Vaccine

A vaccine is a biological preparation that gives active acquired immunity against a particular infectious or malignant disease. Scientists have studied and checked the safety and effectiveness of vaccines widely. A vaccine usually contains something that looks like a disease-causing microorganism. It is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. This helps the immune system learn to recognize the threat, destroy it, and fight off any matching microorganisms it meets later.

Vaccines can be prophylactic, which means they prevent or lessen the effects of a future infection by a natural or "wild" pathogen. They can also be therapeutic, which means they fight a disease that has already happened, such as cancer. Some vaccines provide full sterilizing immunity, which stops an infection from happening at all.

Giving vaccines is called vaccination, and it is the most effective way to prevent infectious diseases. Widespread immunity from vaccination is largely responsible for the worldwide eradication of smallpox. It has also kept diseases such as polio, measles, and tetanus out of much of the world. The World Health Organization (WHO) reports that licensed vaccines are available for twenty-five different preventable infections.

The history of vaccines goes back a long way. The first recorded use of inoculation to prevent smallpox (see variolation) happened in the 16th century in China, and the earliest hints of this practice appeared there in the 10th century. Smallpox was also the first disease for which a vaccine was produced. In 1721, Lady Mary Wortley Montagu brought the folk practice of inoculation against smallpox from Turkey to Britain. The words vaccine and vaccination come from Variolae vaccinae (smallpox of the cow), a term created by Edward Jenner. Jenner developed the idea of vaccines and made the first one, using cowpox. In 1881, Louis Pasteur suggested extending these words to cover new protective inoculations, to honor Jenner. The science of making and producing vaccines is called vaccinology.

Effectiveness

There is overwhelming scientific consensus that vaccines are a very safe and effective way to fight and wipe out infectious diseases. The immune system sees vaccine agents as foreign, destroys them, and "remembers" them. When the virulent version of an agent appears, the body recognizes its protein coat and is ready to respond, first by stopping the agent before it can enter cells, and then by destroying infected cells before the agent can multiply. In 1958, there were 763,094 cases of measles in the United States, and 552 people died. After new vaccines were introduced, the number of cases dropped to fewer than 150 per year. Vaccines led to the eradication of smallpox, one of the most contagious and deadly diseases in humans. Diseases such as polio, chickenpox, and typhoid are now much less common than they were a hundred years ago. When most people are vaccinated, an outbreak is much harder to start or spread, an effect called herd immunity. Polio is the target of an eradication campaign, but reaching every child, cultural misunderstandings, and disinformation have caused the goal date to be missed several times. Vaccines also help prevent antibiotic resistance. By greatly reducing pneumonia caused by Streptococcus pneumoniae, vaccine programs have reduced infections that resist penicillin and other first-line antibiotics.

Vaccines do not always work. Protection can fail for reasons related to the vaccine or how it is given. It can also fail when a person's body does not respond well, which happens in an estimated 2–10% of people because of genetics, age, health, and nutrition. One type of primary immunodeficiency, X-linked agammaglobulinemia, stops the body from making antibodies against a pathogen because an enzyme needed for B cell development is missing. The body's innate immunity can respond within about twelve hours, but adaptive immunity can take one to two weeks to fully develop, so a person can still become infected during that time. Vaccines may give partial or temporary protection, but they can still lower the chance of infection across a population, reduce the mortality rate and morbidity, and speed recovery. Older people often respond less than younger people, a pattern known as Immunosenescence, so Adjuvants are often used to boost their response. A vaccine's efficacy depends on the disease, the strain, whether the vaccination schedule was followed, and personal factors such as genetics. If a vaccinated person still gets the disease, called a breakthrough infection, it is usually milder and less likely to spread.

Safety

Main article: Adverse vaccine event

Vaccines given to children, teenagers, or adults are generally safe, and any side effects are usually mild. How common side effects are depends on the vaccine. Common ones include fever, pain where the shot was given, and muscle aches. Some people may be allergic to an ingredient in a vaccine. The MMR vaccine is rarely linked to febrile seizures. Severe side effects are extremely rare. The Varicella vaccine is rarely linked to problems in people with immunodeficient conditions, and rotavirus vaccines are moderately linked to intussusception. At least 19 countries have no-fault compensation programs that help people who have serious side effects from vaccines. The United States' program is called the National Childhood Vaccine Injury Act, and the United Kingdom uses the Vaccine Damage Payment.

Things about a person, such as genetics, health, sensitivities, allergies, immune competence, age, economic impact, and cultural environment, can affect how serious an infection is and how well a vaccine works. Older people (over 60), people who are allergen-hypersensitive, and obese people may not respond as strongly to vaccines, which is called immunogenicity. Because of this, they may need different vaccine types or repeated booster vaccinations to help limit virus transmission.

Types

Vaccines usually contain weakened or killed germs, or pure parts made from them. Some vaccines use live, weakened germs, such as active viruses that have been grown in ways that make them less harmful. Most of these are viruses, but some are bacteria. Examples include yellow fever, measles, mumps, rubella, and typhoid. The tuberculosis vaccine uses a weakened strain of a contagious germ, and a live weakened strain of Yersinia pestis is used against plague. Other vaccines use germs that have been killed or made inactive, such as the polio vaccine, hepatitis A vaccine, rabies vaccine, and most influenza vaccines.

Some vaccines use toxoids, which are made from harmful substances the germs produce rather than from the germs themselves. Examples include tetanus and diphtheria. Subunit vaccines use only a small piece of a germ, such as the surface proteins of the hepatitis B virus or the human papillomavirus (HPV). Conjugate vaccines link bacteria's outer coats to proteins so the immune system can recognize them. Heterologous vaccines use germs from other animals that cause little or no disease in people, like Jenner's use of cowpox against smallpox. The BCG vaccine from Mycobacterium bovis is used against tuberculosis.

Genetic vaccines work by helping cells make a protein that triggers an immune response. This group includes viral vector vaccines, RNA vaccines, and DNA vaccines. Among the COVID-19 vaccines are several RNA vaccines used during the COVID-19 pandemic. Many newer approaches are also being studied, including dendritic cell vaccines, bacterial vector vaccines, and inverse vaccines that teach the immune system not to respond to certain substances. While most vaccines are made from weakened or killed germs, synthetic vaccines are made mainly from synthetic peptides, carbohydrates, or antigens.

Valence

Vaccines can be monovalent (also called univalent) or multivalent (also called polyvalent). A monovalent vaccine is designed to protect against one antigen or one microorganism. A multivalent vaccine is designed to protect against two or more strains of the same microorganism, or against two or more microorganisms. The number can be shown with a prefix, such as bivalent, trivalent, or tetravalent/quadrivalent. In some cases, a monovalent vaccine may be better for quickly building a strong immune response.

When two or more vaccines are mixed together, they can sometimes interfere with each other. This happens most often with live attenuated vaccines, where one part is stronger than the others and holds back the growth and immune response of the rest. This was seen in the trivalent Sabin polio vaccine, where the amount of serotype 2 virus had to be lowered so it would not stop the serotype 1 and 3 viruses from taking hold. To fix this, the doses of serotypes 1 and 3 were increased in the early 1960s. A 2001 study also found this problem with dengue vaccines, where the DEN-3 serotype dominated and reduced the response to DEN-1, -2 and -4.

Other contents

Main article: Immunologic adjuvant

Vaccines usually contain adjuvants, which help boost the immune response. For example, tetanus toxoid is usually added to alum, which gives a stronger effect than tetanus toxoid alone. Before the 1990 Persian Gulf campaign, a whole cell pertussis vaccine was used as an adjuvant for anthrax vaccine, which produced a faster immune response. Vaccines may also contain preservatives to prevent contamination by bacteria or fungi. Other ingredients can be present too, such as aluminum salts or gels, which help the body respond sooner and more strongly. Antibiotics stop bacteria from growing during production and storage. Egg protein is found in the influenza vaccine and yellow fever vaccine because they are made using chicken eggs. Formaldehyde is used to inactivate bacterial products and to kill unwanted germs. Monosodium glutamate (MSG) and 2-phenoxyethanol help vaccines stay unchanged when exposed to heat, light, acidity, or humidity.

Many vaccines need preservatives to prevent serious problems such as Staphylococcus infection. In one 1928 incident, 12 of 21 children given a diphtheria vaccine that lacked a preservative died. Several preservatives are available, including thiomersal, phenoxyethanol, and formaldehyde. Thiomersal works well against bacteria and helps vaccines stay stable, but because it contains mercury, the US, the European Union, and a few other wealthy countries stopped using it in childhood vaccines as a precaution. Thiomersal was removed from most vaccines, except multi-use influenza vaccines, where a single dose contains less than a microgram of mercury, a level similar to eating ten grams of canned tuna. Although controversial claims say thiomersal contributes to autism, no convincing scientific evidence supports them. A 10–11-year study of 657,461 children found that the MMR vaccine does not cause autism and actually reduced the risk of autism by seven percent.

Nomenclature

Vaccines often have short forms, called abbreviations, that have become fairly standard, though no single group sets them for the whole world. In the United States, vaccine abbreviations are well known and are also used in other countries. The Centers for Disease Control and Prevention has a long, sortable list of them on its website, and anyone can read it for free. The CDC says the abbreviations were standardized by its staff, ACIP work groups, the editors of the Morbidity and Mortality Weekly Report (MMWR) and Epidemiology and Prevention of Vaccine-Preventable Diseases (the Pink Book), ACIP members, and groups that work with the ACIP.

For example, "DTaP" stands for a vaccine against diphtheria, tetanus, and pertussis. "DT" and "Td" are shorter versions for some of these diseases. Capital letters mean full-strength doses, while lowercase "d" and "p" mean smaller doses used for teens and adults. The "a" in DTaP means "acellular," which means the pertussis part contains only a piece of the pertussis germ. The United States Adopted Name system also follows certain rules for the word order of vaccine names, placing head nouns first and adjectives after them. This is why the name for "OPV" is "poliovirus vaccine live oral" instead of "oral poliovirus vaccine."

Licensing

See also: Vaccine trial

A vaccine is licensed, or approved for use, after its development and clinical trials (Phases I–III) show that it is safe, works, and protects people for a long time. Because vaccines are given to healthy people, the safety standards are very high. The World Health Organization (WHO) created international guidelines for making and quality control of vaccines, which countries can use to create their own licensing rules. Review groups such as the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) check the vaccine before a company receives a license. When developing countries follow WHO guidelines, each country issues its own license and monitors the vaccine. Governments and health workers must also build public trust. A new vaccine is often in short supply at first, so plans decide who should get it first.

Vaccines sent worldwide through the United Nations Children's Fund (UNICEF) must be checked by the WHO to meet international standards of quality, safety, and effectiveness. Makers must follow Good Manufacturing Practice (GMP), and countries watch for side effects through postmarketing surveillance. In the European Union, vaccines for diseases such as seasonal influenza may be approved for all member states, for some, or for one country only. The Committee for Medicinal Products for Human Use (CHMP) guides this process. In the United States, the FDA uses the same steps as for the approval process for prescription drugs and requires a Biologics License Application. In India, the Drugs Controller General, who leads the Central Drugs Standard Control Organization, approves vaccines. Because not all adverse events are known early on, makers run Phase IV studies, and the FDA uses the Vaccine Adverse Event Reporting System to track safety concerns.

Scheduling

Main article: Vaccination schedule

For country-specific information on vaccination policies and practices, see Vaccination policy.

Children are recommended to receive vaccines as soon as their immune systems are ready to respond to them. Extra "booster" shots are often needed to build "full immunity," which has led to complex vaccination schedules. The Strategic Advisory Group of Experts issues global recommendations, and each country's advisory committee adapts them to local factors, such as how a disease spreads, whether people accept vaccines, fairness for local communities, and money and program limits. In the United States, the Advisory Committee on Immunization Practices advises the Centers for Disease Control and Prevention on adding vaccines to the schedule. It recommends routine vaccines for children against hepatitis A, hepatitis B, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, HiB, chickenpox, rotavirus, influenza, meningococcal disease and pneumonia.

Because so many vaccines and boosters are recommended, with up to 24 injections by age two, it has become hard for families to keep up. To help, some notification systems have been started and many combination shots are now sold, such as the Pentavalent vaccine and the MMRV vaccine, which protect against several diseases at once. Many vaccines are also recommended for other ages, most often for measles, tetanus, influenza, and pneumonia. Pregnant women are often checked for continued resistance to rubella. As of 2011, the human papillomavirus vaccine was recommended in the US, and as of 2009 in the UK. For older people, recommendations focus on pneumonia and influenza, which are more dangerous for them. In 2006, a vaccine was introduced against shingles, a disease caused by the chickenpox virus that usually affects older people.

Economics of development

Main article: Economics of vaccines

Making vaccines can be hard because of money. Many diseases that most need a vaccine, such as HIV, malaria, and tuberculosis, mostly exist in poor countries. In the United States, financial returns are usually small, while the financial and other risks are large. Most vaccine development so far has relied on "push" funding from governments, universities, and non-profit organizations. Many vaccines have been highly cost effective and good for public health. The number of vaccines given has risen dramatically in recent decades. This rise, especially in the number of different vaccines given to children before they start school, may be due to government rules and support rather than money-making incentives.

According to the World Health Organization (WHO), the biggest barrier to making vaccines in less developed countries has not been patents. Instead, it has been the large amounts of money, infrastructure, and trained workers needed to enter the market. Vaccines are complex mixtures of biological substances, so unlike prescription drugs, there are no true generic vaccines. A new factory's vaccine must go through complete testing for safety and effectiveness by its maker. For most vaccines, specific manufacturing methods are patented, but these can be avoided with other methods if there is the research infrastructure and skilled workforce to do so. For a few newer vaccines, such as the human papillomavirus vaccine, patents may add an extra barrier. When more vaccine production was urgently needed during the COVID-19 pandemic in 2021, the World Trade Organization and governments around the world considered waiving intellectual property rights and patents on COVID-19 vaccines. The goal was to remove barriers to getting affordable COVID-19 medical products, including vaccines and medicines, to people in time.

Production

Making vaccines is very different from other kinds of manufacturing, including pharmaceutical manufacturing. Vaccines are given to millions of people, and most of them are healthy, so the process must follow very strict rules. A vaccine factory can cost US$50 to $500 million to build and needs special equipment, clean rooms, and containment rooms. Skilled workers are in short supply around the world. Apart from Brazil, China, and India, many developing countries' schools cannot train enough qualified people, so vaccine makers there must hire workers from other countries.

Making a vaccine has several stages. First, the antigen is grown. Viruses are grown on chicken eggs or on cultured human cells, and bacteria are grown in bioreactors. After that, the antigen is separated from the cells, and then adjuvants, stabilizers, and preservatives are added. The last step, fill and finish, means filling vials and packaging them, and it is often a bottleneck. The largest vaccine makers include Merck, Sanofi, GlaxoSmithKline, Pfizer, and Novartis. Developing countries, including Serum Institute of India in India and Sinopharm (CNPGC) in China, are playing a growing role in supplying their own needs.

Delivery systems

One of the most common ways to give vaccines is injection. Scientists hope new delivery systems could make vaccines safer and easier to give. Two areas of research are liposomes and ISCOM (immune stimulating complex). Other ideas include a microneedle approach, which uses tiny pointed projections to create paths for the vaccine through the skin. An experimental needle-free patch, about the size of a stamp and similar to an adhesive bandage, is being tested on animals. It has about 20,000 microscopic projections per square cm. This dermal method may work better than injection while needing less vaccine.

Oral vaccines have been another important development. By the 1930s, people were interested in an oral typhoid fever vaccine, although an oral vaccine against bacteria had once been controversial. An oral polio vaccine proved effective when volunteer staff without formal training gave it, and it was easy and efficient to give. Oral vaccines have advantages, such as no risk of blood contamination. As solids, they are often more stable and less likely to be damaged by freezing. This stability reduces the need for a "cold chain," the resources needed to keep vaccines within a set temperature range from manufacturing to administration, which may lower costs.

In veterinary medicine

See also: Influenza vaccine § Veterinary use, and Vaccination of dogs

Animals are vaccinated to keep them from catching diseases and to stop diseases from spreading to people. Pets and farm animals are routinely vaccinated, and sometimes wild animals are too. In one approach, vaccine-filled food is spread in areas where disease is common, which has been used to try to control rabies in raccoons. Where rabies occurs, dogs may be required by law to be vaccinated against it. Other dog vaccines protect against canine distemper, canine parvovirus, infectious canine hepatitis, adenovirus-2, leptospirosis, Bordetella, canine parainfluenza virus, and Lyme disease, among others. Some veterinary vaccines have also been used in people, on purpose or by accident, and a few of these cases caused illness, most notably brucellosis. Such cases are rarely reported, and little is known about their safety. Human exposure to germs not normally carried by people, such as Bordetella bronchiseptica, has likely increased in recent years because of spray vaccination in veterinary clinics.

Animal vaccination can also confuse tests, because both infection and vaccination can cause the body to make antibodies. To solve this, special marker vaccines are made from germs that are missing at least one epitope found in the wild version. A matching test looks for antibodies against that missing part, which shows whether an animal was vaccinated. These are also called "DIVA vaccines." This approach has been used in various countries to remove pseudorabies virus, and a test called an ELISA was developed to detect the antibodies.

Main article: Marker vaccine

Further information: Vaccination § History, and Inoculation § Origins

Before vaccines existed, smallpox could be prevented by variolation, which meant deliberately infecting people with smallpox virus. According to historian Joseph Needham, Taoists in China practiced a form of inoculation as early as the 10th century, though this claim has been criticized because the practice was not written down. The oldest documented use of variolation dates back to the fifteenth century in China, where powdered smallpox material was blown up the nostrils, a method called "nasal insufflation." In 1721, Mary Wortley Montagu had her four-year-old daughter variolated in England after seeing the practice in Turkey.

In 1796, Edward Jenner used material from a milkmaid's cowpox sore to protect an 8-year-old boy, James Phipps, from smallpox. Jenner's vaccine was later shown to be safe and could be passed from arm to arm. Since cowpox vaccination was much safer than smallpox inoculation, the older method was banned in England in 1840. Later, Louis Pasteur developed vaccines in the 1880s, and the polio vaccine was developed in the 1950s. Major achievements in the twentieth century included the eradication of smallpox during the 1960s and 1970s.

First generation vaccines are made from whole germs, either live and weakened or killed. Live vaccines, such as smallpox and polio vaccines, can trigger strong immune responses, but weakened germs can sometimes become dangerous again in people whose immune systems are weak, such as those with AIDS. Killed vaccines avoid this risk. Second generation vaccines were developed to be safer and use specific parts of germs, such as protein pieces from tetanus or diphtheria toxoid. Third generation vaccines include DNA vaccines and RNA vaccines. mRNA vaccines such as BNT162b2 were developed in 2020 and widely used to fight the COVID-19 pandemic.

Trends

Since at least 2013, scientists have been trying to develop synthetic third-generation vaccines by copying the outside structure of a virus. They hoped this would help prevent vaccine resistance. The principles that guide the immune response can now be used to make tailor-made vaccines against many noninfectious human diseases, such as cancers and autoimmune disorders. For example, the experimental vaccine CYT006-AngQb has been studied as a possible treatment for high blood pressure. Trends in vaccine development are shaped by progress in translatory medicine, demographics, regulatory science, and political, cultural, and social responses.

The idea of making vaccines in transgenic plants was identified as early as 2003. Plants such as tobacco, potato, tomato, and banana can have genes added that cause them to make vaccines for people. In 2005, bananas were developed that produce a human vaccine against hepatitis B.

Vaccine hesitancy

Main article: Anti-vaccine activism

Vaccine hesitancy is a delay in accepting vaccines, or refusing them, even when vaccine services are available. It can mean refusing vaccines completely, putting them off, accepting them but feeling unsure about them, or using some vaccines but not others. There is an overwhelming scientific consensus that vaccines are generally safe and effective.

Vaccine hesitancy often leads to disease outbreaks and deaths from vaccine-preventable diseases. The World Health Organization therefore described vaccine hesitancy as one of the top ten global health threats in 2019.