Does prior dengue virus exposure worsen clinical outcomes of Zika virus infection? A systematic review, pooled analysis and lessons learned.

Zika virus (ZIKV) recently caused a pandemic complicated by Guillain-Barre syndrome (GBS) and birth defects. ZIKV is structurally similar to the dengue viruses (DENV) and in vitro studies suggest antibody dependent enhancement occurs in ZIKV infections preceded by DENV; however, the clinical significance of this remains unclear. We undertook a PRISMA-adherent systematic review of all current human and non-human primate (NHP) data to determine if prior infection with DENV, compared to DENV-naive hosts, is associated with a greater risk of ZIKV clinical complications or greater ZIKV peak viremia in vivo. We identified 1146 studies in MEDLINE, EMBASE and the grey literature, of which five studies were eligible. One human study indicated no increase in the risk of GBS in ZIKV infections with prior DENV exposure. Two additional human studies showed a small increase in ZIKV viremia in those with prior DENV exposure; however, this was not statistically significant nor was it associated with an increase in clinical severity or adverse pregnancy outcomes. While no meta-analysis was possible using human data, a pooled analysis of the two NHP studies leveraging extended data provided only weak evidence of a 0.39 log10 GE/mL rise in ZIKV viremia in DENV experienced rhesus macaques compared to those with no DENV exposure (p = 0.22). Using a customized quality grading criteria, we further show that no existing published human studies have offered high quality measurement of both acute ZIKV and antecedent DENV infections. In conclusion, limited human and NHP studies indicate a small and non-statistically significant increase in ZIKV viremia in DENV-experienced versus DENV-naive hosts; however, there is no evidence that even a possible small increase in ZIKV viremia would correlate with a change in ZIKV clinical phenotype. More data derived from larger sample sizes and improved sero-assays are needed to resolve this question, which has major relevance for clinical prognosis and vaccine design. Author summary Zika virus (ZIKV) is a mosquito borne virus that recently caused a large epidemic with some cases complicated by ascending paralysis (Guillain-Barre syndrome) and birth defects. One major concern is that such complications may be more common in those who have had previous infection with the closely related mosquito-borne dengue virus (DENV) which also circulates in the tropics. Here, we undertook a thorough, structured review of all human and high-order animal literature to synthesize the current evidence about whether ZIKV outcomes are worse in those with previous DENV exposure. We further undertook a pooled analysis across the two major non-human primate studies to improve statistical power. We summarize that, in humans and in non-human primates, prior DENV exposure may lead to a small increase in ZIKV viral load during infection. However, we do not show that any possible increase in ZIKV viral replication is associated with a higher rate of Zika complications or Zika clinical severity. We further graded the quality of these published literature and indicate that substantial improvements in the immunological measurement of ZIKV and DENV exposure in humans are needed to answer these and other pertinent questions about these two epidemic pathogens.