Rational Design of a Live Attenuated Dengue Vaccine

2′-O-Methyltransferase Mutants Are Highly Attenuated and Immunogenic in Mice and Macaques

Roland Züst, Hongping Dong, Xiao Feng Li, David C. Chang, Bo Zhang, Thavamalar Balakrishnan, Ying Xiu Toh, Tao Jiang, Shi Hua Li, Yong Qiang Deng, Brett R. Ellis, Esther M. Ellis, Michael Poidinger, Francesca Zolezzi, Cheng Feng Qin, Pei-Yong Shi, Katja Fink

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Dengue virus is transmitted by Aedes mosquitoes and infects at least 100 million people every year. Progressive urbanization in Asia and South-Central America and the geographic expansion of Aedes mosquito habitats have accelerated the global spread of dengue, resulting in a continuously increasing number of cases. A cost-effective, safe vaccine conferring protection with ideally a single injection could stop dengue transmission. Current vaccine candidates require several booster injections or do not provide protection against all four serotypes. Here we demonstrate that dengue virus mutants lacking 2′-O-methyltransferase activity are highly sensitive to type I IFN inhibition. The mutant viruses are attenuated in mice and rhesus monkeys and elicit a strong adaptive immune response. Monkeys immunized with a single dose of 2′-O-methyltransferase mutant virus showed 100% sero-conversion even when a dose as low as 1,000 plaque forming units was administrated. Animals were fully protected against a homologous challenge. Furthermore, mosquitoes feeding on blood containing the mutant virus were not infected, whereas those feeding on blood containing wild-type virus were infected and thus able to transmit it. These results show the potential of 2′-O-methyltransferase mutant virus as a safe, rationally designed dengue vaccine that restrains itself due to the increased susceptibility to the host's innate immune response.

Original languageEnglish (US)
Article numbere1003521
JournalPLoS Pathogens
Volume9
Issue number8
DOIs
StatePublished - Aug 2013
Externally publishedYes

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Dengue Vaccines
Attenuated Vaccines
Macaca
Viruses
Culicidae
Dengue Virus
Dengue
Aedes
Vaccines
Central America
Injections
Urbanization
South America
Adaptive Immunity
Macaca mulatta
Innate Immunity
Haplorhini
Ecosystem
methylcobalamin-coenzyme M methyltransferase
Costs and Cost Analysis

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

Rational Design of a Live Attenuated Dengue Vaccine : 2′-O-Methyltransferase Mutants Are Highly Attenuated and Immunogenic in Mice and Macaques. / Züst, Roland; Dong, Hongping; Li, Xiao Feng; Chang, David C.; Zhang, Bo; Balakrishnan, Thavamalar; Toh, Ying Xiu; Jiang, Tao; Li, Shi Hua; Deng, Yong Qiang; Ellis, Brett R.; Ellis, Esther M.; Poidinger, Michael; Zolezzi, Francesca; Qin, Cheng Feng; Shi, Pei-Yong; Fink, Katja.

In: PLoS Pathogens, Vol. 9, No. 8, e1003521, 08.2013.

Research output: Contribution to journalArticle

Züst, R, Dong, H, Li, XF, Chang, DC, Zhang, B, Balakrishnan, T, Toh, YX, Jiang, T, Li, SH, Deng, YQ, Ellis, BR, Ellis, EM, Poidinger, M, Zolezzi, F, Qin, CF, Shi, P-Y & Fink, K 2013, 'Rational Design of a Live Attenuated Dengue Vaccine: 2′-O-Methyltransferase Mutants Are Highly Attenuated and Immunogenic in Mice and Macaques', PLoS Pathogens, vol. 9, no. 8, e1003521. https://doi.org/10.1371/journal.ppat.1003521
Züst, Roland ; Dong, Hongping ; Li, Xiao Feng ; Chang, David C. ; Zhang, Bo ; Balakrishnan, Thavamalar ; Toh, Ying Xiu ; Jiang, Tao ; Li, Shi Hua ; Deng, Yong Qiang ; Ellis, Brett R. ; Ellis, Esther M. ; Poidinger, Michael ; Zolezzi, Francesca ; Qin, Cheng Feng ; Shi, Pei-Yong ; Fink, Katja. / Rational Design of a Live Attenuated Dengue Vaccine : 2′-O-Methyltransferase Mutants Are Highly Attenuated and Immunogenic in Mice and Macaques. In: PLoS Pathogens. 2013 ; Vol. 9, No. 8.
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