Innate immune responsiveness predicts enhanced cellular immunity and symptomatic disease after controlled human...

Controlled human influenza infection studies can uniquely interrogate the early immune factors associated with clinical outcome. In this study, 27 healthy volunteers with low strain-specific serum neutralizing antibody levels were challenged with influenza A/H3N2 virus. Twenty-two became infected, with 18 developing mild-to-moderate symptoms and four remaining asymptomatic. Local and systemic immune profiling revealed innate pathways that engaged more rapidly and to a higher level in symptomatic participants. Earlier monocyte and dendritic cell activation correlated with higher symptom scores but also enhanced natural killer and CD8⁺ T cell activation thereafter. At baseline, peripheral blood mononuclear cells from symptomatic participants were more responsive to in vitro challenge, indicating a predisposition to divergent immunological outcomes at the time of virus exposure that was subsequently modulated by infection. These results show that human innate cell responsiveness is a predeterminant of both symptomatic disease and cellular immune responses known to promote viral clearance, suggesting potential targets for therapeutic intervention if decoupled.