Before the first successful vaccine was developed in 1796, Americans had little protection against deadly infectious diseases like smallpox, measles and diphtheria.

Over the next 250 years, vaccines helped eliminate or dramatically reduce many vaccine-preventable infectious diseases, preventing millions of illnesses, infections and deaths.

“There is a reason that vaccines are widely considered to be the greatest public health tool after sanitation,” Fox News senior medical analyst Dr. Marc Siegel told Fox News Digital.

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“They are designed to ‘fool’ the immune system into thinking it has seen a disease, creating an ‘immune memory’ to provoke an immune response to the pathogen when it actually does appear.”

“True vaccines have side effects, and there is the risk of vaccine injury — but overall, the benefit to the individual and society vastly outweighs any harm,” Siegel added.

As the U.S. marks its 250th anniversary, the following vaccines stand out among the most significant medical achievements in the country’s history.

No. 1: Smallpox

Smallpox, a highly contagious viral disease caused by the variola virus, was one of the world’s deadliest diseases before vaccination, killing about 30% of those infected, according to CDC data.

The infectious disease had no cure and spread through close person-to-person contact, causing fever, fatigue and a distinctive rash that led to pus-filled blisters. Survivors were often left with permanent scarring or blindness.

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The first successful vaccine, developed by English physician Edward Jenner in 1796, eventually transformed public health in the United States.

Jenner’s smallpox vaccine ultimately led to the global eradication of smallpox, according to the World Health Organization. The vaccine is no longer given routinely to the public and is mainly used for select military, laboratory and emergency-response needs.

“There is a reason that vaccines are widely considered to be the greatest public health tool after sanitation.”

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“The first vaccine against smallpox eradicated a disease that killed 5-10% of all humans who had ever lived for almost all of human history,” Dr. Jacob Glanville, CEO of Centivax, a San Francisco biotechnology company, told Fox News Digital. “Then the drumbeat began of relentless progress right at the eve of the 20th century.”

No. 2: Rabies

A viral disease that attacks the brain and nervous system, rabies spreads through the saliva of infected mammals, most commonly through the bites of dogs, bats, raccoons, skunks and foxes.

Once symptoms begin, rabies is almost always fatal, according to the National Institutes of Health (NIH).

Although there is no cure, vaccination immediately after exposure can prevent the disease. It can also be given before exposure for people at high risk.

Researcher Louis Pasteur created the first rabies vaccine in 1885, according to The Children’s Hospital of Philadelphia (CHOP). Today, prompt vaccination after exposure remains the standard way to prevent an otherwise almost universally fatal disease.

No. 3: Diphtheria

Diphtheria is a bacterial infection that can cause a thick coating in the throat. It was fatal for some, and survivors could face serious complications, including heart damage, paralysis and breathing problems, according to the CDC.

Before the vaccine’s introduction in the 1920s, diphtheria was one of the leading causes of illness and death among youth in the U.S. During that decade, there were 100,000 to 200,000 cases and 13,000 to 15,000 deaths recorded each year, mostly affecting children.

The diphtheria toxoid vaccine was introduced in the 1920s. Diphtheria is now extremely rare in the U.S. due to widespread vaccinations, per the CDC.

The vaccine remains part of the routine childhood immunization schedule as part of the DTaP series, with boosters recommended for teens, adults and pregnant women.

No. 4: Tetanus

Tetanus is a bacterial disease caused by Clostridium tetani, which enters the body through cuts or wounds, according to the CDC. The infection can cause severe muscle spasms, “lockjaw” and death.

Before vaccination, tetanus was often fatal because severe muscle spasms could make it impossible to swallow or breathe. Although the disease is not spread from person to person, hundreds of Americans died from tetanus each year, records show.

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The tetanus toxoid vaccine was developed in the 1920s, according to CHOP. Tetanus vaccination remains part of the routine childhood immunization schedule, with boosters recommended every 10 years and as needed following certain wounds.

No. 5: Pertussis (whooping cough)

Whooping cough (pertussis) is a highly contagious bacterial infection that causes severe coughing fits, often making it difficult to breathe, eat or sleep. Infants are at highest risk, as they can develop pneumonia, seizures, brain damage or even death.

Before widespread vaccination, the U.S. recorded more than 200,000 pertussis cases and thousands of youth hospitalizations each year, the CDC states.

The first pertussis vaccine was introduced in the 1910s, followed by the combination DTP (diphtheria, tetanus and pertussis) vaccine in the 1940s.

After widespread vaccination, cases fell by more than 90% and deaths from the disease became uncommon. The pertussis vaccine remains part of the routine U.S. immunization schedule for children, teens and adults, and doctors recommend vaccination during pregnancy to pass protective antibodies to newborns.

No. 6: Influenza

This contagious viral respiratory illness can cause serious complications, hospitalization and death, CDC data shows.

Before the vaccine was available, seasonal flu epidemics caused widespread illness and death every year. During the 1918 influenza pandemic (“Spanish flu”), an estimated one-third of the world’s population was infected and at least 50 million people died worldwide, including about 675,000 Americans.

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The first U.S. flu vaccine was licensed in 1945, helping launch routine seasonal influenza vaccination programs.

Widespread vaccination has significantly reduced the risk of flu illness, hospitalization and death. The CDC recommends that everyone 6 months and older receives a seasonal flu vaccine each year, with rare exceptions. The vaccine is updated annually to target changing strains.

No. 7: Polio

Polio (poliomyelitis), a highly contagious viral disease caused by poliovirus, spreads mainly through contact with contaminated food, water or stool, per the CDC.

For some, the virus can attack the nervous system, causing permanent paralysis, breathing difficulties and death. During the early 1950s, more than 15,000 cases of paralytic polio were reported each year in the U.S.

In 1955, Jonas Salk’s polio vaccine was introduced in the country, greatly reducing case counts. In 1979, the U.S. was declared free of wild poliovirus, according to the World Health Organization.

Injected polio vaccination is still part of the routine childhood U.S. immunization schedule.

No. 8: MMR (measles, mumps, rubella)

Before vaccines, measles, mumps and rubella were common childhood diseases that infected millions of Americans and could cause serious complications.

Prior to the measles vaccine, nearly all American children contracted the highly contagious viral disease by age 15, according to the NIH. About 400 to 500 Americans died of measles each year, while about 1,000 experienced brain swelling and 48,000 were hospitalized, records show.

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Before the first mumps vaccine, about 186,000 cases were reported in the U.S. each year, and the disease was a common cause of children’s meningitis, per the NIH.

Rubella epidemics also regularly occurred in the U.S. before vaccination. Between 1964 and 1965, about 12.5 million Americans were infected, resulting in approximately 2,100 newborn deaths and 20,000 babies born with congenital rubella syndrome, causing blindness, deafness, heart defects and developmental disabilities.

The measles vaccine was introduced in 1963, followed by mumps in 1967 and rubella in 1969. In 1971, the MMR (measles, mumps and rubella) vaccine became available, protecting against all three contagious viral diseases in a single shot. Prior to the combined vaccine, children typically had to receive three separate shots, the CDC noted.

Widespread vaccination has reduced cases of all three diseases by more than 99% in the United States, per NIH data.

Measles was declared eliminated in the U.S. in 2000, meaning it was no longer spreading continuously within the country. Routine vaccination also led to endemic rubella being declared eliminated in the U.S. in 2004.

No. 9: Hepatitis B

Hepatitis B, a viral infection that attacks the liver, is spread through contact with infected blood and other body fluids, according to the CDC.

Some people develop chronic hepatitis B, which can lead to cirrhosis, liver failure and liver cancer.

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Before vaccination, hepatitis B was a major public health threat in the U.S. In the early 1980s, an estimated 200,000 to 300,000 Americans contracted the infection each year, the NIH states. Infants infected at birth were at particularly high risk, with about 90% developing chronic infection.

The hepatitis B vaccine was licensed in 1981, and the CDC began recommending universal infant vaccination in 1991. Since then, acute hepatitis B cases have declined by more than 80% in the U.S., and infections among children and adolescents have fallen by more than 95%, per the NIH.

No. 10: Hib

Haemophilus influenzae type b (Hib) is a bacterial infection that can cause pneumonia, meningitis, bloodstream infections and severe throat swelling, per the CDC.

Severe cases can lead to hearing loss or brain damage.

Hib was once the leading cause of bacterial meningitis in young children in the U.S., with around 20,000 serious infections and 1,000 deaths reported each year in those 5 and younger.

The first Hib vaccine was licensed in 1985, with routine immunizations reducing invasive disease by more than 99%, according to CDC data. The infection is now rare in the U.S.

No. 11: Chickenpox/varicella

Chickenpox (varicella) is a highly contagious viral disease caused by the varicella-zoster virus that causes an itchy, blister-like rash, fever and fatigue, according to the CDC.

In some people, it can lead to serious complications, including pneumonia, brain inflammation and bacterial skin infections.

“There is a reason that vaccines are widely considered to be the greatest public health tool after sanitation.”

Before the first chickenpox vaccine became available in the U.S. in 1995, about four million Americans were infected each year, with around 100 to 150 deaths and up to 13,000 hospitalizations, according to the CDC and NIH.

Since routine two-dose childhood vaccination began, hospitalizations and deaths have declined by more than 90%, and severe complications have become rare, CDC data shows.

No. 12: Hepatitis A

A highly contagious viral liver infection, hepatitis A spreads mainly through contaminated food or water or close contact with an infected person, per the CDC.

While it does not cause chronic liver disease like hepatitis B, it can cause weeks or months of illness and, in rare cases, liver failure.

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Before vaccination, outbreaks led to as many as 30,000 infections each year.

The first hepatitis A vaccine was licensed in the U.S. in 1995. Since routine childhood vaccination began, infection rates have dropped by more than 95%, according to the NIH.

No. 13: Pneumococcal

Pneumococcal disease, caused by the bacterium Streptococcus pneumoniae, can lead to pneumonia, meningitis, bloodstream infections, ear infections and sinus infections, the CDC states.

Before vaccination, pneumococcal disease caused thousands of cases of meningitis and bloodstream infections and hundreds of deaths among young children, per the NIH. Older adults also faced a high risk of hospitalization from bacterial pneumonia.

The first pneumococcal conjugate vaccine was licensed in 2000. Routine childhood vaccination has dramatically reduced disease rates, and newer vaccines have been developed to protect against emerging bacterial strains.

No. 14: HPV

The most common sexually transmitted infection in the U.S., the human papillomavirus (HPV) can cause cervical, anal, penile, vaginal, vulvar and oropharyngeal cancers, according to the CDC.

The HPV vaccine was licensed in 2006, becoming the first immunization designed to prevent multiple types of cancer.

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Since the vaccine became available, HPV infections, precancers and genital warts have declined significantly, CDC data shows.

HPV vaccination is now part of the routine U.S. immunization schedule, with two doses recommended for those younger than 15 and three doses for those 15 and older.

No. 15: Rotavirus

Rotavirus is a highly contagious virus that primarily affects infants and young children, causing severe diarrhea, vomiting and fever.

Before the vaccine became available in 2006, nearly every child contracted the virus by age 5, often leading to severe dehydrating diarrhea, the CDC states. Up to 70,000 children were hospitalized and 20 to 60 died each year in the U.S.

Since routine rotavirus vaccination began, hospitalizations, emergency room visits and severe illness have declined significantly. Infants receive two or three oral doses as part of the routine immunization schedule.

No. 16: Shingles

Shingles is a painful rash caused by reactivation of the varicella-zoster virus, the same one that causes chickenpox, per the CDC. It can cause severe nerve pain lasting months or even years.

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Before the vaccine was available, about one million Americans developed shingles each year, with adults over age 50 at highest risk.

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The first shingles vaccine was licensed in 2006, and the more effective Shingrix vaccine was introduced in 2017, greatly reducing the risk of shingles and long-term nerve pain, according to the CDC and FDA.

Experts recommend two doses for adults 50 and older and for certain immunocompromised adults ages 19 and older.

No. 17: COVID-19

When the COVID-19 pandemic spread worldwide in 2020, there was no vaccine to prevent severe illness from the infection, which is caused by the SARS-CoV-2 virus.

In the U.S., the contagious virus caused millions of hospitalizations and more than 1.2 million deaths, according to data from the CDC and NIH.

The first COVID-19 vaccines received emergency authorization in December 2020. Multiple studies have shown that the vaccines significantly reduce the risk of severe illness, hospitalization and death, particularly among high-risk groups.

“COVID vaccines saved millions of lives around the world during the COVID pandemic.”

“COVID vaccines saved millions of lives around the world during the COVID pandemic,” Siegel said.

Although the CDC continues to recommend COVID-19 vaccination, specific guidance varies by age, risk level and previous vaccination history.

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Glanville, whose company is currently working to develop a universal flu vaccine, among others, summed up the impact of these and other vaccines in America.

“To truly understand the impact that vaccines have had in the last 100 years, read through the list of pathogens along the timeline until they become familiar to you, until they include things you or your family may have been infected by in your own life,” he advised. “You may barely even recognize most of the pathogens in the first half of the list – because vaccines pushed them out of the human experience. That is the power of vaccines.”

People should contact a doctor to discuss individual recommendations for vaccines, which can vary by age, health status, medical history and risk factors.