mRNA vaccines encoding membrane-anchored RBDs of SARS-CoV-2 mutants induce strong humoral responses and can overcome immune imprinting
We investigated mRNA vaccines encoding a membrane-anchored receptor-binding domain (RBD), each a fusion of a variant RBD, the transmembrane (TM) and cytoplasmic tail fragments of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In naive mice, RBD-TM mRNA vaccines against SARS-CoV-2 variants induced strong humoral responses against the target RBD. Multiplex surrogate viral neutralization (sVNT) assays revealed broad neutralizing activity against a range of variant RBDs. In the setting of a heterologous boost, against the background of exposure to ancestral whole-spike vaccines, sVNT studies suggested that BA.1 and BA.5 RBD-TM vaccines had the potential to overcome the detrimental effects of immune imprinting. A subsequent heterologous boost study using XBB.1.5 booster vaccines was evaluated using both sVNT and authentic virus neutralization. Geometric mean XBB.1.5 neutralization values after third-dose RBD-TM or whole-spike XBB.1.5 booster vaccines were compared with those after a third dose of ancestral spike booster vaccine. Fold-improvement over ancestral vaccine was just 1.3 for the whole-spike XBB.1.5 vaccine, similar to data published using human serum samples. In contrast, the fold-improvement achieved by the RBD-TM XBB.1.5 vaccine was 16.3, indicating that the RBD-TM vaccine induced the production of antibodies that neutralize the XBB.1.5 variant despite previous exposure to ancestral spike protein.
Authors
- Richard A. Bowen (ORCID: https://orcid.org/0000-0002-7576-2881)
- Chee Wah Tan (ORCID: https://orcid.org/0000-0001-9837-1413)
- Steven Rockman
- Hareth Al-Wassiti (ORCID: https://orcid.org/0000-0002-8840-8654)
- Ruby Kochappan
- Samantha L. Grimley (ORCID: https://orcid.org/0000-0002-5803-3222)
- Colin William Pouton (ORCID: https://orcid.org/0000-0003-0224-3308)
- Joan K. Ho (ORCID: https://orcid.org/0000-0002-1139-3810)
- Terry M. Nolan (ORCID: https://orcid.org/0000-0001-6018-3863)
- Paula Ellenberg (ORCID: https://orcid.org/0000-0002-7622-9106)
- Damian F. J. Purcell (ORCID: https://orcid.org/0000-0002-4485-1726)
- Lin‐Fa Wang (ORCID: https://orcid.org/0000-0003-2752-0535)
- Rekha Shandre Mugan
- Marc Pellegrini (ORCID: https://orcid.org/0000-0003-3627-3126)
- Serena L. Y. Teo (ORCID: https://orcid.org/0000-0003-1491-8667)
- Dale Ian Godfrey (ORCID: https://orcid.org/0000-0002-3009-5472)
- James P. Cooney (ORCID: https://orcid.org/0000-0003-3680-4644)
- Chee Leng Lee (ORCID: https://orcid.org/0000-0001-8036-459X)
- Georgia Deliyannis (ORCID: https://orcid.org/0000-0002-6883-797X)
- Stewart A. Fabb (ORCID: https://orcid.org/0000-0002-8887-7661)
- Julie McAuley (ORCID: https://orcid.org/0000-0003-2493-3465)
- Horatio Sicilia
- Thomas J. Payne (ORCID: https://orcid.org/0000-0001-7880-8577)
- Kathryn C. Davidson
- Chinn Yi Wong
- Asuka Takanashi (ORCID: https://orcid.org/0000-0001-7835-7331)
Institutions
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Peter Doherty Institute (AU)
- Duke-NUS Medical School (SG)
- Seqirus (United States) (US)
- Monash University (AU)
- Colorado State University (US)
Publication Details
- Journal
- Molecular Therapy — Methods & Clinical Development
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1016/j.omtm.2024.101380
- Citations
- 2
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.78
Funders
- Monash University
- State Government of Victoria
- Medical Research Council
- National Health and Medical Research Council
- National Medical Research Council