WO2013177172A2 - Herpesvirus compositions and related methods - Google Patents
Herpesvirus compositions and related methods Download PDFInfo
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- WO2013177172A2 WO2013177172A2 PCT/US2013/042039 US2013042039W WO2013177172A2 WO 2013177172 A2 WO2013177172 A2 WO 2013177172A2 US 2013042039 W US2013042039 W US 2013042039W WO 2013177172 A2 WO2013177172 A2 WO 2013177172A2
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Abstract
The present disclosure relates to liquid and dried compositions comprising a live, attenuated or genetically modified herpesvirus and methods of preparing such compositions, in one aspect, the composition comprises at ieast two or more pharmaceutically acceptable exctpients, at ieast one of which is histidsne and at least one of which is a sugar or sugar alcohol. The composstions retain a sufficiently high infectious titre following storage or large-scale manufacturing steps, such as lyophilization.
Description
Herpesvirus Compositions And Related Methods
Cross Reference to Related Applications
This application claims the benefit of, and relies on the filing date of, U.S. provisionai patent application number 61/649,884, fited 21 May 2012, and U.S. provisiona! patent application number 61/792,913, fited 15 March 2013, the entire disclosures of which are herein incorporated by reference.
Field of the Disclosure
The present invention relates to compositions (e.g., pharmaceutical compositions} and more particularly, to herpesvirus compositions.
Background of the Disclosure
The Herpesviridae are a family of enveloped, double-stranded DNA viruses, a number of which cause disease in humans and/or animals. At least seven herpesviruses are associated with infection in humans, including herpes simplex virus type- (HSV- ), herpes simplex virus type-2 (HSV-2), variceiia zoster virus (VZV), Epstein Barr virus (ESV), cytomegalovirus (CMV), human herpesvirus-6 (HHV-6) and human herpesvirus-? (HHV-7). Diseases caused by herpesviruses in humans vary from mild to severe, and in some cases, infection is life-threatening.
Vaccines of various types have been proposed for herpesviruses and have included for example, isolated immunogens (e.g., inactivated whole virus particles, viral subunit proteins), live, attenuated virus, and genetically modified viral mutants (e.g., replication-defective viral mutant strains). Live, attenuated or genetically modified viruses do not induce the disease caused by the corresponding wild-type virus in animals or humans but are nonetheless, capable of inducing a specific immune response in such subjects. Replication -defective viral mutant viruses are specifically defective for viral functions that are essential for replication, Such viruses are propagated in
complementary eel! lines that express the missing viral proteins to allow viral replication. In normal cells, one or more steps in viral replication are blocked, such that normal gene expression within the infected ceil is allowed whereas production of progeny virus is not.
The effectiveness of a live attenuated or genetically modified (e.g., replication- defective) virai vaccine is dependent on, for example, its ability to elicit the required immune response against the disease. Any factor which inactivates the virus can reduce the vaccine efficacy,
Live attenuated and genetically modified herpesviruses are particularly labile and as a result, maintaining viral infectivity in vaccines that include these viruses is often problematic. For example, aqueous compositions of some attenuated or replication- defective herpesviruses are thermally unstable under typical storage temperatures (e.g.,≥ 5°C) as evidenced by significant drops in viral infectious titre. Many aqueous
compositions of HSV, for example, experience significant titre loss when stored for as little of 24 hours at 2-8°C (i.e. , the target storage temperature for a number of vaccines). HSV- 2, in particular, is known to be very unstable in a liquid formulation at 25°C, 2~8°C, or - 20°C. Hansen et ai., (2005) Biotechnoi. Prog, 21 :91 1 -917. Such thermolabi!rty represents a serious problem for manufacturing, shipping and storage.
Attempts have been made to increase viral stability or increase retention of viral infectivity for example, by the addition of one or more additives and/or by iyophilization.
US 5,024,836 (Merck & Co !nc: WJ McAleer et ai) describes a stable Iyophilized live herpesvirus vaccine that comprises from about 0.5% to about 8% moisture, and claims a gas injected Iyophilized live attenuated varicella virus vaccine which comprises 2% to 8% moisture.
US 4,338,335 and BP 0028563 (Merck & Co !nc: WJ McAleer et a!) describe stabilizer for liquid vaccines, and stabilized liquid live viral vaccine containing live virus, partially hydro!yzed gelatin, a monosaccharide or disaccharide, a cell culture medium, L- glutamic acid, L-arginine and buffer to maintain pH at from about 6.0 to about 6.5.
EP 0008255 (Merck & Co. Inc.: WJ McAleer et ai) describes a herpesvirus vaccine {particularly, a Warek's Disease vaccine) and its preparation. The virus is Iyophilized in the presence of a pH controlled buffered stabilizer, so that the vaccine can be
reconstituted with distilled water.
U.S. 6,258,362 (Loudon et. al.; Cantab Pharmaceuticals Research, Ltd.) describes stabilized Iyophilized herpesvirus compositions that include a combination of vegetable peptone, buffer, and saccharide or sugar alcohol, or other mono- or oligosaccharide or derivative thereof (e.g., lactose, sorbitoi). As these formulations include peptone - an undefined mixture of peptides and other components - their use commercially may be problematic.
EP 0252059 (Smithkiine Bioiogicais S.A.: EO'Hondt) describes stabilizers for attenuated vaccines, containing lactose, sorbitol, dextran, casein hydroiysate, L- glutamate, EDTA and buffer at a pH 6.7-7.2.
Zhai et al. (Biotechnoi. Prog. 2004, 20, 1 1 13-1 120) describes Iyophilized HSV formulations comprising sugar (i.e., trehalose, sucrose). Titre loss following iyophilization
was significant however: formulations with sugar concentrations of 10% or less (e.g., 0.25%, 2%, 10% w/v trehalose; 5% w/v sucrose) had low viral tstre recovery following lyophih'zation (e.g., .25 % w/v trehalose had a vira! recovery of about 22 %). Viral litre recovery following iyophilizaiion was higher for formulations including significantly higher concentrations of trehaiose or sucrose (e.g., 27% w/v trehaiose or sucrose) but was still less than optimal (e.g., 80% for 27% w/v trehaiose, and less than 80% for 27% w/v sucrose), in addition, the long term stability of these formulations at various temperatures is questionable.
Formulations for other live, attenuated viruses are also known. U.S. 4,500,512 (institut Pasteur:, MBarme) describes stabilized iyophilized formulations for the yellow fever virus that include a combination, in phosphate buffered saline (PBS), of lactose, sorbitol, the divalent cations, calcium and magnesium, and at feast one amino acid (selected from hisfidine, alanine, valine, threonine, arginine, methionine, hydroxy proline, lysine, isoleucine, phenylalanine and serine). U.S. 8,084,039 describes formulations for live attenuated viruses particularly for fiaviviruses that include a combination, in phosphate buffered saline (PBS), of trehaiose, copolymer potoxamer 407, Piuronic F127® and rHSA. Lyophiiization, however, of PBS buffered formulations often results in significant changes to pH which is undesirable for labile herpesviruses,
These known methods have, nonetheless, failed to yieid a live, attenuated or genetically modified herpesvirus composition that retains a sufficiently high titre or a production method suitable for large scale commercial manufacturing.
Thus, there remains a need for herpesvirus vaccines suitable for iong term storage.
Summary of the Disclosure
The present disclosure relates to methods and compositions comprising an infectious herpesvirus and methods of preparing such compositions, in certain embodiments, the composition is stabilized such that following storage for 8 months at 5°C ± 2°C, the composition retains an infectious titre within 0.25 Logi0 pfu/mL, 0.2 Log10 pfu/ml, or even 0.1 Log-m pfu/ml of the titre measured after the composition is dried. In another embodtment, following storage for 6 months at 25°C ± 2°C, the dried composition retains an infectious titre within 0.5 Logto pfu/mL of the titre measured after the composition is dried.
One embodiment is directed to a composition comprising a live, attenuated or genetically modified herpesvirus, and at Ieast two pharmaceutically acceptable excipienis, at least one of which is hisfidine and at Ieast one of which is a sugar or sugar alcohol in
one emDoasmeni, me composition is a ssquia composition, in one embodiment, the liquid composition remains stable following storage at 2-8 °C for up to 2 weeks, in another embodiment, the liquid composition remains stabie following storage at 25°C ± 2°C for up to 1 week, m another embodiment, the composition is a dried composition. In one embodiment, the dried composition is stable following storage for at least 6 months at 5°C ± 2°C. In another embodiment, the dried composition is stable following storage for at least 6 months at 25°C ± 2°C.
The compositions, in certain embodiments, include a replication defective herpes simplex virus,
The compositions may be pharmaceutical compositions or vaccines. Kits including a first container containing the dried composition and a second container containing an aqueous solution for reconstrtution the dried composition are aiso provided. Methods of preparing vaccines, for example, by reconstitute of the composition with an aqueous solution are also disclosed.
Other aspects provide methods of manufacturing such dried compositions. For example, one embodiment is directed to a method of manufacturing a dried composition comprising a live, attenuated or genetically modified herpesvirus, and at least two or more pharmaceutically acceptable excipients, at least one of which is histidine and at least one of which is a sugar or sugar alcohol, the method comprising; (i) admixing the live, attenuated herpesvirus with the at least two or more pharmaceutically acceptable excipients; and (it) drying the admixture. In certain embodiments, the admixture is dried by means of freeze-drying, foam-drying or spray-drying. Advantageously, these dried compositions have an acceptable final dose target and shelf life.
Detailed Description
The present disclosure provides compositions and methods that can be used as, or for the manufacture of, pharmaceutical products, including viral vaccines, as described further below. The compositions include pharmaceutically acceptable excipients that, as described further below, have been found to be advantageous in the preparation of stabie herpesvirus vaccines that retain viral infectivity under desired storage conditions. The methods include steps, which involve drying that too has been found to be advantageous. These compositions and methods are described further below.
In one embodiment, compositions include a live, attenuated or genetically modified herpesvirus, and at least two pharmaceutically acceptable excipients, at least one of which is histidine and at feast one of which is a sugar or sugar ateohoi. in one embodiment, the composition is in a liquid form. The liquid compositions can be dried and
stored for later use. Alternatively, the liquid compositions may be administered to a subject without being dried. Such liquid compositions can also be stored, in their liquid form, prior to administration. In addition, a dried form of the composition can be reconstituted using an aqueous solution such as, for example, water for injection, or a suitable diluent or buffer solution, to produce a liquid composition.
In another embodiment, the compositions are in a "dried" form which in the context of this disclosure refers to a product that has a residua! moisture content of about 10% or less. Preferably, the residual moisture content is 0.5% - 8.0% and, more preferably, the residual moisture content is 6% or less, 5% or less, 4% or less, or 3% or less. Methods of drying a composition are well known in the art., and snclude for example, but are not limited to freeze-drying, foam-drying and spray-drying. The compositions retain high infectious trtre after being subjected to a drying process (e.g., freeze-drying) and also after storage for at least 8 months at 2-8°C ± 2°C (e.g., 5°C ± 2°C) or at higher temperatures (e.g., at 20-25°C ± 2°C).
Without intending to be bound by any theory, one or more of the pharmaceutically acceptable excipients included in the composition may contribute to viral stability (e.g., viral infectivity, integrity) by, for example, preventing or reducing viral inactivation and/or degradation. One measure of viral stability is viral infectivity which itself may be measured by assessing viral titre. Viral infectivity can be measured following one or more process steps in the manufacture of viral vaccine, such as following a drying (e.g., freeze- drying) step. Virai infectivity can also be measured after storage of the composition at sub zero, moderate (e.g., 5°C ± 2°C), or elevated temperatures (e.g., 25°C ± 2°C). One or more of the pharmaceutically acceptable excipients, including histidine and a sugar or sugar alcohol, may contribute individually or in combination to viral stability (e.g., viral integrity). For example, without intending to be bound by any theory, histidine may contribute to viral stability (e.g., virai integrity) and/or the maintenance of a particular pH level or range.
Histidine may be present in the composition at a concentration of about 1-50 m , 5-20 mM (e.g., 5 mM) or 10 mM. While any suitable form of histidine may be used as is well known in the art, a preferred form is L-histidine.
Sugars that may be used in the compositions include, but are not Iimited, to non- reducing disaccharides (e.g., sucrose, trehalose). Sugar alcohols that may be used in the compositions Include, but are not limited, to sorbitol and mannitol, in certain
embodiments, the compositions include combinations of sugars and/or sugar alcohols. In one embodiment, the composition comprises sucrose and sorbitol. In another embodiment, the composition comprises sucrose. Sugars and/or sugar alcohols may be
present at about 1-10% w/v or 10-20% w/v (e.g., 10%). in one embodiment, the composition includes sucrose at about 1-10% w/v, 1-15% w/v., or 10-20% w/v (e.g., 5 % or 10%).
The composition may also include one more additional pharmaceutically acceptable excipients. Examples of use include but are not limited to buffers, salts, proteins {e.g., albumin), surfactants, bu!king agents, chelating agents, gelling polymers, urea (or its derivatives), and combinations thereof.
Buffers that may be used in the compositions include for example,
tris(hydroxymet'nyl)amino-methane (TRIS), TR!S-acetate, and HEPES (2-(4-(2- hydroxyethyl)~1~piperazinyl)ethanesuifonsc acid). Buffer components such as TRIS, TRiS- acetate and HEPES may be present at a concentration of about 10- 00 mM or 20-75 mM (e.g., 20 mM). In certain examples, compositions may include a mixture of buffer components. The compositions are generally of a pH of about, e.g., 6-9, 6.5-7.5, 6.5-7.0, 6.8, or 7.4. Preferably the pH is about 7.0 or 6.6.
Salts that may be used in the compositions include, for example, giutamate (e.g., potassium giutamate, mono sodium giutamate, sodium giutamate), sodium chloride, potassium chloride, and calcium chloride, in concentrations as is known in the art.
Giutamate may, for example, b© present at a concentration of about 10-100 mM, 25-75 mM (e.g., 25 mM) or 50 mM. Sodium chioride may, for example, be present at a concentration of about 10-100 mM, 00 -200 mM, 80- 60m (e.g., 80 mM, 160 mM). In certain examples, it may be preferable to include one or more salts, in one embodiment, compositions include potassium giutamate or sodium giutamate. In embodiments, compositions may also include sodium chioride.
In one embodiment, the composition comprises histidine and sucrose, in another embodiment, the composition comprises 5-20 mM histidine, 5-15 % w/v sucrose or trehalose, 100-200 mM NaC!, and 25-75 mM potassium giutamate and has a pH of about 6.5 to 7.5. In yet another embodiment, the composition comprises 10 mM histidine, 10% w/v sucrose, 160 mM NaCI, 50 mM potassium giutamate, and has a pH of about 6.5 to 7.5, preferably about 7.0.
The composition may also include one or more surfactants and/or bulking agents.
Surfactants of use include but are not limited poioxamers (e.g., Pluronic®), po!ysorbates (e.g., Tween® 80, Tween® 20), CTAB (hexadecyitrimethyiammonium bromide), or SDS (sodium dodecyi sulfate or sodium lauryi sulfate). Bulking agents of use include but are not limited to PVP, PEG, dextran, mannitol and glycine.
The composition may also include urea (including urea derivatives such as e.g., thiourea, al!ylurea, aceiam!de, methylcarbamate or butyicarbamate) and/or albumin (e.g.,
BSA, rHSA), Gei!sng polymers may also be included such as, for example, gelatin, pectins, alginates, carrageenans and xanthan n concentrations as is known in the art. In certain examples, the stabilizer comprises geiatin.
Examples of herpesviruses suitable for use include, but are not limited to, Herpes Simplex virus type 1 (HSV-1 ) or type 2 (HSV-2), VZV, EBV, CMV, HHV-6, HHV-7 and the non-human equine herpesvirus type-1. Preferably, the virus is a live attenuated virus or a repiication-defective virus. Live attenuated herpesviruses include: (i) viral vectors (e.g., that consist of a backbone herpesvirus, and in which certain genes have been replaced with that of another virus) and (it) genetic mutants rendered nonvirulent by the deletion of one or more viral genes but retaining one or more viral glycoproteins. Examples of genetic mutants include replication defective HSV-1 or HSV-2 with mutations in the genes encoding ICP8, UL5 and/or iCP27, the HSV-2 mutant deficient in glycoprotein gH known as DISC and the HSV-2 mutant known as ICPIGAPK). Examples of replication-defective herpesviruses suitable for use are provided, for example, in U.S. Patent Ho, 7,223,411, which is incorporated herein in its entirety.
In one embodiment, the herpesvirus is a herpes simplex virus 2 (HSV-2), it is known in the art that HSV-2 is more thermolabile, and thus more difficult to stabilize, than HSV-1. Croughan, W. S., & Behbehani, A. . (1988) Journal of Clinical Microbiology, 26(2):2 3-215. In addition, the HSV-529 virus is known to be very unstable in a liquid formulation at 25°C, 2-8'C, or -20°C. Hansen et a!., (2005) Bkrtechno!. Prog, 21:91 -917.
In certain embodiments, the herpesvirus is the replication-defective HSV-2 dl5~29 mutant virus (parent strain 186 syn+-1) genetically modified to contain 2 gene deletions: Ui5 and UL29 as more fuiiy described in Da Costa, ef a/ (2000) J. Virology 74:7963-7971 and WO 99/06089, the disclosures of which are hereby Incorporated by reference in their entirety. The original dl5-29 strain was re-derived and renamed as ACAM529 {Deiagrave S, et al. PLoS ONE, 2012 7(10): e46714). Thus, the terms d!5-29, ACAM529, and HSV- 529 are used interchangeably throughout this application. The UL5 deletion consists of removal of the UL5 gene and part of the nonessential UL4 open reading frame (ORF) from nucleotides 12,244 to 15,143. The UL5 gene is an essential component of the viral he!icase-primase complex and is required for viral DNA synthesis. The UL29 deletion consists of removal of the complete UL29 gene from nucleotides 58,784 to 62,527. The UL29 gene encodes the viral single-stranded DNA binding protein ICP8 (infected cell protein 8), which is essential for viral DNA synthesis. Together, this double mutation results in a virus that only grows on a complementary cell line, AV529-19 Vero ceils containing the UL29 and UL5 genes and does not grow on normal Vero cells.
in one embodiment, the herpesvirus (e.g., HSV-529) is highly purified and contains less than 10 ng host ceil DNA per 1x107 PFU. Such highly purified herpesvirus can be purified using the methods described in PCT7US2013/020780, filed 9 January 2013, which is incorporated herein by reference in its entirety,
In certain embodiments, compositions may comprise multiple herpesviruses (e.g., two, three or more herpesviruses) which may be of the same or different species. In some embodiments, compositions may comprise one or more virus serotypes (e.g., of HSV-1 and/or HSV-2).
In addition to viruses, the compositions may also include one or more peptides, proteins, or polysaccharide antigens optionally conjugated to carrier proteins. For example, compositions may include herpesvirus protein subuniis (such as e.g., HSV glycoproteins gD and gB).
The attenuated herpesvirus may have been cultured on an appropriate celi line (e.g., Vero cei!s) and then purified from the harvested viral culture in one or more steps, A specific example of a cell Sine suitable for propagating a replication-defective HSV-2 strain is described in U.S. 6,841 ,373, which is Incorporated herein in its entirety, in one embodiment, the herpesvirus is grown using serum-free media.
In one aspect, the liquid composition remains stable following storage at 2-8°C. For example, in one embodiment, the liquid composition: has a titre loss of less than 0.3 Log!C pfu/mL following storage at 2-8 for up to 2 weeks, in another embodiment, the liquid composition has a titre ioss of less than 0.3 Logic pfu/mL following storage at 2-8°C for 1 -2 weeks, in another embodiment, the liquid composition has a titre loss of !ess than 0.3 Log io pfu/mL following storage at 2-8°C for up to 1 week.
in another aspect, the liquid composition remains stable following storage at 25aC ± 2aC. For example, in one embodiment, the liquid composition has a titre !oss of less than 0.5 Log 0 pfu/mL following storage at 25"C ± 2°C for up to 1 week.
in yet another aspect, the liquid composition remains stable following storage at - 7Q°C. For example, in one embodiment, the liquid composition has a titre loss of less than 0.1 Logw pfu/mL following storage at -70°C for up to 38 weeks.
in another aspect, liquid composition remains stable following storage at -20°C.
For example, in one embodiment, the liquid composition has a titre loss of less than 0.3 Log™ pfu/mL following storage at -20°C for up to 4 weeks.
In one embodiment, the compositions retain a high level of infectivity following the drying process (e.g., following freeze-drying). For example, in one embodiment, the composition retains an infectious titre of at least 75% or more following drying (e.g.,
following freeze-drying). in another embodiment, foliowing drying (e.g., following freeze- drying), the composition retains an infectious titre within 0.75 Log-jQ pfu/mL, 0.5 Log pfu/mL, or 0.4 Log pfu/mL of the titre measured before the composition Is dried, when the viral titres in the liquid composition are between about 107 to 105 pfu/mL before drying, In addition, dried compositions may optionally retain a high level of infectivity following extended storage at moderate or ambient temperatures. For example, m one embodiment, the composition retains an infectious titre of at least 75% foliowing storage for at ieasi one week at 10°C or less (e.g., 2-8°C ± 2°C), In other embodiments, the composition retains an infectious titre of at least 75% following storage for at least 1 hour and up to 6 months or more at 25°C ± 2°C or less (e.g., 25°C - 20°C; 2-8°C). In certain embodiments, the composition retains; (i) an infectious titre of at least 80% following storage for at least one week at 10°C or iess; (ii) an infectious titre of at least 90% following storage for at least one week at 10°C or less; or (ill) an infectious iitre of at least 95% following storage for at least one week at 10°C or less.
In other embodiments, following storage for 8 months at 5°C ± 2DC, the dried composition retains an infectious titre within 0.25 Logic pfu/mL of the titre measured after the composition is dried, when the viral titres in the liquid composition are between 107 to 105 pfu/mL before drying. In certain embodiments, following storage for 6 months at 5°C ± 2°C, the dried composition retains an infectious titre within 0.2 Log10 pfu/mL of the titre measured after the composition is dried, when the viral titres in the liquid composition are between 1G7 to 105 pfu/mL before drying. In yet other embodiments, following storage for 6 months at 5°C ± 2°C, the dried composition retains an infectious titre within 0.1 Log10 pfu/mL of the titre measured after the composition is dried, when the viral titres in the liquid composition are between 107 to 105 pfu/mL before drying,
in other embodiments, foliowing storage for 6 months at 25°C ± 2°C, the dried composition retains an infectious titre within 0.5 Log-io pfu/rnL of the titre measured after the composition is dried, when the viral titres in the liquid composition range from 107 to 10s pfu/mL before drying.
The present disclosure also relates to a method of manufacturing a dried composition comprising a live attenuated or genetically modified herpesvirus and at feast two pharmaceutically acceptable excipients, at least one of which is histidine and at least one of which is a sugar or sugar alcohol, in one embodiment, the method comprises (i) admixing the live, attenuated or genetically modified herpesvirus with at least two pharmaceutically acceptable excipients, at least one of which is histidine and at least one of which is a sugar or sugar alcohol; and (ii) drying the admixture.
ί iitf auirisxiuie may oe anea Dy means ot any method known in the art. For example, the drying method may be selected from freeze-drying, foam-drying and spray- drying. The admixture may be dried to produce a dried composition having a residual moisture content of 10% or less,. 6% or iess, 5% or less, 4% or less, or 3% or less.
Preferably, the admixture is dried to produce a dried composition having a residual moisture content of 0.5% to 8% (for exampie, as measured using a DL38 Karl Fisher Titrator). The resulting dried composition may be in the form of a solid (e.g., crystalline or amorphous) at 5°C, and at ambient temperature {e.g., 2TQC to at least 37'C).
Manufacturing the compositions in this manner allows the preparation of a dried composition with a minimal reduction of titre loss during the drying process, and results in the preparation of compositions that retain sufficiently high titres under varying conditions of storage.
In certain embodiments, the composition is subjected to a freeze-drying process. Such a process can involve a freezing step, a primary drying (sublimation) step, and a secondary drying (desorption) step preferably for a total time of 48 hours or less.
The drying process may be completed in two steps: for example, in the first step, the aqueous composition may be frozen In the form of uniform particles or beads and in the second step, the frozen particles or beads may be dried so as to obtain a stabilized dried composition in the form of uniform particles or beads.
The total content of the components of the dried composition can be such that upon reconstitute n with sterile liquid for Injection {e.g., water for injection), the
composition can be used to provide an injection which has an acceptable isotonic concentration (e.g., within a range of about 100-1100 mOsm, preferably within about 250- 850 mOsrn.
Also provided are methods of eliciting an immune response in a subject (e.g., a mammal) by administering the compositions to subjects, This may be achieved by the administration of the iiquid com positions to the subject to effect exposure of the live, attenuated or genetically modified herpesvirus to the immune system of the subject.
The dose of virus can be chosen to be such as to yield in the reconstituted Iiquid for injection, a dose for exampie of about 103 to about 10s pfu virus. Typically, a volume of a dose for injection is about 0.5 ml. A preferred dose ranges from 1χ10δ to 5x108 pfu/'dose. Dosages can be increased or decreased as to modulate immune response to be induced in a subject.
To prepare a vaccine for administration, a dried composition may be reconstituted with an aqueous solution such as, for example, water for injection, or a suitable diluent or
buffer solution, in certain examples, the diluent includes histidine. The vaccine may be administered, in a suitable manne as is known in the art, such as for example, subcutaneously, intravenous, intramuscularly, Intradermal, transcutaneousiy, transdermal or muoosally in amounts and in regimens determined to be appropriate by those skilled in the art. For the purposes of prophylaxis or therapy, the vaccine can be administered for example, 1 , 2, 3. or 4 times. When multiple doses are administered, the doses can be separated from one another, by for example, one week, one month or several months (e.g., 3 months, 6 months).
Compositions {e.g. vaccines) may be used to prevent and/or treat herpesvirus infections, in one example, a composition comprising a live, attenuated or genetically modified HSV and a stabilizer may be used to prevent and/or treat HSV-1 and/or HSV-2 infection, in a preferred example, compositions comprising HSV-2 dl5~29 may be used to prevent and/or treat HSV-1 and/or HSV-2 and/or HSV-1 infection (e.g., genital HSV-2 infection). The prophylactic and therapeutic methods invoive vaccination with the composition, for example, in preventing subsequent infection, or in carrying out the treatment itself.
The dried compositions may be included in a vaccine kit. For example, the kit ma comprise a first container containing the dried composition and a second container containing an aqueous solution for reconstituting the composition. The kit may optionally include the device for administration of the reconstituted liquid form of the composition (e.g. hypodermic syringe, microneedle array) and/or instructions for use.
The following examples are provided for illustrative purposes only and are not intended to limit the scope of this disclosure in any way.
Examples
Example 1
The Examples included herein relate to a number of studies that were performed. The production and purification of the viral material utilized in those studies is described in■ this Example. The pharmaceutically acceptable excipients and the container closure system utilized In those studies are set out In Table 1.
Table 1
Chemical Name Vendor CAS No Grade
Sucrose Sigma 57-50-1 BioUltra
Sorbitol Sigma SAP# 2020825 USP
MSG Sigma SAP#200G908 USP
Chemical Name Vendor CAS No Grade
Urea J.T Baker 57-13-6 USP
Glycine J.T Baker 56-40-6 USP
Tris {Trizma Base) Sigma 77-86-1 BioUitra
Tris Acetate (Trizma Acetate) Sigma 6850-28-8 BioUltra t-Histidine J.T Baker 71-00-1 USP
Sodium Chloride EM Science 7647-14-5 USP/EP
PVF Sigma 9003-39-8 USP annitoi J.T Baker 69-65-8 USP
Potassium Glutamate Sigma 8382-01-0 N/A
P!uronic F88 Sigma 9003-11-6 /A
Dextran 40 Sigma 9004-54-0 N/A
Albumin, Human Serum, Caibiochem 70024-90-7 Powder, punty>95% Fraction V (rHSA)
Albumin, Bovine (BSA) Sigma 9048-46-8 Purity>98%
Container closure system:
3 ml Type § borosiiicaie glass BV0030
tubing vsai
13mm Gray Chiorobutyl SAP#: 3101621
Serum Stopper (Latex free)
Caps, 13 mm One Piece CS0001
Aluminium Crimp Cap
Viral Material
The replication-defective HSV-2 virus, dlS-29, re-derived and renamed ACAM529, was propagated on a large scale by growing the virus under serum free conditions on its complementing ceil line AV529-19 {derived from Vero CCL-8 2 (African green monkey) ceils). Liquid crude virus, purified frozen or lyophilized was used for infecting a monolayer of the complementing Vero ceifs. Following the growing period, the virus was harvested from ceils and purified in a number of steps:
1. dislodging ACAM529 viral particles from surface of infected cells with a solution containing Dextran sulfate by exposing the eel! culture to the solution for a sufficient period of time (e,g., 3 hours - 24 hours),
2. Benzonase® endonuciease digestion of residua! ONA in virai preparation,
3. clarification by depth filtration (e.g., using a 0.65 pm depth filter),
4. virus (bind-and-elute) purification by anion exchange chromatography, and
5. virus concentration/buffer exchange by tangential flow uitrafiltration/diafiltration (UR/DF).
An example of the production and purification process that may be utilized is described in co-International Patent Application PCT/US2013/020780, filed 9 January 2013, which is incorporated herein by reference in its entirety.
The purified viral bulk was stored in storage buffer at about -70CC. For formulation, viral bulk was thawed in a water bath at 3?°C ± 2°C. Formulations were prepared for lyophilization as follows: (i) admixed applicable pharmaceutically acceptable excipients to prepare composition; (is) added composition to bulk and admixed together until uniform; and (iii) a!iquoted formulated bulk into vials and loaded vials into programmed freeze-dryer.
Example 2
The viral titre loss experienced by compositions of varying formulations: (i) as a consequence of lyophilization and (ii) following lyophsiization, at certain temperatures for specific time periods were compared.
A number of studies were performed using aqueous compositions thai were prepared under laminar flow conditions by admixing viral bulk material with one or more pharmaceutical excipients as discussed below. The pH of each composition was adjusted to the applicable pH level (as noted in Tables 4 and 5, ± 0.2). Compositions were filtered through a 0.2μ poly-vinyl di-fluoride disposable filter and then stored at 5°C until lyophilization.
Following formulation, the aqueous compositions were freeze-dried (using FTS Lyo Star li). in brief, a dry state was achieved by freezing the aqueous composition and evaporating the resulting ice under vacuum through a sublimation process (without melting). The freeze-drying parameters were varied in each of studies A, S, C, D, and E. The freeze-drying cycle of Study A, B, and C was run substantially as summarized in Table 2 below.
rabie 2
Certain physical parameters of each composition were evaluated, including, pH, osmolality and residua! moisture. In a number of studies, the liquid glass transition temperature (Tg') and solid glass transition (Tg) was aiso assessed by testing liquid compositions (baseline before lyophilization) and iyophiiized product by Conventional MDSC. A number of quatity attributes were used to evaluate formulations, including the attributes set out in Table 3.
Fabie 3
Viral infectious litre and activity of aqueous compositions before !yop iiization (pre- lyo), following iyophilization (post-lyo) and following desired storage periods were measured using a plaque titration assay on the complementing Vero ceil line to assess the stability of the different compositions. The assay was conducted substantially in the following manner: Tissue culture plates (12-weil) were seeded one day prior to inoculation with 4 x 105 ceils per well. Samples were serially diluted, piated and incubated 1 h, 37 "C, 5% C02, with gentle rocking every 15 min. Methyl cellulose overlay medium (in DMEM supplemented with L-glutamine, heat-inactivated FBS and antibiotics) was added (1mL) to each well and the plates were incubated 48 h< Plaques were visualized by staining with 1% crystal violet in 70% methanol. After manual counting of plaques, titers were represented as plaque forming units (PFU)/mL, The assay was assessed as having a standard deviation within the range of 0,04 - 0,16. The physical parameters and stability data for Studies A and B are set out in Table 4.
Ta le 4: Physical Parameters and Stabiiity Data For Studies A and B
*: Storage at -20"C; **: Storage at 2-8°C; ***: Storage at 25°C;"**: Storage at 3?°C; N/A - not available
In Studies C, D, and E, the physical parameters and stability of various compositions comprising histidine and sucrose were evaluated. The freeze-drying parameters of Studies D and E were the same as the parameters for Study C (see Table 2) except for (1} in Study D the hold time for the secondary dry was 200 minutes; and (2) in Study E, the ramp rate for steps A, B, and C of the primary dry was 0.2 ("C/min) and the hold time for the primary dry was 420 minutes.
In Studies C, D, and E, the main composition ("CI") included 10 mM Histidine, 10% sucrose, 160 mM NaC!, 50 mM potassium giutamate, pH 7.0 with or without one or more additional pharmaceutically acceptable excipients. Another composition ("C2") included the same ingredients as C1 but in lesser amounts: 5 mM Histidine, 5% sucrose, 80 mM NaCI, 25 mM potassium giutamate, pH 7,0. The physical parameters off the compositions In Studies C, D, and E are shown in Table 5. le 5: Physical Parameters of Compositions in Studies C, D, and E
* Osmolality above preferred range
The stability data of the compositions in Studies C, D, and E are summarized in Table 6 with the values representing infectious titre (log 10 pfu/ml), which was measured as discussed above.
Two freeze-dried compositions were selected for further long-term storage studies. The first composition (C ) Included: 10 m Histidsne, 10% sucrose, 160 mM NaCl, 50 m
potassium glutamate, pH 7.0 with or without one or more additional pharmaceutically acceptabie excipients. The other composition (C3) included: 20rrt Tris-acetate, 5% sucrose, pH 6.6).
Sample vials were stored at 25°C ± 2°C or -70°C ± 2aC (control) for 3 months (T3 ) or 6 months (T6 ). Following storage for 3 or 6 months, vira! infectious titre was measured using the plaque assay (as described earlier). Composition components and results obtained are set out in Table 7.
Tabie 7
For all of the compositions under the tested conditions, the pH remained stable between ± 0.5 units.
A significant decrease in viral activity was considered a drop in activity of more than about 10% or in some cases more than about 20%. Following 3 months and 6 months of storage at 25°C ± 2°C, no significant decrease in viral activity was seen in the C1 compositions comprising histidine and sucrose. A significant decrease in viral activity could also be considered an infectious titre that is not within 0.5 Logi0 pfu/mL of the titre of the composition measured after iyophilization. Using this standard, the CI composition did not have a significant decrease in viral activity following storage at 25°C ± 2°C for 3 or 6 months. Adding urea and gelatin to the C1 compositions increased overall stability during long-term storage.
Compositions formulated with histidine and a sugar had an overall more optimal long-term stability (including higher titre retention) as compared to compositions formulated without histidine. Although compositions formulated with 20 mM TRIS acetate, 5% sucrose, 0.5% MSG, 1 % rHSA, 0.5% Urea and 2.5% Glycine pH 6.6 had minimal titre loss when subjected to freeze- drying, long-term storage of those compositions and storage at ambient temperatures (e.g., 25°C±2°C) resulted in titre losses that were higher than those seen in many of the histidine and sugar containing compositions. Moreover, compositions formulated with histidine and sugar me the criteria of preferred attributes.
The addition of certain pharmaceutically acceptable excipients to the histidine containing compositions reduced titre loss. For example, gelatin preserved viral titre during the freeze- drying process and the addition of urea and gelatin to the C1 compositions increased overall stability during long-term storage.
In regards to the cycle parameters utilized during the freeze-drying process, a !ower primary dry ramp rate and a reduced secondary dry shelf temperature and ramp rate minimized titre loss.
Example 3
A freeze-thaw study was designed to test the stability of the C1 composition (HSV-529 in
10 m Histidine, 0% sucrose, 160 mM NaCi, 50 m potassium gluiamate, pH 7.0) when exposed to freeze-thaw stress. In one test, 0.7 mL of different iots of the C1 composition was placed into a 3 ml Type I glass vial and stored at either below -60°C or -20UC. Following storage for different amounts of time, the compositions were thawed at 37°C in a water bath, and viral infectious litre was measured using the plaque assay (as described earlier). The results obtained are set forth in Table 8 {below -60°C) and Table 9 (-20°C),
Table 8 (Plaque Assay Following Storage at Below ~6Q°C)
rage at -20°C)
Following storage at below -60°C, the HSV-2 in the CI composition, maintained an infectious titre higher than 6.5 (Log^o pfu/mL) for up to 38 weeks, with a titre loss of less than about 0.1 Logic pfu/mL. Following storage at -20°C, the HSV-2 in the C1 composition, maintained an infectious titre higher than 6.5 (Logio pfu/mL) for up to 8-12 weeks, with a titre loss less than 0,3 Logio pfu/mL for at least 4 weeks, and, in some instances, up to 12 weeks,
In a separate study, larger volumes (25 mL in 2Q0-L algene bottle) of the C1 composition containing HSV-529 were subjected to freeze-thaw stress. Samples were frozen overnight at beiow -60°C and thawed in a 37°C water bath. The infectious titre of HSV-529 in the C1 compositions was measured using the piaque assay, as discussed previously, following multiple freeze-thaw cycles. The results are shown in Table 10, with the CI composition maintaining a high viral titre and a viral titre loss of iess than 0.2 Logic pfu/mL following at feast 3 freeze-thaw cycles.
Table 10 uitiple Freeze-Tbaw Cycles)
A temperature excursion study was designed to simulate GMP manufacturing conditions and to test stability of HSV-529 compositions when temperature was changed from room temperature (25°C) to 2-8°C. Two HSV-529 Sots were compared: 1} HSV-529 in the CI composition (10 mM Histidine, 10% sucrose, 180 mM NaCi, 50 mivl potassium g!utamate, pH 7.0) and 2} HSV-529 in a composition ("C3 + MSG") containing 20m Tris-acetate, 5% sucrose, 0.5% MSG, pH 6.6). The temperature excursion schedule is set forth in Table 11 and was based on a standard GMP process (wait time to packing and labeling is 4 days) and a worst case scenario (wait time to packing and labeling is 17 days).
Table 11 (Temperature Excursion Schedule)
The infectious litre following standard GMP consitions (Case A) and worst case scenario (Case B) was measured using the plaque assay. The results are shown in Tables 12 and 13.
Table 12 (Temperature Excursion Study Case A)
Table 13 (Temperature Excursion Study Case B)
HSV-529 formuiated in C1 resulted in much lower titre loss than HSV-529 formulated in C3 + MSG in both the Case A and Case B temperature excursion studies.
Example 5
Assays were also run to compare the stability of liquid HSV-529 compositions following storage at different temperatures. As above, two compositions were tested, C1 (HSV-529 in 10 mM Histidine, 10% sucrose, 160 mM NaC!, 50 mM potassium giutamate, pH 7,0) and C3 + MSG (HSV-529 in 20mM Tris-acetate, 5% sucrose, 0.5% MSG, pH 6.6). Stability was measured by the plaque assay, as above. The results of the liquid formulation stability assay are set forth in Table 14.
Table 14 (Liquid Stability at Different Temperatures)
Composition Temp. infectious Titre (Iog10 pfu/mL) j
0 j 1 wk : Titre loss j 2 wk Titre !oss j
{1 wk) (2 wk)
C1 2-8°C 7.15 j 6.97 I 0.18 | 6,86 j 0.29
C3 + MSG 2-8°C 7.15 6.61 I 0.54 ~
C1 25°C 6.13 I 5·8 j 0.33 5.68 I 0.45
C3 + MSG 25°C 6.13 j 5.69 0,44 5.59 0.54
The histidine formulation (C1 ) was more stable than the Tris-acetate composition (C3 + MSG) at both 25°C and 2-8°C. The histidine formulation stored at 2-8°C for at least 2 weeks had a viral titre loss of less than 0.3 Log10 pfu/mL.
To investigate the initial titre drop, a modified liquid stability assay was designed. C1 (HSV-529 in 10 mM Histidine, 10% sucrose, 160 mM NaCI, 50 mM potassium giutamate, pH 7.0) was stored at both 25°C and 2-8°C for increasing lengths of time. At the end of the time period, the samples were immediately frozen to below -60°C. The samples were thawed in a 37°C water bath and tested for infectious titre using the plaque assay. The results of this liquid stability assay are presented in Table 15.
Table 15 (Modified Liquid Stability Assay)
In this study, the HSV-529 in the CI composition had a litre loss of less than 0.3 Log 0 pfu/mL for at least 3 days when stored at 2-8°C and for at least 6 hours when stored at 25°C.
Longer-term stability of the liquid C1 composition was also evaluated. 0.7 mL of different lots of the CI composition was placed into a 3 mL Type I glass vial and stored at 2-8°C or 23-27*0 for different amounts of time. The results obtained are set forth in Table 16 (2-8cC) and Table 17 (23-27°C).
Table 16 (Liquid Stability Fo!lowing Storage at 2-8 )
Composition Sam ie# infectious Titre (Lo }10 pfu/rnL)
10 1 wk 2 wk 4 wk 8 wk I 12 wk 26 wk 38 wk
C1 Lot A I 7.25 6.98 6.86 8.68 t 6.32 6.12 5.99
(11-150)
C1 Lot B j 6.91 6.69 6.61 6.59 6,41 j 6.33 5.96
(1 -183)
CI Lot C j 6.62 6.29 6.21 5.85 5.53
(11 -234)
Table 17 (Liquid Stability Following Storage at 23-27°C)
Following storage at 2-8°C, the HSV-2 in the C1 composition maintained an infectious titre higher than 6.5 (Log 0 pfu/mL) for up to 2-8 weeks, depending on the lot and the starting viral titre. Following storage at 23-27°C, the HSV-2 in the C1 composition maintained an infectious titre higher than 6.5 (Log-so pfu/mL) for up to 1 -2 weeks, depending on the lot and the starting viral titre. in addition, depending on the lot, the HSV-2 in the C1 composition had a titre loss of less than 0.3 log-,0 pfu/mL following 1 week, or, in one instance, even 2 weeks, of storage at 2-8°C.
Although preferred embodiments have been described herein, it is understood that variations and modifications are contemplated and are readily apparent to those skilled in the art.
It must also be noted that, as used in this disclosure and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates
otherwise. Optional or optionaiiy means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or
circumstance occurs and instances where it does not. For example, the phrase optionaiiy the composition can comprise a combination means that the composition may comprise a combination of different molecules or may not include a combination such that the description includes both the combination and the absence of the combination (i.e., Individual members of the combination). Ranges may be expressed herein as from about one particular value, and/or to about another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent about, it will be understood that the particular value forms another aspect, it will be further undersiood that the endpoinis of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoini. All references cited in this disclosure are hereb incorporated herein in their entirety.
Claims
1. A composition comprising a live, attenuated or genetically modified herpesvirus, and at least two or more pharmaceutically acceptable excipienis, at feast one of which is hisiidine and at feast one of which is a sugar or sugar alcohol.
2. The composition of claim 1 , wherein the composition further comprises at least one or more additional pharmaceutically acceptable excipients selected from buffers, salts, surfactants, bulking agents, chelating agents, gelling agents, urea, albumin or
combinations thereof.
3. The composition of claim 1 , further comprising one or more buffers selected from the group consisting of TR!S (tris(hydroxymethyl)-aminomethane) and TRIS-acetate, and wherein the composition has a pH of about 6.5 to 7.5.
4. The composition of claim 2, further comprising one or more salts selected from the group consisting of sodium glutamate, potassium glutarnate, sodium chloride, potassium chloride, and calcium chloride.
5. The composition of claim 2, further comprising urea and/or albumin.
6. The composition of claim 1 , wherein the sugar or sugar alcohol is selected from the group consisting of sucrose, trehalose and sorbitol.
7. The composition of claim 6, comprising one or more sugar or sugar alcohols,
8. The composition of claim 6, wherein the sugar comprises sucrose.
9. The composition of claim 8, comprising 1 mM to 50 M hisiidine and 5% to 10% w/v sucrose and having a pH of about 6,5 to 7.5.
10. The composition of claim 9, further comprising 1 mM to 00 mM potassium glutamate or sodium glutamate.
11. The composition of claim 9, further comprising 80 mM to 160 mM sodium chloride and has a pH of about 6.5 to 7.5.
12, The composition of claim 1 , wherein the composition comprises 10 mM histidine, 10% w/v sucrose, 160 mM NaCI, 50 mM potassium glutamate and a pH of about 6.5 to 7.5.
13. The composition of any one of claims 1 to 12, wherein the composition is a liquid.
14, The composition of claim 13, wherein the liquid composition has a titre loss of less than 0.3 Log10 pfu/mL following storage at 2-8°C for 1-2 weeks.
15. The composition of ciaim 3, wherein the liquid composition has a titre loss of less than 0.5 Log-io pfu/mt following storage at 25°C ± 2°C for 1 week.
16. The composition of any one of claims 1 to 12, wherein the composition is in a dried form.
17. The composition of any one of claims 1 to 16, wherein the live, attenuated or genetically modified herpesvirus is a herpes simplex virus 2 (HSV-2).
18. The composition of claim 17, wherein the HSV-2 is a repiication defective HSV-529 strain.
19. The composition of claim 17 or 18, wherein the HSV-2 contains less than 10 ng of host ceil DNA per 1 X 107 pfu/mL
20. The dried composition of claim 16, wherein following storage for 6 months at 5°C ± 2°C, the composition retains an infectious titre within 0.25 Log10 pfu/mL of the titre measured after the composition is dried, when the viral titres in the composition are between 107 to 105 pfu/mL before drying.
21. The dried composition of ciaim 16, wherein following storage for 6 months at 5°C ± 2°C, the composition retains an infectious titre within 0.2 Log 0 pfu/mL of the titre measured after the composition is dried, when the viral titres in the composition are between W to 105 pfu/mL before drying.
22. The dried composition of claim 16, wherein following storage for 6 months at 5°C ± 2°C, the dried composition retains an infectious titre within 0.1 Log10 pfu/mL of the titre measured after the composition is dried, when the viral titres in the composition are between 107 to 10s pfu/mL before drying.
23. The dried composition of c!aim 16, wherein following storage for 6 months at 25°C ± 2°C, the dried composition retains an infectious titre within 0.5 Log 0 pfu/mL of the titre measured after the composition is dried, when the viral titres in the composition range from 107 to 105 pfu/mL before drying,
24. The composition of any one of claims 16 to 23, wherein the composition is freeze-dried, foam-dried or spray-dried.
25. The composition of claim 24, wherein the residual moisture content of the composition is 6% or less.
26. The composition of any one of claims 1 to 25» wherein the herpesvirus is grown using serum-free media.
27. The composition of any one of claims 1 to 26, wherein the composition is a
pharmaceutical composition.
28. The composition of claim 27, wherein the composition is a vaccine,
29. A method of manufacturing a dried composition comprising a live, attenuated or
geneticaiiy modified herpesvirus and stabilizer that comprises at least two or more pharmaceutically acceptable excipients, at least one of which is hisiidine and at least one of which is a sugar or sugar alcohol, the method comprising:
(i) admixing the live, attenuated or geneticaiiy modified herpesvirus with the stabilizer; and
(ii) drying the admixture.
30. The method of claim 29, wherein the admixture is dried by means of a method selected from the group of consisting of freeze-drying, foam-drying, and spray-drying.
31. The method of claim 30 comprising a replication-defective herpes simplex virus.
32. A method of preparing a vaccine, comprising reconstituting the dried composition of any one of claims 16 or 20 to 25 with an aqueous solution.
33. A kit comprising a first container containing the dried composition as claimed in any one of claims 16 or 20 to 25 and a second container containing an aqueous solution for reconstituting the dried composition.
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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EP13793902.1A EP2852662B1 (en) | 2012-05-21 | 2013-05-21 | Herpesvirus compositions and related methods |
US14/402,678 US11260123B2 (en) | 2012-05-21 | 2013-05-21 | Herpesvirus compositions and related methods |
CA2873775A CA2873775C (en) | 2012-05-21 | 2013-05-21 | Herpesvirus compositions and related methods |
US17/576,021 US20220133881A1 (en) | 2012-05-21 | 2022-01-14 | Herpesvirus compositions and related methods |
Applications Claiming Priority (4)
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US201261649884P | 2012-05-21 | 2012-05-21 | |
US61/649,884 | 2012-05-21 | ||
US201361792913P | 2013-03-15 | 2013-03-15 | |
US61/792,913 | 2013-03-15 |
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US14/402,678 A-371-Of-International US11260123B2 (en) | 2012-05-21 | 2013-05-21 | Herpesvirus compositions and related methods |
US17/576,021 Division US20220133881A1 (en) | 2012-05-21 | 2022-01-14 | Herpesvirus compositions and related methods |
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WO2013177172A2 true WO2013177172A2 (en) | 2013-11-28 |
WO2013177172A3 WO2013177172A3 (en) | 2015-01-29 |
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PCT/US2013/042039 WO2013177172A2 (en) | 2012-05-21 | 2013-05-21 | Herpesvirus compositions and related methods |
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US (2) | US11260123B2 (en) |
EP (1) | EP2852662B1 (en) |
CA (1) | CA2873775C (en) |
WO (1) | WO2013177172A2 (en) |
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EP3139745A4 (en) * | 2014-05-09 | 2017-11-08 | Board of Supervisors of Louisiana State University And Agricultural and Mechanical College | Vaccines against genital herpes simplex infections |
WO2018210804A1 (en) * | 2017-05-15 | 2018-11-22 | Janssen Vaccines & Prevention B.V. | Stable virus-containing composition |
WO2018211419A1 (en) * | 2017-05-15 | 2018-11-22 | Janssen Vaccines & Prevention B.V. | Stable virus-containing composition |
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CN114377127B (en) * | 2022-01-25 | 2023-10-24 | 天津市中升挑战生物科技有限公司 | Triple egg yolk antibody preparation and preparation method and application thereof |
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Also Published As
Publication number | Publication date |
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CA2873775C (en) | 2021-04-20 |
US20150150964A1 (en) | 2015-06-04 |
US20220133881A1 (en) | 2022-05-05 |
US11260123B2 (en) | 2022-03-01 |
EP2852662A2 (en) | 2015-04-01 |
EP2852662A4 (en) | 2016-02-10 |
EP2852662B1 (en) | 2020-09-16 |
CA2873775A1 (en) | 2013-11-28 |
WO2013177172A3 (en) | 2015-01-29 |
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