Cross-Reactive T Cell Immunity to Dengue and Zika Viruses: New Insights Into Vaccine Development

Dengue virus (DENV) is a member of the Flavivirus family that includes Zika virus (ZIKV), West Nile virus, Japanese encephalitis virus, and yellow fever virus. As the most prevalent of the flaviviruses, DENV is responsible for tens of millions of infections each year. The clinical manifestations of infection with one of the four DENV serotypes (DENV1-4) range from no symptoms to hemorrhagic fever and shock ("severe dengue"), which is fatal in ~25,000 patients annually. Many factors contribute to the development of severe dengue, including the DENV serotype and host expression of certain HLA alleles; however, it now seems clear that pre-existing immunity to DENV-and possibly other flaviviruses-is a major precipitating factor. While primary infection with one DENV serotype elicits strong cellular and humoral immune responses that likely confer long-lived protection against the same serotype, subsequent infection with a different serotype carries an increased risk of developing severe dengue. Thus, primary DENV infection elicits cross-reactive immunity that may be protective or pathogenic, depending on the context of the subsequent infection. Many flaviviruses share high sequence homology, raising the possibility that cross-reactive immunity to one virus may contribute to protection against or pathogenesis of a second virus in a similar manner. In addition, several flaviviruses are now endemic in overlapping geographic regions, underscoring the need to gain more knowledge about the mechanisms underlying cross-reactive immunity to different DENV serotypes and flaviviruses. Here, we review our current understanding of T cell immunity to DENV, focusing on cross-reactivity with other serotypes and flaviviruses such as ZIKV, and the role of DENV-elicited CD4⁺ and CD8⁺ T cells in protection. Recent work in this area supports a beneficial role for cross-reactive T cells and provides new insights into the design of safe and efficient flavivirus/pan-flavivirus vaccines.