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

Abstract

The Sabin oral poliovirus vaccine (OPV) readily undergoes changes in antigenic sites upon replication in humans. Here, a set of antigenically altered descendants of the three OPV serotypes (76 isolates) was characterized to determine the driving forces behind these changes and their biological implications. The amino acid residues of OPV derivatives that lie within or close to the known antigenic sites exhibited a marked tendency to be replaced by residues characteristic of homotypic wild polioviruses, and these changes may occur very early in OPV evolution. The specific amino acid alterations nicely correlated with serotype-specific changes in the reactivity of certain individual antigenic sites, as revealed by the recently devised monoclonal antibody-based enzyme-linked immunosorbent assay. In comparison to the original vaccine, small changes, if any, in the neutralizing capacity of human or rabbit sera were observed in highly diverged vaccine polioviruses of three serotypes, in spite of strong alterations of certain epitopes. We propose that the common antigenic alterations in evolving OPV strains largely reflect attempts to eliminate fitness-decreasing mutations acquired either during the original selection of the vaccine or already present in the parental strains. Variability of individual epitopes does not appear to be primarily caused by, or lead to, a significant immune evasion, enhancing only slightly, if at all, the capacity of OPV derivatives to overcome immunity in human populations. This study reveals some important patterns of poliovirus evolution and has obvious implications for the rational design of live viral vaccines.

Shedding of Vaccine Viruses with Increased Antigenic and Genetic Divergence after Vaccination of Newborns with Monovalent Type 1 Oral Poliovirus Vaccine

“…The majority of these AD isolates appeared to be derived from the mOPV1 challenge dose provided at the age of 28 days. Replacement of lysine 60 in the VP3 capsid region, as described by previous studies, explains the AD character observed in this study (3,42). This residue is located in the loop of antigenic site III and is also involved in the interaction between the virus and the cellular receptor CD155 (2,22).…”

“…This residue is located in the loop of antigenic site III and is also involved in the interaction between the virus and the cellular receptor CD155 (2,22). This effect was compensated for in one strain by an additional mutation of Ala 59 to valine as shown previously (42).…”

“…Upon replication in the human intestinal tract, the sites of attenuation can mutate, which results in reversion of the Sabin strains toward a parental neurovirulent phenotype. Also as a consequence of replication in the host, antibodies are produced that recognize the antigenic sites of the Sabin strains (42). This immunogenic pressure could favor the selection of antigenically divergent (AD) viruses with substituted residues in parts of these antigenic sites.…”

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

“…Since the receptor-recognizing regions of the capsid proteins overlap the regions comprising immunodominant viral epitopes, acquisition of certain attenuating mutations was accompanied by vaccine-specific alterations in antigenic properties. Thus, the appearance of "non-Sabin-like" antigenic characteristics typical of most VDPV is believed to be due to two independent processes, immune pressure and loss of fitness-decreasing capsid mutations (27). However, the examples of PV2/Bel and PV2/Rus demonstrate that elimination of antigenicity-changing and fitness-decreasing capsid mutations is not an obligatory component of extended OPV evolution.…”

“…In polioviruses, the major epitopes are thought to involve predominantly amino acid residues 91 to 102 of VP1 (antigenic site 1 or AgS1), residues 221 to 226 of VP1, 164 to 170 and 270 of VP2 (AgS2), residues 58 to 60 and 71 to 73 of VP3 (AgS3), and residues 72 of VP2 and 76 of VP3 (AgS4) (16). Of these positions, only Ala-101 was changed to Thr in PV2/Rus, but mutation at this position was previously shown not to alter the Sabin-like enzyme-linked immunosorbent assay response (27).…”