Polio vaccine

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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. Thereafter, Albert Sabin produced an oral polio vaccine 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]

The "Great Race"

In 1936 Maurice Brodie, a research assistant at New York University, had 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]

File:Polio immunization days PHIL 2445.png
Mass polio vaccination in Columbus, Georgia during the early days of the National Polio Immunization Program.

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 would use 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]

The development of two polio vaccines would 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 progress 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 would fall 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]

This 1963 poster featured CDC’s national symbol of public health, the "Wellbee", encouraging the public to receive an oral polio vaccine.

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 would be the oral live-virus vaccine that would enable 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 would become the vaccine of choice in the United States and most other countries of the world, largely replacing the use of the inactivated polio vaccine.[6] A second wave of mass immunizations would lead to a 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 tends 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]

Outbreaks of VAPP occurred independently in Belarus (1965–66), Egypt (1983–1993), Hispaniola (2000–2001), Philippines (2001), Madagascar (2001–2002),[27] and in Haiti (2002), where political strife and poverty have interfered with vaccination efforts.[28] In 2006 an outbreak of vaccine-derived poliovirus occurred in China.[29]

Vaccination Schedule

A child receives oral Polio vaccine.

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.[30]

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 of the vaccine formulation but should be given between 6–18 months of age.[30] Booster vaccination are given at 4 to 6 years of age, for a total of four doses at or before school entry.[31] In some countries a fifth vaccination is given during adolescence.[30] 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.[32]

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.[33] 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.[33]

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.[31] 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.[31] 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.[34]

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).[35] SV40, also discovered in 1960, is a naturally occurring virus that infects monkeys. In 1961, SV40 was found to cause tumors in rodents.[36] 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.[37][38] However, it has not been determined that SV40 causes these cancers.[39]

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 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.[35] 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.[40]

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.[41] 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.[42] 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.[39]

Vaccine mediated polio infection

Oral polio vaccine (OPV) is one of the safest and most effective vaccination programs that prevented millions of cases of polio not only through direct immunization but also through herd immunity. In rare occasions, the vaccine is associated with paralytic polio. There are two subtypes of paralytic polio related to OPV vaccine: vaccine associated paralytic polio and vaccine derived paralytic polio.

Vaccine associated paralytic polio:

By httpwellcomeimages.orgindexplusobf images552aaa8954428275b9f3295c60b39334.jpgGallery httpwellcomeimages.orgindexplusimageL0033971.html, CC BY 4.0, httpscommons.wikimedia.orgwindex.phpcurid=36062710.jpg burnetii, the Q fever causing agent
  • Vaccine associated paralytic polio (VAPP) occurs when the attenuated strain used in the vaccine reverts inside the intestine into more virulent form.[43][44][45]
  • The more virulent form is capable of causing the disease only in the vaccinated child or a close susceptible contact. Therfore, no outbreaks are associated with VAPP.
  • The prevalence of (VAPP) is 1 in 2.7 million doses of the vaccine.
  • In developed countries, the risk of VAPP is increased with the first dose of the vaccine while in developed countries, It’s increased with subsequent doses.

Vaccine derived paralytic polio:

  • Vaccine derived paralytic polio (VDPP) is caused by very rare mutation of the original strain of polio in the vaccine.[43][46]
  • VDPP has the ability to cause the disease in any non immune person whether the vaccinated person or a contact, therefore it has the ability to cause outbreaks or even epidemics especially in communities that are not properly covered with the vaccination program.
  • When it causes outbreaks, VDPP is called circulating vaccine derived paralytic polio (cVDPP).
  • In the last 10 years, 24 VDPP reported outbreaks happened in 21 countries causing 750 cases of paralytic polio.
  • The management of VDPP is conducting extensive vaccination campaigns in the affected community aiming for vaccinating every child and thus preventing the spread of the infection.

References

  1. "A Science Odyssey: People and Discoveries". PBS. 1998. Retrieved 2007-08-14.
  2. Aylward R (2006). "Eradicating polio: today's challenges and tomorrow's legacy". Ann Trop Med Parasitol. 100 (5–6): 401–13. PMID 16899145.
  3. Schonberger L, Kaplan J, Kim-Farley R, Moore M, Eddins D, Hatch M (1984). "Control of paralytic poliomyelitis in the United States". Rev. Infect. Dis. 6 Suppl 2: S424–6. PMID 6740085.
  4. "Update on vaccine-derived polioviruses". MMWR Morb Mortal Wkly Rep. 55 (40): 1093–7. 2006. PMID 17035927.
  5. 5.0 5.1 5.2 5.3 Kew O, Sutter R, de Gourville E, Dowdle W, Pallansch M (2005). "Vaccine-derived polioviruses and the endgame strategy for global polio eradication". Annu Rev Microbiol. 59: 587–635. PMID 16153180.
  6. 6.0 6.1 Pearce J (2004). "Salk and Sabin: poliomyelitis immunisation". J Neurol Neurosurg Psychiatry. 75 (11): 1552. PMID 15489385.
  7. Rainsberger M. "More than a March of Dimes". The University of Texas at Austin. Retrieved 2007-01-29.
  8. "The Nobel Prize in Physiology or Medicine 1954". The Nobel Foundation. Retrieved 2007-01-29.
  9. Hammon W, Coriell L, Wehrle P, Stokes J (1953). "Evaluation of Red Cross gamma globulin as a prophylactic agent for poliomyelitis. IV. Final report of results based on clinical diagnoses". J Am Med Assoc. 151 (15): 1272–85. PMID 13034471.
  10. 10.0 10.1 "Competition to develop an oral vaccine". Conquering Polio. Sanofi Pasteur SA. 2007-02-02. Retrieved 2007-03-12.
  11. Lindner U, Blume S (2006). "Vaccine innovation and adoption: polio vaccines in the UK, the Netherlands and West Germany, 1955-1965". Med Hist. 50 (4): 425–46. PMID 17066127.
  12. Collins, Huntly (2000-11-06). "The Gulp Heard Round the World". Philadelphia Inquirer. pp. Section D, page 1. Retrieved 2007-02-06. Check date values in: |date= (help)
  13. 13.0 13.1 13.2 13.3 13.4 13.5 13.6 Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. (2007). Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book) (PDF) (10th ed. ed.). Washington DC: Public Health Foundation. Retrieved 2007-03-12.
  14. "International Notes Certification of Poliomyelitis Eradication -- the Americas, 1994". Morbidity and Mortality Weekly Report. Centers for Disease Control and Prevention. 43 (39): 720–722. 1994. PMID 7522302.
  15. "Polio Victory Remembered as March of Dimes Marks 50th Anniversary of Salk Vaccine Field Trials". News Desk. 2004-04-26. Retrieved 2007-03-12.
  16. Smith, Jane S. (1990). Patenting the Sun: Polio and the Salk Vaccine. William Morrow & Co. ISBN 0-688-09494-5.
  17. [edited by] Edmund J. Sass with George Gottfried, Anthony Sorem; foreword by Richard Owen (1996). Summary Polio's legacy: an oral history Check |url= value (help). Washington, D.C: University Press of America. ISBN 0-7618-0144-8.
  18. Sabin A, Ramos-Alvarez M, Alvarez-Amezquita J, Pelon W, Michaels R, Spigland I, Koch M, Barnes J, Rhim J. "Live, orally given poliovirus vaccine. Effects of rapid mass immunization on population under conditions of massive enteric infection with other viruses". JAMA. 173: 1521–6. PMID 14440553.
  19. 19.0 19.1 Charles Chan and Roberto Neisa. "Poliomyelitis". Brown University.
  20. Gromeier M, Bossert B, Arita M, Nomoto A, Wimmer E (1999). "Dual stem loops within the poliovirus internal ribosomal entry site control neurovirulence". J Virol. 73 (2): 958–64. PMID 9882296.
  21. Hinman A (1984). "Landmark perspective: Mass vaccination against polio". JAMA. 251 (22): 2994–6. PMID 6371280.
  22. Shimizu H; et al. (2004). "Circulation of type 1 vaccine-derived poliovirus in the Philippines in 2001". J Virol. 78 (24): 13512–21. PMID 15564462.
  23. 23.0 23.1 Cono, Joanne and Lorraine N. Alexander. (2002). VPD (Vaccine Preventable Disease) Surveillance Manual, 3rd Edition, Chapter 10, Poliomyelitis p.10-1.
  24. Kew O; et al. (2002). "Outbreak of poliomyelitis in Hispaniola associated with circulating type 1 vaccine-derived poliovirus". Science. 296 (5566): 356–9. PMID 11896235.
  25. Yang C, Naguib T, Yang S, Nasr E, Jorba J, Ahmed N, Campagnoli R, van der Avoort H, Shimizu H, Yoneyama T, Miyamura T, Pallansch M, Kew O (2003). "Circulation of endemic type 2 vaccine-derived poliovirus in Egypt from 1983 to 1993". J Virol. 77 (15): 8366–77. PMID 12857906.
  26. Racaniello V (2006). "One hundred years of poliovirus pathogenesis". Virology. 344 (1): 9–16. PMID 16364730.
  27. Kew O, Wright P, Agol V, Delpeyroux F, Shimizu H, Nathanson N, Pallansch M (2004). "Circulating vaccine-derived polioviruses: current state of knowledge". Bull World Health Organ. 82 (1): 16–23. PMID 15106296.
  28. Fox, Maggie Polio in Haiti linked to incomplete vaccinations Reuters
  29. Liang X, Zhang Y, Xu W, Wen N, Zuo S, Lee L, Yu J (2006). "An outbreak of poliomyelitis caused by type 1 vaccine-derived poliovirus in China". J Infect Dis. 194 (5): 545–51. PMID 16897650.
  30. 30.0 30.1 30.2 Joint Committee on Vaccination and Immunisation, David Salisbury (Editor), Mary Ramsay (Editor), Karen Noakes (Editor). Immunisation Against Infectious Disease 2006 Chapter 26:Poliomyelitis (PDF). Edinburgh: Stationery Office. pp. 313–329. ISBN 0-11-322528-8.
  31. 31.0 31.1 31.2 "Poliomyelitis prevention: recommendations for use of inactivated poliovirus vaccine and live oral poliovirus vaccine. American Academy of Pediatrics Committee on Infectious Diseases". Pediatrics. 99 (2): 300–5. 1997. PMID 9024465.
  32. Fedson D (1998). "Measuring protection: efficacy versus effectiveness". Dev Biol Stand. 95: 195&ndash, 201. PMID 9855432.
  33. 33.0 33.1 Fine P, Carneiro I (1999). "Transmissibility and persistence of oral polio vaccine viruses: implications for the global poliomyelitis eradication initiative". Am J Epidemiol. 150 (10): 1001–21. PMID 10568615.
  34. Robertson, Susan. "Module 6: Poliomyelitis" (PDF). The Immunological Basis for Immunization Series. World Health Organization (Geneva, Switzerland). Retrieved 2007-03-12.
  35. 35.0 35.1 "Simian Virus 40 (SV40), Polio Vaccine, and Cancer". Centers for Disease Control. April 22, 2004. Retrieved 2007-02-03.
  36. Eddy B, Borman G, Berkeley W, Young R (1961). "Tumors induced in hamsters by injection of rhesus monkey kidney cell extracts". Proc Soc Exp Biol Med. 107: 191–7. PMID 13725644.
  37. Carbone M (1999). "Simian virus 40 and human tumors: It is time to study mechanisms". J Cell Biochem. 76 (2): 189–93. PMID 10618636.
  38. Vilchez R, Kozinetz C, Arrington A, Madden C, Butel J (2003). "Simian virus 40 in human cancers". Am J Med. 114 (8): 675–84. PMID 12798456.
  39. 39.0 39.1 Engels E (2005). "Cancer risk associated with receipt of vaccines contaminated with simian virus 40: epidemiologic research" (PDF). Expert Rev Vaccines. 4 (2): 197–206. PMID 15889993.
  40. Debbie Bookchin (07 July 2004). "Vaccine scandal revives cancer fear". New Scientist. Retrieved 2007-02-03. Check date values in: |date= (help)
  41. Strickler H, Rosenberg P, Devesa S, Hertel J, Fraumeni J, Goedert J (1998). "Contamination of poliovirus vaccines with simian virus 40 (1955-1963) and subsequent cancer rates". JAMA. 279 (4): 292–5. PMID 9450713.
  42. Olin P, Giesecke J (1998). "Potential exposure to SV40 in polio vaccines used in Sweden during 1957: no impact on cancer incidence rates 1960 to 1993". Dev Biol Stand. 94: 227–33. PMID 9776244.
  43. 43.0 43.1 "www.who.int" (PDF).
  44. Nkowane BM, Wassilak SG, Orenstein WA, Bart KJ, Schonberger LB, Hinman AR, Kew OM (1987). "Vaccine-associated paralytic poliomyelitis. United States: 1973 through 1984". JAMA. 257 (10): 1335–40. PMID 3029445.
  45. Sullivan AA, Boyle RS, Whitby RM (1995). "Vaccine-associated paralytic poliomyelitis". Med. J. Aust. 163 (8): 423–4. PMID 7476613.
  46. Khetsuriani N, Prevots DR, Quick L, Elder ME, Pallansch M, Kew O, Sutter RW (2003). "Persistence of vaccine-derived polioviruses among immunodeficient persons with vaccine-associated paralytic poliomyelitis". J. Infect. Dis. 188 (12): 1845–52. doi:10.1086/379791. PMID 14673763.

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