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US-20260124293-A1 - TREATMENT USING A ONE-TO-STOP ATTENUATED SARS-COV-2 VIRUS

US20260124293A1US 20260124293 A1US20260124293 A1US 20260124293A1US-20260124293-A1

Abstract

The invention relates to pharmaceutical product comprising a polynucleotide for use in the prevention or treatment of a SARS-CoV-2 virus infection wherein said SARS-CoV-2 virus is not a Wuhan wild-type SARS-CoV-2 virus. The polynucleotide encodes an attenuated human coronavirus or a fragment thereof, wherein the polynucleotide comprises at least 20 one-to-stop codons, wherein a one-to-stop codon is i) a different but synonymous codon compared to the corresponding codon in a natural human coronavirus genome and ii) differs by one nucleotide from a STOP codon.

Inventors

  • Volker THIEL
  • Jacob SCHÖN
  • Nico Joel HALWE
  • Lorenz ULRICH
  • Nadine EBERT
  • Bettina Salome TRUEB
  • Güliz Tuba BARUT
  • Annika KRATZEL
  • Jörg JORES
  • Fabien LABROUSSAA
  • Martin Beer
  • Donata HOFFMANN

Assignees

  • Universität Bern
  • INSTITUT FÜR VIROLOGIE UND IMMUNOLOGIE (IVI)
  • ROCKETVAX AG

Dates

Publication Date
20260507
Application Date
20231012
Priority Date
20221012

Claims (15)

  1. 1 . A pharmaceutical product comprising a polynucleotide for use in the prevention or treatment of a SARS-CoV-2 virus infection, wherein said polynucleotide encodes an attenuated human coronavirus or a fragment thereof, wherein the polynucleotide comprises at least 20 one-to-stop codons, wherein a one-to-stop codon is i) a different but synonymous codon compared to the corresponding codon in a natural human coronavirus genome and ii) differs by one nucleotide from a STOP codon, and wherein said SARS-CoV-2 virus is not a Wuhan wild-type SARS-CoV-2 virus.
  2. 2 . The pharmaceutical product for use according to claim 1 , wherein said SARS-CoV-2 virus is a variant of the Wuhan wild-type SARS-CoV-2 virus.
  3. 3 . The pharmaceutical product for use according to claim 2 , wherein said variant is of lineage B, preferably B.1, more preferably B.1.1 or B.1.617, again more preferably B.1.1.529 or B.1.617.
  4. 4 . The pharmaceutical product for use according claim 2 or 3 , wherein the variant is selected from the group comprising, or preferably consisting of, Alpha (lineage B.1.1.7), B.1.1.7 with E484K, Beta (lineage B.1.351), Gamma (lineage P.1), Delta (lineage B.1.617.2), Omicron (B.1.1.529), Epsilon (lineages B.1.429, B.1.427, CAL.20C), Zeta (lineage P.2), Eta (lineage B.1.525), Theta (lineage P.3), Iota (lineage B.1.526), Kappa (lineage B.1.617.1), Lambda (lineage C.37), Mu (lineage B.1.621) and a missense variant of a Wuhan wild-type SARS-CoV-2 virus, wherein the genome of said missense variant comprises at least one missense mutation; preferably the variant is selected from the group comprising, or preferably consisting of, Alpha (lineage B.1.1.7), B.1.1.7 with E484K, Beta (lineage B.1.351), Delta (lineage B.1.617.2), Omicron (B.1.1.529), Epsilon (lineages B.1.429, B.1.427, CAL.20C), Eta (lineage B.1.525), Iota (lineage B.1.526), Kappa (lineage B.1.617.1), Mu (lineage B.1.621) and a missense variant of a Wuhan wild-type SARS-CoV-2 virus wherein the genome of said missense variant comprises at least one missense mutation; more preferably the variant is Delta (lineage B.1.617.2), Omicron (B.1.1.529) or a missense variant of a Wuhan wild-type SARS-CoV-2 virus, wherein the genome of said missense variant comprises at least one missense mutation; and again more preferably the variant is Delta (B.1.617.2), Omicron BA.2, Omicron BA.5 or a missense variant of a Wuhan wild-type SARS-CoV-2 virus, wherein the genome of said missense variant comprises at least one missense mutation.
  5. 5 . The pharmaceutical product for use according to claim 4 , wherein said missense mutation is in an ORF encoding a SARS-CoV-2 spike protein, preferably said missense mutation is D614G.
  6. 6 . The pharmaceutical product for use according to claims 2-5 , wherein the variant is selected from the group comprising, or preferably consisting of, Alpha (lineage B.1.1.7), B.1.1.7 with E484K, Beta (lineage B.1.351), Gamma (lineage P.1), Delta (lineage B.1.617.2), Omicron (B.1.1.529), Epsilon (lineages B.1.429, B.1.427, CAL.20C), Zeta (lineage P.2), Eta (lineage B.1.525), Theta (lineage P.3), Iota (lineage B.1.526), Kappa (lineage B.1.617.1), Lambda (lineage C.37), and Mu (lineage B.1.621); preferably the variant is selected from the group comprising, or preferably consisting of, Alpha (lineage B.1.1.7), B.1.1.7 with E484K, Beta (lineage B.1.351), Delta (lineage B.1.617.2), Omicron (B.1.1.529), Epsilon (lineages B.1.429, B.1.427, CAL.20C), Eta (lineage B.1.525), Iota (lineage B.1.526), Kappa (lineage B.1.617.1), and Mu (lineage B.1.621); more preferably the variant is Delta (lineage B.1.617.2) or Omicron (B.1.1.529); and again more preferably the variant is Delta (B.1.617.2), Omicron BA.2 or Omicron BA.5.
  7. 7 . The pharmaceutical product for use according to any one of the preceding claims , wherein the pharmaceutical product is administered intranasally or intramuscularly.
  8. 8 . The pharmaceutical product for use according to any one of the preceding claims , wherein the natural human coronavirus genome is a natural SARS-CoV-2 genome, preferably a) a SARS-CoV-2 sequence comprised in or consisting of a sequence as defined by SEQ ID NO: 7 or b) a SARS-CoV-2 sequence being 80% identical to a sequence comprised in or consisting of a sequence as defined by SEQ ID NO: 7, preferably a SARS-CoV-2 sequence being 80% identical to a sequence comprised in or consisting of sequence as defined by SEQ ID NO: 7 which maintains the ability to encode one or more SARS-CoV-2 virus proteins.
  9. 9 . The pharmaceutical product for use according to any one of the preceding claims , wherein at least one of the one-to-stop codons is in a sequence encoding non-structural proteins; preferably the natural human coronavirus genome is a natural SARS-CoV-2 genome, and at least one of the one-to-stop codons is in a sequence corresponding to ORF1ab in the natural SARS-CoV-2 genome.
  10. 10 . The pharmaceutical product for use according to claim 9 , wherein at least one of the one-to-stop codons is in a sequence corresponding to an Nsp1 to Nsp15, preferably Nsp3 to Nsp15 encoding sequence in the natural SARS-CoV-2 genome.
  11. 11 . The pharmaceutical product for use according to claim 9 or 10 , wherein at least one of the one-to-stop codons is in a sequence corresponding to an Nsp3 to Nsp7 and/or an Nsp12 to Nsp15 encoding sequence in the natural SARS-CoV-2 genome.
  12. 12 . The pharmaceutical product for use according to any one of the preceding claims , wherein the natural human coronavirus genome is a natural SARS-CoV-2 genome, and wherein at least one of the one-to-stop codons has a CDS codon number corresponding to a CDS codon number as indicated in Table 1 or supplementary Table 3 for SEQ ID NO: 7.
  13. 13 . The pharmaceutical product for use according to claim 12 , wherein at least one of the one-to-stop codons is in a sequence corresponding to an Nsp3 to Nsp7 or an Nsp12 to Nsp15 encoding sequence in the natural SARS-CoV-2 genome and at least one of the one-to-stop codons has a CDS codon number corresponding to a CDS codon number as indicated in Table 1 or supplementary Table 3 for SEQ ID NO: 7.
  14. 14 . The pharmaceutical product for use according to claim 12 or 13 , wherein the one-to-stop codons are defined by CDS codon numbers corresponding each to a CDS codon number from 2023 to 6614 as indicated in Table 1 or supplementary Table 3 for SEQ ID NO: 7; preferably, the one-to-stop codons are defined by codon changes and CDS codon numbers corresponding each to a CDS codon number from 2023 to 6614 as indicated in Table 1 or supplementary Table 3 for SEQ ID NO: 7.
  15. 15 . The pharmaceutical product for use according to any one of the preceding claims , wherein the polynucleotide consists of or comprises a sequence as defined in SEQ ID NO: 3-6 or 9-23, preferably SEQ ID NO: 3-6.

Description

RELATED APPLICATIONS This application is a 35 U.S.C. § 371 filing of International Patent Application No. PCT/EP2023/078406, filed Oct. 12, 2023, which claims priority to European Patent Application No. 23185420.9, filed Jul. 13, 2023, International Patent Application No. PCT/EP2023/058069, filed Mar. 28, 2023, and European Patent Application No. 22201198.3, filed Oct. 12, 2022, the entire disclosures of which are hereby incorporated herein by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML file, created on Mar. 28, 2025, is named 763303_VOS9-029US_ST26.xml and is 318,198 bytes in size. The invention relates to pharmaceutical product comprising a polynucleotide for use in the prevention or treatment of a SARS-CoV-2 virus infection wherein said SARS-CoV-2 virus is not a Wuhan wild-type SARS-CoV-2 virus. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 as the causative agent of coronavirus disease 2019 (COVID-19). The virus is highly transmissible among humans. It has spread rapidly around the world within a matter of weeks and the world is still battling with the ongoing COVID-19 pandemic. The rapid development and availability of vaccines are crucial in combating many viruses and bacteria. The production of suitable vaccines is a multi-stage, complex process and is not always successful despite often high investments. Typically, the development of a suitable vaccine takes years. These long development times consist of a major problem, especially with regard to new emerging pathogens, or mutated pathogens, as from an epidemiological point of view it is only possible to react too late, if at all, to the emergence of new diseases. In contrast, the analysis, identification and further detection of new or heavily mutated pathogens are now possible within weeks or even days, which is a huge improvement over the last century. In this context, viruses are of special interest, as they harbor high mutation rates causing the spread from other species to humans. Rapid spreading of these viruses makes them a major challenge for modern medicine. The usual time between the detection/identification of a newly emerging virus and the development of a vaccine is typically years. In a few cases, with sufficient prior knowledge, experimental vaccines could be provided within months. However, this period is much longer than the typical time until thousands or millions of people are infected. Such rapid spread is also a direct consequence of the high mobility of today's society. Ideally, immediately after the identification of a new virus, a vaccine would be available in sufficient quantity and of the highest quality and would allow for a nationwide vaccination of all persons who have somehow come close to the initial outbreak site of the new virus. Furthermore, an ideal method for such a vaccine would be capable of reacting to the evolution and adaptation of the virus. Such an ideal production possibility seems utopian to the person skilled in the art today. In the recent past, in particular, the corona pandemic has dramatically increased the relevance of developing suitable tools for vaccine production. There is unanimous agreement that the development of a vaccine against the coronavirus SARS-CoV-2 is the only proven means of containing the pandemic and the associated global crisis in the long term. The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led not only to global spread, but also to the evolution of various concerning virus variants (https://www.ecdc.europa.eu/en/covid-19/variants-concern). Despite the rapid development of vaccines, the current vaccines primarily target the spike protein antigen, providing limited protection against infection and viral transmission. Consequently, SARS-CoV-2 can evade immunity through spike gene mutations, hindering consistent interruption of infection chains. Therefore, there is an urgent need for more robust and adaptable vaccination strategies. SARS-CoV-2 variant strains are often more contagious or pathogenic than the original wild-type SARS-CoV-2 strain. Such new emerging SARS-CoV-2 strains may lead to a reduced efficiency of first-generation vaccines that were developed against the wild-type SARS-CoV-2 strain. Further, it is unclear whether a vaccination against SARS-CoV-2 to protective immune responses in case a SARS-CoV-2 infection occurs after a long period. Thus, there is a need to provide a vaccine against variants of coronavirus SARS-CoV-2 and vaccines having a long term effect. The above technical problem is solved by the embodiments disclosed herein and as defined in the claims. Accordingly, the invention relates to, inter alia, the following embodiments: 1. A polynucleotide encoding an attenuated human coronavirus or a fragment thereof, wherein the polynu