Lipid nanoparticle encapsulation of a Delta spike-CD40L DNA vaccine improves effectiveness against Omicron challenge in Syrian hamsters
The effectiveness of mRNA vaccines largely depends on their lipid nanoparticle (LNP) component. Herein, we investigate the effectiveness of DLin-KC2-DMA (KC2) and SM-102-based LNPs for the intramuscular delivery of a plasmid encoding B.1.617.2 (Delta) spike fused with CD40 ligand. LNP encapsulation of this CD40L-adjuvanted DNA vaccine with either LNP formulation drastically enhanced antibody responses, enabling neutralization of heterologous Omicron variants. The DNA-LNP formulations provided excellent protection from homologous challenge, reducing viral replication, and preventing histopathological changes in the pulmonary tissues. Moreover, the DNA-LNP vaccines maintained a high level of protection against heterologous Omicron BA.5 challenge despite a reduced neutralizing response. In addition, we observed that DNA-LNP vaccination led to the pulmonary downregulation of interferon signaling, interleukin-12 signaling, and macrophage response pathways following SARS-CoV-2 challenge, shedding some light on the mechanisms underlying the prevention of pulmonary injury. These results highlight the potential combination of molecular adjuvants with LNP-based vaccine delivery to induce greater and broader immune responses capable of preventing inflammatory damage and protecting against emerging variants. These findings could be informative for the future design of both DNA and mRNA vaccines.
Authors
- Michael Rosu‐Myles (ORCID: https://orcid.org/0000-0003-2264-6905)
- Emmanuel Laryea
- Levi A. Tamming (ORCID: https://orcid.org/0000-0003-2851-7311)
- Jegarubee Bavananthasivam
- Anwar M. Hashem (ORCID: https://orcid.org/0000-0002-8471-7011)
- David Safronetz (ORCID: https://orcid.org/0000-0002-9024-728X)
- Anh Tran (ORCID: https://orcid.org/0000-0003-0644-6014)
- Emily E.F. Fekete (ORCID: https://orcid.org/0000-0002-7849-6021)
- Yves Durocher (ORCID: https://orcid.org/0000-0002-2268-4111)
- Wangxue Chen
- Casey Lansdell (ORCID: https://orcid.org/0000-0002-6994-4398)
- Grant Frahm
- Jingxin Cao (ORCID: https://orcid.org/0000-0002-9167-4638)
- Wanyue Zhang
- Marybeth Creskey (ORCID: https://orcid.org/0000-0002-5884-1051)
- Simon Sauvé (ORCID: https://orcid.org/0000-0002-9620-4889)
- Sathya N. Thulasi Raman
- Annabelle Pfeifle
- Andrew Stalker
- Matthew Stuible (ORCID: https://orcid.org/0009-0002-4403-0677)
- Diana Duque
- Wen Xu (ORCID: https://orcid.org/0000-0001-5116-3713)
- Caroline Gravel
- Lisheng Wang (ORCID: https://orcid.org/0000-0002-4161-9905)
- Jian Wu (ORCID: https://orcid.org/0000-0002-3394-1507)
- Xuguang Li (ORCID: https://orcid.org/0000-0003-1155-9128)
- Michael Johnston (ORCID: https://orcid.org/0000-0002-4931-7485)
Institutions
- Health Canada (CA)
- University of Ottawa (CA)
- Public Health Agency of Canada (CA)
- King Abdulaziz University (SA)
- National Research Council Canada (CA)
- Carleton University (CA)
Publication Details
- Journal
- Molecular Therapy — Methods & Clinical Development
- Published
- 2024-08-19
- DOI
- https://doi.org/10.1016/j.omtm.2024.101325
- Citations
- 6
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 2.33
Funders
- University of Ottawa
- Government of Canada
- Health Canada
- National Research Council Canada