Rational Immunogen Design Using Computational Methods

National Institute Of Allergy And Infectious Diseases

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Abstract

The central aim of this segment of our research is to leverage computational structure-based methods to engineer immunogens that elicit broad and potent neutralizing responses against human pathogens. Building on this approach, we focused on influenza H3 hemagglutinin (HA), specifically investigating the N-terminal region as a potential site-of-vulnerability to neutralizing antibodies (Rawi et al., Structure, 2025). Using structure-guided design, we identified and characterized epitope regions at the HA N-terminus that can be targeted to elicit robust antibody responses. Our computational analyses enabled the rational design of immunogens that preserve the native conformation of these vulnerable sites while presenting them in a manner conducive to immune recognition. Experimental evaluation demonstrated that antibodies elicited by these immunogens effectively recognize the HA N-terminal epitope and neutralize viral particles, validating the N-terminus as a promising target for vaccine design. These findings highlight the power of computational immunogen design in identifying novel sites-of-vulnerability and guiding the development of next-generation influenza vaccines.