Live attenuated influenza vaccine with low proportions of defective interfering particles elicits robust immunogenicity and cross-protection.

Summary

Reducing defective interfering particles in an H3N2 LAIV enhanced mucosal and humoral immunity, increased antigen-presenting and mucosal cell subsets, and conferred complete cross-protection against multiple influenza A strains in mice. These data suggest controlling DIPs may be a generalizable lever to improve the efficacy of LAIVs and related replicative RNA virus vaccines.

Key Findings

• Low-DIP H3N2 LAIV showed delayed yet improved upper respiratory tract replication in mice versus high-DIP LAIV.
• Enhanced mucosal (e.g., goblet and microfold cells) and innate/adaptive immune features (increased antigen presentation by dendritic cells).
• Stronger mucosal and humoral responses and cross-neutralization compared with commercial high-DIP LAIV.
• Complete protection against lethal H3N2, H1N1, and H1N1pdm09 challenges.

Clinical Implications

If validated in humans, LAIV production strategies that minimize DIPs could yield vaccines with stronger mucosal immunity and broader cross-strain protection, potentially improving seasonal effectiveness and pandemic preparedness.

Limitations

• Preclinical murine data; human immunogenicity, safety, and effectiveness remain untested.
• Operational measurement/control of DIP proportions at manufacturing scale and across strains needs validation.

Future Directions

Translate to human LAIV manufacturing with standardized DIP quantification, followed by phase 1–2 clinical trials assessing mucosal immunity, breadth, and effectiveness.