Living in the post-Zika world: Impact of interactions between dengue and Zika viruses on diagnostics, antibody dynamics, and correlates of disease risk - SUMMARY
Worldwide, over 3 billion people are at risk of infection and disease caused by dengue virus 1-4 (DENV1-4) and
Zika virus (ZIKV), both potentially severe flaviviral diseases transmitted by Aedes mosquitoes. The devastating
effects of endemic dengue across the tropics and subtropics are well documented. The recent Zika pandemic
galvanized research as Zika swept across Latin America. Three years after the peak of the Zika pandemic, major
dengue epidemics have started to re-occur; however, the future of flaviviral disease across areas with
widespread ZIKV immunity is unknown. In this R01, we propose to develop new tools and address key
knowledge gaps in flaviviral transmission and immunological interactions between DENV and ZIKV to
understand how widespread ZIKV immunity impacts subsequent dengue disease and to inform
evaluation of dengue and Zika clinical vaccine trials and post-licensure studies. Based on our serological,
epidemiological, and clinical data to date, our overall hypothesis is that DENV1-4 and ZIKV are antigenically
closely related and that immune interactions mutually affect transmission and disease severity. We will address
this hypothesis with the ongoing Pediatric Dengue Cohort Study (PDCS, 2004-present), a community-based
prospective cohort study in Managua, Nicaragua, following ~4,000 children, now in its 17th year. Samples from
the PDCS, as well as companion studies in Managua, provide documented infection and disease data, as well
as banked serum samples for over a decade before the arrival of ZIKV. The proposed study extends the cohort,
ensuring that we are able to fully document the interactions of these viruses from the pre- to post-Zika eras. In
Aim 1, we will develop innovative serologic tools based on glycan-fusion-loop-masked envelope proteins and
new algorithms to distinguish DENV and ZIKV infection histories, critical for vaccination and epidemiological
studies of dengue and Zika. We will then test our hypothesis that pre-existing ZIKV immunity can enhance
disease severity caused by DENV3 but protect against DENV1. In Aim 2, we will measure changes in anti-DENV
and anti-ZIKV antibody-mediated immunity over time, estimate annual changes in protective and enhancing
population immunity to each virus, collect entomological data, and use modeling approaches to evaluate popula-
tion susceptibility to DENV and ZIKV infection and the potential for future epidemics by incorporating immunolo-
gical and entomological data. In Aim 3, we will identify determinants of protective and disease-enhancing anti-
body-mediated immunity of prior DENV infection on Zika and prior ZIKV infection on dengue disease and
severity. With support of expert collaborators, we will use state-of-the-art tools (e.g., new monoclonal antibodies,
innovative flavivirus antigens, and antibody Fc profiling) to analyze specific infection histories and uncover
potential immune correlates. Overall, this program will define new vaccine companion diagnostic assays, the
dynamics of the antibody response to DENV and ZIKV, and correlates of protection and pathogenesis for
dengue and Zika, which should be useful for the development and evaluation of dengue and Zika vaccines.
