Molecular characterization of poliovirus isolates from children who contracted vaccine-associated paralytic poliomyelitis (VAPP) following administration of monovalent type 3 oral poliovirus vaccine in the 1960s in Hungary

Abstract

Hungarian children were immunized with monovalent oral poliovaccine (mOPV) delivered at 6-week intervals in the order Sabin 1, Sabin 3, Sabin 2, from 1959 until 1992. During that period, 90 cases of vaccine-associated paralytic poliomyelitis (VAPP) were reported, 52 of which were associated with Sabin 3-related virus (76% of VAPP cases with virologic data). Because of renewed interest in type 3 mOPV (mOPV3), molecular methods were used to reanalyze 18 of the Sabin 3-related isolates from 15 VAPP patients, confirming the original identification. All isolates had the U472C 5'-untranslated region (5'-UTR) substitution associated with reversion to neurovirulence, and from zero to seven nucleotide substitutions in the virus protein 1 (VP1) region. No evidence was found for prolonged mOPV3 replication in the VAPP patients or for spread of Sabin 3-related viruses beyond close vaccinee contacts. The VAPP diseases were prevented by a single dose of inactivated poliovirus vaccine from 1992 to 2006 in Hungary, as proved by continuous surveillance of acute flaccid paralysis.

Oral Poliovirus Vaccine Evolution and Insights Relevant to Modeling the Risks of Circulating Vaccine‐Derived Polioviruses (cVDPVs)

“…Numerous studies show potential attenuating mutations for each serotype of OPV virus based on: (1) sequence comparisons between OPV virus strains and parental WPVs, (75,76) (2) sequence comparisons and/or neurovirulence testing in monkeys or mice of recombinant virus strains (i.e., swapping genetic segments between attenuated and neurovirulent strains) and/or site-directed mutants, (47,50,(77)(78)(79)(80)(81)(82)(83)(84) (3) OPV-related virus mutant strains after exposure to high temperature, (85) (4) OPV-related virus strains excreted by immunocompetent vaccine recipients without VAPP, (48,(86)(87)(88)(89) (5) OPV-related virus strains isolated from VAPP cases, (44)(45)(46)48,(90)(91)(92)(93)(94)(95)(96)(97)(98)(99) (6) strains isolated during cVDPV outbreaks, (15,57,100,101) (7) strains excreted by immunodeficient VDPV excretors, (102-106) (8) strains obtained during sequential passages after OPV administration in humans, (107) (9) strains obtained during sequential passages of OPV-related viruses in monkey tissues, (108) and (10) strains obtained from passages in cell culture. …”

Polio Vaccination: Past, Present and Future

“…The intent of this schedule was to acquire the advantages of both IPV and OPV while minimizing adverse reactions: initial immunization with IPV to promote humoral immunity, which gives children protection from VAPP, and subsequent OPV vaccination to induce higher levels of intestinal immunity and maintain population-level protection. In Hungary, a country with a significant problem with VAPP cases [34] a sequential schedule comprising one dose of IPV followed by OPV led to a complete disappearance of VAPP [35,36]. Another study in Hungary found that one or three doses of IPV followed by three doses of OPV resulted in individual protection against paralytic poliomyelitis as well as reduced cases of VAPP in the population [36,37].…”

Classical Live Viral Vaccines

“…Persistent infections occur particularly in immune deficient subjects. Most cases of VAPP result from infection with revertants at determinants associated with increased neurovirulence, particularly for polio 2 and 3 where attenuation is controlled by only 2 or 3 mutations, including the single 5 0 NCR mutations [60][61][62]. Recombination events (with oral polio vaccine strains and heterologous enteroviruses) are also implicated in VAPP.…”