Poliovirus

From Wikipedia, the free encyclopedia

Poliovirus 1
TEM micrograph of poliovirus virions. Scale bar, 50 nm.
A type 3 poliovirus capsid coloured by chains
Virus classification
(unranked):	Virus
Realm:	Riboviria
(unranked):	incertae sedis
Order:	Picornavirales
Family:	Picornaviridae
Genus:	Enterovirus
Species:	Enterovirus C
Virus:	Poliovirus 1

Poliovirus, the causative agent of polio (also known as poliomyelitis), is a member virus of Enterovirus C, in the family of Picornaviridae.

Poliovirus is composed of an RNA genome and a protein capsid. The genome is a single-stranded positive-sense RNA genome that is about 7500 nucleotides long. The viral particle is about 30 nm in diameter with icosahedral symmetry. Because of its short genome and its simple composition—only RNA and a nonenveloped icosahedral protein coat that encapsulates it, poliovirus is widely regarded as the simplest significant virus.

Poliovirus was first isolated in 1909 by Karl Landsteiner and Erwin Popper. In 1981, the poliovirus genome was published by two different teams of researchers: by Vincent Racaniello and David Baltimore at MIT and by Naomi Kitamura and Eckard Wimmer at Stony Brook University. Poliovirus is one of the most well-characterized viruses, and has become a useful model system for understanding the biology of RNA viruses.

Replication cycle

The replication cycle of poliovirus is initiated (1) by binding to the cell surface receptor CD155. The virion is taken up via endocytosis, and the viral RNA is released (2). Translation of the viral RNA occurs by an IRES-mediated mechanism (3). The polyprotein is cleaved, yielding mature viral proteins (4). The positive-sense RNA serves as template for complementary negative-strand synthesis, producing double-stranded replicative form (RF) RNA(5). Many positive strand RNA copies are produced from the single negative strand (6). The newly synthesized positive-sense RNA molecules can serve as templates for translation of more viral proteins (7) or can be enclosed in a capsid (8), which ultimately generates progeny virions. Lysis of the infected cell results in release of infectious progeny virions (9).

 

Poliovirus infects human cells by binding to an immunoglobulin-like receptor, CD155 (also known as the poliovirus receptor or PVR) on the cell surface. Interaction of poliovirus and CD155 facilitates an irreversible conformational change of the viral particle necessary for viral entry. Attached to the host cell membrane, entry of the viral nucleic acid was thought to occur one of two ways: via the formation of a pore in the plasma membrane through which the RNA is then “injected” into the host cell cytoplasm, or that the virus is taken up by receptor-mediated endocytosis. Recent experimental evidence supports the latter hypothesis and suggests that poliovirus binds to CD155 and is taken up by endocytosis. Immediately after internalization of the particle, the viral RNA is released.

Poliovirus is a positive-stranded RNA virus. Thus, the genome enclosed within the viral particle can be used as messenger RNA and immediately translated by the host cell. On entry, the virus hijacks the cell's translation machinery, causing inhibition of cellular protein synthesis in favor of virus-specific protein production. Unlike the host cell's mRNAs, the 5' end of poliovirus RNA is extremely long—over 700 nucleotides—and highly structured. This region of the viral genome is called internal ribosome entry site (IRES), and it directs translation of the viral RNA. Genetic mutations in this region prevent viral protein production. The first IRES to be discovered was found in poliovirus RNA.

Poliovirus mRNA is translated as one long polypeptide. This polypeptide is then autocleaved by internal proteases into about 10 individual viral proteins. Not all cleavages occur with the same efficiency. Therefore, the amounts of proteins produced by the polypeptide cleavage vary: for example, smaller amounts of 3D^pol are produced than those of capsid proteins, VP1–4. These individual viral proteins are:

The genomic structure of poliovirus type 1

• 3D^pol, an RNA dependent RNA polymerase whose function is to make multiple copies of the viral RNA genome
• 2A^pro and 3C^pro/3CD^pro, proteases which cleave the viral polypeptide
• VPg (3B), a small protein that binds viral RNA and is necessary for synthesis of viral positive and negative strand RNA
• 2BC, 2B, 2C (an ATPase)^[23], 3AB, 3A, 3B proteins which comprise the protein complex needed for virus replication.
• VP0, which is further cleaved into VP2 and VP4, VP1 and VP3, proteins of the viral capsid

After translation, transcription and genome replication which involve a single process (synthesis of (+) RNA) is realized. For the infecting (+) RNA to be replicated, multiple copies of (−) RNA must be transcribed and then used as templates for (+) RNA synthesis. Replicative intermediates (RIs) which are an association of RNA molecules consisting of a template RNA and several growing RNAs of varying length, are seen in both the replication complexes for (−) RNAs and (+) RNAs. The primer for both (+) and (−) strand synthesis is the small protein VPg, which is uridylylated at the hydroxyl group of a tyrosine residue by the poliovirus RNA polymerase at a cis-acting replication element located in a stem-loop in the virus genome. Some of the (+) RNA molecules are used as templates for further (−) RNA synthesis, some function as mRNA, and some are destined to be the genomes of progeny virions.

In the assembly of new virus particles (i.e. the packaging of progeny genome into a procapsid which can survive outside the host cell), including, respectively:

• Five copies each of VP0, VP3, and VP1 which its N termini and VP4 form interior surface of capsid, assemble into a ‘pentamer’ and 12 pentamers form a procapsid. (The outer surface of capsid is consisting of VP1, VP2, VP3; C termini of VP1 and VP3 form the canyons which around each of the vertices; around this time, the 60 copies of VP0 are cleaved into VP4 and VP2.)
• Each procapsid acquires a copy of the virus genome, with VPg still attached at the 5' end.

Fully assembled poliovirus leaves the confines of its host cell by lysis 4 to 6 hours following initiation of infection in cultured mammalian cells. The mechanism of viral release from the cell is unclear, but each dying cell can release up to 10,000 polio virions.

Drake demonstrated that poliovirus is able to undergo multiplicity reactivation. That is, when polioviruses were irradiated with UV light and allowed to undergo multiple infections of host cells, viable progeny could be formed even at UV doses that inactivated the virus in single infections.

Origin and serotypes

Poliovirus is structurally similar to other human enteroviruses (coxsackieviruses, echoviruses, and rhinoviruses), which also use immunoglobulin-like molecules to recognize and enter host cells. Phylogenetic analysis of the RNA and protein sequences of poliovirus suggests that it may have evolved from a C-cluster Coxsackie A virus ancestor, that arose through a mutation within the capsid. The distinct speciation of poliovirus probably occurred as a result of change in cellular receptor specificity from intercellular adhesion molecule-1 (ICAM-1), used by C-cluster Coxsackie A viruses, to CD155; leading to a change in pathogenicity, and allowing the virus to infect nervous tissue.

The mutation rate in the virus is relatively high even for an RNA virus with a synonymous substitution rate of 1.0 x 10⁻² substitutions/site/year and non synonymous substitution rate of 3.0 x 10⁻⁴ substitutions/site/year. Base distribution within the genome is not random with adenosine being less common than expected at the 5' end and higher at the 3' end. Codon use is not random with codons ending in adenosine being favoured and those ending in cytosine or guanine being avoided. Codon use differs between the three genotypes and appears to be driven by mutation rather than selection.

The three serotypes of poliovirus, PV1, PV2, and PV3, each have a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV1 is the most common form encountered in nature, but all three forms are extremely infectious. As of November 2015, wild PV1 is highly localized to regions in Pakistan and Afghanistan. Wild PV2 was declared eradicated in September 2015 after last being detected in October 1999 in Uttar Pradesh, India. As of November 2015, wild PV3 has not been seen since its 2012 detection in parts of Nigeria and Pakistan.

Specific strains of each serotype are used to prepare vaccines against polio. Inactive polio vaccine is prepared by formalin inactivation of three wild, virulent reference strains, Mahoney or Brunenders (PV1), MEF-1/Lansing (PV2), and Saukett/Leon (PV3). Oral polio vaccine contains live attenuated (weakened) strains of the three serotypes of poliovirus. Passaging the virus strains in monkey kidney epithelial cells introduces mutations in the viral IRES, and hinders (or attenuates) the ability of the virus to infect nervous tissue.

Polioviruses were formerly classified as a distinct species belonging to the genus Enterovirus in the family Picornaviridae. In 2008, the Poliovirus species was eliminated and the three serotypes were assigned to the species Human enterovirus C (later renamed Enterovirus C), in the genus Enterovirus in the family Picornaviridae. The type species of the genus Enterovirus was changed from Poliovirus to (Human) Enterovirus C.

Pathogenesis

Electron micrograph of poliovirus

 

The primary determinant of infection for any virus is its ability to enter a cell and produce additional infectious particles. The presence of CD155 is thought to define the animals and tissues that can be infected by poliovirus. CD155 is found (outside of laboratories) only on the cells of humans, higher primates, and Old World monkeys. Poliovirus is, however, strictly a human pathogen, and does not naturally infect any other species (although chimpanzees and Old World monkeys can be experimentally infected).

The CD155 gene appears to have been subject to positive selection. The protein has several domains of which domain D1 contains the polio virus binding site. Within this domain, 37 amino acids are responsible for binding the virus. 

Poliovirus is an enterovirus. Infection occurs via the fecal–oral route, meaning that one ingests the virus and viral replication occurs in the alimentary tract. Virus is shed in the feces of infected individuals. In 95% of cases only a primary, transient presence of viremia (virus in the bloodstream) occurs, and the poliovirus infection is asymptomatic. In about 5% of cases, the virus spreads and replicates in other sites such as brown fat, reticuloendothelial tissue, and muscle. The sustained viral replication causes secondary viremia and leads to the development of minor symptoms such as fever, headache, and sore throat. Paralytic poliomyelitis occurs in less than 1% of poliovirus infections. Paralytic disease occurs when the virus enters the central nervous system (CNS) and replicates in motor neurons within the spinal cord, brain stem, or motor cortex, resulting in the selective destruction of motor neurons leading to temporary or permanent paralysis. In rare cases, paralytic poliomyelitis leads to respiratory arrest and death. In cases of paralytic disease, muscle pain and spasms are frequently observed prior to onset of weakness and paralysis. Paralysis typically persists from days to weeks prior to recovery.

In many respects, the neurological phase of infection is thought to be an accidental diversion of the normal gastrointestinal infection. The mechanisms by which poliovirus enters the CNS are poorly understood. Three nonmutually exclusive hypotheses have been suggested to explain its entry. All theories require primary viremia. The first hypothesis predicts that virions pass directly from the blood into the central nervous system by crossing the blood–brain barrier independent of CD155. A second hypothesis suggests that the virions are transported from peripheral tissues that have been bathed in the viremic blood, for example muscle tissue, to the spinal cord through nerve pathways via retrograde axonal transport. A third hypothesis is that the virus is imported into the CNS via infected monocytes or macrophages.

Poliomyelitis is a disease of the central nervous system. However, CD155 is believed to be present on the surface of most or all human cells. Therefore, receptor expression does not explain why poliovirus preferentially infects certain tissues. This suggests that tissue tropism is determined after cellular infection. Recent work has suggested that the type I interferon response (specifically that of interferon alpha and beta) is an important factor that defines which types of cells support poliovirus replication. In mice expressing CD155 (through genetic engineering) but lacking the type I interferon receptor, poliovirus not only replicates in an expanded repertoire of tissue types, but these mice are also able to be infected orally with the virus.

Immune system avoidance

CD155 molecules complexed with a poliovirus particle. Reconstructed image from cryo-electron microscopy.

 

Poliovirus uses two key mechanisms to evade the immune system. First, it is capable of surviving the highly acidic conditions of the stomach, allowing the virus to infect the host and spread throughout the body via the lymphatic system. Second, because it can replicate very quickly, the virus overwhelms the host organs before an immune response can be mounted. If detail is given at the attachment phase; poliovirus with canyons on the virion surface have virus attachment sites located in pockets at the canyon bases. The canyons are too narrow for access by antibodies, so the virus attachment sites are protected from the host’s immune surveillance, while the remainder of the virion surface can mutate to avoid the host’s immune response.

Individuals who are exposed to poliovirus, either through infection or by immunization with polio vaccine, develop immunity. In immune individuals, antibodies against poliovirus are present in the tonsils and gastrointestinal tract (specifically IgA antibodies) and are able to block poliovirus replication; IgG and IgM antibodies against poliovirus can prevent the spread of the virus to motor neurons of the central nervous system. Infection with one serotype of poliovirus does not provide immunity against the other serotypes, however second attacks within the same individual are extremely rare .

PVR transgenic mouse

Although humans are the only known natural hosts of poliovirus, monkeys can be experimentally infected and they have long been used to study poliovirus. In 1990–91, a small animal model of poliomyelitis was developed by two laboratories. Mice were engineered to express a human receptor to poliovirus (hPVR).

Unlike normal mice, transgenic poliovirus receptor (TgPVR) mice are susceptible to poliovirus injected intravenously or intramuscularly, and when injected directly into the spinal cord or the brain. Upon infection, TgPVR mice show signs of paralysis that resemble those of poliomyelitis in humans and monkeys, and the central nervous systems of paralyzed mice are histocytochemically similar to those of humans and monkeys. This mouse model of human poliovirus infection has proven to be an invaluable tool in understanding poliovirus biology and pathogenicity.

Three distinct types of TgPVR mice have been well studied:

• In TgPVR1 mice, the transgene encoding the human PVR was incorporated into mouse chromosome 4. These mice express the highest levels of the transgene and the highest sensitivity to poliovirus. TgPVR1 mice are susceptible to poliovirus through the intraspinal, intracerebral, intramuscular, and intravenous pathways, but not through the oral route.
• TgPVR21 mice have incorporated the human PVR at chromosome 13. These mice are less susceptible to poliovirus infection through the intracerebral route, possibly because they express decreased levels of hPVR. TgPVR21 mice have been shown to be susceptible to poliovirus infection through intranasal inoculation, and may be useful as a mucosal infection model.
• In TgPVR5 mice, the human transgene is located on chromosome 12. These mice exhibit the lowest levels of hPVR expression and are the least susceptible to poliovirus infection.

Recently, a fourth TgPVR mouse model was developed. These "cPVR" mice carry hPVR cDNA, driven by a β-actin promoter, and have proven susceptible to poliovirus through intracerebral, intramuscular, and intranasal routes. In addition, these mice are capable of developing the bulbar form of polio after intranasal inoculation.

The development of the TgPVR mouse has had a profound effect on oral poliovirus vaccine (OPV) production. Previously, monitoring the safety of OPV had to be performed using monkeys, because only primates are susceptible to the virus. In 1999, the World Health Organization approved the use of the TgPVR mouse as an alternative method of assessing the effectiveness of the vaccine against poliovirus type-3. In 2000, the mouse model was approved for tests of vaccines against type-1 and type-2 poliovirus.

Cloning and synthesis

Model of poliovirus-binding CD155 (shown in purple)

 

In 1981, Racaniello and Baltimore used recombinant DNA technology to generate the first infectious clone of an animal RNA virus, poliovirus. DNA encoding the RNA genome of poliovirus was introduced into cultured mammalian cells and infectious poliovirus was produced. Creation of the infectious clone propelled understanding of poliovirus biology, and has become a standard technology used to study many other viruses. 

In 2002, Eckard Wimmer's group at SUNY Stony Brook succeeded in synthesizing poliovirus from its chemical code, producing the world's first synthetic virus. Scientists first converted poliovirus's published RNA sequence, 7741 bases long, into a DNA sequence, as DNA was easier to synthesize. Short fragments of this DNA sequence were obtained by mail-order, and assembled. The complete viral genome was then assembled by a gene synthesis company. This whole painstaking process took two years. Nineteen markers were incorporated into the synthesized DNA, so that it could be distinguished from natural poliovirus. Enzymes were used to convert the DNA back into RNA, its natural state. Other enzymes were then used to translate the RNA into a polypeptide, producing functional viral particle. The newly minted synthetic virus was injected into PVR transgenic mice, to determine if the synthetic version was able to cause disease. The synthetic virus was able to replicate, infect, and cause paralysis or death in mice. However, the synthetic version was between 1/1,000th and 1/10,000th as lethal as the original virus.

Modification for therapies

A modification of the poliovirus, called PVSRIPO, was tested in early clinical trials as a possible treatment for cancer.^{[58][needs update]}

History of polio

From Wikipedia, the free encyclopedia

An Egyptian stele thought to represent a polio victim. 18th Dynasty (1403–1365 BC).

 

The history of polio (poliomyelitis) infections extends into prehistory. Although major polio epidemics were unknown before the 20th century, the disease has caused paralysis and death for much of human history. Over millennia, polio survived quietly as an endemic pathogen until the 1900s when major epidemics began to occur in Europe; soon after, widespread epidemics appeared in the United States. By 1910, frequent epidemics became regular events throughout the developed world, primarily in cities during the summer months. At its peak in the 1940s and 1950s, polio would paralyze or kill over half a million people worldwide every year.

The fear and the collective response to these epidemics would give rise to extraordinary public reaction and mobilization; spurring the development of new methods to prevent and treat the disease, and revolutionizing medical philanthropy. Although the development of two polio vaccines has eliminated poliomyelitis in all but three countries (Afghanistan, Pakistan and Nigeria), the legacy of poliomyelitis remains, in the development of modern rehabilitation therapy, and in the rise of disability rights movements worldwide.

Early history

Ancient Egyptian paintings and carvings depict otherwise healthy people with withered limbs, and children walking with canes at a young age. It is theorized that the Roman Emperor Claudius was stricken as a child, and this caused him to walk with a limp for the rest of his life. Perhaps the earliest recorded case of poliomyelitis is that of Sir Walter Scott. In 1773 Scott was said to have developed "a severe teething fever which deprived him of the power of his right leg". At the time, polio was not known to medicine. A retrospective diagnosis of polio is considered to be strong due to the detailed account Scott later made, and the resultant lameness of his right leg had an important effect on his life and writing.

The symptoms of poliomyelitis have been described by many names. In the early nineteenth century the disease was known variously as: Dental Paralysis, Infantile Spinal Paralysis, Essential Paralysis of Children, Regressive Paralysis, Myelitis of the Anterior Horns, Tephromyelitis (from the Greek tephros, meaning "ash-gray") and Paralysis of the Morning. In 1789 the first clinical description of poliomyelitis was provided by the British physician Michael Underwood—he refers to polio as "a debility of the lower extremities". The first medical report on poliomyelitis was by Jakob Heine, in 1840; he called the disease Lähmungszustände der unteren Extremitäten ("Paralysis of the lower Extremities"). Karl Oskar Medin was the first to empirically study a poliomyelitis epidemic in 1890. This work, and the prior classification by Heine, led to the disease being known as Heine-Medin disease.

Epidemics

Major polio epidemics were unknown before the 20th century; localized paralytic polio epidemics began to appear in Europe and the United States around 1900. The first report of multiple polio cases was published in 1843 and described an 1841 outbreak in Louisiana. A fifty-year gap occurs before the next U.S. report—a cluster of 26 cases in Boston in 1893. The first recognized U.S. polio epidemic occurred the following year in Vermont with 132 total cases (18 deaths), including several cases in adults. Numerous epidemics of varying magnitude began to appear throughout the country; by 1907 approximately 2,500 cases of poliomyelitis were reported in New York City.

This cardboard placard was placed in windows of residences where patients were quarantined due to poliomyelitis. Violating the quarantine order or removing the placard was punishable by a fine of up to US$100 in 1909 (equivalent to $2,789 in 2018).

Polio was a plague. One day you had a headache and an hour later you were paralyzed. How far the virus crept up your spine determined whether you could walk afterward or even breathe. Parents waited fearfully every summer to see if it would strike. One case turned up and then another. The count began to climb. The city closed the swimming pools and we all stayed home, cooped indoors, shunning other children. Summer seemed like winter then.

Richard Rhodes, A Hole in the World

 

On Saturday, June 17, 1916, an official announcement of the existence an epidemic polio infection was made in Brooklyn, New York. That year, there were over 27,000 cases and more than 6,000 deaths due to polio in the United States, with over 2,000 deaths in New York City alone. The names and addresses of individuals with confirmed polio cases were published daily in the press, their houses were identified with placards, and their families were quarantined. Dr. Hiram M. Hiller, Jr. was one of the physicians in several cities who realized what they were dealing with, but the nature of the disease remained largely a mystery. The 1916 epidemic caused widespread panic and thousands fled the city to nearby mountain resorts; movie theaters were closed, meetings were canceled, public gatherings were almost nonexistent, and children were warned not to drink from water fountains, and told to avoid amusement parks, swimming pools, and beaches. From 1916 onward, a polio epidemic appeared each summer in at least one part of the country, with the most serious occurring in the 1940s and 1950s. In the epidemic of 1949, 2,720 deaths from the disease occurred in the United States and 42,173 cases were reported and Canada and the United Kingdom were also affected.

Prior to the 20th century polio infections were rarely seen in infants before 6 months of age and most cases occurred in children 6 months to 4 years of age. Young children who contract polio generally suffer only mild symptoms, but as a result they become permanently immune to the disease. In developed countries during the late 19th and early 20th centuries, improvements were being made in community sanitation, including improved sewage disposal and clean water supplies. Better hygiene meant that infants and young children had fewer opportunities to encounter and develop immunity to polio. Exposure to poliovirus was therefore delayed until late childhood or adult life, when it was more likely to take the paralytic form.

In children, paralysis due to polio occurs in one in 1000 cases, while in adults, paralysis occurs in one in 75 cases. By 1950, the peak age incidence of paralytic poliomyelitis in the United States had shifted from infants to children aged 5 to 9 years; about one-third of the cases were reported in persons over 15 years of age. Accordingly, the rate of paralysis and death due to polio infection also increased during this time. In the United States, the 1952 polio epidemic was the worst outbreak in the nation's history, and is credited with heightening parents’ fears of the disease and focusing public awareness on the need for a vaccine. Of the 57,628 cases reported that year 3,145 died and 21,269 were left with mild to disabling paralysis.

Historical treatments

In the early 20th century—in the absence of proven treatments—a number of odd and potentially dangerous polio treatments were suggested. In John Haven Emerson's A Monograph on the Epidemic of Poliomyelitis (Infantile Paralysis) in New York City in 1916 one suggested remedy reads: 

“

Give oxygen through the lower extremities, by positive electricity. Frequent baths using almond meal, or oxidising the water. Applications of poultices of Roman chamomile, slippery elm, arnica, mustard, cantharis, amygdalae dulcis oil, and of special merit, spikenard oil and Xanthoxolinum. Internally use caffeine, Fl. Kola, dry muriate of quinine, elixir of cinchone, radium water, chloride of gold, liquor calcis and wine of pepsin.

”

Following the 1916 epidemics and having experienced little success in treating polio patients, researchers set out to find new and better treatments for the disease. Between 1917 and the early 1950s several therapies were explored in an effort to prevent deformities including hydrotherapy and electrotherapy.

In 1935 Claus Jungeblut reported that vitamin C treatment inactivates the polio virus in vitro, making it non-infectious when injected into monkeys. In 1937, Jungeblut injected polio into the brains of monkeys, and found that many more monkeys that also received vitamin C escaped paralysis than controls - the results seemed to indicate that low doses were more effective than high doses. A subsequent study by Jungeblut demonstrated that polio infected monkeys had lower vitamin C levels than others, and that the monkeys that escaped paralysis had the highest vitamin C levels. Jungeblut subsequently confirmed his findings in a larger study, finding that natural vitamin C was more effective than synthetic vitamin C, and as the disease progressed, larger and larger amounts of vitamin C were needed for therapeutic effect.

In 1939, Albert Sabin reported that an experiment, employing the technique of "forcefully expelling the total amount [of Polio] in the direction of the olfactory mucosa, immediately drawing it back into the pipette, and repeating the process 2 to 3 times", was unable to confirm the results of Jungeblut, but found that "monkeys on a scorbutic diet died of spontaneous acute infections, chiefly pneumonia and enterocolitis, while their mates receiving an adequate diet remained well." Following this, Jungeblut found that "with an infection of maximum severity, induced by flooding the nasal portal of entry with large amounts of virus, vitamin C administration fails to exert any demonstrable influence on the course of the disease, but with a less forceful method of droplet instillation, the picture of the disease in control animals becomes so variable that the results cannot be easily interpreted; but the available data suggest that vitamin C treatment may be a factor in converting abortive attacks into an altogether non-paralytic infection." In 1979, R.J. Salo and D.O. Cliver inactivated Poliovirus type 1 by sodium bisulfite and ascorbic acid in an experiment.

In 1949-1953 Fred R. Klenner published his own clinical experience with vitamin C in the treatment of polio, however his work was not well received and no large clinical trials were ever performed. 

Surgical treatments such as nerve grafting, tendon lengthening, tendon transfers, and limb lengthening and shortening were used extensively during this time. Patients with residual paralysis were treated with braces and taught to compensate for lost function with the help of calipers, crutches and wheelchairs. The use of devices such as rigid braces and body casts, which tended to cause muscle atrophy due to the limited movement of the user, were also touted as effective treatments. Massage and passive motion exercises were also used to treat polio victims. Most of these treatments proved to be of little therapeutic value, however several effective supportive measures for the treatment of polio did emerge during these decades including the iron lung, an anti-polio antibody serum, and a treatment regimen developed by Sister Elizabeth Kenny.

Iron lung

This iron lung was donated to the CDC by the family of Barton Hebert of Covington, Louisiana, who had used the device from the late 1950s until his death in 2003.

 

The first iron lung used in the treatment of polio victims was invented by Philip Drinker, Louis Agassiz Shaw, and James Wilson at Harvard, and tested October 12, 1928, at Children's Hospital, Boston. The original Drinker iron lung was powered by an electric motor attached to two vacuum cleaners, and worked by changing the pressure inside the machine. When the pressure is lowered, the chest cavity expands, trying to fill this partial vacuum. When the pressure is raised the chest cavity contracts. This expansion and contraction mimics the physiology of normal breathing. The design of the iron lung was subsequently improved by using a bellows attached directly to the machine, and John Haven Emerson modified the design to make production less expensive. The Emerson Iron Lung was produced until 1970. Other respiratory aids were used such as the Bragg-Paul Pulsator, and the "rocking bed" for patients with less critical breathing difficulties.

During the polio epidemics, the iron lung saved many thousands of lives, but the machine was large, cumbersome and very expensive: in the 1930s, an iron lung cost about $1,500—about the same price as the average home. The cost of running the machine was also prohibitive, as patients were encased in the metal chambers for months, years and sometimes for life: even with an iron lung the fatality rate for patients with bulbar polio exceeded 90%.

These drawbacks led to the development of more modern positive-pressure ventilators and the use of positive-pressure ventilation by tracheostomy. Positive pressure ventilators reduced mortality in bulbar patients from 90% to 20%. In the Copenhagen epidemic of 1952, large numbers of patients were ventilated by hand ("bagged") by medical students and anyone else on hand, because of the large number of bulbar polio patients and the small number of ventilators available.

Passive immunotherapy

In 1950 William Hammon at the University of Pittsburgh isolated serum, containing antibodies against poliovirus, from the blood of polio survivors. The serum, Hammon believed, would prevent the spread of polio and to reduce the severity of disease in polio patients. Between September 1951 and July 1952 nearly 55,000 children were involved in a clinical trial of the anti-polio serum. The results of the trial were promising; the serum was shown to be about 80% effective in preventing the development of paralytic poliomyelitis, and protection was shown to last for 5 weeks if given under tightly controlled circumstances. The serum was also shown to reduce the severity of the disease in patients who developed polio.

The large-scale use of antibody serum to prevent and treat polio had a number of drawbacks, however, including the observation that the immunity provided by the serum did not last long, and the protection offered by the antibody was incomplete, that re-injection was required during each epidemic outbreak, and that the optimal time frame for administration was unknown. The antibody serum was widely administered, but obtaining the serum was an expensive and time-consuming process, and the focus of the medical community soon shifted to the development of a polio vaccine.

Kenny regimen

Early management practices for paralyzed muscles emphasized the need to rest the affected muscles and suggested that the application of splints would prevent tightening of muscle, tendons, ligaments, or skin that would prevent normal movement. Many paralyzed polio patients lay in plaster body casts for months at a time. This prolonged casting often resulted in atrophy of both affected and unaffected muscles.

In 1940, Sister Elizabeth Kenny, an Australian bush nurse from Queensland, arrived in North America and challenged this approach to treatment. In treating polio cases in rural Australia between 1928 and 1940, Kenny had developed a form of physical therapy that—instead of immobilizing afflicted limbs—aimed to relieve pain and spasms in polio patients through the use of hot, moist packs to relieve muscle spasm and early activity and exercise to maximize the strength of unaffected muscle fibers and promote the neuroplastic recruitment of remaining nerve cells that had not been killed by the virus. Sister Kenny later settled in Minnesota where she established the Sister Kenny Rehabilitation Institute, beginning a world-wide crusade to advocate her system of treatment. Slowly, Kenny's ideas won acceptance, and by the mid-20th century had become the hallmark for the treatment of paralytic polio. In combination with antispasmodic medications to reduce muscular contractions, Kenny's therapy is still used in the treatment of paralytic poliomyelitis. 

In 2009 as part of the Q150 celebrations, the Kenny regimen for polio treatment was announced as one of the Q150 Icons of Queensland for its role as an iconic "innovation and invention".

Vaccine development

People in Columbus, Georgia, awaiting polio vaccination during the early days of the National Polio Immunization Program.

 

In 1935 Maurice Brodie, a research assistant at New York University, attempted to produce a polio vaccine, procured from virus in ground up monkey spinal cords, and killed by formaldehyde. Brodie first tested the vaccine on himself and several of his assistants. He then gave the vaccine to three thousand children. Many developed allergic reactions, but none of the children developed an immunity to polio. During the late 1940s and early 1950s, a research group, headed by John Enders at the Boston Children's Hospital, successfully cultivated the poliovirus in human tissue. This significant breakthrough ultimately allowed for the development of the polio vaccines. Enders and his colleagues, Thomas H. Weller and Frederick C. Robbins, were recognized for their labors with the Nobel Prize in 1954.

Two vaccines are used throughout the world to combat polio. The first was developed by Jonas Salk, first tested in 1952, and announced to the world by Salk on April 12, 1955. The Salk vaccine, or inactivated poliovirus vaccine (IPV), consists of an injected dose of killed poliovirus. In 1954, the vaccine was tested for its ability to prevent polio; the field trials involving the Salk vaccine would grow to be the largest medical experiment in history. Immediately following licensing, vaccination campaigns were launched, by 1957, following mass immunizations promoted by the March of Dimes the annual number of polio cases in the United States was reduced, from a peak of nearly 58,000 cases, to 5,600 cases.

Eight years after Salk's success, Albert Sabin developed an oral polio vaccine (OPV) using live but weakened (attenuated) virus. Human trials of Sabin's vaccine began in 1957 and it was licensed in 1962. Following the development of oral polio vaccine, a second wave of mass immunizations led to a further decline in the number of cases: by 1961, only 161 cases were recorded in the United States. The last cases of paralytic poliomyelitis caused by endemic transmission of poliovirus in the United States were in 1979, when an outbreak occurred among the Amish in several Midwestern states.

Legacy

Early in the twentieth century polio became the world's most feared disease.^{[citation needed]} The disease hit without warning, tended to strike white, affluent individuals, required long quarantine periods during which parents were separated from children: it was impossible to tell who would get the disease and who would be spared. The consequences of the disease left polio victims marked for life, leaving behind vivid images of wheelchairs, crutches, leg braces, breathing devices, and deformed limbs. However, polio changed not only the lives of those who survived it, but also affected profound cultural changes: the emergence of grassroots fund-raising campaigns that would revolutionize medical philanthropy, the rise of rehabilitation therapy and, through campaigns for the social and civil rights of the disabled, polio survivors helped to spur the modern disability rights movement. 

In addition, the occurrence of polio epidemics led to a number of public health innovations. One of the most widespread was the proliferation of "no spitting" ordinances in the United States and elsewhere.

Philanthropy

In 1921 Franklin D. Roosevelt became totally and permanently paralyzed from the waist down. Although the paralysis (whether from poliomyelitis, as diagnosed at the time, or from Guillain–Barré syndrome) had no cure at the time, Roosevelt, who had planned a life in politics, refused to accept the limitations of his disease. He tried a wide range of therapies, including hydrotherapy in Warm Springs, Georgia. In 1938 Roosevelt helped to found the National Foundation for Infantile Paralysis (now known as the March of Dimes), that raised money for the rehabilitation of victims of paralytic polio, and was instrumental in funding the development of polio vaccines. The March of Dimes changed the way it approached fund-raising. Rather than soliciting large contributions from a few wealthy individuals, the March of Dimes sought small donations from millions of individuals. Its hugely successful fund-raising campaigns collected hundreds of millions of dollars—more than all of the U.S. charities at the time combined (with the exception of the Red Cross). By 1955 the March of Dimes had invested $25.5 million in research; funding both Jonas Salk's and Albert Sabin's vaccine development; the 1954–55 field trial of vaccine, and supplies of free vaccine for thousands of children.

In 1952, during the worst recorded epidemic, 3,145 people in the United States died from polio. That same year over 200,000 people (including 4,000 children) died of cancer and 20,000 (including 1,500 children) died of tuberculosis. According to David Oshinsky's book Polio: An American Story: "There is evidence that the March of Dimes over-hyped polio, and promoted an image of immediately curable polio victims, which was not true. The March of Dimes refused to partner with other charity organizations like the United Way."

Rehabilitation therapy

A physical therapist assists two polio-stricken children while they exercise their lower limbs.

 

Prior to the polio scares of the twentieth century, most rehabilitation therapy was focused on treating injured soldiers returning from war. The crippling effects of polio led to heightened awareness and public support of physical rehabilitation, and in response a number of rehabilitation centers specifically aimed at treating polio patients were opened, with the task of restoring and building the remaining strength of polio victims and teaching new, compensatory skills to large numbers of newly paralyzed individuals.

In 1926, Franklin Roosevelt, convinced of the benefits of hydrotherapy, bought a resort at Warm Springs, Georgia, where he founded the first modern rehabilitation center for treatment of polio patients which still operates as the Roosevelt Warm Springs Institute for Rehabilitation.

The cost of polio rehabilitation was often more than the average family could afford, and more than 80% of the nation's polio patients would receive funding through the March of Dimes. Some families also received support through philanthropic organizations such as the Ancient Arabic Order of the Nobles of the Mystic Shrine fraternity, which established a network of pediatric hospitals in 1919, the Shriners Hospitals for Children, to provide care free of charge for children with polio.

Disability rights movement

As thousands of polio survivors with varying degrees of paralysis left the rehabilitation hospitals and went home, to school and to work, many were frustrated by a lack of accessibility and discrimination they experienced in their communities. In the early twentieth century the use of a wheelchair at home or out in public was a daunting prospect as no public transportation system accommodated wheelchairs and most public buildings including schools, were inaccessible to those with disabilities. Many children left disabled by polio were forced to attend separate institutions for "crippled children" or had to be carried up and down stairs.

As people who had been paralyzed by polio matured, they began to demand the right to participate in the mainstream of society. Polio survivors were often in the forefront of the disability rights movement that emerged in the United States during the 1970s, and pushed legislation such as the Rehabilitation Act of 1973 which protected qualified individuals from discrimination based on their disability, and the Americans with Disabilities Act of 1990. Other political movements led by polio survivors include the Independent Living and Universal design movements of the 1960s and 1970s.

Polio survivors are one of the largest disabled groups in the world. The World Health Organization estimates that there are 10 to 20 million polio survivors worldwide. In 1977, the National Health Interview Survey reported that there were 254,000 people living in the United States who had been paralyzed by polio. According to local polio support groups and doctors, some 40,000 polio survivors with varying degrees of paralysis live in Germany, 30,000 in Japan, 24,000 in France, 16,000 in Australia, 12,000 in Canada and 12,000 in the United Kingdom.

Herd immunity

From Wikipedia, the free encyclopedia

The top box shows an outbreak in a community in which a few people are infected (shown in red) and the rest are healthy but unimmunized (shown in blue); the illness spreads freely through the population. The middle box shows a population where a small number have been immunized (shown in yellow); those not immunized become infected while those immunized do not. In the bottom box, a large proportion of the population have been immunized; this prevents the illness from spreading significantly, including to unimmunized people. In the first two examples, most healthy unimmunized people become infected, whereas in the bottom example only one fourth of the healthy unimmunized people become infected.

 

Herd immunity (also called herd effect, community immunity, population immunity, or social immunity) is a form of indirect protection from infectious disease that occurs when a large percentage of a population has become immune to an infection, thereby providing a measure of protection for individuals who are not immune. In a population in which a large number of individuals are immune, chains of infection are likely to be disrupted, which stops or slows the spread of disease. The greater the proportion of individuals in a community who are immune, the smaller the probability that those who are not immune will come into contact with an infectious individual.

Individual immunity can be gained by recovering from an infection or through vaccination. Some individuals cannot become immune due to medical reasons and in this group herd immunity is an important method of protection. Once a certain threshold has been reached, herd immunity gradually eliminates a disease from a population. This elimination, if achieved worldwide, may result in the permanent reduction in the number of infections to zero, called eradication. This method was used for the eradication of smallpox in 1977 and for the regional elimination of other diseases. Herd immunity does not apply to all diseases, just those that are contagious, meaning that they can be transmitted from one individual to another. Tetanus, for example, is infectious but not contagious, so herd immunity does not apply.

The term herd immunity was first used in 1923. It was recognized as a naturally occurring phenomenon in the 1930s when it was observed that after a significant number of children had become immune to measles, the number of new infections temporarily decreased, including among susceptible children. Mass vaccination to induce herd immunity has since become common and proved successful in preventing the spread of many infectious diseases. Opposition to vaccination has posed a challenge to herd immunity, allowing preventable diseases to persist in or return to communities that have inadequate vaccination rates.

Effects

Protection of those without immunity

Charlotte Cleverley-Bisman, who had all four limbs partially amputated at the age of seven months due to meningococcal disease, a transmissible disease that may be reduced by herd immunity

 

Some individuals either cannot develop immunity after vaccination or for medical reasons cannot be vaccinated. Newborn infants are too young to receive many vaccines, either for safety reasons or because passive immunity renders the vaccine ineffective. Individuals who are immunodeficient due to HIV/AIDS, lymphoma, leukemia, bone marrow cancer, an impaired spleen, chemotherapy, or radiotherapy may have lost any immunity that they previously had and vaccines may not be of any use for them because of their immunodeficiency. Vaccines are typically imperfect as some individuals' immune systems may not generate an adequate immune response to vaccines to confer long-term immunity, so a portion of those who are vaccinated may lack immunity. Lastly, vaccine contraindications may prevent certain individuals from becoming immune. In addition to not being immune, individuals in one of these groups may be at a greater risk of developing complications from infection because of their medical status, but they may still be protected if a large enough percentage of the population is immune.

High levels of immunity in one age group can create herd immunity for other age groups. Vaccinating adults against pertussis reduces pertussis incidence in infants too young to be vaccinated, who are at the greatest risk of complications from the disease. This is especially important for close family members, who account for most of the transmissions to young infants. In the same manner, children receiving vaccines against pneumococcus reduces pneumococcal disease incidence among younger, unvaccinated siblings. Vaccinating children against pneumococcus and rotavirus has had the effect of reducing pneumococcus- and rotavirus-attributable hospitalizations for older children and adults, who do not normally receive these vaccines. Influenza (flu) is more severe in the elderly than in younger age groups, but influenza vaccines lack effectiveness in this demographic due to a waning of the immune system with age. The prioritization of school-age children for seasonal flu immunization, which is more effective than vaccinating the elderly, however, has shown to create a certain degree of protection for the elderly.

For sexually transmitted infections (STIs), high levels of immunity in one sex induces herd immunity for both sexes. Vaccines against STIs that are targeted at one sex result in significant declines in STIs in both sexes if vaccine uptake in the target sex is high. Herd immunity from female vaccination does not, however, extend to homosexual males. If vaccine uptake among the target sex is low, then the other sex may need to be immunized so that that sex can be sufficiently protected. High-risk behaviors make eliminating STIs difficult since even though most infections occur among individuals with moderate risk, the majority of transmissions occur because of individuals who engage in high-risk behaviors. For these reasons, in certain populations it may be necessary to immunize high-risk persons or individuals of both sexes to establish herd immunity.

Evolutionary pressure

Herd immunity itself acts as an evolutionary pressure on certain viruses, influencing viral evolution by encouraging the production of novel strains, in this case referred to as escape mutants, that are able to "escape" from herd immunity and spread more easily. At the molecular level, viruses escape from herd immunity through antigenic drift, which is when mutations accumulate in the portion of the viral genome that encodes for the virus's surface antigen, typically a protein of the virus capsid, producing a change in the viral epitope. Alternatively, the reassortment of separate viral genome segments, or antigenic shift, which is more common when there are more strains in circulation, can also produce new serotypes. When either of these occur, memory T cells no longer recognize the virus, so people are not immune to the dominant circulating strain. For both influenza and norovirus, epidemics temporarily induce herd immunity until a new dominant strain emerges, causing successive waves of epidemics. As this evolution poses a challenge to herd immunity, broadly neutralizing antibodies and "universal" vaccines that can provide protection beyond a specific serotype are in development.

Serotype replacement

Serotype replacement, or serotype shifting, may occur if the prevalence of a specific serotype declines due to high levels of immunity, allowing other serotypes to replace it. Initial vaccines against Streptococcus pneumoniae significantly reduced nasopharyngeal carriage of vaccine serotypes (VTs), including antibiotic-resistant types, only to be entirely offset by increased carriage of non-vaccine serotypes (NVTs). This did not result in a proportionate increase in disease incidence though since NVTs were less invasive than VTs. Since then, pneumococcal vaccines that provide protection from the emerging serotypes have been introduced and have successfully countered their emergence. The possibility of future shifting remains, so further strategies to deal with this include expansion of VT coverage and the development of vaccines that use either killed whole-cells, which have more surface antigens, or proteins present in multiple serotypes.

Eradication of diseases

A cow with rinderpest in the "milk fever" position, 1982. The last confirmed case of rinderpest occurred in Kenya in 2001 and the disease was officially declared eradicated in 2011.

 

If herd immunity has been established and maintained in a population for a sufficient time, the disease is inevitably eliminated—no more endemic transmissions occurs. If elimination is achieved worldwide and the number of cases is permanently reduced to zero, then a disease can be declared eradicated. Eradication can thus be considered the final effect or end-result of public health initiatives to control the spread of infectious disease. The benefits of eradication include ending all morbidity and mortality caused by the disease, financial savings for individuals, health care providers, and governments, and enabling resources used to control the disease to be used elsewhere. To date, two diseases have been eradicated using herd immunity and vaccination: rinderpest and smallpox. Eradication efforts that rely on herd immunity are currently underway for poliomyelitis, though civil unrest and distrust of modern medicine have made this difficult. Mandatory vaccination may be beneficial to eradication efforts if not enough people choose to get vaccinated.

Free riding

Herd immunity is vulnerable to the free rider problem. Individuals who lack immunity, particularly those who choose not to vaccinate, free ride off the herd immunity created by those who are immune. As the number of free riders in a population increases, outbreaks of preventable diseases become more common and more severe due to loss of herd immunity. Individuals may choose to free ride for a variety of reasons, including the perceived ineffectiveness of a vaccine, believing that the risks associated with vaccines are greater than those associated with infection, mistrust of vaccines or public health officials, bandwagoning or groupthinking, social norms or peer pressure, and religious beliefs. Individuals are more likely to free ride if vaccination rates are high enough so as to convince a person that he or she may not need to be immune since a sufficient number of others already are.

Mechanism

Individuals who are immune to a disease act as a barrier in the spread of disease, slowing or preventing the transmission of disease to others. An individual's immunity can be acquired via a natural infection or through artificial means, such as vaccination. When a critical proportion of the population becomes immune, called the herd immunity threshold (HIT) or herd immunity level (HIL), the disease may no longer persist in the population, ceasing to be endemic. This threshold can be calculated by taking R₀, the basic reproduction number, or the average number of new infections caused by each case in an entirely susceptible population that is homogeneous, or well-mixed, meaning each individual can come into contact with every other susceptible individual in the population, and multiplying it by S, the proportion of the population who are susceptible to infection:

${\displaystyle \ R_{0}\cdot S=1.}$

S can be rewritten as (1 - p) because p is the proportion of the population that is immune and p + S equals one. Then, the equation can be rearranged to place p by itself as follows:

${\displaystyle \ R_{0}\cdot (1-p)=1,}$ → ${\displaystyle 1-p={\frac {1}{R_{0}}},}$ → ${\displaystyle p_{c}=1-{\frac {1}{R_{0}}}.}$

With p being by itself on the left side of the equation, it can now be written as p_c to represent the critical proportion of the population needed to become immune to stop the transmission of disease, or the herd immunity threshold. R₀ functions as a measure of contagiousness, so low R₀ values are associated with lower HITs, whereas higher R₀s result in higher HITs. For example, the HIT for a disease with an R₀ of 2 is theoretically only 50%, whereas with disease with an R₀ of 10 the theoretical HIT is 90%. These calculations assume that the entire population is susceptible, meaning no individuals are immune to the disease. In reality, varying proportions of the population are immune to any given disease at any given time. To account for this, the effective reproductive number R_e, also written as R_t, or the average number of infections caused at time t, can found by multiplying R₀ by the fraction of the population that is still susceptible. When R_e is reduced to and sustained below 1, the number of cases occurring in the population gradually decreases until the disease has been eliminated. If a population is immune to a disease in excess of that disease's HIT, the number of cases reduces at a faster rate, outbreaks are even less likely to happen, and outbreaks that occur are smaller than they would be otherwise. If R_e increases to above 1, then the disease is neither in a steady state nor decreasing in incidence but is actively spreading through the population and infecting a larger number of people than usual.

A second assumption in these calculations is that populations are homogeneous, or well-mixed, meaning that every individual comes into contact with every other individual, when in reality populations are better described as social networks as individuals tend to cluster together, remaining in relatively close contact with a limited number of other individuals. In these networks, transmission only occurs between those who are geographically or physically close to one another. The shape and size of a network is likely to alter a disease's HIT, making incidence either more or less common. In heterogeneous populations, R₀ is now considered to be a measure of the number of cases generated by a "typical" infectious person, which depends on how individuals within a network interact with each other. Interactions within networks are more common than between networks, in which case the most highly connected networks transmit disease more easily, resulting in a higher R₀ and a higher HIT than would be required in a less connected network. In networks that either opt not to become immune or are not immunized sufficiently, diseases may persist despite existing in better-immunized networks.

Boosts

Vaccination

The primary way to boost levels of immunity in a population is through vaccination. Vaccination is originally based on the observation that milkmaids exposed to cowpox were immune to smallpox, so the practice of inoculating people with the cowpox virus began as a way to prevent smallpox. Well-developed vaccines provide protection in a far safer way than natural infections, as vaccines generally do not cause the diseases they protect against and severe adverse effects are significantly less common than complications from natural infections. The immune system does not distinguish between natural infections and vaccines, forming an active response to both, so immunity induced via vaccination is similar to what would have occurred from contracting and recovering from the disease. To achieve herd immunity through vaccination, vaccine manufacturers aim to produce vaccines with low failure rates and policy makers aim to encourage their use. After the successful introduction and widespread use of a vaccine, sharp declines in the incidence of diseases it protects against can be observed, necessarily decreasing the number of hospitalizations and deaths caused by such diseases.

Assuming a vaccine is 100% effective, then the equation used for calculating the herd immunity threshold can be used for calculating the vaccination level needed to eliminate a disease, written as V_c. Vaccines are usually imperfect however, so the effectiveness, E, of a vaccine must be accounted for:

${\displaystyle V_{c}={\frac {1-{\frac {1}{R_{0}}}}{E}}.}$

From this equation, it can be observed that if E is less than (1 − 1/R₀), then it is impossible to eliminate a disease, even if the entire population is vaccinated. Similarly, waning vaccine-induced immunity, as occurs with acellular pertussis vaccines, requires higher levels of booster vaccination to sustain herd immunity. If a disease has ceased to be endemic to a population, then natural infections no longer contribute to a reduction in the fraction of the population that is susceptible. Only vaccination contributes to this reduction. The relation between vaccine coverage and effectiveness and disease incidence can be shown by subtracting the product of the effectiveness of a vaccine and the proportion of the population that is vaccinated, p_v, from the herd immunity threshold equation as follows: 

Measles vaccine coverage and reported measles cases in Eastern Mediterranean countries. As coverage increased, the number of cases decreased.

${\displaystyle (1-{\frac {1}{R_{0}}})-(E\times p_{v}).}$

It can be observed from this equation that, ceteris paribus, any increase in either vaccine coverage or vaccine effectiveness, including any increase in excess of a disease's HIT, further reduces the number of cases of a disease. The rate of decline in cases depends on a disease's R₀, with diseases with lower R₀ values experiencing sharper declines. Vaccines usually have at least one contraindication for a specific population for medical reasons, but if both effectiveness and coverage are high enough herd immunity can protect these individuals. Vaccine effectiveness is often, but not always, adversely affected by passive immunity, so additional doses are recommended for some vaccines while others are not administered until after an individual has lost his or her passive immunity.

Passive immunity

Individual immunity can also be gained passively, in which antibodies to a pathogen are transferred from one individual to another. This can occur naturally, whereby maternal antibodies, primarily immunoglobulin G antibodies, are transferred across the placenta and in colostrum to fetuses and newborns, or artificially, by which antibodies from the serum or plasma of an immune individual are injected into a susceptible person. Protection generated from passive immunity is immediate but wanes over the course of weeks to months, so any contribution to herd immunity is temporary. For diseases that are especially severe among fetuses and newborns, such as influenza and tetanus, pregnant women may be immunized in order to transfer antibodies to the child. In the same way, high-risk groups that are either more likely to experience infection or are more likely to develop complications from infection may receive antibody preparations to prevent these infections or to reduce the severity of symptoms.

Cost–benefit analysis

Herd immunity is often accounted for when conducting cost–benefit analyses of vaccination programs. It is regarded as a positive externality of high levels of immunity, producing an additional benefit of disease reduction that would not occur had no herd immunity been generated in the population. Therefore, herd immunity's inclusion in cost–benefit analyses results in more favorable cost-effectiveness or cost–benefit ratios and an increase in the number of disease cases averted by vaccination. Study designs done to estimate herd immunity's benefit include recording disease incidence in households in which a member was vaccinated, randomizing a population in a single geographic area to be vaccinated or not, and observing disease incidence before and after a vaccination program is introduced. From these, it can be observed that disease incidence may decrease to a level beyond what can be predicted from direct protection alone, indicating that herd immunity contributed to the reduction. When serotype replacement is accounted for, it reduces the predicted benefits of vaccination.

History

Measles cases in the United States before and after mass vaccination against measles began.

 

The term herd immunity was first used in 1923 to refer to an entire population's immunity, in reference to research examining disease mortality in mouse populations with varying degrees of immunity. Herd immunity was first recognized as a naturally occurring phenomenon in the 1930s when A. W. Hedrich published research on the epidemiology of measles in Baltimore and took notice that after many children had become immune to measles, the number of new infections temporarily decreased, including among susceptible children. In spite of this knowledge, efforts to control and eliminate measles were unsuccessful until mass vaccination using the measles vaccine began in the 1960s. Mass vaccination, discussions of disease eradication, and cost–benefit analyses of vaccination subsequently prompted more widespread use of the term herd immunity. In the 1970s, the theorem used to calculated a disease's herd immunity threshold was developed. During the smallpox eradication campaign in the 1960s and 1970s, the practice of ring vaccination, of which herd immunity is integral to, began as a way to immunize every person in a "ring" around an infected individual to prevent outbreaks from spreading.

Since the adoption of mass and ring vaccination, complexities and challenges to herd immunity have arisen. Modeling of the spread of infectious disease originally made a number of assumptions, namely that entire populations are susceptible and well-mixed, which do not exist in reality, so more precise equations have been developed. In recent decades, it has been recognized that the dominant strain of a microorganism in circulation may change due to herd immunity, either because of herd immunity acting as an evolutionary pressure or because herd immunity against one strain allowed another already-existing strain to spread. Emerging or ongoing vaccine controversies and various reasons for opposing vaccination have reduced or eliminated herd immunity in certain communities, allowing preventable diseases to persist in or return to these communities.