Poliovirus and its three serotypes
The global population has likely been battling the continuous spread of poliovirus and its associated disease poliomyelitis throughout history. In 1988, the United States officially declared the Global Eradication Initiative against Polio. 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 was eradicated in 1999, while the other two serotypes (1 and 3) remain endemic.
Poliovirus Structure and Classification
Poliovirus 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 [1]. It is a small virus (27-30 nm) that lacks a viral envelope but has a capsid 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 antigen binding sites (also known as epitopes) to facilitate the antibody binding to the virus to help neutralize it. In some cases they do so by inhibiting its replication, in others making it a better target for phagocytosis or other forms of destruction. 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]. VP1, as well as the other three viral proteins, are also involved in the virus binding to its receptor. All three serotypes bind to the same cell-surface receptor, CD155 [2]. This receptor is present only in human epithelial cells, hence there are no other reservoirs for poliovirus. Its normal function in the body is to establish intercellular adheres between epithelial cells [16].
Poliovirus Causes Poliomyeltis
Infection
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Poliovirus 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 system [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) [13]. The precise mechanism by which this occurs is unknown, but one of the propose methods is entrance through the blood-brain-barrier. It is thought that the virus may travel 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 CNS [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 the photomicrograph image provided by Dr. Karp from Emory University. 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 [8].
Transmission
The virus spreads externally via direct contact with an infected individual, contact with their infected mucus or phlegm from the nose or mouth, or contact with their infected feces. The virus can remain present in the stool from 3-6 weeks. Poliovirus is highly infectious, with seroconversion rates of almost 100% for someone who comes into contact with an infectious child, and over 90% for coming into contact with an infectious adult, meaning an infected child or adult successfully passed on the virus 100% or 90% of time, respectively [12]. The average incubation time for the PV is 7-14 days [1]. After being infected with the virus, it takes between 5-35 days to develop symptoms, if any develop at all.
Symptoms
The actual disease caused by poliovirus is called poliomyelitis. Most people (about 95%) who contract the virus have subclinical infection, which means the virus has not entered the CNS, and they may not develop any symptoms at all [12]. If they do experience symptoms, they generally include headache, red and sore throat, malaise, slight fever, and vomiting. These symptoms may last 72 hours or less. Clinical poliomyelitis is divided into nonparalytic and paralytic forms, both of which may occur after recovery from a subclinical infection. Clinical poliomyelitis primarily affects the nervous system. In the nonparalytic form, the disease manifests as abnormal reflexes, back stiffness, difficulty with certain movements of the head or legs, and neck stiffness. One in 200 cases is paralytic and 5-10% of the paralytic victims die due to immobilization of their breathing muscles [12]. This occurs when the virus is able to reach and destroy cells in the medulla oblongata which is part of the brain stem that controls respiration, leading to respiratory paralysis and arrest. 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. Because the majority of people infected with the virus carry no symptoms, it is difficult to track its spread.
Introduction of Polio Vaccines
Vaccination in the U.S.
There is no cure for poliomyelitis. For this reason, vaccines are immensely important, to prevent infection from occurring in the first place. President Roosevelt, who contracted poliomyelitis himself in 1921, initiated a campaign that, in 1955, resulted in Dr. Jonas Salk developing the inactivated polio vaccine (IPV). This vaccine, which is administered primarily through intramuscular injection[10], was developed using the known technique of growing the virus in the kidney cells of monkeys, then isolating it and inactivating it with formaldehyde[11]. In 1961, Dr. Albert Sabin developed the oral polio vaccine (OPV), using a live, attenuated strain of the virus. This vaccine is created by passage of the parent wild poliovirus strain through non-human animal cells. OPV is administered orally, usually in the form of drops, as shown in figure… Polio has been considered eliminated from the United States since 1979, thanks to the effectiveness of these two vaccines.
Vaccination for Global Eradication
Despite significant progress made in combating poliovirus spread in the U.S., 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 (GPEI) was launched. Although by the year 2000 the number of polio cases had been reduced by more than 99%, the initial goal of global eradication was not met. The target date has since been extended to 2018 [18]. Vaccination has been the key to progress toward polio eradication. OPV was and still is the vaccine of choice in the eradication program, primarily due to its ease of administration and its lower cost compared to IPV. The original OPV vaccines were monovalent for serotype 1 and 2 in 1961 (mOPV1 and mOPV2), then serotype 3 as well in 1962 (mOPV3) [17]. In 1963, the tOPV was licensed and became the primary vaccine, largely replacing IPV [17]. Until 2005, the GPEI relied on trivalent OPV (tOPV) for mass vaccination campaigns. This vaccine contains all three serotypes, and is meant to provide immunity against all three. However, tOPV appeared to have reduced effectiveness, especially in immunizing against serotypes 1 and 3 [15]. This prompted new version of mOPV1 and 3 to be reintroduced and predominantly used in place of tOPV, starting in 2005. Serotype 2 of the poliovirus was declared globally eradicated in 1999, and so mOPV2 was not needed. In late 2009, a bivalent OPV (bOPV) for serotypes 1 and 3 was produced and licensed by WHO, to provide immunity for both in the same vaccine.
The Three Poliovirus Serotypes and Eradication of Serotype 2
The three serotypes are thought to differ only slightly in structure. However, larger-scale patterns of incidence and circulation do reveal differences between the three serotypes, both in their wild-type form and in the vaccine strains. One significant pattern, likely caused by some of the differences between the serotypes, led to the global eradication of WPV serotype 2 in 1999, while the struggle to eradicate serotypes 1 and 3 has continued into 2014.
Differences in Virulence
Structurally, it was been found that there are slight differences in the capsid proteins of each serotype. It is unknown whether these structural differences contribute, but it has also been observed that there are differences in virulence among the three serotypes. A study of the incidence rates of poliomyelitis in the United States was conducted during the peak of its incidence there in 1952 [8]. The data showed that in the highest-incidence regions, 94% of the isolates were serotype 1, the remaining 6% being types 2 and 3 combined. In the lowest-incidence regions, 59% of the isolates were serotype 1, while 41% were types 2 and 3 combined [8]. Thus, it has been indicated in this study, as well as other studies, that serotype 1 is the most virulent of the three serotypes. Large epidemics of poliomyelitis are usually associated with serotype 1, while cases of serotype 3 are more sporadic, as was the pattern with serotype 2 before it was eliminated [7]. In the past, it has been shown that in areas with poor vaccine coverage, WPV serotypes 2 and 3 were previously found at similar frequencies, while in areas with increasingly better coverage, circulation of WPV serotype 2 was found to decrease dramatically. This has been presumed to be caused by the immune system seroconverting serotype 2 with relatively high efficiency. High levels of serotype 2 often indicated deficiencies in polio vaccine coverage [7].
It is thought that the introduction of OPV further contributed to the differences in poliomyelitis incidence among the three serotypes. It has been noted that not long before the height of poliomyelitis and the introduction of polio vaccines, the frequency of the three serotypes were more similar to one another, whereas later with OPV, serotype 1 became the most widespread, the type 2 virus became globally eradicated, and the type 3 virus became intermediately distributed [7].
Differences in Vaccination Effects
Vaccination has been implicated in contributing to the current differences in frequency of the three serotypes, type 1 being the most widespread, 2 being globally eradicated, and 3 being intermediately distributed,
Circulation and Host-cell receptor competition
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 OPV, the vaccine serotype 2 circulates longer and is transmitted more readily than serotypes 1 or 3. The increased circulation time and transmission for OPV serotype 2 in communities has caused children to have increased immunity to the wild-type polio virus (WPV) serotype 2 compared to 1 and 3, likely due to secondary spread of OPV serotype 2 causing indirect immunization (without administering the actual OPV). In tOPV, serotype 2 often out-competes the other two for the binding to the CD155 receptor in the host cells, providing immunity against WPV serotype 2 more frequently, ultimately causing immunity produced by this vaccine against the WPV serotypes 1 and 3 to be less effective [5]. Even with attempts to balance the immunization of this vaccine 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 tOPV, children were three times more likely to lack sufficient immunity for WPV serotypes 1 and 3 compared to 2 [6].
Antigenic sites
The antigenic sites appear to differ between the three serotypes. Serotype 1 has antigenic sites located on VP1 (residues 220-222), VP2 (residues 164-172), and VP3 (residues 58-60, 70, 71, 77, 79). Serotype 2 has and antigenic site only on VP1 (residues 89-100). Serotype 3 also has an antigenic site at this same location, along with another one located on VP1 (residues 286-290). Serotype 3 also shares two other antigenic sites with serotype 1, on VP2 (residues 164-172) and on VP3 (residues 58-60, 70, 71, 77, 79) [8]. The antigenic sites are grouped and shown 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 primary site present on serotype 2 virus, barely present on serotype 1 virus, and one of 4 sites for serotype 3 virus. 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].
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
Recent Eradication Progress
The GPEI is still struggling to eliminate polio in three countries where it remains endemic: Nigeria, Pakistan, and Afghanistan. Some of the main obstacles for achieving this goal involve violent conflicts within and around areas where poliovirus is circulating. In the past couple years, the eradication program has implemented many new strategies in these areas to decreasing circulation, and therefore decrease poliomyelitis incidence. The Independent Monitoring Board (IMB) has met quarterly since December 2010 to discuss successes and areas that have shown need of improvement over the past year. They met October 1-3 this year in London, and their assessment was given to the primary groups leading the eradication efforts, such as UNICEF, WHO, Rotary Club and the U.S. Center for Disease Control, so that they can then implement then evaluate their current efforts and implement the suggested changes. This past year (2013) they met in October, and their report reveals areas that have improved, especially in Nigeria and Afghanistan, and areas that need work, such as many in Pakistan, where incidence of poliomyelitis has actually increased.
The IMB report: http://www.polioeradication.org/Portals/0/Document/Aboutus/Governance/IMB/9IMBMeeting/9IMB_Report_EN.pdf
Endgame Strategy
The GPEI has set a new target goal of 2018 as the of global polio eradication. This plan includes modifications or intensification of current strategies, as well as addressing the problems mentioned in the IMB report referenced in the previous subsection (Recent Eradication Progress).
The 2013-2018 Endgame Plan: http://www.polioeradication.org/Portals/0/Document/Resources/StrategyWork/PEESP_EN_US.pdf
WHO strategy for completing global polio eradication: http://www.who.int/bulletin/volumes/85/6/06-037457/en/
Part of this plan includes replacing OPV with IPV, due to VAPP being a rare but significant side effect of OPV. The majority of VAPP cases are from serotype 2, likely due to removal of that serotype from many the vaccines of some populations, but not others, leaving the former vulnerable to cVDPV serotype 2.
The costs and benefits of this change are currently being studie, as in the following study:
Mangal T.D., Aylward B.R., and Grassly, N.C. (2013). The Potential Impact on Routine Immunization with Inactivated Poliovirus Vaccine on Wild-type or Vaccine-derived Poliovirus Outbreaks in Posteradication Setting
GPEI economic analysis of switching from OPV to IPV: http://www.polioeradication.org/Portals/0/Document/Resources/TS_IPV_econ_analysis.pdf
References
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16) Maier, M.K., Seth, S., Czeloth, N., et al. (2007). The adhesion receptor CD155 determines the magnitude of humoral immune responses against orally ingested antigens. European Journal of Immunology 37 (8): 2214–25.
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18) Mangal, T. D., Aylward, R. B., & Grassly, N. C. (2013). The potential impact of routine immunization with inactivated poliovirus vaccine on wild-type or vaccine-derived poliovirus outbreaks in a posteradication setting. American Journal of Epidemiology, 178(10), 1579-1587.
Edited by Rachael Crooke, a student of Nora Sullivan in BIOL168L (Microbiology) in The Keck Science Department of the Claremont Colleges Spring 2014.
