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Quality checks on the Salk polio vaccine at Glaxo's virus research laboratory in Buckinghamshire, UK, in January 1956.
Quality checks on the Salk polio vaccine at Glaxo's virus research laboratory in Buckinghamshire, UK, in January 1956.
Photo by Fox Photos/Getty Images

How Are Vaccines Made?

Quality checks on the Salk polio vaccine at Glaxo's virus research laboratory in Buckinghamshire, UK, in January 1956.
Quality checks on the Salk polio vaccine at Glaxo's virus research laboratory in Buckinghamshire, UK, in January 1956.
Photo by Fox Photos/Getty Images

Vaccines have long been hailed as one of our greatest public health achievements. They can be made to protect us from infections with either viral or bacterial microbes. Measles and smallpox, for example, are viruses; Streptococcus pneumoniae is a bacterium that causes a range of diseases, including pneumonia, ear and sinus infections, and meningitis. Hundreds of millions of illnesses and deaths have been prevented due to vaccines that eradicated smallpox and significantly reduced polio and measles infections. However, some misunderstanding remains regarding how vaccines are made, and why some scary-sounding ingredients [PDF] are included in the manufacturing process.

The production of our vaccines has greatly evolved since the early days, when vaccination was potentially dangerous. Inoculating an individual with ground-up smallpox scabs usually led to a mild infection (called "variolation"), and protected them from acquiring the disease the "regular" way (via the air). But there was always a chance the infection could still be severe. When Edward Jenner introduced the first true vaccination with cowpox, protection from smallpox became safer, but there were still issues: The cowpox material could be contaminated with other germs, and sometimes was transmitted from one vaccinated person to another, leading to the inadvertent spread of blood-borne pathogens. We’ve come far in the last 200 years.

There are different kinds of vaccines, and each requires different processes to move from the laboratory to your physician's office. The key to all of them is production of one or more antigens—the portion of the microbe that triggers a host immune response.

LIVE ATTENUATED VACCINES AND DEAD, "INACTIVATED" VACCINES

There are several methods to produce antigens. One common technique is to grow a virus in what's called a cell culture. Typically grown in large vats called bioreactors, living cells are inoculated with a virus and placed in a liquid growth medium that contains nutrients—proteins, amino acids, carbohydrates, essential minerals—that help the virus grow in the cells, producing thousands of copies of itself in each infected cell. At this stage the virus is also getting its own dose of protective medicine: antibiotics like neomycin or polymyxin B, which prevent bacterial and fungal contamination that could kill the cells serving as hosts for the virus.

Once a virus completes its life cycle in the host cell, the viruses are purified by separating them from the host cells and growth media, which are discarded. This is often done using several different types of filters; the viruses are small and can pass through holes in the filter that trap larger host cells and cell debris.

This is how "live attenuated vaccines" are created. These vaccines contain viruses that have been modified so that they are no longer harmful to humans. Some of them are grown for many generations in cells that aren't human, such as chicken cells, so that they have mutated to no longer cause harm to humans. Others, like the influenza nasal mist, were grown at low temperatures until they lost the ability to replicate in the warmer temperatures of the lungs. Many of these vaccines you were probably given as a child: measles, mumps, rubella ("German measles"), and chickenpox.

Live attenuated vaccines replicate briefly in the body, triggering a strong—and long-lasting—response from your immune system. Because your immune system kicks into high gear at what it perceives to be a major threat, you need fewer doses of the vaccine for protection against these diseases. And unlike the harmful form of the virus, it is extremely unlikely (because they only replicate at low levels) that these vaccines will cause the host to develop the actual disease, or to spread it to other contacts. One exception is the live polio vaccine, which could spread to others and, extremely rarely, caused polio disease (approximately one case of polio from 3 million doses of the virus). For this reason, the live polio virus was discontinued in the United States in 2000.

Scientists use the same growth technique for what are known as "killed" or "inactivated" vaccines, but they add an extra step: viral death. Inactivated viruses are killed, typically via heat treatment or use of a chemical such as formaldehyde, which modifies the virus's proteins and nucleic acids and renders the virus unable to replicate. Inactivated vaccines include Hepatitis A, the injected polio virus, and the flu shot.

A dead virus can't replicate in your body, obviously. This means that the immune response to inactivated vaccines isn't as robust as it is with live attenuated vaccines; replication by the live viruses alerts many different types of your immune cells of a potential invader, while killed vaccines primarily alert only one part of your immune system (your B cells, which produce antibodies). That's why you need more doses to achieve and maintain immunity.

While live attenuated vaccines were the primary way to make vaccines until the 1960s, concerns about potential safety issues, and the difficulty of making them, mean that few are attempting to develop new live attenuated vaccines today.

COMBINATION, BACTERIAL, AND GENETICALLY ENGINEERED VACCINES

Other vaccines aren't made of whole organisms at all, but rather bits and pieces of a microbe. The combination vaccine that protects against diphtheria, pertussis, and tetanus—all at once—is one example. This vaccine is called the DTaP for children, and Tdap for adults. It contains toxins (the proteins that cause disease) from diphtheria, pertussis, and tetanus bacteria that have been inactivated by chemicals. (The toxins are called "toxoids" once inactivated.) This protects the host—a.k.a. you, potentially—from developing clinical diphtheria and tetanus disease, even if you are exposed to the microorganisms. (Some viruses have toxins—Ebola appears to, for example—but they're not the key antigens, so they're not used for our current vaccines.)

As they do when developing live attenuated or inactivated vaccines, scientists who create these bacterial vaccines need some target bacteria to culture. But because the bacteria don't need a host cell to grow, they can be produced in simple nutrient broths by vaccine manufacturers. The toxins are then separated from the rest of the bacteria and growth media and inactivated for use as vaccines.

Similarly, some vaccines contain just a few antigens from a bacterial species. Vaccines for Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitidis all use sugars that are found on the outer part of the bacteria as antigens. These sugars are purified from the bacteria and then bound to another protein to enhance the immune response. The protein helps to recruit T cells in addition to B cells and create a more robust reaction.

Finally, we can also use genetic engineering to produce vaccines. We do this for Hepatitis B, a virus that can cause severe liver disease and liver cancer. The vaccine for it consists of a single antigen: the hepatitis B surface antigen, which is a protein on the outside of the virus. The gene that makes this antigen is inserted into yeast cells; these cells can then be grown in a medium similar to bacteria and without the need for cell culture. The hepatitis B surface antigen is then separated from the yeast and serves as the primary vaccine component.

OTHER INGREDIENTS IN VACCINES (AND WHY THEY'RE THERE)

Once you have the live or killed viruses, or purified antigens, sometimes chemicals need to be added to protect the vaccine or to make it work better. Adjuvants, such as aluminum salts, are a common additive; they help enhance the immune response to some antigens by keeping the antigen in contact with the cells of the immune system for a longer period of time. Vaccines for DTaP/Tdap, meningitis, pneumococcus, and hepatitis B all use aluminum salts as an adjuvant.

Other chemicals may be added as stabilizers, to help keep the vaccine working effectively even in extreme conditions (such as hot temperatures). Stabilizers can include sugars or monosodium glutamate (MSG). Preservatives can be added to prevent microbial growth in the finished product.

For many years, the most common preservative was a compound called thimerosal, which is 50 percent ethylmercury by weight. Ethylmercury doesn't stick around; your body quickly eliminates it via the gut and feces. (This is different from methylmercury, which accumulates in fish and can, at high doses, cause long-lasting damage in humans.) In 2001, thimerosal was removed from the vaccines given in childhood due to consumer concerns, but many studies have demonstrated its safety.

Finally, the vaccine is divided into vials for shipping to physicians, hospitals, public health departments, and some pharmacies. These can be single-dose or multi-dose vials, which can be used for multiple patients as long as they're prepared and stored away from patient treatment areas. Preservatives are important for multi-dose vials: bacteria and fungi are very opportunistic, and multiple uses increase the potential for contamination of the vaccine. This is why thimerosal is still used in some multi-dose influenza vaccines.

Though some of the vaccine ingredients sound worrisome, most of these chemicals are removed during multiple purification steps, and those that remain (such as adjuvants) are necessary for the vaccine's effectiveness, are present in very low levels, and have an excellent track record of safety.

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Quality checks on the Salk polio vaccine at Glaxo's virus research laboratory in Buckinghamshire, UK, in January 1956.
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Essential Science
What Is Infinity?
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Albert Einstein famously said: “Two things are infinite: the universe and human stupidity. And I'm not sure about the universe.”

The notion of infinity has been pondered by the greatest minds over the ages, from Aristotle to German mathematician Georg Cantor. To most people today, it is something that is never-ending or has no limit. But if you really start to think about what that means, it might blow your mind. Is infinity just an abstract concept? Or can it exist in the real world?

THERE'S MORE THAN ONE KIND

Infinity is firmly rooted in mathematics. But according to Justin Moore, a math researcher at Cornell University in Ithaca, New York, even within the field there are slightly different uses of the word. “It's often referred to as a sort of virtual number at the end of the real number line,” he tells Mental Floss. “Or it can mean something too big to be counted by a whole number.”

There isn't just one type of infinity, either. Counting, for example, represents a type of infinity that is unbounded—what's known as a potential infinity. In theory, you can go on counting forever without ever reaching a largest number. However, infinity can be bounded, too, like the infinity symbol, for example. You can loop around it an unlimited number of times, but you must follow its contour—or boundary.

All infinities may not be equal, either. At the end of the 19th century, Cantor controversially proved that some collections of counting numbers are bigger than the counting numbers themselves. Since the counting numbers are already infinite, it means that some infinities are larger than others. He also showed that some types of infinities may be uncountable, as opposed to collections like the counting numbers.

"At the time, it was shocking—a real surprise," Oystein Linnebo, who researches philosophies of logic and mathematics at the University of Oslo, tells Mental Floss. "But over the course of a few decades, it got absorbed into mathematics."

Without infinity, many mathematical concepts would fall apart. The famous mathematical constant pi, for example, which is essential to many formulas involving the geometry of circles, spheres, and ellipses, is intrinsically linked to infinity. As an irrational number—a number that can't simply be expressed by a fraction—it's made up of an endless string of decimals.

And if infinity didn't exist, it would mean that there is a biggest number. "That would be a complete no-no," says Linnebo. Any number can be used to find an even bigger number, so it just wouldn't work, he says.

CAN YOU MEASURE THE IMMEASURABLE?

In the real world, though, infinity has yet to be pinned down. Perhaps you've seen infinite reflections in a pair of parallel mirrors on opposite sides of a room. But that's an optical effect—the objects themselves are not infinite, of course. "It's highly controversial and dubious whether you have infinities in the real world," says Linnebo. "Infinity has never been measured."

Trying to measure infinity to prove it exists might in itself be a futile task. Measurement implies a finite quantity, so the result would be the absence of a concrete amount. "The reading would be off the scale, and that's all you would be able to tell," says Linnebo.

The hunt for infinity in the real world has often turned to the universe—the biggest real thing that we know of. Yet there is no proof as to whether it is infinite or just very large. Einstein proposed that the universe is finite but unbounded—some sort of cross between the two. He described it as a variation of a sphere that is impossible to imagine.

We tend to think of infinity as being large, but some mathematicians have tried to seek out the infinitely small. In theory, if you take a segment between two points on a line, you should be able to divide it in two over and over again indefinitely. (This is the Xeno paradox known as dichotomy.) But if you try to apply the same logic to matter, you hit a roadblock. You can break down real-world objects into smaller and smaller pieces until you reach atoms and their elementary particles, such as electrons and the components of protons and neutrons. According to current knowledge, subatomic particles can't be broken down any further.

THE INFINITIES OF THE SINGULARITY

Black holes may be the closest we've come to detecting infinity in the real world. In the center of a black hole, a point called a singularity is a one-dimensional dot that is thought to contain a huge mass. Physicists theorize that at this bizarre location, some of the singularity's properties are infinite, such as density and curvature.

At the singularity, most of the laws of physics no longer work because these infinite quantities "break" many equations. Space and time, for example, are no longer two separate entities, and seem to merge.

According to Linnebo, though, black holes are far from being an example of a tangible infinity. "My impression is that the majority of physicists would say that is where our theory breaks down," he says. "When you get infinite curvature or density, you are beyond the area where the theory applies."

New theories may therefore be needed to describe this location, which seems to transcend what is possible in the physical world.

For now, infinity remains in the realm of the abstract. The human mind seems to have created the concept, yet can we even really picture what it looks like? Perhaps to truly envision it, our minds would need to be infinite as well.

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What Is a GMO?
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If you've followed the debate about GMOs with any sort of regularity, there's a strong chance you've come across a picture of a tomato stabbed by a giant syringe. That image, though a complete fiction, seems to perfectly capture what's preventing public acceptance of these foods: We don't really know what makes something a GMO.

GMOs aren't made with syringes and, at the moment, they aren't even made with tomatoes, at least not commercially. But that false image is everywhere, and surveys indicate consumers fear GMOs without knowing much about them.

So what exactly is a GMO?

FROM THE FIRST SWEET POTATO TO THE QUEEN'S CORGI

The initialism stands for "genetically modified organism," but it's a term lacking scientific precision. Moreover, it's hard to find an organism in any way connected to humans that hasn't been genetically modified, says Alison Van Eenennaam, a geneticist at UC-Davis who specializes in animal biotechnology. "I might argue that a great Dane or a Corgi are 'genetically modified' relative to their ancestor, the wolf," she tells Mental Floss. "'GMO' is not a very useful term. Modified for what and why is really the more important question.”

GMOs are often described as if they were a recent invention of our industrial food system, but genetic modification of food isn't new at all. It's been happening for many millennia: As long as farmers have been saving high-performing seeds for future harvests, we've had GMOs. Perhaps the earliest known example of a GMO is the sweet potato, which scientists believe became modified when wild sweet potatoes became infected, quite naturally, by a particular kind of soil bacteria. Realizing these sweet potatoes were edible, people began saving the seeds and cultivating them for future harvests. That was about 8000 years ago.

These days, when people say "GMO," they tend to mean one particular modification method that scientists refer to as transgenesis. As Van Eenennaam explains, transgenesis is "a plant-breeding method whereby useful genetic variation is moved from one species to another using the methods of modern molecular biology, also known as genetic engineering."

Transgenic crops and animals have been modified with the addition of one or more genes from another living organism, using either a "gene gun," Agrobacteria—a genus of naturally occurring bacteria that insert DNA into plants—or electricity, in a process called electroporation.

The first commercial transgenic crops debuted in the early 1990s: a virus-resistant tobacco in China [PDF] and the Flavr-Savr tomato in the U.S., which was genetically altered to not get "squishy." (It's no longer on the market.)

As to the health risks of GMO foods, the scientific consensus is clear: Transgenic crops are no riskier than other crops. Van Eenennaam points to a 20-year history of safe use that includes "thousands of studies, eleven National Academies reports, and indeed [the consensus of] every major scientific society in the world."

THE ROLE OF HERBICIDES AND PESTICIDES

Today, the most ubiquitous transgenic crops in the U.S. food system are cotton, soybeans, and corn, including those modified to resist the effects of the herbicide Roundup. Branded "Roundup Ready," these crops have been modified so that farmers can apply the herbicide directly to crops to control weeds without killing the crops themselves.

For farmers, the result was better weed control and higher yields. For critics of GMOs, these crops became their smoking gun. These opponents argue they're bad for the planet and bad for our health.

There's no question that use of glyphosate, the active ingredient in the herbicide Roundup, has increased since the introduction of GMOs, but measuring its environmental impact is a far more complex equation. For example, as glyphosate use has increased, so has the prevalence of conservation tillage, a beneficial agricultural approach that helps sequester carbon in the soil and mitigate the impacts of climate change.

Bt crops—transgenic crops modified with genes from the all-natural bacterial toxin Bt, short for Bacillus thuringiensis—have also reduced the use of insecticide, according to a 2016 National Academies of Science report.

And though evidence suggests herbicide use has increased since Roundup Ready GMOs were first commercialized in the U.S., herbicide use has increased amongst some non-GMO crops, too. Glyphosate also replaced more toxic herbicides on the market and, if farmers were to stop using it, many would likely replace glyphosate with another herbicide, possibly one that's more toxic. Glyphosate-resistant weeds are a problem, but banning glyphosate, or glyphosate-resistant GMOs for that matter, wouldn't solve the problem.

In recent years, opponents of GMOs have increasingly aimed their fire at glyphosate. The source of many of these claims is a 2015 assessment [PDF] by the International Agency for Research on Cancer (IARC) to categorize glyphosate as "probably carcinogenic." That categorization has been hotly contested by many scientists, as other governmental agencies have concluded glyphosate does not pose a carcinogenic hazard. And, in June, reporting revealed that the lead researcher at IARC withheld important studies from the research group's consideration.

Weighing criticisms of glyphosate against its benefits certainly brings up complex issues in our agricultural system, but ultimately these issues are not unique to GMOs nor would they magically disappear if transgenic technology were eliminated altogether.

OTHER METHODS OF GENETIC MODIFICATION

Most consumers probably can't name all the different methods of genetic modification, but there's a good chance they've eaten foods modified by one of these methods all the same. Layla Katiraeea human molecular geneticist at Integrated DNA Technologies and a science communicator, has written about these methods to illustrate why it makes little sense to single out transgenic crops. Examples include polyploidy, which gave us the seedless watermelon, and mutagenesis, which scientists used to engineer a brightly colored grapefruit. As Katiraee points out, sometimes two different methods can even create a very similar end result. For example, the non-browning Opal apple was developed using traditional cross-breeding, while the non-browning Arctic apple uses transgenic methods to silence the genes that control browning.

Katiraee says the most common objections to GMOs aren't exclusive to transgenic crops: “Don't like ‘Big Ag'? They use all methods of crop modification. Don't like herbicide-tolerant crops? They've been made with other methods. Don't like patents? Crops modified by all methods are patented. If you go through the list, you won't find one [objection] that applies exclusively to transgenesis.”

Katiraee's arguments illustrate why it doesn't make sense to label transgenic crops "GMO" while omitting the non-browning opal apple or a seedless watermelon. And the non-GMO label can often be misleading. Van Eenennaam points to one of the more ridiculous examples: non-GMO salt. "Salt doesn't contain DNA, so salt cannot be genetically engineered," she says. "All salt is 'non-GMO' salt."

DISEASE-RESISTANCE SUCCESSES

The noisy GMO debate has often overshadowed the successes of lesser known, disease-resistant GMOs. Van Eenennaam argues that no one should object to these crops since protecting “plants and animals from disease aligns with most everyone's common interest in decreasing the use of chemicals in agricultural production systems, and minimizing the environmental footprint of food production." Examples include ringspot virus–resistant papaya in Hawaii [PDF] and the American chestnut, both rescued from the devastating effects of lethal plant viruses.

Disease-resistant crops often face an uphill battle for approval. In Uganda, scientists developed a disease-resistant banana that then faced difficult regulatory obstacles until a new law was finally approved in October by the country's Parliament. In Florida, where the disease called citrus greening has caused widespread crop damage and loss to the citrus industry, orange trees have been modified with a spinach gene to help crops resist the virus. But orange juice manufacturers will have to persuade consumers to buy it. 

Scientists have used transgenic modification to address health concerns too. For example, some variations of the wilt-resistant banana also include a boost of vitamin A. Scientists are working on a form of wheat that would be safe for people with celiac disease.

Van Eenennaam fears the controversy over GMOs has meant that, over the years, the public has missed out on important technologies. In the field of animal biotechnology, for example, animals have been produced that are resistant to disease, "that produce less pollution in their manure, [and] that have … elevated levels of omega-3 fatty acids," but none of these have been commercialized in the U.S.

Given that these crops and animals have a 20-year history of safe use, Van Eenennaam argues there's no reason that "fungus-resistant strawberries, disease-resistant bananas, and virus-resistant animals [should] sit on the shelf" unused.

Editor's note: This post has been updated. 

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