Vaccine compositions having improved stability and immunogenicity
Inventors
Smith, Gale • Liu, Ye • Tian, Jing-Hui • MASSARE, Michael J. • BODDAPATI, Sarathi • Shane, Erica • Oliver, Cynthia • Glenn, Gregory
Assignees
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Publication Number
US-11364294-B2
Publication Date
2022-06-21
Expiration Date
Abstract
Disclosed herein are nanoparticles suitable for use in vaccines. The nanoparticles present antigens from pathogens surrounded to and associated with a detergent core resulting in enhanced stability and good immunogenicity. Dosages, formulations, and methods for preparing the vaccines and nanoparticles are also disclosed.
Core Innovation
The invention relates to vaccine compositions and recombinant vaccine nanoparticles comprising a non-ionic detergent core and a viral glycoprotein. In particular, the viral glycoprotein consists of a trimeric influenza HA glycoprotein configured with a head region projecting outward from the non-ionic detergent core and a transmembrane domain associated with the non-ionic detergent core, and the amino acid sequence of the influenza HA glycoprotein has 100% identity to the amino acid sequence of the native influenza HA protein, with the non-ionic detergent core being PS80.
The platform further defines the composition using a pharmaceutically acceptable buffer and, in a vaccine composition embodiment, an ISCOM matrix adjuvant. The nanoparticles are characterized by a transition midpoint (Tm) peak measured by differential scanning calorimetry within specified ranges, including about 60°C to about 75°C, providing a product characteristic associated with stability.
A related aspect of the invention is a method of preparing recombinant influenza nanoparticles by binding an influenza HA glycoprotein-containing protein extract to a protein purification column, performing detergent exchange to replace a first detergent with a second detergent, and eluting the bound influenza glycoprotein in the presence of PS80 to provide the nanoparticle. The method requires that the nanoparticle transition midpoint (Tm), as measured by differential scanning calorimetry, is at least about 60, while using buffers having pH not below 7.0 and maintaining 100% identity of the HA amino acid sequence to native influenza HA.
The documented disclosure emphasizes that the PS80 detergent-core nanoparticle configuration maintains antigenic sites and supports thermostability, while retaining immunogenicity outcomes. Additional embodiments include nanoparticles carrying influenza HA glycoproteins from different influenza strains and additional structural constraints for HA polypeptide components.
Claims Coverage
The identified independent claims are clm-00001, clm-00005, and clm-00010, covering a pharmaceutical composition with PS80-core nanoparticles presenting trimeric influenza HA, a vaccine composition adding a specified buffer and an ISCOM matrix adjuvant, and a preparation method for recombinant influenza nanoparticles via detergent exchange to form PS80-core nanoparticles with thermal-stability constraints. Across these independent claims, the core inventive features are the PS80 non-ionic detergent core with trimeric influenza HA (100% identity to native HA) configured with outward head and detergent-associated transmembrane domain, together with buffer/adjuvant and preparation and Tm/pH constraints.
PS80-core nanoparticles with trimeric influenza HA configured head-out and detergent-associated transmembrane
A composition comprising a nanoparticle comprising a non-ionic detergent core and a viral glycoprotein, wherein the viral glycoprotein consists of a trimeric 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 amino acid sequence of the influenza HA glycoprotein has 100% identity to the amino acid sequence of the native influenza HA protein; wherein the non-ionic detergent is PS80.
Pharmaceutically acceptable buffer with PS80-core trimeric influenza HA nanoparticles
A composition comprising a pharmaceutically acceptable buffer together with a nanoparticle comprising a non-ionic detergent core and a viral glycoprotein, wherein the viral glycoprotein consists of a trimeric influenza HA glycoprotein configured with a head region that projects outward and a transmembrane domain associated with the non-ionic detergent core, wherein the amino acid sequence of the influenza HA glycoprotein has 100% identity to the native influenza HA protein, and wherein the non-ionic detergent is PS80.
Vaccine composition with PS80-core trimeric influenza HA nanoparticles, specified buffer, and ISCOM matrix adjuvant
A vaccine composition comprising a nanoparticle comprising a non-ionic detergent core and a viral glycoprotein, wherein the viral glycoprotein consists of a trimeric influenza HA glycoprotein, and wherein the non-ionic detergent is PS80, 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 amino acid sequence of the influenza HA glycoprotein has 100% identity to the amino acid sequence of the native influenza HA protein; a buffer comprising 25 mM sodium phosphate, pH 7.5, and 150 mM sodium chloride; and an ISCOM matrix adjuvant.
Method by detergent exchange using PS80 to prepare recombinant influenza nanoparticles with trimeric influenza HA head-out and detergent-associated transmembrane
A method of preparing a recombinant influenza nanoparticle comprising steps of binding a protein extract comprising a first detergent and influenza HA glycoprotein to a protein purification column, wherein the column binds the influenza glycoprotein; performing a detergent exchange by substantially replacing the first detergent with a second detergent; and eluting the bound influenza glycoprotein from the column in the presence of the second detergent to provide the nanoparticle, wherein the second detergent is PS80; wherein the transition midpoint (Tm) of the nanoparticle, as measured by differential scanning calorimetry is at least about 60, wherein no buffer used during preparation has a pH of below 7.0, and wherein the amino acid sequence of the influenza HA glycoprotein has 100% identity to the amino acid sequence of the native influenza HA glycoprotein, and wherein the nanoparticle consists of a viral glycoprotein and a non-ionic detergent core, wherein the viral glycoprotein is a trimeric HA glycoprotein, and wherein the 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, and wherein the non-ionic detergent is PS80.
Overall, the claim set concentrates on PS80-based non-ionic detergent-core nanoparticles that present a trimeric influenza HA glycoprotein with a head region projecting outward and a detergent-associated transmembrane domain, while maintaining 100% identity to native influenza HA. The independent claims further cover formulation with a pharmaceutically acceptable buffer or with a specified sodium phosphate/sodium chloride buffer plus an ISCOM matrix adjuvant, and they include a preparation method that uses detergent exchange to produce PS80-core nanoparticles meeting differential scanning calorimetry Tm and buffer pH constraints.
Stated Advantages
Resistance to degradation under stressors including thermal, pH extremes, oxidation, and agitation.
Improved protease/trypsin resistance for properly folded influenza HA.
Maintained antigenic sites.
Improved thermostability.
Improved immunogenicity and improved epitope presentation.
Cross-neutralization outcomes in the documented disclosure and maintained neutralizing responses.
Documented Applications
Vaccine compositions and protective immunogenicity outcomes for Ebola with a Matrix-M/ISCOM matrix adjuvant context described in the disclosure.
Influenza vaccination outcomes including immunogenicity and neutralizing responses, including cross-neutralization as described in the disclosure.
RSV antigenic site II consistency and neutralizing response outcomes described in the disclosure.
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