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Vaccine-associated paralytic poliomyelitis in the Russian Federation in 1998–2014

  • Olga E. Ivanova
    Correspondence
    Corresponding author at: Department of Poliomyelitis and Other Enteroviral Infections, Chumakov FSC R&D IBP RAS, Moscow, 108819, Russia.
    Affiliations
    Institute of Poliomyelitis and Viral Encephalitides, Chumakov Federal Scientific Centre for Research and Development of Immune-and-Biological Products of the Russian Academy of Sciences (FSBSI “Chumakov FSC R&D IBP RAS”), Moscow, 108819, Russia

    Sechenov First Moscow State Medical University, Moscow, 119991, Russia
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  • Tatyana P. Eremeeva
    Affiliations
    Institute of Poliomyelitis and Viral Encephalitides, Chumakov Federal Scientific Centre for Research and Development of Immune-and-Biological Products of the Russian Academy of Sciences (FSBSI “Chumakov FSC R&D IBP RAS”), Moscow, 108819, Russia
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  • Nadezhda S. Morozova
    Affiliations
    Federal Centre of Hygiene and Epidemiology, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, Moscow, 117105, Russia
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  • Armen K. Shakaryan
    Affiliations
    Institute of Poliomyelitis and Viral Encephalitides, Chumakov Federal Scientific Centre for Research and Development of Immune-and-Biological Products of the Russian Academy of Sciences (FSBSI “Chumakov FSC R&D IBP RAS”), Moscow, 108819, Russia

    Pirogov Russian National Research Medical University, 117997, Moscow, Russia
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  • Ekaterina A. Korotkova
    Affiliations
    Institute of Poliomyelitis and Viral Encephalitides, Chumakov Federal Scientific Centre for Research and Development of Immune-and-Biological Products of the Russian Academy of Sciences (FSBSI “Chumakov FSC R&D IBP RAS”), Moscow, 108819, Russia

    A.N. Belozersky Institute of Physical-Chemical Biology, Lomonosov Moscow State University, Moscow, 119899, Russia
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  • Liubov I. Kozlovskaya
    Affiliations
    Institute of Poliomyelitis and Viral Encephalitides, Chumakov Federal Scientific Centre for Research and Development of Immune-and-Biological Products of the Russian Academy of Sciences (FSBSI “Chumakov FSC R&D IBP RAS”), Moscow, 108819, Russia

    Sechenov First Moscow State Medical University, Moscow, 119991, Russia
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  • Olga Y. Baykova
    Affiliations
    Institute of Poliomyelitis and Viral Encephalitides, Chumakov Federal Scientific Centre for Research and Development of Immune-and-Biological Products of the Russian Academy of Sciences (FSBSI “Chumakov FSC R&D IBP RAS”), Moscow, 108819, Russia
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  • Alexandr Y. Krasota
    Affiliations
    Institute of Poliomyelitis and Viral Encephalitides, Chumakov Federal Scientific Centre for Research and Development of Immune-and-Biological Products of the Russian Academy of Sciences (FSBSI “Chumakov FSC R&D IBP RAS”), Moscow, 108819, Russia

    A.N. Belozersky Institute of Physical-Chemical Biology, Lomonosov Moscow State University, Moscow, 119899, Russia
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  • Author Footnotes
    1 Deceased.
    Anatoly P. Gmyl
    Footnotes
    1 Deceased.
    Affiliations
    Institute of Poliomyelitis and Viral Encephalitides, Chumakov Federal Scientific Centre for Research and Development of Immune-and-Biological Products of the Russian Academy of Sciences (FSBSI “Chumakov FSC R&D IBP RAS”), Moscow, 108819, Russia

    Sechenov First Moscow State Medical University, Moscow, 119991, Russia
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  • Author Footnotes
    1 Deceased.
Open AccessPublished:September 07, 2018DOI:https://doi.org/10.1016/j.ijid.2018.08.017

      Highlights

      • During the period of only OPV use rVAPP cases prevailed.
      • Polioviruses types 3 and 2 were isolated more often.
      • Vaccine derived polioviruses were isolated only from cVAPP cases.
      • The incidence of VAPP was higher during OPV use than during IPV–OPV scheme.
      • The risk of VAPP exists if OPV remains in the vaccination schedule.

      Abstract

      Objectives

      Different polio vaccination schemes have been used in Russia: oral polio vaccine (OPV) was used in 1998–2007 and inactivated polio vaccine (IPV) followed by OPV in 2008–2014. This article presents the characteristics of vaccine-associated paralytic poliomyelitis (VAPP) cases in Russia during this period.

      Methods

      VAPP cases were identified through the acute flaccid paralysis surveillance system, classified by the National Expert Classification Committee. Criteria for a ‘recipient VAPP’ (rVAPP) case were poliomyelitis symptoms 6–30 days after OPV administration, isolation of the vaccine virus, and residual paralysis 60 days after disease onset. Unvaccinated cases with a similar picture 6–60 days after contact with an OPV recipient were classified as ‘contact VAPP’ (cVAPP) cases.

      Results

      During 1998–2014, 127 VAPP cases were registered: 82 rVAPP and 45 cVAPP. During the period in which only OPV was used, rVAPP cases prevailed (73.8%); cases of rVAPP were reduced during the sequential scheme period (15%). Poliovirus type 3 (39.5%) and type 2 (23.7%) were isolated more often. Vaccine-derived poliovirus types 1, 2, and 3 were isolated from three cases of cVAPP. The incidence of VAPP cases was higher during the period of OPV use (1 case/1.59 million OPV doses) than during the sequential scheme period (1 case/4.18 million doses).

      Conclusion

      The risk of VAPP exists if OPV remains in the vaccination schedule.

      Keywords

      Introduction

      In 1996, the Russian Federation (Russia) adopted the National Polio Eradication Programme based on the World Health Organization (WHO) strategy, which included high coverage of the child population with polio vaccination through routine immunization and additional vaccination measures, as well as surveillance of acute flaccid paralysis (AFP) (
      • Hull H.F.
      • Birmingham M.E.
      • Melgaard B.
      • Lee J.W.
      Progress toward Global Polio Eradication.
      ). Vaccination against poliomyelitis in Russia is carried out within the framework of the national immunization schedule (NIS). From 1959 to 2008, a trivalent oral polio vaccine (tOPV) was used for vaccination. In 2006–2007, certain categories of children (those suffering from oncological diseases, primary immunodeficiency disorders, blood diseases, frequently and chronically ill children) were individually vaccinated with the inactivated polio vaccine (IPV). In 2008, IPV was introduced into the NIS of Russia: the sequential immunization scheme consists of two IPV doses followed by one OPV dose, and revaccination includes three OPV doses.
      In 2002, Russia was certified as a polio-free country (
      • CDC
      Certification of poliomyelitis eradication — European Region, June 2002.
      ). However, from 1998 through 2014, 146 polio cases were recorded, of which 19 were caused by wild poliovirus type 1 imported into Russia in 2010 (
      • Yakovenko M.L.
      • Gmyl A.P.
      • Ivanova O.E.
      • Eremeeva T.P.
      • Ivanov A.P.
      • Prostova M.A.
      • et al.
      The 2010 outbreak of poliomyelitis in Tajikistan: epidemiology and lessons learnt.
      ); the remaining 127 were cases of vaccine-associated paralytic poliomyelitis (VAPP). The possibility of VAPP is a well-known drawback of OPV (
      • Dowdle W.R.
      • De Gourville E.
      • Kew O.M.
      • Pallansch M.A.
      • Wood D.J.
      Polio eradication: the OPV paradox.
      ). In the USSR (and then in Russia), cases of VAPP were recorded, but their detection was rather accidental. The introduction of the poliomyelitis/AFP surveillance system, which requires identification and then clinical, epidemiological, and virological study, as well as a final classification of each case, made it possible to systematically record cases of VAPP.
      This article presents a characterization of VAPP cases in Russia covering a 17-year period (1988–2014), during which different vaccination schedules were used.

      Materials and methods

      The anti-polio vaccination schedule used in Russia

      The complete immunization schedule consists of six vaccine administrations to children aged 3, 4.5, 6, 18, and 20 months, and 14 years. Before 2007, tOPV was used. The sequential immunization schedule was started in 2008. This includes two doses of IPV at age 3 months and 4.5 months and a single dose of OPV at age 6 months, followed by three revaccinations with OPV at age 18 months, 20 months, and 14 years.

      Identification and classification of VAPP cases

      Cases of VAPP were detected and investigated in laboratory in accordance with the AFP assay algorithm in Russia (

      Federal Centre for Hygiene and Epidemiology of the Service for Surveillance on Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor). [Sanitary rules 3.1.2951-11. Prevention of poliomyelitis]. Moscow; 2011. Russian.

      ) and the WHO recommendations (
      • World Health Organization (WHO)
      Report of the second meeting of the technical consultation group for global eradication of poliomyelitis. WHO/EPI/GEN/98/04.
      ). Two faecal samples (with 24–48 h between samplings) and two serum samples (with a 3-week interval between samplings) were collected for the primary investigation. In the case of virus isolation, samples of faeces were collected on day 60 and day 90 following the onset of paralysis and then at intervals of 1 month until a negative result was obtained. The final classification of the AFP case was performed by the National Expert Classification Committee as recommended by the WHO (
      • World Health Organization (WHO)
      Report of the second meeting of the technical consultation group for global eradication of poliomyelitis. WHO/EPI/GEN/98/04.
      ) and national regulations (
      • Leschinskaya E.V.
      • Latysheva I.N.
      The clinic, diagnosis and treatment of acute poliomyelitis. Guidelines.
      ).
      An AFP case was classified as ‘recipient VAPP’ (rVAPP) when typical clinical symptoms appeared during the period from 6 to 30 days after vaccination with OPV, a virus of vaccine origin was isolated, and residual paralysis remained 60 days after disease onset. A case of AFP in an unvaccinated person with typical clinical symptoms and vaccine poliovirus isolation appearing within 60 days after direct contact with an OPV recipient (or direct contact was not revealed) was classified as ‘contact VAPP’ (cVAPP). If a disease with a typical clinical appearance occurred between 6 and 30 days after immunization with OPV, but a poliovirus was not isolated despite adequate timing of faecal sampling, the case was classified as ‘poliomyelitis of unclear aetiology, possibly rVAPP’. If the poliovirus (either from an OPV recipient or not) was not isolated due to late faecal collection (>14 days after disease onset), the case was classified as ‘compatible with polio’. If, at the same time, it was reliably known that the paralysis had developed during the period from 6 to 30 days after an OPV vaccination, the case was classified as rVAPP.

      Ethical statement

      Samples were collected as a part of the Russian state programme for polio surveillance. Written informed consent was obtained from all subjects or their legal representatives at the primary clinical sites.

      Laboratory investigations and epidemiological data сollection

      Virological studies were conducted in the WHO Polio Regional Reference Laboratory at Chumakov Institute of Poliomyelitis and Viral Encephalitides (“Chumakov FSC R&D IBP RAS”) in accordance with the WHO guidelines. The viruses were isolated on RD, L20B, or Hep-2c cell lines. Virus identification was performed in a neutralization assay (
      • World Health Organization (WHO)
      Manual for the virological investigation of polio.
      ). The intratypic differentiation was conducted using a direct ELISA (
      • van der Avoort H.G.A.M.
      • Hull B.P.
      • Hovi T.
      • Pallansch M.A.
      • Kew O.M.
      • Crainic R.
      • et al.
      A comparative study of five methods of intratypic differentiation of polioviruses.
      ,
      • World Health Organization (WHO)
      Manual for the virological investigation of polio.
      ), RT-PCR, or real-time RT-PCR (
      • Kilpatrick D.R.
      • Yang C.F.
      • Ching K.
      • Vincent A.
      • Iber J.
      • Campagnoli R.
      • et al.
      Rapid group-, serotype-, and vaccine strain-specific identification of poliovirus isolates by real-time reverse transcription-PCR using degenerate primers and probes containing deoxyinosine residues.
      ). Isolation of total RNA from the suspension of infected cells, reverse transcription, PCR amplification of the poliovirus genome fragments encoding the VP1 protein, and their purification and sequencing were performed as described previously (
      • Yakovenko M.L.
      • Gmyl A.P.
      • Ivanova O.E.
      • Eremeeva T.P.
      • Ivanov A.P.
      • Prostova M.A.
      • et al.
      The 2010 outbreak of poliomyelitis in Tajikistan: epidemiology and lessons learnt.
      ).
      Serological assays included the determination of poliovirus neutralizing antibodies in serum. This was performed by neutralization assay with Sabin strains types 1, 2, and 3 in Нер-2c cells (
      • World Health Organization (WHO)
      Manual for virological investigation of poliomyelitis. WHO/EPI/GEN/97.1.
      ).
      Information about the clinical appearance of the disease and the premorbid and immunological statuses of the children was obtained from the case histories.
      The estimates of VAPP incidence were obtained using two indicators: the number of doses of OPV administered over a certain period of time per one case of VAPP and the number of cases of VAPP that occurred within a certain period of time per one million newborns. The incidence of VAPP as a whole, for recipients of OPV, for recipients of the first dose of OPV, and for contact patients was assessed. Data on the number of newborns were obtained from the website of the

      Federal State Statistics Service of the Russian Federation, Population of Russia. http://www.gks.ru/wps/wcm/connect/rosstat_main/rosstat/ru/statistics/population/demography/# (data for 1998–2014).

      Federal State Statistics Service (1998–2014).
      Data on the number of AFP cases and the number of OPV doses distributed were provided by the Federal Centre for Hygiene and Epidemiology of the Service for Surveillance on Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor); the number of OPV doses included those used for routine vaccination and for additional polio immunization activities.

      Statistical methods

      The reliability of comparing the results was evaluated as described by
      • Gubler E.V.
      Computational methods of analysis and recognition of pathological processes.
      , and using Microcal Origin 8.0 (Student t-test after checking samples with a normality test or Fisher’s exact test).

      Results

      During the years 1998–2014, there were 6643 cases of AFP in Russia, 127 of which were cases of VAPP (Table 1, Figure 1). The National Expert Classification Committee classified 82 cases as rVAPP, as follows: 71 cases were fully in compliance with the definition, six cases were ‘compatible with poliomyelitis’, and five cases were ‘poliomyelitis of unclear aetiology’. Forty-two cases that were fully compliant with the criteria for cVAPP, two cases that were ‘compatible with poliomyelitis’, and one case of ‘poliomyelitis of unclear aetiology’ were classified as cVAPP. During the period of OPV use (1998–2007), the prevailing cases were rVAPP (73.8%), and during the period in which the sequential scheme was used (2008–2014), cases were mostly cVAPP (85%).
      Table 1Cases of VAPP in Russia recorded during the period 1998–2014, when different vaccination schemes were used.
      1998–20072008–20141998–2014
      RecipientContactTotalRecipientContactTotalRecipientContactTotal
      Number of cases7928107317208245127
      SexMale622385314176537102
      Female175223317825
      Mean age, months (pt< 0.05)6.2 ± 0.58.4 ± 16.8 ± 0.524.0 ± 9.317.0 ± 3.318.1 ± 3.16.9 ± 6.011.6 ± 10.18.6 ± 8.1
      Poliovirus

      type
      1549549
      27111818981927
      3271037178281745
      1 + 21111
      1 + 3617617
      2 + 31717111818
      1 + 2 + 37777
      Virus not isolated101112210313
      Number of OPV doses received1696752271677
      2881199
      3123123
      41111
      Not vaccinated202017173737
      VAPP, vaccine-associated paralytic poliomyelitis; OPV, oral polio vaccine.
      Figure 1
      Figure 1VAPP cases recorded in Russia during 1998–2017.
      Most of the VAPP patients were male: 80.3% over the entire follow-up period, 79.4% in 1998–2007, and 85% in 2008–2014. Male subjects also prevailed among OPV recipients and among contact patients, 79.3% and 82.2%, respectively, for the entire follow-up period; 78.5% and 82.1% in 1998–2007; 100% and 82.4% in 2008–2014 (Table 1).
      The age of VAPP patients ranged from 1 month to 5 years 5 months; children under 1 year comprised 74% (94 of 127). The age of all patients, recipients, and contacts was lower during OPV use (1998–2007) than in the period of the sequential vaccination schedule (pt< 0.05) (Table 1).
      Ninety (70.9%) of the 127 VAPP patients were vaccinated against poliomyelitis. The majority of them (85.6%) had received one dose of OPV, while 10% had received two doses, 3.3% three doses, and 1.1% four doses.
      Among the rVAPP cases, 86.6% occurred after the first dose of OPV; nine children (10.9%) were paralysed after receiving the second dose of OPV, one child became ill after receiving the third dose (1.2%), and one after the fourth dose (1.2%; Bruton agammaglobulinemia was diagnosed in this child who fell ill after receiving the fourth OPV dose). The time between OPV administration and the onset of paralysis was 20.9 ± 8.7 days (ranging from 2 to 35 days).
      Among the children with cVAPP, 82.2% were not vaccinated and 17.8% (eight children) had information about vaccination. Six children had been vaccinated with OPV once and two children had information on three doses of OPV. These cases were classified as contact cases based on the virological results (poliovirus isolation), epidemiological data (close contact with a newly vaccinated child or occurrence of the disease a long time after vaccination, i.e. 1.5 months to 1.5 years), and serological results (presence of neutralizing antibodies only to the type of poliovirus isolated).
      Cases of VAPP were registered in 54 regions of Russia. No geographical or seasonal patterns of their distribution were observed.
      The overwhelming majority of children lived in families. Twelve children with cVAPP and one child with rVAPP were from orphanages and three children with cVAPP belonged to migrating groups of the population (gypsies).
      Information on the localization of the neurological lesion was available for 123 patients. The most common form was monoparesis, 39.8% (49 cases). Paraparesis and tetraparesis occurred in 37.4% (46 patients) and 21.1% (26 patients) of the cases, respectively. Triparesis was the rarest form, occurring in 1.6% (two patients). Two VAPP cases had a fatal outcome.
      Before disease onset, 71 children (55.9%) had suffered from various health abnormalities: frequent respiratory diseases, immunity disorders (hypogammaglobulinemia), paraproctitis, congenital organ development pathologies, Down syndrome, atopic dermatitis, and food allergies. Most often (53.5%, 38 children) there was a perinatal central nervous system lesion in combination with various diseases (such as paraproctitis, atopic dermatitis, pyoderma, and candidiasis of the oral cavity).
      Data on the state of immunity were available for 54 patients. Thirty-six (66.7%) had various immunological disorders: hypogammaglobulinemia (36.1%, 13 children), common variable immunodeficiency (25%, nine children), selective IgA deficiency (16.7%, six children), transient immunological failure (8.3%, three children), agammaglobulinemia (8.3%, three children), and selective IgA and IgG deficiency with hyper-IgM syndrome (one child, 2.8%).
      Polioviruses were isolated from 114 patients (72 rVAPP and 42 cVAPP; Table 1). In general, a single virus type was isolated more often (71.1%, p< 0.01, Fisher’s exact test) than poliovirus mixtures from these VAPP cases. Type 3 and type 2 polioviruses dominated (p< 0.05, Fisher’s exact test) and comprised 39.5% and 23.7%, respectively. Isolates from rVAPP were mostly single types (56.9%) or mixtures (43.1%), and type 3 (38.9%) and mixtures of types 2 and 3 (25.0%) prevailed. In cases of cVAPP, types 2 (42.2%) and 3 (37.8%) were predominantly isolated. During the time period during which only OPV was administered (1998–2007), the VAPP cases yielded mostly type 3 (38.5%): rVAPP isolates were type 3 (69.2%) or mixtures of types 2 and 3 (56.7%), and cVAPP cases yielded types 2 (44%) and 3 (40%). When the sequential vaccination scheme was introduced (2008–2014), individual serotypes were mostly isolated: 85% from cases of VAPP in general and 100% from cVAPP. During the same time period, no case was associated with poliovirus type 1.
      All isolated polioviruses had a vaccine origin. The degree of divergence from the Sabin strains in the genome region encoding the VP1 protein did not exceed 0.5% nucleotide substitutions, except for vaccine-derived polioviruses (VDPV) (
      • World Health Organization (WHO)
      Classification and reporting of vaccine-derived polioviruses (VDPV). GPEI guidelines.
      ) isolated from three cases of cVAPP. Poliovirus type 1 had 2.65% nucleotide substitutions (
      • Cherkasova E.A.
      • Korotkova E.A.
      • Yakovenko M.L.
      • Ivanova O.E.
      • Eremeeva T.P.
      • Chumakov K.M.
      • et al.
      Long-term circulation of vaccine-derived poliovirus that causes paralytic disease.
      ), type 2 had 1.44% substitutions (
      • Yakovenko M.L.
      • Korotkova E.A.
      • Ivanova O.E.
      • Eremeeva T.P.
      • Samoilovich E.
      • Uhova I.
      • et al.
      Evolution of the Sabin vaccine into pathogenic derivaties without appreciable changes in antigenic properties: need for improvement of current poliovirus surveillance.
      ), and type 3 had 1.3% substitutions. Polioviruses types 1 and 2 were multiple recombinants: type 1/type 2/type 1 and type 2/type 3/type 2/type 1, respectively. The three children from whom these strains were isolated did not have immunological disorders and lived in different orphanages. These strains were classified as ambiguous VDPV (aVDPV) (
      • World Health Organization (WHO)
      Classification and reporting of vaccine-derived polioviruses (VDPV). GPEI guidelines.
      ).
      None of the 63 children whose faeces were taken repeatedly excreted the virus for longer than 4 months after the onset of disease. Forty-six children were examined on day 60, 37 on day 90, and 20 on day 120: the polioviruses were excreted by nine (19.6%), three (8.1%), and two (10%) children, respectively. Non-polio enteroviruses (CVB3, CVB5, CVA14, CVA24, E14, E25) or adenoviruses were isolated from seven (15.2%), seven (18.9%), and two children (10%), respectively. The isolated polioviruses did not differ significantly (only up to 0.44%) in nucleotide sequences from the Sabin strains, and a long evolution was recorded in only two cases.
      Poliovirus type 2 isolated from a cVAPP case (RUS-03066022002) in 2003 on day 14 after onset of the disease had 0.1% nucleotide differences; the virus isolated on day 112 showed 0.8% differences. The child had Bruton agammaglobulinemia, and the virus was classified as immunodeficiency-related VDPV (iVDPV) (
      • World Health Organization (WHO)
      Classification and reporting of vaccine-derived polioviruses (VDPV). GPEI guidelines.
      ). The child was subsequently lost to follow-up; the faeces sampled 1 year after onset of the disease were negative.
      Poliovirus type 3 of vaccine origin, which was isolated in 2013 from a patient with cVAPP (RUS-13053401008) on day 6 after disease onset, had 0.66% of nucleotide substitutions. Faecal samples collected on day 60 and day 90 contained type 1 polioviruses, which had 0.22% and 1.1% nucleotide substitutions, respectively. This latter isolate was assigned to VDPV. Samples of faeces taken on days 120 and 128 were negative. It appears that the secondary infection with type 1 occurred as a result of OPV vaccination of persons in the immediate environment of the patient in the gypsy community.
      The incidence of VAPP cases in Russia (Table 2) in 1998–2014 was 1 case per 1.99 million OPV doses distributed and 4.74 cases per 1 million newborns. The incidence of VAPP during the period of OPV use (1998–2007) was higher at 1 case per 1.59 million doses and 7.64 cases per 1 million newborns than the incidence following the introduction of IPV into the immunization schedule (2008–2014) at 1 case per 4.18 million doses and 1.56 cases per 1 million newborns (p< 0.05, Fisher’s exact test).
      Table 2VAPP frequency in the Russian Federation.
      Observation periodNumber of VAPP recordedNumber of doses administered, millionNumber of children born, millionNumber of OPV doses per VAPP case, millionNumber of VAPP cases per 1 million newborns
      TotalRecipientContactTotalOPV recipientsFirst OPV dose recipientsContacts
      1998–20141278245253.126.81.994.743.062.611.68
      1998–20071077928169.614.01.597.645.644.931.99
      2008–20142031783.512.84.181.560.230.081.33
      VAPP, vaccine-associated paralytic poliomyelitis; OPV, oral polio vaccine.
      The frequency of VAPP in OPV recipients (3.06 per 1 million newborns) and recipients of the first dose of OPV (2.61 per 1 million newborns) over the entire period (1998–2014) was higher (p< 0.05, Fisher’s exact test) than for contacts (1.68 per 1 million newborns). The same trend was observed during the exclusive use of OPV during 1998–2007: the incidence of VAPP in recipients was 5.64, in recipients of the first dose was 4.93, and in contacts was 1.99 per 1 million newborns (p< 0.05, Fisher’s exact test). During use of the sequential immunization schedule (2008–2014), the incidence of VAPP in contacts was higher (p< 0.05, Fisher’s exact test) than in recipients and recipients of the first dose: 1.33, 0.23, and 0.08 cases per 1 million newborns, respectively.

      Discussion

      Since the widespread introduction of OPV, polio cases have been classified as VAPP in many countries around the world (
      • Sutter R.W.
      • Kew O.M.
      • Cochi S.L.
      • Aylward R.B.
      Poliovirus vaccine — live.
      ,
      • Platt L.R.
      • Estivariz C.F.
      • Sutter R.W.
      Vaccine-associated paralytic poliomyelitis: a review of the epidemiology and estimation of the global burden.
      ). In Russia, tOPV was introduced in 1959, and cases of poliomyelitis in children who had received one dose of live vaccine (trivalent or monovalent type 1) with a typical clinical picture and residual paralysis that occurred within 1 month after vaccination were described as early as 1961 (
      • Bartoshevich E.N.
      • Belyaeva A.P.
      • Markova A.Y.
      • Sokolova I.S.
      Clinical characteristics of paralytic poliomyelitis in children immunized with Sabin oral live vaccine (preliminary communication).
      ).
      The observations made in the present study, following implementation of the polio AFP surveillance system, covered a 10-year period of tOPV use and a 7-year period of the use of the sequential IPV–tOPV immunization schedule, allowing the main characteristics of VAPP in Russia to be established. The findings were mainly in accordance with well-known aspects of the disease: the absence of geographical and seasonal patterns in the occurrence of cases, the prevalence of males, and the prevalence of children under 1 year of age. Cases of rVAPP that occurred after the first dose of OPV manifested mainly on day 21 after administration of the vaccine.
      An important factor in the development of VAPP was the presence of immunity disorders in the children. In this study, half of the children before the disease had a burdened premorbid status and 67% had various immunological disorders. As reported previously by
      • Khetsuriani N.
      • Prevots D.R.
      • Quick L.
      • Elder M.E.
      • Pallansch M.
      • Kew O.
      • et al.
      Persistence of vaccine-derived polioviruses among immunodeficient persons with vaccine-associated paralytic poliomyelitis.
      , hypogammaglobulinemia predominated. Data on the number of VAPP patients with immune system defects vary widely in different countries of the world, from 22% in the USA (
      • Sutter R.W.
      • Prevots R.
      Vaccine-associated paralytic poliomyelitis among immunodeficient persons.
      ), up to 30–75% in Belarus (
      • Samoĭlovich E.O.
      • Ermolovich M.A.
      • Kotova I.F.
      • Svirchevskaia Elu
      • Shimanovich V.P.
      • Kozhemiakin A.K.
      • et al.
      The experience of surveillance for acute flaccid paralysis in Belarus.
      ). This may be due to differences in the system of detection in each country and the criteria used to assess the immunodeficiency state. The common healthcare system in Russia and Belarus in the past explains the similarity in the results.
      VAPP cases in Russia were more often associated with poliovirus types 3 and 2 (as individual serotypes or mixtures), which is in agreement with the global data (
      • Platt L.R.
      • Estivariz C.F.
      • Sutter R.W.
      Vaccine-associated paralytic poliomyelitis: a review of the epidemiology and estimation of the global burden.
      ). Poliovirus type 3 prevailed among both VAPP and rVAPP cases, and type 2 among cVAPP. The frequency of occurrence of VAPP in Russia is comparable to that in many other countries (
      • Platt L.R.
      • Estivariz C.F.
      • Sutter R.W.
      Vaccine-associated paralytic poliomyelitis: a review of the epidemiology and estimation of the global burden.
      ).
      The introduction of IPV into the NIS has changed the epidemiology of VAPP: the incidence decreased sharply and the ratio of rVAPP/cVAPP changed towards an increase in the latter: 1/0.35 in 1998–2007 compared to 1/5.78 in 2008–2014. The prevalence of cases among unvaccinated children (cVAPP) led to an increase in the age of patients by more than two-fold. It also resulted in the fact that practically no mixtures of polioviruses were isolated from VAPP cases, and poliovirus type 1 was not isolated at all.
      The main goal of the introduction of IPV into the NIS in 2008 was the prevention of VAPP, but this was not achieved. VAPP cases occurred mainly in unvaccinated children as a result of contact with an OPV recipient and also in recipients, who, for various reasons, received OPV in violation of the vaccination schedule: vaccination was done with OPV, and not IPV. Unvaccinated inhabitants of closed children’s institutions were at significant risk, and there were also occasional VAPP outbreaks in orphanages (
      • Korotkova E.A.
      • Gmyl A.P.
      • Yakovenko M.L.
      • Ivanova O.E.
      • Eremeeva T.P.
      • Kozlovskaya L.I.
      A cluster of paralytic poliomyelitis cases due to transmission of slightly diverged Sabin 2 vaccine poliovirus.
      ); 41.2% (7 of 17) of cVAPP cases were registered in this risk group.
      The algorithm for the follow-up of VAPP patients in Russia (immunological examination and repeated faeces analysis) significantly enhances surveillance for poliovirus, including iVDPV. This investigation allowed the identification of a case of transformation of type 2 poliovirus isolated from a child with agammaglobulinemia (RUS-03066022002) into iVDPV. This is important, since special studies to identify iVDPV conducted in Russia (
      • Li L.
      • Ivanova O.
      • Driss N.
      • Tiongco-Recto M.
      • da Silva R.
      • Shahmahmoodi S.
      • et al.
      Poliovirus excretion among persons with primary immune deficiency disorders: summary of a seven-country study series.
      ,
      • Aghamohammadi A.
      • Abolhassani H.
      • Kutukculer N.
      • Wassilak S.G.
      • Pallansch M.A.
      • Kluglein S.
      • et al.
      Patients with primary immunodeficiencies are a reservoir of poliovirus and a risk to polio eradication.
      ) have not revealed any VDPV excretors. Due to the algorithm for the follow-up of VAPP patients, the repeated infection of a child with cVAPP (RUS-13053401008) by poliovirus of another type originating from tOPV used to conduct vaccination measures in the effective disease area and its transformation into VDPV was recorded. This example draws attention to some problematic aspects of OPV vaccination campaigns.
      Currently, the world is phasing out the use of OPV from Sabin strains and is introducing IPV into immunization schedules (
      • World Health Organization (WHO)
      Polio eradication and endgame strategic plan 2013-2018.
      ). The experience of countries that have implemented sequential (IPV–OPV) immunization schedules has shown that VAPP has been successfully eliminated (
      • Alexander L.N.
      • Seward J.F.
      • Santibanez T.A.
      • Pallansch M.A.
      • Kew O.M.
      • Prevots D.R.
      • et al.
      Vaccine policy changes and epidemiology of poliomyelitis in the United States.
      ,
      • Wattigney W.A.
      • Mootrey G.T.
      • Braun M.M.
      • Chen R.T.
      Surveillance for poliovirus vaccine adverse events, 1991 to 1998: impact of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine.
      ,
      • Zhao D.
      • Ma R.
      • Zhou T.
      • Yang F.
      • Wu J.
      • Sun H.
      • et al.
      Introduction of inactivated poliovirus vaccine and impact on vaccine-associated paralytic poliomyelitis — Beijing, China, 2014-2016.
      ). At the same time, introduction of a sequential schedule in Russia has led to a significant reduction in the incidence of VAPP, but such cases continue to occur. The possibility of VAPP has remained after changing the formulation of the OPV (withdrawal of poliovirus type 2): six cases of VAPP were registered in Russia after the switch from trivalent to bivalent in April 2016.
      As the world approaches the global eradication of poliomyelitis and the number of cases caused by wild poliovirus reduces sharply, the occurrence of VAPP cases becomes particularly unacceptable. Currently, OPV from Sabin strains in the form of a bivalent vaccine is present in the immunization schedules of 143 countries around the world (calculated using data from
      • World Health Organization (WHO)
      WHO vaccine-preventable diseases: monitoring system. 2018 global summary.
      ), and OPV of various formulations (bivalent, monovalent) is used for supplementary immunization activities. If OPV from Sabin strains in any formulation remains in any vaccination schedule, the risk of VAPP also remains.

      Acknowledgements

      In loving memory of our colleague and friend Anatoly Gmyl.
      We thank the Service for Surveillance on Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor), the Federal Centre of Hygiene and Epidemiology of Rospotrebnadzor, and the Polio Laboratory Network of the Russian Federation for their assistance in the collection and delivery of the clinical specimens, providing epidemiological data, and additional clinical investigation of VAPP cases. We express our gratitude to the members of the National Expert Classification Committee: Dr O.P. Chernyavskaya, Prof. V.K. Tatochenko, Dr O. Zinovieva, Dr O. Rogovina, and Mrs Y.M. Mikhailova for their participation in the classification of VAPP cases.

      Funding

      The research was carried out with support from the Federal Budget of the Russian Federation allocated for the implementation of the Polio Eradication Programme in the Russian Federation, the WHO Polio Eradication Programme, the WHO Regional Office for Europe, and a Russian Science Foundation grant (project No. 15-15-00147). The work of OEI, KLI, and APG were partially supported by Russian academic excellence project “5–100”.

      Ethical approval

      Ethical approval was obtained.

      Conflict of interest

      None declared.

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