Vertically transmitted chikungunya, Zika and dengue virus infections: The pathogenesis from mother to fetus and the implications of co-infections and vaccine development.

Chikungunya (CHIKV), Zika (ZIKV), and Dengue viruses (DENV) exhibit similar epidemiological and clinical patterns but have different pathophysiological mechanisms of disease manifestations. Differences occur in the severity of clinical presentations with the highest mortality in the general population attributed to DENV and neurological morbidity due to ZIKV. ZIKV and DENV infections can cause fetal loss with ZIKV exhibiting teratogenesis. CHIKV is associated with severe complications in the newborn. Co-circulation of the three viruses and the cross-reactive immune response between ZIKV and DENV viruses has implications for an attenuated clinical response and future vaccine development. Co-infections could increase due to the epidemiologic synergy, but there is limited evidence about the clinical effects, especially for the vulnerable newborn. The purpose of this paper is to review the pathophysiological basis for vertically transmission manifestations due to CHIKV, DENV, and ZIKV, to determine the potential effects of co-circulation on newborn outcomes and the potential for vaccine protection. Inflammatory cytokines are responsible for placental breaches in DENV and ZIKV; Hofbauer cells facilitate the transfer of ZIKV from the placenta to the fetal brain, and high viral loads and mechanical placental disruption facilitate the transmission of CHIKV. Co-infection of these viruses can present with severe manifestations, but the clinical and serologic evidence suggests that one virus predominates which may influence fetal transmission. All three viruses are in different stages of vaccine development with DENV vaccine being fully licensed. Antibody-enhanced infections in seronegative vaccinated candidates who develop natural infection to dengue limit its use and have implications for ZIKV vaccine development. Targeting transmission capacity in the vector could prevent transmission to all three viruses, and breast milk immunity could provide further clues for vaccine development.