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Natural selection for rash-forming genotypes of the varicella-zoster vaccine virus detected within immunized human hosts.

ABSTRACT: The Oka vaccine strain is a live attenuated virus that is routinely administered to children in the United States and Europe to prevent chickenpox. It is effective and safe but occasionally produces a rash. The vaccine virus has accumulated mutations during its attenuation, but the rashes are not explained by their reversion, unlike complications reported for other viral vaccines. Indeed, most of the novel mutations distinguishing the Oka vaccine from the more virulent parental virus have not actually become fixed. Because the parental alleles are still present, the vaccine is polymorphic at >30 loci and therefore contains a mixture of related viruses. The inoculation of >40 million patients has consequently created a highly replicated evolutionary experiment that we have used to assess the competitive ability of these different viral genotypes in a human host. Using virus recovered from rash vesicles, we show that two vaccine mutations, causing amino acid substitutions in the major transactivating protein IE62, are outcompeted by the ancestral alleles. Standard interpretations of varicella disease severity concentrate on the undeniably important effects of host genotype and immune status, yet our results allow us to demonstrate that the viral genotype is associated with virulence and to identify the key sites. We propose that these loci have pleiotropic effects on the immunogenic properties of the virus, rash formation, and its epidemiological spread, which mould the evolution of its virulence. These findings are of practical importance for reducing the incidence of vaccine-associated rash and promoting public acceptance of the vaccine.

SUBMITTER: Quinlivan ML

PROVIDER: S-EPMC1765436 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

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Natural selection for rash-forming genotypes of the varicella-zoster vaccine virus detected within immunized human hosts.

Quinlivan Mark L ML Gershon Anne A AA Al Bassam Mahmoud M MM Steinberg Sharon P SP LaRussa Philip P Nichols Richard A RA Breuer Judith J

Proceedings of the National Academy of Sciences of the United States of America 20061220 1

The Oka vaccine strain is a live attenuated virus that is routinely administered to children in the United States and Europe to prevent chickenpox. It is effective and safe but occasionally produces a rash. The vaccine virus has accumulated mutations during its attenuation, but the rashes are not explained by their reversion, unlike complications reported for other viral vaccines. Indeed, most of the novel mutations distinguishing the Oka vaccine from the more virulent parental virus have not ac ...[more]

PMID: 17182747

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Project description:Varicella-zoster virus (VZV), a double-stranded DNA alphaherpesvirus, is associated with seasonal outbreaks of varicella in nonimmunized populations. Little is known about whether these outbreaks are associated with a single or multiple viral genotypes and whether new mutations rapidly accumulate during transmission. Here, we take advantage of a well-characterized population cohort in Guinea-Bissau and produce a unique set of 23 full-length genome sequences, collected over 7 months from eight households. Comparative sequence analysis reveals that four distinct genotypes cocirculated among the population, three of which were present during the first week of the outbreak, although no patients were coinfected, which indicates that exposure to infectious virus from multiple sources is common during VZV outbreaks. Transmission of VZV was associated with length polymorphisms in the R1 repeat region and the origin of DNA replication. In two cases, these were associated with the formation of distinct lineages and point to the possible coevolution of these loci, despite the lack of any known functional link in VZV or related herpesviruses. We show that these and all other sequenced clade 5 viruses possess a distinct R1 repeat motif that increases the acidity of an ORF11p protein domain and postulate that this has either arisen or been lost following divergence of the major clades. Thus, sequencing of whole VZV genomes collected during an outbreak has provided novel insights into VZV biology, transmission patterns, and (recent) natural history.VZV is a highly infectious virus and the causative agent of chickenpox and shingles, the latter being particularly associated with the risk of painful complications. Seasonal outbreaks of chickenpox are very common among young children, yet little is known about the dynamics of the virus during person-to-person to transmission or whether multiple distinct viruses seed and/or cocirculate during an outbreak. In this study, we have sequenced chickenpox viruses from an outbreak in Guinea-Bissau that are supported by detailed epidemiological data. Our data show that multiple different virus strains seeded and were maintained throughout the 6-month outbreak period and that viruses transmitted between individuals accumulated new mutations in specific genomic regions. Of particular interest is the potential coevolution of two distinct parts of the genomes and our calculations of the rate of viral mutation, both of which increase our understanding of how VZV evolves over short periods of time in human populations.

Dataset Information

Natural selection for rash-forming genotypes of the varicella-zoster vaccine virus detected within immunized human hosts.

Publications

Natural selection for rash-forming genotypes of the varicella-zoster vaccine virus detected within immunized human hosts.

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