Poliovirus and its three serotypes

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The world has been battling the continuous spread of poliovirus and its associated disease poliomyelitis for a long time, with the United States officially declaring the Global Eradication Initiative against Polio in 1988. Throughout the past 26 years of eradication effort, various patterns have been observed in the spread and pathogenesis of the poliovirus. One interesting pattern is that, of the three serotypes of the virus, serotype 2 (PV2) was eradicated in 1999, while the other two serotypes (PV1 and PV3) remain endemic.

Poliovirus structure and pathogenesis


The poliovirus (PV) is a type of enterovirus, meaning it enters through the oropharynx (mouth and nasal cavities) and then replicates in the submucosal tissues of the pharynx and the gastrointestinal tract. The virus continues to be excreted from the stool for several weeks after replication begins [1]. The average incubation time for the PV is 7-14 days. During this time the virus enters the lymphoid tissues, can enter… It is a small virus (27-30 nm) that does not have an envelope but has capsids that surround its single-stranded, positive-sense RNA genome, which is about 7,500 nucleotides long [3]. The capsid is made up of 60 copies of four structural proteins: VP1, VP2, VP3, and VP4 [8]. The surfaces of structural proteins VP1, VP2, and VP3 contain antigenic sites (epitopes) to facilitate the antibody binding to the virus to neutralize it. The fourth protein, VP4, is located completely inside the capsid and plays no known role in inducing antibodies. VP1 has the most exposed surface of all the proteins, and therefore plays an important role in the immune response of all three poliovirus serotypes [4]. All three serotypes bind to the same cell-surface receptor, CD155 [2]. This receptor is present only in human cells, hence there are no other reservoirs for poliovirus.

This is an image of the external structure of the poliovirus. The different colors indicate the different surface structural proteins: VP1, VP2, and VP3. Image provided by AJ Cann




Poliomyelitis is caused by the poliovirus, which enters the human body through the mouth or nose (oropharynx), multiplies in the tissues of the pharynx and gastrointestinal tract, and is then absorbed and spread through the circulatory and lymphatic system³[12]. Primary, or minor, transient viremia (entrance of the virus into the blood stream) occurs in most infected individuals, allowing it to spread to reticuloendothelial tissue (connective tissues, spleen, liver, lungs, bone marrow, and lymph nodes), while causing no symptoms. A secondary occurrence of viremia occurs in 4-8% of individulas, and causes minor illness, including headache, sore throat, and fever. In rare cases, less than 1%, the viremia is persistent enough that the virus can enter the central nervous system (CNS)(8)[13].

This is a photomicrograph of the cerivical spinal cord, specifically the anterior horn, where the poliovirus tends to cause the most damage in the CNS. This specific damage is caused by poliovirus serotype 3. The image is provided by the CDC and Dr. Karp, Emory University. ID# 2759. URL: http://phil.cdc.gov/Phil/details.asp

The precise mechanism by which this occurs is unknown, but one of the propose methods is entrance through the blood-brain-barrier. It remains unknown how exactly the virus breeches the blood-brain barrier, but it is thought that it travels on nerve fibers, independent of its receptor. It has also been proposed that if mononuclear phagocytes can permit viral replication, they would act as carriers for the virus to enter the CNS⁴[14]. Once inside the CNS, it characteristically causes lesions in motor neurons of the anterior horn of the cervical and lumbar regions of the spinal cord. This damage is shown in Figure…. In more severe cases, lesions are also observed in the intermediate and posterior gray columns and in sensory spinal ganglia. Most areas of the brain are unaffected, but in the brain stem, the motor and sensory nuclei of cranial nerves are affected, as well as the precentral gyrus, which is the primary motor cortex. A second prevalent theory that has been empirically supported by studies with mice indicates that the virus enters the CNS through retrograde axonal transport from muscle to spinal cord (FIG. 5 illustrates (8)). The variation of the degree to which the virus causes physical symptoms has been one of the problems in the effort to eradicate poliovirus globally.


The eradication effort

A child receiving an oral polio vaccine. This image is provided by the 1988 Pan American Health Organization (PAHO) and the World Health Organization (WHO). ID: 13195 URL: http://phil.cdc.gov/Phil/download.asp


President Roosevelt, who contracted poliomyelitis himself in 1921, initiated a campaign to develop a vaccine during the height of the presence of poliomyelitis in the United States in 1953, This campaign was successful 2 years later in 1955 when Dr. Jonas Salk officially developed the first, inactivated, injectable polio vaccine²[10]. He did so by using the known technique of growing the virus in the kidney cells of monkeys, then isolating it and inactivating it with formaldehyde⁷[11]. In 1961, Dr. Albert Sabin developed an attenuated, live, oral vaccine. This vaccine is created by passage of the parent wild poliovirus strains through non-human animal cells. Polio has been considered eradicated from the United States since 1979, thanks to the effectiveness of the vaccines.

In the 1970s, it was established that the poliovirus was widespread globally, especially in many developing countries. In 1988, the World Health Organization (WHO) passed a resolution to eradicate polio by the year 2000, and the Global Polio Eradication Initiative was launched. Until 2005, the Global Polio Eradication Initiative relied on the trivalent oral poliovirus vaccine in their mass vaccination campaigns. This vaccine contains all three serotypes in it. However, this vaccine type appeared to have reduced effectiveness, especially in immunizing against serotypes 1 and 3 [15]. This prompted monovalent versions of the OPV to be licensed and used in placed of the trivalent OPV, starting in 2005. The monovalent vaccines contain only one serotype, one with serotype 1 and another with serotype 3. Serotype 2 of the poliovirus was declared globally eradicated in 1999. In late 2009, a bivalent vaccine was produced and licensed by WHO. In the pre-vaccination era, the three serotypes were relatively equal in their frequency. This indicates that it was not until the introduction of the OPV that the type 1 virus became the most widespread, the type 2 virus became no longer endemic, and the type 3 virus became intermediately distributed [7].


The three serotypes


Structural differences:
It has been shown that, in the U.S., during the height of polio’s damage in 1952, the vast majority of the virus isolates samples were PV1. In the highest incidence regions, 94% were PV1, while the remaining 6% were PV2 and PV3 combined [8]. Each serotype has slight differences in its capsid protein.



Differences in vaccine functioning for each serotype:
The three serotypes of the PV are known as PV1, PV2, and PV3. There is minimal heterotypic immunity between these three (“immunity to one serotype does not produce immunity to the others”) [1]. It has been observed in analysis that, with the OPV, serotype 2 circulates longer and is transmitted more readily than serotypes 1 or 3. The increased circulation time for serotype 2 in communities has caused children to have increased immunity to PV2 compared to 1 and 3, likely due to secondary spread of the serotype, causing indirect immunization, without administering the actual OPV. In this live trivalent vaccine, the serotype 2 often out-competes the other two for the binding to the CD155 receptor in the host cells, which causes the production of the correct antibodies, providing immunity against that serotype of the virus, ultimately causing immunity produced by this vaccine against the PV1 and PV3 less effective [5]. This has caused problems with the trivalent vaccine. Even with attempts to balance the immunization of this vaccine more by decreasing the amount of serotype 2, preferential seroconversion for PV2 has still been observed in recipients of the vaccine. Studies of many lower-income countries have shown that, after three doses of OPV, children were three times more likely to lack sufficient immunity for PV1 and PV3 compared to PV2 [6]. The antigenic sites appear to differ between the three serotypes. PV1 has antigenic sites located on VP1 (residues 220-222), VP2 (residues 164-172), and VP3 (residues 58-60, 70, 71, 77, 79). PV2 has and antigenic site only on VP1 (residues 89-100). PV3 also has an antigenic site at this same location, along with another one located on VP1 (residues 286-290). PV3 also shares two other antigenic sites with PV1, on VP2 (residues 164-172) and on VP3 (residues 58-60, 70, 71, 77, 79) [8]. The antigenic sites are grouped in Table 1. Studies with mice have shown that the site shared by PV2 and PV3 is known to be immunodominant (the immune response gears more toward the markers of this site) [4]. This immunodimnant site is the only site present on PV2, not present at all in PV1, and one of 4 sites for PV3. However, this immunodominance has not yet been demonstrated in humans. One study showed that there was no significant difference in the immunodominance of site 1 and site 3, specifically in serotype 3 [4].

This table shows the location of occurrence of the immunodominantn antigenic sites in each of the three poliovirus serotypes. is adapted from Table 7 of the paper by Minor et al. titled: Antigenic Structure of Poliovirus Of Serotypes 1, 2 and 3.


It has been shown that trypsin in the gut lumen can cleave epitopes at the antigenic site 1 of serotypes 1 and 3, specifically at residue 98 arginine [4]. The viruses are still infectious, but the antigenic properties are drastically altered. This only affects these two serotypes in the OPV, not the IPV, because the latter does not pass through the gut, but is intramuscularly injected instead⁴.



Further Reading

[Sample link] Ebola Hemorrhagic Fever—Centers for Disease Control and Prevention, Special Pathogens Branch

References

[Sample reference] Takai, K., Sugai, A., Itoh, T., and Horikoshi, K. "Palaeococcus ferrophilus gen. nov., sp. nov., a barophilic, hyperthermophilic archaeon from a deep-sea hydrothermal vent chimney". International Journal of Systematic and Evolutionary Microbiology. 2000. Volume 50. p. 489-500.
1) “Poliomyelitis.” Center for Disease Control and Prevention (May 7, 2012). http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/polio.pdf.

2) Schwartz A., Robert. Wallace R., Mark. Sinha, Smeeta. Kapila, Rejendra. Velazquez, Alexander. Dua, Pratibha. “Enteriviruses.” Medscape (March 2014). http://emedicine.medscape.com/article/217146-overview#aw2aab6b2b2aa

3) Wallace, Gregory S. Alexander, James P. Wassilak, Steven G.F. “Traveler’s Health: Poliomyelitis.” Center for Disease Control and Prevention (August 2013). http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-3-infectious-diseases-related-to-travel/poliomyelitis

4) Herremans, T, J.H.J Reimerink, and M.P.G. Koopmans. “Antibody Responses to Antigenic Sites 1 and 3 of Serotype 3 Poliovirus after Vaccination with Oral Live Attenuated or Inactivated Poliovirus Vaccine and after Natural Exposure.” Clinical and Vaccine Immunology 7, no. 1 (January 2000): 40–44. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC95819/


5) Troy, Stephanie. Ferreyra-Reyes, Leticia. Huang, ChunHong. Sarnquist, Clea. Canizales-Quintero, Serigio. Nelson, Christine. Baez-Saldana, Renata. “Community Circulation Patterns of Oral Polio Vaccine Serotypes 1, 2, and 3 after Mexican National Immunization Week.” Journal of Infectious Diseases no. 5 (December 23, 2013): 1–25. doi:10.1093/infdis/jit831.

6) Grassly, Nicholas C. “The Final Stages of Global Eradication of Poliomyelitis.” Philosophical Transactions of The Royal Society B 368, no. 1623 (June 24, 2013). doi:10.1098/rstb.2012.0140.
7) Kew, Olen M., Mick M. Mulders, Galina Yu. Lipskaya, Edson E. da Silva, and Mark A. Pallansch. “Molecular Epidemiology of Polioviruses.” Virology 6 (1995): 401–414. February 26, 2014.

8) Nathanson, Neal. Kew, Olen M. “From Emergence to Eradication: The Epidemiology of Poliomyelitis Deconstructed.” American Journal of Epidemiology 172, no. 11 (August 2010): 1213-1229. http://aje.oxfordjournals.org/content/172/11/1213.full#ref-14

9) Minor, Philip D. Ferguson, Morag. Evans, Davin M.A. Almond, Jeffrey W. Icenogle, Joseph P. “Antigenic Structure of Polioviruses of Serotypes 1, 2, and 3.” Virology no. 67 (1986): 1283-1291.

10) “Polio and Prevention: The History of Polio.” Global Polio Eradication Initiative (2010). http://www.polioeradication.org/Polioandprevention/Historyofpolio.aspx
11) Vaccinated: One Man’s Quest to Defeat the World’s Deadliest Diseases. Paul A. Offit, MD.

12) “Poliovirus.” MedlinePlus (1997-2014). http://www.nlm.nih.gov/medlineplus/ency/article/001402.htm

13) Mueller, Steffen. Wimmer, Eckard. Cello, Jeronimo. “Poliovirus and poliomyelitis: A tale of guts, brains, and an accidental event. Virus Research 111 no. 1(August 2005): 175-193. http://www.sciencedirect.com/science/article/pii/S016817020500122X

14) Molecular bio of PV PDF…. Kew, Olen M. Mulders, Mick N. Lipskaya, Galina Yu. da Silva, Edson E. Pallansch, Mark A. “Molecular epidemiology of polioviruses.” Virology 6 (1995): 401-414.

15) http://www.sciencedirect.com/science/article/pii/S0140673612606485 O'Reilly, K M (2012). "The effect of mass immunisation campaigns and new oral poliovirus vaccines on the incidence of poliomyelitis in Pakistan and Afghanistan, 2001-11: a retrospective analysis". The Lancet (British edition) (2012): 491.


Edited by (your name here), a student of Nora Sullivan in BIOL168L (Microbiology) in The Keck Science Department of the Claremont Colleges Spring 2014.