IP Library › Granted Patent US 12,491,240
Granted Patent B2
US 12,491,240 · App. 17/435,590 · Granted Dec 9, 2025

Method for producing influenza HA split vaccine

Inventors: Yoshimasa Takahashi (Tokyo, JP); Yu Adachi (Tokyo, JP); Manabu Ato (Tokyo, JP)
Assignees: JAPAN as represented by DIRECTOR GENERAL of National Institute of Infectious Diseases; Sumitomo Pharma Co., Ltd.
A61K39/145A61P31/16
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,491,240
App. No.
17/435,590
Granted
Dec 9, 2025
Kind
B2
Abstract

Provided is a method for producing an influenza HA split vaccine which produces an antibody that binds to an HA stem region of influenza, the HA stem region being less likely to cause antigenic variation, An influenza HA split vaccine is subjected to an acidic treatment. Through the acidic treatment, an influenza HA split vaccine which produces an antibody that binds to an LAH of the HA stem region is obtained. This influenza HA split vaccine has an excellent ability against infection of other influenza viruses of different antigenicity.

Claims (30)

1 . A method for producing an influenza hemagglutinin (HA) split vaccine which is capable of producing an antibody that binds to a long alpha helix (LAH) of an HA stem region, the method comprising:

treating influenza virus particles with ether to obtain a current HA split vaccine; and

subjecting the current HA split vaccine, which has not undergone a formalin treatment, to an acidic treatment at 38° C. to 55° C., thus producing the influenza HA split vaccine.

2 . A method for producing an influenza HA split vaccine which is capable of producing an antibody that binds to an LAH of an HA stem region, the method comprising:

treating influenza virus particles with ether to obtain a current HA split vaccine;

subjecting the current HA split vaccine to an acidic treatment at 38° C. to 55° C., thus producing the influenza HA split vaccine; and

thereafter, subjecting the influenza HA split vaccine to a formalin treatment.

3 . The method of claim 1 , the method further comprising:

after subjecting the current HA split vaccine to the acidic treatment to produce the influenza HA split vaccine, subjecting the influenza HA split vaccine to the formalin treatment.

4 . A method for producing an influenza HA split vaccine which is capable of producing an antibody that binds to an LAH of an HA stem region and which has a protective effect against an antigen-mutated influenza virus, the method comprising:

treating influenza virus particles with ether to obtain a current HA split vaccine; and

subjecting the current HA split vaccine to an acidic treatment at 38° C. to 55° C.

5 . The method of claim 1 , wherein the acidic treatment is performed at a pH of 4.4 to 5.8.

6 . The method of claim 1 , wherein the influenza HA split vaccine is of type H3N2 or type H1N1.

7 . A vaccine which has a protective effect against an antigen-mutated influenza virus, and which is capable of producing an antibody that binds to an LAH of an HA stem region, the vaccine being produced by subjecting a current HA split vaccine to an acidic treatment at 38° C. to 55° C. to produce an influenza HA split vaccine.

8 . The method of claim 2 , wherein the acidic treatment is performed at a pH of 4.4 to 5.8.

9 . The method of claim 2 , wherein the influenza HA split vaccine is of type H3N2 or type H1N1.

10 . The method of claim 3 , wherein the acidic treatment is performed at a pH of 4.4 to 5.8.

11 . The method of claim 3 , wherein the influenza HA split vaccine is of type H3N2 or type H1N1.

12 . The method of claim 4 , wherein the acidic treatment is performed at a pH of 4.4 to 5.8.

13 . The method of claim 4 , wherein the influenza HA split vaccine is of type H3N2 or type H1N1.

14 . The vaccine of claim 7 , the HA influenza split vaccine being produced by treating influenza virus particles with ether to obtain the current HA split vaccine, and then subjecting the current HA split vaccine to the acidic treatment.

15 . The method of claim 1 , wherein the acidic treatment is performed at a pH of 3.0 to 6.5.

16 . The method of claim 1 , wherein the acidic treatment is performed at a pH of 4.0 to 6.0.

17 . The method of claim 2 , wherein the acidic treatment is performed at a pH of 3.0 to 6.5.

18 . The method of claim 2 , wherein the acidic treatment is performed at a pH of 4.0 to 6.0.

19 . The method of claim 3 , wherein the acidic treatment is performed at a pH of 3.0 to 6.5.

20 . The method of claim 3 , wherein the acidic treatment is performed at a pH of 4.0 to 6.0.

21 . The method of claim 4 , wherein the acidic treatment is performed at a pH of 3.0 to 6.5.

22 . The method of claim 4 , wherein the acidic treatment is performed at a pH of 4.0 to 6.0.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 23, 2022
From: TAKAHASHI, YOSHIMASA; ADACHI, YU; ATO, MANABU
To: JAPAN AS REPRESENTED BY DIRECTOR GENERAL OF NATIONAL INSTITUTE OF INFECTIOUS DESEASES
Reel/Frame 060876/0299 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 23, 2022
From: JAPAN AS REPRESENTED BY DIRECTOR GENERAL OF NATIONAL INSTITUTE OF INFECTIOUS DESEASES
To: JAPAN AS REPRESENTED BY DIRECTOR GENERAL OF NATIONAL INSTITUTE OF INFECTIOUS DESEASES; SUMITOMO PHARMA CO., LTD.
Reel/Frame 060876/0327 →
Priority Claims (1)
JP 2019-038662 · Mar 4, 2019 · national
Continuity (1)
Related Publication 20220152191A1 · May 19, 2022
References Cited (92)
US 10912825B2 · Ni · 2021 [cited by examiner]
US 11732031B2 · Takahashi · 2023 [cited by examiner]
US 12059462B2 · Takahashi · 2024 [cited by examiner]
US 20090136543A1 · Ballou · 2009 [cited by examiner]
US 20100099870A1 · Isobe et al. · 2010 [cited by applicant]
US 20120270255A1 · Graninger et al. · 2012 [cited by applicant]
US 20130209499A1 · Garcia-Sastre et al. · 2013 [cited by applicant]
US 20150098966A1 · Ni et al. · 2015 [cited by applicant]
US 20160045590A1 · Milner et al. · 2016 [cited by applicant]
US 20160052997A1 · Hong et al. · 2016 [cited by applicant]
US 20180021258A1 · Graham et al. · 2018 [cited by applicant]
US 20180179256A1 · De Groot · 2018 [cited by examiner]
US 20180282334A1 · Ban · 2018 [cited by examiner]
US 20190142930A1 · Ni et al. · 2019 [cited by applicant]
US 20190345231A1 · Takahashi et al. · 2019 [cited by applicant]
US 20200121600A1 · Fukushima · 2020 [cited by examiner]
US 20210353737A1 · Takahashi et al. · 2021 [cited by applicant]
US 20220072126A1 · Onita · 2022 [cited by examiner]
US 20220133875A1 · Glenn · 2022 [cited by examiner]
US 20230201329A1 · Hanon · 2023 [cited by examiner]
US 20250009869A1 · Takahashi et al. · 2025 [cited by applicant]
CN 101524538 · 2009 [cited by applicant]
CN 102939096 · 2013 [cited by applicant]
JP 2016516090 · 2016 [cited by applicant]
JP 2018501801 · 2018 [cited by applicant]
JP 2019043937 · 2019 [cited by applicant]
KR 1020110047193 · 2011 [cited by applicant]
KR 1020110102198 · 2011 [cited by applicant]
WO WO2008054481 · 2008 [cited by applicant]
WO WO2009143457A2 · 2009 [cited by examiner]
WO WO2010047509 · 2010 [cited by applicant]
WO WO2011123495 · 2011 [cited by applicant]
WO WO2013173256 · 2013 [cited by applicant]
WO WO2020022272 · 2020 [cited by applicant]
Chun et al., “Universal antibodies and their applications to the quantitative determination of virtually all subtypes of the influenza A viral hemagglutinins,” Vaccine, Nov. 2008, 26(48):6068-6076. [cited by applicant]
Extended European Search Report in European Appln. No. 19842246.1, dated Mar. 21, 2022, 12 pages. [cited by applicant]
Kazaks et al., “Production and purification of chimeric HBc virus-like particles carrying influenza virus LAH domain as vaccine candidates,” BMC Biotechnology, Nov. 2017, 17(1), 79, 11 pages. [cited by applicant]
White et al., “Anti-peptide antibodies detect steps in a protein conformational change: low-pH activation of the influenza virus hemagglutinin,” The Journal of Cell Biology, Dec. 1987, 105(6):2887-2896. [cited by applicant]
Zhou et al., “Improving influenza vaccines: challenges to effective implementation,” Current Opinion in Immunology, Apr. 2018, 53:88-95. [cited by applicant]
Puri et al., “Conformational Changes and Fusion Activity of Influenza Virus Hemagglutinin of the H2 and H3 Subtypes: Effects of Acid Pretreatment”, J. Virol., Aug. 1990, 64(8):3824-3832. [cited by applicant]
Extended European Search Report in European Appln. No. 20766488.9, dated Aug. 25, 2022, 7 pages. [cited by applicant]
Office Action in U.S. Appl. No. 16/292,065, dated Aug. 17, 2022, 8 pages. [cited by applicant]
Office Action in U.S. Appl. No. 16/292,065, dated Jan. 20, 2022, 8 pages. [cited by applicant]
Office Action in U.S. Appl. No. 16/292,065, dated Oct. 12, 2021, 7 pages. [cited by applicant]
Office Action in U.S. Appl. No. 16/292,065, dated Oct. 5, 2020, 10 pages. [cited by applicant]
Ren et al., “Epitope-focused vaccine design against influenza A and B viruses,” Curr. Opin. Immunol., 2016, 42:83-90. [cited by applicant]
Iwami Kagaku Dictionary, Saburo Nagakura et al. (ed.), Fifth Edition, Nov. 2003, Iwanami Shoten, 327, 3 pages (with partial English translation). [cited by applicant]
Notice of Allowance in U.S. Appl. No. 16/292,065, dated Mar. 3, 2023, 9 pages. [cited by applicant]
Chen et al., “Protection against Multiple Subtypes of Influenza Viruses by Virus-Like Particle Vaccines Based on a Hemagglutinin Conserved Epitope,” Biomed Res. Int., Feb. 2015, 2015(901817), 12 pages. [cited by applicant]
Notice of Allowance in U.S. Appl. No. 16/292,065, dated Jun. 2, 2023, 9 pages. [cited by applicant]
Notice of Allowability in U.S. Appl. No. 16/292,065, dated Jun. 22, 2023, 5 pages. [cited by applicant]
Graves et al., “Preparation of Influenza Virus Subviral Particles Lacking the HA1 Subunit of Hemagglutinin: Unmasking of Cross-Reactive HA2 Determinants,” Virology, Apr. 1983, 126(1):106-116. [cited by applicant]
Notice of Allowance in U.S. Appl. No. 16/292,065, dated Dec. 8, 2022, 9 pages. [cited by applicant]
Notice of Allowance in U.S. Appl. No. 17/262,021, dated Nov. 8, 2023, 15 pages. [cited by applicant]
Office Action in U.S. Appl. No. 17/262,021, dated Aug. 4, 2022, 8 pages. [cited by applicant]
U.S. Appl. No. 18/341,960, filed Jun. 27, 2023, Takahashi et al. [cited by applicant]
[No Author Listed] “The 16th Awaji International Forum on Infection and Immunity Program at a Glance,” Poster, Presented at The 16th Awaji International Forum on Infection and Immunity, Japan, Sep. 5-8, 2017, 1 page. [cited by applicant]
Adachi et al., “Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies,” Nature Communications, Aug. 2019, 10(3883):1-13. [cited by applicant]
Byrd-Leotis et al., “Influenza Hemagglutinin (HA) Stem Region Mutations That Stabilize or Destabilize the Structure of Multiple HA Subtypes,” Journal of Virology, Apr. 2015, 89(8):4504-4516. [cited by applicant]
Doms et al., “Quaternary Structure of Influenza Virus Hemagglutinin after Acid Treatment,” Journal of Virology, Dec. 1986, 60(3):833-839. [cited by applicant]
EP Extended European Search Report in European Appln. No. 18852584.4, dated Mar. 31, 2021, 7 pages. [cited by applicant]
Garcia et al., “Dynamic Changes during Acid-Induced Activation of Influenza Hemagglutinin,” Structure, Apr. 2015, 23(4):665-676, 13 pages. [cited by applicant]
International Preliminary Report on Patentability in International Appln. No. PCT/JP2020/008974, mailed Sep. 16, 2021, 13 pages (with English translation). [cited by applicant]
International Search Report and Written Opinion in International Appln. No. PCT/JP2020/008974, mailed Jun. 9, 2020, 16 pages (with English translation). [cited by applicant]
National Institute of Infectious Diseases, “Minimum Requirements for Biological Products,” retrieved from URL <https://www.niid.go.jp/niid/images/qa/seibutuki/MRBP_english/mrbp_2006.pdf>, 2006, 339 pages (English versio… [cited by applicant]
PCT International Preliminary Report on Patentability in International Appln. No. PCT/JP2018/032537, dated Mar. 10, 2020, 9 pages (with English translation). [cited by applicant]
PCT International Search Report in International Appln. No. PCT/JP2018/032537, mailed Nov. 20, 2018, 6 pages (with English translation). [cited by applicant]
PCT Written Opinion in International Appln. No. PCT/JP2018/032537, mailed Nov. 20, 2018, 7 pages (with English translation). [cited by applicant]
Quan et al., “Immunogenicity of low-pH treated whole viral influenza vaccine,” Virology, Aug. 2011, 417(1):196-202. [cited by applicant]
Sanofi Pasteur, “450 Fluzone Quadrivalent,” retrieved from URL <https://www.seacoastmedical.com/storefrontCommerce/forms/ProductInfo/Fluzone%20Quadrivalent%20PI.pdf>, Jun. 2013, 31 pages. [cited by applicant]
Takahashi, “Abstract: Broadly protective antibodies and vaccines,” Presented at U.S.—Japan Cooperative Medical Sciences Program (USJCMSP), 22nd International Conference on Emerging Infectious Diseases in the Pacific Rim… [cited by applicant]
Takahashi, “Broadly protective antibodies and vaccines,” Presented at U.S.—Japan Cooperative Medical Sciences Program (USJCMSP), 22nd International Conference on Emerging Infectious Diseases in the Pacific Rim, Bangkok,… [cited by applicant]
Takahashi, “Regulation of antibody breadth to mutating viruses through distinct germinal center selection,” Poster, Presented at The 16th Awaji International Forum on Infection and Immunity, Japan, Sep. 5-8, 2017, 21 pa… [cited by applicant]
Zheng et al., “Influenza H7N9 LAH-HBc virus-like particle vaccine with adjuvant protects mice against homologous and heterologous influenza viruses,” Vaccine, Nov. 2016, 34(51):6464-6471. [cited by applicant]
Zost et al., “Immunodominance and Antigenic Variation of Influenza Virus Hemagglutinin: Implications for Design of Universal Vaccine Immunogens,” The Journal of Infectious Diseases, Apr. 2019, 219(Suppl 1): S38-S45. [cited by applicant]
Goff et al., “Adjuvants and Immunization Strategies to Induce Influenza Virus Hemagglutinin Stalk Antibodies,” PLoS One, Nov. 2013, 8(11):e79194, 11 pages. [cited by applicant]
Impagliazzo et al., “A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen,” Science, Sep. 18, 2015, 349(6254):1301-1306, 7 pages. [cited by applicant]
Kostolansky et al., “Inhibition of influenza virus haemolytic and haemagglutination activities by monoclonal antibodies to haemagglutinin glycopolypeptides HAI and HA2,” Acta Virologica, Dec. 1989, 33(6):504-512, 7 page… [cited by applicant]
Krammer, “Novel universal influenza virus vaccine approaches,” Current Opinion in Virology, Apr. 17, 2016:95-103. [cited by applicant]
Krammer, “The Quest for a Universal Flu Vaccine: Headless HA 2.0,” Cell Host Microbe, Oct. 14, 2015, 18(4):395-397. [cited by applicant]
Nachbagauer et al., “A chimeric haemagglutinin-based influenza split virion vaccine adjuvanted with AS03 induces protective stalk-reactive antibodies in mice,” NPJ Vaccines, Sep. 2016, 1:16015, 10 pages. [cited by applicant]
Nachbagauer et al., “A universal influenza virus vaccine candidate confers protection against pandemic H1N1 infection in preclinical ferret studies,” NPJ Vaccines, Sep. 14, 2017, 13 pages. [cited by applicant]
Office Action in U.S. Appl. No. 17/262,021, dated Dec. 23, 2022, 14 pages. [cited by applicant]
Steinhagen et al., “TLR-based immune adjuvants,” Vaccine, Apr. 2011, 29(17):3341-3355. [cited by applicant]
Valkenburg et al., “Stalking influenza by vaccination with pre-fusion headless HA mini-stem,” Scientific Reports, Apr. 2016, 11 pages. [cited by applicant]
Yassine et al., “Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection,” Nature Medicine, Aug. 2015, 21(9):1065-1070, 9 pages. [cited by applicant]
Office Action in U.S. Appl. No. 17/262,021, dated Aug. 30, 2023, 13 pages. [cited by applicant]
Harrison, “Viral membrane fusion,” Nat. Struct. Mol. Biol., Jul. 2008, 15(7):690-698. [cited by applicant]
Nguyen et al., “Targeting Antigens for Universal Influenza Vaccine Development,” Viruses, May 2021, 13(6):973, 21 pages. [cited by applicant]
Notice of Allowability in U.S. Appl. No. 16/292,065, dated Mar. 29, 2023, 8 pages. [cited by applicant]
U.S. Appl. No. 18/759,117, filed Jun. 28, 2024, Takahashi et al. [cited by applicant]
Office Action in U.S. Appl. No. 18/341,960, dated Nov. 7, 2024, 6 pages. [cited by applicant]