Evaluating the Breadth and Reliability of Influenza Vaccine Protection Indicators: A Secondary Analysis of an Animal...

Hemagglutination inhibition (HAI) titers are key correlates of influenza vaccine protection, yet a systematic comparison of HAI-based immunogenicity indicators is lacking for guiding vaccine development. This study aimed to compare these indicators by evaluating their correlation with influenza disease outcomes.

We performed a secondary analysis of a mouse challenge study, in which 14 groups of mice were first challenged and received different H3N2 vaccines and were subsequently infected with H3N2 (A/Kansas/14/2017). Disease outcomes were measured by weight loss and lung viral load. HAI titers were assessed against 9 H3N2 strains, including the infecting strain, vaccine strains, and others, generating 11 HAI-based indicators considering that the HAI titer was against the vaccine strains, the infecting strain, and the similarity between strains based on 2 antigenic distance algorithms. Correlations with disease outcomes were evaluated using linear regression models, with R2 values and bootstrap resampling estimating variance.

HAI titers against vaccine strains showed the weakest correlation with disease outcomes due to strain mismatch. The proportion of seroprotection among the 9 strains demonstrated the strongest correlation, with R2 values of approximately 0.4 (weight loss) and approximately 0.6 (lung viral load). Indicators based on antigenic distance were also predictive but not superior.

Relying solely on HAI titers against a single virus is insufficient for assessing influenza vaccine effectiveness. Calculating the proportion of seroprotection, a computationally efficient metric, offers robust predictive power and may be superior to traditional single-strain titer even when it matches the infecting strain.