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BR-122025027285-A2 - Uses of a composition to prevent viral infection and method for producing a recombinant RSV F glycoprotein nanoparticle.

BR122025027285A2BR 122025027285 A2BR122025027285 A2BR 122025027285A2BR-122025027285-A2

Abstract

This descriptive report reveals nanoparticles suitable for use in vaccines. The nanoparticles feature pathogen antigens surrounded and associated with a detergent core, resulting in increased stability and good immunogenicity. Dosages, formulations, and methods for preparing the vaccines and nanoparticles are also disclosed.

Inventors

  • Gale Smith
  • Ye Liu
  • Jing-Hui Tian
  • Michael Massare
  • Sarathi BODDAPATI
  • Erica Shane
  • Cynthia Oliver
  • Gregory Glenn

Assignees

  • NOVAVAX, INC.

Dates

Publication Date
20260317
Application Date
20160906
Priority Date
20150903

Claims (16)

  1. 1. Use of a composition in the manufacture of a medicament to prevent viral infection in an individual, the composition characterized by comprising: (i) a nanoparticle comprising a nonionic detergent core and an influenza HA glycoprotein, wherein the influenza HA glycoprotein contains a head region projecting outward from the nonionic detergent core and a transmembrane domain that is associated with the nonionic detergent core, wherein the influenza HA glycoprotein is an HA0 glycoprotein, wherein the amino acid sequence of the influenza HA glycoprotein is 100% identical to the amino acid sequence of the native influenza HA protein; wherein the nonionic detergent is PS80; and (ii) a pharmaceutically acceptable buffer.
  2. 2. Use according to claim 1, characterized in that the composition comprises an adjuvant.
  3. 3. Use according to claim 2, characterized in that the adjuvant is an aluminum adjuvant and at least 80% of the adjuvant is attached to the nanoparticle.
  4. 4. Use according to claim 1, characterized in that the composition does not contain an added adjuvant.
  5. 5. Use of a composition in the manufacture of a medicament to prevent viral infection in an individual, the composition characterized by comprising: (i) a nanoparticle comprising a PS80 detergent core and an influenza HA glycoprotein, wherein the influenza HA glycoprotein contains a head region that projects outward from the non-ionic detergent core and a transmembrane domain that is associated with the non-ionic detergent core, wherein the influenza HA glycoprotein is an HA0 glycoprotein, wherein the amino acid sequence of the influenza HA glycoprotein is 100% identical to the amino acid sequence of the native influenza HA protein; (ii) a buffer comprising 25 mM sodium phosphate, pH 7.5 and 150 mM sodium chloride; and (iii) an ISCOM matrix adjuvant.
  6. 6. Use according to claim 5, characterized in that the ISCOM matrix adjuvant comprises a first ISCOM matrix containing fraction A and a second ISCOM matrix containing fraction C.
  7. 7. Use according to claim 6, characterized in that the first ISCOM matrix comprises 70% to 95% by weight of the total ISCOM matrix and the second ISCOM matrix comprises the remainder.
  8. 8. Use according to claim 7, characterized in that the first ISCOM matrix comprises 85% by weight of the total ISCOM matrix and the second ISCOM matrix comprises the remainder.
  9. 9. Use, according to claim 1 or 5, characterized in that the influenza HA protein subtype is selected from the group consisting of H1, H3, H4, H5 and H7.
  10. 10. Use, according to claim 1 or 5, characterized in that the nanoparticle has a transition midpoint peak (Tm) in a range of about 60 °C to about 75 °C and wherein Tm is measured by differential scanning calorimetry.
  11. 11. Use, according to claim 1 or 5, characterized in that the composition further comprises a second nanoparticle comprising a second influenza HA glycoprotein, wherein the HA glycoprotein contains a head region that projects outward from the nonionic detergent core and a transmembrane domain, which is associated with the nonionic detergent core, wherein the second influenza HA glycoprotein comprises an HA1 polypeptide and an HA2 polypeptide connected by a disulfide bond, wherein the nonionic detergent is PS80.
  12. 12. Use, according to claim 1 or 5, characterized in that the composition comprises a second nanoparticle, wherein the HA glycoprotein in the first nanoparticle is from a different influenza strain than that of the second nanoparticle.
  13. 13. Use, according to claim 1 or 5, characterized in that the composition comprises three nanoparticles, wherein the HA glycoprotein in each nanoparticle is from a different influenza strain than the other two nanoparticles.
  14. 14. Use, according to claim 1 or 5, characterized in that the composition comprises four nanoparticles, wherein the HA glycoprotein in each nanoparticle is from a different influenza strain than the other three nanoparticles.
  15. 15. Method for producing a recombinant RSV F glycoprotein nanoparticle characterized by comprising the steps of: (i) binding a protein extract comprising a first detergent and an RSV F glycoprotein to a protein purification column, wherein the column binds to the RSV F glycoprotein; (ii) performing a detergent exchange that substantially replaces the first detergent with a second detergent; and (iii) eluting the bound RSV F glycoprotein from the column in the presence of the second detergent to provide the nanoparticle, wherein the second detergent is PS80.
  16. 16. Method according to claim 15, characterized in that the first detergent is NP-9.

Description

CROSS-REFERENCE WITH RELATED ORDERS [001] This application incorporates the disclosures of U.S. Provisional Applications Serial Nos. 62/213,947 filed September 3, 2015; 62/255,786 filed November 16, 2015; 62/309,216 filed March 16, 2016; and 62/350,973 filed June 16, 2016 in their entirety for all purposes. DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY [002] The content of the text file submitted electronically with this application is incorporated into this descriptive report by reference in its entirety: A machine-readable copy of the Sequence Listing (file name: NOVV_060_03US_SeqList_ST25.txt, date saved: September 6, 2016; file size: 91 kilobytes). TECHNICAL FIELD [003] The present disclosure relates generally to nanoparticles useful for stimulating immune responses. The nanoparticles deliver antigens, for example, glycoprotein antigens, associated with a detergent core and are typically produced using recombinant approaches. The nanoparticles possess enhanced stability and enhanced epitope presentation. The disclosure also provides compositions containing the nanoparticles, methods for their production, and methods for stimulating immune responses. FUNDAMENTALS [004] Infectious diseases remain a problem worldwide. Although progress has been made in developing vaccines against some pathogens, many remain a threat to human health. Most notably HIV, for which a vaccine remains elusive. Attempts have been made to produce vaccines for certain pathogens, but have resulted in failure that has caused additional pathology. Other pathogens also remain a problem, including Ebola, which sporadically emerges as an epidemic—particularly in Africa—and gives rise to loss of life and global economic impact. The influenza virus is yet another virus for which the existing vaccine provides some protection, but technical challenges in producing the virus mean that seasonal influenza vaccines may provide inadequate protection. [005] The distribution of an effective vaccine relies on a combination of achievements. The vaccine must stimulate an effective immune response that reduces infection or disease by a sufficient amount to be beneficial. A vaccine must also be stable enough to be used in challenging environments where refrigeration may not be available. [006] Therefore, there is a continuing interest in producing vaccines against viruses that pose public health concerns across the globe, and there remains a permanent need to produce effective vaccines with good stability. SUMMARY OF THE INVENTION [007] The present disclosure provides nanoparticles suitable for inducing immune responses against pathogens. The nanoparticles offer increased stability as well as effective immunogenicity. In particular, the pathogen is a virus and, typically, the antigen used to produce a viral nanoparticle is a viral glycoprotein. [008] In one aspect, the development provides nanoparticles containing viral proteins that have increased stability. In some embodiments, the development comprises a vaccine composition comprising a nanoparticle comprising a nonionic detergent, a viral glycoprotein, and a pharmaceutical buffer. In typical embodiments, the nonionic detergent may be selected from the group consisting of PS20, PS40, PS60, PS65, and PS80. In some embodiments, the composition does not comprise any free nonionic detergent. One or more glycoprotein antigen molecules surround a detergent core, which contains the nonionic detergent, and this provides a nanoparticle structure that promotes immunogenicity and inhibits antigen degradation. [009] In some embodiments, the antigen is selected from the group consisting of an RSV F protein, an influenza HA protein, an influenza NA protein, and combinations thereof. Other antigens may be used, including Ebola. Typically, the antigen is a glycoprotein. [0010] Optionally, the RSV F protein is a trimeric RSV F protein. The RSV F protein induces the production of neutralizing antibodies. In further embodiments, the neutralizing antibodies recognize the RSV F protein in a post-fusion and/or pre-fusion state. In a further aspect, each PS80 particle may comprise between 4 and 7 RSV F proteins. [0011] In some embodiments, an RSV F composition may comprise sodium phosphate at a concentration between 15 mM and 25 mM; NaCl at a concentration between 125 mM and 175 mM; histidine between 0.25% and 2% w/v; and the pH of the composition is between 5.8 and 7.2. [0012] In some embodiments, an influenza HA or NA composition may comprise sodium phosphate at a concentration between 15 mM and 25 mM; NaCl at a concentration between 125 mM and 300 mM; histidine between 0.25% and 2% w/v; and the pH of the composition is a pH above 6.8 and typically a pH below about 8.0. [0013] In some embodiments, the composition includes an adjuvant. In additional embodiments, the adjuvant is alum or Matrix M™. In some embodiments, the composition does not include an adjuvant. [0014] In some embodiments, a method of infection pre