Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
Eric Sun
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
Jamie Sookhoo
Canadian Food Inspection Agency, National Centre for Foreign Animal Disease, Winnipeg, MB R3E 3M4, Canada; Department of Immunology, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
Krithika Muthuraman
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada
Kayluz Frias Boligan
Canadian Blood Services, Keenan Research Centre, Toronto, ON M5B 1W8, Canada
Iga Kucharska
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
Edurne Rujas
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain; Pharmacokinetic, Nanotechnology and Gene Therapy Group, Faculty of Pharmacy, University of the Basque Country UPV/EHU, 01006 Vitoria, Spain; Bioaraba, Microbiology, Infectious Disease, Antimicrobial Agents, and Gene Therapy, 01006 Vitoria, Spain
Arif Jetha
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
Donald R. Branch
Canadian Blood Services, Keenan Research Centre, Toronto, ON M5B 1W8, Canada; University of Toronto, Departments of Medicine and Laboratory Medicine and Pathobiology, Toronto, ON M5S 1A8, Canada
Shawn Babiuk
Canadian Food Inspection Agency, National Centre for Foreign Animal Disease, Winnipeg, MB R3E 3M4, Canada; Department of Immunology, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
Brian Barber
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
Jean-Philippe Julien
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Corresponding author
Summary: Subunit vaccines typically require co-administration with an adjuvant to elicit protective immunity, adding development hurdles that can impede rapid pandemic responses. To circumvent the need for adjuvant in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccine, we engineer a thermostable immunotargeting vaccine (ITV) that leverages the pan-HLA-DR monoclonal antibody 44H10 to deliver the viral spike protein receptor-binding domain (RBD) to antigen-presenting cells. X-ray crystallography shows that 44H10 binds to a conserved epitope on HLA-DR, providing the basis for its broad HLA-DR reactivity. Adjuvant-free ITV immunization in rabbits and ferrets induces robust anti-RBD antibody responses that neutralize SARS-CoV-2 variants of concern and protect recipients from SARS-CoV-2 challenge. We demonstrate that the modular nature of the ITV scaffold with respect to helper T cell epitopes and diverse RBD antigens facilitates broad sarbecovirus neutralization. Our findings support anti-HLA-DR immunotargeting as an effective means to induce strong antibody responses to subunit antigens without requiring an adjuvant.
