Polio vaccine

When the IPV (injection) is used, 90% or more of individuals develop protective antibodies to all three serotypes of polio virus after two doses of inactivated polio vaccine (IPV), and at least 99% are immune to polio virus following three doses. The duration of immunity induced by IPV is not known with certainty, although a complete series is thought to provide protection for many years.[14]

Oral polio vaccines were easier to administer than IPV, as it eliminated the need for sterile syringes and therefore was more suitable for mass vaccination campaigns. OPV also provided longer-lasting immunity than the Salk vaccine, as it provides both humoral immunity and cell-mediated immunity.[15]

One dose of OPV produces immunity to all three poliovirus serotypes in roughly 50% of recipients.[16] Three doses of live-attenuated OPV produce protective antibodies 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.[17] The live virus used in the vaccine can rarely shed in the stool and can rarely spread to others within a community. 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.[14]

The trivalent (against wild types 1, 2, and 3) OPV has been used to nearly eradicate polio infection worldwide.[18] Led by the Global Polio Eradication Initiative, 155 countries switched to use the bivalent (against wild types 1 and 3) between 17 April and 1 May 2016.[19] The bivalent OPV is more effective against types 1 and 3, but does not cover type 2.[20] The United States as of 2017 continues to recommend the use of a trivalent version, but a fully inactivated version.[18]

Share of one-year-olds vaccinated against polio in 2015[21]

In countries with endemic polio or where the risk of imported cases is high, the WHO recommends OPV vaccine at birth followed by a primary series of three OPV and at least one IPV doses starting at 6 weeks of age, with a minimum of 4 weeks between OPV doses. In countries with >90% immunization coverage and low risk of importation, the WHO recommends one or two IPV doses starting at 2 months of age followed by at least two OPV doses, with the doses separated by 4–8 weeks depending on the risk of exposure. In countries with the highest levels of coverage and the lowest risks of importation and transmission, the WHO recommends a primary series of three IPV injections, with a booster dose after an interval of six months or more if the first dose was administered before 2 months of age.[2]

cVPDV cases (red line) outnumbered wild polio cases (blue line) for the first time in 2017

A potential, adverse effect of the OPV is its known ability to recombine to a form that causes neurological infection and paralysis.[22] This genetic reversal of the pathogen to a virulent form takes a considerable time (at least 12 months) and does not affect the person who was originally vaccinated. The vaccine-derived attenuated virus is normally excreted from vaccinated people for a limited period. Thus, in areas with poor sanitation and low vaccination coverage, the spontaneous reversal of the vaccine-derived virus to a virulent form and its spreading in the environment can lead to unvaccinated people becoming infected.[23] Clinical disease, including paralysis, caused by vaccine-derived poliovirus (VDPV) is indistinguishable from that caused by wild polioviruses.[24] Outbreaks of vaccine-associated paralytic poliomyelitis (VAPP), caused by a circulating vaccine-derived poliovirus (cVDPV),[25] 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.[26][27] With wild polio cases at record lows, 2017 was the first year where more cases of cVDPV were recorded than the wild poliovirus, a trend that is expected to continue.[28]

To combat this, the WHO in 2016, decided to switch from the trivalent polio vaccine to the bivalent polio vaccine.[29] This vaccine no longer contains the type 2 polio virus because it was eradicated in 1999.[30]

In 1960, the rhesus monkey kidney cells used to prepare the poliovirus vaccines were determined to be infected with the simian virus-40 (SV40),[31] which was also discovered in 1960 and is a naturally occurring virus that infects monkeys. In 1961, SV40 was found to cause tumors in rodents.[32] More recently, the virus was found in certain forms of cancer in humans, for instance brain and bone tumors, pleural and peritoneal mesothelioma, and some types of non-Hodgkin lymphoma.[33][34] However, SV40 has not been determined to cause these cancers.[35]

SV40 was found to be present in stocks of the injected form of the IPV in use between 1955 and 1963.[31] It is not found in the OPV form.[31] Over 98 million Americans received one or more doses of polio vaccine between 1955 and 1963 when a proportion of vaccine was contaminated with SV40; an estimated 10–30 million Americans may have received a dose of vaccine contaminated with SV40.[31] 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.[36]

In 1998, the National Cancer Institute undertook a large study, using cancer case information from the institute's SEER database. The published findings from the study revealed no increased incidence of cancer in persons who may have received vaccine containing SV40.[37] 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.[38] 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.[35]

Doses of oral polio vaccine are added to sugar cubes for use in a 1967 vaccination campaign in Bonn, West Germany

During the race to develop an oral polio vaccine, several large-scale human trials were undertaken. By 1958, the National Institutes of Health had determined that OPV produced using the Sabin strains were the safest.[39] Between 1957 and 1960, however, Hilary Koprowski continued to administer his vaccine around the world. In Africa, the vaccines were administered to roughly one million people in the Belgian territories (now the Democratic Republic of the Congo, Rwanda, and Burundi).[40][41] The results of these human trials have been controversial,[42] and unfounded accusations in the 1990s arose that the vaccine had created the conditions necessary for transmission of simian immunodeficiency virus from chimpanzees to humans, causing HIV/AIDS. These hypotheses, however, have been conclusively refuted.[40] By 2004, cases of poliomyelitis in Africa had been reduced to just a small number of isolated regions in the western portion of the continent, with sporadic cases elsewhere. Recent local opposition to vaccination campaigns have evolved due to lack of adequate information,[43][44] often relating to fears that the vaccine might induce sterility.[45] The disease has since resurged in Nigeria and in several other African nations without necessary information, which epidemiologists believe is due to refusals by certain local populations to allow their children to receive the polio vaccine.[46]

The Salk 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.[47] 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.

In the United States, vaccine is administered along with the tetanus, diphtheria, and acellular pertussis vaccines (DTaP) and a pediatric dose of hepatitis B vaccine.[16] In the UK, IPV is combined with tetanus, diphtheria, pertussis, and Haemophilus influenzae type b vaccines.[48]

Sabin immunization certificate

Example of OPV in dragee candy

OPV is an attenuated vaccine, produced by the passage of the virus through nonhuman cells at a subphysiological temperature, which produces spontaneous mutations in the viral genome.[49] Oral polio vaccines were developed by several groups, one of which was led by Albert Sabin. Other groups, led by Hilary Koprowski and H.R. Cox, developed their own attenuated vaccine strains. In 1958, the National Institutes of Health created a special committee on live polio vaccines. The various vaccines were carefully evaluated for their ability to induce immunity to polio, while retaining a low incidence of neuropathogenicity in monkeys. Large-scale clinical trials performed in the Soviet Union in late 1950s to early 1960s by Mikhail Chumakov and his colleagues demonstrated safety and high efficacy of the vaccine.[50][51] Based on these results, the Sabin strains were chosen for worldwide distribution.[39] Fifty-seven nucleotide substitutions 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.[47] The primary attenuating factor common to all three Sabin vaccines is a mutation located in the virus's internal ribosome entry site,[52] which alters stem-loop structures and reduces the ability of poliovirus to translate its RNA template within the host cell.[53] 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. 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 (TOPV) 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.[54] A second wave of mass immunizations led to a further dramatic decline in the number of polio cases. Between 1962 and 1965, about 100 million Americans (roughly 56% of the population at that time) received the Sabin vaccine. The result was a substantial reduction in the number of poliomyelitis cases, even from the much-reduced levels following the introduction of the Salk vaccine.[55]

OPV is usually provided in vials containing 10–20 doses of vaccine. A single dose of oral polio vaccine (usually two drops) contains 1,000,000 infectious units of Sabin 1 (effective against PV1), 100,000 infectious units of the Sabin 2 strain, and 600,000 infectious units of Sabin 3. The vaccine contains small traces of antibiotics—neomycin and streptomycin—but does not contain preservatives.[56]

Two separate teams, led by John Kolmer and Maurice Brodie respectively, developed polio vaccines and reported their results at the annual meeting of the American Public Health Association in November 1935. Despite promising results, both were cancelled as a result of the angry reaction from other researchers, as vaccinated children had died in both studies. It would be another 20 years before a successful polio vaccine achieved government licensure.[57]

John Kolmer (1886–1962), of Temple University, presented his findings first. He had developed an attenuated poliovirus vaccine, which he tested in about 10,000 children across much of the United States and Canada.[57] Five of these children died of polio and 10 more were paralyzed, usually in the arm where the vaccine was injected, and frequently affecting children in towns where no polio outbreak had occurred.[57] He had no control group, but asserted that many more children would have gotten sick.[57] The response from other researchers was uncharacteristically blunt; one of them directly called Kolmer a murderer.[57]

Maurice Brodie, a young researcher at New York University and the New York City Health Department, presented his results afterwards, but the feelings of the researchers were already unfavorable before he started because of Kolmer's report.[57] Brodie and his team had prepared a formaldehyde-killed poliovirus vaccine, testing it first on himself and five co-workers, and eventually on 7,500 children and adults, with another 4,500 people serving as a control group.[57] In the control group, Brodie reported that one out of 900 developed polio; in the group receiving the vaccine, only one out of 7,500 developed polio, making the vaccine 88% effective during the first year. However, other researchers believed that the one case was likely caused by the vaccine, and two more possible cases were reported later.[57]

After this meeting, Brodie, whose polio vaccine was at least partially effective and reasonably safe, and who developed several ground-breaking ideas about vaccination whose validity was confirmed two decades later with the development of the Salk vaccine, was immediately fired and had trouble finding employment again. Brodie died three and a half years later.[57] Kolmer, an established researcher whose vaccine was unsafe and probably ineffective, kept his job, was given a second appointment as professor of medicine at the Temple University School of Dentistry the next year, continued to publish research papers, and received multiple awards throughout his academic career.[57][58]

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.[59] This group had recently successfully grown mumps in cell culture. In March 1948, Thomas H. Weller was attempting to grow varicella virus in embryonic lung tissue. He had inoculated the planned number of tubes when he noticed that there were a few unused tubes. He retrieved a sample of mouse brain infected with polio virus and added it to the remaining test tubes, on the off chance that the virus might grow. The varicella cultures failed to grow, but the polio cultures were successful. 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 in 1954 for their labors with a Nobel Prize in Physiology or Medicine.[60] Other important advances that led 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 prior to 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.[47][61]

1955 newspaper headlines on the development of an effective polio vaccine

During the early 1950s, polio rates in the U.S. were above 25,000 annually; in 1952 and 1953, the U.S. experienced an outbreak of 58,000 and 35,000 polio cases, respectively, up from a typical number of some 20,000 a year, with deaths in those years numbering 3,200 and 1,400.[62] 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. Also working at Lederle was Polish-born virologist and immunologist Hilary Koprowski of the Wistar Institute in Philadelphia, who tested the first successful polio vaccine, in 1950.[8][41] His vaccine, however, being 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-virus injectable vaccine) had reached the market. Koprowski's attenuated vaccine was prepared by successive passages through the brains of Swiss albino mice. By the seventh passage, the vaccine strains could no longer infect nervous tissue or cause paralysis. After one to three further passages on rats, the vaccine was deemed safe for human use.[39][63] On 27 February 1950, Koprowski's live, attenuated vaccine was tested for the first time on an 8-year-old boy living at Letchworth Village, an institution for the physically and mentally disabled located in New York. After the child suffered no side effects, Koprowski enlarged his experiment to include 19 other children.[39][64]

Administration of the polio inoculation, including by Salk himself, in 1957 at the University of Pittsburgh, where his team had developed the vaccine

Mass polio vaccination in Columbus, Georgia circa 1961 for the National Polio Immunization Program

The first effective polio vaccine was developed in 1952 by Jonas Salk and a team at the University of Pittsburgh that included Julius Youngner, Byron Bennett, L. James Lewis, and Lorraine Friedman, which required years of subsequent testing. Salk went on CBS radio to report a successful test on a small group of adults and children on 26 March 1953; two days later, the results were published in JAMA.[57] Leone N. Farrell invented a key laboratory technique that enabled the mass production of the vaccine by a team she led in Toronto.[65][66] Beginning 23 February 1954, the vaccine was tested at Arsenal Elementary School and the Watson Home for Children in Pittsburgh, Pennsylvania.[67]

Salk's vaccine was then used in a test called the Francis Field Trial, led by Thomas Francis, the largest medical experiment in history at that time. The test began with about 4,000 children at Franklin Sherman Elementary School in McLean, Virginia,[68][69] and eventually involved 1.8 million children, in 44 states from Maine to California.[70] 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.[39] The results of the field trial were announced 12 April 1955 (the tenth anniversary of the death of President Franklin D. Roosevelt, whose paralytic illness was generally believed to have been caused by polio). 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.[71] Soon after Salk's vaccine was licensed in 1955, children's vaccination campaigns were launched. In the U.S, following a mass immunization campaign promoted by the March of Dimes, the annual number of polio cases fell from 35,000 in 1953 to 5,600 by 1957.[72] By 1961 only 161 cases were recorded in the United States.[73]

A week before the announcement of the Francis Field Trial results in April 1955, Pierre Lépine at the Pasteur Institute in Paris had also announced an effective polio vaccine.[74][75]

In April 1955, soon after mass polio vaccination began in the US, the Surgeon General began to receive reports of patients who contracted paralytic polio about a week after being vaccinated with Salk polio vaccine from Cutter pharmaceutical company, with the paralysis limited to the limb the vaccine was injected into. The Cutter vaccine had been used in vaccinating 200,000 children in the western and midwestern United States.[76] Later investigations showed that the Cutter vaccine had caused 40,000 cases of polio, killing 10.[76] In response the Surgeon General pulled all polio vaccine made by Cutter Laboratories from the market, but not before 250 cases of paralytic illness had occurred. Wyeth polio vaccine was also reported to have paralyzed and killed several children. It was soon discovered that some lots of Salk polio vaccine made by Cutter and Wyeth had not been properly inactivated, allowing live poliovirus into more than 100,000 doses of vaccine. In May 1955, the National Institutes of Health and Public Health Services established a Technical Committee on Poliomyelitis Vaccine to test and review all polio vaccine lots and advise the Public Health Service as to which lots should be released for public use. These incidents reduced public confidence in polio vaccine, leading to a drop in vaccination rates.[77]

Albert Sabin (right) with Robert Gallo, circa 1985

At the same time that Salk was testing his vaccine, both Albert Sabin and Hilary Koprowski continued working on developing a vaccine using live virus. During a meeting in Stockholm to discuss polio vaccines in November 1955, Sabin presented results obtained on a group of 80 volunteers, while Koprowski read a paper detailing the findings of a trial enrolling 150 people.[39] Sabin and Koprowski both eventually succeeded in developing vaccines. Because of the commitment to the Salk vaccine in America, Sabin and Koprowski both did their testing outside the United States, Sabin in Mexico[49] and the Soviet Union,[78] Koprowski in the Congo and Poland.[41] In 1957, Sabin developed a trivalent vaccine containing attenuated strains of all three types of poliovirus.[78] In 1959, ten million children in the Soviet Union received the Sabin oral vaccine. For this work, Sabin was given the medal of the Order of Friendship Among Peoples, described as the Soviets' highest civilian honor,[79] Sabin's oral vaccine using live virus came into commercial use in 1961.[2]

Once Sabin's oral vaccine became widely available, it supplanted Salk's injected vaccine, which had been tarnished in the public's opinion by the Cutter incident of 1955, in which Salk vaccines improperly prepared by one company resulted in several children dying or becoming paralyzed.[57]

An enhanced-potency IPV was licensed in the United States in November 1987, and is currently the vaccine of choice there.[16] The first dose of polio vaccine is given shortly after birth, usually between 1 and 2 months of age, and a second dose is given at 4 months of age.[16] The timing of the third dose depends on the vaccine formulation, but should be given between 6 and 18 months of age.[48] A booster vaccination is given at 4 to 6 years of age, for a total of four doses at or before school entry.[17] In some countries, a fifth vaccination is given during adolescence.[48] 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.[16] In 2002, a pentavalent (five-component) combination vaccine (called Pediarix)[80][81] containing IPV was approved for use in the United States.[82][81]

A Somali boy is injected with inactivated poliovirus vaccine (Mogadishu, 1993)

A global effort to eradicate polio, led by the World Health Organization (WHO), UNICEF,[83] and the Rotary Foundation, began in 1988, and has relied largely on the oral polio vaccine developed by Albert Sabin and Mikhail Chumakov (Sabin-Chumakov vaccine).[84]

Polio was eliminated in the Americas by 1994.[85] The disease was officially eliminated in 36 Western Pacific countries, including China and Australia, in 2000.[86][87] Europe was declared polio-free in 2002.[88] Since January 2011, no cases of the disease have been reported in India, hence in February 2012, the country was taken off the WHO list of polio-endemic countries. In March 2014, India was declared a polio-free country.[89][90][91]

Although poliovirus transmission has been interrupted in much of the world, transmission of wild poliovirus does continue and creates an ongoing risk for the importation of wild poliovirus into previously polio-free regions. If importations of poliovirus occur, outbreaks of poliomyelitis may develop, especially in areas with low vaccination coverage and poor sanitation. As a result, high levels of vaccination coverage must be maintained.[85] In November 2013, the WHO announced a polio outbreak in Syria. In response, the Armenian government put out a notice asking Syrian Armenians under age 15 to get the polio vaccine.[92] As of 2014, polio virus had spread to 10 countries, mainly in Africa, Asia, and the Middle East, with Pakistan, Syria, and Cameroon advising vaccinations to outbound travelers.[93]

Polio vaccination programs have received resistance from some people in Pakistan, Afghanistan, and Nigeria (the three countries as of 2017 with remaining polio cases). Some Muslim religious leaders believe that the vaccines are secretly being used for sterilization of Muslims.[46] The fact that the CIA organized a fake vaccination program in 2011 to help find Osama Bin Laden is an additional cause of distrust.[94] In 2015, the WHO announced a deal with the Taliban to encourage them to distribute the vaccine in areas they control.[95] However, the Pakistani Taliban was not supportive. On 11 September 2016, two unidentified gunmen associated with the Pakistani Taliban, Jamaat-ul-Ahrar, shot Zakaullah Khan, a doctor who was administering polio vaccines in Pakistan. The leader of the Jamaat-ul-Ahrar claimed responsibility for the shooting and stated that the group would continue this type of attack. Such resistance to and skepticism of vaccinations has consequently slowed down the polio eradication process within the three remaining endemic countries.[94]

The Global Alliance for Vaccines and Immunization supplies the inactivated vaccine to developing countries for as little as €0.75 (about US$0.86) per dose in 10-dose vials, in 2015.[123]

A misconception has been present in Pakistan that polio vaccine contained haram ingredients and could cause impotence and infertility in male children, leading some parents not to have their children vaccinated. This belief is most common in the Khyber Pakhtunkhwa province and the FATA region. Attacks on polio vaccination teams have also occurred, thereby hampering international efforts to eradicate polio in Pakistan and globally.[124][125]