Oral yeast-displayed SARS-CoV-2 spike protein vaccine enhanced by trimerization and flagellin peptide.
Peptide innovation just hit another milestone: researchers in Iran have engineered an oral yeast-based vaccine that targets SARS-CoV-2, and they’ve supercharged it with peptide tech. This vaccine uses Pichia pastoris yeast to display the spike protein’s receptor-binding domain (RBD), but the real kicker is what they added—a trimerization domain and a flagellin peptide fragment.
Sci Rep
by Saveii T, Arjmand S, Haririan I et al.
“Oral yeast-displayed SARS-CoV-2 spike protein vaccine enhanced by trimerization and flagellin peptide. Saveii T(1), Arjmand S(2)(3), Haririan I(4)(5), Pourzardosht N(6)(7), Sajedi RH(8). Author information: (1)Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran. (2)Department of Biochemistry and Bioprocess Engineering, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran. (3)Protein Research Center, Shahid Beheshti University, Tehran, Iran. (4)Department of Pharmaceutical Biomaterials, and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. (5)Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. (6)Cellular and Molecular Research Center, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran. (7)Department of Biochemistry and Biophysics, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran. (8)Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran. sajedi_r@modares.ac.ir. The global COVID-19 pandemic has underscored the need for innovative vaccine strategies, including oral vaccines, to improve accessibility and enhance immunity. In this study, we explored a novel oral vaccine approach by using yeast surface display to express the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein on Pichia pastoris using SED1 as a carrier protein. The constructs included a fibritin foldon domain from bacteriophage T4 for trimerization and truncated flagellin from Salmonella typhimurium (FliC) as an adjuvant to boost immunogenicity. Three recombinant yeast constructs were designed and evaluated: construct I (RBD-SED1), construct II (RBD-foldon-SED1), and construct III (FliC-RBD-foldon-SED1). Structural integrity, proper folding, and trimerization (in construct III) were modeled and confirmed using ColabFold. These constructs were successfully expressed on the yeast surface and confirmed through fluorescence microscopy, flow cytometry, and ELISA. Oral immunization of BALB/c mice with the recombinant yeast significantly induced spike protein-specific IgG antibodies in serum and IgA in fecal samples, indicating strong humoral and mucosal immune responses. Notably, construct III induced the highest immune response. These findings suggest that yeast-based oral vaccines expressing trimerized SARS-CoV-2 spike protein RBD, combined with a peptide fragment from flagellin, as an immunomodulatory adjuvant, can elicit robust immunity, offering a promising alternative for future COVID-19 vaccination strategies. © 2026. The Author(s). Conflict of interest statement: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: All animal experiments in this study were conducted in accordance with the ethical guidelines and regulations approved by the Research Ethics Committee of Tehran University of Medical Sciences (TUMS). Ethical approval was granted under the approval code IR.TUMS.TIPS.REC.1401.009. The study is reported in accordance with the ARRIVE (Animal Research: Reporting of in vivo Experiments) guidelines 2.0 to ensure transparent and comprehensive reporting of in vivo animal research.”
Here’s the breakdown:
Three engineered yeast constructs were built: a basic RBD, an RBD fused to a trimerization domain, and a third with both the trimerization domain and a truncated flagellin peptide (an immune-boosting adjuvant).
The trimerization domain ensures the spike protein is presented in its native, three-part form—crucial for mimicking the real virus and getting the immune system’s attention.
The flagellin peptide (from Salmonella) acts as a potent signal booster, ramping up immune responses.
The constructs were validated using advanced modeling (ColabFold), and successful expression was confirmed with multiple assays. When administered orally to mice, the yeast-based vaccine triggered strong antibody responses—both IgG in blood and IgA in the gut.
Key takeaway: The construct with both trimerization and flagellin (construct III) outperformed the others, driving the strongest immune reaction. This points to the power of combining protein engineering and peptide adjuvants in oral vaccine development.
If you’re following peptide research, this study is a clear win for the field. It shows how peptide fragments like flagellin can boost vaccine performance, all in a simple, oral format. That’s good news for anyone interested in scalable, accessible vaccine platforms—or just the future of peptide-enabled biotechnology.
The peptide community keeps pushing boundaries. Watch this space for more breakthroughs.
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