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Vaccination of volunteers with low-dose, live-attenuated, dengue viruses leads to serotype-specific immunologic and virologic profiles.

ABSTRACT: There are currently no vaccines or therapeutics to prevent dengue disease which ranges in severity from asymptomatic infections to life-threatening illness. The National Institute of Allergy and Infectious Diseases (NIAID) Division of Intramural Research has developed live, attenuated vaccines to each of the four dengue serotypes (DENV-1-DENV-4). Two doses (10PFU and 1000PFU) of three monovalent vaccines were tested in human clinical trials to compare safety and immunogenicity profiles. DEN4?30 had been tested previously at multiple doses. The three dengue vaccine candidates tested (DEN1?30, DEN2/4?30, and DEN3?30/31) were very infectious, each with a human infectious dose 50%? 10PFU. Further, infectivity rates ranged from 90 to 100% regardless of dose, excepting DEN2/4?30 which dropped from 100% at the 1000PFU dose to 60% at the 10PFU dose. Mean geometric peak antibody titers did not differ significantly between doses for DEN1?30 (92 ± 19 vs. 214 ± 97, p=0.08); however, significant differences were observed between the 10PFU and 1000PFU doses for DEN2/4?30, 19 ± 9 vs. 102 ± 25 (p=0.001), and DEN3?30/31, 119 ± 135 vs. 50 ± 50 (p=0.046). No differences in the incidences of rash, neutropenia, or viremia were observed between doses for any vaccines, though the mean peak titer of viremia for DEN1?30 was higher at the 1000PFU dose (0.5 ± 0 vs. 1.1 ± 0.1, p=0.007). These data demonstrate that a target dose of 1000PFU for inclusion of each dengue serotype into a tetravalent vaccine is likely to be safe and generate a balanced immune response for all serotypes.

SUBMITTER: Lindow JC

PROVIDER: S-EPMC3777849 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Vaccination of volunteers with low-dose, live-attenuated, dengue viruses leads to serotype-specific immunologic and virologic profiles.

Lindow Janet C JC Durbin Anna P AP Whitehead Stephen S SS Pierce Kristen K KK Carmolli Marya P MP Kirkpatrick Beth D BD

Vaccine 20130602 33

There are currently no vaccines or therapeutics to prevent dengue disease which ranges in severity from asymptomatic infections to life-threatening illness. The National Institute of Allergy and Infectious Diseases (NIAID) Division of Intramural Research has developed live, attenuated vaccines to each of the four dengue serotypes (DENV-1-DENV-4). Two doses (10PFU and 1000PFU) of three monovalent vaccines were tested in human clinical trials to compare safety and immunogenicity profiles. DEN4Δ30 ...[more]

PMID: 23735680

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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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Dataset Information

Vaccination of volunteers with low-dose, live-attenuated, dengue viruses leads to serotype-specific immunologic and virologic profiles.

Publications

Vaccination of volunteers with low-dose, live-attenuated, dengue viruses leads to serotype-specific immunologic and virologic profiles.

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