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

Abstract

For the final stages in the eradication of poliovirus type 1 (P1), the World Health Organization advocates the selective use of monovalent type 1 oral poliovirus vaccine (mOPV1). To compare the immunogenicity of mOPV1 with that of trivalent OPV (tOPV) in infants, a study was performed in Egypt in 2005. Newborns were vaccinated with mOPV1 or tOPV immediately after birth and were challenged with mOPV1 after 1 month. Vaccination with mOPV1 at birth resulted in significantly higher seroconversion against P1 viruses and lower excretion of P1 viruses than vaccination with tOPV. Intratypic differentiation of the viruses shed by the newborns revealed the presence of remarkably high numbers of antigenically divergent (AD) P1 isolates, especially in the mOPV1 study group. The majority of these AD P1 isolates (71%) were mOPV1 challenge derived and were shed by newborns who did not seroconvert to P1 after the birth dose. Genetic characterization of the viruses revealed that amino acid 60 of the VP3 region was mutated in all AD P1 isolates. Isolates with substitution of residue 99 of the VP1 region had significantly higher numbers of nonsynonymous mutations in the VP1 region than isolates without this substitution and were preferentially shed in the mOPV1 study group. The widespread use of mOPV1 has proven to be a powerful tool for fighting poliovirus circulation in the remaining areas of endemicity. This study provides another justification for the need to achieve high vaccination coverage in order to prevent the circulation of AD strains.

Sabin Vaccine Reversion in the Field: a Comprehensive Analysis of Sabin-Like Poliovirus Isolates in Nigeria

“…This study provides the first estimates of the whole-genome substitution rate of Sabin-like isolates from immunologically experienced individuals in a region of endemicity. It also confirms key results from the analysis of van der Sanden et al of vaccine reversion in newborns (14): that VP1 substitutions in Sabin-like poliovirus shed by primary vaccine recipients occur at rates faster than those observed in circulating wild-type isolates.…”

“…With the aid of a detailed intrahost model of poliovirus infection (27), we confirm that the VP1 substitutions accumulate at significantly higher rates in Sabin-like isolates than in circulating wild-type poliovirus and that the rates observed in this OPV-experienced population are consistent with the rates observed in newborns (14). We confirm that many key attenuating sites known to be responsible for the low neurovirulence and reduced replicative fitness of the vaccine strains revert in days to weeks during primary vaccine-induced infections.…”

“…To check the plausibility of our model-based estimates of the VP1 substitution rates, we compared our VP1 substitution rate for Sabin type 1 to the result reported in a recent longitudinal study of shedding after monovalent OPV type 1 challenge in vaccinated infants in Egypt (14). Both studies produced similar estimates for the expected number of substitutions over time, despite substantial differences in the study designs (Fig.…”

“…Most of these substitutions are synonymous (d n /d s ϭ 0.03, where d n is the rate of nonsynonymous substitutions and d s is the rate of synonymous substitutions) (8). However, previous studies have indicated that in Sabin strains, reversion of known attenuating sites can occur within the duration of a single infection and that VP1 substitutions accumulate more quickly than would be expected from the wild-type neutral substitution rate; multiple VP1 substitutions occur within the first month after administration of the vaccine dose (10)(11)(12)(13)(14)(15). In addition, most reported cVDPV isolates are recombinants with Sabin-derived capsid and enterovirus C (poliovirus and nonpoliovirus) noncapsid sequences, although the role of selection pressure in this process is not clear (1,2,11,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Multiple Independent Emergences of Type 2 Vaccine-Derived Polioviruses during a Large Outbreak in Northern Nigeria

“…Uncertainties in the estimates were greatest for the least divergent isolates, such as BOS06-02 and ANS07-01, for which the random nature of nucleotide substitution is evident by the strong localization of substitutions to the VP1 region (Table 1), leading to nearly 3-fold-higher substitution rate estimates for the VP1 region than for the P1/capsid region. Although early selection against the Sabin 2 allele at VP1 143 (and the possible effects of any hitchhiker substitutions) may violate our assumption of a constant rate of substitution into the P1/ capsid region (77,78), the primary source of uncertainty appears to derive from the stochastic nature of the clock.…”