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EP-4735028-A1 - GENETICALLY DETOXIFIED MUTANT OF NEISSERIA AND OUTER MEMBRANE VESICLE (OMV) VACCINE

EP4735028A1EP 4735028 A1EP4735028 A1EP 4735028A1EP-4735028-A1

Abstract

Disclosed are isolated PorA - PorB - RmpM - LpxL1 - N . meningitidis and compositions including an effective amount of OMVs produced from these PorA - PorB - RmpM - LpxL1 - N. meningitidis . Also disclosed are methods for using these compositions to induce an immune response to Neisseria , such as N. meningitidis and N. gonorrhoeae.

Inventors

  • BASH, MARGARET C.
  • MATTHIAS, Kathryn

Assignees

  • The United States of America, as represented by The Secretary, Department of Health and Human Services

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. 1. An isolated PorA PorB RmpM LpxLl Neisseria (N.) meningitidis.
  2. 2. The isolated PorA'PorB'RmpM'LpxLT N. meningitidis of claim 1, wherein the PorA'PorB' RmpM'LpxLl' Neisseria meningitidis is also SiaD-.
  3. 3. The isolated PorA PorB RmpM LpxLl' N. meningitidis of claim 1 or claim 2, wherein the N. meningitidis is serogroup A, B or C.
  4. 4. An immunogenic composition comprising an effective amount of outer membrane microvesicles from the isolated PorA PorB RmpM LpxLl' N. meningitidis of any one of claims 1-3, and a pharmaceutically acceptable carrier.
  5. 5. The immunogenic composition of claim 4, wherein the outer membrane microvesicles are microvesicles, blebs, or a combination thereof.
  6. 6. The immunogenic composition of any one of claims 1-5, further comprising an adjuvant.
  7. 7. A method of inducing an immune response to Neisseria in a mammalian subject, comprising administering to the mammalian subject the immunogenic composition of any one of claims 4-6, thereby inducing the immune response.
  8. 8. The method of claim 7, wherein the immune response is a protective immune response.
  9. 9. The method of claim 8, wherein the protective immune response is for an N. meningitidis infection.
  10. 10. The method of claim 8, wherein the protective immune response is for an N. gonorrhoeae infection.
  11. 11. The method of claim 7, wherein the immune response is a therapeutic response.
  12. 12. The method of claim 7, wherein the subject has a N. meningitidis infection, and administration of the immunogenic composition increases clearance of the TV. meningitidis.
  13. 13. The method of claim 7, wherein the subject has a N. gonorrhoeae infection, and administration of the immunogenic composition increases clearance of N. gonorrhoeae .
  14. 14. The method of claim 7, wherein the mammalian subject is a healthy subject.
  15. 15. The method of any one of claims 7-14, wherein the mammalian subject is a human.
  16. 16. A method of inducing an immune response to Neisseria gonorrhoeae in a mammalian subject, comprising administering to the mammalian subject an immunogenic composition comprising an effective amount of outer membrane microvesicles from a PorA PorB RmpM LpxLl N. meningitidis and a pharmaceutically acceptable carrier, thereby inducing the immune response to Neisseria gonorrhoeae.
  17. 17. The method of claim 16, wherein the PorA PorB" N. meningitidis is SiaD '.
  18. 18. The method of claim 16 or 17, wherein the outer membrane microvesicles are micro vesicles, blebs, or a combination thereof.
  19. 19. The method of any one of claims 16-18, wherein the N. meningitidis is serogroup A, B or C.
  20. 20. The method of any one of claims 16-19, wherein the immunogenic composition further comprises an adjuvant.

Description

GENETICALLY DETOXIFIED MUTANT OF NEISSERIA AND OUTER MEMBRANE VESICLE (OMV) VACCINE CROSS REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No. 63/524,512, filed June 30, 2023, which is incorporated by reference in its entirety. FIELD OF THE DISCLOSURE This relates to immunogenic compositions comprising outer membrane microvesicles (OMVs) from PorA PorB RmpM LpxLl' Neisseria, such asPorA PorB RmpM LpxLI SiaD' Neisseria (N.) meningitidis, that are of use to induce an immune response to Neisseria, including N. meningitidis and N. gonorrhoeae. BACKGROUND Neisseria is a genus of Gram-negative bacteria that colonize the mucosal surfaces of many animals. There are eleven species that colonize human, of which two, N. meningitidis and N. gonorrhoeae, are pathogenic. N. meningitidis is the causative agent of meningitis and meningococcal septicemia. N. gonorrhoeae is the causative agent of gonorrhea. The genomes of at least ten of the Neisseria species have been completely sequenced. Neisseria meningitidis is estimated to cause 1.2 million cases of invasive disease annually, resulting in approximately 135,000 deaths. Characterized by rapid onset and disease progression, infection with N. meningitidis is also associated with high morbidity, with approximately 20% of invasively infected individuals suffering permanent, debilitating sequelae, including brain damage, hearing loss, and necrosis of the limbs, necessitating amputation. The majority of invasive meningococcal disease is caused by six serogroups, A, C, W, Y, X, and B. Vaccines that target the capsular polysaccharides of serogroups A, C, W, Y, and X have been licensed or are currently in the developmental phase. In contrast, the capsular polysaccharide of scrogroup B meningococcus (McnB) closely resembles a sugar moiety present on human cells and is, as a consequence, poorly immunogenic. MenB-specific vaccines, therefore, must necessarily target bacterial subcapsular antigens. A need remains for additional compositions that can be used to induce an immune response to N. meningitidis and N. gonorrhoeae. SUMMARY OF THE DISCLOSURE Disclosed are isolated PorA PorB RmpM LpxLI . meningitidis (also called APorAAPorBARmpMALpxL) and compositions including an effective amount of OMVs produced from these PorA PorB RmpM LpxLl ?/. meningitidis. Also disclosed are methods for using these compositions to induce an immune response to Neisseria, such as N. meningitidis and N. gonorrhoeae. Also disclosed are methods for inducing an immune response to N. gonorrhoeae in a mammalian subject. These methods include administering to the mammalian subject an immunogenic composition comprising an effective amount of OMVs from PorA PorB RmpM LpxL I \-V. meningitidis and a pharmaceutically acceptable carrier, thereby inducing the immune response to N. gonorrhoeae. In some aspects, the PorA PorB RmpM LpxLl V. meningitidis is a PorA PorB RmpM LpxLLSiaD- N. meningitidis. The foregoing and other features and advantages of the invention will become more apparent from the following detailed description of several aspects which proceeds with reference to the accompanying figures. BRIEF DESCRIPTION OF THE FIGURES FIG. 1. Diagram of the lipid A structure of N. meningitidis lipooligosaccharide (LOS). The hatched rectangle indicates the lauroyl chain added to the lipid A backbone by LpxLl. FIGS. 2A-2B. Diagram of the mechanism of action of the tetR-sacB protein products. FIG. 2A: In the absence of chlortetracycline (cTc), the tetR gene is transcribed and translated to produce the Tet repressor, which binds to the Ptet promoter, preventing binding of RNA polymerase (RNAP). The sacB gene cannot be transcribed, and le vansucrase will not be produced, allowing for growth of bacteria on plates containing sucrose. FIG. 2B: When present, cTc will bind to the Tet repressor, inducing a conformational change that relieves DNA binding, allowing RNAP to bind to the Ptet promoter. The sacB gene can be transcribed and translated, producing levansucrase, which cleaves sucrose into a product that is toxic to N. meningitidis . FIGS. 3A-3C. Cloning strategy for generation of markerless mutant strains. (FIG. 3 A) The 5’ and 3’ untranslated regions (UTRs) of the gene to be deleted (e.g., IpxLl) were amplified from MC58 genomic DNA (gDNA) using primer pairs incorporating restriction enzyme sites RE1/RE2 and RE2/RE3, respectively. The 5’ and 3’ UTR sequences were then sequentially cloned into pGEM-3Z via restriction enzyme digest, creating plasmid pINT. (FIG. 3B) The positive/negative selection tetR-sacB-nptll cassette was amplified from plasmid pJJ260 using primers bearing RE2 restriction enzyme site sequences. The PCR product was then cloned into pINT between the 5’ and 3’ UTR sequences via digestion, creating plasmid pDEL. (FIG. 3C) Transformation of pDEL into MC58 functioned to replace the native gene (e.g., IpxLl) with the tetR-sacB-nptll cassette, creating a new str