Abstract
Human infections with viruses of the genus Flavivirus, including dengue virus (DENV) and Zika virus (ZIKV), are of increasing global importance. Owing to antibody-dependent enhancement (ADE), secondary infection with one Flavivirus following primary infection with another Flavivirus can result in a significantly larger peak viral load with a much higher risk of severe disease. Although several mathematical models have been developed to quantify the virus dynamics in the primary and secondary infections of DENV, little progress has been made regarding secondary infection of DENV after a primary infection of ZIKV, or DENV-ZIKV co-infection. Here, we address this critical gap by developing compartmental models of virus dynamics. We first fitted the models to published data on dengue viral loads of the primary and secondary infections with the observation that the primary infection reaches its peak much more gradually than the secondary infection. We then quantitatively show that ADE is the key factor determining a sharp increase/decrease of viral load near the peak time in the secondary infection. In comparison, our simulations of DENV and ZIKV co-infection (simultaneous rather than sequential) show that ADE has very limited influence on the peak DENV viral load. This indicates pre-existing immunity to ZIKV is the determinant of a high level of ADE effect. Our numerical simulations show that (i) in the absence of ADE effect, a subsequent co-infection is beneficial to the second virus; and (ii) if ADE is feasible, then a subsequent co-infection can induce greater damage to the host with a higher peak viral load and a much earlier peak time for the second virus, and for the second peak for the first virus.
Highlights
Dengue virus (DENV), transmitted by Aedes aegypti and Aedes albopictus mosquitoes, infects 50–100 million people yearly, including 500 000 dengue hemorrhagic fever (DHF) cases and 22 000 deaths [1,2]
We fit model (2.2) to the data of dengue viral load from Zika virus (ZIKV) convalescence macaque super-infected with DENV, estimate the cross-immune response related parameter values (κ, σsz, θd, Amin, Amax), the initial ZIKV-specific antibody (Az(0)), and their standard deviations, which are listed in table 1 as well
We developed and examined a within-host mathematical model of secondary DENV infection with a primary infection of ZIKV, and a within-host mathematical model describing the virus dynamics for the co-infection of DENV and ZIKV
Summary
Dengue virus (DENV), transmitted by Aedes aegypti and Aedes albopictus mosquitoes, infects 50–100 million people yearly, including 500 000 dengue hemorrhagic fever (DHF) cases and 22 000 deaths [1,2]. Several studies [7,8,9] have reported that prior ZIKV infection can induce significant low levels or no cross-neutralizing effect of secondary infection with any dengue serotype, suggesting that ZIKV lies outside the DENV serocomplex [8]. DENV-specific antibodies can bind ZIKV but are unable to neutralize the virus, and facilitate ZIKV infection with a high level of Zika viral loads in the host. This phenomenon is referred as antibodydependent enhancement (ADE) [10,11,12,13]. Driven by ADE, a secondary infection of dengue with a different serotype from the first infection is much more severe than the primary infection, and has been linked with the increase in DHF [18,19]
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