A CXCL10-Expressing Influenza Vector Induces Robust Adaptive Immunity Despite Strong Attenuation

Area of Science:

• Virology
• Immunology
• Vaccine Development

Background:

• Influenza A viruses with truncated NS1 proteins are attenuated but may still antagonize innate immunity.
• Strategies incorporating cytokines like IL-2 have improved influenza vector immunogenicity.
• Further enhancement of these vectors is needed for optimal immune responses and protection.

Purpose of the Study:

• To engineer an NS1-truncated influenza virus expressing the chemokine CXCL10.
• To evaluate the safety, replication, immunogenicity, and protective efficacy of the CXCL10-expressing vector.

Main Methods:

• Engineered a PR8-based influenza virus (PR8/NS124) to express CXCL10 from the NS segment.
• Compared the recombinant virus (NS124_SS_CXCL10) with the parental vector in cell culture and mouse models.
• Assessed viral replication, innate immune responses, T-cell activation, and protection against influenza challenge.

Main Results:

• CXCL10 expression severely reduced viral replication in mouse lungs, creating a near-non-replicating phenotype.
• The CXCL10-expressing vector showed an attenuated phenotype, without weight loss, and altered innate immune signaling.
• Both intranasal and intraperitoneal immunization induced comparable or enhanced antigen-specific T-cell responses, including effector-memory cells.
• The CXCL10 vector demonstrated protective efficacy against heterologous H3N2 challenge, similar to the parental vector, with an improved safety profile.

Conclusions:

• Incorporating CXCL10 into NS1-truncated influenza vectors improves safety and T-cell immunogenicity.
• CXCL10 enhances the protective efficacy and safety profile of influenza vectors.
• This strategy holds promise for developing safer and more effective influenza vaccines.