Poliovirus Vaccine–Live

History of the Disease

Poliomyelitis probably has affected humankind since ancient times, as demonstrated by the depiction in an Egyptian stele dated between 1403 and 1365 BCE, of a “crippled young man, apparently a priest, with a withered and shortened right leg, and with his foot held in a typical equinus position characteristic of prior flaccid paralysis.” However, it was not until 1789 that Michael Underwood provided the first description of the disease as a separate entity. The term Poliomyelitis anterior acuta, which is based on the anatomic location of lesions within the spinal cord, and the shortened terms, poliomyelitis or polio , became the standard designation for the disease in the early 1900s. Poliomyelitis is constructed from the Greek words polios (i.e., gray) and myelos (i.e., marrow, the gray matter of the spinal cord) with the ending “-itis” to imply inflammation.

In the late 19th and early 20th centuries, a change in the epidemiology of poliomyelitis from a predominantly endemic to an epidemic form was observed in Sweden and Norway, heralding similar changes in other industrialized countries. ^{, , ,} Epidemic poliomyelitis in the early part of the 20th century was associated with severe morbidity and mortality. Improvements in hygiene and sanitation delayed the median age of poliovirus infection and allowed the accumulation of large numbers of people susceptible to poliomyelitis between outbreaks. Because older age of infection is associated with higher risk of bulbar paralysis, a high proportion of cases required respiratory support or died. The case-fatality rate reached 27.1% during the New York epidemic of 1916, and whole wards of iron lungs were devoted to caring for poliomyelitis victims in the 1940s and 1950s.

Landsteiner and Popper reported in 1908, that a “filtrable agent” (i.e., virus) was the cause of poliomyelitis, and investigative efforts culminated in 1951 with the conclusion that only three serotypes of poliovirus, designated types 1, 2, and 3, caused poliomyelitis. ^, The determination of the number of poliovirus serotypes, the ability for large-scale growth of the virus reported in 1949, and the demonstration that circulating antibody had a protective effect against poliomyelitis ^, were essential preconditions for the development of effective poliovirus vaccines. Two approaches for vaccine development were successful: inactivation of poliovirus by formalin, fully developed by Jonas Salk and colleagues, licensed as IPV in 1955 ¹⁹ ; and the attenuation of the three serotypes of poliovirus by Albert Sabin, licensed in 1961 as mOPV and in 1963 as trivalent OPV (tOPV). The widespread use of IPV and OPV over the next few decades rapidly controlled poliomyelitis in industrialized countries, and paved the way for a resolution by the World Health Assembly to achieve global eradication of poliomyelitis by the year 2000.

The use of Sabin tOPV in routine immunization and campaigns together with surveillance for acute flaccid paralysis led to the disappearance of poliomyelitis caused by wild poliovirus types 2 (1999) and 3 (2012) worldwide. By early 2021, only indigenous wild poliovirus type 1 remains circulating in two countries (Afghanistan and Pakistan). In response to new challenges in the last miles to global polio eradication, the Global Polio Eradication Initiative (GPEI) has introduced new strategies to vaccinate children in hard-to-reach areas because of insecurity or geographical isolation, and new vaccines to overcome vaccine failure in areas with high force of infection and to prevent emergence of polio outbreaks caused by circulating vaccine-derived poliovirus (cVDPV). ^, The novel type-2 oral poliovirus vaccine (nOPV2), approved by the World Health Organization under Emergency Use Listing in November 2020, was developed by genetically engineering the Sabin strain to stabilize the attenuations and reduce reversion to neurovirulent variants, while maintaining antigenic properties.

The history of poliomyelitis has been reviewed in detail by Paul and Eggers and previous editions of this chapter in Vaccines .

Clinical Description

Poliovirus exposure in a susceptible individual results in one of the following consequences: (a) inapparent infection without symptoms, (b) minor illness, (c) nonparalytic poliomyelitis (aseptic meningitis), or (d) paralytic poliomyelitis. ^, Inapparent infection with viral replication along the gastrointestinal tract, and viral shedding through oropharyngeal secretions and stools without symptoms, is the most frequent outcome (72%). Minor illness is the most frequent form (24%) of the disease, characterized by a few days of fever, malaise, drowsiness, headache, nausea, vomiting, constipation, or sore throat, in various combinations. Nonparalytic poliomyelitis (aseptic meningitis) is a relatively rare outcome (4%) of poliovirus infection. It begins usually as a minor illness characterized by fever, sore throat, vomiting, and malaise. About 1–2 days later, signs of meningeal irritation become apparent, including stiffness of the neck or back; vomiting; severe headache; and pain in the limbs, back, and neck. The clinical course lasts 2–10 days, and recovery is usually rapid and complete. In a small proportion of these cases, the disease advances to transient mild muscle weakness or paralysis.

Paralytic poliomyelitis is a rare outcome of poliovirus infection. The ratio of paralytic cases to infections has been estimated at approximately 1:200 for type 1, 1:1,900 for type 2 and 1:1,100 for type 3. Paralysis results when polioviruses reach the motor neurons of the anterior horn cells in the spinal cord or brainstem and cause cell destruction. The clinical course in children is often characterized by a minor illness of several days and a symptom-free period of 1–3 days, followed by rapid onset of flaccid paralysis with fever and progression to the maximum extent of paralysis within a few days. ^, After the resolution of fever, usually there is no further progression of paralysis. Among adolescents and adults, the minor illness is often absent, and pain in the affected extremities is usually more severe. Paralysis is usually asymmetric, associated with diminished or complete loss of deep tendon reflexes and an intact sensory system. Paralytic manifestations in extremities begin proximally and progress to involve distal muscle groups (i.e., descending paralysis); when paralysis is incomplete, it is more pronounced proximally. Depending on the anatomic location of motor neuron damage in the spinal cord or in the brainstem, spinal, mixed spinal-bulbar, or bulbar paralysis involving primarily respiratory muscles may be observed. Because the anterior horn cells (and brainstem cells) cannot be regenerated or replaced, paralysis is usually permanent. Nevertheless, because of compensation of other, still functioning muscles, partial or total recovery can be achieved, usually within the first 6 months after onset of disease. Detailed clinical descriptions may be found in a number of reviews and books.

Complications

Bulbar or spinal-bulbar paralysis affecting respiratory muscles is the major cause of death in poliomyelitis. The case-fatality rate is variable and depends primarily on the age groups affected and availability of respiratory support. The highest case-fatality rates were observed during the early 20th century ^{, ,} epidemics (27% during the 1916 epidemic in New York), and decreased in the 1930’s and 1940’s, to around 5–10%. ^, partly because of the use of the Drinker respirator (i.e., the “iron lung”). During the 1990–2000s, high fatality rates have often been observed in outbreaks affecting adolescents and young adults disproportionately. A poliomyelitis outbreak in Cape Verde Islands in 2000, had an overall case fatality of 21% (7 out of 33 reported cases), with 0%, 20%, and 57% among cases in person younger than age 5 years, 5–14 years of age, and 15 years of age or older, respectively. Type 1 poliovirus outbreaks in Namibia in 2006 and in the Republic of Congo in 2011 following importations from India, affected males older than 15 years predominantly (100% in Namibia, >68% in Congo), and resulted in case-fatality rates above 30% (32% in Namibia and 41% in the Congo).

Persons with underlying immunodeficiency disorders also have higher risk for complications and fatal outcomes with poliomyelitis (see “Side Effects” later).

Postpolio syndrome, a term coined in the early 1980s, has been described mostly in people infected during the large epidemics of the first half of the 20th century. After an interval of 15–40 years, about 25–40% of individuals who contracted paralytic poliomyelitis in their childhood experience muscle pain and exacerbation of existing weakness or may develop new weakness or paralysis. Factors that enhance the risk of postpolio syndrome include: (a) increasing time since acute poliovirus infection, (b) presence of permanent residual impairment after recovery from the acute illness, and (c) female sex. The exact cause of these late effects is unknown, although it is not a consequence of persistent infection. The pathogenesis of postpolio syndrome is thought to involve late attrition of oversized motor units that developed during the recovery process of paralytic poliomyelitis. An excellent summary of scientific knowledge of postpolio syndrome was published in 1995.

Virology

Modes of Transmission

Poliomyelitis is transmitted by person-to-person spread through fecal–oral and oral–oral routes or, less frequently, by recent contamination of a common vehicle (e.g., water, milk, or fomites). ^, After polioviruses enter the oral cavity, replication and shedding in susceptible individuals occurs for about 2 weeks in oropharyngeal secretions and for 3 to 6 weeks in feces, independently of the presence of disease. Among those who develop paralysis, they are more infectious immediately before and 1–2 weeks after onset of paralytic disease. The incubation period between infection and first symptoms (minor illness) is 3–6 days and from infection to onset of paralytic disease is usually 7–21 days, with a range of 3–35 days. Among individuals previously exposed to serotype-specific poliovirus orally (wild or vaccine strains), mucosal immunity prevents viral replication in the oropharynx, and reduces duration and amount of poliovirus excreted in stools after a new exposure. Among individuals vaccinated exclusively with IPV, nasopharyngeal shedding is reduced but poliovirus shedding in stools and potential for transmission via the fecal-oral route is similar to that observed in susceptible individuals (see “Immune Response” later). The highest rates of transmission have been observed among infants and young children (tropical areas) and school-age children (temperate zones).

In settings with good sanitation, oral-oral transmission appears to be the major route for community spread, with the fecal-oral route playing a more important role for transmission within households and among young children. Secondary infection rates of susceptible household or institutional contacts are greater than 90%. In countries with low sanitation levels, both routes are important; with crowding and exposure to high dose of infection potentiating transmissibility. ^, The basic reproductive number (a measure of infectivity) of wild poliovirus in the absence of vaccine was estimated at between 2 and 4 in countries with good sanitation, compared with 10–12 in a tropical settings with poor sanitation ( Fig. 50.1 ).

There is no significant animal reservoir for poliovirus. Apes, such as chimpanzees, gorillas, and orangutans, can experience paralytic disease after poliovirus infection; outbreaks of poliomyelitis in apes have been reported in captivity and in the wild. However, it is unlikely that apes have any role in sustained transmission of poliovirus. because of the limited size of the ape populations, and the fact that monkeys cannot be infected by oral administration of poliovirus.

Clinical Course

Paralytic poliomyelitis caused by imported wild poliovirus or by vaccine-related poliovirus has become a rare disease in the United States and other industrialized countries. Therefore, physicians may not be familiar with the disease or consider the diagnosis of poliomyelitis until other more frequent causes of acute flaccid paralysis (AFP) have been ruled out. The diagnosis of paralytic poliomyelitis is dependent on the following: (a) clinical course, (b) virologic testing, and (c) special studies. For surveillance purposes, in the United States, any case with physician-diagnosed suspected poliomyelitis is investigated and a case is confirmed if a panel of independent experts determines that the case definition ¹

1 “A patient must have had paralysis clinically and epidemiologically compatible with poliomyelitis and, at 60 days after onset of symptoms, had residual neurologic deficit, had died, or had no information available on neurologic residua.” This case definition was formerly known as best available paralytic poliomyelitis case count.

for paralytic poliomyelitis has been met. Countries using the WHO AFP surveillance system to identify poliomyelitis use a sensitive screening case definition: any case of AFP in a person younger than 15 years of age or a case in a person of any age in whom poliomyelitis is suspected. This sensitive screening definition is balanced by a specific case classification system (i.e., virologic case classification scheme) that relies on isolation of poliovirus from stool specimens to confirm cases of AFP as poliomyelitis. As countries improved quality and timeliness of AFP surveillance, the virologic case classification replaced the clinical case classification scheme (see “Disease Control Strategies” later). However, the clinical course is still used to support the virologic case definition. Data from studies in the developing world assessing the sensitivity and specificity of different clinical case definitions compared with the “gold standard” of confirmed poliomyelitis based on poliovirus detection in stool specimens suggested that residual paralysis 60 days after onset of paralysis was the strongest predictor for confirmed poliomyelitis. A case definition that included age younger than 6 years, fever at onset, and rapid progress to maximum extent of paralysis (≤4 days) had a sensitivity of 64% and a specificity of 82% The addition of a specific pattern of paralysis (proximal, unilateral, or absence of paralysis in all four extremities) increased the specificity with varying degrees of loss in sensitivity. Based upon this information, AFP cases with negative poliovirus detection but with stool specimens collected >14 days after paralysis onset or with specimens of insufficient quality or quantity, undergo a 60-day follow-up examination to assess the persistence of neurologic deficit. The deficit may be apparent as complete flaccid paralysis of one or more extremities or partial paralysis or weakness of muscles or muscle groups, because of partial compensation from intact muscles. For those with persistent neurological deficit after 60 days, an Expert Committee reviews medical history and results of available tests to identify other causes of AFP or diagnose the case as “polio compatible.” The 60-day follow-up and medical review of potential “false negative” cases, is an important surveillance tool to identify areas where wild poliovirus circulation may have been missed.

Serologic Testing

Standard protocols for neutralization assays to determine levels of antibody to poliovirus are available, but only a small number of laboratories can perform these assays currently, because they require handling wild poliovirus strains which is restricted to certain laboratories (“See Poliovirus C-containment” later). Serologic testing for poliomyelitis diagnosis requires collection of paired serum specimens to demonstrate rise in antibody titers and may cause confusion because (a) antibody rise may have already occurred by the time the first specimen has been collected, (b) there are no reliable means of distinguishing antibody induced by vaccine-related versus wild poliovirus, and (c) heterotypic responses may be observed to one serotype after exposure to another serotype. Furthermore, immunocompromised individuals may be infected despite having two specimens with undetectable antibodies. Because of the limitations described and the advantages of laboratory confirmation through poliovirus isolation in stool specimens (see “Virologic Testing” above), serology is not a useful tool for the diagnosis of poliomyelitis. On the other hand, measurement of type-specific neutralizing serum antibody levels in clinical trials and serosurveys are useful tools for the GPEI to evaluate efficacy and effectiveness of polio vaccines and vaccination strategies. Intrathecal immune responses can be measured and offer the advantage of attributing a causal relationship between a poliovirus serotype and paralytic disease, but it is rarely used.

Special Studies

Nerve conduction and electromyography studies can point to the anatomic location of the paralysis —destruction of anterior horn cells in the spinal cord versus a demyelinating or axonal degenerative process in the peripheral nerves—helping to exclude the most frequent cause of nonpolio AFP, Guillain-Barré syndrome. Radiography, computed tomography or magnetic resonance imaging are used to rule out spinal cord compression, and in at least one patient with poliomyelitis, magnetic resonance imaging highlighted the anterior column of the spinal cord. Analysis of spinal fluid may be helpful in ruling out bacterial or other viral infections of the nervous system. In paralytic poliomyelitis, the cerebrospinal fluid contains an increased number of leukocytes, usually 10–200/mL, and seldom more than 500/mL. ^, At the onset of signs of CNS involvement, the ratio of polymorphonuclear cells to lymphocytes is high, but within a few days, the ratio is reversed. The total white blood cell count slowly subsides to normal levels. The protein content of the cerebrospinal fluid initially is elevated only slightly (average, in nonparalytic cases, is approximately 46 mg/100 mL [range: 15–165 mg/100 mL]; in paralytic cases, the average is approximately 68 mg/100 mL [range: 25–250 mg/100 mL]), but it rises gradually in paralytic cases until the third week, generally returning to normal by the sixth week. Glucose levels are usually within the normal range. In fatal cases, spinal cord and brainstem tissue samples should be examined for the typical lesions caused by viral replication and destruction of the motor neuron cells.

Differential Diagnosis

The list of underlying causes of AFP is extensive and vary by age and geographic region. The causes can be classified according to the pathophysiologic mechanisms and anatomic sites of the etiologic factors ( Table 50.1 ). Poliovirus damages primarily the anterior horn cells of the spinal cord which leads to paralysis of extremity muscles ( Fig. 50.2 ). The most distinguishing features of poliomyelitis and other common causes of AFP—Guillain-Barré syndrome, transverse myelitis, and traumatic neuritis secondary to injections)—are given in Table 50.2 .

In general, in the absence of wild virus-induced poliomyelitis, Guillain-Barré syndrome accounts for 50% or more of the cases of AFP in industrialized countries such as the United Kingdom and Australia, and in developing countries in Latin America. At times, nonpolio enteroviruses have been associated with cases of polio-like paralytic disease. Coxsackie virus A7 has been associated with outbreaks of paralytic disease, and enterovirus A71 has been involved in several outbreaks of CNS disease, including polio-like paralysis, resulting in fatal cases, ^, with recent large outbreaks in East Asia. ^, More recently, biennial increases in cases of acute flaccid myelitis observed in the United States since 2014 have been associated with enterovirus D68 infection. The typical clinical presentation of these cases is acute limb weakness or paralysis following prodromal respiratory viral illness. Enterovirus D68 is thought to be a major cause based upon epidemiological and temporal association between enterovirus D68 circulation and increases in cases of acute flaccid myelitis. However, the disease is a very rare complication of enterovirus D68 infection, and virus detection in the cerebrospinal fluid or other specimens is rare. Japanese encephalitis infection seems to be an important contributing cause of AFP in areas where this virus is endemic. West Nile virus (a flavivirus) may damage the anterior horn cells of the spinal cord and cause acute flaccid paralysis with or without meningoencephalitis, following infection among elderly adults. ^,

Two motor neuron diseases in childhood are Werdnig-Hoffmann disease, a rapidly progressing, often fatal disorder of early childhood, and Wohlfart-Kugelberg-Welander disease, a more benign disorder with a generally later onset that can be diagnosed through electromyographic findings. ^, China paralytic syndrome, has been described among children and adults in northern China. Early symptoms of this disease include leg weakness and resistance to neck flexion. The weakness ascends rapidly, affects symmetrically the arms and respiratory muscles, and progresses to a maximum extent of weakness within 6 days on average. Electromyography indicates denervation potentials in weak muscles and suggests that this entity may be a reversible distal motor nerve terminal or anterior horn lesion. Tick-bite paralysis occurs infrequently and is manifested by flaccid ascending paralysis that usually resolves rapidly after tick removal. Flaccid paralysis of muscles innervated by cranial nerves can be observed rarely in bulbar and bulbar-spinal poliomyelitis and can be caused by other agents. Botulism toxins cause descending paralysis—characterized by symmetric impairment of cranial nerves, followed by a descending pattern of weakness or paralysis of the extremities and trunk. Diphtheria toxin may cause in approximately 10–15% of patients paralysis of the soft palate and peripheral nerves. Tetanus toxin can cause flaccid paralysis of the muscles innervated by the affected cranial nerves (i.e., cephalic tetanus).

The following signs and symptoms help in distinguishing poliomyelitis from other causes of AFP: (a) fever present at onset of paralysis, (b) rapid progression to maximum paralysis, (c) usually asymmetric paralysis, and (d) more pronounced paralysis proximally than distally (i.e., descending paralysis). However, as poliomyelitis becomes an increasingly rare disease, unusual clinical manifestations, such as symmetric paralysis of the lower extremities (many cases caused by intramuscular injections, which increase the risk of paralytic manifestations in the extremity that, in the absence of intramuscular injections, would not have become paralyzed) or mild paralysis or weakness in partially immune children, may be seen.

Treatment and Prevention With Antivirals

In response to a recommendation by the National Academy of Sciences in 2006, the Poliovirus Antiviral Initiative was established to develop poliovirus antiviral drugs to supplement available tools for the posteradication era, specifically the treatment of persons with B-cell immunodeficiencies who are excreting iVDPV ^, (see “Surveillance” section later). Efforts to develop poliovirus antiviral agents have resulted in the identification of two promising compounds. Pocapavir (V-073), is a capsid inhibitor, which was found to be well-tolerated and accelerated clearance of poliovirus following a dose of type 1 monovalent OPV compared with placebo. Pocapavir has been administered to patients with iVDPV excretion under compassionate use. A second compound, V-7404, a 3C protease inhibitor, has shown in vitro synergistic antiviral activity with Pocapavir. A combination antiviral compound expected to result in lower antiviral resistance, will be tested in upcoming clinical trials.

Individual Risk Factors for Paralysis Following Poliovirus Infection

Paralytic manifestations are a rare outcome of poliovirus infections. On the basis of serologic surveys in the prevaccine era ^, and lameness surveys in developing countries, paralytic disease will develop in approximately 1 in 200 children (0.5%), in the absence of a control program with vaccines. Poliovirus type 1 is the most neurovirulent of the three serotypes and was responsible for most epidemic and endemic cases in the prevaccine era. The ratio of paralytic cases per 100 infections has been estimated at approximately 0.5 for serotype 1, 0.05 for serotype 2 and 0.09 for serotype 3.

A review of 48 outbreaks between 1976 and 1995, involving about 17,000 cases of paralytic poliomyelitis found that outbreaks involved primarily unvaccinated or inadequately vaccinated subgroups and were caused predominantly by poliovirus type 1 (74%). Cases in developing countries occurred mostly among children younger than 2 years of age, whereas cases in industrialized countries tended to occur in older people who had remained susceptible to poliomyelitis. With the progress of polio eradication efforts, some outbreaks in developing countries involved a substantial proportion of cases in adolescents and young adults and were associated with high case-fatality rates. ^{, ,} (see “Complications” earlier).

Besides age and being unvaccinated or inadequately vaccinated, several factors have been shown to increase the risk of acquiring paralytic manifestations, including intramuscular injections with diphtheria and tetanus toxoids and pertussis vaccine (DTP) ^, or antibiotics, strenuous exercise, ^, injury such as fractures, and pregnancy. Provocation poliomyelitis describes the enhanced risk of paralytic manifestations that follows injection in the 30 days preceding paralysis onset. More than 40 years ago, Nathanson and Bodian ^, demonstrated that retrograde axonal transport is responsible for the poliovirus invasion of the CNS in provocation poliomyelitis. Gromeier et al. ^, suggested that the temporary expression of the human PVR on peripheral neurons during the repair process of injured nerves may enhance poliovirus access into peripheral neurons. Retrograde transport in the axon via the fast system shortens the period for the virus reaching the motor neuron cells of the CNS, thus limiting the time during which the immune system could develop an effective response. Aggravation poliomyelitis describes the elevated risk of paralytic disease that follows strenuous exercise (24–48 hours before paralysis onset). ^,

Removal of tonsils and adenoids predisposes to bulbar poliomyelitis. In the early 20th century Von Magnus and Melnick demonstrated that, if cynomolgus monkeys were given poliovirus by the oral route, their susceptibility was greatly enhanced in animals with recently removed tonsils. Ogra and Ogra and Karzon studied 40 children 3–11 years old vaccinated with OPV, before and after removal of tonsils and adenoids. Before tonsillectomy, IgA poliovirus antibody was present in appreciable titers in the nasopharynx of all children, but no IgM or IgG antibody was detectable. After tonsillectomy, preexisting IgA poliovirus antibody levels in the nasopharynx sharply declined in all children studied. Mean antibody titers decreased threefold to fourfold. Thus, removal of tonsils may eliminate a valuable source of immunocompetent tissue important in conferring resistance to poliovirus.

Lower socioeconomic status is a risk for paralytic poliomyelitis in developing countries, probably because children belonging to the lower socioeconomic group experience more intense exposure to poliovirus (i.e., a higher virus inoculum, which has been shown in experimental studies to be a risk factor for paralytic disease ). In addition, these children are at higher risk for primary vaccine failure after OPV because of more frequent concurrent enterovirus infections, diarrheal disease and/or malnutrition

In a study of twins, concordance with regard to paralytic poliomyelitis was found in 36% of monozygous pairs compared with 6% of dizygous pairs. The authors concluded that the data were consistent with “the theory that susceptibility may be conditioned by the homozygous state of a recessive gene.” A human leukocyte antigen complex study suggested that human leukocyte antigen–encoded genetic factors control resistance to the paralytic form of poliomyelitis. Data on genetic susceptibility to poliomyelitis were reviewed by Wyatt, who proposed that multiple-linked genes determine whether an infection with poliovirus results in paralytic disease.

Epidemiologic Patterns of Incidence of Poliomyelitis

Poliomyelitis was once a ubiquitous, highly contagious, seasonal viral disease (more pronounced in moderate-climate countries) that infected nearly every person in a given population in the absence of vaccination. Important exceptions are island or isolated populations (e.g., Eskimo), which can remain unaffected by the virus for varying periods and, after reintroduction, can experience outbreaks of poliomyelitis that affect all age groups that were not affected by the previous wave of infection.

The epidemiology of poliomyelitis changed substantially during the last century. Three epidemiologic patterns have been observed: (a) endemic, (b) epidemic (prevaccine), and (c) vaccine era. Polioviruses probably circulated in an uninterrupted endemic manner for many centuries, infecting new cohorts of susceptible infants continuously, almost all early in life, when maternally derived antibodies transferred from mother to newborn still provided some protection against paralysis.

A change from endemic transmission to periodic epidemics was first observed in some temperate-climate countries (e.g., Norway, Sweden, the United States) late in the 19th century and at the beginning of the 20th century. The delay in median age of poliovirus exposure permitted the accumulation of sufficient children susceptible to poliomyelitis to result in periodic outbreaks. In the United States, the median age of poliovirus infection increased from younger than 5 years of age at the beginning of the 20th century to 5–9 years of age in the 1940s, before poliovirus vaccine licensure. In contrast, approximately 80% of the cases were in children younger than 5 years of age during the large epidemic in New York in 1916. The generally accepted explanation, supported by numerous studies, is that, in a temperate-zone climate with increased economic development and correspondingly improved resources for community sanitation and household hygiene, exposure to polioviruses was postponed to later in life. Epidemic transmission became the primary epidemiologic pattern in temperate-climate countries, such as the industrialized countries in Europe and North America, until poliomyelitis was brought under control after introduction of effective vaccines ( Fig. 50.3 ).

In developing countries, particularly tropical areas, an endemic epidemiologic pattern predominated until more recently. Poliovirus exposure occurred early in life and younger children were more often affected by paralysis A series of lameness surveys conducted in developing countries during the 1970’s reported between 5 and 10 lameness cases per 1000 children in the age group studied, suggesting that approximately one in 100 to one in 200 children acquire paralytic disease attributable to poliovirus. The WHO estimates that, in the absence of vaccination, at least one of every 200 children would become paralyzed by poliovirus and there would be approximately 650,000 cases of paralytic disease annually, the great majority of which would occur in children from developing countries. With improving vaccination coverage, a shift from an endemic to an epidemic pattern of poliovirus transmission has been observed in some developing countries that experienced large epidemics. ^,

The vaccine era began in the United States and in many European countries, Canada, Australia, New Zealand, and Japan after introduction of IPV in 1955. The incidence of paralytic poliomyelitis decreased rapidly from 18,308 reported cases in the United States in 1954, the year immediately preceding IPV licensure, to 2499 cases in 1957, a decline of 86% only 3 years after the availability and widespread use of IPV. The relative upswing in reported cases in 1959 (6289 cases), with many cases having a history of receiving several prior doses of IPV, raised concerns regarding the clinical efficacy of IPV in preventing paralytic disease. Nevertheless, continued and accelerated IPV use decreased the incidence of paralytic poliomyelitis to nearly record low levels (2525 cases) in the United States by 1960. Widespread use of IPV in other countries was followed by substantial decreases in the incidence of poliomyelitis and, in some European countries, including Finland, Iceland, The Netherlands, and Sweden, resulted in the apparent elimination of indigenous wild poliovirus transmission. ^,

The OPV era started in the United States with licensure of mOPV in 1961, followed by licensure of tOPV in 1963. Although live attenuated OPV was developed in the United States, the first large-scale production and the large field trials that proved the safety and efficacy of the vaccine took place in the former Soviet Union. A mass immunization program was initiated in the Soviet Union in 1959 and completed in 1960, covering 77.5 million people, or 36.7% of the entire population. The immunization campaign was followed by a sharp decrease in the incidence of poliomyelitis, from 10.6 per 100,000 population in 1958 to 0.43 per 100,000 population in 1963. Between 1964 and 1979, the incidence remained at a level of 0.01 to 0.1 per 100,000 population. Similar declines in the incidence of poliomyelitis were observed in other European countries, Australia, New Zealand, Canada, and the United States after the introduction of OPV. In the United States, mOPV was administered initially in mass vaccination campaigns in 1962, called Sabin Oral Saturdays/Sundays, followed by a routine vaccination program that administered vaccine to infants year-round. ^{, ,} The impact of administering OPV to a population that already had high immunity levels generated by previous natural infection or vaccination with IPV was impressive. Substantial reductions in the reported number of poliomyelitis cases were observed from 988 cases in 1961 to 61 cases in 1965. In 1973, only seven cases of poliomyelitis were reported. Epidemic poliomyelitis also was brought under control, with the last outbreak in the general population occurring in Texas along the U.S.–Mexico border in 1970, followed by small outbreaks in 1972 and 1979 among religious groups whose members object to vaccination. The last indigenously acquired case of poliomyelitis caused by wild poliovirus was detected in 1979. Between 1985 and 2000, aside from three imported cases of poliomyelitis (the most recent was reported in 1993), all cases were vaccine-associated.

The history of controlling poliomyelitis in developing, particularly tropical, countries has been more recent and more complicated. There is a notable exception: Cuba seems to have interrupted wild poliovirus after two rounds of mass vaccination campaigns in 1962. In many other developing countries, however, national vaccination programs were not operational until the late 1970s and early 1980s, and global OPV coverage with three doses among children 1 year of age only reached 80% by 1990 (∼70% by WHO/UNICEF estimated coverage). Despite low coverage with OPV in routine immunization, the incidence of poliomyelitis decreased by more than would be expected, but endemic transmission of polioviruses continued. In addition to achieving high routine coverage with three doses of OPV, control of poliomyelitis required additional supplemental doses of OPV that were incorporated into the routine vaccination schedule in some countries; other countries needed to administer supplemental doses of OPV in mass campaigns. In Brazil, the initiation of mass campaigns in 1980 had a dramatic effect; the number of reported cases decreased from 1290 in 1980 to 122 in 1981, a decrease of more than 90%.

Results from mathematical modeling suggest that the force of poliovirus infection, measured primarily by the average age at infection among populations in the prevaccine era, is substantially higher in developing countries compared with industrialized countries. For example, the basic reproductive number (a measure of infectivity) of wild poliovirus is between 3 and 5 in the United States, which means that, on average, an infected person introduced into a fully susceptible population would transmit the poliovirus to three to five contacts. In contrast, the average infected person in a developing tropical setting would be expected to have transmitted the infection to 10–12 contacts. ^, As population immunity increases and many of the contacts of an infected person are no longer susceptible, the number of transmissions decreases. When the reproductive rate is less than 1 because of high population immunity, transmission will eventually cease. The herd immunity threshold is the level of immunity in the population (e.g., in the “herd”) at which an infected person, on average, would transmit the infection to less than one susceptible contact.

Whereas poliomyelitis outbreaks in industrialized countries can be prevented with overall population immunity levels of approximately 66–80%, outbreaks in developing countries with inadequate sanitation and hygiene could still occur with immunity levels as high as 94–97% ( Fig. 50.1 ). These findings may be helpful in explaining why there was no spread to the general population after importations and small outbreaks in The Netherlands, Canada, and the United States ^, and why widespread transmission among well-vaccinated populations occurred in many outbreaks in developing countries. ^, A seroprevalence survey of poliovirus antibodies during the final stage of polio eradication in Egypt suggested that between 97% and 100% immunity against poliovirus type 1 may have been needed to interrupt type 1 transmission in a country with almost ideal conditions for poliovirus circulation. Seroprevalence surveys in Northern India, conducted in the 2009–11 period, after intensive use of bivalent OPV (types 1 and 3) and just before elimination of wild poliovirus 1 transmission (2011), found high seroprevalence levels of antibodies against poliovirus type 1 (98–99%) among infants 6–7 months old, but considerably lower levels against poliovirus types 2 and 3.

Significance as a Public Health Problem

In the absence of effective control programs with poliovirus vaccine, paralysis develops in approximately one of every 200 children (see “Risk Factors for Paralysis” earlier) after exposure to polioviruses, followed in most cases by permanent disability; 5–10% of patients with paralytic disease have a fatal outcome. ^, Thus, with a global birth cohort of approximately 143 million surviving infants in 2020, approximately 700,000 children would be expected to acquire paralytic poliomyelitis resulting in permanent disability each year, and between 35,500 and 70,000 of the cases would result in poliomyelitis-associated deaths. In addition to the acute manifestations of poliomyelitis, patients may experience postpolio syndrome decades after the acute episode that may require additional therapy, rehabilitation, and respiratory support. In the United States, a report estimated that, in the absence of a control program, more than $3 billion ($926 million in direct costs and $2.1 billion in indirect costs) would be required each year to cover the treatment and other related costs of patients with poliomyelitis. A recent study modeling different control scenarios suggested these scenarios will be more costly in the long run than finishing the eradication effort.

Despite the availability of two highly effective vaccines, poliomyelitis still exerts a significant public health impact in the world. In the United States in the prevaccine era, the peak incidence year of poliomyelitis was 1952, when 57,879 cases of poliomyelitis were reported (including 21,269 cases of paralytic disease). After the widespread use of poliovirus vaccines beginning in 1955, poliomyelitis was rapidly controlled in industrialized countries and in other areas where vaccines were used effectively. Globally, the Expanded Programme on Immunization, a program of the WHO established in 1974, provided leadership and technical guidance to national programs in most developing countries to improve vaccination coverage. Coverage levels apparently reached 80% with three doses of OPV among children 1 year of age for the first time in 1990, resulting in substantial decreases in the global morbidity and mortality burden of poliomyelitis. Despite this success, the WHO estimated that approximately 350,000 cases of paralytic poliomyelitis associated with permanent disability occurred in 1988, the year the global polio eradication target was adopted. Because of rapid progress toward polio eradication, the worldwide number of poliomyelitis cases caused by wild poliovirus was only 1,352 in 2000 , 140 in 2020 and 6 in 2021 (data as of April 26, 2022 at www.polioeradication.org ). During this same period, quality of AFP surveillance has improved ^, ; and it is unlikely that significant poliovirus circulation has been missed although some AFP cases may have been undetected in areas inaccessible owing to conflict and in populations that are difficult to survey, such as nomads.

Paralytic poliomyelitis continues to be a serious threat to children in polio-infected countries and occasionally to people residing in countries that eliminated wild poliovirus many years before. ^, Even in countries with well-vaccinated populations that eliminated indigenous wild poliovirus circulation decades ago, gaps in population immunity among groups objecting to vaccination for religious or other reasons and among communities that are not reached effectively by national vaccination programs (e.g., Roma, previously referred to as “gypsies”) ^, or individuals and groups with vaccine hesitancy, may allow establishment of epidemic transmission following importation. In the United States, the last two outbreaks of poliomyelitis occurred in 1972 and 1979 among members of certain religious groups objecting to vaccination. ^{, ,} The 1979 outbreak was an extension of an outbreak affecting first The Netherlands in 1978 and then Canada, and was caused by importation of a wild poliovirus type 1 strain circulating in Turkey. ^{, ,} Another outbreak of poliomyelitis affecting the same religious group occurred during 1992–1993 in the Netherlands, caused by a wild poliovirus type 3 most likely imported from the Indian subcontinent. In several countries in Europe the last cases and outbreaks of poliomyelitis were detected among Roma children: in Spain during 1980–81, in Bulgaria in 1990–91 and in 2000, ^, and in Romania in 1991–92.

Molecular Epidemiology of Poliovirus

The application of genomic sequencing of poliovirus isolates has added a new dimension to the understanding of the epidemiology of poliomyelitis. Because fewer than 1% of susceptible children infected with wild poliovirus show signs of paralysis, AFP surveillance alone has limited ability to track the patterns of poliovirus spread, especially over wide geographic areas. However, the combined genetic and surveillance data can be used to detect links between poliomyelitis cases, reconstruct chains of transmission at high-resolution, and unequivocally establish the sources and timing of importations from the remaining poliovirus reservoirs.

The high resolution of poliovirus molecular epidemiology follows from the very high rate of evolution of the poliovirus RNA genome. ^{, , ,} Most of the nucleotide substitutions generate synonymous codons, and the basic biological properties of wild polioviruses remain unchanged. Estimates of the rates of total nucleotide substitution into poliovirus capsid regions average approximately 10 ⁻² substitutions per site per year ( Table 50.3 ). ^{, , , ,} The rates appear to be similar across the three poliovirus serotypes and for both circulating polioviruses and polioviruses associated with chronic infections, and constitute a robust poliovirus molecular clock. The clock is stochastic, and estimates of dates of infections obtained over short time periods may have wide confidence intervals such that wider sequence windows may be needed to improve estimates. ^{, ,} In addition, the Sabin strains are subject to selection against the attenuating substitutions during the early phases of replication in the human intestine, which, when coupled with active recombination and incorporation of “hitchhiker” mutations, can accelerate the initial rates of substitution. Consequently, estimates from the molecular clock of the duration of shedding of newly emergent VDPVs can be longer than those inferred from the vaccination records, ^{, ,} even as molecular clock estimates for the duration of more prolonged infections may closely match the clinical data. ^{, ,} After approximately 10 years of divergence, variable nucleotide sites become increasingly saturated, yielding underestimates of the total time of virus replication, and requiring special analytic methods to obtain more robust estimates. ^,

Sequence analyses offer an additional tool to monitor the progress of the GPEI, and has shown that poliovirus genotypes (viruses within a genotype differ by <15% in their nucleotide sequences) and genetic clusters within genotypes (viruses within a cluster differ by <5% in their nucleotide sequences) disappear sequentially through intensive immunization efforts ( Fig. 50.4 ). Experience shows that in settings of sensitive surveillance a genotype that is not detected for more than a year has probably become extinct. Molecular epidemiology has established the existence of numerous poliovirus genotypes that had been endemic to different regions of the world ( Fig. 50.4 ). The last indigenous wild poliovirus type 2 isolate (detected in India 1999) was a representative of the South Asian type 2 genotype, the last of many wild type 2 genotypes in circulation during the prevaccine era ( Fig. 50.4 ). Similarly, representatives of the last two wild poliovirus type 3 genotypes were most recently detected in Pakistan in April 2012 and in Nigeria in November 2012. The most recent detection of wild poliovirus type 1 in Borno State, Nigeria, in August 2016 was a genotype indigenous to northern Nigeria. The certification of eradication of wild poliovirus in the WHO AFRO region in 2020, confirmed elimination of this genotype, leaving only the wild poliovirus type 1 SOAS genotype indigenous to Afghanistan and Pakistan still in circulation ( Fig. 50.4 ). Although molecular epidemiologic analyses show that poliovirus type 3 appears to transmit less efficiently than type 1 and cause smaller outbreaks, both serotypes have been associated with importations from neighboring countries and with intercontinental or global spread of the virus. ^{, , , ,} In some settings, different genotypes of poliovirus type 1 have been found to have cocirculated in a geographically limited area. ^{, , ,}

Molecular epidemiologic methods are routinely used to help identify reservoir communities with low population immunity, and where demographic and environmental conditions favor poliovirus circulation. During the peak months of poliovirus circulation, virus spreads from the reservoir communities to adjacent nonreservoir indicator communities (where the density of nonimmune, susceptible children can support some poliovirus circulation during the peak transmission season). Although many importations over long distances have been documented, ^, reservoir communities and their associated indicator communities frequently overlap international borders, ^, underscoring the importance of regional synchronization of National Immunization Days (NIDs) and Subnational Immunization Days. Equally important are the patterns of importation from reservoir communities to indicator communities within a country. ^{, ,}

Sequence analysis led to the recognition of highly divergent iVDPVs ^, and cVDPVs ^{, ,} (see “Vaccine-Derived Polioviruses” later), and it has been used to resolve, at high resolution, chains of cVDPV transmission ^, and separate iVDPV lineages in individual immunodeficient patients with prolonged infections. ^{, ,}

Molecular epidemiologic methods have also opened a new avenue for detecting gaps in polio surveillance. In areas with good surveillance, poliovirus isolates representing frequent sampling of a single chain of transmission are typically closely related (usually >99.5% VP1 sequence identity among the closest relatives). These closely related viruses are routinely visualized as sequences connected by short branches on phylogenetic trees. Long-branch connections between isolate sequences indicate missing information. If the virus is imported, the missing information may be recovered from the sequence relationships to viruses from the source reservoir. However, in many other circumstances, no closely related viruses can be found, and the recent virologic history of the isolate lineage is indeterminate.

Sequence analysis can be used to distinguish contaminants from true clinical isolates. When wild polioviruses isolated at different times and locations have identical VP1 sequences, contamination is suspected, because such sequence identities are inconsistent with the rapid rate of evolution of the poliovirus genomes. Contamination can be definitively confirmed (or ruled out) by sequencing of complete genomes, which has become more common with sequencing technology advances; recently this has been called genomic epidemiology. Complete genomes of vaccine-derived polioviruses have been sequenced using Sanger sequencing technology for the past 20 years ^{, , ,} or, more recently, next generation sequencing technology such as Illumina or Nanopore MinIon. Additional information about outbreaks can be provided by recombination junctions that are unique or shared among poliovirus isolates, or specific nucleotide substitutions that serve as biomarkers.

Early Approaches

Research on inducing active immunity in monkeys and inactivating poliovirus using formalin was performed as early as 1910 and 1911. Small-scale administering formalin-inactivated poliovirus to rhesus monkeys, adult volunteers, and children, were also conducted in the 1930s, but the approach was abandoned due to concerns about efficacy and safety. ^, In retrospect, it is also clear that, without knowledge of the number of poliovirus serotypes and a better understanding of the differences between attenuation and chemical inactivation, these early vaccine development efforts were doomed to failure.

Advances in tissue culture growth of poliovirus in the late 1940s renewed interest in poliovirus vaccines. In the early 1950s, attenuated strains were developed by several passages of virus in cell cultures of rodent CNS tissue or non-nervous system tissue from monkeys, followed by selection of attenuated variants at limiting dilutions or from single plaques.

Description of Vaccine

Genetic Determinants of Attenuation of the Sabin Oral Polio Vaccine Strains

Identification of the genetic determinants of attenuation of the Sabin OPV strains has been comprehensively reviewed. ^{, ,} Two basic approaches have been taken: (a) sequence comparisons between the Sabin strains and their neurovirulent wild parents (types 1 and 3) or neurovirulent revertants (types 2 and 3) obtained from patients with VAPP, and (b) investigation of the contribution of specific nucleotide substitutions to attenuation using infectious complementary DNA (cDNA) clones (see “Genetic Stability of Vaccine Seed Strains” later). A common feature of the Sabin strains is the presence of nucleotide substitutions in the IRES in the 5′-UTR, which have been clearly shown to be critical attenuating mutations ( Fig. 50.5 ). Additional mutations encoding amino acid substitutions in the capsid region contribute to and stabilize the attenuated phenotype.

Sabin 1

The 57 nucleotide substitutions distinguishing the Sabin 1 strain from its neurovirulent parent, Mahoney/USA41, are scattered throughout the genome. Six map to the 5′-UTR, 49 map to the coding region (21 of which encode amino acid substitutions), and two map to the 3′-UTR. Infectious cDNA constructs containing different combinations of blocks of Sabin 1 and Mahoney sequences were tested for neurovirulence in monkeys or transgenic mice expressing the CD155 receptor, for temperature sensitivity, and for other phenotypic properties distinguishing the two strains. ^, The single most important determinant of the attenuated phenotype of Sabin 1 was the A→G substitution at position 480 (abbreviated A480G) in the IRES. Four other substitutions contributing to the attenuated phenotype mapped to the capsid region (one in VP4, one in VP3, and two in VP1), and a substitution contributing to the temperature-sensitive phenotype (but not to the attenuated phenotype) mapped to the 3D ^pol region encoding the RNA-dependent RNA polymerase (see Fig. 50.5 ). ^{, ,} The relatively high stability of the attenuated phenotype of Sabin 1 is attributed to multiple attenuating substitutions and their relative contributions to the phenotype. However, neurovirulent revertants have been selected in the laboratory that have only two (U525C, a suppressor that restores base pairing at 480G [see below] and C6203U, a histidine→tyrosine back-mutation in the 3D-polymerase) or three mutations.

Sabin 2

Only two nucleotide substitutions (G481A in the IRES, and C2909U encoding a threonine→isoleucine substitution at position 143 of VP1) appear to be main determinants of the attenuated phenotype of Sabin 2 (see Fig. 50.5 ). ^, Because P712 has inherently low neurovirulence, identification of critical attenuating sites in Sabin 2 involved determination of the effects of introduction of sequences derived from a minimally divergent neurovirulent revertant of Sabin 2 (obtained from a case of VAPP) into infectious cDNA constructs derived from Sabin 2. ^, Weakly attenuating substitutions mapped to nucleotide positions 437 in the 5′-UTR, and/or 868 (VP4 region), and/or 4076 (2B region).

Sabin 3

Detailed analysis of the attenuated phenotype of Sabin 3 has been possible because the neurovirulent parental strain, Leon/USA37, differs from Sabin 3 by only 10 nucleotide substitutions. In addition, numerous neurovirulent revertants of the Sabin 3 strain have been isolated from patients with VAPP and from healthy OPV recipients. Only two substitutions—C472U in the IRES and C2034U encoding a serine→phenylalanine substitution at position 91 of VP3—appear to be the main determinants of the attenuated phenotype (see Fig. 50.5 ). ^{, ,} A third substitution, U2493C encoding an isoleucine→threonine substitution at position 6 of VP1, appears to be a minor determinant of attenuation that also reduces the replicative fitness of Sabin 3. The U2493C substitution is strongly selected against during cell culture passage and during replication in the human intestine.

Quantitative determination of the contributions of each substitution is complicated by several factors: (a) the role of minor determinants of attenuation is difficult to measure, (b) some substitutions have pleiotropic effects on phenotype, (c) some Sabin strain phenotypes require a combination of substitutions, (d) second-site mutations can suppress the attenuated phenotype in various ways, and (e) the outcome of experimental neurovirulence tests may vary with the choice of experimental animals (monkeys vs transgenic mice) or the route of injection (intraspinal vs intracerebral). ^{, ,} Examples of substitutions with pleiotropic effects are: (a) the serine→phenyalanine substitution at position 91 of VP3 which confers both attenuation and temperature sensitivity to Sabin 3 and (b) the tyrosine→histidine substitution at position 73 of the 3D polymerase of Sabin 1, which is an important determinant of temperature sensitivity ^, and a minor contributor to attenuation. The relationship between poliovirus neurovirulence in experimental animals (where virus is introduced directly into the CNS) and pathogenicity for humans (where virus is introduced by ingestion) cannot be measured in controlled experiments, and remains ambiguous. There is no orally infectable animal model for paralysis that uses physiologically relevant amounts of poliovirus and, likewise, there is no animal model for poliovirus transmission. Although an orally infectable transgenic mouse model exists, the mice are transgenic for CD155 human poliovirus receptor and are also knockouts for IFNAR, interferon alpha receptor, an important component of innate immunity. ^,

Clearly the Sabin OPV strains are several orders of magnitude less neurovirulent than wild polioviruses, as indicated by the very low incidence of VAPP compared with the high incidence of paralytic poliomyelitis in areas where wild polioviruses are circulating. ^, The attenuating substitutions of the Sabin strains are sometimes described as mutations impairing the specific determinants of poliovirus neurovirulence. However, attenuation is a specific phenotype of each Sabin strain. Poliovirus neurovirulence, by contrast, is a much more complex property. Expression of a neurovirulent phenotype requires the efficient function of numerous steps in the natural life cycle of the virus and, thus, the efficient expression of several viral genes. Impairment in the expression of any of these poliovirus genes can reduce replicative fitness and confer a more attenuated phenotype. However, such mutants may not be suitable candidates for live-virus vaccines. The Sabin strains contain specific genetic defects that are not found among the highly diverse population of circulating wild polioviruses. These exceptional defects are unstable to replication in the human intestine, and variants with higher replicative fitness are regularly selected. Other combinations of substitutions can produce highly attenuated polioviruses potentially suitable for vaccine use. However, the attenuating substitutions of the Sabin strains were shown to confer highly favorable biological properties, making these strains the best available candidates in the early 1960s for licensure as OPVs (see “How Strains Were Developed” earlier).