Replicating RNA platform enables rapid response to the SARS-CoV-2 Omicron variant and elicits enhanced protection in naïve hamsters compared to ancestral vaccine
David W. Hawman,
Kimberly Meade-White,
Chad Clancy,
Jacob Archer,
Troy Hinkley,
Shanna S. Leventhal,
Deepashri Rao,
Allie Stamper,
Matthew Lewis,
Rebecca Rosenke,
Kyle Krieger,
Samantha Randall,
Amit P. Khandhar,
Linhue Hao,
Tien-Ying Hsiang,
Alexander L. Greninger,
Michael Gale, Jr,
Peter Berglund,
Deborah Heydenburg Fuller,
Kyle Rosenke,
Heinz Feldmann,
Jesse H. Erasmus
Affiliations
David W. Hawman
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
Kimberly Meade-White
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
Chad Clancy
Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
Jacob Archer
HDT Bio, Seattle, WA 98102, USA
Troy Hinkley
Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98109, USA
Shanna S. Leventhal
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
Deepashri Rao
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
Allie Stamper
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
Matthew Lewis
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
Rebecca Rosenke
Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
Kyle Krieger
HDT Bio, Seattle, WA 98102, USA
Samantha Randall
Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98109, USA
Amit P. Khandhar
HDT Bio, Seattle, WA 98102, USA
Linhue Hao
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Tien-Ying Hsiang
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Alexander L. Greninger
Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98109, USA
Michael Gale, Jr
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Peter Berglund
HDT Bio, Seattle, WA 98102, USA
Deborah Heydenburg Fuller
Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98109, USA
Kyle Rosenke
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
Heinz Feldmann
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA; Corresponding author at: Rocky Mountain Laboratories, Hamilton, MT, 59840, USA.
Jesse H. Erasmus
HDT Bio, Seattle, WA 98102, USA; Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98109, USA; Corresponding author at: HDT Bio, Seattle, WA 98102, USA.
Summary: Background: In late 2021, the SARS-CoV-2 Omicron (B.1.1.529) variant of concern (VoC) was reported with many mutations in the viral spike protein that were predicted to enhance transmissibility and allow viral escape of neutralizing antibodies. Within weeks of the first report of B.1.1.529, this VoC has rapidly spread throughout the world, replacing previously circulating strains of SARS-CoV-2 and leading to a resurgence in COVID-19 cases even in populations with high levels of vaccine- and infection-induced immunity. Studies have shown that B.1.1.529 is less sensitive to protective antibody conferred by previous infections and vaccines developed against earlier lineages of SARS-CoV-2. The ability of B.1.1.529 to spread even among vaccinated populations has led to a global public health demand for updated vaccines that can confer protection against B.1.1.529. Methods: We rapidly developed a replicating RNA vaccine expressing the B.1.1.529 spike and evaluated immunogenicity in mice and hamsters. We also challenged hamsters with B.1.1.529 and evaluated whether vaccination could protect against viral shedding and replication within respiratory tissue. Findings: We found that mice previously immunized with A.1-specific vaccines failed to elevate neutralizing antibody titers against B.1.1.529 following B.1.1.529-targeted boosting, suggesting pre-existing immunity may impact the efficacy of B.1.1.529-targeted boosters. Furthermore, we found that our B.1.1.529-targeted vaccine provides superior protection compared to the ancestral A.1-targeted vaccine in hamsters challenged with the B.1.1.529 VoC after a single dose of each vaccine. Interpretation: Our data suggest that B.1.1.529-targeted vaccines may provide superior protection against B.1.1.529 but pre-existing immunity and timing of boosting may need to be considered for optimum protection. Funding: This research was supported in part by the Intramural Research Program, NIAID/NIH, Washington Research Foundation and by grants 27220140006C (JHE), AI100625, AI151698, and AI145296 (MG).
