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. 2003 Jan;77(2):1653-7.
doi: 10.1128/jvi.77.2.1653-1657.2003.

A live, attenuated dengue virus type 1 vaccine candidate with a 30-nucleotide deletion in the 3' untranslated region is highly attenuated and immunogenic in monkeys

Stephen S Whitehead  1 , Barry Falgout, Kathryn A Hanley, Joseph E Blaney Jr, Lewis Markoff, Brian R Murphy
Affiliations

A live, attenuated dengue virus type 1 vaccine candidate with a 30-nucleotide deletion in the 3' untranslated region is highly attenuated and immunogenic in monkeys

Stephen S Whitehead et al. J Virol. 2003 Jan.

Abstract

The Delta30 deletion mutation, which was originally created in dengue virus type 4 (DEN4) by the removal of nucleotides 172 to 143 from the 3' untranslated region (3' UTR), was introduced into a homologous region of wild-type (wt) dengue virus type 1 (DEN1). The resulting virus, rDEN1Delta30, was attenuated in rhesus monkeys to a level similar to that of the rDEN4Delta30 vaccine candidate. rDEN1Delta30 was more attenuated in rhesus monkeys than the previously described vaccine candidate, rDEN1mutF, which also contains mutations in the 3' UTR, and both vaccines were highly protective against challenge with wt DEN1. Both rDEN1Delta30 and rDEN1mutF were also attenuated in HuH-7-SCID mice. However, neither rDEN1Delta30 nor rDEN1mutF showed restricted replication following intrathoracic inoculation in the mosquito Toxorhynchites splendens. The ability of the Delta30 mutation to attenuate both DEN1 and DEN4 viruses suggests that a tetravalent DEN vaccine could be generated by introduction of the Delta30 mutation into wt DEN viruses belonging to each of the four serotypes.

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Figures

FIG. 1.
FIG. 1.
The Δ30 mutation removes 30 contiguous nucleotides from the 3′ UTR of DEN4. (A) Predicted secondary structure of the TL2 region of DEN1 and DEN4 (15). Nucleotides that are removed by the Δ30 mutation are boxed. (B) Nucleotide sequence alignment of the TL2 region of DEN4 and DEN1 and their Δ30 derivatives. Nucleotides of DEN4 are numbered starting at the 3′ terminus of the genome. Underlining indicates nucleotide pairing to form the predicted stem structure.
FIG. 2.
FIG. 2.
(A) Viremia in monkeys inoculated with DEN1 vaccine candidates. Groups of four rhesus monkeys were inoculated subcutaneously with 5.0 log10 PFU of the indicated virus in a 1-ml dose. Serum was collected daily, and virus titers were determined by plaque assays in Vero cells. Mean virus titers are shown for monkeys in each group. The lower level of virus detection was 0.7 log10 PFU/ml. (B) For comparison, viremia levels in monkeys inoculated previously with vaccine candidate rDEN4Δ30 (6) are shown. Groups of four monkeys were inoculated in a manner identical to that described above.
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