Evolution of the Sabin type 1 poliovirus in humans: characterization of strains isolated from patients with vaccine-associated paralytic poliomyelitis

Abstract

Attenuated strains of the Sabin oral poliovirus vaccine replicate in the human gut and in rare cases cause vaccine-associated paralytic poliomyelitis (VAPP). Reversion of vaccine strains toward a pathogenic phenotype is probably one of the main causes of VAPP, a disease most frequently associated with type 3 and type 2 strains and more rarely with the type 1 (Sabin 1) strain. To identify the determinants and mechanisms of safety versus pathogenicity of the Sabin 1 strain, we characterized the genetic and phenotypic changes in six Sabin 1-derived viruses isolated from immunocompetent patients with VAPP. The genomes of these strains carried either few or numerous mutations from the original Sabin 1 genome. As assessed in transgenic mice carrying the human poliovirus receptor (PVR-Tg mice), all but one strain had lost the attenuated phenotype. Four strains presented only a moderate neurovirulent phenotype, probably due at least in part to reversions to the wild-type genotype, which were detected in the 5 noncoding region of the genome. The reversions found in most strains at nucleotide position 480, are known to be associated with an increase in neurovirulence. The construction and characterization of Sabin 1 mutants implicated a reversion at position 189, found in one strain, in the phenotypic change. The presence of 71 mutations in one neurovirulent strain suggests that a vaccine-derived strain can survive for a long time in humans. Surprisingly, none of the strains analyzed were as neurovirulent to PVR-Tg mice as was the wild-type parent of Sabin 1 (Mahoney) or a previously identified neurovirulent Sabin 1 mutant selected at a high temperature in cultured cells. Thus, in the human gut, the Sabin 1 strain does not necessarily evolve toward the genetic characteristics and high neuropathogenicity of its wild-type parent.

Genomic Features of Intertypic Recombinant Sabin Poliovirus Strains Excreted by Primary Vaccinees

“…Only two type 1 VdRec have been reported in previous studies of strains isolated from patients with VAPP (11,15). However, the rarity of type 1 VdRec could not be clearly ascertained due to the small number of type 1 vaccine strains implicated in vaccine-associated disease (14,16,21). We analyzed 174 type 1 strains.…”

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. …”

“…These studies characterized mutations conferring attenuation of neurovirulence and/or increased temperature sensitivity, which correlates with attenuation, throughout the genome (e.g., nt 21 (5 -UTR), 189 (5 -UTR), 480 (5 -UTR), 935 (VP4-65), 2438 (VP3-225), 2795 (VP1-106), 2879 (VP1-134), 6203 (3D-73), 7441 (3 -UTR)) and identified the mutation at nt position 480 as one of the most critical, although the degree to which each potential attenuating mutation influences neurovirulence remains unclear. (77,81,82,97,111) Several studies show that some of the attenuating mutations of OPV1 revert in primary vaccine recipients over the period of excretion, although reversion at nt position 480, which can occur by direct reversion or by a compensating substitution at nt position 525, varies with respect to the proportion of primary vaccine recipients and time in different studies. (18,79,112) The virus strains isolated from type 1 VAPP cases also show the reversion of several attenuating mutations, most notably at nt position 480.…”

“…(18,79,112) The virus strains isolated from type 1 VAPP cases also show the reversion of several attenuating mutations, most notably at nt position 480. (48,51,86,88,89,91,(93)(94)(95)(96)(97) One study in transgenic mice with uncertain extrapolation to humans showed that the PD 50 values range from 4.5 to 5.8 for VAPP viruses, which suggests greater neurovirulence than OPV1 (PD 50 around 8.0) and lower neurovirulence than the lab-adapted WPV1 Mahoney strain (PD 50 around < 2.3). (91) Another study suggests relatively lower neurovirulence of OPV-related viruses from type 1 VAPP cases (PD 50 ranging from 5.7 to 7.5), and gives bounding values for OPV1 (≥7.7) and Mahoney (2.4).…”

Prevalence of vaccine-derived polioviruses in stools of immunodeficient children in South Africa

“…Isolates (P095-AJ699401, P140-AJ783775, P052-AJ783776, P020-AJ783777, P085-AJ783778, P069-AJ783779 and P114-AJ783780) had mutations at position 480 in the 5¢UTR, which involved a direct reversion of a G base (found in the vaccine strain) to an A base (found in the virulent strain). This mutation is the key mutation responsible for reversion of the attenuated Sabin PV type 1 to increased neurovirulence (Li et al 1996;Georgescu et al 1997;.…”