Enhanced dengue vaccine virus replication and neutralizing antibody responses in immune primed rhesus macaques

McCracken, Michael K.; Kuklis, Caitlin H.; Kannadka, Chandrika B.; Barvir, David A.; Sanborn, Mark A.; Waickman, Adam T.; Siegfried, Hayden C.; Victor, Kaitlin A.; Hatch, Kristin L.; De La Barrera, Rafael; Walls, Shannon D.; Rutvisuttinunt, Wiriya; Currier, Jeffrey R.; Friberg, Heather; Jarman, Richard G.; Gromowski, Gregory D.

Antibody-dependent enhancement (ADE) is suspected to influence dengue virus (DENV) infection, but the role ADE plays in vaccination strategies incorporating live attenuated virus components is less clear. Using a heterologous prime-boost strategy in rhesus macaques, we examine the effect of priming with DENV purified inactivated vaccines (PIVs) on a tetravalent live attenuated vaccine (LAV). Sera exhibited low-level neutralizing antibodies (NAb) post PIV priming, yet moderate to high in vitro ADE activity. Following LAV administration, the PIV primed groups exhibited DENV-2 LAV peak viremias up to 1,176-fold higher than the mock primed group, and peak viremia correlated with in vitro ADE. Furthermore, PIV primed groups had more balanced and higher DENV-1–4 NAb seroconversion and titers than the mock primed group following LAV administration. These results have implications for the development of effective DENV vaccine prime-boost strategies and for our understanding of the role played by ADE in modulating DENV replication.