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Attenuated dengue viruses are genetically more diverse than their respective wild-type parents.

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.

SUBMITTER: Bifani AM

PROVIDER: S-EPMC8138019 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Most live-attenuated tetravalent dengue virus vaccines in current clinical trials are produced from Vero cells. In a previous study we demonstrated that an infectious cDNA clone-derived dengue type 4 (DEN-4) virus retains higher genetic stability in MRC-5 cells than in Vero cells. For this study we investigated two DEN-4 viruses: the infectious cDNA clone-derived DEN-4 2A and its derived 3' NCR 30-nucleotide deletion mutant DEN-4 2A?30, a vaccine candidate. Mutations in the C-prM-E, NS2B-NS3, and NS4B-NS5 regions of the DEN genome were sequenced and compared following cell passages in Vero and MRC-5 cells. Our results indicate stronger genetic stability in both viruses following MRC-5 cell passages, leading to significantly lower RNA polymerase error rates when the DEN-4 virus is used for genome replication. Although no significant increases in virus titers were observed following cell passages, DEN-4 2A and DEN-4 2A?30 virus titers following Vero cell passages were 17-fold to 25-fold higher than titers following MRC-5 cell passages. Neurovirulence for DEN-4 2A and DEN-4 2A?30 viruses increased significantly following passages in Vero cells compared to passages in MRC-5 cells. In addition, more severe DEN-induced hemorrhaging in mice was noted following DEN-4 2A and DEN-4 2A?30 passages in Vero cells compared to passages in MRC-5 cells. Target mutagenesis performed on the DEN-4 2A infectious clone indicated that single point mutation of E-Q(438)H, E-V(463)L, NS2B-Q(78)H, and NS2B-A(113)T imperatively increased mouse hemorrhaging severity. The relationship between amino acid mutations acquired during Vero cell passage and enhanced DEN-induced hemorrhages in mice may be important for understanding DHF pathogenesis, as well as for the development of live-attenuated dengue vaccines. Taken together, the genetic stability, virus yield, and DEN-induced hemorrhaging all require further investigation in the context of live-attenuated DEN vaccine development.

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Attenuated dengue viruses are genetically more diverse than their respective wild-type parents.

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