Vaccines have been hailed as the greatest achievement in the history of medicine. The 20th century introduced several immensely successful vaccines to combat diseases such as hepatitis A and B, diphtheria, rabies, and measles. Other major accomplishments were the development of the polio vaccine in the 1950s and the eradication of smallpox in the late 1970s. Over the last century, vaccines saved hundreds of millions of lives throughout the world.
How Do Vaccines Work?
What is a vaccine? A vaccine is a biological preparation that improves immunity to a particular disease. It contains an agent resembling a disease-inducing microorganism– a bacterium, virus or toxin – that activates the body’s immune system. White blood cells – APCs, B cells, and T-cells – recognize, destroy and “remember” this version of the pathogen. That way, the immune system can quickly recognize and destroy this harmful microorganism later on. A vaccine is essentially a pathogen-imposter.
Today, there are five main types of vaccines. Live, attenuated vaccines fight viruses and contain a weakened version of the living virus (e.g., measles-mumps-rubella and varicella vaccine). Inactivated vaccines also fight viruses and contain the killed virus (e.g., polio vaccines). Toxoid vaccines prevent diseases caused by bacteria that produce toxins in the body and contain weakened toxins (e.g., diphtheria and tetanus vaccine). Subunit vaccines include only the essential antigens of the virus or bacteria (e.g. whooping cough vaccine). Conjugate vaccines fight a different type of bacteria which
have antigens with an outer coating of sugar-like substances (polysaccharides) that “hide”the antigen from the child’s immature immune system; the vaccine connects (conjugates) the polysaccharides to antigens, so the immune system can react.
Once the altered pathogen is introduced into the bloodstream, it is captured by antigen-presenting cell (APC), which float around looking for invaders. When an APC detects the vaccine antigen, it ingests it, breaks it apart, and displays a piece of the antigen on its surface. Then, it travels to areas where immune cells cluster (e.g. lymph nodes) and where so-called naïve T cells specific to the antigen recognize it as foreign and become activated. These T helper cells alert other nearby cells. Naïve B cells recognize the antigens carried by the APCs as well and also become activated.
A vaccine is essentially a pathogen-imposter
Some naïve B cells mature into plasma B cells after activation by vaccine antigens and reception of signals from activated helper T cells. They produce antibodies which are “y” shaped proteins that are released at high levels every second. Each antibody tightly attaches to a specific target antigen (like a lock and a key), which can prevent the antigen from entering a cell or mark the antigen for destruction. If the vaccine contains weakened viruses, they enter the cells which are then killed by Killer T cells. What follows is the development of memory (B, T helper and killer T) cells that memorize the vaccine antigen and recognize the real pathogen in the future.
This means that the body’s response will be stronger and faster than if it had never encountered the pathogen before. This is called a secondary response to the pathogen. Furthermore, secondary responses will result in the production of more antibodies to fight the pathogen and more memory cells to identify it promptly. Thus, vaccinations “program” the immune system to remember a specific disease-inducing microorganism by letting it “practice” with a weakened, killed or inactivated version of the pathogen
Vaccines can prevent outbreaks of contagious diseases through herd immunity (or community immunity). This means that a sufficient portion of the population must be immune to an infectious disease (by vaccination and/or prior illness), so that the disease is less likely to spread from one person to another. As the number of vaccinated people increases, the protective effect of herd immunity increases as well. While the herd immunity threshold may start with 40% of the population vaccinated for some diseases, most diseases require vaccination rates as high as 80% – 95% to prevent outbreaks. Moreover, herd immunity protects those who cannot be vaccinated or for whom the vaccination was not successful, such as people with weak immune systems, chronic illnesses or allergies.
Vaccinations are essentially prophylactic, although there has been an effort in recent years to develop therapeutic vaccinations for infectious diseases like AIDS, tuberculosis, cancer, and various autoimmune diseases. There are also potential vaccinations in development for myasthenia gravis, lupus and diabetes, as well as for cognitive diseases such as Alzheimer’s disease, prion diseases and Huntington’s disease.
Usually, vaccinations are administered in the form of an injection into the skin or a liquid taken orally. However, some vaccinations may also be processed by inhalation through mouth/nose or application onto the skin. The vaccines risks are very low. Most vaccine reactions are usually minor and temporary (i.e. sore arm, fatigue or an elevated temperature). Very serious side effects like severe allergic reactions are extremely rare and are carefully monitored and investigated. The vaccine benefits definitely outweigh the vaccine dangers. In fact, it is far more likely to be seriously harmed by a vaccine-preventable disease than by the vaccine itself.
In recent years, the anti-vaccination movement has been claiming that there is a link between vaccinations and autism. The reason for these claims is a 1998 study, which suggested that the measles-mumps-rubella (MMR) vaccine might cause autism. Its publication started a panic among parents that led to dropping vaccination rates, resulting in subsequent outbreaks of vaccine-preventable diseases. However, this study turned out to be seriously flawed, and the paper was even retracted by the journal that published it. There is absolutely no evidence of a link between vaccines and autism or autistic disorders.
History of Vaccines
While Edward Jenner is commonly considered the inventor of the first vaccine – he used material from cowpox pustules as an immunization for smallpox – the vaccine history actually goes back much farther. In fact, the history of vaccinations begins with the discovery of infectious diseases. The earliest records of such infections date back to 400 BC, when Hippocrates described the symptoms of mumps, diphtheria, epidemic jaundice, malaria, and tetanus, among others. Persian physician Rhazes was the first to publish an account attempting to describe the differences between measles and smallpox in 400 BC.
Furthermore, evidence suggests that the Chinese used smallpox inoculation (i.e. variolation, the purposeful infection of a person with smallpox to minimize severity of disease and immunize against future infections) as early as 1000 BC. The son of a Chinese statesman is said to have inhaled pulverized smallpox scabs through his nose. Another method was to scratch material from a smallpox scab into the skin. Variations of variolation have been noted in Turkey, Africa, China, and in parts of Europe and the Americas.
Colonial Times – Smallpox and yellow fever ravage Europe and the New World
In 1545, a smallpox epidemic hit India, presumably introduced by Portuguese colonizers, and killed 8,000 children in Goa. Paris was affected by a pertussis (whooping cough) epidemic in 1578. In the 16th and 17th century, smallpox was imported to North America by European colonizers. Smallpox had devastating effects on the native population across the colonial America. It killed many French Jesuits and Native Americans in Canada in 1625, as well as a large number of English settlers and Native Americans in Massachusetts in 1633.
Yellow fever spread epidemically in Cuba, Barbados, and the Yucatan, so Boston established a strict quarantine for ships from the West Indies in 1648. Nine years later, measles appeared in the city for the first time. In 1659, symptoms most likely pertaining to diphtheria were described as “bladders in the windpipe.” Around the same time, Chinese Emperor K’ang encouraged inoculation against smallpox among his subjects after he had survived the disease (his father Emperor Fu-lin had died of smallpox).
In 1667, English physician Thomas Sydenham published an article documenting details about measles and differentiating it from smallpox and scarlet fever. In 1678, a medical pamphlet on smallpox was published in response to the epidemic in New England. In 1684, Sydenham observed that the rich seemed to have a higher mortality rate from smallpox than the poor. He concluded that the medical treatments of the time, such as bloodletting from the tongue, might be rather harmful since they were only accessible for the rich. Queen Mary of England the II died of a severe case of smallpox in 1694.
In 1699, yellow fever broke out in the North American colonies, killing vast numbers of people. Boston minister Cotton Maher discovered in 1706 that an African Slave named Onesimus had a scar from a smallpox variolation and found that many slaves had been variolated and thought to be immune against the disease. Thus, Maher read up about variolation in English journals and promoted the practice in Massachusetts. In 1718, Lady Mary Montagu, wife of the British Ambassador to Turkey (who was disfigured by smallpox) had her son variolated in Turkey, where it was common, and endorsed the procedure back in England. In 1721, variolation was officially introduced in the American colonies as smallpox raged across the continent.
The practice was controversial as 2 – 3% of variolated people died of smallpox (in comparison to 15 – 40% who would die naturally of the disease). The 1730s saw devastating epidemics of smallpox, yellow fever and diphtheria. In 1740, German physician Friedrich Hoffmann identified “German measles,” rubella. Scottish physician Francis Home discovered that the measles virus is present in blood. Meanwhile, inoculation against smallpox became increasingly popular, though English farmer Benjamin Jesty already used cowpox to inoculate his wife and sons in 1774. Smallpox was also used as a weapon of war in 1776, which lead to mandatory inoculation of the Continental Army a year later.
The Industrial Age – Vaccine research leaps forward
Philadelphia saw a ruinous outbreak of yellow fever after a 31-year absence in 1793. New York physician noted that the disease was especially rampant among those who lived close to ships. In 1796, Edward Jenner discovered how to use the material of cowpox pustules as immunization against smallpox and published his work the next year. Harvard professor Benjamin Waterhouse introduced vaccinations in the United States in 1800, using the smallpox vaccine on his children. The vaccination was endorsed by the Empress of Russia, as well as the State of Massachusetts in the following years. Jenner credited his friend, physician Richard denning, with the origin of the term “vaccination” form the Latin word for cow, vacca.
In 1803, King Charles IV of Spain sent 22 vaccinated (abandoned) children with royal physician Francisco Xavier de Balmis to the Spanish colonies to initiate vaccination in the Americas. U.S. Congress and President James Madison established the National Vaccine Agency in in 1813. While smallpox infections dropped significantly in the next decades, deadly cholera pandemics sweep countries all over the world. In 1826, diphtheria (after the Greek word for leather, describing the coating of the throat) is given its name after being called many different terms beforehand. The 1830s saw the first cases of rabies in humans in France after being bitten by animals.
In the late 1830s and early 1840s, new methods to increase potency and supply of the smallpox vaccine, like retro- and serial vaccination of cows, were developed. Britain banned variolation in 1840. In 1841, the term “rubella” was first used to describe the outbreak of this disease in India. In 1854, Italian physician Filippo Pacini identified the Cholera bacterium and linked to the disease itself. During the cholera epidemic in London in the 1850s, physician John Snow made the connection between the disease and contaminated water. In 1855, Massachusetts became the first state introduce a law requiring school children to be vaccinated.
However, smallpox and measles broke out among the troops during the Civil War in the 1860s. Meanwhile in France, chemist and microbiologist Louis Pasteur began his research regarding infectious diseases with silkworms. Concerns about the transmission of diseases like syphilis or leprosy via arm-to-arm vaccinations led to the development of the animal vaccine in France, where a calf would be inoculated with cowpox. This practice was adopted by the United States and other countries the 1860s and 1870s. Germany introduced a compulsory smallpox vaccination law in 1874.
Measles was still killing many children in the American Southwest in the second half of the 19th century. Yellow fever crippled the Mississippi Valley in 1878, rendering it one of the most devastating medical disasters in the history of the United States. In 1877, Pasteur identified the anthrax bacilli, which led to the anthrax vaccine for livestock a few years later. In the 1880, Pasteur started to investigate rabies. A year later, Pasteur and U.S. Army physician George Miller Sternberg both (separately) discovered the Streptococcus pneumoniae bacterium which is responsible for pneumonia and meningitis, as well as other diseases.
Cuban physician Carlos Finlay identified the mosquito as the transmitter of yellow fever in 1881, though this wasn’t widely acknowledged until two decades later. The early 1880s was also when the first anti-vaccine arguments spread in the United States. In 1882, German physician and microbiologist Robert Koch discovered the bacillus that causes tuberculosis and subsequently began to work on a vaccine against the disease. Koch also travelled to Egypt and India to investigate cholera. He isolated the cholera bacillus in 1884. Around the same time, Edwin Klebs, a Swiss-German pathologist, identified and described the bacterium that causes diphtheria, while German bacteriologist Friedrich Loeffler identified the agent that caused diphtheria.
Spanish physician Jamie Ferrán developed a vaccine against cholera in 1885. The same year, the animal vaccine against rabies was successfully used in humans. English physician S. Monkton Copeman demonstrated that glycerin acted as a germicide when added to vaccines in 1891. The United States saw its first polio outbreak in 1894, while its contagious nature was established in 1905. The disease would kill and paralyze thousands and thousands of Americans in the next decades. In 1895, the Mulford Company of Philadelphia began producing diphtheria antitoxin in the United States. Anti-vaccination movements became louder in parts of Europe in the United States; Britain began to allow exemptions for “conscientious objectors.”
The 20th Century – Vaccinations become safer and many diseases vanish
French researcher Albert Calmette and veterinarian Jean-Marie Camille Guérin accomplished to attenuate the bacterium causing tuberculosis. After extensive mosquito control, North America saw its last yellow fever in 1905 in New Orleans. In 1906, the bacteria responsible for whooping cough were isolated. In 1909, the air-dried vaccine for smallpox was developed in Paris. After years of experimentation, an effective mixture between diphtheria toxin and antitoxin was developed by William H. Park and started to be used as immunization in 1914. The antibodies of measles were finally identified in 1916 by French researchers Charles Nicolle and Ernest Conseil.
In 1918, the Vaccine Institute in Pairs developed freeze-dried vacuum smallpox vaccines that were to be used in the tropical French colonies. Smallpox vaccinations became mandatory for schoolchildren across the United States in the early 1920s. Veterinarian Gaston Ramon and physician Alexander Thomas Glenny independently developed diphtheria toxoid in 1923. In 1929, the Iron Lung, an artificial respirator for patients with paralytic polio, was first successfully used in Boston. Two years later, American researcher Margaret Pittman classified different types of Haemophilus influenzae bacteria and found that the type b strain caused nearly all cases of Haemophilus influenzae meningitis.
In 1936, Max Theiler and his colleagues developed a live attenuated vaccine for yellow fever using tissue cultures prepared from embryonated chicken eggs. American bacteriologist Pearl Kendrick and her colleague Grace Elderding published an article about the effectiveness of the pertussis (whooping cough) vaccine in 1939. Australian ophthalmologist Norman McAlister Gregg linked rubella during pregnancy to congenital cataracts. His observation was the first of what eventually became a collection of reports linking rubella during pregnancy to various congenital defects.
After a hepatitis outbreak in the early 1940s among U.S. Army troops, human plasma was completely removed from the yellow fever vaccine. World War II also lead to massive diphtheria outbreaks in Europe: in 1943, there were 1 million cases and 50,000 deaths. In 1944, Maurice Hilleman helped develop a Japanese encephalitis vaccine to protect American troops in the Pacific. The first influenza vaccine was approved for military use in the United States in 1945 and civilian use in 1946. Around the same time, the pneumococcal vaccine was developed, but largely ignored due to the widespread use of penicillin against pneumococcal infections. After a merchant travelling from Mexico fell ill with smallpox in New York and thus brought the disease back, the city launched a massive vaccination effort in 1947.
The first combined DTP (diphtheria, tetanus, and pertussis) vaccines became available in the United States in 1948. The next year, David Bodian and Isabel Morgan, researchers at Johns Hopkins University School of Medicine, published a paper identifying three types of poliovirus, which would become crucial for developing a vaccine, as a vaccine would have to produce immunity to all poliovirus types. The same year, John Enders, Thomas Weller and Frederick Robbins showed that they could grow polioviruses in human embryonic skin and muscle tissue, making the production of the vaccine less difficult and expensive.
The early 1950s saw a surge in polio infections, stimulating research to develop a vaccine against the disease. Researcher Jonas Salk and his team accomplished to cultivate the poliovirus in monkey kidney tissue, which would later allow to produce the virus in large quantities for a vaccine. In 1953, physician Thomas Weller was the first to isolate the varicella virus which is responsible for chickenpox. Physician Thomas Peebles isolates the virus responsible for measles in 1954. The same year, the Vaccine Advisory Committee approved a field test of Salk’s polio vaccine; million children participated in the trial. The vaccine turned out to be was 80-90% effective against paralytic polio and the U.S. government licensed Salk’s vaccine immediately. The polio vaccine production was suspended for a month after the “Cutter Incident” (faulty manufacturing methods in several vaccine-producing facilities led to deaths and paralysis).
In 1957, Maurice Hilleman and his colleagues identified a new influenza virus that caused the Asian influenza pandemic. They jump-started vaccine production. Worldwide, from 1957-1958, about 2 million people died from Asian flu, with about 70,000 deaths in the United States. Some predicted that the U.S. death toll would have reached 1 million without the vaccine that Hilleman called for. In 1959, the Soviet Union began trials with an oral polio vaccine developed by Albert Sabin. A year later, Merck researchers, under Maurice Hilleman’s direction, detected a simian virus in the monkey kidney cells used to grow poliovirus for Merck’s polio vaccine. As the virus caused tumors in hamsters, the Salk-type polio vaccine production was halted (though no link between the virus and human cancer could be found). Today, all polio vaccines are screened for viruses.
In 1960, Sabin’s oral polio vaccine was licensed in the United States. In 1962, Maurice Hilleman and colleagues developed an attenuated measles vaccine, which was licensed the following year. The early 1960s saw a large number of rubella infections in the United States, while the country also started massive anti-mosquito measures. Hillman and his colleagues also began testing a mumps vaccine on the mid-1960s. In 1965, the bifurcated needle was developed to administer smallpox vaccinations more effectively. In 1968, Hillman’s team developed a new attenuated measles vaccine. His rubella vaccine was licensed in 1969.
In 1971, the measles, mumps and rubella vaccine became licensed. The same year, a new inactivated rabies vaccine was developed. In addition, the U.S. government licensed Merck’s measles, mumps, and rubella combination vaccine (MMR vaccine). In 1974, many childhood diseases had almost disappeared from developed countries. These diseases, however, continued to take many lives in poorer countries, so the WHO kept promoting diphtheria, polio, tuberculosis, pertussis, measles, and tetanus vaccinations. The swine flu vaccine was developed in 1976, after a swine flu outbreak in New Jersey. The next year, a multi-serotype pneumococcal vaccine was licensed after an Austrian report had shown that pneumonia had caused hundreds of fatalities within a 10-year span despite antibiotic treatment.
The World Health Assembly accepted the WHO Global Commission’s recommendation and declared the world free from smallpox in 1980. The following year, the FDA licensed Hilleman’s human-blood-derived hepatitis B vaccine, Heptavax-B. It was the first subunit viral vaccine developed in the United States. While the vaccine proved effective at preventing hepatitis B, concerns about HIV infections gave way to a product in 1986 that did not use human serum. 1981 was also the year the attenuated chickenpox vaccine was licensed in the United States. The first vaccine against Haemophilus influenzae type b (Hib) disease was licensed in the United States in 1985. Two year later, a conjugated Hib vaccine was licensed. First developed in 1975, the Ty21a oral typhoid vaccine was licensed for use in the United States 1989. Low vaccination rates in the late 1980s caused severe measles outbreaks across the country, especially in Philadelphia where 1,500 children died.
In 1994, the Pan American Health Organization reported that three years had passed since the last case of wild polio in the Americas. The FDA licensed Maurice Hilleman’s hepatitis A vaccine in 1995. 2000 marked the year endemic measles was eliminated from the United States (though U.S. residents remained at risk for infection from imported cases). Sanofi’s quadrivalent meningococcal polysaccharide-protein conjugate vaccine was licensed in the United States in January 2005. In 2006, the Advisory Committee on Immunization Practices (ACIP) recommended infant immunization for hepatitis A and rotavirus of all children. Decreased vaccination rates caused increased outbreaks of measles and pertussis (whooping cough) in the United States in the late 2000s. Cholera emerged in Haiti in the aftermath of January 12, 2010, earthquake there.
Different Types of Vaccines
As mentioned earlier, there are five main types of vaccines: attenuated (live) vaccines, inactivated vaccines, toxoid vaccines, subunit vaccines, and conjugate vaccines. The first vaccines for humans against viruses used weakened or attenuated viruses to generate immunity without causing serious illness (e.g. the early smallpox vaccine that was derived from cowpox). The rabies vaccine was the first human vaccine where the virus was attenuated in a laboratory. Let’s take a closer look at the list of vaccines according to vaccine type:
Live, attenuated vaccine list:
- Vaccinia (smallpox)
- Measles, mumps, rubella (MMR combined vaccine)
- Varicella (chickenpox)
- Influenza (nasal spray)
- Zoster (shingles)
- Yellow fever
Inactivated/killed vaccine list:
- Polio (IPV)
- Hepatitis A
Toxoid (inactivated toxin) vaccine list:
- Diphtheria, tetanus (part of DTaP combined immunization)
Subunit/conjugate vaccine list:
- Hepatitis B
- Influenza (injection)
- Haemophilus influenzae type b (Hib)
- Pertussis (part of DTaP combined immunization)
- Human papillomavirus (HPV)