Abstract: Zika virus (ZIKV) is a mosquito-transmitted positive-sense RNA virus in the family
Flaviviridae. Candidate live-attenuated vaccine (LAV) viruses with engineered deletions in the
3? untranslated region (UTR) provide immunity and protection in animal models of ZIKV infection,
and phenotypic studies show that LAVs retain protective abilities following in vitro passage. The
present study investigated the genetic diversity of wild-type (WT) parent ZIKV and its candidate
LAVs using next generation sequencing analysis of five sequential in vitro passages. The results show
that genomic entropy of WT ZIKV steadily increases during in vitro passage, whereas that of LAVs
also increased by passage number five but was variable throughout passaging. Additionally, clusters
of single nucleotide variants (SNVs) were found to be present in the pre-membrane/membrane (prM),
envelope (E), nonstructural protein NS1 (NS1), and other nonstructural protein genes, depending
on the specific deletion, whereas in the parent WT ZIKV, they are more abundant in prM and NS1.
Ultimately, both the parental WT and LAV derivatives increase in genetic diversity, with evidence of
adaptation following passage.
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