Thermophilic Filamentous Fungus C1-Cell-Cloned SARS-CoV-2-Spike-RBD-Subunit-Vaccine Adjuvanted with Aldydrogel®85 Protects K18-hACE2 Mice against Lethal Virus Challenge

Ram Nechooshtan, Sharon Ehrlich, Marika Vitikainen, Arik Makovitzki, Eyal Dor, Hadar Marcus, Idan Hefetz, Shani Pitel, Marilyn Wiebe, Anne Huuskonen, Lilach Cherry, Edith Lupu, Yehuda Sapir, Tzvi Holtzman, Moshe Aftalion, David Gur, Hadas Tamir, Yfat Yahalom-Ronen, Yuval Ramot, Noam KronfeldDavid Zarling, Anne Vallerga, Ronen Tchelet, Abraham Nyska, Markku Saloheimo, Mark Emalfarb, Yakir Ophir (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

Abstract

SARS-CoV-2 is evolving with increased transmission, host range, pathogenicity, and virulence. The original and mutant viruses escape host innate (Interferon) immunity and adaptive (Antibody) immunity, emphasizing unmet needs for high-yield, commercial-scale manufacturing to produce inexpensive vaccines/boosters for global/equitable distribution. We developed DYAI-100A85, a SARS-CoV-2 spike receptor binding domain (RBD) subunit antigen vaccine expressed in genetically modified thermophilic filamentous fungus, Thermothelomyces heterothallica C1, and secreted at high levels into fermentation medium. The RBD-C-tag antigen strongly binds ACE2 receptors in vitro. Alhydrogel®‘85’-adjuvanted RDB-C-tag-based vaccine candidate (DYAI-100A85) demonstrates strong immunogenicity, and antiviral efficacy, including in vivo protection against lethal intranasal SARS-CoV-2 (D614G) challenge in human ACE2-transgenic mice. No loss of body weight or adverse events occurred. DYAI-100A85 also demonstrates excellent safety profile in repeat-dose GLP toxicity study. In summary, subcutaneous prime/boost DYAI-100A85 inoculation induces high titers of RBD-specific neutralizing antibodies and protection of hACE2-transgenic mice against lethal challenge with SARS-CoV-2. Given its demonstrated safety, efficacy, and low production cost, vaccine candidate DYAI-100 received regulatory approval to initiate a Phase 1 clinical trial to demonstrate its safety and efficacy in humans.

Original languageEnglish
Article number2119
JournalVaccines
Volume10
Issue number12
DOIs
Publication statusPublished - 11 Dec 2022
MoE publication typeA1 Journal article-refereed

Keywords

  • adjuvant
  • alum
  • aluminum-based vaccine adjuvants
  • antigen
  • baculovirus
  • BALB/c mice
  • biomanufacturing
  • C-tag
  • CHO-cell
  • COVID-19
  • dyadic
  • efficacy
  • glycans
  • glycoprotein
  • glycosylation
  • IgG
  • IgG1 and IgG2b
  • insect cells
  • intranasal challenge
  • K18-hACE-2 mice
  • Myceliophthora thermophila
  • neutralizing antibodies
  • pandemic
  • RBD
  • receptor binding domain
  • recombinant protein subunit vaccine
  • SARS-CoV-2
  • stability
  • Thermothelomyces heterothallica
  • toxicology
  • vaccine
  • variants of concern
  • virus
  • zoonotic

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