The sequential introduction into the Americas of chikungunya virus (CHIKV) in 2013 and Zika virus (ZIKV) in 2015 and their co-circulation with dengue virus (DENV) has resulted in an unprecedented public health challenge. The burden of disease caused by these arboviruses (ArboV) is worsened by long-term sequelae in chikungunya and Zika, and by the link between ZIKV infection and severe congenital defects. However, little is known about the clinical presentation of Zika or long-term sequelae in pediatric populations, nor about immune responses to ZIKV infection and possible reciprocal immune enhancement between the two flaviviruses, ZIKV and DENV. Reports of disease enhancement across flavivirus species have been comple- mented by recent reports of in vitro enhancement of ZIKV infection by anti-DENV Abs and vice versa, as both infections generate cross-reactive antibodies, especially in secondary (2) infections. Thus, there is an urgent need to determine whether immune enhancement occurs between DENV and ZIKV and vice versa and to document the clinical outcome. Another consequence of the ArboV co-circulation has been a basic diagnostic challenge. Conventional serological assays are unable to distinguish accurately between 2 DENV and ZIKV infections, impeding regional surveillance systems and studies. Hence, it is critical to develop new serological diagnostic tools that discriminate between anti-ZIKV and anti-DENV antibodies. The proposed study builds on >25 years of collaborative studies with the Nicaraguan Ministry of Health, strengthened by our current, successful IRIDA grant that was initially focused on repeat DENV infections, but expanded to include chikungunya and Zika via administrative supplements as these diseases swept into the region.
We aim to address specific and fundamental gaps by leveraging unique, existing research infrastructure and resources to continue two ongoing, complementary studies of pediatric arboviroses in Managua, Nicaragua. The long-running community-based cohort study follows ~3,500 children and allows early capture of Zika, chikungunya, and dengue cases and reconstruction of the immune history of the partici- pants. The hospital study enables the capture and folllow-up of more severe disease cases and has a broader catchment area.
In Aim 1, we will characterize the epidemiology of the 3 ArboV, describe the natural history of ZIKV and CHIKV infection including long-term follow-up, and analyze risk factors for clinical outcome of ArboV infections.
In Aim 2, we will develop and evaluate traditional and novel next-generation serological diagnostic tools to differentiate ZIKV and DENV infection.
In Aim 3, we will examine the effect of prior immunity to DENV/ ZIKV on infection/disease outcome and characterize the quality, breadth and magnitude of immune responses in sequential infections using innovative methods. This proposal addresses major gaps in the knowledge of the natural history and immunology of ZIKV, DENV, and CHIKV infections, and responds directly to a critical need to develop next-generation serological assays to distinguish ZIKV and DENV infections.!
The co-circulation of Zika (ZIKV), dengue (DENV) and chikungunya (CHIKV) arthropod-borne viruses in the tropical and subtropical regions of the Americas, including Nicaragua, has resulted in an unprecedented public health emergency. Our unique, existing infrastructure of complementary long-term prospective community- based cohort and hospital studies conducted in close collaboration with the Nicaraguan Ministry of Health combined with the results of our current, productive IRIDA grant will allow us to study novel and urgent questions regarding the current arboviral pandemics in the region. Critical issues to be addressed include studying epidemiological, clinical and immunological aspects of ZIKV, DENV, and CHIKV infections simultaneously in pediatric populations, evaluating new, next-generation serological diagnostic assays to differentiate ZIKV and DENV infections, and determining whether clinical or immunological enhancement occurs between DENV and ZIKV and vice versa.
|Premkumar, Lakshmanane; Collins, Matthew; Graham, Stephen et al. (2018) Development of Envelope Protein Antigens To Serologically Differentiate Zika Virus Infection from Dengue Virus Infection. J Clin Microbiol 56:|
|Balmaseda, Angel; Zambrana, José Victor; Collado, Damaris et al. (2018) Comparison of Four Serological Methods and Two Reverse Transcription-PCR Assays for Diagnosis and Surveillance of Zika Virus Infection. J Clin Microbiol 56:|
|Katzelnick, Leah C; Ben-Shachar, Rotem; Mercado, Juan Carlos et al. (2018) Dynamics and determinants of the force of infection of dengue virus from 1994 to 2015 in Managua, Nicaragua. Proc Natl Acad Sci U S A 115:10762-10767|
|Gordon, Aubree; Gresh, Lionel; Ojeda, Sergio et al. (2018) Differences in Transmission and Disease Severity Between 2 Successive Waves of Chikungunya. Clin Infect Dis 67:1760-1767|
|Mishra, Nischay; Caciula, Adrian; Price, Adam et al. (2018) Diagnosis of Zika Virus Infection by Peptide Array and Enzyme-Linked Immunosorbent Assay. MBio 9:|
|Thézé, Julien; Li, Tony; du Plessis, Louis et al. (2018) Genomic Epidemiology Reconstructs the Introduction and Spread of Zika Virus in Central America and Mexico. Cell Host Microbe 23:855-864.e7|
|Andrade, Paulina; Coloma, Josefina; Harris, Eva (2018) ELISPOT-Based ""Multi-Color FluoroSpot"" to Study Type-Specific and Cross-Reactive Responses in Memory B Cells after Dengue and Zika Virus Infections. Methods Mol Biol 1808:151-163|
|Zambrana, José Victor; Bustos Carrillo, Fausto; Burger-Calderon, Raquel et al. (2018) Seroprevalence, risk factor, and spatial analyses of Zika virus infection after the 2016 epidemic in Managua, Nicaragua. Proc Natl Acad Sci U S A 115:9294-9299|
|Tsai, Wen-Yang; Youn, Han Ha; Tyson, Jasmine et al. (2018) Use of Urea Wash ELISA to Distinguish Zika and Dengue Virus Infections. Emerg Infect Dis 24:1355-1359|
|Tan, Yi; Pickett, Brett E; Shrivastava, Susmita et al. (2018) Differing epidemiological dynamics of Chikungunya virus in the Americas during the 2014-2015 epidemic. PLoS Negl Trop Dis 12:e0006670|
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