vaccines are made up of :: Article CreatorWe Need A Reminder Of What The Pre-Vaccine Era Was Like
A girl with polio meets one of the first children to get a polio vaccine.
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Of the more than 200 Americans infected by the measles outbreak in Texas and beyond, nearly all were unvaccinated — including a 6-year-old child who died — or had an unknown immunization status. While a measles epidemic affecting hundreds of people across state lines is hard to imagine in 2025, the vaccine fears that help fuel these outbreaks are as old as vaccination itself. Even when some of the worst diseases known to humankind threaten lives, there have always been those who fear the vaccine more than the disease.
In the early 1800s, some people rejected the smallpox vaccine because they didn't trust the doctors and scientists promoting them, or because they saw vaccines as an affront to God's will, or because they worried about dangers they'd heard or witnessed. That the early version of the vaccine occasionally spread infection only heightened those fears.
So governments increasingly made vaccination mandatory. Over a century ago, refusers could face quarantine, fines or even jail time. Vaccination objections grew. People argued that mandatory vaccination undermined individual liberty, or that the diseases the vaccines prevented weren't that serious.
A boy wearing a bandage typical for mumps patients, with his dog wearing a matching bandage.
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A boy taking part in the clinical trials for the live-virus measles vaccine.
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Those ideas persist today. Popular influencers are calling diseases like measles and mumps "no big deal."
The modern-day childhood vaccine schedule has allowed children to grow into healthy adults — something all parents hoped for in the centuries when diseases emptied towns, destroyed economies, ravaged battalions, overwhelmed hospitals and vexed nurses and doctors. For people who've never seen them, the worst manifestations of some of these preventable diseases are almost unimaginable. It's worth remembering their toll.
To understand how common these diseases were before vaccines, we reviewed historical surveys asking parents if their children had contracted them. The estimates are rough, but underscore just how much these diseases have faded from public memory.
Smallpox Vaccine created in 1798
Smallpox caused fever, headache, nausea, racking body aches and a rash of excoriating, pus-filled blisters. Sleepless victims suffered night terrors and delusions. In the worst historical cases, the pustules spread so densely that they covered the surface of the body, crusted over the eyes, and coursed over the mucous membranes until internal hemorrhaging led to certain death. A smallpox outbreak could kill up to 30 percent of people infected. Survivors were often left pock-marked and blind.
The smallpox vaccine, originally developed with virus from a milder animal disease, cowpox, led to smallpox's global eradication in 1980 — the ultimate vaccination success story.
Diphtheria Vaccine created in 1914
At its height over a century ago, diphtheria was often mistaken for a sore throat. Bad cases were identifiable only by the sweet-smelling, putrid-colored membrane of bacteria and decaying cells covering the patient's tonsils and throat. Diphtheria bacteria churn out a toxin that can cause paralysis, but in 19th-century epidemics, sick children often died of suffocation first. In the deadliest outbreaks, 30 percent to 50 percent of infected children perished.
Diphtheria was an unpredictable roulette of mild and deadly outbreaks until a vaccine was developed that could finally protect children from the disease's terrors.
Pertussis Vaccine created in 1914
Formally known as pertussis, whooping cough often begins like a minor cough or cold. Weeks later, the cough is still there, unrelenting. Before antibiotics or vaccines, the patient's cough would grow violent and uncontrollable, terminating in its namesake "whoop" sound. In young children, the whoop would often lead to vomiting. In a severe case lasting weeks, a child might whoop and vomit several times an hour. Babies couldn't forcefully take in enough air to whoop, and the lack of oxygen meant they'd turn blue.
The first pertussis vaccines were manufactured in 1914, and a modern version was developed in the 1930s. A combined diphtheria, pertussis and tetanus vaccine was created and given to many American children by the end of the 1940s.
Polio Vaccine created in 1955
The first U.S. Polio epidemic was documented in the 1890s and further outbreaks followed. It peaked as other infectious diseases, like smallpox and measles, were fading from view and concern. Most polio infections are minor, with some causing a fever and sore throat. In less than 1 percent of infections, the virus attacks nerve cells in the brain and spinal cord that control movement. Some patients are partly paralyzed. Others lose the ability to swallow properly, walk or breathe. The worst cases were fatal.
The first polio vaccine was approved for use in 1955, and the disease was eliminated from the Americas by 1994. Today, polio regularly circulates in just two countries, but outbreaks crop up where war and deprivation allow it to take root.
Measles Vaccine created in 1961
When the first European colonists brought measles to the Americas, it was so infectious that it spared almost no one. It caused a vivid red rash and fevers that spiked so high and for so long that the sick searched desperately for relief from measles' fiery heat. In populations that had never seen the virus before, measles could kill up to a quarter of people. In previously exposed populations, it could still kill 20 percent of children.
In the mid-20th-century United States, thanks to overall improvements in nutrition, hygiene and medical care, measles death rates remained low. But the virus can have alarming complications, including pneumonia, brain swelling, rare but terrifying brain inflammation and an altered immune system that lasts long after the disease itself resolves.
The scientific developments behind the first polio vaccine helped make the first measles vaccines possible in the 1960s. With the vaccine's growing use, cases began to tumble.
Mumps Vaccine created in 1967
A military doctor caring for 18th-century British infantrymen was troubled by what happened when his troops caught the "gangrenous" sore throat that was spreading across Europe. In his patients, jaws and testicles swelled to an alarming size. At least one of his men died; others recovered with their testicles permanently atrophied. After two more centuries, doctors eventually agreed mumps could similarly affect women's breasts, ovaries and other reproductive organs. By the mid-20th century, scientific focus shifted to children, whose mumps led to huge and painful swelling of the salivary glands, which could spread to the brain and leave a child deaf.
The measles vaccine inspired one for mumps, and by the end of the 1970s it was recommended for all American children, with cases diminishing over the next decade.
Rubella Vaccine created in 1969
Children used to catch rubella without much fanfare, developing little more than cold symptoms. But when contagious children passed the disease to pregnant women, the fetus was at grave risk. The virus, which typically invades the airways, can travel to the placenta and disrupt the fetus's rapidly dividing cells. Before children were given the vaccine, rubella infections resulted in many miscarriages and stillbirths. Many children were born with birth defects such as cataracts, hearing loss and severe heart and bone deficiencies. In very rare cases, children developed neurological deficits, leaving them with chronic seizures and physical and intellectual disabilities.
A 1964 epidemic affected 20,000 infants and prompted research for a vaccine that was ultimately folded into the combined M.M.R. Vaccine in 1971. Today, the United States sees only a few cases a year.
How we came up with these estimates
Data on the number of cases for these diseases from the pre-vaccine era is hard to come by, and even the case counts are extremely unreliable. Many estimates suggest that perhaps only 10 percent of cases for most of these diseases were reported. As a result, we turned to historical surveys.
For mumps, rubella, diphtheria, measles, and whooping cough we used two surveys from before 1930, one that surveyed 14 communities and another that surveyed three.
For smallpox, we relied on secondary references to the prevalence during the 18th century. For polio, we made a rough calculation of the probability that a child would contract polio over his childhood based on average annual case rates acquired from Project Tycho.
All of the rates given are for approximately how many kids got each disease at some point during their childhoods.
Building A Better COVID-19 Vaccine
Even before the World Health Organization declared the COVID-19 outbreak a pandemic on March 11, 2020, the scientific community was mobilizing to develop vaccines with the hope of protecting us all.
Scientists estimate that COVID-19 vaccines saved roughly 14 million–20 million lives across the globe in their first year of use (Lancet Infect. Dis. 2022, DOI: 10.1016 /S1473-3099(22)00320-6). But the vaccines were, and still are, far from perfect.
SARS-CoV-2, the virus that causes COVID-19, evolved rapidly to evade some of the immune defenses the vaccines induced. Vaccination was generally very effective at keeping people out of overloaded hospitals and morgues, but vaccinated people would still get sick when infected, albeit to a lesser extent. And the vaccines didn't stop the virus from spreading. Moreover, the messenger RNA (mRNA) shots that have made up the bulk of the US vaccination campaign are often themselves an unpleasant experience, causing flu-like side effects for a day or two in many people and more serious injuries in some cases, and they require special cold storage for distribution.
Scientists in the pharmaceutical industry and academia see opportunities to improve on the original COVID-19 vaccines. Since April 2023, a month before the US Department of Health and Human Services (HHS) declared an end to the COVID-19 public health emergency, the HHS and the Office for Pandemic Preparedness have been working to fund some of those scientists through Project NextGen, a $5 billion initiative to develop new vaccines and therapies for the disease.
Two years later, no next-generation COVID-19 vaccines have reached the market, but some are getting close. Researchers are developing vaccines that ditch the needle and lose the side effects while remaining shelf stable. And other vaccines are in the works that could potentially stop a future coronavirus pandemic in its tracks.
Here's why you still got sick
Getting the next COVID-19 vaccine right means knowing where the previous vaccines went wrong. The biggest problem with the first COVID-19 vaccines was that they weren't very effective at preventing infections. Research conducted soon after the first vaccines were released suggested they were only 34% effective at preventing infection from a household member who had an infection caused by SARS-CoV-2's delta variant (Lancet Infect. Dis. 2021, DOI: 10.1016 /S1473-3099(21)00648-4).
To understand why, we need to get to know our immune systems.
Alba Grifoni is a T-cell immunologist and expert in pandemic preparedness at the La Jolla Institute for Immunology. She says the best way for a vaccine to prevent infections is by making the body produce neutralizing antibodies.
Antibodies, the Y-shaped proteins produced by a class of white blood cells called B cells, recognize and bind to antigens, which can include viral proteins. Neutralizing antibodies are a subclass of antibodies that can prevent viruses from entering and infecting cells. In theory, if you stop cells from being infected, the virus can't replicate, so it never has the chance to be passed on to someone else.
Early in the pandemic, researchers suspected that the SARS-CoV-2 spike protein helped the virus enter cells, so it was the ideal target for vaccine-induced neutralizing antibodies, Grifoni says.
The first mRNA COVID-19 vaccines worked by using the body's natural ability to translate mRNA into protein to make a bunch of SARS-CoV-2's spike protein. B cells would then learn to produce antibodies that could bind to the spike protein; that lesson made sure there were antibodies ready to recognize the real thing in the event of exposure to the virus.
The sheer scale of the pandemic meant that new variants soon emerged. By the time the first vaccines were released in December 2020, the most dominant variants had amassed several key mutations in the spike protein. Those changes allowed them to evade neutralizing antibodies induced by vaccines and cause breakthrough infections.
But the vaccines also activate CD4+ helper T cells—which stimulate antibody-producing B cells and help coordinate the overall immune response—and CD8+ killer T cells—which directly kill infected cells.
Immunity to viruses through T cells is much less specific than immunity through neutralizing antibodies. T cells can recognize smaller fragments of viral proteins as antigens; this allows them to recognize parts of viruses that don't change as quickly, giving them the ability to respond to multiple strains of a virus.
Grifoni says the original mRNA COVID-19 vaccines were able to induce a "very good CD4+ and CD8+ T-cell response," which made those vaccines effective at preventing severe disease and hospitalization, even when someone was infected with a new strain. But because the vaccines couldn't induce the production of neutralizing antibodies that matched circulating strains, vaccinated people could still get infected and pass the virus along to others.
Keys to immunity
T
Antibodies and T cells are two components of the immune system that vaccine makers target. Both are needed for a vaccine to prevent severe disease and infection.
Credit: Yang H. Ku/C&EN/Shutterstock
Better than a shot in the arm
Some researchers think a change in format might boost protection.
One avenue for new vaccine development is mucosal vaccines. In theory, dosing the vaccine directly into the respiratory tract allows for robust antibody and T-cell responses where SARS-CoV-2 generally first enters the body. Such vaccination could help prevent an infection from taking hold better than intramuscular injections.
Michael Diamond, an immunologist at the Washington University School of Medicine in St. Louis, has helped develop one such nasal spray vaccine. Whereas the Pfizer and Moderna COVID-19 vaccines suspend mRNA in lipid nanoparticles, the vaccine developed by WashU Medicine uses an adenovirus vector to deliver its payload.
Adenoviruses are DNA viruses that have easily modifiable genomes. Scientists can deactivate the genes in them and insert DNA coding for antigens to build a vaccine. Diamond says, "DNA is sensed differently by the host cell than RNA, and that seems to help serve as an adjuvant," enhancing the immune response to the vaccine.
Diamond also says the preclinical data have been encouraging. "In preclinical studies that we've done in many different animal models, [the nasal spray vaccine] has shown a really robust ability to generate mucosal immunity in the upper airway," he says. Last year, Diamond and colleagues published research demonstrating in hamsters that the nasal vaccine completely prevented the transmission of SARS-CoV-2, whereas an intramuscular mRNA vaccine made by Pfizer and BioNTech was less effective (Sci. Adv. 2024, DOI: 10.1126/sciadv.Adp1290).
In the US, the WashU vaccine is licensed by the biotech firm Ocugen and Phase 1 clinical trials are expected to begin later this year. A version has been available in India since 2022 through the biotech company Bharat Biotech.
Vaccines based on adenovirus vectors may also solve another problem: that of storing the vaccine. The mRNA COVID-19 vaccines need to be kept at –80 °C for long-term storage because RNA is a fairly unstable and short-lived molecule.
Adenovirus vaccines are easier to store. "Adenoviruses can live on surfaces, and that's why we get adenoviral infections. The [virus] particle itself is very compact and very stable and resistant to the environment," Diamond says.
Another company, Vaxart, has taken the thermostable characteristic of an adenovirus-based vaccine to the extreme to create dry, shelf-stable vaccine tablets—essentially a vaccine in pill form. Chief Scientific Officer Sean Tucker and his team take adenoviruses, weaken them so they can't replicate, and insert DNA that codes for the SARS-CoV-2 spike protein. Vaxart researchers then dry these DNA-filled viruses and apply a coating that allows them to survive our stomach acid and be delivered to our intestines. There, the immune system can pick them up, and with the help of some proprietary tech, the vaccine induces an antibody and T-cell response in the respiratory tract.
Preclinical studies showed that the vaccine generated robust antibody responses in hamsters, effective against multiple SARS-CoV-2 strains (Sci. Transl. Med. 2022, DOI: 10.1126/scitranslmed.Abn6868). A paper published to a preprint server suggests the oral vaccine was able to induce mucosal immunity in humans in a Phase 1 trial, although the study has not yet undergone peer review (medRxiv 2022, DOI: 10.1101/2022.07.16.22277601).
Both Vaxart's vaccine pill and the mucosal vaccine Diamond helped develop could also have fewer side effects than the injectable mRNA vaccines. Vaxart chief medical officer James Cummings says the pill's "side effect profile is the same as placebo."
Tucker hopes that a shelf-stable, oral vaccine could minimize the supply chain burden and the number of professionals needed to administer a vaccine. "They send heart medications by mail. Why couldn't you eventually have your vaccine come by mail?" he says.
Credit: Vaxxas
Vaxxas's microneedle vaccine patch contains thousands of tiny vaccine-coated needles over 1 cm2. The patch is inside of a spring-loaded device, which when activated launches the patch toward the skin, gently piercing it, to deliver the vaccine.
Another COVID-19 vaccine modality may also make its debut soon. Australian company Vaxxas has developed a microneedle patch that can deliver different vaccines, including mRNA-, DNA-, and protein-based vaccines without the need for cold storage. CEO David Hoey says that simply drying out the vaccine and covering the vaccine-coated needles with foil is enough to make them temperature stable. To administer the vaccine, a health-care professional removes the foil and activates a small spring so that the "patch fires at about 20 meters per second," Hoey says. "It feels like you've been flicked on the skin."
Hoey says that delivering the vaccine right under the skin means the vaccine goes directly to dendritic cells, a special type of immune cell that presents antigens to T cells. That results in a much more potent immune response, he claims. The company's needle-free COVID-19 vaccine is going through Phase 2 clinical trials in Australia, and clinical trials for vaccines for several other diseases using the needle-free tech are also underway.
But one of the vaccines in development now faces a new hurdle. On Feb. 21, Vaxart received a stop work order from the US Department of Health and Human Services (HHS), which was funding Vaxart's vaccine pill program to the tune of just over $450 million through Project NextGen. The order puts a pause on all activities related to the company's 10,000-person Phase 2b study for up to 90 days. If the stop work order isn't canceled or extended before then, the trial will be terminated, according to a statement Vaxart wrote and is providing to the press. The order does not apply to a 400-person cohort designed to assess the safety of the vaccine over a 30-day period, the statement says.
An HHS spokesperson tells C&EN via email that "while it is crucial that the U.S. Department and Health and Human Services support pandemic preparedness, four years of the Biden administration's failed oversight have made it necessary to review agreements for vaccine production."
"The Company is working through the impact of the stop work order and will provide an update when we have additional information," Vaxart says in its statement.
Helping those who haven't yet been helped
Traditional, injectable vaccines still have their benefits.
GeoVax Labs does not intend to abandon the needle for its COVID-19 vaccine in development. The company has received $24 million from Project NextGen to create a COVID-19 vaccine that uses modified vaccinia Ankara (MVA) as a vector. MVA was first developed during the 1950s and '60s to vaccinate against smallpox and has today been used in more vaccinations worldwide than any other vector. It was created by culturing the vaccinia virus, a kind of poxvirus, in chicken fibroblast cells for hundreds of generations until it lost its pathogenicity.
MVA can induce strong immune responses without adding any other viral proteins, according to GeoVax CEO David Dodd. But MVA can also be used as a vector with a large loading capacity, meaning you can design a vaccine that "encodes multiple antigens or proteins," Dodd says. "We've done as many as five before," he says, though the firm's current formulation undergoing Phase 2 trials uses just the spike and nucleocapsid proteins.
One benefit to using the older MVA technology is decades of research evaluating its safety profile. That's partly why Dodd and GeoVax are working to get their vaccine approved specifically for use in immunocompromised individuals. "There are about 40 million adults in the United States, and over 400 million worldwide, for whom the pandemic has never ended" because they have some condition that prevents the currently available vaccines from being effective, Dodd says. "MVA was developed specifically for people with compromised immune systems," he says in reference to the original MVA smallpox vaccines. Building an MVA-based COVID-19 vaccine could help those people too.
Once again, it's all about T cells. Currently available vaccines aren't necessarily dangerous to immunocompromised individuals; rather, those with weak immune systems often can't produce enough neutralizing antibodies in response to the vaccines—a common problem with vaccines. However, MVA smallpox vaccines have been shown to induce a strong T- cell response in immunocompromised people, and Dodd hopes this means an MVA COVID-19 vaccine will do the same. The GeoVax vaccine candidate is undergoing two Phase 2 trials evaluating its effectiveness in individuals with chronic lymphocytic leukemia and people preparing for stem-cell therapy, as well as a third Phase 2 trial testing how well it works in individuals without an immune-compromising condition.
Vaccinating beyond COVID-19
Beyond developing protection against COVID-19, Grifoni, Diamond, and their colleagues are also working on a project to design a pancoronavirus vaccine—one that would protect against the entire family of coronaviruses, including mild respiratory viruses, severe acute respiratory syndrome, and Middle East respiratory syndrome (MERS).
Grifoni says the key is to induce T-cell responses to the proteins that are genetically similar among all coronaviruses. "If we go outside the spike protein, there are other proteins of SARS-CoV-2 that are good antigens for T-cell responses, and they are more conserved in the general coronaviruses," she says.
Three SARS-CoV-2 proteins have similar structures across the coronavirus family tree and could be useful in a pancoronavirus vaccine: the nucleoprotein and nonstructural proteins 12 and 13. Building select portions of those proteins into a vaccine could lead to protection against most coronaviruses.
"The question is, How far can we go?" Grifoni asks. She says the most dangerous coronaviruses are all part of the β-coronavirus subfamily, which contains SARS-CoV-2, SARS-CoV-1, and MERS. She thinks it's possible to target the entire subfamily with a single vaccine.
The real hope is that any pancoronavirus vaccine would protect us against the coronavirus that could come next, avoiding another pandemic before it starts. Grifoni says that a pancoronavirus vaccine could be used as the first line of defense to reduce hospitalizations while the scientific community works on more-specific vaccines.
Much of the nuance on where the first COVID-19 vaccines succeeded and where they failed has been lost in the public discourse. "It's so easy to be critical today," Dodd says, looking back at the COVID-19 vaccine rollout.
But vaccines did and will protect people. "The mRNA vaccines really rescued society," Diamond says. "People forget that if we didn't have those, a lot more people would have died."
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MMR Vaccine For Adults
The MMR vaccine protects you from measles, mumps, and rubella. All three of these diseases spread easily, so it's important to get this vaccine. (Photo Credit: E+/Getty Images)
The MMR vaccine protects against measles, mumps, and rubella. (Rubella is also called German measles). Many children in the U.S. Are immunized as infants and toddlers. But not everyone gets vaccinated as a child. Many adults move to the U.S. From countries without immunization programs. World travel increases the chances of these diseases spreading.
Adults who were born before 1957 are usually immune to (protected against) measles, mumps, and rubella. This is because most people got these diseases as children before vaccines were available. If you were born in 1957 or after, The CDC recommends that you get the MMR vaccine unless you have:
Lab results showing that you're immune to all three diseases Medical records showing you've had all three diseases Proof that you've been vaccinated for all three diseases, whether you were vaccinated as a child or after The three diseases covered by the MMR vaccine are highly contagious. Viruses cause all three of these illnesses, and they spread through the air. They can pass from person to person through coughing, sneezing, or just breathing.
Measles. This disease causes a fever, runny nose, rash, and in severe cases, hospitalization, pneumonia, encephalitis, or death. It attacks your throat and lungs. Vaccinations have helped stop the spread of measles in the U.S., but there are still cases reported. While immunization rates are on the rise around the world, the World Health Organization (WHO) estimates there were 207,500 measles deaths in 2019. Measles outbreaks often happen in countries without strong childhood immunization programs. But outbreaks have also happened in Europe, South Africa, and the Philippines.
Mumps. This disease causes fever, fatigue, head and muscle aches, and swelling of your salivary glands. In men, it can cause the testicles to become inflamed. Mumps can lead to a loss of hearing, infection of the covering around your brain and spinal cord, and other serious problems. Mumps outbreaks do still happen in the U.S., but rarely.
Rubella (German measles). This disease can cause a fever and rash. It's especially dangerous if you're pregnant. Rubella can lead to serious birth defects, including heart problems, deafness, liver and spleen damage, and mental disability. If you have rubella while pregnant, there's at least a 20% chance your baby will have health problems.
The CDC says most adults born in 1957 or later should get at least one dose of the MMR vaccine. All women of childbearing age should get the MMR vaccine unless they're pregnant, have proof of immunity, or proof of already being vaccinated.
The CDC says adults at greater risk of measles or mumps should get two doses of MMR vaccine, the second one four weeks after the first. This includes adults who:
Have been exposed to measles or mumps or live in an area where an outbreak has happened Are students in colleges or trade schools Travel internationally Work in health care For measles, the CDC advises a second dose for adults who:
Were previously given a vaccine made with "killed" measles instead of the live, attenuated (weakened) vaccine used today Were given an MMR vaccine between 1963 and 1967 but there's no record of what type. If you were born before 1957 but can't show proof that you're immune to or had measles, mumps, and rubella, it's best to get the MMR vaccine. If you're a health care professional born before 1957 and you don't have proof or immunity or disease, you should get two doses of the MMR vaccine, given at least 28 days apart.
Adults don't need the MMR vaccine if:
They have proof of vaccination already. They have proof that they've already had measles or mumps and rubella. Adults who shouldn't get the MMR vaccine include people in these groups:
Pregnancy. If you're pregnant, you shouldn't get the MMR vaccine because of risks to your baby. People who get the MMR vaccine should wait four weeks before getting pregnant.
Life-threatening allergic reactions. Adults who have had a life-threatening allergic reaction to gelatin, a previous MMR vaccine, or a medication called neomycin shouldn't get the vaccine.
Medical conditions. Adults should talk with their doctor if they:
Have HIV Have any other immune system disorder Have cancer or are being given cancer drugs or X-rays Are taking steroids or other drugs that affect the immune system Have had a low platelet count (a blood disorder) Have had a blood transfusion or took blood products Have a moderate or severe illness As with many vaccines, the MMR vaccine works with your immune system to build up protection by putting a small amount of the weakened virus into your body. The safest and most effective ingredients in the MMR vaccine used today include "attenuated" forms of each virus. This means they're live forms of the virus that have been made weak in medical labs.
For most adults, the benefits of the MMR vaccine outweigh the risks. A few people develop a short-term mild rash, fever, swollen glands, or pain and stiffness in their joints after getting the shot. More serious and rare side effects include a temporarily low platelet count or serious allergic reaction.
Call your doctor if you have trouble breathing, dizziness, rapid heartbeat, hives, weakness, or other problems after vaccination.
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