Evaluating the Breadth and Reliability of Influenza Vaccine Protection Indicators: a Secondary Analysis of an Animal Challenge Trial

Yao Lu; James D Allen; Ted M Ross; Benjamin Cowling; Andreas Handel; Kehinde Ogunyemi; Katia J Bruxvoort; Yang Ge; Ye Shen

doi:10.1093/infdis/jiaf331

Evaluating the Breadth and Reliability of Influenza Vaccine Protection Indicators: a Secondary Analysis of an Animal Challenge Trial

J Infect Dis. 2025 Jun 20:jiaf331. doi: 10.1093/infdis/jiaf331. Online ahead of print.

Authors

Yao Lu¹, James D Allen², Ted M Ross², Benjamin Cowling³, Andreas Handel^{1

4}, Kehinde Ogunyemi¹, Katia J Bruxvoort⁵, Yang Ge¹, Ye Shen¹

Affiliations

¹ College of Public Health, University of Georgia, Athens, 30602, GA, USA.
² Cleveland Clinic, Florida Research and Innovation Center, Port St. Lucie, 34987, FL, USA.
³ WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.
⁴ Center for the Ecology of Infectious Diseases, University of Georgia, Athens, 30602, GA, USA.
⁵ School of Public Health, University of Alabama at Birmingham, Birmingham, 35294, AL, USA.

PMID: 40578602
DOI: 10.1093/infdis/jiaf331

Abstract

Objective: 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.

Method: 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 nine H3N2 strains, including the infecting strain, vaccine strains, and others, generating 11 HAI-based indicators considering the HAI titer was against the vaccine strains, the infecting strain, and the similarity between strains based on two antigenic distance algorithms. Correlations with disease outcomes were evaluated using linear regression models, with R-squared values and bootstrap resampling estimating variance.

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

Conclusions: 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.

Keywords: Antigenic distance; Antigenic mismatch; Correlates of protection; Hemagglutination inhibition (HAI); Immunogenicity indicators; Influenza vaccine; Vaccine efficacy.

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