CD8+ T cells and Humoral Immunity Influence the Development of Antibody-Dependent Enhancement: Implications for Vaccine Design

Dengue virus (DENV) infection is a major and growing global health threat. The development of a safe and effective vaccine regardless of prior dengue immunity remains an unmet need. Virus-specific antibodies typically limit viral replication. In contrast, low-to-intermediate dengue-specific antibody titers can enhance viral replication and increase disease severity--a phenomenon known as antibody-dependent enhancement (ADE). ADE complicates dengue vaccine development; signals of ADE 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 both humoral immunity and CD8+ T cells. Model simulations predict that severe disease is most likely when dengue-specific antibody titers are intermediate and dengue-specific CD8+ T-cell immunity is low at the time of infection. In our simulations, increasing pre-infection levels of CD8+ T-cell immunity reduces disease severity in a dose-dependent manner and can mitigate ADE. Our results suggest a mechanistic interaction between antibody levels and CD8+ T-cell immunity that may influence whether enhanced viral replication leads to severe disease. The model provides a possible explanation for why ADE is frequently observed in infections of nonhuman primates following passive antibody transfer, yet is less common during secondary infections in humans with memory CD8+ T cells. These findings may help interpret differences in reported clinical outcomes of dengue vaccine trials and highlight the importance of considering CD8+ T-cell responses in the design of future dengue vaccines. ImportanceVaccines, including those against dengue viruses, are typically designed to elicit humoral (antibody-mediated) immunity, as antibody titers are commonly used as primary correlates of protection. Because CD8+ T-cell responses are not usually primary correlates and are more challenging to measure, they have received comparatively less attention. For viruses such as dengue, however, antibodies can exacerbate disease severity through antibody-dependent enhancement (ADE), underscoring the need to understand how humoral and cellular immunity interact. Here, we present a mechanistic model showing that severe dengue disease arises not only from low-to-intermediate antibody levels but also from insufficient CD8+ T-cell immunity at the time of infection. The model predicts that CD8+ T-cell responses can mitigate ADE-associated pathology and may help explain the differing levels of protection observed for CYD-TDV and TAK-003 vaccines. These findings suggest that evaluating CD8+ T-cell responses alongside antibody titers may be important for assessing vaccine safety and protection.