Poliomyelitis Research Paper Example

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What Is Polio? Definitions, Description Of The Disease, And Surveillance

Polio is the abbreviation for the disease poliomyelitis, caused by poliovirus. It typically causes a mild enteric or febrile infection, but it can spread systemically and affect the nervous system. The early twentieth-century technical term was acute anterior poliomyelitis or paralytic poliomyelitis, and its diagnosis was clinical without laboratory support. The site of pathology in typical paralytic poliomyelitis is the anterior horn motor neurons in the gray (polios) matter of the spinal cord (myelos). When motor neuron death and local inflammation reaches a threshold, limb paralysis occurs. In 20–30% of subjects, recovery from paralysis occurs, but in the majority, paralysis is permanent, leading to muscle atrophy and joint deformities. Other infections (such as other enteroviruses or West Nile virus) may cause limb muscle paralysis known as acute flaccid paralysis (AFP) syndrome, but only that caused by polioviruses (antigenic types 1, 2, or 3, one species of the genus Enterovirus, family Picornaviridae) is poliomyelitis; hence laboratory confirmation test has become essential to the diagnosis of polio. Indeed, when paralysis of a facial nerve occurs due to poliovirus infection, it is still called poliomyelitis, even though the site of pathology is not in the spinal cord. Thus, the term poliomyelitis is now based on etiology rather than symptoms.

Most poliovirus infections are asymptomatic (subclinical). Infection with minor symptoms is termed nonparalytic polio. Only one in 160–200 persons infected with poliovirus type 1, and one in about 1000 infected with type 2 or 3, develop paralysis. One infection is sufficient for lifelong immunity, but immunity is type-specific.

Poliovirus attaches to cell surfaces via the poliovirus receptor (PVR), a membrane protein (CD155) of the immunoglobulin superfamily. Only polioviruses bind to PVR, which is expressed mainly on the nasopharyngeal mucosa, Peyer’s patch M cells of small intestines, and the anterior horn motor neurons of the spinal cord and medulla oblongata. These are the main anatomic sites where polioviruses multiply inside the host. Almost all cultured human and primate cells express PVR, support growth of polioviruses and develop cytopathology (CPE), and have become the standard cells for virus isolation, detection, and cultivation for clinical and research purposes. The human PVR gene has been introduced into transgenic mice, and a fibroblastic cell line from them (L20B cells) has become very useful in primary isolation of polioviruses from clinical specimens.

Infection with poliovirus was essentially universal until the advent of vaccination. Polio was first clinically recognized in 1840 and an 1887 Swedish polio epidemic was described in 1891. No country was able to control or interrupt polio transmission solely by sanitation, clean water supply, personal hygiene, or very high living standards. Although dogma is that transmission was primarily through contaminated water and food (fecal–oral) there is compelling evidence to show that direct person-to-person transmission during ordinary social contact is a critical factor during outbreaks. Polio is highly contagious and can be transmitted via the respiratory route by inhalation of droplets or aerosols containing virus expelled through saliva or nasal secretions. Polio has now been eliminated from most of the world through vaccination, and this research paper will focus on the development of the polio vaccine and eradication efforts.

In developing countries, acute flaccid paralysis (AFP) in children under 15 years of age is monitored. From children with AFP, stool samples collected within 2 weeks of onset are sent to a poliovirus diagnostic laboratory for virological investigation. Globally laboratories are networked in three tiers: Global reference centers, national or regional reference laboratories, and local diagnostic laboratories. Poliovirus isolates are typed locally and submitted to the next higher level for differentiation as wild or vaccine-derived.

The World Health Organization (WHO) has established performance standards for surveillance sensitivity, stool collection, and virus isolation. Every country has its own polio elimination certification committee and when 3 consecutive years pass without any wild virus isolation, that country is certified to have achieved success. Countries are aggregated by WHO into six regions, and some regions (the Americas, Western Pacific, and Europe) have achieved regional elimination. The surveillance, stool collection, and laboratory standards are satisfactory in the four currently polio-endemic countries.

The Rise And Fall Of Polio In The Twentieth Century: The Need For A Vaccine

Until the 1930s, polio was predominantly in infants and young children and called infantile paralysis. In countries with high birth rates and crowded living, about half of paralytic cases occurred in infancy and the remaining mostly before the age of 5. Infants were often infected during the first few months of life when maternal antibody protected them from disease (passive immunity), while the infection itself induced long-lasting active immunity. The total incidence of clinical disease was low and in younger children.

As nations became richer with improved living standards and housing, many children escaped infection in early childhood and remained nonimmune. Poliovirus spread rapidly during summer and fall, particularly when older, susceptible children aggregated for school or social activities such as summer camps. During the 1930s–1950s, the age range in Europe and North America shifted to older children, while the incidence of clinical polio increased. In older children and young adults, poliovirus increasingly affects the brain stem, resulting in more lethal respiratory paralysis or bulbar polio in contrast to the limb paralysis of spinal polio seen in infants. These annual outbreaks, suddenly paralyzing or killing healthy children and adolescents, caused much anxiety. This shift was originally attributed to improving sanitation, but in retrospect better housing with less crowding and fluctuating birth rates may have been more important. As improved sanitation, hygiene, and water supplies did not reduce the risk of polio, scientists and opinion leaders realized that polio could only be prevented by vaccination. The development of polio vaccines has indeed led to a tremendous decrement in the incidence of polio, while providing important lessons about bioethics, the nature of scientific discourse, and the selection of appropriate vaccines for different populations.

Early Poliovirus Research, The Development Of The Inactivated Polio Virus Vaccine, And The Debate About The Vaccine

Early Research

Spinal cord extracts were inoculated into monkeys and the disease was replicated by Landsteiner and Popper in 1908. Through primate experiments the three known antigenic types (or serotypes) were identified. The infectious agent of polio was found in the feces of infected children, identifying the gastrointestinal tract as one major site of infection, and indeed monkeys were infected by oral feeding and the infectious agent (not as yet identified as a virus) recovered from feces. Thus the paradigm of poliovirus fecal–oral transmission in humans arose, which had important repercussions on future vaccine development and use. Subsequent early poliovirus vaccine attempts (1930s–1950s) were sometimes crude, sometimes sophisticated, sometimes ethically dubious, and largely unregulated. In the 1930s, Brodie and Park as well as Kolmer used monkey spinal cord preparations to inoculate children without knowing of the three antigenic types, nor that the cord myelin would induce allergic encephalomyelitis, and without reliable markers for complete virus inactivation or attenuation. The results were disastrous, as no protection was demonstrated and some children developed polio after inoculation. Poliovirus vaccine development identified the need for state regulations for quality, safety, and disease surveillance (monitoring and measuring vaccine efficacy and adverse reactions) as general principles for the current era.

In 1947–48, Isabel Morgan inoculated monkeys with formalin-inactivated virus from infected monkey neuronal tissues, which protected them from serotype-specific disease, providing proof-of-principle evidence for a killed virus vaccine. In the early 1950s, Hammon and colleagues showed that injected human serum gamma globulin protected against polio paralysis, demonstrating that serum antibodies protect against disease, and vaccination research was resurrected.

Cell Culture Adaptation Of Polioviruses

Enders, Robbins and Weller discovered in 1949 that polioviruses could be grown in human and animal cell culture, for which they received the 1954 Nobel Prize. This led to several unsuccessful attempts to create either killed (inactivated) virus vaccine or live (attenuated) virus vaccine, using cell culture-grown virus stock. The prototype vaccines had residual neurovirulence and were unsuitable for human use. All these early studies lacked stringent laboratory standards or ethical clearance for human use. Rectifying such obvious errors, Jonas Salk and Albert Sabin succeeded in developing satisfactory inactivated and live vaccines, respectively, during the late 1950s. These vaccines were developed with private agency funding in North America.

In 1921 Franklin Delano Roosevelt, who became President of the United States in 1932, developed paralytic polio of both legs at the age of 39. Roosevelt’s law partner Basil O’Connor formed a National Foundation for Infantile Paralysis (NFIP) in 1938, with Roosevelt as its patron. Innumerable local chapters were organized, and gave all sectors of society the opportunity to participate in a national fight against polio, which was seen as the nation’s most important challenge in children’s health. Millions of small contributions were donated to NFIP with the catchy name of the March of Dimes (a dime being a tenth of a dollar coin). NFIP thus became the largest private philanthropic institution in the United States and indeed the world. Funds were liberally distributed nationally for the treatment and rehabilitation of affected persons, building treatment facilities in hospitals, purchasing necessary equipment, particularly the expensive iron lungs (Drinker apparatus, for noninvasive ventilation-assistance by alternate application of positive and negative air pressure), training of health-care personnel, and for research. O’Connor believed in the idea of a polio vaccine developed through science that would be the final answer to the crippling disease. It turned out he was right and his detractors, mostly renowned virologists who were experts in their own field but not necessarily in the ways of the world, were wrong.

Despite Roosevelt’s death in 1945, contributions to the NFIP increased as cases of polio also increased. The NFIP had a Research Committee that guided research, but its work on a vaccine was slow, and O’Connor established an Immunization Committee that focused on vaccine development. Jonas Salk and Albert Sabin, among others, were recipients of NFIP funds for research. However, only Salk took the direct route of research toward a vaccine.

Salk’s Success In Creating The Inactivated Polio Vaccine

Salk, unlike most polio experts, believed that an inactivated virus preparation would be both safe and immunogenic. Salk and Thomas Francis had already developed and proved that killed influenza virus vaccine was safe and effective. Others discounted this approach as earlier viral vaccines used live attenuated viruses (smallpox, rabies, yellow fever). In 1952, Salk showed that formaldehyde inactivated polioviruses were highly immunogenic both in animals and in children. Despite opposition, O’Connor and NFIP research director Harry Weaver established a new Vaccine Advisory Committee, which funded Thomas Francis to conduct a field trial of an inactivated vaccine. Bulk concentrated vaccine was made in Canada by Connaught Laboratories and supplied to U.S. vaccine manufacturers who prepared vials of both vaccine and a placebo. Children were given three doses 1 month apart. The results showed inactivated polio vaccine (IPV) to be completely safe and highly effective. Vaccine efficacy correlated well with vaccine potency, and vaccine batches that induced high frequencies of antibody response showed 80–90% protection. In April 1955, the result was publicized and immediately the U.S. Government licensed IPV for wide usage.

IPV owes its birth to Basil O’Connor, Harry Weaver, and Thomas Francis in addition to Jonas Salk. They demonstrated vision, conviction, maneuvering ability, and an astute understanding of immunology. IPV was truly a people’s vaccine, developed by people’s money and Salk was a public hero, who was (partly consequently) shunned by the scientific establishment.

Once IPV was licensed, new problems arose. The NFIP bought up all the vaccine made by various manufacturers and gave it free of charge first to the placebo recipients in the trial, and then to children in the first and second grades of school, who were the most vulnerable age group. This upset the medical profession, the U.S. government, and to a certain extent, the pharmaceutical industry, as it was akin to socialized medicine, contrary to the principles of private, free-market enterprise. In contrast, the Canadian government manufactured, distributed, and regulated a plentiful, low-cost IPV of high quality. In the United States, the drug companies prevailed and six of them began marketing their product directly to doctors. Gradually, the selling price also rose. Obviously, IPV safety demanded full inactivation of the virus, which was not the case with a few batches made in the United States by private manufacturers. Due to faulty quality and manufacturing controls, a number of U.S. children developed polio after taking IPV, leading the U.S. Government to establish vaccine safety testing and polio surveillance standards, the principles of which are still used today. While no further mishaps occurred, these events fueled the schism between IPV supporters and live vaccine protagonists.

From 1955 to 1961, IPV was used exclusively in the United States and Canada. The effect on polio incidence was immediate and remarkable. In the United States, a 90% reduction occurred within 4 years and 99% within the next 4 years. However, vaccination coverage had not reached 90% and the greater decline than accounted for by vaccination was interpreted as the result of indirect effect on virus circulation, or the herd effect of vaccination (Stickle, 1964). Studies in Houston, Texas, showed vaccine efficacy remaining at 96% through 2 consecutive years, likely due to the direct protective effect and added herd effect (Melnick et al., 1961).

In 1962, the live vaccine, developed by Sabin and other live-vaccine proponents, was licensed in the United States and it gradually replaced IPV, which was no longer manufactured in the United States from 1965. For children with immune system defects, IPV was imported from Canada where IPV continued to be used in some provinces while others switched to live vaccine. Today the situation is the reverse, as will be described in the section titled ‘Use of IPV in countries outside North America: Demonstration of herd effect.’

Use Of IPV In Countries Outside North America: Demonstration Of The Herd Effect

The original IPV trial included parts of Canada and Finland. Upon release of the trial results, Finland embarked on a nationwide vaccination program using IPV made by the Dutch public sector vaccine manufacturer and when IPV coverage reached approximately 60% in 1961, disease incidence became zero and poliovirus could no longer be detected in sewage, confirming the absence of excretion by infected individuals and to the high degree of a herd protective effect. Many other European countries introduced IPV during the late 1950s and brought down the incidence of polio rapidly.

Safety And Efficacy Of IPV

While Salk had originally formulated IPV with a mineral oil adjuvant, which led to high antibody levels after a single dose, the NFIP found the local inflammatory response to the adjuvant unacceptable, and it persuaded Salk to make adjuvant-free vaccine to be given in three doses. Without adjuvant, IPV was rendered totally safe from any serious adverse reaction; anaphylaxis, although theoretically possible, has not been reported, and the minor local reactions of many injected vaccines are usually absent.

The efficacy of IPV, as measured by the proportion of the vaccinated being protected when exposed to infection, was moderate to high in the original trial, and with subsequent manufacturing refinements is over 99%. Poliovirus neutralizing antibody is a reliable surrogate for protection from disease. After receiving three doses of IPV at intervals of 4 weeks or more, nearly 100% of children become antibody-positive and protected. The vast majority of vaccinated children develop antibody titers in greater than 1:256, whereas with the live vaccine the antibody response is quite variable and usually below 1:128.

Basic Properties Of The Original IPV

The key to the success of the IPV was the presence of the capsid protein (D antigen) that acts as the viral ligand that binds PVR on the host cell. IPV contained approximately 20, 2, and 4 D antigen units of poliovirus types 1, 2, and 3, respectively, in a liquid form without adjuvant. Residual traces of formaldehyde acted as a preservative, and in multidose vials an added alcoholic preservative (2-phenoxyethanol) provided protection against the multiplication of accidentally introduced organisms. Residual traces of antimicrobials used in the cell culture were also present. Aluminum salts and Thiomersal, both of which have been used for inactivated bacterial and toxoid vaccines, are absent from IPV.

In some countries, IPV was given as stand-alone vaccine, while in others it was presented as a combination vaccine containing DTP and IPV.

IPV Technology Improvements

Although the United States replaced IPV with oral polio vaccine (OPV), Dutch scientists continued to improve the vaccine. After demonstrating that IPV immunogenicity was due to the D antigen, they established standards for antibody responses in animal models. In order to improve vaccine yield, innovative techniques such as growing host cells on polystyrene beads in fermentation tanks were developed, so as to increase the total surface area of host cells and thus virus yield from cell culture. While the original Salk vaccine possessed about 20, 2, and 4 D antigen units of poliovirus types 1, 2, and 3, respectively, they established that the optimum vaccine antigen potency was 40, 8, and 32 D antigen units, respectively. This formulation was called enhanced potency IPV (e-IPV or IPV-E) to distinguish it from the original product, and since 1991 all manufacturers have adopted this formulation. Other advances have included the adoption of human diploid cells or Vero cells (of vervet monkey kidney origin) for virus production, so as to avoid the risk of contaminating viruses in primary monkey kidney cells that have theoretical potential for inducing tumors.

Safety And Efficacy Of New Formulation IPV

Nearly all high-income nations and a few middle-income nations use IPV, and their experience confirms the efficacy and safety of the product. Only the low-income countries cannot afford IPV, as it has higher production costs than OPV and the limited global supply is currently all purchased by richer nations. Only five companies in the world make IPV (four in Europe and one in North America). OPV, on the other hand, is made by many companies in Asia, Europe, and Latin America.

IPV is one of the safest vaccines in current use. Apart from injection site discomfort, no serious adverse events have been reported to be due to IPV. Although anaphylaxis is listed as a potential adverse reaction, it has not been reported (to the author’s knowledge) anywhere.

IPV induces immune response according to the prime boost principle. Therefore, a minimum of two and an optimum of three doses should be offered for primary vaccination, followed by one or more booster doses after long intervals. The presence of even moderate titers of maternal antibody in the young infant tends to dampen the antibody response to IPV, reducing the frequency of responders and the antibody titer. Therefore, wherever possible, the first dose of IPV should be given at or after 8 weeks (2 months) of age. The recommended age for commencing vaccination with DTP and OPV in developing countries (under the Expanded Program on Immunization, EPI, designed by WHO) is 6 weeks. IPV may be given at 6 weeks, provided two more doses are given to complete the primary series and a booster dose is given during the 2nd year of life.

The interval between the first and second doses also affects the immune response, as a 4-week interval is inferior to 8 weeks. The EPI schedule is to give the second dose of DTP and OPV 4 weeks after the first, namely at 10 weeks of age. IPV may be given in this schedule, but for predictable immune response three doses must be given and followed by at least one booster during the 2nd year of life.

The WHO has consistently stated that developing countries must use OPV. Thus, data on IPV efficacy and in developing countries is mostly limited to short-term research studies. All but one such study have shown that IPV efficacy in developing countries is as good as in developed countries. This is in contrast to OPV, which has very large degree of variation in vaccine efficacy, illustrated by the frequent occurrence of polio in children in some countries even after taking the recommended three doses (and more). In contrast, there has not been even a single report of a child developing polio after receiving three e-IPV doses.

Countries Using IPV In National Vaccination Programs

Only a few countries continued to use IPV when OPV became the vaccine of choice according to WHO. However, a number of countries have now switched to IPV because of the rare but continued occurrence of OPV-associated polio. As of 2006, Andorra, Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Luxemburg, Monaco, Portugal, Netherlands, Norway, New Zealand, Slovakia, Slovenia, South Korea, Spain, Sweden, Switzerland, UK, and the United States exclusively use IPV.

In addition, in many countries in Latin America and Asia, IPV is registered as an alternative to OPV, but used mainly in the private sector health-care system. In many countries listed above, IPV is given to children as one component of a combination vaccine – using DTP as the base platform, but may contain hepatitis B vaccine, and/or Haemophilus influenzae type b vaccine. All such combinations use the acellular pertussis (aP) vaccine, whereas many developing countries continue to use whole cell killed pertussis (wP) bacterial vaccine. Currently no combination vaccine containing DTwP vaccine is available on the market, although such a combination vaccine was available before DTaP vaccine became the accepted one in most high-income countries.

The Live, Attenuated Oral Polio Vaccine

The Early History Of The OPV

During the early vaccine development period of the 1930s through 1950s, two schools of thought existed, one favoring inactivated virus and the other live, attenuated virus for vaccine. Both approaches were funded by the NFIP, including Sabin and Salk. Concerns about insufficient attenuation of live vaccine were fueled not only by the early monkey experiments, but also by the experience of Koprowski, who conducted studies on a live vaccine in relative secrecy for the Lederle company. He administered prototype vaccines to children (without proper ethical review) in both the United States and in Ireland, but residual neurovirulence showed that the attenuation was incomplete.

After IPV licensure in 1955, the NFIP ended funding for an attenuated live vaccine. Through other funding, Sabin completed the attenuation of all three poliovirus strains in a series of elegant investigations that included testing for neurovirulence via direct inoculation of candidate strains of poliovirus into monkey spinal cord. Of note, the live attenuated vaccine that was shed in feces (and possibly respiratory secretions) after vaccination had the capacity to immunize other people, but also to revert to a more virulent neurotropic virus.

By the time Sabin had completed his work in 1959–60, IPV had been adopted in the United States, Canada, and Europe, removing the opportunity for a large-scale OPV trial in these regions. Sabin donated his strains to the Soviet Union where OPV was adopted, with a dramatic decline in polio incidence there and in Eastern Europe. The WHO experts who reviewed OPV were also supporters of the live virus vaccine strategy and concluded that the OPV was effective and safe. Based on this information, the U.S. Government approved the live vaccine (first in monovalent forms, and then a trivalent form) in 1962, and the WHO endorsed it for use globally. In retrospect, many have criticized this decision because the shed virus can establish transmission and circulation, resulting in virulent virus derived from the vaccine strain.

Monovalent And Trivalent OPVs: Balancing The Infection Rates

In July 1961, the American Medical Association (AMA), perhaps influenced by the strong live vaccine lobby, passed a resolution that IPV should be replaced in the United States with the oral live vaccine OPV upon its licensure. In September, type 1 vaccine (monovalent, mOPV-1) was licensed, and by 1962, so were types 2 and 3 vaccines (mOPV-2 and mOPV-3).

When 105 virus doses (median cell culture infectious dose, or CCID50) of any of the monovalent vaccines was given to children, 80–100% responded with antibody production, proving effective intestinal infection and protection against the wild-type infection by the same serotype. However, when all three were included in a trivalent preparation (tOPV), the response was reduced, particularly for types 1 and 3, as type 2 infection was dominant over the others; type 1 is the least infectious and type 3 is intermediate. Robertson and colleagues in Canada made a balanced tOPV in which the highest (106) content of type 1, the lowest (105) of type 2, and intermediate (105.5) content of type 3 were mixed in one dose, with optimum results, but not near-100% responses. Type 2 is dominant in terms of infection frequency and antibody response; type 1 is the least infectious, and type 3 falls between the two. Thus, the tOPV content is balanced for 10:1:3 ratios of types 1, 2, and 3. When three doses were given, virtually all children tested in developed countries responded to all three virus types. The U.S. government licensed the tOPV in 1963, although the safety and effects of tOPV had not yet been established with the same rigor as IPV. Indeed, many pediatricians practiced a sequential schedule of one dose of Salk IPV vaccine followed by one or more doses of the OPV so as to prevent any untoward problem from OPV. By 1963, polio had already declined by some 99% in the United States, a fact that did not seem to attract much attention.

Efficacy Of Trivalent OPV: Geographic Variations

The immune responses induced by vaccines are, in general, relatively uniform across various human populations, with rare exceptions. Hence, it was anticipated that children in all populations and countries would respond to OPV also in a satisfactory manner. That was not the case. As OPV was introduced in Africa and Asia in the early 1960s, response rates were lower than expected and several problems emerged. Potential reasons for this include low antibody response rates, loss of vaccine viability due to inadequate refrigeration, and possible interference by concurrent infection with other enteroviruses.

Inadequate refrigeration affects many vaccines and not just OPV, and this problem did not explain low antibody response rates when vaccine was properly shipped and stored. In addition, research has not shown that concurrent infection with other viruses is operant; indeed, no enterovirus other than poliovirus binds to PVRs, hence enterovirus interference has no biological plausibility. Investigations in the author’s laboratory in the late 1960s and 1970s confirmed very low vaccine efficacy of OPV in India, particularly against types 1 and 3 polioviruses. Concurrent or antecedent infection with echoor coxsackie viruses did not affect the frequency of response. The problem was identified as low frequency of fecal virus shedding – the tell-tale sign of intestinal infection – of vaccine virus take. When a dose of tOPV was fed to Indian children, approximately 60–65% developed type 2 virus infection with an antibody response; roughly 25–30% responded to type 3, and 20–25% responded to type 1. The mean frequency of response to any poliovirus was 37–40% in South India, as against approximately 80% in the United States, South Africa, or Russia. Each additional dose improved the response rate according to an arithmetic proportional increment; thus in the Unites States, 16 of the remaining 20% would respond to the second dose and 3 of the remaining 4% would respond to a third dose, adding up to 99% with three doses of OPV. In India, a second OPV dose would seroconvert roughly 24% after the second dose and 14% after the third dose, for a total of 78% after three doses, lower than the 80% seroconversion with one dose in the United States. With five doses, the response would be 92%, lower than that of two doses in the United States. To achieve 99% response, it would take (theoretically) nine doses of OPV. This anomaly was first reported in South India in 1972 and since then vaccine failure polio has been found to be widespread in many developing countries, especially in the tropical and subtropical zones. This striking variation in immune response to a vaccine was unprecedented and of uncertain reason. It was clear that the variation was geographical – with varying response frequencies in different locales – the worst in heavily populated communities with very poor sanitation and hygiene.

Perhaps the world’s lowest OPV efficacy is in the adjacent northern Indian states of Uttar Pradesh and Bihar. A team of WHO officials determined the perdose efficacy of tOPV against type 1 poliovirus as just 9%, with the protective efficacy after three doses only 24% (Grassly et al., 2006). Thus, children fully vaccinated with the WHO-recommended three OPV doses were inadequately immunized. Consequently, the majority of children with polio in recent decades were by definition fully immunized yet still susceptible, and consequently innumerable children had suffered paralytic polio that could have been prevented with additional OPV doses or the use of IPV. As an oral vaccine without the need of injection, it would have been very easy to give five to seven doses of OPV during infancy, thus protecting at least the majority of vaccinated children. When seroconversion rates to three doses of fully potent tOPV are measured, the problem becomes clear, in that 20–30% of vaccinated children remain without antibody responses against types 1 and 3 polioviruses, yet more than 90% seroconvert to type 2. Thus the problem is the biological response to the type 1 and 3 components of the vaccine, not the vaccine’s potency. Unlike IPV where the immune response is of the prime-boost type, with OPV the vaccine viruses have to infect the child before an immune response can occur. Should infection fail to occur, then no protective antibody will develop and the child remains susceptible to polio. Each additional dose of OPV infects some more children, reducing their immunity gap.

In contrast to the experience in India and other developing countries, nearly all children seroconvert to all three serotypes of poliovirus in North America, Europe, Japan, and Australia with three doses of the balanced tOPV. Thus, the reputation of tOPV in all rich nations (with low birth rates and good sanitation and hygiene) is that it is highly efficacious with three doses. There have not been any cases of polio in children in rich countries if they have received three doses of OPV.

When poliovirus transmission was interrupted in Brazil in 1990, the mean number of OPV doses consumed by under-5 children was nine. In India, only when the mean number of doses reached or exceeded nine did the transmission of type 2 wild virus cease, later followed by cessation of type 1 and type 3 transmission in most states. Recently, it has been shown that there are locations in India where the per-dose vaccine efficacy is approximately 10% where wild-type 1 transmission continued, even after the mean number of OPV doses in under-5 children reached 15. The very low vaccine efficacy of OPV has been identified as the major reason for the inability to interrupt poliovirus transmission even in 2007, which is 7 years after the target year for global eradication.

The reason for this geographic variation in vaccine efficacy does not appear to be genetic or ethnic, but is apparently related to gastrointestinal factors associated with poor environmental sanitation and personal hygiene, as other theories relating to the cold chain and concurrent infections have been eliminated.

Attempts To Improve The Vaccine Efficacy Of OPV

Four methods have been tried to improve vaccine efficacy (VE) of OPV in developing countries. The first was to increase the virus content of each OPV dose tenfold, which increases seroconversion rates, but at least three doses are still required to achieve very high response frequencies, and the cost of production also rises. By doubling the type 3 virus content in tOPV, marginally better response rates were obtained; however, this newformulation OPV was unsuccessful in eliminating type 3 poliovirus transmission in parts of India where it continues to circulate in 2007. Moreover, the safety of enhanced potency OPV has not been established.

The second method was to simply increase the number of doses given to each child. Since each dose acts as an infectious inoculum, those who did not get infected previously get another chance each time the vaccine is given. In developing countries, at least five doses must be given as primary series, requiring at least five contacts between a health worker and the infant, which fortunately fits within the schedule for the global EPI. Countries such as Oman and Taiwan, and the Tamil Nadu state in India, which adopted this schedule rapidly, controlled polio and even interrupted wild virus transmission.

The third method has been to give the three doses of OPV over an 8-week period (4 weeks between doses) in annual drives, or pulses. Rather than improving vaccine efficacy, this method improves the inhibitory herd effect of OPV on the wild poliovirus transmission in the community. After the pulse, the speed of wild virus circulation slows down and for a period of time all children enjoy low incidence; by the time this effect wears down, the next annual pulse is due. The principle here is that pulse vaccination reduces the size of the susceptible pool of children by a sharp short vaccination effort. Unfortunately, this method has not been widely accepted by any country. A hidden advantage of pulse vaccination is that the remaining 10 months are available for the health staff to improve the performance of EPI in the community.

The fourth approach, currently widely practiced in Asia and Africa, is to give monovalent OPV, which avoids the intertype interference seen with tOPV. Since type 2 wild virus has been eliminated from circulation globally, mOPV-1 or mOPV-3 can be used where type 1 or 3 wild virus is still circulating. The infection rate for a specific type of mOPV is higher than what would occur for that specific type when given in tOPV. In its rebirth, mOPV type 1 is made with 106 CCID50 per dose (the same as in tOPV), whereas the original had only 105 CCID50, potency. Thus two improvements are combined in this approach: One, monovalent vaccine to avoid competition by other types, and two, enhanced potency to improve infection frequency.

Intertype Interference Between OPV Vaccine Viruses

As the infection rate of each poliovirus type is lower when given as tOPV than as mOPV, this phenomenon indicates that some form of intertype interference occurs. The reason for this is not understood. The site of infection of orally fed OPV polioviruses appears to be at the Peyer’s patches of ileum, as PVRs are found on the M cells of Peyer’s patches but not elsewhere in the small intestinal mucosa. Although over 105 virus particles of each type are fed in a dose of OPV, and there are innumerable M cells in the ileum, actual take does not occur every time vaccine is fed, and for unknown reasons type 2 infection is more common than type 1 or 3. However, when mOPV type 1 or 2 is given, the take rate improves to the level of type 2 in tOPV, suggesting some degree of PVR competition by the three types, with type 2 most successful. The idea of a balanced tOPV preparation arose out of this observation: The formula of 10:1:3 was originally set for the proportions of the three types in tOPV, but later it was changed to 10:1:6 to improve the type 3 take rate.

In tropical settings where the take rates are low, there is yet another curious phenomenon. When children seroconvert to one type, they are more likely to seroconvert to another type, than those who did not. This has been interpreted to suggest that the intertype interference is weaker than the inhibitory factor(s) already present in the intestines of tropical children. In other words, if one type is able to reach the site with PVR, overcoming the barrier of the inhibitory factor(s), then another type is more likely to reach that site.

Safety of OPV: Vaccine-Associated Paralytic Polio

When IPV was introduced in the United States in 1955, there was concern about incomplete inactivation of virus particles, which in fact plagued the very early commercial batches of IPV when it was first licensed. When OPV was licensed (with the strong recommendation of the American Medical Association), the general belief was that it was completely safe as intra-spinal-cord injection did not cause paralysis in monkeys. However, soon after OPV licensure, suspicion arose among public health officials that children were developing paralytic polio within one polio incubation period, or vaccine-associated paralytic polio (VAPP). An expert committee examined all evidence on cases that had occurred within 24 months of the introduction of OPV and concluded that VAPP cases were temporally associated with OPV administration, but there was no laboratory test then available to prove such association to be causal. Today there is ample laboratory evidence proving that such cases are indeed caused by one or another of the three OPV viruses.

This problem was further examined by another WHO expert committee, which came to the conclusions that OPV does induce polio in a rare child given OPV; the frequency is geographically nonuniform; VAPP occurs not only in OPV-vaccinated children but also in children who directly or indirectly acquired vaccine virus infection from vaccinated children. Such VAPP in unvaccinated children is called contact VAPP to distinguish it from VAPP in vaccinated children. WHO estimates that developing countries using OPV may have an annual total of 250–500 cases of VAPP.

As OPV contains live infectious viruses, it is no surprise that they may, albeit rarely, spread to susceptible children near the vaccinated child. If transmission occurs beyond that second generation into a state of widespread circulation, the viruses would have regained two characteristics reduced drastically but not completely during attenuation, namely neurovirulence and transmissibility. Since OPV is fed by mouth and infection is in the intestines, the term enterovirulence is sometimes applied to the infection efficiency. Vaccine-derived virus that has regained enterovirulence may cause sporadic or epidemic polio. Such outbreak-associated viruses are named circulating vaccine-derived polioviruses (cVDPV). Episodes of cVDPV-caused polio outbreaks have occurred in Egypt, Dominican Republic and Haiti, Madagascar (thrice), Philippines, China, Indonesia, the United States, Nigeria, and Myanmar. All of them except the one in Egypt have been detected since 2000, suggesting that such episodes may be anticipated at the frequency of at least one per year as long as OPV is in use anywhere. Declined or declining coverage with OPV (leaving more susceptible children) seems to set the stage for its emergence/evolution. Continued use of OPV at very high coverage is the necessary deterrent against cVDPV.

Individuals with B cell defects and consequent immunodeficiency are prone to two adverse events with OPV. They have significantly more risk of VAPP, and some of them develop chronic infection and may continue fecal shedding of vaccine-derived poliovirus with increased neurovirulence over months or years. Such viruses are called immunodeficiency-associated VDPV (iVDPV). There has been one instance in which an iVDPV strain spread to several children, thus acting like cVDPV, showing that any VDPV is a potential source for transmission, circulation, and consequent polio outbreak.

Genetics Of Wild And Vaccine Viruses

When Sabin developed attenuated strains of polioviruses by laboratory cultivation under selected conditions, only phenotypic differences were known between wild and vaccine viruses. Vaccine polioviruses did not grow well above 39ºC, whereas wild polioviruses grew efficiently at 40ºC. Plaque sizes were larger for wild than vaccine strains. Wild viruses caused severe inflammation, neuronal death, and paralysis in monkeys inoculated by intraspinal cord vaccination, whereas vaccine viruses did not cause any of them.

Subsequent knowledge regarding viral genetics has explained some of these phenotypic differences, sometimes even identifying the exact genetic changes associated with the attenuation. A single nucleotide G → A substitution at position 480 (in the 50 untranslated or noncoding) region (UTR) is sufficient to render the Sabin type 1 strain neurovirulent in the monkey and in the transgenic mouse model. Similarly, A →G substitution at position 481, and U→C substitution at position 472 in 50 UTR are critical for regaining neurovirulence for Sabin types 2 and 3, respectively. In addition, there are 56 other nucleotide substitutions distinguishing the wild parent and attenuated Sabin type 1, but only a few of them appear to contribute to the attenuation phenotype. Among the three types of Sabin strains, type 1 is the least likely to revert to neurovirulence. For types 2 and 3 just one additional mutation is also contributory to attenuation; hence these types tend to show genetic reversion more often than type 1. Type 3 revertants are commonest in vaccinated VAPP cases, whereas type 2 revertants are more common among contact VAPP cases.

The Global Eradication Of Poliomyelitis

The Concept And Definition Of Polio Eradication

Human mastery over infectious diseases takes several forms, such as specific etiologic diagnosis, specific therapy against the pathogen, and prevention (all at individual level) as well as control (community level, large or small), elimination (country or regional level), eradication or extinction (global level). Eradication is achieving and maintaining zero infection incidence worldwide by targeted intervention against the pathogen, such that there should be no risk of infection even in the absence of any intervention, particularly vaccination. The biologic criteria for eradicable infectious diseases include lack of a nonhuman reservoir, availability of intervention tactic or tool to reduce its reproductive rate (mean number of infections generated from one infected individual) to below 1 over time and also the availability of diagnostic tool(s) to monitor progress and certify eradication. To date, the only precedent for eradication is smallpox using smallpox vaccination and case-monitoring as intervention tools; there is no precedent for extinction (as smallpox virus, variola is held in viable form in frozen state in at least two countries). Currently, another disease is under eradication efforts – the parasitic disease Guinea worm ulcer (dracunculiasis) – here its transmission between the definitive and intermediate hosts is targeted for interruption such that eradication will also mean extinction as the life cycle is interrupted.

Eradication requires wide political support, cooperation of all affected countries, and a willingness to pay for the costs of eradication efforts by affording agencies. Rightly or otherwise, these prerequisites were fulfilled for polio, setting the stage for the goal of the global polio eradication initiative created during the second half of the 1980s.

History Of The Eradication Effort And Its Progress

A global effort to eradicate poliomyelitis is currently under way. After the introduction of IPV and OPV, and the establishment of national vaccination programs during the late 1950s and early 1960s, all polio disappeared in countries using IPV, and polio due to wild (natural) polioviruses disappeared in some countries using OPV. Vaccine-induced polio (VAPP) continued to occur at very low incidence level. By the mid-1980s, some 68 countries were wild-polio-free, while 125 countries remained endemic (with periodic outbreaks). In the western hemisphere, wild-type polio outbreaks had been eliminated or drastically reduced in incidence, due to good national vaccination programs. In Asia and Africa, polio remained mostly uncontrolled despite the availability of the vaccines and attempts to adhere to the WHO-designed Expanded Program of Immunisation (EPI) which was established between 1974 and 1978. The failure to control polio was a stark reminder of the lack of success of EPI, but instead of fixing that problem, polio was singled out for a global onslaught in the 125 polio-endemic countries. That decision was not made by any special global public health think tank, but it was arrived at through serendipity.

In 1984, Rotary International (RI) resolved to provide financial assistance to all developing countries to purchase and give five doses of OPV to all under-5 children. This commitment started in 1985, so as to enable the world to achieve an undefined polio-free world by 2005, the centenary of RI’s establishment. Polio was a highly visible and evocative problem of children of special concern to the Rotary movement, as many members of RI were involved in rehabilitation of the disabled in Asian and African countries.

Assured of financial assistance by RI, the Pan American Health Organization (PAHO, the regional WHO body for the Americas) resolved to eliminate polio in the Americas by 1990, and established vaccination and monitoring systems to achieve the same. Where polio occurred despite high routine vaccination rates in South and Central America, two annual OPV campaigns for all under-5 children were conducted, irrespective of prior vaccination. Clinical and virological surveillance was also established to monitor progress and finally to certify elimination in the Americas. While PAHO was on the road to success, the WHO had to address the reality of uncontrolled polio in Africa and Asia. WHO designed a global polio eradication goal and plan of action in 1988, with a target date of 2000. A global polio eradication initiative (GPEI) was established by the WHO, with participation by the UN, WHO, UNICEF, the U.S. Centers for Disease Control and Prevention, and RI and a total direct budget of US$2 billion.

The WHO and CDC provided technical guidance and also design of interventions including vaccination and monitoring of progress; WHO, UNICEF, and RI participated in implementation of action in developing countries that needed assistance; all partners raised funds from rich country governments, bilateral aid agencies, and philanthropic organizations. In many developing countries, the costs of vaccine delivery and other logistical support (utilizing health system institutions and personnel) were met by the governments themselves, assisted by the partners in GPEI.

The Overall Global Polio Eradication Strategy

The following four-item overall strategy was adapted from PAHO:

To reach and maintain consistent high routine vaccination coverage in infancy and early childhood;
To offer supplementary vaccination by large-scale campaigns;
To establish adequate clinical and virologic surveillance to effectively monitor progress and the ultimate success;
To provide local-level, small-scale mop-up vaccination when stray instances of persistent virus occurred.

While transplanting the PAHO experience to Asia and Africa, attention was not paid to certain details. GPEI ignored the strengthening of EPI and the poor vaccine efficacy of tOPV, and went ahead with the remaining three elements of the eradication strategy. This approach was successful in most countries or regions with reasonably high routine immunization coverage, but failed where routine coverage was extremely low, such as in Nigeria and Uttar Pradesh and Bihar states in India, where, even in 2007, the task of eradication remains unfinished. In retrospect, had routine coverage (where low) been improved through strengthening EPI, these eradication failures might have been avoided.

The world’s last wild poliovirus type 2 was isolated in Uttar Pradesh, India, in October 1999, and can now be considered globally eradicated. As mentioned above, the vaccine efficacy of tOPV is very high against type 2 wild virus, which accounts for the success against that type. This picture shows that adequate vaccine coverage with tOPV could have interrupted all transmission, if only the vaccine had satisfactory vaccine efficacy. The delay in interrupting transmission of types 1 and 3 wild viruses in India is also in part due to very low vaccine efficacy of tOPV against these two virus types.

By 2000, the Western-Pacific–East-Asia and European regions were also declared polio eliminated (in addition to the Americas), leaving only Southeast Asia, Eastern Mediterranean, and African regions with some endemic polio (types 1 and 3). In total, 119 of the original 125 polio-endemic countries had achieved elimination status, with just six remaining endemic for polio, namely, India, Pakistan, and Afghanistan in Asia and Egypt, Nigeria, and Niger in Africa. By 2005, Egypt and Niger eliminated polio, leaving just four countries with some loci or the other with wild virus transmission. As of 2007, types 1 and 3 continue to be endemic in these four countries.

The Risk Of Importation Of Polioviruses From Endemic To Polio Free Countries

Although only Nigeria, India, Pakistan, and Afghanistan continue to be endemic for polio types 1 and 3, the wild poliovirus type 1 has traveled to territories that had earlier eliminated them. Such importation has occurred in neighboring countries (e.g., from India to Nepal, Bangladesh and Myanmar; from Nigeria to Niger, Chad, Sudan, Ethiopia, and Somalia) and also to distant continents (e.g., from India to Angola, Namibia, and Central African Republic of Congo; from Nigeria to Yemen and Saudi Arabia, and from the latter to Indonesia; from Pakistan to Australia). Some countries had only sporadic cases after importation, while others had widespread outbreaks. Thanks to the high-quality surveillance system, these importations were quickly identified and quelled with supplementary OPV (tOPV or mOPV-1). Where the outbreaks were large (e.g., in Yemen, Indonesia, and Bangladesh), OPV campaigns in under-5 children, covering the entire country, had to be conducted on average seven times in order to dislodge the virus. The current target of the GPEI is to interrupt transmission of wild viruses in these four countries in 2008. Since 2005, Saudi Arabia insists on proof of recent polio vaccination for Hajj pilgrims, especially from currently or recently polio-affected countries. From 2007–08, wild poliovirus will be counted a globally notifiable infection, in order to minimize the probability of intercountry transmission.

The Posteradication Global Scenario: How It Will Be Defined And The Potential Role Of IPV

As mentioned earlier, the working definition of eradication is zero incidence of infection pertaining only to the wild polioviruses. As long as live virus vaccine (OPV) is used, VAPP, cVDPV, and iVDPV may continue to occur; hence, true eradication has been redefined as zero incidence of infection with wild and vaccine polioviruses. This requires discontinuing the use of OPV, but stopping is also not without risk. Most cVDPV outbreaks have occurred where the coverage of OPV, especially in multiple doses per child, had declined. Abrupt stoppage will result in a period of time when vaccine-shedding children and unvaccinated children (new birth cohorts) would overlap and if vaccine virus gets into the latter group, potentially cVDPVs will develop.

The current plan of the GPEI is to stockpile large amounts of mOPVs, so that any cVDPV outbreak could be immediately doused. On the other hand, many experts believe that reintroduction of OPV into the community after it had been withdrawn is too risky and perhaps even unethical for that reason. They have proposed a transition into using IPV in the EPI system, to achieve high (over 80%) coverage in infants, and then and then only to withdraw OPV.

The prospects of introducing IPV on a large, even global, level may be improving, as there is renewed interest in IPV in many countries. Earlier in this research paper, the countries using exclusively IPV were listed. With increasing demand, newer vaccine manufacturers are gearing up for increasing production and supply. After resisting registering (licensing) of IPV in India for five decades (for reasons elaborated earlier), the national regulatory authority in India has licensed it as of June 2006, signaling a change in perception regarding the two vaccines. Virtually all of Europe has begun using IPV and has stopped the entry of OPV in their territories. The IPV has been licensed in several Asian and a few Latin American countries and is gaining popularity in the private sector health-care system. IPV seems to be the vaccine of the future.

Discontinuation Of Polio Immunization After Eradication

By definition, eradication is qualified by the absence of any further need of intervention, as the pathogen does not exist in human communities or the environment. Thus the world discontinued smallpox vaccination once it was eradicated and thus certified in 1978. Indeed, the economic benefit of not vaccinating against the disease is one major incentive for the investment of the cost of eradication. For polio, the savings have been calculated at $1 billion per annum if the world stopped all polio immunization. Since the GPEI journey began, the world has changed in some ways due to terrorism. There are some issues that worry world experts in this regard.

Obviously, immunization (using IPV) has to be continued until all risk from cVDPV is gone, a few to several years after discontinuing OPV. Most likely, IPV will be used as a combination vaccine with DPT, Hib, and HBV.

Within the overall cost of a national immunization program, the additional cost of IPV in such combination form will be so small that it will not be as attractive a saving for a country. In view of the lurking fear of the use of wild poliovirus as a weapon of bioterrorism, the self-perceived vulnerable countries are unlikely to stop IPV. Even if all stocks of wild and vaccine strains of polioviruses are destroyed (extinction, an unlikely event), polioviruses can be synthesized in the laboratory because its genome is small and its sequence is known. Therefore the threat of deliberate introduction will remain real in the current world scenario of confrontational politics between various incompatible ideologies and military approaches to resolve them. If one is forced to predict, the likelihood is that all rich nations will continue to opt for IPV while some low-income countries may discontinue it.

By describing the history and science behind the historic events surrounding the development of polio vaccines, we hope that these lessons can be applied to the challenges of the future.

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