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EP-4739343-A2 - CIRCULAR RNA VACCINES FOR SEASONAL FLU AND METHODS OF USES

EP4739343A2EP 4739343 A2EP4739343 A2EP 4739343A2EP-4739343-A2

Abstract

Disclosed herein are immunogenic compositions having circular RNAs as vaccines for influenza viruses. Related methods for manufacture and therapeutic uses thereof are also provided herein.

Inventors

  • YANG, YUN

Assignees

  • Shanghai Circode Biomed Co., Ltd

Dates

Publication Date
20260513
Application Date
20240708

Claims (20)

  1. A circular ribonucleotide acid (circRNA) , wherein the circRNA comprises, a translation initiation (TI) sequence and a protein-coding (Z) sequence, and wherein the Z sequence comprises a hemagglutinin sequence (HA sequence) encoding a hemagglutinin antigen (HA antigen) or a neuraminidase sequence (NA sequence) encoding a neuraminidase antigen (NA antigen) .
  2. The circRNA of claim 1, wherein the Z sequence comprises a first HA (HA 1 ) sequence encoding an HA antigen from a first influenza virus that is type A or B.
  3. The circRNA of claim 2, wherein the Z sequence further comprises a second HA (HA 2 ) sequence encoding an HA antigen from a second influenza virus that is type A or B.
  4. The circRNA of claim [0068] comprising in the following order: TI, HA 1 , L, and HA 2 , wherein L is a linker sequence or absent; and wherein the first and second influenza viruses are types (1) A1 and A2; (2) B1 and B2; (3) A and B; or (4) B and A; wherein A1 and A2 are the first and second subtypes of influenza A viruses; and B1 and B2 are the first and second subtypes of influenza B viruses.
  5. The circRNA of claim 3, wherein the Z sequence further comprises a third HA (HA 3 ) sequence encoding an HA antigen from a third influenza virus that is type A or B.
  6. The circRNA of claim [0070] comprising in the following order: TI, HA 1 , L 1 , HA 2 , L 2 , and HA 3 , wherein L 1 and L 2 each is independently a linker sequence or absent; and wherein the first, second and third viruses are types (1) A1, A2 and B; (2) A1, B, and A2; or (3) B, A1, and A2; (4) A, B1, and B2; (5) B1, A, and B2; or (6) B1, B2, and A; wherein A1 and A2 are the first and second subtypes of influenza A viruses; and B1 and B2 are the first and second subtypes of influenza B viruses.
  7. The circRNA of claim [0070] , wherein the Z sequence further comprises a fourth HA (HA 4 ) sequence encoding an HA antigen from a fourth influenza virus that is type A or B.
  8. The circRNA of claim [0072] comprising in the following order: TI, HA 1 , L 1 , HA 2 , L 2 , HA 3 , L 3 , and HA 4 ; wherein L 1 , L 2 and L 3 each is independently a linker sequence or absent; and wherein the first, second, third and fourth influenza viruses are types (1) A1, A2, B1, and B2; (2) , A1, B1, A2, and B2; (3) B1, A1, B2, and A2, or (4) B1, B2, A1, and A2;wherein A1 and A2 are the first and second subtypes of influenza A viruses; and B1 and B2 are the first and second subtypes of influenza B viruses.
  9. The circRNA of claim 1, wherein the Z sequence comprises a first NA (NA 1 ) sequence encoding an NA antigen from a first influenza virus that is type A or B.
  10. The circRNA of claim [0074] , wherein the Z sequence further comprises a second NA (NA 2 ) sequence encoding an NA antigen from a second influenza virus that is type A or B.
  11. The circRNA of claim [0075] comprising in the following order: TI, NA 1 , L, and NA 2 ; wherein L is a linker sequence or absent; and wherein the first and second influenza viruses are types (1) A1 and A2; (2) B1 and B2; (3) A and B; or (4) B and A; wherein A1 and A2 are the first and second subtypes of influenza A viruses; and B1 and B2 are the first and second subtypes of influenza B viruses.
  12. The circRNA of claim [0075] , wherein the Z sequence further comprises a third NA (NA 3 ) sequence encoding an NA antigen from a third influenza virus that is type A or B.
  13. The circRNA of claim [0077] comprising in the following order: TI, NA 1 , L 1 , NA 2 , L 2 , and NA 3 ; wherein L 1 and L 2 each is independently a linker sequence or absent; and wherein the first, second, and third influenza viruses are types (1) A1, A2 and B; (2) A1, B, and A2; or (3) B, A1, and A2; (4) A, B1, and B2; (5) B1, A, and B2; or (6) B1, B2, and A; wherein A1 and A2 are the first and second subtypes of influenza A viruses; and B1 and B2 are the first and second subtypes of influenza B viruses.
  14. The circRNA of claim [0077] , wherein the Z sequence further comprises a fourth NA (NA 4 ) sequence encoding an NA antigen from a fourth influenza virus that is type A or B.
  15. The circRNA of claim [0079] comprising in the following order: TI, NA 1 , L 1 , NA 2 , L 2 , NA 3 , L 3 , and NA 4 ; wherein L 1 , L 2 and L 3 each is independently a linker sequence or absent; and wherein the first, second, third and fourth influenza viruses are types (1) A1, A2, B1, and B2; (2) , A1, B1, A2, and B2; (3) B1, A1, B2, and A2, or (4) B1, B2, A1, and A2; wherein A1 and A2 are the first and second subtypes of influenza A viruses; and B1 and B2 are the first and second subtypes of influenza B viruses.
  16. The circRNA of claim 1, wherein the Z sequence comprises a first HA (HA 1 ) sequence encoding an HA antigen, and a first NA (NA 1 ) sequence encoding an NA antigen, and the HA and NA antigens are from a first influenza virus that is type A or B.
  17. The circRNA of claim [0081] comprising in the following order: (1) TI, HA 1 , L, and NA 1 ; or (2) TI, NA 1 , L, and HA 1 ; wherein L is a linker sequence or absent.
  18. The circRNA of claim [0081] , wherein the Z sequence further comprises a second HA (HA 2 ) sequence encoding an HA antigen and a second NA (NA 2 ) sequence encoding an NA antigen, wherein the HA and NA antigens are from a second influenza virus that is type A or B.
  19. The circRNA of claim [0083] comprising in the following order: (1) TI, HA 1 , L 1 , NA 1 , L 2 , HA 2 , L 3 , and NA 2 ; (2) TI, NA 1 , L 1 , HA 1 , L 2 , NA 2 , L 3 , and HA 2 ; (3) TI, HA 1 , L 1 , HA 2 , L 2 , NA 1 , L 3 , and NA 2 ; or (4) TI, NA 1 , L 1 , NA 2 , L 2 , HA 1 , L 3 , and HA 2 ; wherein L 1 , L 2 and L 3 each is independently a linker sequence or absent; and wherein the first and second influenza viruses are types (1) A1 and A2; (2) B1 and B2; (3) A and B; or (4) B and A; wherein A1 and A2 are the first and second subtypes of influenza A viruses; and B1 and B2 are the first and second subtypes of influenza B viruses.
  20. The circRNA of claim [0083] , wherein the Z sequence further comprises a third HA (HA 3 ) sequence encoding an HA antigen and a third NA (NA 3 ) sequence encoding an NA antigen, wherein the HA and NA antigens are from a third influenza virus that is type A or B.

Description

CIRCULAR RNA VACCINES FOR SEASONAL FLU AND METHODS OF USES Related applications The application claims priority to, and the benefit of PCT Application No. PCT/CN2023/106381, filed on July 7, 2023, the contents of which are incorporated herein by reference in their entirety. Incorporation by reference of sequence listing The contents of electronic sequence listing (TFH01060PCT-sequence listing. xml; Size: 1, 080, 415 bytes; and Date of Creation: July 8, 2024) are herein incorporated by reference in its entirety. 1.Field The present invention relates to the field of molecular biology and immunology, in particular to constructs and methods for the manufacture and therapeutic use of circular RNAs as vaccines for influenza viruses. 2.Background Circular RNAs (circRNAs) are a category of RNA molecules formed by head-to-tail ligation, which were demonstrated to have multiple biological functions in recent years. (Yang et al., Cell Research, 27 (5) : 626-641 (2017) ; Abe et al., Scientific Reports, 5: 16435 (2015) ; Gao et al., Nature Cell Biology, 23 (3) : 278-291 (2021) ; Pamudurti et al., Molecular Cell, 66 (1) : 9-21 (2017) ) . Compared with linear RNAs, circRNAs have better stability and therefore provide a promising new platform for RNA drugs. Influenza is an acute respiratory infection caused by influenza viruses -influenza A and influenza B viruses -that circulate the world. Vaccination plays a critical role in controlling annual influenza epidemics. Vaccines elicit immune responses that attack the viral glycoprotein hemagglutinin (HA) and the viral enzyme neuraminidase (NA) found on the surface of the influenza virus. Improved immunogenic compositions against influenza are in great need. The compositions provided herein, which comprise circular RNAs as vaccines for influenza viruses, as well as related methods and systems address this need and provide related advantages. 3.Summary Provided herein are circular ribonucleotide acid (circRNA) scomprising, a translation initiation (TI) sequence and a protein-coding (Z) sequence, and wherein the Z sequence comprises a hemagglutinin sequence (HA sequence) encoding a hemagglutinin antigen (HA antigen) or a neuraminidase sequence (NA sequence) encoding a neuraminidase antigen (NA antigen) . In some embodiments, the Z sequence comprises a first HA (HA1) sequence encoding an HA antigen from a first influenza virus that is type A or B. In some embodiments, the Z sequence further comprises a second HA (HA2) sequence encoding an HA antigen from a second influenza virus that is type A or B. In some embodiments, the circRNAs comprise in the following order: TI, HA1, L, and HA2, wherein L is a linker sequence or absent; and wherein the first and second influenza viruses are types (1) A1 and A2; (2) B1 and B2; (3) A and B; or (4) B and A; wherein A1 and A2 are the first and second subtypes of influenza A viruses; and B1 and B2 are the first and second subtypes of influenza B viruses. In some embodiments, the Z sequence further comprises a third HA (HA3) sequence encoding an HA antigen from a third influenza virus that is type A or B. In some embodiments, the circRNAs comprise in the following order: TI, HA1, L1, HA2, L2, and HA3, wherein L1 and L2 each is independently a linker sequence or absent; and wherein the first, second and third viruses are types (1) A1, A2 and B; (2) A1, B, and A2; or (3) B, A1, and A2; (4) A, B1, and B2; (5) B1, A, and B2; or (6) B1, B2, and A; wherein A1 and A2 are the first and second subtypes of influenza A viruses; and B1 and B2 are the first and second subtypes of influenza B viruses. In some embodiments, the Z sequence further comprises a fourth HA (HA4) sequence encoding an HA antigen from a fourth influenza virus that is type A or B. In some embodiments, the circRNAs comprise in the following order: TI, HA1, L1, HA2, L2, HA3, L3, and HA4; wherein L1, L2 and L3 each is independently a linker sequence or absent; and wherein the first, second, third and fourth influenza viruses are types (1) A1, A2, B1, and B2; (2) , A1, B1, A2, and B2; (3) B1, A1, B2, and A2, or (4) B1, B2, A1, and A2; wherein A1 and A2 are the first and second subtypes of influenza A viruses; and B1 and B2 are the first and second subtypes of influenza B viruses. In some embodiments, the Z sequence comprises a first NA (NA1) sequence encoding an NA antigen from a first influenza virus that is type A or B. In some embodiments, the Z sequence further comprises a second NA (NA2) sequence encoding an NA antigen from a second influenza virus that is type A or B. In some embodiments, the circRNAs comprise in the following order: TI, NA1, L, and NA2; wherein L is a linker sequence or absent; and wherein the first and second influenza viruses are types (1) A1 and A2; (2) B1 and B2; (3) A and B; or (4) B and A; wherein A1 and A2 are the first and second subtypes of influenza A viruses; and B1 and B2 are the first and second subtypes of influenza B viruses. In some embodiments, the Z