Generation of live attenuated influenza vaccine through selective autophagy

Manipulating viral protein stability and degradation is a promising strategy to conditionally regulate viral replication, thereby converting viruses into live whole-virion vaccines. Recently, we developed a live attenuated vaccine approach based on the autophagy-lysosomal degradation pathway. By incorporating an autophagosome-targeting motif (ATM) into the influenza A virus genome, we generated an autophagy-targeting (AUTOTAR) virus that is highly attenuated in conventional cells but retains efficient replication capacity in engineered production cells. Despite this attenuation, the AUTOTAR virus elicits strong humoral, mucosal, and cellular immune responses and confers complete protection against both homologous and heterologous viral challenges. These findings establish selective autophagy as a rational and tunable strategy for live vaccine design.