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-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.

近期暴发的寨卡病毒（Zika virus, ZIKV）疫情并发吉兰-巴雷综合征（Guillain-Barre syndrome, GBS）与出生缺陷，引发全球公共卫生关切。寨卡病毒结构与登革病毒（dengue viruses, DENV）高度相似，体外研究提示，既往感染登革病毒的个体在遭遇寨卡病毒感染时，可能发生抗体依赖增强（antibody dependent enhancement）效应，但该现象的临床意义迄今尚未明确。
本研究遵循PRISMA报告规范开展系统综述，检索了当前所有已发表的人类与非人类灵长类动物（non-human primate, NHP）相关数据，旨在明确与登革病毒未暴露宿主相比，既往登革病毒感染是否会增加寨卡病毒临床并发症风险，或提升体内寨卡病毒峰值病毒载量。
研究团队在MEDLINE、EMBASE及灰色文献中共检索到1146项研究，其中5项符合纳入标准。1项人类研究显示，既往登革病毒暴露并未增加寨卡病毒感染者发生吉兰-巴雷综合征的风险。另有2项人类研究表明，既往登革病毒暴露者的寨卡病毒血症水平小幅升高，但该差异无统计学意义，且与临床严重程度升高或不良妊娠结局无关联。
尽管人类研究数据无法开展荟萃分析，但对2项非人类灵长类动物研究的扩展数据进行合并分析后发现，与未暴露登革病毒的恒河猴相比，既往感染登革病毒的恒河猴寨卡病毒血症仅小幅升高0.39 log10 GE/mL，差异无统计学意义（p=0.22）。
采用定制化质量分级标准进一步分析显示，目前已发表的人类研究均未同时对急性寨卡病毒感染与既往登革病毒感染进行高质量检测。
综上，现有有限的人类与非人类灵长类动物研究数据表明，与登革病毒未暴露宿主相比，既往暴露于登革病毒者的寨卡病毒血症仅存在小幅且无统计学意义的升高；尚无证据显示哪怕是轻微的寨卡病毒血症升高会伴随寨卡病毒临床表型的改变。该问题对临床预后与疫苗研发具有重要意义，亟需更大样本量的研究与更精准的血清学检测方法以明确该科学问题。