Applying valency-based immuno-selection to generate broadly cross-reactive antibodies against influenza hemagglutinins

Daniëla Maria Hinke, Ane Marie Anderson, Kirankumar Katta, Marlene Fyrstenberg Laursen, Demo Yemane Tesfaye, Ina Charlotta Werninghaus, Davide Angeletti, Gunnveig Grødeland, Bjarne Bogen () and Ranveig Braathen ()
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Daniëla Maria Hinke: University of Oslo
Ane Marie Anderson: University of Oslo
Kirankumar Katta: University of Oslo and Oslo University Hospital
Marlene Fyrstenberg Laursen: University of Oslo and Oslo University Hospital
Demo Yemane Tesfaye: University of Oslo and Oslo University Hospital
Ina Charlotta Werninghaus: University of Oslo and Oslo University Hospital
Davide Angeletti: University of Gothenburg
Gunnveig Grødeland: University of Oslo
Bjarne Bogen: University of Oslo
Ranveig Braathen: University of Oslo

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Conserved epitopes shared between virus subtypes are often subdominant, making it difficult to induce broadly reactive antibodies by immunization. Here, we generate a plasmid DNA mix vaccine that encodes protein heterodimers with sixteen different influenza A virus hemagglutinins (HA) representing all HA subtypes except H1 (group 1) and H7 (group 2). Each single heterodimer expresses two different HA subtypes and is targeted to MHC class II on antigen presenting cells (APC). Female mice immunized with the plasmid mix produce antibodies not only against the 16 HA subtypes, but also against non-included H1 and H7. We demonstrate that individual antibody molecules cross-react between different HAs. Furthermore, the mix vaccine induces T cell responses to conserved HA epitopes. Immunized mice are partially protected against H1 viruses. The results show that application of valency-based immuno-selection to diversified antigens can be used to direct antibody responses towards conserved (subdominant) epitopes on viral antigens.

Date: 2024
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DOI: 10.1038/s41467-024-44889-w

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