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Rates of vaccine evolution show strong effects of latency: implications for varicella zoster virus epidemiology.

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Weinert, Lucy A 
Depledge, Daniel P 
Kundu, Samit 
Gershon, Anne A 
Nichols, Richard A 


Varicella-zoster virus (VZV) causes chickenpox and shingles, and is found in human populations worldwide. The lack of temporal signal in the diversity of VZV makes substitution rate estimates unreliable, which is a barrier to understanding the context of its global spread. Here, we estimate rates of evolution by studying live attenuated vaccines, which evolved in 22 vaccinated patients for known periods of time, sometimes, but not always undergoing latency. We show that the attenuated virus evolves rapidly (∼ 10(-6) substitutions/site/day), but that rates decrease dramatically when the virus undergoes latency. These data are best explained by a model in which viral populations evolve for around 13 days before becoming latent, but then undergo no replication during latency. This implies that rates of viral evolution will depend strongly on transmission patterns. Nevertheless, we show that implausibly long latency periods are required to date the most recent common ancestor of extant VZV to an "out-of-Africa" migration with humans, as has been previously suggested.



molecular dating, whole-genome sequencing, within-patient evolution, Base Sequence, Chickenpox, Chickenpox Vaccine, Child, Evolution, Molecular, Herpes Zoster, Herpesvirus 3, Human, Humans, Molecular Sequence Data, Vaccines, Attenuated, Virus Latency

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Mol Biol Evol

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Oxford University Press (OUP)
The authors thank Tony Brooks (UCL Genomics) for Illumina sequencing, and reviewers and the editor for constructive comments that improved the manuscript. The authors acknowledge the infrastructure support provided the Medical Research Council Centre for Molecular Medical Virology (grant number G0900950), the National Institute for Health Research UCL/UCLH Biomedical Research Centre and the use of the UCL Legion High Performance Computing Facility, and associated support services, in the completion of this work. The work was supported by a Medical Research Council grant (grant number G0700814). L.W. and F.B. were supported by European Research Council Grant (grant number 260801-BIG_IDEA). D.D. was supported an Medical Research Council Centre Grant (grant number G0900950) and S.K. by the National Institute for Health Research UCL/UCLH Biomedical Research centre, from which J.B. also receives funding. Newly reported sequences have GenBank IDs KF853225–33. L.W., R.N., F.B., J.W., and J.B. conceived the study; D.D. and S.K. produced the data; L.W., D.D., and J.W. analyzed the data; A.G. contributed samples; L.W., D.D., R.N., F.B., J.W., and J.B. wrote the paper