest ones, which often means they are less effective. So the soreness in the area of a vaccine usually should not be seen as a negative side effect, but rather part of the main effect. It is a sign that your body is doing what it should be doing: working at the cellular level to develop long-term cell-based protection against disease. A sore arm for a day is a small price to pay. Of course, the science of developing newer better human vaccine adjuvants has also progressed along with a greater understanding of the molecules and cellular mechanisms that lead to an effective immune response.

Hopefully, this discussion has helped to shine some light of understanding on these strange and mysterious things known as vaccines. Perhaps the mystery and even fear that many face when getting their shots can be replaced with a more appropriate sense of true awe and wonder. It is truly wonderful and amazing that our bodies are able to defend themselves with the training provided by vaccines. Everyone should retain a healthy skepticism of anything you are being asked to take into your body, or any medicine for that matter, and seek answers to the basic scientific question: How does it work? This is just a good approach, and should lead to a personal investigation for well-sourced and reliable information from people who speak clearly and aim to educate, not instill fear, or sell a product or service.

Herd Immunity and Loving our Neighbor

When we are vaccinated, we contribute to a societal effort to minimize disease. Several years ago, I spent a research sabbatical at the Dana-Farber Cancer Institute, in Boston. As a biologist who teaches immunology, and has a reasonably good idea of how vaccines do what they do, I tend to ask folks I meet—like my barber or other friends—whether they have gotten their seasonal flu vaccine, and it always surprises me how many don’t get it for various reasons. Well, at the Dana-Farber, you cannot work there without proof of having had the flu vaccine. You are required to display your “I’m vaccinated” sticker on your ID. So is the Dana-Farber just extra concerned that its staff and doctors are able to continue coming to work to do the essential research and care for their patients? No, that’s not the main reason at all! The reason to require vaccination of all working at the Dana-Farber is that the building is full of people undergoing chemotherapy who have a weakened immune system, and they must be protected. But this is also true outside of the hospital. You encounter all kinds of strangers continually as you move through the world. By vaccinating yourself, you are protecting those you encounter who for various reasons either cannot be vaccinated or are immune-compromised. Once a high percentage of the population is immune to a given pathogen, epidemiologists speak of “herd immunity” having been achieved.

Herd immunity is a goal for societies to achieve. But what does this mean? Much like a herd that circles around and protects the young and vulnerable, a high level of immunity in a population protects those who are non-immune or susceptible to disease by preventing it from reaching them. This high level of immunity can come naturally from infection and recovery, or after widespread vaccination. Unfortunately, herd immunity may not be easily achievable naturally for some diseases. Natural herd immunity is harder to achieve when, like measles, the disease spreads easily. Interestingly, with COVID-19, superspreader incidents suggest it also may be hard to rely on any natural herd effect for protection.

Although it may sound funny to refer to ourselves as part of a herd, in the context of immune protection and from the viewpoint of a virus, that is what we are. We are biologically very much a part of the natural world. Of course, scripturally and theologically, Christians believe we are much more than the other animals—God cares about us personally (1 John 4:10). Yet, the Bible also refers to our sheep-like personal tendencies (Isaiah 53:6), and this should give us pause as we realize that even at the cellular level the reality of our animal-like biology is more accurate than we may like to admit! Certainly the pandemic has provided a strong motivation for each of us to learn more about the science of vaccines, and as the field is rapidly developing, unless you are one of the heroes working directly in vaccine development, there is something for everyone to learn.


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Craig M. Story
About the Author

Craig M. Story

Craig Story is Professor of Biology at Gordon College, a small non-denominational Christian college located on the North Shore of Massachusetts. There, he teaches a number of cell biology courses including immunology and biochemistry, and serves as the health professions advisor. He studied antibody transport in pregnancy for his doctoral research at Brandeis University, and in his postdoctoral training at MIT and Harvard Medical School he worked on an unusual virus immune evasion process. Since 2013, Dr. Story has worked with church leaders, seminary professors, and the public to foster important conversations about science and the Christian faith. He keeps busy with beekeeping, gardening and observing God’s marvelous creation.
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