Antigen spacing on protein nanoparticles influences antibody responses to vaccination

Author:

Ellis, Daniel

Dosey, Annie

Boyoglu-Barnum, Seyhan

Park, Young-Jun

Gillespie, Rebecca

Syeda, Hubza

Hutchinson, Geoffrey B

Tsybovsky,Yaroslav

Murphy, Michael

Pettie, Deleah

Matheson, Nick

Chan, Sidney

Ueda, George

Fallas, Jorge A

Carter, Lauren

Graham, Barney S

Veesler, David

Kanekiyo, Masaru

King, Neil P
Author Address

Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, WA 98195, USA., Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA., Vaccine Research Center Electron Microscopy Unit, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA., Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: neilking@uw.edu.,

Abstract:

Immunogen design approaches aim to control the specificity and quality of antibody responses elicited by next-generation vaccines. Here, we use computational protein design to generate a nanoparticle vaccine platform based on the receptor-binding domain (RBD) of influenza hemagglutinin (HA) that enables precise control of antigen conformation and spacing. HA RBDs are presented as either monomers or native-like closed trimers that are connected to the underlying nanoparticle by a rigid linker that is modularly extended to precisely control antigen spacing. Nanoparticle immunogens with decreased spacing between trimeric RBDs elicit antibodies with improved hemagglutination inhibition and neutralization potency as well as binding breadth across diverse H1 HAs. Our "trihead" nanoparticle immunogen platform provides insights into anti-HA immunity, establishes antigen spacing as an important parameter in structure-based vaccine design, and embodies several design features that could be used in next-generation vaccines against influenza and other viruses. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

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