Designing a reoriented H5 hemagglutinin to generate stem-directed, heterosubtypic immunity to influenza A viruses
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Human infections with the highly pathogenic avian influenza viruses highlight the risk of novel pandemics, against which seasonal vaccines provide limited cross-protection. Whereas antibody responses to current vaccine candidates are typically biased toward the immunodominant and variable head region of hemagglutinin (HA), the stem region of HA is highly conserved and targeted by broadly neutralizing antibodies. Here we describe a reoriented H5 HA (reoH5HA Phe , based on A/Vietnam/1203/2004) displayed on alum as a vaccine candidate to elicit stem-directed antibody responses and confer cross-protective immunity. We show that a single immunization with reoH5HA Phe protected naïve mice against heterologous H5N1 lethal challenge (A/Texas/37/2024), and boosting with reoH5HA Phe conferred complete heterologous protection in mice pre-immunized with seasonal vaccines. The stem-directed response elicited by reoH5HA Phe also protected against heterosubtypic H1N1 challenge in both naïve and pre-immune mice. Electron microscopy polyclonal epitope mapping revealed that reoH5HA Phe elicited antibodies targeting the central stem and anchor epitopes on heterologous H5 and H1 HAs, alongside antibodies against the (H5) vestigial esterase or (H1) lateral patch epitopes. Despite limited cross-neutralizing activity, increased stem-directed responses with balanced IgG1 and IgG2 subclasses reduced viral replication and improved survival. Our results highlight antigen reorientation as an effective approach for designing variant-resilient vaccines and demonstrate the potential of reoH5HA Phe as an H5 pandemic influenza vaccine candidate that confers protective immunity against both emerging and seasonal influenza viruses.
Significance Statement
The global spread and human infections of avian H5N1 influenza viruses raise concerns of novel pandemics, against which humans lack pre-existing immunity. Whereas current vaccine strategies, including mRNA vaccines, mostly protect against sequence-matched viruses, pandemic preparedness requires vaccine design that resists antigenic variation and viral evolution. Here we employ molecular control of antigen orientation to focus antibody responses toward evolutionarily conserved sites of influenza hemagglutinin. We designed a reoriented H5 hemagglutinin based on the historical sequence (A/Vietnam/1203/2004) and demonstrated robust protection against the contemporary virus (A/Texas/37/2024). Vaccinations with reoriented H5 hemagglutinin also conferred protection against historical and contemporary H1N1 viruses. Our approach has potential to provide protection against emerging, pandemic-potential viruses, while simultaneously boosting immunity to seasonal influenza viruses.
