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Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP)

These revised recommendations of the Advisory Committee on Immunization Practices (ACIP) replace recommendations on poliomyelitis issued in 1982 and 1987, and present a new ACIP poliovirus vaccination policy that increases reliance on inactivated poliovirus vaccine (IPV). This change in policy is the most substantive since the introduction of oral poliovirus vaccine (OPV) in 1961. ACIP has determined that the risk-benefit ratio associated with the exclusive use of OPV for routine immunization has changed because of rapid progress in global polio eradication efforts. In particular, the relative benefits of OPV to the U.S. population have diminished because of the elimination of wild-virus-associated poliomyelitis in the Western Hemisphere and the reduced threat of poliovirus importation into the United States. The risk for vaccine-associated poliomyelitis caused by OPV is now judged less acceptable because of the diminished risk for wild-virus-associated disease (indigenous or imported). Consequently, ACIP recommends a transition policy that will increase use of IPV and decrease use of OPV during the next 3-5 years. The revised recommendations include three options for poliovirus vaccination, all of which meet acceptable standards of care: sequential vaccination with IPV followed by OPV, OPV alone, or IPV alone. For overall public health benefit, ACIP recommends a sequential vaccination schedule of two doses of IPV followed by two doses of OPV for routine childhood vaccination. Vaccination schedules that include OPV alone or IPV alone are also acceptable and are preferred in some situations (e.g., IPV alone is recommended for children who are immunosuppressed; OPV alone is preferred for children who begin the primary vaccination schedule after 6 months of age). Implementation of these recommendations should reduce the risk for vaccine-associated paralytic poliomyelitis and facilitate a transition to exclusive use of IPV following further progress in global polio eradication.

Adult↗

Inactivated poliovirus vaccine and the final stages of poliovirus eradication.

The use of the inactivated poliovirus vaccine (IPV) will increase before and probably also after the global eradication of the wild type poliovirus. Before eradication, the switch from the use of oral poliovirus vaccine (OPV) to IPV has been due to the better safety record of IPV. Introduction of IPV in the regular immunisation schedules is made easier by the development of several combination vaccines, including IPV. Maternal antibodies and young age, often considered problematic for early initiation of IPV schedules, did not compromise optimal maintenance of seropositivity during infancy or long-term persisting antibody levels in our studies. OPV-derived, potentially pathogenic and transmissible poliovirus strains, excreted by some individuals for years, may present a problem for a blunt stopping of all polio immunisations after eradication. Our recent results suggest that locally excreted IgA might have a role in the elimination of poliovirus infection in the intestinal tissues.

Antibodies, Viral↗

Comparison of neuropathogenicity of poliovirus type 3 in transgenic mice bearing the poliovirus receptor gene and cynomolgus monkeys.

To clarify the similarities of poliovirus infection in cynomolgus monkeys and transgenic mice bearing the poliovirus receptor, TgPVR21, we compared the pathological changes of these animals following intraspinal inoculation of two strains of poliovirus type 3 using immunohistochemical detection of the capsid antigen. All of the monkeys inoculated with 10(6) TCID(50) viruses showed flaccid paralysis 2 or 3 days post-inoculation (p.i.). TgPVR21 mice showed paralysis starting from 2 to 3 days p.i. Histologically, neurons having pyknotic nuclei and eosinophilic cytoplasm and neuronophagia were characteristically observed in both animals, but central chromatolysis was not observed in infected TgPVR21. The median lesion scores in the monkeys and TgPVR21 were well correlated, though the distribution of poliovirus-infected lesions in the central nervous system was different. In both animals the motor neurons and the brainstem nuclei responsible for flaccid paralysis were infected by the virus, while the cerebral cortex and thalamus were infected in the monkeys but not in TgPVR21. These results confirmed the reliability of neurovirulence tests using TgPVR21 as a substitute for monkeys, in respect to the spinal and brainstem lesions of poliovirus type 3.

Animals↗

Interaction of the poliovirus receptor with poliovirus.

The structure of the extracellular, three-domain poliovirus receptor (CD155) complexed with poliovirus (serotype 1) has been determined to 22-A resolution by means of cryo-electron microscopy and three-dimensional image-reconstruction techniques. Density corresponding to the receptor was isolated in a difference electron density map and fitted with known structures, homologous to those of the three individual CD155 Ig-like domains. The fit was confirmed by the location of carbohydrate moieties in the CD155 glycoprotein, the conserved properties of elbow angles in the structures of cell surface molecules with Ig-like folds, and the concordance with prior results of CD155 and poliovirus mutagenesis. CD155 binds in the poliovirus "canyon" and has a footprint similar to that of the intercellular adhesion molecule-1 receptor on human rhinoviruses. However, the orientation of the long, slender CD155 molecule relative to the poliovirus surface is quite different from the orientation of intercellular adhesion molecule-1 on rhinoviruses. In addition, the residues that provide specificity of recognition differ for the two receptors. The principal feature of receptor binding common to these two picornaviruses is the site in the canyon at which binding occurs. This site may be a trigger for initiation of the subsequent uncoating step required for viral infection.

Amino Acid Sequence↗

Rapid detection of poliovirus by reverse transcription and polymerase chain amplification: application for differentiation between poliovirus and nonpoliovirus enteroviruses.

This report describes a rapid method of detection of poliovirus from viral isolates of clinical specimens using a single set of primers selected from the conserved 5' noncoding region of the poliovirus genome. Of the 144 clinical viral isolates examined, 81 were positive for polioviruses and 50 were positive for nonpoliovirus enteroviruses by tissue culture neutralization and infectivity. All 81 (100%) of the viral isolates identified as poliovirus by tissue culture infectivity were also positive by polymerase chain reaction. Of 50 nonpoliovirus enterovirus isolates found to be negative for poliovirus by tissue culture neutralization and infectivity, 48 were also negative by polymerase chain reaction. The high sensitivity (100%) and specificity (96%) of the primer set indicate that this assay has potential clinical applicability in the diagnosis of nonpoliovirus enterovirus infection.

Base Sequence↗

Down regulation of poliovirus receptor RNA in HeLa cells resistant to poliovirus infection.

A line of HeLa cells (SOFIA) was previously isolated that is resistant to poliovirus infection and does not express functional virus binding sites at the cell surface. The expression of the poliovirus receptor (PVR) gene in SOFIA cells was examined to determine the molecular basis for the failure of these cells to express PVRs. Southern blot analysis of genomic DNA revealed that the PVR gene in SOFIA cells did not contain gross alterations. However, PVR transcripts were not detected in Northern (RNA) blot analysis of SOFIA cell RNA. In vitro nuclear run-on analysis showed that transcription of PVR-specific RNA was reduced in SOFIA cells. Treatment of SOFIA cells with 5-azacytidine restored susceptibility to poliovirus infection, which correlated with the appearance of PVRs at the cell surface, as detected with anti-PVR monoclonal antibody D171. PVR RNA was detected in clones derived from 5-azacytidine-treated SOFIA cells. SOFIA cells were converted to poliovirus sensitivity at a rate of 5 to 7%, suggesting that down regulation of PVR expression involved few cellular targets. Resistance of SOFIA cells to poliovirus infection therefore appears to result from down regulation of PVR RNA, leading to lack of PVR expression at the cell surface. Methylation may play a role in regulating the expression of the PVR gene, which is not essential for survival of HeLa cells.

Azacitidine↗

Poliovirus proteinase 3C converts an active form of transcription factor IIIC to an inactive form: a mechanism for inhibition of host cell polymerase III transcription by poliovirus.

In HeLa cells, RNA polymerase III (pol III)-mediated transcription is severely inhibited by poliovirus infection. This is due primarily to a reduction in the transcriptional activity of TFIIIC, a transcription factor which binds in a sequence specific manner to the internal promoter of pol III genes. Using gel retardation assays, we have shown previously that inhibition of pol III transcription by poliovirus is correlated with disappearance of a transcriptionally active form of TFIIIC (complex I) concomitant with the appearance of a faster mobility, transcriptionally inactive form of TFIIIC (complex III). We show here that a poliovirus with a point mutation in the proteinase 3C (3Cpro) region failed to produce complex III and is limited in its ability to inhibit pol III transcription compared with the wild-type virus. Incubation of purified 3Cpro, expressed in Escherichia coli, with transcriptionally active TFIIIC (complex I) in vitro resulted in generation of the transcriptionally inactive complex III form of TFIIIC. In an in vitro transcription assay, treatment of the complex I form of TFIIIC with 3Cpro almost completely inhibited pol III transcription. Finally expression of the 3Cpro gene in transfected HeLa cells resulted in significant inhibition of pol III-mediated transcription. The results presented here suggest that proteolysis of the transcriptionally active form of TFIIIC by poliovirus 3Cpro is a mechanism by which poliovirus inhibits host cell RNA pol III transcription.

3C Viral Proteases↗

Murine neurovirulence studies with a chimeric poliovirus: in vivo generation of a mutant base-paired stable attenuated poliovirus.

We investigated the neurovirulence of a chimeric poliovirus consisting of the coding region of Lansing type 2 poliovirus and the 5'NCR of type 3 poliovirus. Specifically we carried out studies on the effects of stable base pairing, between nucleotides 472 and 537, on neurovirulence. Mice were injected intracranially with the attenuated chimeric virus MAS 27 plaque 1 having the following nucleotide base pair at 472-537, G-G. Mutants recovered from the CNS of inoculated mice were divided into three groups according to the nucleotide sequence of the 5'NCR; MAS 27C type viruses having a single base change (G-C) at the position 472, MAS 27G type mutants having a single base change (G-C) at the position 537, and MAS 27U type viruses having a single base change (G-U) at the position 537. The isolate MAS 27C had back-mutated to the wild type, and 100 000 fold more virulent than attenuated MAS 27G and MAS 27U. MAS 27C type mutants were predominant, suggesting that base C at position 472 is favoured to form a stable secondary structure with guanine at position 537. Attenuated MAS 27G, however, carries guanine and cytosine at nucleotides 472 and 537 respectively, and was a stable attenuated virus following passage in four serial generations of mice. Furthermore, attenuated MAS 27G poliovirus produced viral proteins less efficiently and had slower growth rates than the revertant MAS 27C. The stable attenuated base paired MAS 27G might provide the basis for a prototype for a live attenuated stable type 3 poliovaccine.

Animals↗

Poliovirus-specific intestinal antibody responses coincide with decline of poliovirus excretion.

Antibody responses to poliovirus type 3 were studied in fecal samples of 66 children immunized with 3 doses of enhanced-potency inactivated poliovirus vaccine (E-IPV), followed by 1 dose of monovalent oral poliovirus vaccine (OPV, type 3 Sabin). One fecal sample taken before OPV vaccination and 9 collected thereafter were tested for neutralizing antibodies by a microneutralization assay and for class-specific responses by heavy chain-capture radioimmunoassays. Both neutralizing antibody and IgA responses usually occurred during the second week and coincided with ceasing of virus excretion or a decrease in the excreted virus titer. Half of the vaccinees had received a trypsin-modified E-IPV, but their responses did not differ from those of children immunized with the regular E-IPV. These results are in agreement with the view that an intestinal antibody response, mainly consisting of IgA, may be involved in the ceasing of a primary poliovirus excretion.

Feces↗

Comparison of inactivated poliovirus vaccine and oral poliovirus vaccine programs in Israel.

In spite of high vaccination coverage, paralytic poliomyelitis still occurs in Israel, either in sporadic form in the urban area or in small outbreaks in the rural, non-Jewish segment. At high risk are mainly very young infants, not yet protected by poliovirus vaccine and children who have failed to seroconvert after a full course of oral poliovirus vaccine ( OPV ). In these circumstances, a new program for vaccination of young infants early in life with a quadruple vaccine containing inactivated poliovirus vaccine (IPV) and diphtheria, tetanus, and pertussis vaccines (DTP) has been tested. Administration of two doses of IPV up to the age of three and one-half months followed by a booster at the age of 10 months has produced a very satisfactory antibody response (100% seroconversion and high geometric mean titers of antibody to the three antigens), which has occurred early in life and persisted up to two years after booster. This response was similar to that observed after four doses of trivalent OPV ( TOPV ) reinforced with one dose of monovalent type 1 OPV . Two doses of the quadruple vaccine have also induced an antibody response to pertussis antigen in greater than 90% of the infants. After booster, a greater than 99% conversion rate has been recorded, which has remained unchanged at one year of follow-up. The above data have led to the modification of the poliovirus vaccination schedule in the areas at risk.

Antibodies, Viral↗

Mucosal immunity following oral poliovirus vaccine and enhanced potency inactivated poliovirus vaccine immunization.

Mucosal immunity is considered to be an important barrier for inhibiting person-to-person transmission of naturally occurring (wild type) poliovirus infection. This review briefly summarizes the results of a previously published study in which 79 oral poliovirus vaccine (OPV) vaccinated children and 93 enhanced-potency inactivated poliovirus vaccine (IPV) children were challenged with one of two doses of type 1 OPV virus to test the oropharyngeal and gastrointestinal mucosal immunity conferred by each type of poliovirus vaccine. Although both OPV and IPV produced excellent oropharyngeal immunity, OPV was clearly superior in decreasing fecal shedding of the challenge virus.

Child, Preschool↗

Current issues in evaluating the efficacy of oral poliovirus vaccine and inactivated poliovirus vaccine immunization.

Although epidemic poliomyelitis in the United States has been eliminated, there are a number of current issues that concern the use of oral attenuated poliovirus vaccine in comparison with the new enhanced-potency inactivated vaccine. Although wild-type poliovirus is almost eradicated in developed nations, vaccine-induced polio exists, at a low but persistent rate. This article reviews the current issues and suggests a return to the Institute of Medicine's 1988 recommendations concerning combined immunization with inactivated poliovirus vaccine and oral poliovirus vaccine.

Humans↗

Poliovirus-specific immunoglobulin A in persons vaccinated with inactivated poliovirus vaccine in The Netherlands.

In The Netherlands the inactivated poliovirus vaccine (IPV) is used for protection against poliomyelitis. It is not clear if parenteral vaccination with IPV can lead to priming of the mucosal immune system. We developed and evaluated enzyme-linked immunosorbent assays for the detection of poliovirus serotype-specific immunoglobulin A (IgA) and secretory IgA antibodies. Using these assays we examined the kinetics of the IgA response in sequential serum samples from 15 poliomyelitis patients after natural infection with serotype 3 poliovirus. In 36% of the patients IgA remained present for up to 5 months postinfection. Furthermore, we examined, in an IPV-vaccinated population, the presence of IgA antibodies in sera from young children (4 to 12 years of age; n = 177), sera from older children (between 13 and 15 years of age; n = 123), sera from healthy blood donors (n = 66), and sera from naturally immune elderly persons (n = 54). The seroprevalence of IgA to all three serotypes was low in young vaccinated children (5 to 7%), and the seroprevalence of IgA types 2 and 3 was low in older vaccinated children (2 to 3%). The seroprevalence of antibodies to type 1 was significantly higher (18%) in older children than in younger children. This higher seroprevalence is most likely explained by the persistence of IgA following infection with the serotype 1 wild-type poliovirus strain during the 1978 epidemic. In healthy adults, the seroprevalence of type 1- and type 2-specific IgA was significantly higher than that in young children. These results suggest that at least part of the IgA found in the older population is induced by infections unrelated to the IPV vaccination schedule. Finally, we found that parenteral vaccination with IPV was able to boost secretory IgA responses in 74 to 87% of a naturally exposed elderly population (n = 54). While the presence of secretory IgA in IPV-vaccinated persons has been documented previously, our findings suggest that mucosal priming with live virus is necessary to obtain an IgA response after IPV booster vaccination.

Adolescent↗

Selective isolation of poliovirus in recombinant murine cell line expressing the human poliovirus receptor gene.

Sixty-eight laboratory strains representing 49 enterovirus, 10 adenovirus, and 3 reovirus serotypes were inoculated in a recombinant murine cell line expressing the human poliovirus receptor gene (L alpha cells). Only polioviruses caused cytopathic effect over a 10-day period. Likewise, only polioviruses were isolated, by use of L alpha cells, from 168 fecal specimens from children from developing countries. These results suggest that the recombinant L alpha cells can be used for selective isolation of poliovirus from clinical specimens.

Animals↗

Poliovirus-binding inhibition ELISA for evaluation of immune response to oral poliovirus vaccine: a possible alternative to the neutralization test.

This study describes an ELISA variant (Binding Inhibition ELISA, BI ELISA) for the quantitative determination of neutralization-relevant antibodies to polioviruses. The test differs from previously described analogs by utilizing polyclonal immune reagents: capture antibodies and biotin-labeled detecting antibodies. The BI ELISA was compared with the conventional neutralization test (NT) by testing live Sabin and wild-type poliovirus strains. The comparison of 68 serum samples taken from Oral Poliovirus Vaccine (OPV) recipients showed 100% specificity and sensitivity for Sabin 1 and Sabin 2, and 100% sensitivity and 97% specificity for Sabin 3. Good correlations (r = 0.7, 0.77, 0.65 for Sabin 1, 2, 3, respectively) were demonstrated between the NT and BI ELISA results. These results indicate that the BI ELISA can be used as a reliable alternative to the NT for determination of neutralization-relevant antibodies to polioviruses in vaccinees and in large-scale sero-epidemiological studies.

Animals↗

Identification of 50- and 23-/25-kDa HeLa cell membrane glycoproteins involved in poliovirus infection: occurrence of poliovirus specific binding sites on susceptible and nonsusceptible cells.

Glycoproteins in the range 50 and 23/25 kDa were identified as poliovirus specific binding sites on HeLa cells with the monoclonal antibody mAb 122. mAb 122 is characterized by its partial inhibiting effect on poliovirus reproduction and adsorption when prebound to HeLa cells. The binding sites are endocytosed in native cells and specific for poliovirus as mAb 122 did not interfere with the adsorption of human rhinovirus type 14 (HRV 14). The poliovirus binding sites are present also on nonprimate so called nonsusceptible cells, e.g., mouse L-cells, as could be shown with sensitive ELISA based binding assays and performance of binding studies with fixed cells at 37 degrees.

Animals↗

Interaction of the poliovirus receptor CD155 with the dynein light chain Tctex-1 and its implication for poliovirus pathogenesis.

The cellular receptor for poliovirus CD155 (or PVR) is the founding member of a new class of membrane-associated immunoglobulin-like proteins, which include the mouse tumor-associated antigen E4 (Tage4) and three proteins termed "nectins." Using a yeast two-hybrid screen we have discovered that the cytoplasmic domain of CD155 associates strongly and specifically with Tctex-1, a light chain of the dynein motor complex, the latter representing the major driving force for retrograde transport of endocytic vesicles and membranous organelles. We confirmed the interaction biochemically and by co-immunoprecipitation, and we mapped the Tctex-1 binding site to a SKCSR motif within the juxtamembrane region of CD155. Tctex-1 immunoreactivity was detected in mouse sciatic nerve and spinal cord (two tissues of central importance for poliovirus pathogenesis) in punctate, possibly vesicular, patterns. We propose that the cytoplasmic domain may target CD155-containing endocytic vesicles to the microtubular network. Neurotropic viruses like poliovirus, herpesvirus, rabies virus, and pseudorabies virus all utilize neuronal retrograde transport to invade the central nervous system. Association with Tctex-1 and, hence, with the dynein motor complex may offer an explanation for how poliovirus hijacks the cellular transport machinery to retrogradely ascend along the axon to the neuronal cell body.

Amino Acid Motifs↗

Immunofluorescence analysis of poliovirus receptor expression in Peyer's patches of humans, primates, and CD155 transgenic mice: implications for poliovirus infection.

Oral transmission of poliovirus is restricted to humans and certain primate species. The expression of the human poliovirus receptor (CD155) within gastrointestinal-associated lymphoid tissues from species that are susceptible (human) or resistant (rhesus macaque and CD155 transgenic [Tg] mice) to oral poliovirus infection was examined. Sensitivity to oral infection correlated with CD155 expression not only in the intestinal epithelium, including the follicle-associated epithelium (FAE) and microfold (M) cells of Peyer's patches, but also in germinal centers within the Peyer's patches. CD155 expression in rhesus macaques was reduced in FAE and, significantly, absent in germinal centers. In CD155 Tg mice, CD155 expression was barely observable in the intestinal epithelium, absent in germinal centers, but prominent in the tunica muscularis. This suggests that productive poliovirus infection of the gut is dependent on the expression of CD155 within the FAE, including the M cells, and on cells within Peyer's patches, most likely within germinal centers.

Animals↗