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EP-4739700-A1 - RESPIRATORY SYNCYTIAL VIRUS MUTANTS, FUSION PEPTIDES, PARTICLES, NUCLEIC ACIDS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE

EP4739700A1EP 4739700 A1EP4739700 A1EP 4739700A1EP-4739700-A1

Abstract

Disclosed herein are compositions and methods for managing respiratory syncytial virus (RSV) infections. In certain embodiments, vaccines and pharmaceutical compositions comprise or encode an RSV G protein comprising a mutation or fusion protein arrangement disclosed herein. In certain embodiments, virus particles/virus like particles, nucleic acids, vectors, or attenuated RSV vaccines are used in methods reported herein.

Inventors

  • ANDERSON, Larry James
  • HA, BINH
  • SUN, Heying

Assignees

  • Emory University
  • Children's Healthcare of Atlanta, Inc.

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. 1. A recombinant RSV G protein comprising R15K, G29C, M48I, I49V, N81S, T87P, and R197K mutations.
  2. 2. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIV (SEQ ID NO: 27).
  3. 3. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIA AIIFIASANHKVTPTTAIIQDATSQIKNT (SEQ ID NO: 17, Ga 1-86).
  4. 4. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIA AIIFIASANHKVTPTTAIIQDATSQIKNTPP (SEQ ID NO: 18, Ga 1-86 C-terminal PP), MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIA AIIFIASANHKVTPTTAIIQDATSQIKNTTPTYLTQNPQ (SEQ ID NO: 34, Ga 1-96), or MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIA AIIFIASANHKVTPTTAIIQDATSQIKNTTPTYLTQNPQLGISPSNPSE (SEQ ID NO: 35, Ga 1- 106).
  5. 5. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of PSKPNNDFHFEVFNFVPCSICSNNPTCWAICKRIPNKKPGKKTTTKPTKKP (SEQ ID NO: 19, Ga 155-206), QRQNKPP SKPNNDFHFEVFNF VPC SIC SNNPTCWAICKRIPNKKPGKKTTTKPTK KPTLK (SEQ ID NO: 36, Ga 150-210), or TPRLKNPPKKPKDDYHFEVFNFVPCSICGNNQLCKSICKTIPSNKPKKKPTIKPTN KPTTKT (SEQ ID NO: 37, Gb 150-210).
  6. 6. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIA AIIFIAS ANHKVTPTT AIIQD AT SQIKNTPP SKPNNDFHFEVFNF VPC SIC SNNPTC WAICKR IPNKKPGKKTTTKPTKKP (SEQ ID NO: 1, Ga 1-86 plus 155-206 (Ga)).
  7. 7. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIA AIIFIASANHKVTPTTAIIQDATSQIKNTQRQNKPPSKPNNDFHFEVFNFVPCSICSNNPTC WAICKRIPNKKPGKKTTTKPTKKPTLKTPRLKNPPKKPKDDYHFEVFNFVPCSICGNNQL CKSICKTIPSNKPKKKPTIKPTNKPTTKT (SEQ ID NO: 5, group A 1-86 plus 150-210 plus group B 150-210, tandem Ga plus Gb (T-Ga/Gb)).
  8. 8. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of KPTLKTPRL (SEQ ID NO: 21, linker Gb).
  9. 9. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of QRQNKPP SKPNNDFHFEVFNF VPC SIC SNNPTCWAICKRIPNKKPGKKTTTKPTK KPTLKTPRLKNPPKKPKDDYHFEVFNFVPCSICGNNQLCKSICKTIPSNKPKKKPTIKPTN KPTTKT (SEQ ID NO: 20, Gb 150-210).
  10. 10. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIAAIIFIAS ANHKVTPTTAIIQDATSQIKNTKPTTKQRQNKPPSKPNNDFHFEVFNFVPCSICSNNPTC WAIACKRIPNKKPGKKTTTKPTKKP (SEQ ID NO: 9, Ga CX4C 1-86 plus 145-206).
  11. 11. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of KPTTKQRQNK (SEQ ID NO: 28, Ga 145-154).
  12. 12. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of CWAIAC (SEQ ID NO: 22, Ga CX4C).
  13. 13. The recombinant RSV G protein of claim 1 comprising the amino acid sequence of MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIA AIIFIASANHKVTPTTAIIQDATSQIKNTKPTTKQRQNKPPSKPNNDFHFEVFNFVPCSICR NNPTCWAICKRIPNKKPGKKTTTKPTKKP (SEQ ID NO: 11, Ga 1-86 plus 145-206 S177R) or MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIA AIIFIASANHKVTPTTAIIQDATSQIKNTKPTTKQRQNKPPSKPNNDFHFEVFNFVPCSICQ NNPTCWAICKRIPNKKPGKKTTTKPTKKP (SEQ ID NO: 13, Ga 1-86 plus 145-206 S177Q).
  14. 14. The recombinant RSV G protein of claim 1 comprising a S177R and/or S177Q mutation.
  15. 15. A virus like particle comprising any of the recombinant RSV G protein as provided in claims 1-14.
  16. 16. A nucleic acid encoding the recombinant RSV G protein as provided in claims 1-14 in operable combination with a heterologous promoter.
  17. 17. The nucleic acid of claim 16 which is RNA or DNA.
  18. 18. A live attenuated RSV strain comprising an RSV G protein as provided in any of claims 1- 14.
  19. 19. A vector comprising a nucleic acid of claim 16 or encoding the recombinant RSV G protein as provided in claims 1-14.
  20. 20. A method of vaccinating against or treating for an RSV infection comprising administering an effective amount of a vaccine or pharmaceutical composition comprising RSV G protein, virus like particle, viral particle, nucleic acid, attenuated RSV stain, attenuated RSV virus, or vector as provided for in any of claims 1-19 to a subject in need thereof.

Description

RESPIRATORY SYNCYTIAL VIRUS MUTANTS, FUSION PEPTIDES, PARTICLES, NUCLEIC ACIDS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/525,447 filed July 7, 2023. The entirety of this application is hereby incorporated by reference for all purposes. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED AS AN XML FILE VIA THE OFFICE ELECTRONIC FILING SYSTEM The Sequence Listing associated with this application is provided in XML format and is hereby incorporated by reference into the specification. The name of the XML file containing the Sequence Listing is 22148PCT.xml. The XML file is 43 KB, was created on July 2, 2024, and is being submitted electronically via the USPTO patent electronic filing system. BACKGROUND Human respiratory syncytial virus (RSV) causes acute lower respiratory infections. It is a major cause of hospital visits for premature babies and newborns. RSV infections also pose athreat for the elderly and immune compromised. Palivizumab is a humanized chimeric antibody that binds the RSV fusion protein (RSV F) that is clinically approved for prevention of serious lower respiratory tract disease caused by RSV in certain high-risk infants. Palivizumab has limited efficacy and sometimes causes allergic reactions. Thus, there is a need to identify additional RSV therapies. Vaccines are often killed (inactivated) or weakened (attenuated) versions of a live viral strain. Kim et al. report that administration of a formalin-inactivated RSV vaccine was not sufficiently effective. Am J Epidemiol 89, 422-434 (1969). Attenuated RSV vaccine candidates face significant safety hurdles, and the development of pediatric RSV live-attenuated vaccine (LAV) strains that are sufficiently attenuated and immunogenic have been elusive. See Collins et al. Progress in understanding and controlling respiratory syncytial virus: still crazy after all these years. Virus Res, 2011,162, 80-99. Quan et al. report virus-like particles (VLPs) consisting of an influenza virus matrix (Ml) protein core and RSV-F or -G on the surface. JID, 2011, 204:987-95. Hotard et al. report residues in the human RSV fusion protein that modulate fusion activity and pathogenesis. J Virol, 2015, 89:512-522. Rostad et al. report a recombinant respiratory syncytial virus vaccine candidate attenuated by a low-fusion F protein is immunogenic and protective against challenge in cotton rats. J Virol, 2016, 90(16):7508-7518. Ha et al. report RSV platforms for G, F, or G plus F Protein VLPs. Viruses, 2020, 12(9): 906. Brakel et al. report codon-optimization of the respiratory syncytial virus (RSV) G protein expressed in a vesicular stomatitis virus (VSV) vector improves immune responses in a cotton rat model. Virology, 2022, 575, 101-110. See also US Patent Nos. 10,626,378 11,235,050, US2019/0292228, WO2014/152534, W02015/013551, and WO2017/075125. References cited herein are not an admission of prior art. SUMMARY This disclosure relates to compositions and methods for managing respiratory syncytial virus (RSV) infections. In certain embodiments, this disclosure relates to vaccines and pharmaceutical compositions comprising an RSV G protein comprising a mutation or fusion protein arrangement disclosed herein. In certain embodiments, this disclosure relates to virus particles/virus like particles, nucleic acids, vectors, or attenuated RSV vaccines for uses reported herein. In certain embodiments, this disclosure relates to methods of vaccinating, treating, or preventing RSV infections comprising administering to a subject in need thereof an effective amount of a composition reported herein. In certain embodiments, this disclosure relates to recombinant RSV G proteins comprising R15K, G29C, M48I, I49V, N81S, T87P, and/or R197K mutation(s). In certain embodiments, this disclosure relates to recombinant RSV G proteins comprising the amino acid sequence of MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIV (SEQ ID NO: 27). In certain embodiments, the recombinant RSV G protein comprises the amino acid sequence of MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIA AIIFIAS ANHKVTPTT AIIQD AT SQIKNTPP SKPNNDFHFEVFNF VPC SIC SNNPTC WAICKR IPNKKPGKKTTTKPTKKPPPSKPNNDFHFEVFNFVPC SIC SNNPTC WAICKRIPNKKPGKK TTTKPTKKP (SEQ ID NO: 3, Ga 1-86 plus 155-206 plus 155-206, tandem Ga plus Ga (T- Ga/Ga)). In certain embodiments, the recombinant RSV G protein comprises the amino acid sequence of MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIA AIIFIASANHKVTPTTAIIQDATSQIKNT (SEQ ID NO: 17, Ga 1-86). In certain embodiments, the recombinant RSV G protein comprises the amino acid sequence of MSKNKDQRTAKTLERTWDTLNHLLFISSCLYKLNLKSVAQITLSILAIVISTSLIIA AIIFIASANHKVTPTTAIIQDATSQIKNTPP (SEQ ID NO: 18, Ga 1-86 C-terminal PP). In certain embodiments, the recombinant RSV G protein comprises the amino acid sequence of P SKPNNDFHFEVFNF VPC SIC SNNPTC WAICKRIPNKKPGKKTTTKPT