Vaccine design via antigen reorientation

Duo Xu; Joshua J Carter; Chunfeng Li; Ashley Utz; Payton A B Weidenbacher; Shaogeng Tang; Mrinmoy Sanyal; Bali Pulendran; Christopher O Barnes; Peter S Kim

doi:10.1038/s41589-023-01529-6

Vaccine design via antigen reorientation

Nat Chem Biol. 2024 Aug;20(8):1012-1021. doi: 10.1038/s41589-023-01529-6. Epub 2024 Jan 15.

Authors

Duo Xu^{1

2}, Joshua J Carter^{2

3

4}, Chunfeng Li⁵, Ashley Utz^{2

3

4}, Payton A B Weidenbacher^{2

6}, Shaogeng Tang^{1

2}, Mrinmoy Sanyal^{1

2}, Bali Pulendran^{5

7

8}, Christopher O Barnes^{2

9

10}, Peter S Kim^{11

12

13}

Affiliations

¹ Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.
² Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
³ Stanford Biophysics Program, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA.
⁶ Department of Chemistry, Stanford University, Stanford, CA, USA.
⁷ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Department of Biology, Stanford University, Stanford, CA, USA.
¹⁰ Chan Zuckerberg Biohub, San Francisco, CA, USA.
¹¹ Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹² Sarafan ChEM-H, Stanford University, Stanford, CA, USA. [email protected].
¹³ Chan Zuckerberg Biohub, San Francisco, CA, USA. [email protected].

Abstract

A major challenge in creating universal influenza vaccines is to focus immune responses away from the immunodominant, variable head region of hemagglutinin (HA-head) and toward the evolutionarily conserved stem region (HA-stem). Here we introduce an approach to control antigen orientation via site-specific insertion of aspartate residues that facilitates antigen binding to alum. We demonstrate the generalizability of this approach with antigens from Ebola, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses and observe enhanced neutralizing antibody responses in all cases. We then reorient an H2 HA in an 'upside-down' configuration to increase the exposure and immunogenicity of HA-stem. The reoriented H2 HA (reoH2HA) on alum induced stem-directed antibodies that cross-react with both group 1 and group 2 influenza A subtypes. Electron microscopy polyclonal epitope mapping (EMPEM) revealed that reoH2HA (group 1) elicits cross-reactive antibodies targeting group 2 HA-stems. Our results highlight antigen reorientation as a generalizable approach for designing epitope-focused vaccines.

MeSH terms

Alum Compounds / chemistry
Animals
Antibodies, Neutralizing / immunology
Antibodies, Viral / immunology
Antigens, Viral / chemistry
Antigens, Viral / immunology
COVID-19 / immunology
COVID-19 / prevention & control
COVID-19 / virology
COVID-19 Vaccines / chemistry
COVID-19 Vaccines / immunology
Cross Reactions / immunology
Ebolavirus / immunology
Epitope Mapping
Epitopes / chemistry
Epitopes / immunology
Hemagglutinin Glycoproteins, Influenza Virus / chemistry
Hemagglutinin Glycoproteins, Influenza Virus / immunology
Humans
Influenza A virus / immunology
Influenza Vaccines* / chemistry
Influenza Vaccines* / immunology
Mice
SARS-CoV-2* / immunology

Substances

Influenza Vaccines
Antibodies, Neutralizing
Antibodies, Viral
Hemagglutinin Glycoproteins, Influenza Virus
Antigens, Viral
Epitopes
Alum Compounds
aluminum sulfate
COVID-19 Vaccines

Abstract

MeSH terms

Substances

Grants and funding