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Molecular determinants of plaque size as an indicator of dengue virus attenuation.

Publication ,  Journal Article
Goh, KCM; Tang, CK; Norton, DC; Gan, ES; Tan, HC; Sun, B; Syenina, A; Yousuf, A; Ong, XM; Kamaraj, US; Cheung, YB; Gubler, DJ; Davidson, A ...
Published in: Sci Rep
May 17, 2016

The development of live viral vaccines relies on empirically derived phenotypic criteria, especially small plaque sizes, to indicate attenuation. However, while some candidate vaccines successfully translated into licensed applications, others have failed safety trials, placing vaccine development on a hit-or-miss trajectory. We examined the determinants of small plaque phenotype in two dengue virus (DENV) vaccine candidates, DENV-3 PGMK30FRhL3, which produced acute febrile illness in vaccine recipients, and DENV-2 PDK53, which has a good clinical safety profile. The reasons behind the failure of PGMK30FRhL3 during phase 1 clinical trial, despite meeting the empirically derived criteria of attenuation, have never been systematically investigated. Using in vitro, in vivo and functional genomics approaches, we examined infections by the vaccine and wild-type DENVs, in order to ascertain the different determinants of plaque size. We show that PGMK30FRhL3 produces small plaques on BHK-21 cells due to its slow in vitro growth rate. In contrast, PDK53 replicates rapidly, but is unable to evade antiviral responses that constrain its spread hence also giving rise to small plaques. Therefore, at least two different molecular mechanisms govern the plaque phenotype; determining which mechanism operates to constrain plaque size may be more informative on the safety of live-attenuated vaccines.

Duke Scholars

Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

May 17, 2016

Volume

6

Start / End Page

26100

Location

England

Related Subject Headings

  • Virulence
  • Viral Plaque Assay
  • Vaccines, Attenuated
  • Humans
  • Host-Pathogen Interactions
  • Dengue Virus
  • Dengue Vaccines
  • Cricetinae
  • Cell Line
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Goh, K. C. M., Tang, C. K., Norton, D. C., Gan, E. S., Tan, H. C., Sun, B., … Ooi, E. E. (2016). Molecular determinants of plaque size as an indicator of dengue virus attenuation. Sci Rep, 6, 26100. https://doi.org/10.1038/srep26100
Goh, Kenneth Choon Meng, Choon Kit Tang, Diana Catherine Norton, Esther Shuyi Gan, Hwee Cheng Tan, Bo Sun, Ayesa Syenina, et al. “Molecular determinants of plaque size as an indicator of dengue virus attenuation.Sci Rep 6 (May 17, 2016): 26100. https://doi.org/10.1038/srep26100.
Goh KCM, Tang CK, Norton DC, Gan ES, Tan HC, Sun B, et al. Molecular determinants of plaque size as an indicator of dengue virus attenuation. Sci Rep. 2016 May 17;6:26100.
Goh, Kenneth Choon Meng, et al. “Molecular determinants of plaque size as an indicator of dengue virus attenuation.Sci Rep, vol. 6, May 2016, p. 26100. Pubmed, doi:10.1038/srep26100.
Goh KCM, Tang CK, Norton DC, Gan ES, Tan HC, Sun B, Syenina A, Yousuf A, Ong XM, Kamaraj US, Cheung YB, Gubler DJ, Davidson A, St John AL, Sessions OM, Ooi EE. Molecular determinants of plaque size as an indicator of dengue virus attenuation. Sci Rep. 2016 May 17;6:26100.

Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

May 17, 2016

Volume

6

Start / End Page

26100

Location

England

Related Subject Headings

  • Virulence
  • Viral Plaque Assay
  • Vaccines, Attenuated
  • Humans
  • Host-Pathogen Interactions
  • Dengue Virus
  • Dengue Vaccines
  • Cricetinae
  • Cell Line
  • Animals