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A vaccine is a biological preparation that provides active
acquired immunity The adaptive immune system, also referred as the acquired immune system, is a subsystem of the immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, G ...
to a particular
infectious disease An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host A host is a person responsible for guests at an event or for providing hospitality during it. Host may ...
. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
to recognize the agent as a threat, destroy it, and to further recognize and destroy any of the microorganisms associated with that agent that it may encounter in the future. Vaccines can be
prophylactic Preventive healthcare, or prophylaxis, consists of measures taken for disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental health and efficienc ...
(to prevent or ameliorate the effects of a future
infection An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host A host is a person responsible for guests at an event or for providing hospitality during it. Host may ...

infection
by a natural or "wild"
pathogen In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanism ...
), or
therapeutic A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health Health is a state of physical, mental and social well-being Well-being, also known as ''wellness'', ''prudential value'' or ''quality ...
(to fight a disease that has already occurred, such as
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumor A benign tumor is a mass of cells Cell most often refers to: * Cell (biolo ...
). Some vaccines offer full sterilizing immunity, in which infection is prevented completely. The administration of vaccines is called
vaccination Vaccination is the administration of a vaccine A vaccine is a biological preparation that provides active to a particular . A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from we ...

vaccination
. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of
smallpox Smallpox was an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), host tissues to the infectious ...

smallpox
and the restriction of diseases such as
polio Poliomyelitis, commonly shortened to polio, is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology ...

polio
,
measles Measles is a highly contagious infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), host tissues to ...
, and
tetanus Tetanus, also known as lockjaw, is a bacterial infection Pathogenic bacteria are bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), biological cell. They constitute a large domain (biology), do ...
from much of the world. The effectiveness of vaccination has been widely studied and verified; for example, vaccines that have proven effective include the
influenza vaccine Influenza vaccines, also known as flu shots or flu jabs, are vaccines that protect against infection by influenza viruses. New versions of the vaccines are developed twice a year, as the influenza virus rapidly changes. While their effectiveness ...
, the
HPV vaccine Human papillomavirus (HPV) vaccines are vaccines that prevent infection by certain types of human papillomavirus (HPV). Available HPV vaccines protect against either two, four, or nine types of HPV. All HPV vaccines protect against at least HPV ...
, and the chickenpox vaccine. The
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations United Nations Specialized Agencies are autonomous organizations working with the United Nations and each other through the co-ordinating machinery of the Unit ...
(WHO) reports that licensed vaccines are currently available for twenty-five different preventable infections. The terms ''vaccine'' and ''vaccination'' are derived from ''Variolae vaccinae'' (smallpox of the cow), the term devised by
Edward Jenner Edward Jenner, (17 May 1749 – 26 January 1823) was a British physician A physician (American English), medical practitioner (English in the Commonwealth of Nations, Commonwealth English), medical doctor, or simply doctor, is a pro ...

Edward Jenner
(who both developed the concept of vaccines and created the first vaccine) to denote
cowpox Cowpox is an infectious disease caused by the cowpox virus (CPXV). The virus, part of the genus ''Orthopoxvirus ''Orthopoxvirus'' is a genus of virus A virus is a submicroscopic infectious agent that Viral replication, replicates on ...
. He used the phrase in 1798 for the long title of his ''Inquiry into the Variolae vaccinae Known as the Cow Pox'', in which he described the protective effect of cowpox against
smallpox Smallpox was an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), host tissues to the infectious ...

smallpox
. In 1881, to honor Jenner,
Louis Pasteur Louis Pasteur (, ; 27 December 1822 – 28 September 1895) was a French chemist and microbiologist renowned for his discoveries of the principles of vaccination, fermentation, microbial fermentation, and pasteurization. His research in chemi ...

Louis Pasteur
proposed that the terms should be extended to cover the new protective
inoculation Inoculation is a set of methods of artificially inducing immunity against various infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and ...

inoculation
s then being developed. The science of vaccine development and production is termed ''
vaccinology A vaccine is a biological preparation that provides active acquired immunity The adaptive immune system, also referred as the acquired immune system, is a subsystem of the immune system The immune system is a network of biological processe ...
''.


Effects

There is overwhelming scientific consensus that vaccines are a very safe and effective way to fight and eradicate infectious diseases. The
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
recognizes vaccine agents as foreign, destroys them, and "remembers" them. When the
virulent Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most contexts, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host (biology), host. The Pathogen#Pathogenicity, ...
version of an agent is encountered, the body recognizes the protein coat on the virus, and thus is prepared to respond, by first neutralizing the target agent before it can enter cells, and secondly by recognizing and destroying infected cells before that agent can multiply to vast numbers. Limitations to their effectiveness, nevertheless, exist. Sometimes, protection fails because of vaccine-related failures such as failures in vaccine attenuation, vaccination regimes or administration or host-related failure due to the host's immune system simply does not respond adequately or at all. Lack of response commonly results from genetics, immune status, age, health or nutritional status. It also might fail for genetic reasons if the host's immune system includes no strains of
B cell #REDIRECT B cell 3D rendering of a B cell B cells, also known as B lymphocytes, are a type of white blood cell White blood cells (WBCs), also called leukocytes or leucocytes, are the cells of the immune system The immune system is a ne ...
s that can generate
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique mo ...

antibodies
suited to reacting effectively and binding to the
antigen In immunology Immunology is a branch of biology that covers the study of immune systems in all organisms. Immunology charts, measures, and contextualizes the Physiology, physiological functioning of the immune system in states of both health ...
s associated with the
pathogen In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanism ...
. Even if the host does develop antibodies, protection might not be adequate; immunity might develop too slowly to be effective in time, the antibodies might not disable the pathogen completely, or there might be multiple strains of the pathogen, not all of which are equally susceptible to the immune reaction. However, even a partial, late, or weak immunity, such as a one resulting from cross-immunity to a strain other than the target strain, may mitigate an infection, resulting in a lower
mortality rate Mortality rate, or death rate, is a measure of the number of death Death is the permanent, irreversible cessation of all biological functions that sustain a living Living or The Living may refer to: Common meanings *Life, a conditi ...
, lower
morbidity A disease is a particular abnormal condition that negatively affects the structure A structure is an arrangement and organization of interrelated elements in a material object or system A system is a group of Interaction, interact ...
, and faster recovery.
AdjuvantsIn pharmacology Pharmacology is a branch of medicine and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a bioch ...
commonly are used to boost immune response, particularly for older people whose immune response to a simple vaccine may have weakened. The
efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness Effectiveness is the capability of producing a desired result or the ability to produce desired output. When ...
or performance of the vaccine is dependent on several factors: * the disease itself (for some diseases vaccination performs better than for others) * the strain of vaccine (some vaccines are specific to, or at least most effective against, particular strains of the disease) * whether the
vaccination schedule A vaccination schedule is a series of vaccinations, including the timing of all doses, which may be either recommended or compulsory, depending on the country of residence. A vaccine is an antigenic preparation used to produce active immunity to ...
has been properly observed. * idiosyncratic response to vaccination; some individuals are "non-responders" to certain vaccines, meaning that they do not generate antibodies even after being vaccinated correctly. * assorted factors such as ethnicity, age, or genetic predisposition. If a vaccinated individual does develop the disease vaccinated against ( breakthrough infection), the disease is likely to be less virulent than in unvaccinated victims. Important considerations in an effective vaccination program: # careful modeling to anticipate the effect that an immunization campaign will have on the epidemiology of the disease in the medium to long term # ongoing surveillance for the relevant disease following introduction of a new vaccine # maintenance of high immunization rates, even when a disease has become rare In 1958, there were 763,094 cases of measles in the United States; 552 deaths resulted. After the introduction of new vaccines, the number of cases dropped to fewer than 150 per year (median of 56). In early 2008, there were 64 suspected cases of measles. Fifty-four of those infections were associated with importation from another country, although only thirteen percent were actually acquired outside the United States; 63 of the 64 individuals either had never been vaccinated against measles or were uncertain whether they had been vaccinated. Vaccines led to the eradication of
smallpox Smallpox was an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), host tissues to the infectious ...

smallpox
, one of the most contagious and deadly diseases in humans. Other diseases such as rubella,
polio Poliomyelitis, commonly shortened to polio, is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology ...
, measles, mumps,
chickenpox Chickenpox, also known as varicella, is a highly contagious Contagious may refer to: * Contagious disease Literature * Contagious (magazine), a marketing publication * Contagious (novel), ''Contagious'' (novel), a science fiction thriller ...

chickenpox
, and
typhoid Typhoid fever, also known as typhoid, is a disease caused by ''Salmonella ''Salmonella'' is a genus Genus /ˈdʒiː.nəs/ (plural genera /ˈdʒen.ər.ə/) is a taxonomic rank used in the biological classification of extant taxon, living an ...
are nowhere near as common as they were a hundred years ago thanks to widespread vaccination programs. As long as the vast majority of people are vaccinated, it is much more difficult for an outbreak of disease to occur, let alone spread. This effect is called
herd immunity Herd immunity (also called herd effect, community immunity, population immunity, or mass immunity) is a form of indirect protection from infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pa ...

herd immunity
. Polio, which is transmitted only among humans, is targeted by an extensive eradication campaign that has seen endemic polio restricted to only parts of three countries (Afghanistan, Nigeria, and Pakistan). However, the difficulty of reaching all children as well as cultural misunderstandings have caused the anticipated eradication date to be missed several times. Vaccines also help prevent the development of antibiotic resistance. For example, by greatly reducing the incidence of pneumonia caused by ''
Streptococcus pneumoniae ''Streptococcus'' is a genus Genus /ˈdʒiː.nəs/ (plural genera /ˈdʒen.ər.ə/) is a taxonomic rank In biological classification In biology Biology is the natural science that studies life and living organisms, including ...

Streptococcus pneumoniae
'', vaccine programs have greatly reduced the prevalence of infections resistant to penicillin or other first-line antibiotics. The measles vaccine is estimated to prevent a million deaths every year.


Adverse effects

Vaccinations given to children, adolescents, or adults are generally safe. Adverse effects, if any, are generally mild. The rate of side effects depends on the vaccine in question. Some common side effects include fever, pain around the injection site, and muscle aches. Additionally, some individuals may be allergic to ingredients in the vaccine.
MMR vaccine The MMR vaccine is a vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often m ...

MMR vaccine
is rarely associated with
febrile seizure A febrile seizure, also known as a fever fit or febrile convulsion, is a seizure A seizure, formally known as an epileptic seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain A brain ...
s. Host-("vaccinee")-related determinants that render a person susceptible to infection, such as
genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, ...

genetics
, health status (underlying disease, nutrition, pregnancy, sensitivities or
allergies Allergies, also known as allergic diseases, are a number of conditions caused by hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, ...

allergies
), immune competence, age, and
economic impact An economic impact analysis (EIA) examines the effect of an event on the economy An economy (; ) is an area of the Production (economics), production, Distribution (economics), distribution and trade, as well as Consumption (economics), consu ...
or cultural environment can be primary or secondary factors affecting the severity of infection and response to a vaccine. Elderly (above age 60), allergen-hypersensitive, and
obese Obesity is a medical condition A disease is a particular abnormal condition that negatively affects the structure or function (biology), function of all or part of an organism, and that is not due to any immediate external injury. ...

obese
people have susceptibility to compromised
immunogenicity Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted: * Wanted immunogenicity typically relates to vaccines, where the injecti ...
, which prevents or inhibits vaccine effectiveness, possibly requiring separate vaccine technologies for these specific populations or repetitive booster vaccinations to limit virus transmission. Severe side effects are extremely rare.
Varicella vaccine Varicella vaccine, also known as chickenpox vaccine, is a vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious disease. A vaccine typically contains an agent that resembles a dis ...

Varicella vaccine
is rarely associated with complications in
immunodeficient Immunodeficiency, also known as immunocompromisation, is a state in which the immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, Greek: ὀργα ...
individuals, and
rotavirus vaccine Rotavirus vaccine is a vaccine A vaccine is a biological preparation that provides active acquired immunity The adaptive immune system, also referred as the acquired immune system, is a subsystem of the immune system The immune system ...
s are moderately associated with intussusception. At least 19 countries have no-fault compensation programs to provide compensation for those suffering severe adverse effects of vaccination. The United States’ program is known as the
National Childhood Vaccine Injury Act The National Childhood Vaccine Injury Act (NCVIA) of 1986 (42 U.S.C. §§ 300aa-1 to 300aa-34) was signed into law by United States President Ronald Reagan Ronald Wilson Reagan ( ; February 6, 1911June 5, 2004) was an American politician ...
, and the United Kingdom employs the Vaccine Damage Payment.


Types

Vaccines typically contain attenuated, inactivated or dead organisms or purified products derived from them. There are several types of vaccines in use. These represent different strategies used to try to reduce the risk of illness while retaining the ability to induce a beneficial immune response.


Attenuated

Some vaccines contain live, attenuated microorganisms. Many of these are active
viruses A virus is a wikt:submicroscopic, submicroscopic infectious agent that Viral replication, replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, incl ...
that have been cultivated under conditions that disable their virulent properties, or that use closely related but less dangerous organisms to produce a broad immune response. Although most attenuated vaccines are viral, some are bacterial in nature. Examples include the viral diseases
yellow fever Yellow fever is a viral disease of typically short duration. In most cases, symptoms include fever Fever, also referred to as pyrexia, is defined as having a above the due to an increase in the body's temperature . There is not a singl ...
,
measles Measles is a highly contagious infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), host tissues to ...
,
mumps Mumps is a viral disease A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infection, infectious virus particles (virions) attach to and enter susceptible cells. Structural characteris ...

mumps
, and
rubella Rubella, also known as German measles or three-day measles, is an infection An infection is the invasion of an organism's body by , their multiplication, and the reaction of tissues to the infectious agents and the s they produce. An inf ...

rubella
, and the bacterial disease
typhoid Typhoid fever, also known as typhoid, is a disease caused by ''Salmonella ''Salmonella'' is a genus Genus /ˈdʒiː.nəs/ (plural genera /ˈdʒen.ər.ə/) is a taxonomic rank used in the biological classification of extant taxon, living an ...
. The live ''Mycobacterium
tuberculosis Tuberculosis (TB) is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), host tissues to the in ...

tuberculosis
'' vaccine developed by Calmette and Guérin is not made of a
contagious Contagious may refer to: * Contagious disease Literature * Contagious (magazine), a marketing publication * Contagious (novel), ''Contagious'' (novel), a science fiction thriller novel by Scott Sigler Music Albums *Contagious (Peggy Scott-Adams ...
strain but contains a virulently modified strain called " BCG" used to elicit an immune response to the vaccine. The live attenuated vaccine containing strain ''
Yersinia pestis ''Yersinia pestis'' (''Y. pestis'') (formerly ''Pasteurella __NOTOC__ ''Pasteurella'' is a genus Genus (plural genera) is a taxonomic rank Taxonomy (general) is the practice and science of classification of things or concepts, including th ...

Yersinia pestis
'' EV is used for plague immunization. Attenuated vaccines have some advantages and disadvantages. Attenuated, or live, weakened, vaccines typically provoke more durable immunological responses. But they may not be safe for use in immunocompromised individuals, and on rare occasions mutate to a virulent form and cause disease.


Inactivated

Some vaccines contain inactivated, but previously virulent, micro-organisms that have been destroyed with chemicals, heat, or radiation"ghosts", with intact but empty bacterial cell envelopes. They are considered an intermediate phase between the inactivated and attenuated vaccines. Examples include IPV (
polio vaccine Polio vaccines are vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often ...
), hepatitis A vaccine,
rabies vaccine The rabies vaccine is a vaccine used to prevent rabies. There are a number of rabies vaccines available that are both safe and effective. They can be used to prevent rabies before, and for a period of time after, exposure to the rabies virus, whi ...

rabies vaccine
and most
influenza vaccines Influenza, commonly known as "the flu", is an infectious disease caused by ''influenza viruses''. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These sympto ...
.


Toxoid

Toxoid A toxoid is an inactivated toxin A toxin is a harmful substance produced within living cells or organisms; synthetic toxicants created by artificial processes are thus excluded. The term was first used by organic chemist Ludwig Brieger (1849 ...
vaccines are made from inactivated toxic compounds that cause illness rather than the micro-organism. Examples of toxoid-based vaccines include
tetanus Tetanus, also known as lockjaw, is a bacterial infection Pathogenic bacteria are bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), biological cell. They constitute a large domain (biology), do ...
and
diphtheria Diphtheria is an infection caused by the bacteria, bacterium ''Corynebacterium diphtheriae''. Most infections are asymptomatic or have a mild Course (medicine), clinical course, but in some outbreaks more than 10% of those diagnosed with the di ...

diphtheria
. Not all toxoids are for micro-organisms; for example, ''
Crotalus atrox The western diamondback rattlesnake or Texas diamond-backWright AH, Wright AA. (1957). ''Handbook of Snakes''. Comstock Publishing Associates. (7th printing, 1985). . (''Crotalus atrox'') is a venomous snake, venomous rattlesnake species found in ...

Crotalus atrox
'' toxoid is used to vaccinate dogs against
rattlesnake Rattlesnakes are a group of venomous snakes of the genus, genera ''Crotalus'' and ''Sistrurus'' of the subfamily Crotalinae (the pit vipers). All rattlesnakes are vipers. The scientific name ''Crotalus'' is derived from the Greek language, Greek ...

rattlesnake
bites.


Subunit

Rather than introducing an inactivated or attenuated micro-organism to an immune system (which would constitute a "whole-agent" vaccine), a subunit vaccine uses a fragment of it to create an immune response. One example is the subunit vaccine against hepatitisB, which is composed of only the surface proteins of the virus (previously extracted from the
blood serum Serum () is the fluid and solute component of blood Blood is a body fluid Body fluids, bodily fluids, or biofluids are liquid A liquid is a nearly incompressible In fluid mechanics or more generally continuum mechanics, incompres ...
of chronically infected patients but now produced by of the viral genes into
yeast Yeasts are eukaryotic Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular ...

yeast
). Another example is edible algae vaccines, such as the
virus-like particle Virus-like particles (VLPs) are molecules that closely resemble viruses, but are non-infectious because they contain no viral genetic material. They can be naturally occurring or synthesized through the individual expression of viral structural prot ...
(VLP) vaccine against
human papillomavirus Human papillomavirus infection (HPV infection) is an infection An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host A host is a person responsible for g ...
(HPV), which is composed of the viral major
capsid A capsid is the protein shell of a virus A virus is a that only inside the living of an . Viruses infect all , from animals and plants to s, including and . Since 's 1892 article describing a non-bacterial infecting tobacco plants ...
protein. Another example is the
hemagglutinin In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, mechan ...
and
neuraminidase Neuraminidase (Sialidase) enzymes are glycoside hydrolase enzymes that cleave (cut) the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The best-known neuraminidase is the viral ne ...

neuraminidase
subunits of the
influenza Influenza, commonly known as "the flu", is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), ...

influenza
virus. A subunit vaccine is being used for plague immunization.


Conjugate

Certain bacteria have a
polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrate A carbohydrate () is a biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallograp ...
outer coat that is poorly
immunogenic Immunogenicity is the ability of a foreign substance, such as an antigen In immunology, an antigen (Ag) is a molecule or molecular structure, such as may be present on the outside of a pathogen, that can be bound by an antigen-specific antibo ...
. By linking these outer coats to proteins (e.g., toxins), the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the ''Haemophilus influenzae'' type B vaccine.


Outer membrane vesicle

Outer membrane vesicles (OMVs) are naturally immunogenic and can be manipulated to produce potent vaccines. The best known OMV vaccines are those developed for serotype B meningococcal disease.


Heterotypic

Heterologous vaccines also known as "Jennerian vaccines", are vaccines that are pathogens of other animals that either do not cause disease or cause mild disease in the organism being treated. The classic example is Jenner's use of cowpox to protect against smallpox. A current example is the use of
BCG vaccine Bacillus Calmette–Guérin (BCG) vaccine is a vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious disease. A vaccine typically contains an agent that resembles a disease-causing mi ...
made from ''
Mycobacterium bovis ''Mycobacterium bovis'' (''M. bovis'') is a slow-growing (16- to 20-hour generation time) aerobic bacterium and the causative agent of tuberculosis Tuberculosis (TB) is an infectious disease usually caused by ''Mycobacterium tuberculosi ...
'' to protect against
tuberculosis Tuberculosis (TB) is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), host tissues to the in ...

tuberculosis
.


Genetic vaccine

The subgroup of genetic vaccines encompass viral vector vaccines, RNA vaccines and DNA vaccines.


Viral vector

Viral vector vaccines use a safe
virus A virus is a submicroscopic infectious agent In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecu ...

virus
to insert pathogen genes in the body to produce specific
antigen In immunology Immunology is a branch of biology that covers the study of immune systems in all organisms. Immunology charts, measures, and contextualizes the Physiology, physiological functioning of the immune system in states of both health ...
s, such as surface
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
s, to stimulate an
immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, Parasitism, parasites, and Fungus ...

immune response
.


RNA

An mRNA vaccine (or
RNA vaccine An mRNA vaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine RNA transfection, delivers molecules of antigen-encoding mRNA into dendritic cell, immune cells, which us ...
) is a novel type of vaccine which is composed of the nucleic acid RNA, packaged within a vector such as lipid nanoparticles. Among the
COVID-19 vaccine A COVID‑19 vaccine is a vaccine A vaccine is a biological preparation that provides active acquired immunity The adaptive immune system, also referred as the acquired immune system, is a subsystem of the immune system The immune ...
s are a number of RNA vaccines under development to combat the
COVID-19 pandemic The COVID-19 pandemic is an ongoing global pandemic A pandemic (from , , "all" and , , "local people" the 'crowd') is an of an that has spread across a large region, for instance multiple or worldwide, affecting a substantial numbe ...

COVID-19 pandemic
and some have been approved or have received
emergency use authorization#REDIRECT Emergency Use Authorization {{Redirect category shell, {{R from move {{R from other capitalisation {{R unprintworthy ...
in some countries. For example, the Pfizer-BioNTech vaccine is approved for use in adults, while the vaccine has emergency use authorization in the US.


DNA

DNA vaccination A DNA vaccine is a type of vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is oft ...
– The proposed mechanism is the insertion and of viral or bacterial DNA in human or animal cells (enhanced by the use of
electroporation Electroporation, or electropermeabilization, is a microbiology Microbiology (from Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country loca ...
), triggering immune system recognition. Some cells of the immune system that recognize the proteins expressed will mount an attack against these proteins and cells expressing them. Because these cells live for a very long time, if the
pathogen In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanism ...
that normally expresses these proteins is encountered at a later time, they will be attacked instantly by the immune system. One potential advantage of DNA vaccines is that they are very easy to produce and store. In August 2021, Indian authorities gave emergency approval to ZyCoV-D. Developed by
Cadila Healthcare Cadila Healthcare Limited (also known as Zydus Cadila) is an Indian multinational pharmaceutical A medication (also referred to as medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug File:Aspirine macro shot.jpg, Un ...
, it is the first DNA vaccine approved for humans.


Experimental

Many innovative vaccines are also in development and use. * Dendritic cell vaccines combine
dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammal Mammals (from Latin language, Latin , 'breast') are a group of vertebrate animals constituting the class (biology), class Mammalia (), an ...

dendritic cell
s with antigens to present the antigens to the body's white blood cells, thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumors and are also tested in malignant melanoma. *
RecombinantRecombinant may refer to: * Recombinant organism A genetically modified organism (GMO) is any organism whose genetic material has been altered using genetic engineering techniques. The exact definition of a genetically modified organism and wha ...

Recombinant
vector Vector may refer to: Biology *Vector (epidemiology) In epidemiology Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and risk factor, determinants of health and disease conditions in defined pop ...
by combining the physiology of one micro-organism and the
DNA Deoxyribonucleic acid (; DNA) is a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the set of physical ...

DNA
of another, immunity can be created against diseases that have complex infection processes. An example is the
RVSV-ZEBOV vaccine Recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV), also known as Ebola Zaire vaccine live and sold under the brand name Ervebo, is an Ebola vaccine for adults that prevents Ebola virus disease, Ebola caused by the Zaire eb ...
licensed to Merck that is being used in 2018 to combat ebola in Congo. * T-cell receptor peptide vaccines are under development for several diseases using models of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to modulate cytokine production and improve cell-mediated immunity. * Targeting of identified bacterial proteins that are involved in complement inhibition would neutralize the key bacterial virulence mechanism. * The use of plasmids has been validated in preclinical studies as a protective vaccine strategy for cancer and infectious diseases. However, in human studies, this approach has failed to provide clinically relevant benefit. The overall efficacy of plasmid DNA immunization depends on increasing the plasmid's
immunogenicity Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted: * Wanted immunogenicity typically relates to vaccines, where the injecti ...
while also correcting for factors involved in the specific activation of immune effector cells. * Vector (epidemiology), Bacterial vector – Similar in principle to viral vector vaccines, but using bacteria instead. * Antigen-presenting cell vaccine, Antigen-presenting cell While most vaccines are created using inactivated or attenuated compounds from micro-organisms, synthetic vaccines are composed mainly or wholly of synthetic peptides, carbohydrates, or antigens.


Valence

Vaccines may be ''monovalent'' (also called ''univalent'') or ''multivalent'' (also called ''polyvalent''). A monovalent vaccine is designed to immunize against a single antigen or single microorganism. A multivalent or polyvalent vaccine is designed to immunize against two or more strains of the same microorganism, or against two or more microorganisms. The valency of a multivalent vaccine may be denoted with a Greek or Latin prefix (e.g., ''tetravalent'' or ''quadrivalent''). In certain cases, a monovalent vaccine may be preferable for rapidly developing a strong immune response. When two or more vaccines are mixed in the same formulation, the two vaccines can interfere. This most frequently occurs with live attenuated vaccines, where one of the vaccine components is more robust than the others and suppresses the growth and immune response to the other components. This phenomenon was first noted in the trivalent Sabin
polio vaccine Polio vaccines are vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often ...
, where the amount of serotype2 virus in the vaccine had to be reduced to stop it from interfering with the "take" of the serotype1 and3 viruses in the vaccine. This phenomenon has also been found to be a problem with the dengue vaccines currently being researched, where the DEN-3 serotype was found to predominate and suppress the response to DEN-1, −2 and −4 serotypes.


Other contents


Adjuvants

Vaccines typically contain one or more adjuvants, used to boost the immune response. Tetanus toxoid, for instance, is usually adsorbed onto alum. This presents the antigen in such a way as to produce a greater action than the simple aqueous tetanus toxoid. People who have an adverse reaction to adsorbed tetanus toxoid may be given the simple vaccine when the time comes for a booster. In the preparation for the 1990 Persian Gulf campaign, the whole cell pertussis vaccine was used as an adjuvant for anthrax vaccine. This produces a more rapid immune response than giving only the anthrax vaccine, which is of some benefit if exposure might be imminent.


Preservatives

Vaccines may also contain preservatives to prevent contamination with bacteria or fungi. Until recent years, the preservative thiomersal ( ''Thimerosal'' in the US and Japan) was used in many vaccines that did not contain live viruses. As of 2005, the only childhood vaccine in the U.S. that contains thiomersal in greater than trace amounts is the influenza vaccine, which is currently recommended only for children with certain risk factors. Single-dose influenza vaccines supplied in the UK do not list thiomersal in the ingredients. Preservatives may be used at various stages of the production of vaccines, and the most sophisticated methods of measurement might detect traces of them in the finished product, as they may in the environment and population as a whole. Many vaccines need preservatives to prevent serious adverse effects such as ''Staphylococcus'' infection, which in one 1928 incident killed 12 of 21 children inoculated with a
diphtheria Diphtheria is an infection caused by the bacteria, bacterium ''Corynebacterium diphtheriae''. Most infections are asymptomatic or have a mild Course (medicine), clinical course, but in some outbreaks more than 10% of those diagnosed with the di ...

diphtheria
vaccine that lacked a preservative. Several preservatives are available, including thiomersal, phenoxyethanol, and formaldehyde. Thiomersal is more effective against bacteria, has a better shelf-life, and improves vaccine stability, potency, and safety; but, in the U.S., the European Union, and a few other affluent countries, it is no longer used as a preservative in childhood vaccines, as a precautionary measure due to its Mercury (element), mercury content. Although Thiomersal controversy, controversial claims have been made that thiomersal contributes to autism spectrum disorder, autism, no convincing scientific evidence supports these claims. Furthermore, 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.


Excipients

Beside the active vaccine itself, the following excipients and residual manufacturing compounds are present or may be present in vaccine preparations: * Aluminum salts or gels are added as adjuvants. Adjuvants are added to promote an earlier, more potent response, and more persistent immune response to the vaccine; they allow for a lower vaccine dosage. * Antibiotics are added to some vaccines to prevent the growth of bacteria during production and storage of the vaccine. * Egg
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
is present in the
influenza vaccine Influenza vaccines, also known as flu shots or flu jabs, are vaccines that protect against infection by influenza viruses. New versions of the vaccines are developed twice a year, as the influenza virus rapidly changes. While their effectiveness ...
and yellow fever vaccine as they are prepared using chicken eggs. Other proteins may be present. * Formaldehyde is used to inactivate bacterial products for toxoid vaccines. Formaldehyde is also used to inactivate unwanted viruses and kill bacteria that might contaminate the vaccine during production. * Monosodium glutamate (MSG) and 2-phenoxyethanol are used as stabilizers in a few vaccines to help the vaccine remain unchanged when the vaccine is exposed to heat, light, acidity, or humidity. * Thiomersal is a mercury-containing antimicrobial that is added to vials of vaccines that contain more than one dose to prevent contamination and growth of potentially harmful bacteria. Due to the controversy surrounding thiomersal, it has been removed from most vaccines except multi-use influenza, where it was reduced to levels so that a single dose contained less than a microgram of mercury, a level similar to eating ten grams of canned tuna.The mercury levels in the table, unless otherwise indicated, are taken fro
Mercury Levels in Commercial Fish and Shellfish (1990-2010)
U.S. Food and Drug Administration. Accessed 8January 2012.


Nomenclature

Various fairly standardized abbreviations for vaccine names have developed, although the standardization is by no means centralized or global. For example, the vaccine names used in the United States have well-established abbreviations that are also widely known and used elsewhere. An extensive list of them provided in a sortable table and freely accessible is available at a US Centers for Disease Control and Prevention web page. The page explains that "The abbreviations [in] this table (Column 3) were standardized jointly by staff of the Centers for Disease Control and Prevention, Advisory Committee on Immunization Practices, ACIP Work Groups, the editor of the ''Morbidity and Mortality Weekly Report'' (MMWR), the editor of ''Epidemiology and Prevention of Vaccine-Preventable Diseases'' (the Pink Book), ACIP members, and liaison organizations to the ACIP." Some examples are "DTaP" for diphtheria and tetanus toxoids and acellular pertussis vaccine, "DT" for diphtheria and tetanus toxoids, and "Td" for tetanus and diphtheria toxoids. At its page on tetanus vaccination, the CDC further explains that "Upper-case letters in these abbreviations denote full-strength doses of diphtheria (D) and tetanus (T) toxoids and pertussis (P) vaccine. Lower-case "d" and "p" denote reduced doses of diphtheria and pertussis used in the adolescent/adult-formulations. The 'a' in DTaP and Tdap stands for 'acellular', meaning that the pertussis component contains only a part of the pertussis organism." Another list of established vaccine abbreviations is at the CDC's page called "Vaccine Acronyms and Abbreviations", with abbreviations used on U.S. immunization records. The United States Adopted Name system has some conventions for the word order of vaccine names, placing head (linguistics), head nouns first and postpositive adjective, adjectives postpositively. This is why the USAN for "polio vaccine, OPV" is "poliovirus vaccine live oral" rather than "oral poliovirus vaccine".


Licensing

A vaccine ''licensure'' occurs after the successful conclusion of the development cycle and further the clinical trials and other programs involved through Phases of clinical research, PhasesI–III demonstrating safety, immunoactivity, immunogenetic safety at a given specific dose, proven effectiveness in preventing infection for target populations, and enduring preventive effect (time endurance or need for revaccination must be estimated). Because preventive vaccines are predominantly evaluated in healthy population cohorts and distributed among the general population, a high standard of safety is required. As part of a multinational licensing of a vaccine, the World Health Organization ''Expert Committee on Biological Standardization'' developed guidelines of international standards for manufacturing and quality control of vaccines, a process intended as a platform for national regulatory agencies to apply for their own licensing process. Vaccine manufacturers do not receive licensing until a complete clinical cycle of development and trials proves the vaccine is safe and has long-term effectiveness, following scientific review by a multinational or national regulatory organization, such as the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA). Upon Developing country, developing countries adopting WHO guidelines for vaccine development and licensure, each country has its own responsibility to issue a national licensure, and to manage, deploy, and monitor the vaccine throughout its use in each nation. Building trust and acceptance of a licensed vaccine among the public is a task of communication by governments and healthcare personnel to ensure a vaccination campaign proceeds smoothly, saves lives, and enables economic recovery. When a vaccine is licensed, it will initially be in limited supply due to variable manufacturing, distribution, and logistical factors, requiring an allocation plan for the limited supply and which population segments should be prioritized to first receive the vaccine.


World Health Organization

Vaccines developed for multinational distribution via the UNICEF, United Nations Children's Fund (UNICEF) require pre-qualification by the WHO to ensure international standards of quality, safety, immunogenicity, and efficacy for adoption by numerous countries. The process requires manufacturing consistency at WHO-contracted laboratories following Good Manufacturing Practice (GMP). When UN agencies are involved in vaccine licensure, individual nations collaborate by 1) issuing marketing authorization and a national license for the vaccine, its manufacturers, and distribution partners; and 2) conducting postmarketing surveillance, including records for adverse events after the vaccination program. The WHO works with national agencies to monitor inspections of manufacturing facilities and distributors for compliance with GMP and regulatory oversight. Some countries choose to buy vaccines licensed by reputable national organizations, such as EMA, FDA, or national agencies in other affluent countries, but such purchases typically are more expensive and may not have distribution resources suitable to local conditions in developing countries.


European Union

In the European Union (EU), vaccines for pandemic pathogens, such as seasonal influenza, are licensed EU-wide where all the Member state of the European Union, member states comply ("centralized"), are licensed for only some member states ("decentralized"), or are licensed on an individual national level. Generally, all EU states follow regulatory guidance and clinical programs defined by the European Committee for Medicinal Products for Human Use (CHMP), a scientific panel of the European Medicines Agency (EMA) responsible for vaccine licensure. The CHMP is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution.


United States

Under the FDA, the process of establishing evidence for vaccine clinical safety and efficacy is the same as for Drug approval, the approval process for prescription drugs. If successful through the stages of clinical development, the vaccine licensing process is followed by a Biologics License Application which must provide a scientific review team (from diverse disciplines, such as physicians, statisticians, microbiologists, chemists) and comprehensive documentation for the vaccine candidate having efficacy and safety throughout its development. Also during this stage, the proposed manufacturing facility is examined by expert reviewers for GMP compliance, and the label must have a compliant description to enable health care providers' definition of vaccine-specific use, including its possible risks, to communicate and deliver the vaccine to the public. After licensure, monitoring of the vaccine and its production, including periodic inspections for GMP compliance, continue as long as the manufacturer retains its license, which may include additional submissions to the FDA of tests for potency, safety, and purity for each vaccine manufacturing step.


India

Drugs Controller General of India is the head of department of the Central Drugs Standard Control Organization of the Government of India responsible for approval of licences of specified categories of drugs such as vaccines AND others like blood and blood products, IV fluids, and sera in India.


Postmarketing surveillance

Until a vaccine is in use for the general population, all potential Vaccine adverse event, adverse events from the vaccine may not be known, requiring manufacturers to conduct Phases of clinical research#Phase IV, PhaseIV studies for postmarketing surveillance of the vaccine while it is used widely in the public. The WHO works with UN member states to implement post-licensing surveillance. The FDA relies on a Vaccine Adverse Event Reporting System to monitor safety concerns about a vaccine throughout its use in the American public.


Scheduling

In order to provide the best protection, children are recommended to receive vaccinations as soon as their immune systems are sufficiently developed to respond to particular vaccines, with additional "booster" shots often required to achieve "full immunity". This has led to the development of complex vaccination schedules. Global recommendations of vaccination schedule are issued by Strategic Advisory Group of Experts and will be further translated by National Immunization Technical Advisory Group, advisory committee at the country level with considering of local factors such as disease epidemiology, acceptability of vaccination, equity in local populations, and programmatic and financial constraint. In the United States, the Advisory Committee on Immunization Practices, which recommends schedule additions for the Centers for Disease Control and Prevention, recommends routine vaccination of children against hepatitis A, hepatitis B virus, hepatitis B, polio, mumps, measles, rubella,
diphtheria Diphtheria is an infection caused by the bacteria, bacterium ''Corynebacterium diphtheriae''. Most infections are asymptomatic or have a mild Course (medicine), clinical course, but in some outbreaks more than 10% of those diagnosed with the di ...

diphtheria
, pertussis,
tetanus Tetanus, also known as lockjaw, is a bacterial infection Pathogenic bacteria are bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), biological cell. They constitute a large domain (biology), do ...
, Haemophilus influenzae, HiB, chickenpox, rotavirus,
influenza Influenza, commonly known as "the flu", is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), ...

influenza
, meningococcal disease and pneumonia. The large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance. To combat declining compliance rates, various notification systems have been instituted and many combination injections are now marketed (e.g., Pentavalent vaccine and MMRV vaccine), which protect against multiple diseases. Besides recommendations for infant vaccinations and boosters, many specific vaccines are recommended for other ages or for repeated injections throughout lifemost commonly for measles, tetanus, influenza, and pneumonia. Pregnant women are often screened for continued resistance to rubella. The
human papillomavirus Human papillomavirus infection (HPV infection) is an infection An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host A host is a person responsible for g ...
vaccine is recommended in the U.S. (as of 2011) and UK (as of 2009). Vaccine recommendations for the elderly concentrate on pneumonia and influenza, which are more deadly to that group. In 2006, a vaccine was introduced against Herpes zoster, shingles, a disease caused by the chickenpox virus, which usually affects the elderly. Scheduling and dosing of a vaccination may be tailored to the level of immunocompetence of an individual and to optimize population-wide deployment of a vaccine when it supply is limited, e.g. in the setting of a pandemic.


Economics of development

One challenge in vaccine development is economic: Many of the diseases most demanding a vaccine, including HIV, malaria and tuberculosis, exist principally in poor countries. Pharmaceutical firms and biotechnology companies have little incentive to develop vaccines for these diseases because there is little revenue potential. Even in more affluent countries, financial returns are usually minimal and the financial and other risks are great. Most vaccine development to date has relied on "push" funding by government, universities and non-profit organizations. Many vaccines have been highly cost effective and beneficial for public health. The number of vaccines actually administered has risen dramatically in recent decades. This increase, particularly in the number of different vaccines administered to children before entry into schools may be due to government mandates and support, rather than economic incentive.


Patents

According to the World Health Organization, the biggest barrier to vaccine production in less developed countries has not been patents, but the substantial financial, infrastructure, and workforce requirements needed for market entry. Vaccines are complex mixtures of biological compounds, and unlike the case for prescription drugs, there are no true generic drug, generic vaccines. The vaccine produced by a new facility must undergo complete clinical testing for safety and efficacy by the manufacturer. For most vaccines, specific processes in technology are patented. These can be circumvented by alternative manufacturing methods, but this required R&D infrastructure and a suitably skilled workforce. In the case of a few relatively new vaccines, such as the
human papillomavirus Human papillomavirus infection (HPV infection) is an infection An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host A host is a person responsible for g ...
vaccine, the patents may impose an additional barrier. When increased production of vaccines was urgently needed during the
COVID-19 pandemic The COVID-19 pandemic is an ongoing global pandemic A pandemic (from , , "all" and , , "local people" the 'crowd') is an of an that has spread across a large region, for instance multiple or worldwide, affecting a substantial numbe ...

COVID-19 pandemic
in 2021, the World Trade Organization and governments around the world evaluated whether to waive intellectual property rights and patents on
COVID-19 vaccine A COVID‑19 vaccine is a vaccine A vaccine is a biological preparation that provides active acquired immunity The adaptive immune system, also referred as the acquired immune system, is a subsystem of the immune system The immune ...
s, which would "eliminate all potential barriers to the timely access of affordable COVID-19 medical products, including vaccines and medicines, and scale up the manufacturing and supply of essential medical products."


Production

Vaccine production is fundamentally different from other kinds of manufacturingincluding regular pharmaceutical manufacturingin that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy. This fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products. Depending upon the antigen, it can cost anywhere from US$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, Cleanroom, clean rooms, and containment rooms. There is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines. With the notable exceptions of Brazil, China, and India, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going. Vaccine production has several stages. First, the antigen itself is generated. Viruses are grown either on primary cells such as Chicken as biological research model, chicken eggs (e.g., for influenza) or on continuous cell lines such as cultured human cells (e.g., for hepatitis A). Bacteria are grown in bioreactors (e.g., ''Haemophilus influenzae'' type b). Likewise, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures. After the antigen is generated, it is isolated from the cells used to generate it. A virus may need to be inactivated, possibly with no further purification required. Recombinant proteins need many operations involving ultrafiltration and column chromatography. Finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials. Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved. The final stage in vaccine manufacture before distribution is fill and finish, which is the process of filling vials with vaccines and packaging them for distribution. Although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines. Vaccine production techniques are evolving. Cultured mammalian cells are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. Recombination technology that produces genetically detoxified vaccines is expected to grow in popularity for the production of bacterial vaccines that use toxoids. Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns.


Vaccine manufacturers

The companies with the highest market share in vaccine production are Merck & Co., Merck, Sanofi, GlaxoSmithKline, Pfizer and Novartis, with 70% of vaccine sales concentrated in the EU or US (2013). Vaccine manufacturing plants require large capital investments ($50 million up to $300 million) and may take between 4 and 6 years to construct, with the full process of vaccine development taking between 10 and 15 years. Manufacturing in developing countries is playing an increasing role in supplying these countries, specifically with regards to older vaccines and in Brazil, India and China. The manufacturers in India are the most advanced in the developing world and include the Serum Institute of India, one of the largest producers of vaccines by number of doses and an innovator in processes, recently improving efficiency of producing the measles vaccine by 10 to 20-fold, due to switching to a MRC-5 cell culture instead of chicken eggs. China's manufacturing capabilities are focused on supplying their own domestic need, with Sinopharm, Sinopharm (CNPGC) alone providing over 85% of the doses for 14 different vaccines in China. Brazil is approaching the point of supplying its own domestic needs using technology transferred from the developed world.


Delivery systems

One of the most common methods of delivering vaccines into the human body is Injection (medicine), injection. The development of new delivery systems raises the hope of vaccines that are safer and more efficient to deliver and administer. Lines of research include liposomes and ''ISCOM'' (immune stimulating complex). Notable developments in vaccine delivery technologies have included oral vaccines. Early attempts to apply oral vaccines showed varying degrees of promise, beginning early in the 20th century, at a time when the very possibility of an effective oral antibacterial vaccine was controversial. By the 1930s there was increasing interest in the prophylactic value of an oral typhoid fever vaccine for example. An Polio vaccine, oral polio vaccine turned out to be effective when vaccinations were administered by volunteer staff without formal training; the results also demonstrated increased ease and efficiency of administering the vaccines. Effective oral vaccines have many advantages; for example, there is no risk of blood contamination. Vaccines intended for oral administration need not be liquid, and as solids, they commonly are more stable and less prone to damage or spoilage by freezing in transport and storage. Such stability reduces the need for a "cold chain": the resources required to keep vaccines within a restricted temperature range from the manufacturing stage to the point of administration, which, in turn, may decrease costs of vaccines. A microneedle approach, which is still in stages of development, uses "pointed projections fabricated into arrays that can create vaccine delivery pathways through the skin". An experimental needle-free vaccine delivery system is undergoing animal testing. A stamp-size patch similar to an adhesive bandage contains about 20,000 microscopic projections per square cm. This Dermis, dermal administration potentially increases the effectiveness of vaccination, while requiring less vaccine than injection.


In veterinary medicine

Vaccinations of animals are used both to prevent their contracting diseases and to prevent transmission of disease to humans. Both animals kept as pets and animals raised as livestock are routinely vaccinated. In some instances, wild populations may be vaccinated. This is sometimes accomplished with vaccine-laced food spread in a disease-prone area and has been used to attempt to control rabies in raccoons. Where rabies occurs, rabies vaccination of dogs may be required by law. Other canine vaccines include canine distemper, canine parvovirus, infectious canine hepatitis, Adenoviridae#Animals, adenovirus-2, leptospirosis, ''Bordetella'', canine parainfluenza virus, and Lyme disease, among others. Cases of veterinary vaccines used in humans have been documented, whether intentional or accidental, with some cases of resultant illness, most notably with brucellosis. However, the reporting of such cases is rare and very little has been studied about the safety and results of such practices. With the advent of aerosol vaccination in veterinary clinics, human exposure to pathogens not naturally carried in humans, such as ''Bordetella bronchiseptica'', has likely increased in recent years. In some cases, most notably Rabies vaccine, rabies, the parallel veterinary vaccine against a pathogen may be as much as orders of magnitude more economical than the human one.


DIVA vaccines

DIVA (Differentiation of Infected from Vaccinated Animals), also known as SIVA (Segregation of Infected from Vaccinated Animals) vaccines, make it possible to differentiate between infected and vaccinated animals. DIVA vaccines carry at least one epitope less than the equivalent wild microorganism. An accompanying diagnostic test that detects the antibody against that epitope assists in identifying whether the animal has been vaccinated or not. The first DIVA vaccines (formerly termed marker vaccines and since 1999 coined as DIVA vaccines) and companion diagnostic tests were developed by J. T. van Oirschot and colleagues at the Central Veterinary Institute in Lelystad, The Netherlands. They found that some existing vaccines against pseudorabies (also termed Aujeszky's disease) had deletions in their viral genome (among which was the gE gene). Monoclonal antibodies were produced against that deletion and selected to develop an ELISA that demonstrated antibodies against gE. In addition, novel genetically engineered gE-negative vaccines were constructed. Along the same lines, DIVA vaccines and companion diagnostic tests against bovine herpesvirus1 infections have been developed. The DIVA strategy has been applied in various countries to successfully eradicate pseudorabies virus from those countries. Swine populations were intensively vaccinated and monitored by the companion diagnostic test and, subsequently, the infected pigs were removed from the population. Bovine herpesvirus1 DIVA vaccines are also widely used in practice. Considerable efforts are ongoing to apply the DIVA principle to a wide range of infectious diseases, such as classical swine fever, avian influenza, ''Actinobacillus pleuropneumonia'' and ''Salmonella'' infections in pigs.


History

Prior to the introduction of vaccination with material from cases of cowpox (heterotypic immunisation), smallpox could be prevented by deliberate variolation with smallpox virus. The earliest hints of the practice of variolation for smallpox in China come during the tenth century. The Chinese also practiced the oldest documented use of variolation, dating back to the fifteenth century. They implemented a method of "nasal Insufflation (medicine), insufflation" administered by blowing powdered smallpox material, usually scabs, up the nostrils. Various insufflation techniques have been recorded throughout the sixteenth and seventeenth centuries within China. Two reports on the Chinese practice of
inoculation Inoculation is a set of methods of artificially inducing immunity against various infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and ...

inoculation
were received by the Royal Society in London in 1700; one by Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. Mary Wortley Montagu, who had witnessed variolation in Turkey, had her four-year-old daughter variolated in the presence of physicians of the Royal Court in 1721 upon her return to England. Later on that year, Charles Maitland (physician), Charles Maitland conducted an experimental variolation of six prisoners in Newgate Prison in London. The experiment was a success, and soon variolation was drawing attention from the royal family, who helped promote the procedure. However, in 1783, several days after Prince Octavius of Great Britain was inoculated, he died. In 1796, the physician
Edward Jenner Edward Jenner, (17 May 1749 – 26 January 1823) was a British physician A physician (American English), medical practitioner (English in the Commonwealth of Nations, Commonwealth English), medical doctor, or simply doctor, is a pro ...

Edward Jenner
took pus from the hand of a milkmaid with
cowpox Cowpox is an infectious disease caused by the cowpox virus (CPXV). The virus, part of the genus ''Orthopoxvirus ''Orthopoxvirus'' is a genus of virus A virus is a submicroscopic infectious agent that Viral replication, replicates on ...
, scratched it into the arm of an 8-year-old boy, James Phipps, and six weeks later variolated the boy with smallpox, afterwards observing that he did not catch smallpox. Jenner extended his studies and, in 1798, reported that his vaccine was safe in children and adults, and could be transferred from arm-to-arm, which reduced reliance on uncertain supplies from infected cows. In 1804, the Spanish Balmis Expedition, Balmis smallpox vaccination expedition to Spain's colonies Mexico and Philippines used the arm-to-arm transport method to get around the fact the vaccine survived for only 12 days ''in vitro''. They used cowpox. Since vaccination with cowpox was much safer than smallpox inoculation, the latter, though still widely practiced in England, was banned in 1840. Following on from Jenner's work, the second generation of vaccines was introduced in the 1880s by
Louis Pasteur Louis Pasteur (, ; 27 December 1822 – 28 September 1895) was a French chemist and microbiologist renowned for his discoveries of the principles of vaccination, fermentation, microbial fermentation, and pasteurization. His research in chemi ...

Louis Pasteur
who developed vaccines for chicken cholera and anthrax, and from the late nineteenth century vaccines were considered a matter of national prestige. National vaccination policies were adopted and compulsory vaccination laws were passed. In 1931 Alice Miles Woodruff and Ernest Goodpasture documented that the fowlpox virus could be grown in embryonated chicken egg. Soon scientists began cultivating other viruses in eggs. Eggs were used for virus propagation in the development of a yellow fever vaccine in 1935 and an
influenza vaccine Influenza vaccines, also known as flu shots or flu jabs, are vaccines that protect against infection by influenza viruses. New versions of the vaccines are developed twice a year, as the influenza virus rapidly changes. While their effectiveness ...
in 1945. In 1959 growth media and cell culture replaced eggs as the standard method of virus propagation for vaccines. Vaccinology flourished in the twentieth century, which saw the introduction of several successful vaccines, including those against
diphtheria Diphtheria is an infection caused by the bacteria, bacterium ''Corynebacterium diphtheriae''. Most infections are asymptomatic or have a mild Course (medicine), clinical course, but in some outbreaks more than 10% of those diagnosed with the di ...

diphtheria
,
measles Measles is a highly contagious infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), host tissues to ...
,
mumps Mumps is a viral disease A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infection, infectious virus particles (virions) attach to and enter susceptible cells. Structural characteris ...

mumps
, and
rubella Rubella, also known as German measles or three-day measles, is an infection An infection is the invasion of an organism's body by , their multiplication, and the reaction of tissues to the infectious agents and the s they produce. An inf ...

rubella
. Major achievements included the development of the
polio vaccine Polio vaccines are vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often ...
in the 1950s and the eradication of smallpox during the 1960s and 1970s. Maurice Hilleman was the most prolific of the developers of the vaccines in the twentieth century. As vaccines became more common, many people began taking them for granted. However, vaccines remain elusive for many important diseases, including herpes, herpes simplex, malaria, gonorrhea, and HIV.


Generations of vaccines

First generation vaccines are whole-organism vaccineseither live and Attenuated virus, weakened, or killed forms. Live, attenuated vaccines, such as smallpox and polio vaccines, are able to induce Cytotoxic T cell, killer T-cell (TC or CTL) responses, Helper T cell, helper T-cell (TH) responses and antibody Immune system, immunity. However, attenuated forms of a
pathogen In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanism ...
can convert to a dangerous form and may cause disease in immunocompromised vaccine recipients (such as those with AIDS). While killed vaccines do not have this risk, they cannot generate specific killer T cell responses and may not work at all for some diseases. Second generation vaccines were developed to reduce the risks from live vaccines. These are subunit vaccines, consisting of specific
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
antigen In immunology Immunology is a branch of biology that covers the study of immune systems in all organisms. Immunology charts, measures, and contextualizes the Physiology, physiological functioning of the immune system in states of both health ...
s (such as
tetanus Tetanus, also known as lockjaw, is a bacterial infection Pathogenic bacteria are bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), biological cell. They constitute a large domain (biology), do ...
or
diphtheria Diphtheria is an infection caused by the bacteria, bacterium ''Corynebacterium diphtheriae''. Most infections are asymptomatic or have a mild Course (medicine), clinical course, but in some outbreaks more than 10% of those diagnosed with the di ...

diphtheria
toxoid) or Recombinant DNA, recombinant protein components (such as the hepatitis B surface antigen). They can generate TH and antibody responses, but not killer T cell responses.
RNA vaccine An mRNA vaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine RNA transfection, delivers molecules of antigen-encoding mRNA into dendritic cell, immune cells, which us ...
s and DNA vaccines are examples of third generation vaccines. In 2016 a DNA vaccine for the Zika virus began testing at the National Institutes of Health. Separately, Inovio Pharmaceuticals and GeneOne Life Science began tests of a different DNA vaccine against Zika in Miami. Manufacturing the vaccines in volume was unsolved as of 2016. Clinical trials for DNA vaccines to prevent HIV are underway. mRNA vaccines such as BNT162b2 were developed in the year 2020 with the help of Operation Warp Speed and massively deployed to combat the
COVID-19 pandemic The COVID-19 pandemic is an ongoing global pandemic A pandemic (from , , "all" and , , "local people" the 'crowd') is an of an that has spread across a large region, for instance multiple or worldwide, affecting a substantial numbe ...

COVID-19 pandemic
. In 2021, Katalin Karikó and Drew Weissman received Columbia University's Horwitz Prize for their pioneering research in mRNA vaccine technology.


Trends

Since at least 2013, scientists were trying to develop synthetic third-generation vaccines by reconstructing the outside structure of a
virus A virus is a submicroscopic infectious agent In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecu ...

virus
; it was hoped that this will help prevent vaccine resistance. Principles that govern the immune response can now be used in tailor-made vaccines against many noninfectious human diseases, such as cancers and autoimmune disorders. For example, the experimental vaccine CYT006-AngQb has been investigated as a possible treatment for hypertension, high blood pressure. Factors that affect the trends of vaccine development include progress in translatory medicine, demographics, Regulatory Science, regulatory science, political, cultural, and social responses.


Plants as bioreactors for vaccine production

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


See also

* Biologics Control Act * Coalition for Epidemic Preparedness Innovations * Flying syringe * Immunization registry * Immunotherapy * List of vaccine ingredients * List of vaccine topics * Non-specific effect of vaccines * OPV AIDS hypothesis * Preventive healthcare * Reverse vaccinology * TA-CD * Timeline of vaccines * Virosome * Vaccinator * Vaccine adverse event (safety issues) * Vaccine cooler * Vaccine failure * Vaccine hesitancy * Vaccinov * Viral vector * Virus-like particle * Nasal vaccine


References


External links

*
WHO Vaccine preventable diseases and immunization

World Health Organization position papers on vaccines

The History of Vaccines
from the College of Physicians of Philadelphia *: This website was highlighted by ''Genetic Engineering & Biotechnology News'' in its "Best of the Web" section in January 2015. See: {{Authority control Vaccines, Virology 18th-century inventions Preventive medicine,