Next-generation T cell-activating vaccination increases influenza virus mutation prevalence

Area of Science:

• Virology and Immunology
• Vaccine Development
• Genomic Analysis

Background:

• Understanding viral adaptation to host immune responses is crucial for effective vaccine design.
• T cell-mediated immunity plays a significant role in controlling influenza virus infections.
• Evaluating novel vaccine strategies against influenza is an ongoing public health priority.

Purpose of the Study:

• To investigate viral genome adaptation in response to an experimental T cell-based influenza vaccine (Wyeth/IL-15/5Flu).
• To compare viral evolution under vaccination with an H5N1-based viral vectored vaccinia vaccine, seasonal inactivated influenza vaccine (IIV), and unvaccinated conditions.
• To determine the role of T cell responses in driving influenza virus diversification.

Main Methods:

• Next-generation sequencing (NGS) was employed for direct ex vivo analysis of the full influenza virus genome from infected mice.
• Comparative analysis of viral mutations was performed across different vaccination groups (Wyeth/IL-15/5Flu, IIV, unvaccinated).
• CD4+ and CD8+ T cell depletion experiments were conducted to assess the impact of T cell subsets on viral mutants.

Main Results:

• Wyeth/IL-15/5Flu vaccination correlated with increased mutation incidence and frequency across the influenza genome.
• Mutations were not enriched in T cell epitope regions; however, high-frequency mutations emerged in conserved hemagglutinin stem regions and PB2 mammalian adaptive sites.
• Depletion of CD4+ and CD8+ T cells significantly reduced mutant frequencies in vaccinated mice, highlighting T cell-driven diversification.

Conclusions:

• The Wyeth/IL-15/5Flu vaccine does not appear to generate T cell escape mutants.
• Vaccine-mediated T cell responses are key drivers of influenza virus diversification.
• The vaccine may enhance stochastic viral adaptation events through stringent bottleneck effects.