Investigating the efficacy of monovalent and tetravalent dengue vaccine formulations against DENV-4 challenge in AG129 mice

Fuchs, Jeremy F.; Chu, Haiyan; O'Day, Peter M.; Pyles, Richard B.; Bourne, Nigel; Das, Subash C.; Milligan, Gregg N.; Barrett, Alan D.T.; Partidos, Charalambos D.; Osorio, Jorge E.

doi:10.1016/j.vaccine.2014.08.087

Cited by 27 publications

(23 citation statements)

References 32 publications

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“…Recently, this 703-4 model was used to evaluate a candidate live attenuated dengue vaccine. The tetravalent dengue vaccine reduced viraemia and protected mice against lethal 703-4 challenge (Fuchs et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Characterization of lethal dengue virus type 4 (DENV-4) TVP-376 infection in mice lacking both IFN-α/β and IFN-γ receptors (AG129) and comparison with the DENV-2 AG129 mouse model

Sarathy

Infante

et al. 2015

Journal of General Virology

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Dengue is a mosquito-borne disease caused by four related but distinct dengue viruses, DENV-1 to DENV-4. Dengue is endemic in most tropical countries, and over a third of the world's population is at risk of being infected. Although the global burden is high, no vaccine or antiviral is licensed to combat this disease. An obstacle complicating dengue research is the lack of animal challenge models that mimic human disease. Advances in immunocompromised murine infection models resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice, which are deficient in both the IFN-a/b receptor (IFN-a/bR) and the IFN-c receptor (IFN-cR). These models mimic features of dengue disease in humans. Here, we characterized lethal infection of AG129 mice by DENV-4 strain TVP-376 and found that AG129 mice developed clinical signs of illness and high viral loads in multiple tissues and succumbed 5 days after infection. Moreover, the splenic and hepatic histopathology of TVP-376-infected mice demonstrated the presence of cell activation and destruction of tissue architecture. Furthermore, infected mice had heightened levels of circulating cytokines. Comparison of the virulence phenotypes of DENV-4 strain TVP-376 and DENV-2 strain D2S10 revealed that TVP-376-induced mortality occurred in the absence of both IFN-a/bR and IFN-cR signalling, but not with intact signalling from the IFN-cR, whereas D2S10 required the absence of IFN-a/bR signalling only, indicating that it is more virulent than TVP-376. In conclusion, TVP-376 is lethal in AG129 mice, and this model provides a useful platform to investigate vaccine candidates and antivirals against DENV-4.

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Section: Introductionmentioning

confidence: 99%

Characterization of lethal dengue virus type 4 (DENV-4) TVP-376 infection in mice lacking both IFN-α/β and IFN-γ receptors (AG129) and comparison with the DENV-2 AG129 mouse model

Sarathy

Infante

et al. 2015

Journal of General Virology

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“…Lastly, the use of immunocompromised mice is a factor that affects the course of disease and evaluation of vaccines. Specifically, studies with live vaccines have shown that AG129 mice generate protective responses [88][89][90]. However, AG129 mice are lacking aspects of cellular immunity that appear to impact their ability to produce protection following immunization with a non-replicating vaccine [93].…”

Section: Discussionmentioning

confidence: 99%

“…TDV was recently tested against lethal challenge with the disseminated DENV-4 703–4 model in AG129 mice [89]. Mice immunized with a single dose of TDV, monovalent TDV-4 or monovalent TDV-2 survived lethal challenge, but all control mice succumbed to infection by day 8.…”

Section: Vaccine Testing In Dengue Mouse Modelsmentioning

confidence: 99%

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Mouse models of dengue virus infection for vaccine testing

Sarathy

Milligan

Bourne

et al. 2015

Vaccine

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Dengue is a mosquito-borne disease caused by four serologically and genetically related viruses termed DENV-1 to DENV-4. With an annual global burden of approximately 390 million infections occurring in the tropics and subtropics worldwide, an effective vaccine to combat dengue is urgently needed. Historically, a major impediment to dengue research has been development of a suitable small animal infection model that mimics the features of human illness in the absence of neurologic disease that was the hallmark of earlier mouse models. Recent advances in immunocompromised murine infection models have resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice that are deficient in both the Interferon-α/β receptor (IFN-α/β R) and the interferon-γ receptor (IFN-γR). These models mimic many hallmark features of dengue disease in humans, such as viremia, thrombocytopenia, vascular leakage, and cytokine storm. Importantly AG129 mice develop lethal, acute, disseminated infection with systemic viral loads, which is characteristic of typical dengue illness. Infected AG129 mice generate an antibody response to DENV, and antibody-dependent enhancement (ADE) models have been established by both passive and maternal transfer of DENV-immune sera. Several steps have been taken to refine DENV mouse models. Viruses generated by peripheral in vivo passages incur substitutions that provide a virulent phenotype using smaller inocula. Because IFN signaling has a major role in immunity to DENV, mice that generate a cellular immune response are desired, but striking the balance between susceptibility to DENV and intact immunity is complicated. Great strides have been made using single-deficient IFN-α/βR mice for DENV-2 infection, and conditional knockdowns may offer additional approaches to provide a panoramic view that includes viral virulence and host immunity. Ultimately, the DENV AG129 mouse models result in reproducible lethality and offer multiple disease parameters to evaluate protection by candidate vaccines.

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“…In a mouse model, neutralizing antibodies induced by TDV neutralized a number of contemporary DENV-4 isolates from different geographical locations and DENV-4 genotypes [45]. TDV vaccination provided partial protection against mortality and signs of morbidity following DENV-4 challenge in AG129 mice [45].…”

Section: Dengue-dengue Chimera (Tdv)mentioning

confidence: 99%