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. 2012 Feb 14;30(8):1513-20.
doi: 10.1016/j.vaccine.2011.11.072. Epub 2011 Dec 13.

Immunogenicity and efficacy of chimeric dengue vaccine (DENVax) formulations in interferon-deficient AG129 mice

Joseph N Brewoo  1 , Richard M Kinney, Tim D Powell, John J Arguello, Shawn J Silengo, Charalambos D Partidos, Claire Y-H Huang, Dan T Stinchcomb, Jorge E Osorio
Affiliations

Immunogenicity and efficacy of chimeric dengue vaccine (DENVax) formulations in interferon-deficient AG129 mice

Joseph N Brewoo et al. Vaccine. .

Abstract

Formulations of chimeric dengue vaccine (DENVax) viruses containing the pre-membrane (prM) and envelope (E) genes of serotypes 1-4 expressed in the context of the attenuated DENV-2 PDK-53 genome were tested for safety, immunogenicity and efficacy in interferon receptor knock-out mice (AG129). Monovalent formulations were safe and elicited robust neutralizing antibody responses to the homologous virus and only limited cross-reactivity to other serotypes. A single dose of monovalent DENVax-1, -2, or -3 vaccine provided eighty or greater percent protection against both wild-type (wt) DENV-1 (Mochizuki strain) and DENV-2 (New Guinea C strain) challenge viruses. A single dose of monovalent DENVax-4 also provided complete protection against wt DENV-1 challenge and significantly increased the survival times after challenge with wt DENV-2. In studies using tetravalent mixtures, DENVax ratios were identified that: (i) caused limited viremia, (ii) induced serotype-specific neutralizing antibodies to all four DENV serotypes with different hierarchies, and (iii) conferred full protection against clinical signs of disease following challenge with either wt DENV-1 or DENV-2 viruses. Overall, these data highlight the immunogenic profile of DENVax, a novel candidate tetravalent dengue vaccine and the advantage of sharing a common attenuated genomic backbone among the DENVax monovalent vaccines that confer protection against homologous or heterologous virus challenge.

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Figures

Fig. 1
Fig. 1
Protection afforded after vaccination with a single dose of monovalent DENVax. Groups of 10 AG129 mice were immunized SC with each of the monovalent DENVax vaccines. Additional control groups were injected by the same route only with FTA. On day 35 all animals were split into two groups of five animals per group and were challenged IP with 106 pfu of DENV-1 Mochizuki virus (A) or 106 pfu of mouse adapted DENV-2 New Guinea C virus (B). Animals were monitored daily for clinical signs of disease for five weeks and survival rates were recorded.
Fig. 2
Fig. 2
Viremia following vaccination with monovalent DENVax viruses. Groups of eight AG129 mice were immunized SC with DENVax Formulation 2 (A) or 3 (B). On day three post vaccination blood samples were collected and serum from each individual mouse was analyzed for viremia by immune focus assay with DENV serotype-specific MAbs.
Fig. 3
Fig. 3
Neutralizing antibody responses against all four DEN virus serotypes following immunization with DENVax Formulations 1, 2 and 3. Groups of eight AG129 mice were immunized SC with DENVax bearing different ratios of component vaccine viruses. Additional control groups were injected by the same route only with FTA. A booster SC injection of the same range of doses was given on day 42 post-priming. Blood samples were collected at 30 and 56 days post-primary vaccination and used to measure the neutralizing antibody response to the four DEN viruses by PRNT50. Bars represent geometric mean titer (GMT) ± SE. Geometric mean titer of neutralizing antibody responses elicited in control mice immunized with FTA were lower than 40 against all four DEN virus serotypes.
Fig. 4
Fig. 4
Protection afforded after vaccination with different DENVax formulations. Groups of eight AG129 mice were immunized subcutaneously with DENVax bearing different ratios of component vaccine viruses. Additional control groups were injected by the same route only with FTA. A booster SC injection of the same range of doses was given on day 42 post-priming. On day 70 all animals were split into two groups of four animals per group and were challenged intraperitoneally with 106 pfu of DENV-1 Mochizuki virus (A) or 106 pfu of mouse adapted DENV-2 New Guinea C virus (B). Animals were monitored daily for clinical signs of disease for three weeks and survival rates were recorded.
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