Abstract
Dengue poses a significant burden of individual health, health systems and the economy in dengue endemic regions. As such, dengue vaccine development has been an active area of research. Previous studies selected attenuated vaccine candidates based on plaque size. However, these candidates led to mixed safety outcome in clinical trials, suggesting it is insufficiently informative as an indicator of dengue virus (DENV) attenuation. In this study, we examined the genome diversity of wild-type DENVs and their attenuated derivatives developed by Mahidol University and tested in phase 1 clinical trials. We found that the attenuated DENVs, in particular the strain under clinical development by Takeda Vaccines, DENV2 PDK53, showed significantly higher genome diversity than its wild-type parent, DENV2 16681. The determinant of genomic diversity was intrinsic to the PDK53 genome as infectious clone of PDK53 showed greater genomic diversity after a single in vitro passage compared to 16681 infectious clone. Similar trends were observed with attenuated DENV1 and DENV4, both of which were shown to be attenuated clinically, but not DENV3 that was not adequately attenuated clinically. Taken together, evidence presented here suggests that genome diversity could be developed into a marker of DENV attenuation.
Highlights
Dengue is the most common mosquito-borne viral diseases globally
We first performed high throughput sequencing on wild-type DENV2 16681 and its attenuated derivative, PDK53
Significance was assessed by Mann–Whitney U test. c The percentage of single nucleotide variants (SNVs) with an allele frequency of ≤1, 1 < x < 10, or ≥10% in DENV2 16681 and PDK53. d The percentage of SNVs that locate to the 1st, 2nd, or
Summary
An estimated 100 million people around the world develop acute dengue annually, some of whom progress to lifethreatening severe dengue[1]. As the geographic footprints of both DENVs and their principal mosquito vector, Aedes aegypti expand from the tropics to the subtropics, the number of people living in at risk regions is set to increase to over 6.1 billion people by 20802. These trends underscore the urgency for an effective dengue vaccine to protect those living and traveling to at risk areas.
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