CD8+ T cells and humoral immunity may mitigate the effects of antibody-dependent enhancement: implications for dengue vaccine design

Dengue vaccine development is complicated by antibody-dependent enhancement (ADE)—a phenomenon in which antibodies paradoxically boost viral growth. Signals of immune-mediated enhancement were observed in the CYD-TDV (Dengvaxia) vaccine trials, but have not yet been reported for trials of TAK-003 (Qdenga). To better understand how prior immunity influences dengue infection outcomes, we developed a mechanistic within-host model of acute dengue infection dynamics that incorporates ADE as well as humoral and CD8+ T-cell immunity. Model simulations illustrate a potentially very important difference between enhancement by antibody, enhancement by humoral immunity, and enhanced severity of secondary infection. Model results also suggest that recipients of CYD-TDV may have been more likely to experience immune-mediated enhancement because of its yellow fever virus backbone and corresponding lack of dengue-specific CD8+ T-cell epitopes. The model provides a possible explanation for differences in reported outcomes of dengue vaccine trials and suggests incorporating DENV backbones from all four serotypes as a potentially promising way forward in the design of future dengue vaccines. IMPORTANCE Vaccines are typically designed to elicit humoral (antibody-mediated) immunity, and antibody titers are commonly used as correlates of protection. Because CD8+ T-cell responses are more challenging to measure, they are not typically used as correlates of protection and have received comparatively less attention. For viruses such as dengue, where antibodies may increase viral replication and thus the risk of severe disease through antibody-dependent enhancement, it is necessary to understand how humoral and cellular immunity interact during infection. Our model suggests that low antibody levels can enhance viral replication but that this effect can be mitigated by humoral and CD8+ T-cell immunity. This result offers a hypothesis to explain the observed differences in outcomes between the CYD-TDV and TAK-003 trials and suggests that evaluating CD8+ T-cell responses alongside antibody titers may be important for designing and assessing the safety and efficacy of future dengue vaccines.