Intratypic Recombination among Lineages of Type 1 Vaccine-Derived Poliovirus Emerging during Chronic Infection of an Immunodeficient Patient

Abstract

We determined the complete genomic sequences of nine type 1 immunodeficient vaccine-derived poliovirus (iVDPV) isolates obtained over a 337-day period from a poliomyelitis patient from Taiwan with common variable immunodeficiency. The iVDPV isolates differed from the Sabin type 1 oral poliovirus vaccine (OPV) strain at 1.84% to 3.15% of total open reading frame positions and had diverged into at least five distinct lineages. Phylogenetic analysis suggested that the chronic infection was initiated by the fifth and last OPV dose, given 567 days before onset of paralysis, and that divergence of major lineages began very early in the chronic infection. Key determinants of attenuation in Sabin 1 had reverted in the iVDPV isolates, and representative isolates of each lineage showed increased neurovirulence for PVR-Tg21 transgenic mice. None of the isolates had retained the temperature-sensitive phenotype of Sabin 1. All isolates were antigenic variants of Sabin 1, having multiple amino acid substitutions within or near neutralizing antigenic sites 1, 2, and 3a. Antigenic divergence of the iVDPV variants from Sabin 1 followed two major independent evolutionary pathways. The emergence of distinct coreplicating lineages suggests that iVDPVs can replicate for many months at separate sites in the gastrointestinal tract. Some isolates had mosaic genome structures indicative of recombination across and within lineages. iVDPV excretion apparently ceased after 30 to 35 months of chronic infection. The appearance of a chronic VDPV excretor in a tropical, developing country has important implications for the strategy to stop OPV immunization after eradication of wild polioviruses.The central strategy of the World Health Organization Global Polio Eradication Initiative is widespread use of oral poliovirus vaccine (OPV) at high rates of coverage. This strategy has reduced the global incidence of polio by over 99% since the start of the Initiative in 1988 and restricted wild poliovirus circulation to countries in western and central Africa and southern Asia (87). However, use of OPV is associated with some rare adverse events, including the appearance of cases of vaccine-associated paralytic poliomyelitis among OPV recipients and contacts (76), and the occurrence of polio outbreaks associated with circulating vaccine-derived poliovirus (cVDPV) (36). While cVDPV outbreaks can be prevented by maintenance of high rates of OPV coverage, the occurrence of vaccine-associated paralytic poliomyelitis is associated with the inherent genetic instability of the live, attenuated OPV strains (56).In immunocompetent individuals, the risk of vaccine-associated paralytic poliomyelitis is very low, estimated in the United States at 1 case per 2.4 million OPV doses distributed (75,76).

Antigenic Evolution of Vaccine-Derived Polioviruses: Changes in Individual Epitopes and Relative Stability of the Overall Immunological Properties

“…A high degree of nucleotide sequence divergence of some vaccine-derived (VDPV) poliovirus strains isolated from paralytic cases as well as from healthy individuals and environments (5,7,10,11,27,29,37,38,55,58,59,69,71) suggests that they might have circulated in communities for years. The solid body of evidence accumulated recently clearly demonstrates that the transformation of vaccine poliovirus into virulent strains is not an exception but, rather, a consistent pattern of their natural evolution.…”

Molecular Analysis of Enteroviruses

“…Nucleotide substitutions accumulate at an overall rate of approximately 1% per year at all sites, and at approximately 3% per year at synonymous sites, calculated primarily on the VP1 region or P1/ capsid region [106,120,121]. Evolution rates appear to be similar across serotypes and between wild-type and vaccine-derived PVs [56,106].…”

“…In contrast, interserotypic recombinants excreted by recent vaccinees exposed to tOPV and recombinants among circulating wild-type PVs and vaccinederived PVs usually have crossovers restricted to the noncapsid region [142]. PVs recombine actively with each other and with other closely related EV-C members, a process which might offset the effects of accumulation of deleterious mutations arising in some lineages [46,121,142,143]. In fact, the recombination between PVs and other EV-C viruses is a normal feature of PV evolution in nature.…”

Evolution of the Sabin Vaccine into Pathogenic Derivatives without Appreciable Changes in Antigenic Properties: Need for Improvement of Current Poliovirus Surveillance

“…1), a feature which appears to be not infrequent among VDPV and which poses problems for precise evaluation of the viral "age." In some cases, such unevenness could be explained by intratypic recombination (8,28). This explanation seems to be especially realistic for PV2/Rus, whose history involved multiple recombination events apparently occurring between partners of different "ages."…”