WO2022269343A1 - Vaccin multivalent pour la protection contre une infection à virus multiples - Google Patents
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- C—CHEMISTRY; METALLURGY
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- C—CHEMISTRY; METALLURGY
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- C—CHEMISTRY; METALLURGY
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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Definitions
- the present invention is generally related to the composition of a multivalent vaccine for protection against multiple virus infections (e.g., coronavirus, influenza) and method for the preparation thereof.
- virus infections e.g., coronavirus, influenza
- HA Hemagglutinin
- HA protein comprises two region HA1 (globular head domain) and HA2 (stem domain), wherein HA1 is more variable than HA2 region.
- a vaccine that can protect subjects against both of these pathogens including their various strains and variants.
- proper structural conformation of viral proteins is key to host receptor binding and the following host cell infection.
- Homotrimeric structure of viral proteins is required for effective infection in several virus types including corona virus, influenza virus, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV).
- HIV human immunodeficiency virus
- RSV respiratory syncytial virus
- trimeric S protein of SARS-CoV and SARS- CoV-2 is required for its binding to host receptor ACE2
- trimeric S protein of MERS-CoV is required for its binding to host receptor dipeptidyl peptidase 4 (DPP4).
- a multivalent vaccine comprising a recombinant chimeric protein wherein the recombinant chimeric protein comprises a receptor-interacting domain derived from any strain or variant of coronavirus and a stem region derived from any strain or variant of conservative region of hemagglutinin (HA) of influenza virus.
- the stem region derives from HA2 region.
- the HA comprises subtype H1, H2, H3, H4, H5, H6, H7 or H8.
- the receptor-interacting domain of the coronavirus is derived from receptor binding domain (RBD) of coronavirus.
- a method of preparation of the multivalent vaccine of the present invention comprising the steps of isolating a gene fragment encoding a receptor-interacting domain derived from any strain or variant of coronavirus; isolating a gene fragment encoding a stem region derived from conservative region of HA of any strain or variant of influenza virus; preparing a gene fragment comprising a trimerization domain; fusing the gene fragments of step 1, step 2 and step 3; expressing the recombinant chimeric protein of claim 1 using the fused gene fragment of step 4; and purifying the recombinant chimeric protein of claim 1 expressed from step 5.
- FIG. 1A illustrates protein structure of acute respiratory syndrome coronavirus 2 (SARS CoV 2) spike protein
- FIG. 1A illustrates protein structure of acute respiratory syndrome coronavirus 2 (SARS CoV 2) spike protein
- FIG. 1B illustrates an embodiment of the recombinant chimeric protein of the present invention HA-C-RBD_spike.
- FIG. 2A illustrates the SDS-PAGE results of Spike-dTM, HA-C-RBD-spike, RBD-FH6 and RBD-F c
- FIG. 2B illustrates size-exclusion chromatography of Spike-dTM, HA-C-RBD- spike, RBD-FH6 and RBD-Fc.
- FIG. 3A illustrates the genetic fragment capable of expressing the recombinant chimeric protein of the present invention HA-C-RBD_spike
- FIG. 3B illustrates purification results of various embodiments of multivalent HA-C-RBD_spike chimeric protein of the present invention each corresponding to RBD region derived from RBD region of the Wuhan, B.1.1.7, B.1.617.2 and B.1.617.1 variants of the SARS-CoV-2.
- FIG. 4 illustrates receptor-binding activity of spike protein, HA, HA stem, RBD-FH6, and HA- C-RBD_spike with ACE2 receptor binding ELISA.
- FIG. 5 illustrates antigenicity determination of spike protein, HA, HA stem, RBD-FH6, and HA- C-RBD_spike with FI6 conformational mAb.
- FIG. 4 illustrates receptor-binding activity of spike protein, HA, HA stem, RBD-FH6, and HA- C-RBD_spike with FI6 conformational mAb.
- FIG. 6 illustrates the expression and purification results of fully-glycosylated (fg) and mono- glycosylated (mg) HA-C-RBD_spike chimeric protein.
- FIG. 7A depicts the ACE2 receptor binding assay, and FIG. 7B illustrates the receptor binding activity of glycosylated HA-C-RBD_spike chimeric protein of the present invention.
- FIG. 8A depicts FI6 binding to HA-stem, and FIG. 8B illustrates activity of glycosylated HA-C- RBD_spike chimeric protein in inducing HA stem domain-neutralizing antibodies.
- FIG. 9 illustrates the antibody binding activities against H1N1 subtype HA proteins, H3, and H7 in mice immunized with HA-C-RBD_spike chimeric protein.
- FIG. 10A illustrates the weight change
- FIG. 10B illustrates survival analysis of X- 181(H1N1)-challenged mice with spike protein or HA-C-RBD_spike vaccination.
- FIG. 11A illustrates the evaluation of the SARS-CoV-2 neutralizing antibody titers of vaccinated mice with pseudotype virus strain Wuhan D614G
- FIG. 11B illustrates the evaluation of the SARS-CoV-2 neutralizing antibody titers of vaccinated mice with pseudotype virus strain Omicron shown.
- compositions of the present invention can comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein, as well as any of the additional or optional ingredients, components, or limitations described herein.
- the singular form “a” “an” and “the” include plural references unless the context clearly dictates otherwise.
- the term “a” cell includes a plurality of cells, including mixtures thereof.
- “About” in the context of amount values refers to an average deviation of maximum ⁇ 20%, preferably ⁇ l0% based on the indicated value.
- an amount of about 30 mol % anionic lipid refers to 30 mol % ⁇ 6 mol % and preferably 30 mol % ⁇ 3 mol % anionic lipid with respect to the total lipid/amphiphile molarity.
- An “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results.
- An effective amount can be administered in one or more administrations, applications or dosages.
- a “subject,” “individual” or “patient” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human.
- Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets.
- the term “derived from” in the context of a genetic fragment that is derived from a naturally occurring genetic sequence means that the genetic fragment has genetic sequence at least 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% identical to the naturally occurring genetic sequence.
- the term “derived from” in the context of a recombinant protein that is derived from a naturally occurring protein means that the recombinant protein comprises amino acid sequence at least 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% identical to the amino acid sequence of naturally occurring protein.
- the present invention provides a multivalent vaccine for protection against at least one of the various strains or variants of influenza as well as at least one of the various strains or variants of coronavirus, including but not limited to severe acute respiratory syndrome coronavirus 2 (SARS CoV 2).
- SARS CoV 2 severe acute respiratory syndrome coronavirus 2
- the multivalent vaccine of the present invention comprises a therapeutically effective amount of recombinant chimeric protein comprising a receptor- interacting domain derived from one of any strain or variant of the coronavirus and a stem region derived from conservative region of hemagglutinin (HA) of one of any strain or variant of influenza virus.
- the stem region comprises amino acid at least 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% identical to amino acid sequence of HA2 region of the one of the any strain or variant of influenza virus.
- the stem region does not comprise naturally occurring receptor binding domain (RBD) of the HA protein.
- the receptor-interacting domain is derived from the RBD of one of the any strain or variant of the coronavirus. In an embodiment, the receptor-interacting domain is derived from the RBD of one of any variant of the SARS-CoV-2. In an embodiment, the receptor-interacting domain derived from the RBD of one of any strain or variant of the coronavirus is fused at the C- terminus of the stem region derived from the conservative HA region of the one of the any strain or variant of the influenza virus.
- An embodiment of the recombinant chimeric protein of the present invention HA-C-RBD_spike is illustrated in FIG. 1B.
- the stem region may be derived from any HA subtypes including H1, H2, H3, H4, H5, H6, H7, H8 as well as other subtypes.
- the chimeric protein of the present invention is derived from the HA protein wherein the RBD of the HA is replaced with RBD of the coronavirus.
- the stem region is formed by removing the amino acid at position 46-306 of the HA1 region of the H1 subtype as shown in FIG. 3A.
- the influenza virus comprises any strain of the influenza virus including type A, B, C, and D.
- the receptor-interacting domain derived from the receptor-interacting domain of the coronavirus does not comprise full-length spike (S) protein of the coronavirus.
- the receptor-interacting domain is derived from the S1 domain of the coronavirus spike protein.
- the receptor-interacting domain does not comprise the full-length S1 subunit of S protein of the coronavirus.
- the receptor-interacting domain is derived from the RBD domain of the coronavirus spike protein of one of any strain or variant of the coronavirus.
- the receptor-interacting domain of the present invention may be derived from receptor-interacting domain of one of any variant of the SARS- CoV-2 including alpha, beta, gamma, delta, and omicron.
- the receptor interacting domain of the present invention comprises amino acid sequence at least 85%, 90%, 95%, 98% or 99% identical to SEQ NO. 1:
- Any embodiment of recombinant chimeric protein of the present invention may further comprise one or more trimerization domains.
- the one or more trimerization domain comprises GCN4 leucine zipper, phage T4 fibritin foldon, trimerization motif from the lung surfactant protein, collagen or a combination thereof.
- the GCN4 leucine zipper comprises an amino acid sequence at least 85%, 90%, 95%, 98% or 99% identical to SEQ NO. 2:
- the foldon comprises amino acid sequence at least 85%, 90%, 95%, 98% or 99% identical to SEQ NO. 3:
- the stem region may be mutated to promote trimerization of the recombinant protein.
- the stem region is derived from the HA protein of the H1 from A/Brisbane/59/2007 (H1N1) influenza virus mutated with point mutations R310C, I323K, I326K and/or R329Q in HA1 region, I10T, F63Y, V66I, K68C, F70Y and/or L73S in HA2 region, and replacement of amino acid residue 75-90 in HA2 region with SEQ NO. 2.
- the stem region may be mutated to integrate with a trimerization domain.
- the stem region may be mutated to integrate with a trimerization domain wherein the trimerization domain does not affect the conserved conformational epitopes natural occurring on HA conservative region.
- the stem region mutated to integrate with a trimerization domain comprises amino acid sequence at least 85%, 90%, 95%, 98% or 99% identical to SEQ NO. 4 (integrated trimerization domain in boldface):
- a trimerization domain is fused in between the receptor-interacting domain and the stem region.
- the foldon trimerization domain is fused in between the receptor-interacting domain and the stem region an embodiment of which is illustrated in FIG. 1B and FIG. 3A.
- Any embodiment of the recombinant chimeric protein of the present invention further comprises one or more linkers comprises amino acid sequence at least 85%, 90%, 95%, 98% or 99% identical to SEQ NO. 5:
- Any embodiment of the chimeric protein of the present invention may have at least one amino acid residue of the recombinant protein glycosylated.
- glycosylation comprises N-glycosylation and/or O-glycosylation.
- at least one glycosylation site is fully glycosylated.
- Full glycosylation is defined as glycosylation resulting from the method of preparation described in the Method section below.
- at least one glycosylation site is monoglycosylated wherein the monoglycosylation is a single GlcNAc.
- monoglycosylated recombinant chimeric protein of the present invention is shown to illicit higher antigenicity than fully glycosylated recombinant chimeric protein of the present invention.
- the recombinant protein of the present invention comprises an amino acid sequence at least 85%, 90%, 95%, 98% or 99% identical to SEQ ID NO.
- the multivalent vaccine of the present invention comprises a homotrimer of the recombinant protein comprising a receptor-interacting domain, wherein the recombinant protein in trimeric form promotes its interaction with host cells.
- the recombinant protein in trimeric form promotes the binding of the receptor-interacting domain to respective host receptor protein.
- the recombinant protein comprises amino acid derived from the RBD of any strains or variant of coronavirus such as SARS-CoV or SARS-CoV-2 and respective host receptor protein is angiotensin-converting enzyme 2 (ACE2).
- ACE2 angiotensin-converting enzyme 2
- the recombinant protein comprises fusion of a polyhistidine tag (His6) at the C-terminal to facilitate protein purification process.
- the multivalent vaccine of the present invention comprises a subunit vaccine that does not comprise any virus-like particles (VLPs).
- the multivalent vaccine further comprises an adjuvant, wherein the adjuvant can comprise squalene-based emulsion adjuvant or any aluminum-based vaccine adjuvant.
- the squalene-based emulsion adjuvant of the present invention comprises squalene and sorbitan trioleate.
- the squalene-based emulsion adjuvant of the present invention comprises about 20 to 50 mg/mL squalene oil such as about 20 about 25 about 30 about 35 about 40 about 45 or about 50 mg/mL including all ranges and numbers fall within these values.
- the squalene-based emulsion adjuvant of the present invention comprises about 3 to 6 mg/mL sorbitan trioleate such as about 3 about 3.5 about 4 about 4.5 about 5 about 5.5 or about 6 mg/mL including all ranges and numbers fall within these values.
- the squalene-based emulsion adjuvant comprises MF59®.
- the present invention also provides a method of preparation of the multivalent vaccine of the present invention.
- FIG. 13 An embodiment of the method of preparation of the multivalent vaccine of the present invention is illustrated in FIG. 13.
- the method of the present invention begins with step 10 of isolating a gene fragment encoding any embodiment of the receptor-interacting domain of the present invention as well as step 20 of isolating a gene fragment encoding any embodiment of the stem region of the present invention.
- the gene fragment comprises a plasmid, RNA or mRNA.
- step 26 the two gene fragments of steps 10 and 20 are fused together to form a fused gene fragment.
- the fused gene fragment is then used to express an embodiment of the chimeric protein of the present invention in step 40.
- the expressed chimeric protein is purified.
- any embodiment the adjuvant of the present invention maybe added in step 60.
- the method of the present invention may optionally further comprise step 22 of mutating the gene fragment encoding the stem region to promote trimerization of recombinant protein.
- the gene fragment encoding mutated stem region with an integrated trimerization domain comprise an amino acid sequence at least 85%, 90%, 95%, 98% or 99% identical to SEQ NO. 4.
- the method of the present invention may optionally further comprise step 24 of isolating a gene fragment encoding a trimerization domain capable of expressing protein comprising an amino acid sequence at least 85%, 90%, 95%, 98% or 99% identical to SEQ NO.
- the method of the present invention may optionally further comprise step 28 of isolating a gene fragment encoding polyhistidine tag and step 29 fusing the polyhistidine tag at the end of the gene fragment encoding the stem region.
- the method of the present invention may optionally further comprise step 30 of fusing various genetic fragment using linkers.
- the method of preparation of multivalent vaccine may optionally further comprise performing the step 34 of glycosylation of the recombinant chimeric protein. In an embodiment, fully glycosylation is applied.
- the fully glycosylated recombinant proteins are treated with Endo H to generate monoglycosylated proteins wherein the monoglycosylation is a single GlcNAc.
- the fusing step of the method in the present invention is performed using recombinant DNA technology.
- the step of expressing the chimeric protein of the method in the present invention is performed using human embryonic kidney cells 293 or insect cells sf9.
- the present invention also comprises a method of treatment for protection against at least one strain or variant of coronavirus and at least one strain or variant of influenza virus.
- the method of administration comprises parenteral as well as via nasal passage spray.
- the chimeric protein of any embodiment discloses comprises about 15-45 ⁇ g/0.5 mL or about 30 ⁇ g/0.5 mL.
- the method of treatment of the present invention further comprises administration of any embodiment of the multivalent vaccine of the present invention two or more times with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks in between each administration.
- the plasmid that encodes the HA-C-RBD_spike, RBD-FH6, RBD-Fc and Spike-dTM were each transfected into the human embryonic kidney cell lines of either HEK293F or the GnTI ⁇ HEK293S cells by using polyethyleneimine and was cultured in Freestyle 293 expression medium (Invitrogen) supplemented with 0.5% bovine calf serum.
- the plasmid that encodes HA- C-RBD_spike expresses protein comprising amino acid SEQ NO 6.
- the plasmid that encodes RBD-FH6 expresses protein comprising amino acid SEQ NO 7:
- the plasmid that encodes RBD-Fc expresses protein comprising amino acid SEQ NO 8:
- the plasmid that encodes Spike-dTM expresses protein comprising amino acid SEQ NO 9:
- the supernatant was collected 72 h after transfection and cleared by centrifugation.
- HA- C-RBD_spike proteins were purified with Nickel-chelation chromatography to obtain fully glycosylated HA-C-RBD_spikefg (fully glycosylated) and high-mannose-type HA-C- RBD_spikehm.
- HA-C-RBD_spikehm was treated with Endo H overnight at 4 °C to produce HA-C-RBD_spike protein with a single GlcNAc at the glycosylation sites, the monoglycosylated HA-C-RBD_spikemg. Endo H was removed by size-exclusion chromatography. RBD-FH6 and RBD-FC proteins were purified with Nickel-chelation chromatography and Protein A chromatography, respectively.
- TMB 3,3’,5,5’- Tetramethylbenzidine
- TMB 3,3’,5,5’- Tetramethylbenzidine
- the absorbance (OD 450 nm) of the wells was read by Microplate Reader. Evaluation of influenza virus neutralizing antibody in sera samples from immunized mice using competition ELISA HA stem-specific antibody (FI6) was expressed by Human embryonic kidney 293F cells and purified by Protein A agarose. Sera from immunized mice were first added to HA-coated 96-well plates with two-fold serial dilution and incubated for 1 hour at 37°C. FI6 was added into wells for 1 hour at 37°C.
- FI6 was detected by Anti human IgG-HRP.
- the absorbance (OD 450 nm) of the wells were read by Microplate.
- Serum samples from immunized mice were collected on day 28, 49 and 70.
- the mice were challenged with a lethal dose (10 LD50) of H1N1 influenza virus (A/reassortant/NYMC X- 181(California/07/2009 x NYMC X-157)) on day 77.
- the challenged mice were monitored every two day of survival and weight loss for 14 days and euthanized if they exceeded 30% loss of body weight by carbon dioxide asphyxiation. Animals were humanely sacrificed by CO2 inhalation at the end of experiments. Evaluation of SARS-CoV-2 neutralizing antibody in sera samples from immunized mice using ELISA 96-well ELISA plates were coated overnight at room temperature with hACE2-Fc in PBS.
- SARS-CoV-2 neutralizing antibody in sera samples from immunized mice using pseudovirus neutralizing assay
- serum samples from immunized mice were heat- inactivated, serially diluted and incubated with 1,000 transduction units (TU) of SARS-CoV-2 (WT or variants) pseudotyped lentivirus in DMEM (supplemented with 1% FBS) for 1 hour at 37°C.
- TU transduction units
- SARS-CoV-2 WT or variants pseudotyped lentivirus
- DMEM supplied with 1% FBS
- FIG. 4 shows results of ACE2-binding activities of HA-Stem, HA-C-RBD_spike, HA, Spike protein of SARS-CoV-2 and RBD-FH6. As shown in FIG.
- HA-C-RBD_spike and RBD-FH6 both showed similar or even better activity in binding to receptor ACE2 compared to positive control group using spike protein of SARS-CoV2. Negative control using HA only or HA-stem did not show any binding activity to ACE2. These results indicated that HA-C-RBD_spike and RBD-FH6 presents proper structure for ACE2 binding and therefore presents antigenicity for eliciting neutralizing antibodies against spike RBD.
- Example 2 Determination of antigenicity of HA-C-RBD_spike protein with broadly neutralizing antibody FI6 (conformational) FIG.
- HA-C-RBD_spike shows results of FI6-binding activities of HA-Stem, HA-C-RBD_spike, HA, Spike protein of SARS-CoV-2 and RBD-FH6.
- HA-C-RBD_spike showed similar or even better activity in neutralizing FI6 compared to positive control groups using HA only or HA-stem.
- RBD-FH6 did not show any neutralizing activity and display a similar result compared to negative control group using spike protein only.
- FIG. 7B shows results of ACE2-binding activities of HA-Stem, fully glycosylated Spike protein of SARS-CoV-2, fully glycosylated HA-C-RBD_spikefg and monoglycosylated HA-C- RBD_spikemg 2.
- HA-C-RBD_spikefg and HA-C-RBD_spikemg each showed activity over 80% on inhibiting ACE2 binding of spike RBD (HRP-RBD in FIG. 7A) (FIG. 7B).
- FIG. 8B shows results of HA-binding activities of fully glycosylated Spike protein of SARS-CoV-2, fully glycosylated HA stem, monoglycosylated HA stem, fully glycosylated HA- C-RBD_spikefg and monoglycosylated HA-C-RBD_spikemg. As shown in FIG.
- FIG. 9 shows protection resulting from vaccination using HA-C-RBD_spikemg against Cal/09, Bri/07, Bri/18, Bri/18FL variants of H1N1 HA proteins as well as H3 and H7 influenza viruses.
- HA proteins are divided into 2 groups based on phylogenic similarity wherein group 1 includes H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17 and H18 and the rest in group 2.
- FIGs. 10A and 10B illustrate weight change and survival of mice vaccinated with either Spike protein of SARS-CoV-2 or HA-C-RBD_spike.
- mice vaccinated with either spike protein or HA-C-RBD_spike suffered from weight loss within 7 days post infection.
- all mice vaccinated with spike protein were euthanized due to the exceeded 30% loss of body weight (FIG. 10A).
- FIG. 11A and 11B shows neutralization activity of sera samples from mice vaccinated with spike protein (spikefg) or HA-C-RBD_spike (HFRfg) against two different variants of SARS-CoV-2. As shown in FIGs.
- mice vaccinated with spike protein or HA-C-RBD_spike (HFRfg) were used to determine the neutralizing antibody titers with pseudotype virus.
- Activity of sera from HFRfg group was better than that from spikefg group in neutralizing the original SARS-CoV-2 Wuhan D614G strain with around 8-fold decrease in PRNT50 value.
- the activity of both group is decreased ( ⁇ 2- to 16-fold increase in PRNT50 value) in neutralizing a newer SARS-CoV-2 strain Omicron with no significant differences in PRNT50 between the data from spikefg and HFRfg.
- Example 8 Compatible immunogenicity of quadrivalent HA-C-RBD_spike vaccine in mice
- a quadrivalent vaccine comprising HA-C-RBD_spike comprising RBD isolated from four different strains (Wuhan, B.1.1.7 (UK), B.1.617.2 (India), and B.1.617.1 (India)) can provide simultaneous protection against four SARS-CoV-2 strains (Wuhan, B.1.1.7 (UK), B.1.617.2 (India), and B.1.617.1 (India)) with comparable activity to respective monovalent vaccines.
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Abstract
La présente invention concerne un vaccin multivalent pour la protection contre au moins l'une des diverses souches de la grippe ainsi qu'au moins l'une des diverses souches de coronavirus, comprenant, mais de façon non exhaustive, le coronavirus du syndrome respiratoire aigu sévère 2 (SARS CoV 2) Dans un mode de réalisation, le vaccin multivalent de la présente invention comprend une quantité thérapeutiquement efficace de protéine chimérique recombinante comprenant un domaine d'interaction avec le récepteur dérivé d'un quelconque variant du coronavirus et d'une région tige dérivée de la région conservatrice de l'hémagglutinine (HA) de n'importe quel variant du virus de la grippe.
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CN116763915B (zh) * | 2023-08-17 | 2023-11-03 | 山东兴瑞生物科技有限公司 | 一种用于治疗和预防流感病毒的多价疫苗 |
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