T Cell Responses Induced by Attenuated Flavivirus Vaccination Are Specific and Show Limited Cross-Reactivity with Other Flavivirus Species
Alba Grifoni, Hannah Voic, Sandeep Kumar Dhanda, Conner K. Kidd, James D. Brien, Søren Buus, Anette Stryhn, Anna P. Durbin, Stephen S. Whitehead, Sean A. Diehl, Aruna Dharshan De Silva, Ángel Balmaseda, Eva Harris, Daniela Weiskopf, Alessandro Sette
Abstract
The envelope (E) protein is the dominant target of neutralizing antibodies for dengue virus (DENV) and yellow fever virus (YFV). Accordingly, several DENV vaccine constructs use the E protein in a live attenuated vaccine format, utilizing a backbone derived from a heterologous flavivirus (such as YF) as a delivery vector. This backbone comprises the nonstructural (NS) and capsid (C) antigens, which are dominant targets of T cell responses. Here, we demonstrate that cross-reactivity at the level of T cell responses among different flaviviruses is very limited, despite high levels of sequence homology. Thus, the use of heterologous flavivirus species as a live attenuated vaccine vector is not likely to generate optimal T cell responses and might thus impair vaccine performance.