Polio vaccine

Two polio vaccines are used throughout the world to combat polio. The first was developed by Jonas Salk, first tested in 1952, and announced to the world by Salk on April 12, 1955. It consists of an injected dose of inactivated (dead) poliovirus. The second was an oral vaccine developed by Albert Sabin using attenuated poliovirus. Human trials of Sabin's vaccine began in 1957 and it was licensed in 1962.^[1] The two vaccines have eradicated polio from most of the countries in the world^[2][3] and reduced the worldwide incidence from an estimated 350,000 cases in 1988 to fewer than 2000 cases in 2006.^[4][5]

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The "great race"

In 1936 Maurice Brodie, a research assistant at New York University, attempted to produce a formaldehyde-killed polio vaccine from ground-up monkey spinal cords. His initial attempts were hampered by the difficulty of obtaining enough virus. Brodie first tested the vaccine on himself and several of his assistants. He then gave the vaccine to three thousand children: many developed allergic reactions, but none developed immunity to polio.^[6] Philadelphia pathologist John Kollmer also claimed to have developed a vaccine that same year, but it too produced no immunity and was blamed for causing a number of cases, some of them fatal.^[7]

A breakthrough came in 1948 when a research group headed by John Enders at the Children's Hospital Boston successfully cultivated the poliovirus in human tissue in the laboratory. This development greatly facilitated vaccine research and ultimately allowed for the development of vaccines against polio. Enders and his colleagues, Thomas H. Weller and Frederick C. Robbins, were recognized for their labors with a Nobel Prize in Physiology or Medicine in 1954.^[8] Other important advancements that lead to the development of polio vaccines were: the identification of three poliovirus serotypes (Poliovirus type 1 (PV1 or Mahoney), PV2 (Lansing), and PV3 (Leon)), the finding that preceding paralysis, the virus must be present in the blood, and the demonstration that administration of antibodies in the form of gamma-globulin protects against paralytic polio.^[5][9]

In 1952 and 1953 the U.S. experienced an outbreak of 58,000 and 35,000 polio cases, up from a typical number of around 20,000 cases a year. Amid this U.S. polio epidemic, millions of dollars were invested in finding and marketing a polio vaccine by commercial interests, including Lederle Laboratories in New York under the direction of H. R. Cox. Polish-born virologist and immunologist Hilary Koprowski, who also worked at Lederle, claims to have created the first successful polio vaccine (in 1950) but his vaccine, a live attenuated virus taken orally, was still in the research stage and would not be ready for use until five years after Jonas Salk's polio vaccine (a dead inject-able vaccine) reached the market. The samples of difficult-to-manufacture attenuated virus Albert Sabin used to develop his oral polio vaccine were given to him by Hilary Koprowski. "Koprowski would later complain that the polio vaccine he had discovered became known as the Sabin vaccine."^[10] Koprowski's own vaccine was ultimately tested, but the outcome was a failure. After the attenuated live virus entered the body, it sometimes reverted to a virulent state.^[11] Nevertheless, from 1957 to 1960, large scale tests were carried out in the Congo. The results have been controversial^[12], and accusations in the 1990s arose that the vaccine created the conditions necessary for the transmission of SIV from chimpanzees to humans, causing HIV/AIDS.

The development of two polio vaccines lead to the first modern mass inoculations. The last cases of paralytic poliomyelitis caused by endemic transmission of wild virus in the United States were in 1979, when an outbreak occurred among the Amish in several Midwest states.^[13] The disease was entirely eradicated in the Americas by 1994.^[14]

Salk's "inactivated polio vaccine"

The first effective polio vaccine was developed in 1952 by Jonas Salk at the University of Pittsburgh. The Salk vaccine, or inactivated poliovirus vaccine (IPV), is based on three wild, virulent reference strains, Mahoney (type 1 poliovirus), MEF-1 (type 2 poliovirus), and Saukett (type 3 poliovirus), grown in a type of monkey kidney tissue culture (Vero cell line), which are then inactivated with formalin.^[5] The injected Salk vaccine confers IgG-mediated immunity in the bloodstream, which prevents polio infection from progressing to viremia and protects the motor neurons, thus eliminating the risk of bulbar polio and post-polio syndrome. However, because it offers no protection to the mucosal lining of the intestine, people vaccinated with Salk's vaccine can still carry the disease and spread it to unvaccinated individuals.

Salk's vaccine was licensed in 1955, and immediately children's vaccination campaigns were launched. In 1954, the vaccine was tested at Arsenal Elementary School and the Watson Home for Children in Pittsburgh, Pennsylvania. Salk's vaccine was then used in a test called the Francis Field Trial, led by Thomas Francis; the largest medical experiment in history. The test began with some 4,000 children at Franklin Sherman Elementary School in McLean, Virginia, and would eventually involve 1.8 million children, in 44 states from Maine to California.^[15] By the conclusion of the study, roughly 440,000 received one or more injections of the vaccine, about 210,000 children received a placebo, consisting of harmless culture media, and 1.2 million children received no vaccination and served as a control group, who would then be observed to see if any contracted polio.^[10] The results of the field trial were announced April 12, 1955 (the tenth anniversary of the death of Franklin Roosevelt). The Salk vaccine had been 60 - 70% effective against PV1 (poliovirus type 1), over 90% effective against PV2 and PV3, and 94% effective against the development of bulbar polio.^[16] In the U.S, following a mass immunization campaign promoted by the March of Dimes, the annual number of polio cases fell to 5,600 by 1957.^[17] The IPV vaccine was used extensively in the U.S. until the early 1960s. An enhanced-potency IPV was licensed in the United States in November 1987, and is currently the vaccine of choice in the United States.^[13]

Sabin's "oral polio vaccine"

Eight years after Salk's success, Albert Sabin developed the oral polio vaccine (OPV).^[18] The OPV is a live-attenuated vaccine, produced by the passage of the virus through non-human cells at a sub-physiological temperature, which produces spontaneous mutations in the viral genome.

There are 57 nucleotide substitutions which distinguish the attenuated Sabin 1 strain from its virulent parent (the Mahoney serotype), two nucleotide substitutions attenuate the Sabin 2 strain, and 10 substitutions are involved in attenuating the Sabin 3 strain.^[5] The primary attenuating factor common to all three Sabin vaccines is a mutation located in the virus's internal ribosome entry site (or IRES)^[19] which alters stem-loop structures, and reduces the ability of poliovirus to translate its RNA template within the host cell.^[20]

The attenuated poliovirus in the Sabin vaccine replicates very efficiently in the gut, the primary site of infection and replication, but is unable to replicate efficiently within nervous system tissue. The OPV proved to be superior in administration, and also provided longer lasting immunity than the Salk vaccine.^[19] Although Salk's vaccine had reduced the incidence of polio to a tiny fraction of what it was in the early 1950s, it was the oral live-virus vaccine that enabled the complete elimination of the wild polio virus in the United States.

In 1961, type 1 and 2 monovalent oral poliovirus vaccine (MOPV) was licensed, and in 1962, type 3 MOPV was licensed. In 1963, trivalent OPV was licensed, and became the vaccine of choice in the United States and most other countries of the world, largely replacing the inactivated polio vaccine.^[6] A second wave of mass immunizations lead to a further dramatic decline in the number of polio cases. In 1961, only 161 cases were recorded in the United States.^[21]

Iatrogenic (vaccine-induced) polio

A major concern attributable to the oral polio vaccine (OPV) is that it can revert to a virulent form.^[22] Clinical disease caused by vaccine-derived poliovirus (VDPV) is indistinguishable from that caused by wild polioviruses.^[23] This is believed to be a rare event, but outbreaks of vaccine-derived poliovirus (VDPV) have been reported, and tend to occur in areas of low coverage by OPV, presumably because the OPV is itself protective against the related outbreak strain.^[24][25] Reversion is not possible in IPV vaccinations used in the U.S., and thus vaccine-induced polio is not a concern.

The rate of vaccine-associated paralytic poliomyelitis (VAPP) varies by region but is generally about 1 case per 750,000 vaccine recipients.^[26] VAPP is more likely to occur in adults than in children. In immunodeficient children, the risk of VAPP is almost 7,000 times higher, particularly for persons with B-lymphocyte disorders (e.g., agammaglobulinemia and hypogammaglobulinemia), which reduce the synthesis of protective antibodies.^[23]

The World Health Organisation considers the benefits of vaccination to far outweigh the risk of vaccine derived polio. Outbreaks of vaccine derived polio have been stopped by multiple rounds of high-quality vaccination, in order to immunise the entire population.^[27]

Outbreaks of VAPP occurred independently in Belarus (1965–66), Egypt (1983–1993), Hispaniola (2000–2001), Philippines (2001), Madagascar (2001–2002),^[28] and in Haiti (2002), where political strife and poverty have interfered with vaccination efforts.^[29] In 2006 an outbreak of vaccine-derived poliovirus occurred in China.^[30] Cases have been reported from Cambodia (2005-2006), Myanmar (2006-2007), Iran (1995, 2005-2007), Syria, Kuwait and Egypt, while in northern Nigeria, 69 cases were reported in 2007.^[31]

Vaccination schedule

Following the widespread use of poliovirus vaccine in the mid-1950s, the incidence of poliomyelitis declined rapidly in many industrialized countries. As the incidence of wild polio diminishes, nations transition from use of the oral vaccine back to the injected vaccine because the risk of latrogenic polio outweighs the risk of subclinical transmission.

The use of OPV was discontinued in the United States in 2000, but it continues to be used around the globe.^[13] In 2002, a pentavalent (5-component) combination vaccine (called Pediarix) containing IPV was approved for use in the United States. The vaccine also contains combined diphtheria, tetanus, and acellular pertussis vaccines (DTaP) and a pediatric dose of hepatitis B vaccine.^[13] In the UK the change from OPV to IPV occurred in 2004 and for convenience polio vaccine was combined with tetanus, diphtheria, pertussis and Haemophilus influenzae type b vaccines.^[32]

The first dose of polio vaccine is given shortly after birth, usually between 1-2 months of age, a second dose is given at 4 months of age.^[13] The timing of the third dose depends on the vaccine formulation but should be given between 6–18 months of age.^[32] Booster vaccination are given at 4 to 6 years of age, for a total of four doses at or before school entry.^[33] In some countries a fifth vaccination is given during adolescence.^[32] Routine vaccination of adults (18 years of age and older) in developed countries is neither necessary nor recommended because most adults are already immune and have a very small risk of exposure to wild poliovirus in their home countries.^[13]

Efficacy

In the generic sense, vaccination works by priming the immune system with an 'immunogen'. Stimulating immune response, via use of an infectious agent, is known as immunization. Vaccine efficacy is defined by the amount of immunity against infection a particular vaccine provides, and is often measured by detection of protective antibodies in the blood.^[34]

The development of immunity to polio efficiently blocks person-to-person transmission of wild poliovirus, thereby protecting both individual vaccine recipients and the wider community.^[35] Because there is no long term carrier state for poliovirus in immunocompetent individuals, polioviruses have no non-primate reservoir in nature, and survival of the virus in the environment for an extended period of times appears to be remote, interruption of person-to person transmission of the virus by vaccination is the critical step in global polio eradication.^[35]

After two doses of inactivated polio vaccine (IPV), ninety percent or more of individuals develop protective antibody to all three serotypes of poliovirus, and at least 99% are immune to poliovirus following three doses. A single dose of oral polio vaccince produces immunity to all three poliovirus serotypes in approximately 50% of recipients.^[13] Three doses of live-attenuated OPV produce protective antibody to all three poliovirus types in more than 95% of recipients. OPV produces excellent immunity in the intestine, the primary site of wild poliovirus entry, which helps prevent infection with wild virus in areas where the virus is endemic.^[33] IPV produces less gastrointestinal immunity than does OPV, so persons who receive IPV are more easily infected with wild poliovirus. In regions without wild poliovirus, inactivated polio vaccine is the vaccine of choice.^[33] In regions with higher incidence of polio, and thus a different relative risk between efficacy and reversion of the vaccine to a virulent form, live vaccine is still used. The live virus also has stringent requirements for transport and storage, which are a problem in some hot or remote areas.

As with other live-virus vaccines, immunity initiated by OPV is probably lifelong. The duration of immunity induced by IPV is not known with certainty, although a complete series is thought to provide protection for many years.^[36]

Contamination concerns

In 1960, it was determined that the rhesus monkey kidney cells used to prepare the poliovirus vaccines were infected with a virus called SV40 (or Simian Virus-40).^[37] SV40, also discovered in 1960, is a naturally occurring virus that infects monkeys. In 1961, SV40 was found to cause tumors in rodents.^[38] More recently, the virus was found in certain forms of cancer in humans, for instance brain and bone tumors, mesotheliomas, and some types of non-Hodgkin's lymphoma.^[39][40] However, it has not been determined that SV40 causes these cancers.^[41]

SV40 was found to be present in stocks of the injected form of the polio vaccine (IPV) in use between 1954 to 1962, it is not found in the OPV form (which was licensed later). Over 98 million Americans received one or more doses of polio vaccine between 1955 to 1963 when a proportion of vaccine was contaminated with SV40; it has been estimated that 10 - 30 million Americans may have received a dose of vaccine contaminated with SV40.^[37] Later analysis suggested that vaccines produced by the former Soviet bloc countries until 1980, and used in the USSR, China, Japan, and several African countries, may have been contaminated; meaning hundreds of millions more may have been exposed to SV40.^[42]

In 1998, the National Cancer Institute undertook a large study, using cancer case information from the Institutes SEER database. The published findings from the study revealed that there was no increased incidence of cancer in persons who may have received vaccine containing SV40.^[43] Another large study in Sweden examined cancer rates of 700,000 individuals who had received potentially contaminated polio vaccine as late as 1957; the study again revealed no increased cancer incidence between persons who received polio vaccines containing SV40 and those who did not.^[44] The question of whether SV40 causes cancer in humans remains controversial however, and the development of improved assays for detection of SV40 in human tissues, will be needed to resolve the controversy.^[41]

See also

• The mathematics of mass vaccination
• Herd immunity
• March of Dimes
• OPV AIDS hypothesis

References