Interferon-producing universal sarbecovirus vaccines, and uses thereof
Inventors
Assignees
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Publication Number
US-12186388-B2
Publication Date
2025-01-07
Expiration Date
Abstract
The present invention relates to universal sarbecovirus vaccines that specifically express an interferon. This live universal sarbecovirus vaccine elicits mucosal immunity and heterotypic immunity against various sarbecoviruses, including SARS-CoV-1, SARS-CoV-2, and its variants. Interferon directly encoded from the genome of the live universal sarbecovirus overrides the virus-induced “delayed type-I interferon”, resulting in enhancement of mucosal T cell responses. The present invention further relates to uses of the vaccines for the preparation of pharmaceutical compositions, methods of treating or preventing viral infections, and kits comprising the vaccines.
Core Innovation
A construct is provided that comprises a modified genome of a sarbecovirus. The modified genome comprises a modified envelope gene and a nucleic acid encoding an interferon integrated into the modified genome. The modified envelope gene comprises one or more stop codons and does not produce a functional envelope protein of the sarbecovirus.
The construct is replication incompetent as a result of the modified envelope gene not producing a functional envelope protein. In particular implementations, the nucleic acid encoding the interferon replaces open reading frame 8 (ORF8), and the interferon is type I interferon, including interferon-beta.
The described vaccine uses a live, defective universal sarbecovirus vaccine construct with an interferon payload integrated into the viral genome while the modified envelope gene is inactivated with stop codons. The disclosure describes an envelope-inactivated interferon-beta integrated SARS-CoV-2 vaccine (IBIS) and reports characterization of interferon-beta production and antiviral activity.
Claims Coverage
The independent claim coverage centers on one engineered sarbecovirus construct. The core inventive combination is a stop-codon inactivated envelope gene that prevents functional envelope protein production together with an interferon-encoding nucleic acid integrated into the modified sarbecovirus genome, yielding replication incompetence.
Replication-incompetent sarbecovirus construct with modified envelope and integrated interferon
A construct comprising a modified genome of a sarbecovirus, wherein the modified genome comprises a modified envelope gene of the sarbecovirus and a nucleic acid encoding an interferon integrated into the modified genome of the sarbecovirus; the modified envelope gene comprises one or more stop codons that prevent production of a functional envelope protein; and the construct is replication incompetent as a result of the modified envelope gene not producing functional envelope protein.
Stop-codon-enriched modified envelope gene
The construct where the modified envelope gene includes at least three stop codons.
5′-terminal-positioned stop codons in the modified envelope gene
The construct where at least one stop codon is present within the 5′-terminal 100 nucleotides of the modified envelope gene.
Interferon-encoding nucleic acid replacing ORF8
The construct where the nucleic acid encoding the interferon replaces open reading frame 8 (ORF8).
Type I interferon payload
The construct where the interferon is a type I interferon.
Mucosal, nasal spray, or parenteral sarbecovirus vaccine formulation
The sarbecovirus vaccine formulated for mucosal administration, nasal spray, or parenteral administration.
The claim coverage is directed to engineered sarbecovirus constructs that combine a modified envelope gene containing stop codons and an integrated interferon-encoding nucleic acid, resulting in replication incompetence. The additional features include ORF8 replacement, type I interferon, further stop-codon constraints, and vaccine formulation routes including mucosal, nasal spray, or parenteral administration.
Stated Advantages
Replication incompetence of the construct due to the modified envelope gene not producing a functional envelope protein.
Enhances mucosal immunity.
Provides heterotypic protection against multiple sarbecoviruses and variants, including SARS-CoV-1 and SARS-CoV-2 variants.
Reduces infection/transmission in animal models.
Preferentially boosts polyfunctional mucosal CD4+ T cell responses.
Interferon-beta expression inhibits viral infection in an interferon bioassay.
Suppresses Omicron replication in human cell models.
Documented Applications
Sarbecovirus vaccination using an interferon-beta integrated, envelope-inactivated SARS-CoV-2 vaccine (IBIS).
Mucosal administration including nasal spray/intranasal administration and parenteral administration such as intramuscular/intradermal for the sarbecovirus vaccine.
Transmission blocking and cross-protection against SARS-CoV-1 and protection/impeded transmission for SARS-CoV-2 variants including Delta and Omicron (BA.2).
Assessment of interferon-beta production and antiviral activity in human cells using a human IFNβ IBIS variant.
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