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    • 专利摘要:
    A vaccine composition comprising a VZV gE antigen truncated to remove the carboxy-terminal anchoring region, in combination with an adjuvant comprising a saponin, a TLR-4 agonist and liposomes, usable in a method to protect against or prevent herpes zoster (HZ or shingles) and / or postherpetic neuralgia for at least 4 years after vaccination.
    公开号:BE1022523B1
    申请号:E2014/5165
    申请日:2014-12-31
    公开日:2016-05-20
    发明作者:Thomas Heineman；Edouard Ledent；Y De Bassols Vinals
    申请人:Glaxosmithkline Biologicals Sa；
    IPC主号:
    专利说明:

    VACCINATION
    Technical area
    The present invention provides methods for protecting against and preventing herpes zoster (shingles) or post-herpetic neuralgia with high efficacy, particularly in elderly and immunocompromised human patients.
    Background Herpes Zoster (HZ), also known as shingles, is a common and often debilitating disease that occurs primarily in elderly or immunocompromised individuals. Shingles is caused by the symptomatic reactivation of latent varicella-zoster virus (VZV) in the dorsal root ganglia and the cranial ganglia. The virus is usually acquired during childhood in the form of chicken pox.
    The only vaccine currently available with proven efficacy against shingles or post-herpetic neuralgia is a live attenuated vaccine based on the VZV OKA strain, marketed as Zostavax®. At the level of the world population (> 60 years), Zostavax® reduced the incidence of shingles by 51.3% (p-value <0.001), although its effectiveness decreases with the age of the vaccinee. In particular, vaccine efficacy (EV) fell to 37.6% among people in the oldest groups (> 70 years). Zostavax® is contraindicated in people with immunodeficiency due to malignancy, human immunodeficiency virus (HIV) infection, or immunosuppressive medical therapy. (Zostavax®EMA SPC 2012, Oxman et al., NEJM 2005, Schmader et al., CID 2012).
    Morrison V.A. et al. reported, regarding the decline in efficacy of Zostavax®, that it is increasingly limited beyond 5 to 8 years after vaccination and is no longer statistically significant beyond 8 years (Morrison and CID advance access publication 20 November, 2014).
    A VZV adjuvanted vaccine composition of the subunit type is described in WO2006 / 094756. Leroux-Roels I. et al. (JID 2012: 206 1280-1290) describe a phase I / II clinical trial of the adjuvanted vaccine comprising VZV gE subunits assessing its safety and immunogenicity. To date, no protective immunological correlates have been identified.
    There is still a need for high efficacy zoster vaccination for all populations at risk and / or having a prolonged protection profile, as well as a favorable safety profile.
    Statement of the invention
    The present invention relates to methods of protection against shingles having an unprecedented effectiveness and protection time with a minimum number of administrations of the vaccine.
    In addition, after immunization of human individuals with herpes zoster (HZ) or post-herpetic neuralgia (NPH) using the vaccine composition, efficacy does not decline with age and remains unusually high at advanced ages. These high levels of effectiveness also remain consistently high years after immunization. The invention therefore relates to a vaccine composition comprising a truncated VZV gE antigen for removing the carboxy-terminal anchoring region, in combination with an adjuvant comprising a saponin, a TLR-4 agonist and liposomes, for use in a method intended to protect against or prevent shingles (herpes zoster - HZ) and / or post-herpetic neuralgia for at least 4 years after vaccination. The invention further relates to a vaccine composition comprising a truncated VZV gE antigen for removing the carboxy-terminal anchoring region, in combination with an adjuvant comprising a saponin, a TLR-4 agonist and liposomes, usable in a method for protecting against or preventing shingles (herpes zoster - HZ) and / or postherpetic neuralgia comprising the step of administering 2 doses of the vaccine composition to an individual over 70 years of age. The invention also relates to a method for protecting against or preventing shingles (herpes zoster - HZ) and / or post-herpetic neuralgia for at least 4 years after vaccination comprising the step of administering to an individual of a vaccine composition comprising a truncated VZV gE antigen to remove the carboxy-terminal anchoring region, in combination with an adjuvant comprising a saponin, a TLR-4 agonist and liposomes.
    Description of the drawings
    Figure 1 schematically represents the design of the study relating to the clinical trial described in Example 1.
    detailed description
    The vaccine composition according to the invention comprises a recombinant VZV gE antigen in combination with an adjuvant. The VZV gE antigen according to the present invention is the glycoprotein gE (also known as gpl) of VZV or an immunogenic variant thereof, truncated to remove the carboxy-terminal anchoring region. The wild-type or complete gE protein is composed of 623 amino acids comprising a signal peptide, the main portion of the protein, a hydrophobic anchoring region (residues 546-558) and a C-terminal tail. In one aspect, a C-terminal gE truncation of VZV (also referred to as truncated gE or truncation) is used, which truncation removes from 4 to 20 percent of the total amino acid residues of the carboxy terminus, e.g. residues 547 to 623. In another aspect, the truncated gE is deprived of its carboxy-terminal anchoring region (suitably about amino acids 547 to 558 of the wild-type sequence). In another embodiment, the VZV gE antigen is a truncated gE comprising the sequence of SEQ ID NO: 1. The VZV gE antigen and its non-anchored variants (which are also immunogenic variants) and their production are described in EP0405867 and references cited therein [see also Vafai A. Antibody binding sites on truncated forms of varicella-zoster virus gpl (gE) glycoprotein Vaccine · 1994 12: 1265-9]. EP0192902 also describes gE and its production.
    The truncated gE protein is also described by Haumont et al. Virus Research (1996) Vol 40, p. 199-204, incorporated herein in its entirety by reference. An adjuvant-compatible VZV gE composition according to the present invention is disclosed in WO2006 / 094756, that is a truncated gE at its carboxy terminus in combination with an adjuvant comprising QS21, 3D-MPL and liposomes additionally containing a cholesterol. Leroux-Roels I. et al. (JID 2012: 206-1280-1290) described a Phase I / II clinical trial evaluating the VZV truncated gE subunit-adjuvanted vaccine.
    As used herein, the term "variant" or "immunogenic variant" refers to an antigen that is modified from its natural form. The variants according to the present invention are sufficiently similar to the native antigens to retain antigenic properties and remain capable of inducing an immune response having cross-reactions with the native antigen. A polypeptide variant may contain a number of substitutions, preferably conservative substitutions, (for example, 1 to 50, such as 1 to 25, especially 1 to 10, and especially 1 amino acid residue (s) may be altered) compared to the reference sequence. Suitably, these substitutions do not occur in the region of a major epitope, and therefore do not have a significant impact on the immunogenic properties of the antigen. Protein variants may also include those in which additional amino acids are inserted relative to the reference sequence, such inserts may, for example, occur at 1-10 positions (such as at 1-5 positions, suitably at 1 or 2 positions, particularly at 1 position) and which may, for example, involve the addition of 50 amino acids or less at each position (such as 20 or less, especially 10 or less, especially 5 or less). Conveniently, these insertions do not occur in the region of an epitope, and therefore do not have a significant impact on the immunogenic properties of the antigen. An example of insertion includes a short extension of histidine residues (eg, 2-6 residues) to facilitate the expression and / or purification of the antigen in question. Variants also include those in which amino acids have been deleted as compared to the reference sequence, such deletions may, for example, occur at 1-10 positions (such as at 1-5 positions, conveniently at 1 or 2 positions in particular at 1 position) and which may, for example, involve deletion of 20 amino acids or less at each position (such as 10 or less, especially 5 or less, especially 2 or less). Conveniently, these deletions do not occur in the region of an epitope, and therefore do not have a significant impact on the immunogenic properties of the antigen. One skilled in the art will appreciate that a particular protein variant may include substitutions, deletions, and additions (or any combination thereof). The variants preferably have an identity of at least about 70%, more preferably an identity of at least about 80%, and most preferably an identity of at least about 90%. at least about 95%, at least about 98% or at least about 99%) to the associated reference sequence. Examples of algorithms for determining sequence identity and percent sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., Nue. Acids Res. 25: 3389-3402 (1977) and Altschul et al., J. Mol. Biol. 215: 403-410 (1990), respectively. Whether a given variant triggers an immune response or not can be measured by an appropriate immunoassay such as ELISA or flow cytometry. 1
    The amount of VZV antigen selected is the amount that induces an immunoprotective response without negative side effects, significant in typical vaccinates. This amount will vary depending on the specific antigen that is used and the way it is presented. Generally, each dose should comprise from 1 to 1000 μg of protein, such as from 2 to 100 μg, or from 5 to 60 μg. When the VZV gE antigen is used, then in an aspect of 25 to 100 μg of gE can be used in humans, such as for example 40 to 100 μg of gE for human use, in an aspect of about 25 μg. , about 50 μg or about 100 μg of gE, suitably 25, 50 or 100 μg of gE. In a preferred embodiment, the VZV gE antigen is used at a dose of 50 μg. The adjuvant according to the invention comprises a TLR-4 agonist, and a saponin in a liposomal formulation.
    By "liposomal formulation" is meant that the saponin and the TLR-4 agonist are formulated with liposomes. In the context of the present invention, the liposomes contain a neutral lipid, for example a phosphatidylcholine, which is conveniently non-crystalline at room temperature, for example an egg yolk phosphatidylcholine, a dioleoylphosphatidylcholine (DOPC) or a dilauryl phosphatidylcholine. In a preferred embodiment, the liposomes according to the present invention contain a DOPC. The liposomes may also contain a charged lipid which enhances the stability of the liposome-QS21 structure of liposomes composed of saturated lipids. In such cases, the amount of lipid loaded is suitably from 1 to 20% w / w, preferably from 5 to 10%.
    Saponin is provided in its least reactive composition where it is deactivated with an exogenous sterol. Suitable sterols include β-sitosterol, stigmasterol, ergosterol, ergocalciferol and cholesterol. In a particular embodiment, the composition of the adjuvant comprises cholesterol as sterol. These sterols are well known in the art, for example cholesterol is described in the Merck Index, 11th ed., Page 341, as a sterol naturally present in animal fat. There are several particular forms of less reactogenic compositions in which QS21 is deactivated by exogenous cholesterol. The saponin / sterol structure is formulated in a liposomal formulation. Methods for obtaining saponin / sterol structures in a liposomal formulation are described in WO 96/33739, particularly Example 1. The ratio of sterol to phospholipid is 1 to 50% (mol / mol), suitably 20 to 25%.
    A particularly suitable saponin for use in the present invention is Quil A and its derivatives. Quil A is a saponin preparation isolated from the South American tree Quillaja Saponaria Molina which was first described by Dalsgaard et al. in 1974 ("Saponin adjuvants", Archiv., .für .... die gesamte Virusforschung, Vol 44, Springer Verlag, Berlin, pp. 243-254) as having adjuvant activity.
    Purified fractions of Quil A that retain this adjuvant activity without the Quil A toxicity were isolated by HPLC (EP 0 362 278), for example QS7 and QS21 (also known as QA7 and QA21). QS21 is a natural saponin derived from the bark of Quillaja saponaria Molina, which typically induces CD8 + cytotoxic T cells (CTL), Th1 cells and a predominant IgG2a antibody response and is a preferred saponin in the context of the present invention. .
    When the active saponin fraction is QS21, the QS21: sterol ratio will typically be in the range of 1: 100 to 1: 1 (w / w), suitably 1:10 to 1: 1 (w / w), and preferably from 1: 5 to 1: 1 (w / w). Sterol in excess is advantageously present, the ratio QS21: sterol being at least 1: 2 (w / w). In one embodiment, the ratio QS21: sterol is 1: 5 (w / w). Suitably, the sterol is cholesterol.
    The aqueous adjuvant composition comprises a TLR-4 agonist. A suitable example of a TLR-4 agonist is a lipopolysaccharide, suitably a nontoxic derivative of lipid A, particularly monophosphorylated lipid A or more particularly 3-deacylated monophosphoryl lipid A (3D-MPL).
    3D-MPL is marketed as MPL by GlaxoSmithKline Biologicals N.A., and is referred to herein as MPL or 3D-MPL, see, for example, US Pat. 4,436,727; 4,877,611; 4,866,034 and 4,912,094. 3D-MPL primarily promotes CD4 + T cell responses having an IFN-γ (Th1) phenotype. It can be produced according to the methods described in GB 2 220 211 A. Chemically it is a mixture of monophosphorylated lipid A 3-deacylated with 4, 5 or 6 acylated chains. In the compositions according to the present invention, a small particle 3D-MPL may be used to prepare the aqueous adjuvant composition. 3D-MPL small. particles has a particle size such that it can be sterilized by 0.22 μm membrane filtration. These preparations are described in WO94 / 21292. Preferably, a powdered 3D-MPL is used to prepare the aqueous adjuvant compositions according to the present invention. Other TLR4 agonists that can be used are glucosaminide alkylphosphates (AGP) such as those described in WO 98/50399 or US Pat. No. 6,303,347 (processes for preparing AGP are also described), suitably RC527. or RC529 or the pharmaceutically acceptable salts of AGP described in US Pat. No. 6,764,840. Some AGPs are TLR-4 agonists, others are TLR-4 antagonists. In the present invention, the use of a TLR-4 agonist is contemplated. Other suitable TLR-4 ligands are those described in WO 2003/011223 and in WO 2003/099195, such as compound I, compound II and compound III described on pages 4-5 of WO2003 / 011223 or on pages 3-4 of WO2003 / 099195 and in particular the compounds described in WO2003 / 011223 such as ER803022, ER803058, ER803732, ER804053, ER804057, ER804058, ER804059, ER804442, ER804680, and ER804764. For example, a suitable TLR-4 ligand is ER804057.
    The aqueous adjuvant composition comprises both a saponin and a TLR4 agonist. In a specific example, the aqueous adjuvant composition comprises QS21 and 3D-MPL.
    A TLR-4 agonist such as a lipopolysaccharide such as 3D-MPL can be used in amounts between 1 and 100 μg per human dose of adjuvant composition. 3D-MPL can be used at about 50 μg, for example between 40-60 μg, suitably between 45-55 μg or between 49 and 51 μg or 50 μg. In another embodiment, the human dose of the adjuvant composition contains 3D-MPL at about 25 μg, for example, between 20-30 μg, suitably between 21-29 μg or between 22-28 μg or between 23 and 27 pg or between 24 and 26 pg, or 25 pg.
    A saponin, such as QS21, can be used in amounts between 1 and 100 μg per human dose of adjuvant composition. QS21 can be used at about 50 μg, for example between 40-60 μg, suitably between 45-55 μg or between 49 and 51 μg or 50 μg. In another embodiment, the human dose of the adjuvant composition contains QS21 at a level of about 25 μg, for example, between 20-30 μg, suitably between 21-29 μg or between 22-28 μg or between 23 and 25 μg. 27 pg or between 24 and 26 pg, or 25 pg.
    The weight ratio of the TLR-4 agonist to saponin is suitably 1: 5 to 5: 1, suitably 1: 1. For example, when -3D-MPL is present in an amount of 50 or 25 μg, then the saponin QS21 may also be present in an amount of 50 or 25 μg per human dose of aqueous adjuvant composition. WO2013 / 041572, in particular examples 3 and 4, furthermore discloses methods for producing a liposome bulk preparation - of the DOPC liposome type additionally containing cholesterol and 3D-MPL, intended to be furthermore mixed with a saponin QS21, to thereby obtain an adjuvant that can be used according to the present invention.
    The immunization schedule may comprise several doses of the vaccine composition. In one embodiment of the invention, at least 2 doses of the vaccine composition are administered to the individual. In another embodiment, the vaccination consists of 2 doses of vaccine composition, namely that after an initial two-dose vaccination, the individual receives no further administration of the vaccine composition for at least 3, 4, 5, 6, 7, 8, 9, 10, etc. years. The composition is typically administered intramuscularly, although alternative routes, eg, intradermal or subcutaneous may be considered. The interval between the administration of several (or two) doses of the vaccine may vary between 1 week and about 1 year (ie 12 months), or between 1 month and 1 year, or between 1 and 3 months, or between 2 and 12 months, or between 2 and 6 months. In one embodiment the interval is 2, 6 or 12 months. In particular, the interval is 2 months. In particular also, the interval is 12 months. Alternatively, the interval is 1 year.
    The vaccine composition according to the invention is used in vaccination, namely for protecting against or preventing the reactivation of herpes zoster (HZ), also called shingles, and / or * of post-herpetic neuralgia (NPH) in the man. In one embodiment, the vaccine composition is used to protect against or prevent the incidence of shingles. When herpes zoster (HZ) occurs, then the severity of shingles is appropriately reduced compared to an unvaccinated individual (ie, shingles improvement). In addition, when shingles occur, other pathological syndromes may develop such as post-herpetic neuralgia (NPH). In another embodiment, the invention relates to use for the purpose of protecting against or preventing the incidence of postherpetic neuralgia. When NPH occurs, then its severity is appropriately reduced compared to an unvaccinated individual (ie, improved NPH). The use or the method of protection according to the present invention (vaccination) generates exceptionally high efficiencies. In one embodiment, the effectiveness of vaccination is expressed as a reduction in the occurrence of herpes zoster in a population that received the vaccine composition compared to placebo. The effectiveness of vaccination in reducing the occurrence of herpes zoster in a population compared to placebo is 60% or more, suitably 70% or more, suitably 80% or more, appropriately 85% or more, suitably 90% or more, suitably 95% or more, or even 97% or more. In particular embodiments, the efficiency is 80% or more, or the efficiency is 90% or more.
    In one embodiment, efficacy is expressed as a reduction in the occurrence of postherpetic neuralgia in a population that received the vaccine composition compared to placebo. The effectiveness of vaccination in terms of reducing the occurrence of N PH in a population compared to placebo is 70% or more, suitably 80% or more, suitably 85% or more suitably 90% or more, suitably 95% or more, or suitably 97% or more.
    In addition, it has been surprisingly found that the efficacy of the present invention is exceptionally high in all target populations. In contrast to the usual decline in vaccine efficacy in subjects with defective immune systems, the effectiveness of vaccination with the vaccine composition of the present invention is exceptionally high in all target populations, even in individuals. over 70 years old.
    The particular target populations considered according to the present invention are human individuals> 50 years old,> 60 years old,> 70 years old, between 50 and 59 years old, or between 60 and 69 years old; and more particularly, the subjects considered are those of> 70 years of age, such as> 71 years old, e.g. > 72 years old, such as> 73 years, eg. > 74 years, such as> 75 years old, eg. > 80 years old or> 81 years old. In a particular embodiment, the target population comprises human individuals over 70 years of age. Other particular populations are immunocompromised populations or individuals, such as HIV positive patients or AIDS patients, eg transplant patients. patients who have undergone renal transplantation or hematopoietic cell transplantation, patients with hematological malignancies, patients with solid tumors, or patients who may otherwise have acquired immunodeficiency e. patients receiving or enrolled to receive immunosuppressive therapy, such as chemotherapy or radiotherapy.
    In addition, it has surprisingly been found that the effectiveness according to the present invention is prolonged for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 years after the vaccination, namely after the last administration of a dose of the vaccine composition administered to the individual. In one embodiment, protection or prevention is provided for at least 5 years after vaccination. In another embodiment, protection or prevention is provided for at least 8 years after vaccination. In yet another embodiment, protection or prevention is provided for at least 10 years after vaccination.
    Preferred embodiments of the invention include: - A vaccine composition comprising a truncated VZV gE antigen to remove the carboxyterminal anchoring region or a derivative thereof, in combination with an adjuvant comprising a QS21 saponin, a 3D -MPL and liposomes containing cholesterol usable in a method for protecting against or preventing herpes zoster (HZ or shingles) and / or post-herpetic neuralgia in individuals 70 years of age or older for at least 5 years. A vaccine composition comprising a truncated VZV gE antigen to remove the carboxy-terminal anchoring region or a derivative thereof, in combination with an adjuvant comprising a QS21 saponin, a 3D-MPL and liposomes containing usable cholesterol in a method for protecting against or preventing herpes zoster (HZ or herpes zoster) and / or post-herpetic neuralgia in individuals over 70 years of age for at least 5 years.
    A vaccine composition comprising a truncated VZV gE antigen to remove the carboxy-terminal anchoring region or a derivative thereof, in combination with an adjuvant comprising a QS21 saponin, a 3D-MPL and liposomes containing usable cholesterol in a method for controlling or preventing herpes zoster (HZ or zoster) and / or post-herpetic neuralgia in immunocompromised individuals for at least 5 years. A vaccine composition comprising a truncated VZV gE antigen to remove the carboxyterminal anchoring region or a derivative thereof, in combination with an adjuvant comprising a QS21 saponin, a 3D-MPL and liposomes containing cholesterol usable in a a method to protect against or prevent herpes zoster (HZ or shingles) and / or post-herpetic neuralgia in individuals 50 years of age or older reducing the incidence of shingles by at least 80% for at least 5 years . A vaccine composition comprising a truncated VZV gE antigen to remove the carboxyterminal anchoring region or a derivative thereof, in combination with an adjuvant comprising a QS21 saponin, a 3D-MPL and liposomes containing cholesterol usable in a a method for protecting against or preventing herpes zoster (HZ or shingles) and / or post-herpetic neuralgia in individuals over 70 years of age who reduce the incidence of shingles by at least 80% for at least 5 years years. A vaccine composition comprising a truncated VZV gE antigen to remove the carboxy-terminal anchoring region or a derivative thereof, in combination with an adjuvant comprising a QS21 saponin, a 3D-MPL and liposomes containing usable cholesterol in a method for protecting against or preventing herpes zoster (HZ or herpes zoster) and / or post-herpetic neuralgia in immunosuppressed individuals reducing the incidence of shingles by at least 80% for at least 5 years.
    Particularly preferred embodiments are the above preferred embodiments in which method 1 provides protection for at least 8 years after vaccination. More preferred embodiments are the above preferred embodiments wherein the method provides protection for at least 10 years after vaccination.
    Also particularly preferred embodiments are the above preferred embodiments in which the method reduces the incidence of shingles by at least 90%.
    More preferred embodiments are the above preferred embodiments wherein the method reduces the incidence of shingles by at least 95%.
    Still more preferred embodiments are each of the above preferred and particularly preferred embodiments wherein the VZV gE antigen has the sequence of SEQ ID NO: 1 and is present at a dose of 50 μg, and which QS21 and 3D-MPL are also present at a dose of 50 μg.
    The present invention is illustrated by the following nonlimiting examples.
    Example 1 Example 1 describes a multicentre, randomized, placebo-controlled, randomized, placebo-controlled clinical vaccination trial for the observer to evaluate the prophylactic efficacy, safety, and immunogenicity of the gE / ASOle vaccine. GSK Biologicals when administered intramuscularly on a 0-2 month schedule to adults 50 years of age and older.
    The study population includes both men and women without pathologies characteristic of severely immunocompromised patients in the age groups 50-59, 60-69, 70-79 and> 80 years of age. Strata 70-79 and> 80 years old were combined for "primary analyzes." The distribution of about 20-25% of the cohort> 70 years in the age group> 80 years guaranteed that this particularly vulnerable population is represented adequately.
    The candidate vaccine against shingles tested in this trial is a recombinant vaccine with VZV gE adjuvant. A saline solution was used as a negative control (placebo) in the study to evaluate the efficacy and safety profile of the candidate vaccine against shingles.
    The objectives of the clinical vaccination trial included evaluating the effectiveness of the vaccine in preventing shingles, as measured by the risk reduction for herpes zoster, compared to placebo in subjects in each of the following age groups: 59 years old, 60-69 years old and> 70 years old.
    The design of the study is illustrated in Figure 1. The study included two treatment groups, a placebo group and a vaccine group. The placebo group received a NaCl solution as a control. The NaCl solution was provided in single dose vials (0.5 mL / dose) containing 150 mM NaCl per 0.5 mL dose. The vaccine group received the vaccine from the study. Each 0.5 mL dose of the vaccine in the study contained 50 μg of VZV gE antigen, 50 μg of 3D-MPL, 50 μg of QS21, and liposomes (DOPC + cholesterol). The study vaccine was provided in 2 vials, one containing VZV gE antigen and the other AS01B adjuvant system. • The AS01B Adjuvant System is supplied as a liquid formulation in single-dose vials, each vial containing at least 0.5 mL of adjuvant. A 0.5 mL dose of AS01B formulation contains 50 μg of 3D-MPL and 50 μg of QS21 mixed with liposomes. The adjuvant system was formulated according to the preparation method described in Examples 3 and 4 of WO 2013/041572. The VZV gE antigen was a truncated gE having the sequence of SEQ ID NO: 1. The α-antigen was obtained according to the method described in Example 2 of WO2006 / 094756. The VZV gE antigen was provided in freeze-dried form in single dose vials. Each vial contained 62.5 μg of purified recombinant gE and formulation excipients. Therefore, when the 62.5 μg of VZV gE in each vial were reconstituted with AS01B adjuvant volume, each dose of vaccine contained 50 μg of VZV gE antigen per 0.5 ml dose. reconstituted vaccine.
    The vaccination schedule was two doses of the study vaccine or control saline for the vaccine group and the placebo group, respectively, the first dose in month 0 (visit 1) and the second in month 2 (visit 2 ). The vaccine was administered intramuscularly.
    Eligible subjects were randomized to vaccine / placebo groups in a ratio (vaccine: placebo) of 1: 1. Subjects were stratified by age: 50-59 years; 60-69 years; 7079 years and 80 years in a ratio of about 8: 5: 3: 1. Strata 70-79 years and 80 years were combined for primary analyzes. The primary efficacy analysis for shingles occurred when the following condition was satisfied: at least 196 cases of confirmed herpes zoster were accumulated in the modified total vaccine cohort (mTVc). The mTVC cohort is the primary cohort for efficacy analysis that excludes from the efficacy analysis those subjects in the TVc cohort who did not receive the second vaccination or who developed a confirmed case of herpes zoster in the month following the second vaccination.
    Table 1 shows the number of subjects in the mTVc cohort included in the primary analysis.
    Suspected cases of herpes zoster have been confirmed in two ways: 1. Polymerase Chain Reaction (PCR):
    Scratch lesion samples were collected from subjects clinically diagnosed as suspected cases of shingles. The samples were transferred to GSK Biologicals or a validated laboratory designated by GSK
    Biologicals by standardized and validated procedures for diagnostic purposes of shingles in laboratory PCR. 2. By a confirmation committee of shingles:
    All suspected cases of herpes zoster have been submitted to a Confirmation Committee for Herpes Zoster (HZAC). The HZAC Committee classified all cases submitted as "shingles" or "non-shingles". However, the classification of the Committee was used to define a final case only when the case could not be confirmed or excluded by PCR, eg when all samples from a given subject were inadequate, or when none sample for a given subject was available. Therefore, the final PCR results, if available, determined the final allocation of cases of shingles. In these cases, the classification of the HZAC Committee did not contribute to the decision to determine cases of shingles.
    The HZAC committee consisted of three to five expert zoster doctors. The members of the committee, participating in this study as an investigator, did not evaluate the cases from their own study site. They were "blind" to treatment assignments. In each case, each HZAC member was asked to clinically determine whether the case was shingles or not based on a review of available clinical information (eg, summary of scraping and pain, digital photographs of the subject's scratching, and notes of clinical course). A suspected case of shingles was considered a "shingles" if HZAC members agreed unanimously; otherwise, it was classified as "non-shingles". As described above, case assignment by the HZAC Committee was considered final case assignment only if definitive PCR results were not available.
    Table 2 shows the result of the primary efficacy analysis of shingles.
    N = number of subjects included in each group n = number of subjects with at least one confirmed case of shingles (herpes zoster - HZ) n / T (per 1000) = Incidence rate of subjects reporting at least one event per year LL , UL = 95% confidence limits Low (LL) and High (UL) SEQUENCE LIST <110> Glaxosmithkline biologicals <T20> vaccine <160> 1 <170> FastSEQ for Windows Version 4.0 <210> 1.
    <211> 546 <212> PRT <213> truncated gE of VZV <400> 1
    Met Gly Thr Val Asn Lys Pro Val Val Gly Val Leu Met Gly Phe Gly 15 10 15
    Ile Ile Thr Gly Thr Leu Arg Isle Thr Asn Pro Val Arg Ala Ser Val 20 25 30
    Leu Arg Tyr Asp Asp Phe His Asp Asp Asp Asp Asp Leu Asp Asp Asp 35 40 45
    Ser Val Tyr Glu Pro Tire Tyr His Ser Asp His Ala Glu Ser Ser Trp 50 55 60
    Val Asn Arg Gly Glu Ser Ser Arg Lys Ala Asp Asp Asn Ser Pro 65 70 75 80
    Tyr Isle Trp Pro Arg Asn Asp Asp Asp Gly Phe Leu Glu Asn Ala His 85 90 95
    Glu His His Gly Val Tyr Asn Gin Gly Arg Gly Asp Asp Gly Glu 100 100 110
    Arg Leu Met Gin Pro Thr Gin Met Ser Ala Gin Asp Glu Leu Gly Asp 115 120 125
    Asp Thr Gly Ile His Val Pro Ile Leu Leu Asn Gly Asp Asp Arg His 130 135 140
    Lys Val Asn Val Asp Asp Gin Arg Gin Tyr Gly Asp Val Phe Lys Gly 145 150 155 160
    Asp Leu Asn Pro Lys Pro Gin Gly Gin Arg Leu Isle Glu Val Ser Val 165 170 175
    Glu Glu Asn His Pro Phe Thr Ala Arg Ala Pro Gin Island Arg Tyr Island 180 185 190
    Gly Val Arg Tyr Thr Glu Trp Ser Phe Leu Pro Ser Leu Thr Cys 195 200 205
    Thr Gly Asp Ala Ala Pro Ala Island Gin His Island Cys Leu Lys His Thr 210 215 220
    Thr Cys Phe Gin Asp Val Val Asp Asp Asp Val Cys Ala Glu Asn Thr 225 230 235 240
    Lily Glu Asp Gin Leu Ala Glu Isle Ser Tyr Arg Phe Gin Gly Lily Lys 245 250 255
    Glu Ala Asp Gin Pro Trp Val Val Asn Island Thr Thr Thr Leu Phe Asp 260 265 270
    Glu Leu Glu Leu Asp Pro Pro Glu Glu Island Pro Gly Val Leu Lys Val 275 280 285
    Leu Arg Thr Glu Lilies Gin Tyr Leu Gly Val Tyr Ile Trp Asn Met Arg 290 295 300
    Gly Ser Asp Gly Thr Ser Thr Tyr Ala Thr Phe Leu Val Thr Trp Lys 305 310 315 320
    Gly Asp Glu Lys Thr Arg Asn Pro Thr Pro Ala Val Thr Pro Gin Pro 325 330 335
    Arg Gly Ala Glu Phe His Met Trp Asn Tyr His Ser His Val Phe Ser 340 345 350
    Val Gly Asp Thr "Phe Ser Leu Ala'-Met His I.-eu Gl π Tyr Lys Island His 355 360 365
    Glu Ala Pro Phe Asp Leu Leu Leu Leu Leu Leu Tyr Val Pro Ile Asp 370 375 380
    Pro Thr Cys Gin Pro Met Arg Leu Tyr Ser Ser Cys Leu Tyr His Pro 385 390 395 400
    Asn Ala Pro Gin C, ys Leu Ser His Met Asn Ser Gly Cys Thr Phe Thr 405 410 415
    Ser Pro His Leu Ala Gin Arg Val Ala Ser Thr Val Tyr Gin Asn Cys 420 425 430
    Glu His Ala Asp Asn Tire Thr Ala Tyr Cys Leu Gly Island Ser His Met 435 440 445
    Glu Pro Ser Phe Gly Leu Ile Leu His Asp Gly Gly Thr Thr Leu Lys 450 455 460
    Phe Val Asp Thr Pro Glu Ser Leu Gly Leu Tyr Val Phe Val Val 465 470 475 480
    Tyr Phe Asn Gly His Val Glu Ala Val Ala Tire Thr Thr Val Val Ser Thr 485 490 495
    Val Asp His Phe Val Asn Ala Island Glu Glu Arg Gly Phe Pro Pro Thr 500 505 510
    Ala Gly Pro Gin Pro Ala Thr Thr Lys Pro Lys Glu Thr Island Pro Val 515 520 525
    Asn Pro Gly Thr Ser Pro Leu Isle Arg Tyr Ala Ala Thr Trp Gly Gly 530 535 540
    Leu Ala 545
    权利要求:
    Claims (36)
    [1]
    A vaccine composition comprising a truncated VZV gE antigen to remove the carboxy-terminal anchor region, in combination with an adjuvant comprising a saponin, a TLR-4 agonist and liposomes, usable in a method to protect against or to prevent herpes zoster (HZ or herpes zoster) and / or post-herpetic neuralgia for at least 4 years after vaccination.
    [2]
    2. A vaccine composition according to claim 1 for use in a method for protecting against or preventing herpes zoster (HZ or zoster) and / or postherpetic neuralgia for at least 5, 6, 7, 8, 9, 10 , 12 or 15 years after vaccination.
    [3]
    3. Vaccine composition according to any one of the preceding claims, usable in a method for protecting against or preventing herpes zoster (HZ or zoster) and / or post-herpetic neuralgia for at least 5 years after vaccination.
    [4]
    4. A vaccine composition according to claim 1 or 2, usable in a method for protecting against or preventing herpes zoster (HZ or zoster) and / or postherpetic neuralgia for at least 8 years after vaccination.
    [5]
    5. Vaccine composition according to any one of the preceding claims, usable in a human subject having> 50 years,> 60 years,> 70 years, between 50 and 59 years, or between 60 and 69 years.
    [6]
    6. A vaccine composition according to any one of the preceding claims, usable in a human subject having> 70 years,> 71 years,> 72 years,> 73 years,> 74 years,> 75 years or> 80 years.
    [7]
    7. Vaccine composition according to any one of the preceding claims, usable in a human subject over 70 years.
    [8]
    8. Vaccine composition according to any one of the preceding claims, usable in an immunocompromised individual.
    [9]
    A vaccine composition according to any one of the preceding claims, wherein the method has an efficacy of reducing the occurrence of shingles by 60% or more.
    [10]
    A vaccine composition according to any one of the preceding claims, wherein the method is intended to reduce the occurrence of shingles by 60% or more.
    [11]
    11. A vaccine composition according to any one of the preceding claims, for reducing the occurrence of shingles by 60% or more.
    [12]
    A vaccine composition according to any one of the preceding claims, wherein the occurrence of shingles is reduced by 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 97% or more.
    [13]
    13. A vaccine composition according to any one of the preceding claims, wherein the method comprises administering 2 doses of the vaccine composition.
    [14]
    14. A vaccine composition according to any one of the preceding claims, wherein two doses of the vaccine composition are administered at an interval between 1 week and 12 months.
    [15]
    15. A vaccine composition according to claims 13 or 14, wherein the two doses of the vaccine composition are administered at an interval of 2, 6 or 12 months.
    [16]
    16. The vaccine composition according to any one of claims 13 to 15, wherein the two doses of the vaccine composition are administered at an interval of 2 months.
    [17]
    A vaccine composition according to any one of the preceding claims, wherein the VZV gE antigen is not in the form of a fusion protein.
    [18]
    A vaccine composition according to any one of the preceding claims, wherein the VZV gE antigen comprises the sequence of SEQ ID NO: 1.
    [19]
    A vaccine composition according to any one of the preceding claims, wherein the VZV gE antigen is present in an amount of 20 to 100 μg, such as 25 μg, 50 μg or 100 μg per dose.
    [20]
    A vaccine composition according to any one of the preceding claims, wherein the VZV gE antigen is present in an amount of 50 μg per dose. ,
    [21]
    21. A vaccine composition according to any one of the preceding claims, wherein the saponin is QS21.
    [22]
    22. A vaccine composition according to any one of the preceding claims, wherein the saponin such as QS21 is present in an amount of 1 to 100 μg, such as 25 μg or 50 μg per dose.
    [23]
    23. A vaccine composition according to any one of the preceding claims, wherein the saponin such as QS21 is present in an amount of 50 μg per dose.
    [24]
    24. A vaccine composition according to any one of the preceding claims, wherein the TLR-4 agonist is 3D-MPL.
    [25]
    A vaccine composition according to any one of the preceding claims, wherein the TLR-4 agonist such as 3D-MPL is present in an amount of 25 or 50 μg per dose, such as 50 μg per dose.
    [26]
    26. A vaccine composition according to any one of the preceding claims, wherein the liposomes further comprise a sterol, suitably a cholesterol.
    [27]
    27. A vaccine composition according to any one of the preceding claims, wherein the liposomes comprise or consist of a liposomal lipid of dioleylphosphatidylcholine (DOPC) type and cholesterol.
    [28]
    28. A vaccine composition according to any one of the preceding claims comprising no other VZV antigen, such as live VZV attenuated or killed live OKA strain.
    [29]
    29. A vaccine composition comprising a truncated VZV gE antigen to remove the carboxy-terminal anchoring region, in combination with an adjuvant comprising a saponin, a TLR-4 agonist and liposomes, usable in a method to protect against or to prevent herpes zoster (HZ or shingles) and / or post-herpetic neuralgia comprising the step of administering 2 doses of the vaccine composition to an individual over 70 years of age.
    [30]
    30. The vaccine composition of claim 29, further comprising one or more of the features of claims 2 to 4, 6, 8 to 12, and 14 to 28.
    [31]
    31. A vaccine composition comprising a truncated VZV gE antigen to remove the carboxy-terminal anchoring region, in combination with an adjuvant comprising QS21, 3D-MPL and sterol-containing liposomes, for use in a method to protect against or to prevent herpes zoster (HZ or herpes zoster) and / or post-herpetic neuralgia for at least 5 years after vaccination in an individual aged 70 years or over, the method comprising two administrations of the vaccine composition at an interval of 2, 6 or 12 months.
    [32]
    The vaccine composition of claim 31, further containing one or more of the features of claims 18, 19, 20, 22, 23 or 25.
    [33]
    33. Method for protecting against or preventing herpes zoster (HZ or shingles) and / or post-herpetic neuralgia for at least 4 years after vaccination comprising the step of administering to a human individual a composition vaccine comprising a truncated VZV gE antigen to remove the carboxy-terminal anchor region in combination with an adjuvant comprising a saponin, a TLR-4 agonist and liposomes.
    [34]
    The method of claim 33, further comprising one or more of the features of any one of claims 2 to 28.
    [35]
    35. A method for protecting against or preventing herpes zoster (HZ or herpes zoster) and / or post-herpetic neuralgia comprising the step of administering 2 doses of a vaccine composition comprising a truncated VZV gE antigen. remove the carboxyl-terminal anchoring region, in combination with an adjuvant comprising a saponin, an agonist. TLR-4 and liposomes to a human individual over 70 years old.
    [36]
    36. The method of claim 35, further comprising a. or more of the features of any one of claims 2 to 4, 6, 8 to 12, and, 14 to 28.
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    同族专利:
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    AR103030A1|2017-04-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2006094756A2|2005-03-03|2006-09-14|Glaxosmithkline Biologicals S.A.|Varicella zoster virus vaccine|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB201422686|2014-12-18|
    GB1422686.4|2014-12-18|
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