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

Abstract

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-naïve 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-naïve 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.

Significant control of Zika infection in macaques depends on the elapsing time after dengue exposure

“…Differences were also observed in B-cells and T-cells activation and cytokines and chemokines profile (24). Our previous results have been recently validated in a metanalysis using most of the NHP available data (32) and more relevant, in two studies presenting real settings of humans living in DENV-endemic areas (32-34). In this work, we aimed to establish the contribution of different DENV convalescent periods (3 months or early and 12 months or middle convalescent periods) on the immune response and disease course after ZIKV infection.…”

Health outcomes associated with Zika virus infection in humans: a systematic review of systematic reviews

“…After screening titles and abstracts, we selected 85 for full-text screening. Of these, 21 met our inclusion criteria 15–35. The main reasons for exclusion at the full-text stage were articles not being SRs (but rather overviews or literature reviews) and studies only reported symptoms but not outcomes.…”

“…The types of studies eligible for inclusion in the SRs varied across studies; four SR did not include any information on the included studies,21 24 28 30 all other SRs included observational studies (one limited to only cohort studies18) and the majority (71%; n=15) included case reports and case series. Three SRs considered evidence from modelling studies, animal experiments and in vitro experiments 15 33 35. Another did not limit to reports of primary data and included SRs, narrative reviews and news articles 20…”

“…Of the 21 included SRs, the most commonly reported outcome was microcephaly, reported in 14 SRs,15–26 30 32 12 SRs reported on GBS,15 16 19 20 22 23 25 27 29–31 33 11 SRs reported on malformations or congenital abnormalities,18–20 22 26 30–34 9 reported on brain,15 17 21 24–26 28 30 32 7 SRs reported on ocular disorders15 18 21 24 25 30 32 and 6 SRs on termination of pregnancy, fetal death and perinatal death 15 18–20 30 33. Three SRs or fewer reported on auditory disorder,15 26 34 cardiovascular damage,18 26 35 neurological complications,16 25 33 intrauterine growth restrictions,15 25 abnormal amniotic fluid,15 epilepsy21 and death due Zika infection 16…”

Does structurally-mature dengue virion matter in vaccine preparation in post-Dengvaxia era?

“…The emergence of Zika virus (ZIKV) in DENV-endemic regions has raised the critical question of how the pre-existing ZIKV immunity modulates the immune response to and clinical outcomes of subsequent DENV vaccination and vice versa. Studies in human, mouse or monkey demonstrated that pre-existing anti-DENV antibodies can either contribute to cross-protection or mediate ADE, depending on the quality and quantity of antibodies generated (see reviews [84][85][86][87] ). Few studies evaluating immune response of flavivirus vaccines in human or mice pre-exposed with JEV or DENV suggested no impact on the induction of virus-specific neutralizing antibody response; however, cross-reactive antibody response was observed.…”