比利时专利BE1022355B1 NEW METHODS OF INDUCING AN IMMUNE RESPONSE

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专利摘要:
une réponse immunitaire consistant à réaliser au moins deux administrations d’une composition immunogène, la seconde administration étant donnée avec une dose plus faible que celle de la première administration, et la seconde administration pouvant ne pas comprendre d’adjuvant. Methods and uses to induce Figure 1 an immune response consisting of performing at least two administrations of an immunogenic composition, the second administration being given with a lower dose than that of the first administration, and the second administration may not include adjuvant.
公开号:BE1022355B1
申请号:E2015/5209
申请日:2015-04-02
公开日:2016-03-26
发明作者:William Ripley Ballou Jr；Arnaud Michel Didierlaurent；Der Most Robbert Gerrit Van
申请人:Glaxosmithkline Biologicals S.A.；
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NEW METHODS OF INDUCING AN IMMUNE RESPONSE Technical Area
The present invention relates to methods for inducing an immune response, particularly immunization methods comprising administering at least two times an adjuvant-containing immunogenic composition, wherein the dose administered the second time is lower than the first.
Context of the invention
Vaccination is one of the most effective methods for preventing infectious diseases. However, the single administration of an antigen is often insufficient to confer complete immunity and / or induce a durable response. Some approaches include adding adjuvants to the vaccine and / or boosting doses (in other words, restimulating the immune response by administering one or more other doses of the antigen) to establish immunity. strong and sustainable vis-à-vis the specific pathogen. The booster vaccine and the primary vaccine may be the same (homologous booster) or different (heterologous booster). The most common approach for the homologous booster is not only to administer the same vaccine, but also to administer it at the same dose each time.
Malaria is one of the diseases for which vaccination requires multiple injections. Malaria is one of the major health problems on a global scale. In 2010, the World Health Organization estimated that there were 219 million cases of malaria in the world. Malaria is caused by the protozoan parasite of the genus Plasmodium.
The life cycle of the parasite is complex and requires two hosts, the man and the mosquito, to be complete. Human infection results from the inoculation of sporozoites through the saliva of the infected mosquito. The sporozoite stage has been identified as a potential target for an antimalarial vaccine. The main surface protein of the sporozoite is known as the circumsporozoite protein (CS protein). RTS, S, an antigen based on Plasmodium CS protein, has been in development for more than 25 years and is currently the most advanced candidate for a malaria vaccine.
At the very beginning of the project, RTS, S was studied in a small clinical trial, in combination with an adjuvant composed of QS21 and 3D-MPL combined with an oil-in-water emulsion (Stoute et al., 1997). NEJM 336: 86). This study included a schedule for the administration of three full doses, but because of excessive reactogenicity, the third injection was reduced to one-fifth of the full dose and was administered later than originally planned. In the end, this study protected six of the seven participating subjects. In subsequent work, a full three-dose immunization schedule was used, and in more recent studies using the same schedule, the RTS, S was supplemented with a liposomal preparation including QS21 and 3D-MPL. This adjuvant is designated AS01 and is described, in particular, in WO 96/33739 and WO2007 / 068907). Recent data from a large Phase III clinical trial, where the RTS, S / AS01 vaccine was administered in three identical doses at 1-month intervals, showed that over 18 months of follow-up, the RTS vaccine, S / AS01 almost halved the number of malaria cases in young children (5 to 17 months at the time of first vaccination) and reduced the number of malaria cases in infants by almost a quarter (6 to 12 months). weeks at the time of the first vaccination) over a follow-up period of 18 months.
While significant progress has been made in the field of vaccine research and development, the fact remains that efforts must be continued to develop new immunogenic compositions and new methods of immunization against certain vaccines. diseases, including malaria, that are extremely effective, safe, cost-effective, sustainable and that induce a broad spectrum of cross-reactive immune responses. Summary of the invention
It has been surprisingly found that with a multi-dose immunization method using an adjuvanted malaria vaccine, immunization is more effective when the booster dose is lower than the primary dose (primer dose). ) only when the doses are the same. The adjuvant used comprises a TLR4 agonist, 3D-MPL and QS21, an immunologically active saponin fraction.
In a first aspect, the invention therefore relates to a method for inducing an immune response in humans and of administering to the subject a first immunogenic composition comprising one or more antigens and a first adjuvant, then a second immunogenic composition comprising a or a plurality of antigens and a second adjuvant, the first and second compositions having at least one antigen in common, the first and second adjuvants comprising an LRT agonist and / or an immunologically active saponin and having at least one of them components in common and • the second adjuvant containing a smaller amount of the common component than the first adjuvant, and / or • the antigen in common being RTS, S and the second composition containing a lower amount of RTS, S than the first composition, provided that the first and second composition do not both include the RTS, S and QS21 and 3D-MPL associated with an oil emulsion in water.
In another aspect, the invention relates to a method for inducing an immune response in humans by administering to the subject a first immunogenic composition comprising RTS, S and an adjuvant, followed by a second immunogenic composition comprising RTS, S, the adjuvant comprising a TLR agonist and / or an immunologically active saponin, and the second immunogenic composition containing no adjuvant.
Brief description of the figures
Figure 1: Percentage of vaccinees who did not develop parasitaemia after challenge over a 28-day follow-up period. Fx refers to the group "Subsequent dose fraction", RRR the "0, 1, 2 months" group, and CTL the control group
Figure 2: Sequence of RTS
Figure 3: Sequence of VZV antigen
detailed description
As described above, the invention relates, in a first aspect, to a method for inducing an immune response in humans and of administering to the subject a first immunogenic composition comprising one or more antigens and a first adjuvant, then a second immunogenic composition comprising one or more antigens and a second adjuvant, the first and second compositions having at least one antigen in common, the first and second adjuvants comprising a TLR agonist and / or an immunologically active saponin and having at least one one of these two components in common, • the second adjuvant containing a smaller amount of the common component than the first adjuvant, and / or • the antigen in common being RTS, S and the second composition containing a quantity of RTS, S lower than the first composition, provided that the first and second composition do not both include the RTS, S and QS21 and 3D-MPL associated with an oil-in-water emulsion. The invention also relates to a first immunogenic composition used in a method for inducing an immune response in humans and comprising administering to the subject a first immunogenic composition comprising one or more antigens and a first adjuvant, then a second immunogenic composition comprising one or more antigens and a second adjuvant, the first and second compositions having at least one antigen in common, the first and second adjuvants comprising a TLR agonist and / or an immunologically active saponin and having at least one of these antigens; two components in common, • the second adjuvant containing a smaller amount of the common component than the first adjuvant, and / or • the antigen in common being RTS, S and the second composition containing a lower amount of RTS, S that the first composition, provided that the first and the second composition do not both include the RTS, S and a QS21 and 3D-MPL associated with an oil-in-water emulsion. The invention also relates to a second immunogenic composition used in a method for inducing an immune response in humans and comprising administering to the subject a first immunogenic composition comprising one or more antigens and a first adjuvant, then a second immunogenic composition comprising one or more antigens and a second adjuvant, the first and second compositions having at least one antigen in common, the first and second adjuvants comprising a TLR agonist and / or an immunologically active saponin and having at least one of these antigens; two components in common, • the second adjuvant containing a smaller amount of the common component than the first adjuvant, and / or • the antigen in common being RTS, S and the second composition containing a lower amount of RTS, S that the first composition, provided that the first and the second composition do not both include the RTS, S and the QS21 and 3D-MPL associated with an oil-in-water emulsion. In another aspect, the invention relates to the use of a second immunogenic composition comprising one or more antigens and a second adjuvant in the manufacture of a medicament for inducing an immune response in humans, said subject having already received a first immunogenic composition comprising one or more antigens and a first adjuvant, the first and second compositions having at least one antigen in common, the first and second adjuvants comprising a TLR agonist and / or an immunologically active saponin and having at least one of these two components in common, • the second adjuvant containing a smaller amount of the common component than the first adjuvant, and / or • the antigen in common being RTS, S and the second composition containing a amount of RTS, S lower than the first composition, provided that the first and second composition do not both include the RTS, S and QS21 and the 3D-MPL associated with an oil-in-water emulsion. In another aspect, the invention provides a method of inducing an immune response in humans by administering to the subject a first immunogenic composition comprising RTS, S and an adjuvant, followed by a second immunogenic composition comprising RTS. , S, the adjuvant comprising a TLR agonist and / or an immunologically active saponin, and the second immunogenic composition containing no adjuvant. In one embodiment of this method, the first and second composition comprise both 25 micrograms of RTS, S or 50 micrograms of RTS, S. In general, the method of the invention seeks to induce a protective immune response, in other words to immunize or vaccinate the subject against the pathogen from which the antigen originates. In one embodiment, the vaccine efficacy of the method of the invention is improved over a regimen wherein the first composition and the second composition are the same. For example, the vaccine efficacy, according to the example included here, can be improved by at least 10%, for example by 25%. In one embodiment, the vaccine efficacy obtained is greater than 80%, for example greater than 90%, according to the example included here. The method can therefore be used to prevent infectious diseases (that is, prophylaxis). The method can also be used in immunotherapy, that is, to treat a disease, for example cancer, by inducing or stimulating an immune response.
Adjuvants Used in the Method of the Invention As previously described, the first adjuvant and the second adjuvant comprise a TLR agonist and / or an immunologically active saponin and have at least one of these two components in common.
In one embodiment, both the first adjuvant and the second adjuvant both comprise a TLR agonist. In another embodiment, the first adjuvant and the second adjuvant both comprise an immunologically active saponin. In yet another embodiment, the first adjuvant and the second adjuvant both comprise a TLR agonist and an immunologically active saponin.
In one embodiment, the first adjuvant and the second adjuvant consist of the same components. In this embodiment, the components of the two adjuvants are therefore the same, but are not necessarily present in the same relative proportions. For example, the first adjuvant and the second adjuvant may both be a TLR agonist and a saponin in a liposomal preparation, but the ratio of TLR agonist to saponin may be 5: 1 in the first adjuvant and 1: 1 in the second adjuvant.
In another embodiment, the first adjuvant and the second adjuvant consist of the same components and the relative proportions are the same. But in this embodiment, if the relative proportions of the components of the adjuvant are the same, their absolute amounts may be different. For example, the absolute amounts of all components present in the second adjuvant may, for example, be one fifth of the absolute amounts of all the components present in the first adjuvant.
As previously described, in one embodiment, the second adjuvant contains a lower amount of the common component (i.e., a lower amount of the TLR agonist or a lower amount of the saponin or smaller amount of both) than the first adjuvant.
In one embodiment, the amount in the second adjuvant is at least 10% lower, for example at least 25% lower, for example at least two times lower, for example at least three times lower, for example at least less four times lower, for example at least five times lower, for example at least six times lower, for example at least seven times lower, for example at least eight times lower, for example at least nine times lower for example at least ten times lower, for example at least 15 times lower, for example at least 20 times lower than in the first adjuvant.
In another embodiment, the amount in the second adjuvant is between 2 and 50 times lower, for example between 2 and 20 times lower, for example between 2 and 15 times lower, for example between 2 and 10 times more low, for example between 3 and 7 times lower, for example between 4 and 6 times lower than in the first adjuvant.
As previously described, in one embodiment, the first adjuvant and the second adjuvant comprise a Toll-like receptor (TLR) agonist. The use of TLR agonists in adjuvants is well known in the state of the art and has been reviewed for example by Lahiri et al. (2008), Vaccine 26: 6777. Among the TLRs that can be stimulated to achieve an adjuvant effect are TLR2, TLR4, TLR5, TLR7, TLR8 and TLR9. TLR2, TLR4, TLR7 and TLR8 agonists, and particularly TLR4 agonists, are preferred.
Suitable TLR4 agonists include lipopolysaccharides, for example monophosphoric lipid A (MPL) and 3-0-deacylated monophosphoric lipid A (3D-MPL). U.S. Patent 4,436,727 describes MPL and its manufacture. U.S. Patent 4,912,094 and Reexamination Certificate B1,4912,094 describe 3D-MPL and a method for making it. Glucopyranosyl lipid adjuvant (GLA, adjuvant glucopyranosyl lipid) is another TLR4 agonist; it is a synthetic molecule similar to lipid A (see, for example, Fox et al (2012) Clin, Vaccine Immunol 19: 1633). In yet another embodiment, the TLR4 agonist may be a synthetic TLR4 agonist, for example a synthetic disaccharide molecule, of structure similar to MPL and 3D-MPL, or it may be monosaccharide molecules synthetic, for example, aminoalkyl glucosaminide phosphate (AGP) compounds described, for example, in WO9850399, WO0134617, WO0212258, WO06565806, WO04062599, WO006016997, WO0612425, WO003066065 and WO00190129.
These molecules have also been described in the scientific literature and that of patents in the form of "lipid A mimetics". "A mimetic lipids" appropriately share some of the functional and / or structural activity with lipid A, and in one aspect are recognized by TLR4 receptors. AGPs as described herein are sometimes referred to as "lipid A mimetics" in the state of the art. In a preferred embodiment, the TLR4 agonist is 3D-MPL. TLR4 agonists, for example monophosphoric lipid A 3-O-deacylated (3D-MPL), and their use as adjuvants in vaccines have, for example, been described in WO 96/33739 and WO2007 / 068907 and have reviewed by Alving et al. (2012) Curr Opln in Immunol 24: 310.
In another embodiment of the method of the invention, the first adjuvant and the second adjuvant comprise an immunologically active saponin, for example an immunologically active saponin fraction, for example QS21.
Adjuvants comprising saponins have been described in the state of the art. Saponins are described by Lacaille-Dubois and Wagner (1996) A review of the biological and pharmacological activities of saponins. Phytomedicine vol 2: 363. Saponins are known to be used as adjuvants in vaccines. For example, Quil-A® saponin (derived from the bark of Quillaja saponaria Molina, a tree native to South America) has been described by Dalsgaard et al. in 1974 ("Saponin Adjuvants", Archiv, fur die gesamte Virusforschung, Vol 44, Springer Verlag, Berlin, 243) to have adjuvant activity. Purified fractions of Quil-A® were isolated by HPLC which retain the adjuvant activity of Quil-A® without the associated toxicity (Kensil et al (1991) J. Immunol 146: 431. Quil-A fractions Also described in U.S. Patent 5,057,540 and "Saponin As Vaccinia Adjuvants", Kensil, CR Crit Rev Ther Drug Carrier System, 1996, 12 (1-2): 1-55.
The two fractions QS7 and QS21 (also known as QA-7 and QA-21) are the two fractions suitable for use in the present invention, with QS21 being a preferred immunologically active saponin moiety. QS21 was reviewed by Kensil (2000) in O'Hagan, Adjuvant Vaccine: Preparation methods and research protocols. Homana Press, Totowa, NJ, Chapter 15. Particle adjuvant systems comprising Quil-A® fractions, for example QS21 and QS7, are described in particular in WO 96/33739, WO 96/11711 and WO2007 / 068907.
In addition to other components, the adjuvant preferably comprises a sterol. The presence of a sterol may further reduce the reactogenicity of compositions comprising saponins, see for example EP0822831. Beta-sitosterol, stigmasterol, ergosterol, ergocalciferol and cholesterol are among the appropriate sterols. Cholesterol is particularly appropriate. Suitably, the immunologically active saponin fraction is QS21 and the ratio of QS21: sterol is 1: 100 to 1: 1 w / w, for example 1:10 to 1: 1 w / w, for example 1 : 5 to 1: 1 p / p
In a preferred embodiment of the method of the invention, the TLR4 agonist is 3D-MPL and the immunologically active saponin is QS21.
In some embodiments, the adjuvant is in the form of an oil-in-water emulsion, including, for example, squalene, alpha-tocopherol and a surfactant (see, for example, WO95 / 17210) or the form of a liposome, the liposomal presentation being the preferred form.
The term "liposome" as used herein refers to single or multilamellar lipid structures (particularly 2, 3, 4, 5, 6, 7, 8, 9 or 10 lamellae depending on the number of lipid membranes formed) surrounding an aqueous medium. . Liposomes and liposome preparations are well known in the state of the art. Liposomal presentations are described, for example, in WO 96/33739 and WO2007 / 068907. Lipids that are capable of forming liposomes include all substances having lipid or lipid properties. The lipids which may constitute the lipids of liposomes may be selected from the group comprising glycerides, glycerophospholipids, glycerophosphinolipids, glycerophospholipids, sulpholipids, sphingolipids, phospholipids, isoprenolides, steroids, stearins, sterols, archaeolipids synthetic cationic lipids and carbohydrates containing lipids. In a particular embodiment of the invention, the liposomes comprise a phospholipid. Suitable phospholipids include (but are not limited to): phosphocholine (PC) which is an intermediate in the synthesis of phosphatidylcholine; natural phospholipid derivatives: egg phosphocholine, soy phosphocholine, hydrogenated soy phosphocholine, sphingomyelin as natural phospholipids; and synthetic phospholipid derivatives: phosphocholine (didecanoyl-L-phosphatidylcholine [DDPC], dilauroylphosphatidylcholine [DLPC], dimyristoylphosphatidylcholine [DMPC], dipalmitoyl phosphatidylcholine [DPPC], distearoyl phosphatidylcholine [DSPC], dioleoyl phosphatidylcholine [DOPC] ], 1-palmitoyl, 2-oleoylphosphatidylcholine [POPC], dielaidoyl phosphatidylcholine [DEPC]), phosphoglycerol (1,2-dimyristoyl-sn-glycero-3-phosphoglycerol [DMPG], 1,2-dipalmitoyl- sn-glycero-3-phosphoglycerol [DPPG], 1,2-distearoyl-sn-glycero-3-phosphoglycerol [DSPG], 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol [POPG]), phosphatidic acid (1,2-dimyristoyl-sn-glycero-3-phosphatidic acid [DMPA], dipalmitoyl phosphatidic acid [DPPA], distearoylphosphatidic acid [DSPA]), phosphoethanolamine dimyristoyl-sn-glycero-3-phosphoethanolamine [DMPE], 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine [ DPPE], 1,2-distearoyl-sn-glycero-3-phosphoethanolamine [DSPE], 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine [DOPE]), phoshoserine, polyethylene glycol [PEG] phospholipid .
The size of the liposomes can vary from 30 nm to several μm depending on the composition of the phospholipids and the method used to prepare them. In particular embodiments of the invention, the size of the liposomes is in the range of 50 nm to 500 nm, and in other embodiments of 50 nm to 200 nm. Diffusion of dynamic laser light is a method used to measure the size of liposomes and well known to those skilled in the art.
In a particularly suitable embodiment, the liposomes used in the invention include DOPC and a sterol, especially cholesterol. In a particular embodiment, the compositions of the invention thus comprise QS21 in any amount described herein as a liposome, said liposome comprising DOPC and a sterol, particularly cholesterol.
Preferably, the first adjuvant and the second adjuvant comprise 3D-MPL and QS21 in a liposomal preparation.
In one embodiment, the first adjuvant comprises between 25 and 75, for example 50 micrograms, of 3D-MPL and between 25 and 75, for example 50 micrograms of QS21 in a liposomal preparation and the second adjuvant comprises between 5 and 15, for example 10 micrograms of 3D-MPL and between 5 and 15, for example 10 micrograms of QS21 in a liposomal preparation.
In another embodiment, the first adjuvant comprises between 12.5 and 37.5, for example 25 micrograms, 3D-MPL and between 12.5 and 37.5, for example 25 micrograms of QS21 in a liposomal preparation and the second adjuvant comprises between 2.5 and 7.5, for example 5 micrograms of 3D-MPL and between 2.5 and 7.5, for example 5 micrograms of QS21 in a liposomal preparation.
It is well known that for parenteral administration, the solutions must be physiologically isotonic (i.e., have a pharmaceutically acceptable osmolality) to prevent cell deformation or lysis. An "isotonicity agent" is a compound that is physiologically tolerated and that imparts appropriate tonicity to a preparation (eg, the immunogenic compositions of the invention) to prevent the net flow of water through the membranes of the cells in question. contact with the preparation. Aqueous adjuvant compositions which contain 100 mM sodium chloride or more, for example the adjuvant system A (ASA) contained in the documents WO 2005/112991 and WO2008 / 142133, or the liposomal adjuvants described in the document WO2007 / 068907, are unknown.
In some embodiments, the isotonicity agent used for the composition is a salt. In other embodiments, however, the composition comprises a nonionic isotonicity agent and the concentration of the sodium chloride or the ionic strength of the composition is less than 100 mM, for example less than 80 mM, for example lower than at 30 mM, for example less than 10 mM or less than 5 mM. In a preferred embodiment, the nonionic isotonicity agent is a polyol, for example sorbitol. The concentration of sorbitol may, for example, be from about 3% to about 15% (w / v), for example from about 4% to about 10% (w / v). Adjuvants comprising an immunologically active saponin fraction and a TLR4 agonist where the isotonicity agent is a salt or a polyol have been described in WO2010142685, especially in Examples 1 and 2 of WO2010142685.
In another embodiment, the first adjuvant and / or the second adjuvant do not include aluminum.
Antigens used in the method of the invention.
In one embodiment of the method of the invention, the second composition contains an amount of the antigen in common lower than in the first composition.
In one embodiment, the amount of the antigen in common in the second composition is at least 10% lower, for example at least 25% lower, for example at least two times lower, for example at least three times weaker, for example at least four times lower, for example at least five times lower, for example at least six times lower, for example at least seven times lower, for example at least eight times lower, for example at least nine times lower, for example at least ten times lower, for example at least 15 times lower, for example at least 20 times lower than in the first composition.
In another embodiment, the amount of the antigen in common in the second composition is between 2 and 50 times lower, for example between 2 and 20 times lower, for example between 2 and 15 times lower, for example between 2 and 10 times lower, for example between 3 and 7 times lower, for example between 4 and 6 times lower than in the first composition.
As previously described, the first immunogenic composition and the second immunogenic composition have at least one antigen in common. In some embodiments, the antigens present in the first and second composition are all the same.
In one embodiment, the antigen in common is a Plasmodium antigen, for example a P. falciparum or P. vivax antigen. In one embodiment, the antigen in common is the circumsporozoite protein (CP) or an immunogenic fragment or variant thereof, for example the P. falciparum CS protein or an immunogenic fragment or variant thereof. or the P. vivax CS protein or an immunogenic fragment or variant thereof.
In another embodiment, the antigen in common is CelTOS (accession number Q8I5P1: P. falciparum 3D7
CelTOS; GenBank: AAN36249).), TRAP (accession number: CAD52497.1 GI: 23615505) or Pfs25 (accession number: AAN35500.1 GI: 23495169) or an immunogenic fragment or variant of CelTOS, TRAP, and / or or Pfs25.
In another embodiment, the antigen in common is an immunogenic protein consisting of the hepatitis B virus surface antigen S (HBsAg) or an immunogenic fragment thereof, or an immunogenic protein comprising HBsAg or an immunogenic fragment thereof, for example an HBsAg fusion protein with a different antigen.
In another embodiment, the antigen in common is a VZV antigen, for example the glycoprotein gE (or gpl) of VZV or an immunogenic derivative thereof. The wild type or full length gE protein consists of 623 amino acids comprising a signal peptide, most of the protein, a hydrophobic anchor region (residues 546-558) and a C-terminal tail. In one aspect, a truncated C end of gE (also referred to as truncated gE) is used, truncation removing 4 to 20 percent of the total number of amino acid residues of the carboxy terminus. In another aspect, the truncated gE lacks the carboxylic end anchoring region (conveniently, approximately amino acids 547-623 of the wild-type sequence). In another aspect, the gE is a truncated gE of sequence SEQ ID NO. 2. The gE antigen, its non-anchored derivatives (which are also immunogenic derivatives) and their production are described in EP0405867 and the references of the present disclosure (see also Vafai (1994) Vaccine 12: 1265). EP192902 also describes the gE and its production. The truncated gE whose sequence is illustrated in FIG. 3 is also described by Haumont et al. Virus Research (1996) 40: 199, and is hereby fully incorporated by reference.
In another embodiment, the antigen in common is a CMV antigen, e.g., gB or an immunogenic fragment thereof or a variant thereof. Suitable gB-derived antigens have been described in WO 2012/049317, published in the US as US2013216613 and which is incorporated by reference to describe the appropriate proteins for use in the present invention.
In another embodiment, the antigen in common is an RSV antigen, e.g., RSV F protein or an immunogenic fragment thereof or a variant thereof. Suitable F-protein derived antigens have been described in WO2010149745, for example the F protein variants illustrated in SEQ ID NO: 18, SEQ ID NO: 20 and SEQ ID NO: 22 of WO2010149745. Other suitable RSV antigens have been described in WO2011008974 and WO2012158613.
In another embodiment, the antigen in common is a dengue virus antigen, for example an inactivated or live attenuated whole dengue virus. The composition may be multivalent and contain, for example, four or more strains of the dengue virus.
In another embodiment, the antigen in common is a Haemophilus influenzae virus antigen, e.g., protein E and / or pilin A, or immunogenic fragments thereof or variants thereof, e.g. described in WO2012139225.
In another embodiment, the antigen in common is a M. tuberculosis antigen, for example the M72 antigen, for example the antigen described in WO2006 / 117240, or US Pat. No. 8,470,338. and which is incorporated by reference to describe the appropriate proteins for use in the present invention.
An immunogenic fragment may be of any length provided that it retains its immunogenic properties. The fragment may, for example, comprise 5 or more consecutive amino acids, for example 10 or more consecutive amino acids, for example 20 consecutive amino acids or more, for example 50 or more consecutive amino acids, for example 100 or more consecutive amino acids. of the CS protein.
In another embodiment, the antigen in common comprises or consists of a variant of the CS protein.
A polypeptide variant may contain a number of substitutions, preferably conservative substitutions (the modification may for example relate to 1 to 50, for example 1 to 25, in particular 1 to 10, and especially 1 residue (s) of amino acid (s) relative to the reference sequence). Suitably, such substitutions do not occur in the region of an epitope and therefore do not have a significant effect on the immunogenic properties of the antigen.
The variants of the proteins may also be variants containing additional amino acids with respect to the reference sequence; these insertions may, for example, occur in 1 to 10 sites (for example 1 to 5 sites, suitably 1 or 2 sites, in particular 1 site) and may, for example, involve the addition of 50 amino acids or less at each of the sites (for example 20 amino acids or less, in particular 10 amino acids or less, in particular 5 amino acids 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. A brief extension of histidine residues (for example 2 to 6 residues) which promotes the expression and / or purification of the antigen in question is an example of insertion.
The variants may also be variants where amino acids have been deleted with respect to the reference sequence; these deletions may, for example, occur in 1 to 10 sites (for example 1 to 5 sites, suitably 1 or 2 sites, in particular 1 site) and may, for example, involve the deletion of 50 amino acids or less. at each of the sites (for example 20 amino acids or less, in particular 10 amino acids or less, in particular 5 amino acids or less). Suitably, these deletions do not occur in the region of an epitope and therefore do not have a significant effect on the immunogenic properties of the antigen. Those skilled in the art will recognize that the variant of a protein may contain substitutions, deletions, and insertions (or any of these associations).
The variants preferably have an identity of at least about 70%, preferably at least about 80%, and most preferably at least about 90% (e.g. at least about 95%, at least about 98%, or at least about 90%). minus about 99%) with the associated reference sequence.
The BLAST and BLAST 2.0 algorithms, which are described by Altschul et al., Nue. Acids Res. 25: 3389-3402 (1977) and Altschul et al., J. Mol. Biol. 215: 403-410 (1990), respectively, are examples of suitable algorithms for determining the percent identity and similarity between two sequences.
An appropriate variant of the CS protein may be a variant where portions of the CS protein are in the form of a hybrid protein with the hepatitis B virus surface antigen S (HBsAg). The CS variant antigen may, for example, be in the form of a hybrid protein comprising substantially the entire C-terminal portion of the CS protein, four or more tandem repeats of the immunodominant region of the CS protein, and HBsAg. The hybrid protein may comprise a sequence that contains at least 160 amino acids and is substantially homologous to the C-terminal portion of the CS protein, but lacking the hydrophobic anchoring sequence. The CS protein can be devoid of the last 12 amino acids of the C-terminus. It may also contain 4 or more, for example at least 10 Asn-Ala-Asn-Pro (NANP) tetrapeptide repeats or more.
The hybrid protein used in the invention may be a protein which comprises a portion of the P. falciparum CS protein substantially corresponding to amino acids 207-395 of the clone 3D7 of P. falciparum, from the NF54 strain fused in phase with the intermediate of a linear linker linker at the N-terminus of HBsAg. The linker linker may comprise a portion of preS2 from HBsAg. The CS constructs suitable for use in the present invention are set forth in WO 93/10152, which resulted in United States Patent Nos. 5,928,902 and 6,169,171, both of which are incorporated by reference. to describe the appropriate proteins for use in the present invention.
The hybrid protein known as RTS (Figure 2) [described in WO93 / 10152 (where it is designated RTS * and in WO98 / 05355)] is a specific hybrid protein used in the invention and is constituted of: - a methionine residue - three amino acid residues: Met Ala Pro - an 189 amino acid lengthening representing amino acids 207 to 395 of the P. falciparum CS protein, strain 3D7 - a glycine residue - four residues of amino acids, Pro Val Thr Asn, representing the four residues of the carboxyterminal end of the preS2 protein of hepatitis B virus (serotype adw), and - an elongation of 226 amino acids, encoded by nucleotides 1653 to 2330 , and designating the protein S of the hepatitis B virus (serotype adw).
The RTS may be in the form of mixed particles of RTS, S. The RTS, S particles comprise two polypeptides, RTS and S, which can be simultaneously synthesized and spontaneously form composite particle structures (RTS, S).
The RTS protein can be expressed in yeast, for example S. cerevisiae. In this type of host, the RTS protein will be expressed as lipoprotein particles. The host yeast strain may already carry in its genome several integrated copies of an S expression cassette of hepatitis B virus. The resulting strain then synthesizes two polypeptides, S and RTS, which unite spontaneously to form mixed particles of lipoproteins (RTS, S). These particles may have the CSP sequences of the hybrid on their surface. The RTS and S antigens in these mixed particles may be present in a specific ratio, for example 1: 4.
RTS, S has been reviewed for example by Vekemans et al. (2009) Vaccine 275: G67 and Regules et al. (2011) Expert Rev. Vaccines 10: 589.
In one embodiment, the first immunogenic composition comprises between 25 and 75, for example 50 micrograms, RTS, S and the second immunogenic composition comprises between 5 and 15, for example 10 micrograms of RTS, S.
In another embodiment, the first immunogenic composition comprises between 12.5 and 37.5, for example 25 micrograms, RTS, S and the second immunogenic composition comprises between 2.5 and 7.5, for example 5 micrograms of RTS, S.
In another embodiment, the antigen in common is derived from the P. vivax CS protein. Suitable variants of the P. vivax CS protein have been described. For example, WO2008009652, published in the United States under the reference US20100150998 and incorporated by reference to describe the appropriate proteins for use in the present invention, discloses immunogenic fusion fusion proteins comprising: a. at least one repeating unit derived from the repetitive region of a P. vivax type I circumsporozoite protein, b. at least one repeating unit derived from the repetitive region of a P. vivax type II circumsporozoite protein, and c. surface antigen S derived from hepatitis B virus, or a fragment. The sequence SEQ ID NO: 17 of WO2008009652 describes a specific fusion fusion protein, called CVS-S. When expressed together with the surface antigen S derived from hepatitis B virus, CSV-5 particles are formed (WO2008009652). These particles can also be used in the present invention.
In another embodiment, the antigen in common is a mixture of particles comprising RTS and CSV-S. These particles have been described in WO2008009650, published in the US as US20100062028 and incorporated by reference to describe the appropriate proteins for use in the present invention.
Immunization patterns, target populations, and modes of administration
As described above, the method of the invention consists in administering a first immunogenic composition comprising one or more antigens and a first adjuvant, then a second immunogenic composition comprising one or more antigens and a second adjuvant.
In one embodiment, the delay between the administration of the first composition and the administration of the second composition is between 1 and 24 months, for example between 1 and 18 months, for example between 1 and 12 months, for example between 2 and 10 months, for example between 3 and 9 months, for example between 4 and 8 months.
The method of the invention may comprise one or more other administrations of immunogenic compositions in addition to administering the first composition and administering the second composition. The subject may, for example, receive several doses of the first composition before administration of the second composition. Thus, for example, in one embodiment, the first composition is administered twice before administration of the second composition. The subject may, if not or additionally, receive several other doses of the second composition after the first administration of the second composition. In one embodiment of the method of the invention, the second composition is thus administered one or more other times. Here are the possible, non-limiting schemes: a. First composition and second composition b. First composition then first composition then second composition c. First composition then second composition then second composition d. First composition then first composition then first composition then second composition e. First composition then first composition then second composition and second composition f. First composition then second composition then second composition and second composition
The deadlines for the scheme b. can for example be 0, 1, 5 (i.e., Month 0, Month 1, Month 5) or 0, 1, 6 or 0, 1, 7 or 0, 1, 8 or 0, 1, 12 Similarly, the deadlines for the scheme c. can for example be 0, 1, 5 or 0, 1, 6 or 0, 1, 7 or 0, 1, 8 or 0, 1, 12. Shorter times for the schemes b. and c. can for example be Day 0, Day 7, Day 14.
In another embodiment, the second composition may for example be administered in the form of a recurring annual booster, for example for 1 to 5 years or more.
The human subject to be treated according to the method of the invention may be of any age. The method of the invention can be used as part of a malaria eradication program, in which case it may be useful to substantially immunize the entire population, i.e., any age group. In one embodiment, however, the human subject is over 18 years old when the first composition is administered. In another embodiment, the human subject is less than five years old when the first composition is administered. In another embodiment, the subject is 6 to 12 weeks old or 5 to 17 months old. Subjects traveling to areas where malaria is endemic are another particularly appropriate population.
The first and second compositions may be administered by a variety of suitable routes, including the parenteral route, for example intramuscular or subcutaneous.
In a particular embodiment, the second composition is administered intradermally. The term intradermal, as used herein, refers to the application of antigens in the dermis and / or epidermis of the human subject. The intradermal application of an immunogenic composition can be carried out by any cutaneous method known to those skilled in the art, including but not limited to, by means of a short injection device (device comprising a micro-needle from about 0.2 to about 0.6 mm in length) or by means of a skin patch. Suitable devices used with the skin vaccines described herein include micro needle devices e.g. those disclosed in US 4,886,499, US 5,190,521, US 5,328,483, US 5,527,288, US 4,270,537, US 5,015,235, US 5,141,496, US 5,417,662 and EP1092444. Cutaneous vaccines may also be administered by devices which limit the depth of effective penetration of the needle into the skin, for example those described in WO99 / 34850. Jet injectors that administer liquid vaccines into the dermis via a liquid jet injector or a needle are also suitable. Powdered / ballistic particle delivery devices that use a compressed gas for the powdered vaccine to pass rapidly through the outer layers of the skin to access the dermis are also suitable. Skin patches typically include a carrier containing a solid substrate. The patches deliver the antigen and adjuvant of the invention into the dermis or epidermis. In a particular embodiment, the patches of the present invention comprise a plurality of microprojections. The microprojections can be of any suitable shape to pierce the stratum corneum, epidermis and / or dermis, and administer the antigen and adjuvant into the epidermis or dermis. In a particular embodiment, the microprojections are biodegradable and comprise a biodegradable polymer.
The immunogenic compositions used in the invention can be manufactured by mixing the one or more antigens and the adjuvant. Said antigen may be provided in freeze-dried form or in a liquid preparation. For each composition, a kit may be provided comprising a first container containing the antigen and a second container containing the adjuvant.
Suitably, the immunogenic compositions according to the present invention have a human dose-volume of between 0.05 ml and 1 ml, for example between 0.1 and 0.5 ml, in particular a dose-volume of approximately 0, 5 ml, or 0.7 ml. The volume of the second immunogenic composition can be reduced, for example between 0.05 ml and 0.5 ml, for example between 0.1 and 0.2 ml. The volumes of the compositions used may depend on the routes of administration, the smaller volumes being administered intradermally.
The references in this application, including patent applications and granted patents, are all incorporated herein by reference. The terms "comprising", "include" and "includes", used herein, may be substituted by the terms "consisting of", "consisting of" and "consisting of", respectively. The following example makes it possible to continue the description of the present invention, but is not limiting so far: EXAMPLE: Vaccination using RTS, S and AS01 adjuvant and experimental "challenge" of malaria.
Vaccine
RTS, S is produced in yeast (S. cerevisiae) essentially as described in WO 93/10152.
A "standard" dose of RTS, S / AS01 contains 50 μg of freeze-dried RTS, S antigen reconstituted in 500 μl of AS01 adjuvant containing the 3D-MPL® immunostimulants (GlaxoSmithKline Biologicals, Montana, USA) and QS21 (50 μg of each) in a preparation with liposomes.
A "dose fraction" of RTS, S / AS01 represents 100 μl of the above solution, i.e. it contains 10 μg of lyophilized RTS, S antigen, 10 μg of 3D-MPL and 10 μg of QS21 with liposomes. Methodology
A clinical trial was conducted to evaluate the safety, reactogenicity, and efficacy of an anti-malarial vaccine containing RTS, S antigen and AS01 adjuvant against a "sporozoite challenge". administered intramuscularly in healthy volunteers aged 18 to 50 who have never been affected by malaria. The "later dose fraction" group received two standard doses, at 0 and 1 month, and a dose fraction [one-fifth (1 / 5th) of the standard dose] at 7 months. The "0, 1, 2 months" group received three standard doses at one month intervals. 4 6 subjects were recruited in two cohorts and were divided into the above groups: "Subsequent dose fraction" (30 subjects) and "0, 1, 2 months" (16 subjects). 12 other subjects were included in the control group "infectivity", that is to say volunteers who received no immunization, but who were subjected to the "challenge to sporozoites".
For each cohort, the volunteers were subjected to a standardized "primary challenge" of malaria (Chulay et al., (1986) Am J Trop Med Hyg: 35:66), also known as "challenge to sporozoites", approximately 3 weeks after the third dose of each of the groups above. The "primary challenge" was to leave five Anophelese stevensi mosquitoes infected with the P. falciparum sporozoite to prick each volunteer for a period of five minutes.
After the "challenge", the subjects were followed daily for at least 30 days to study at home the development or absence of development of the infection. The detection of the infection consisted of identifying, by light microscopy and after staining of May-Grünwald Giemsa, asexual stage parasites in peripheral blood. The presence of parasites at the asexual stage indicates that the subject is at a productive stage of infection, with parasites that have been released from the liver and progressing to the erythrocyte stage, which means that the sterile protection vis-à-vis the "challenge" is not effective.
At the first sign of infection, subjects were found to be malaria positive and received a curative dose of chloroquine. Sterile protection, that is, the subject never develops asexual stage parasitaemia, was the primary efficacy criterion. In addition, the delay between the "challenge" and the appearance of parasitaemia among those who were not completely protected was recorded. Protection was assessed by the proportion of immunized participants who remained free from P. falciparum infection after 'sporozoite challenge' and by a delay in the parasitic incubation period leading to infection. Vaccine efficacy (EV) is defined by the calculation: 100 * (1-Relative Risk). Fisher's exact likelihood test was used to compare the incidence of malaria between each of the "subsequent dose fraction" and "0, 1, 2 months" groups and the "infectivity" control group. Results
* Mantel-Haenszel test (time to develop parasitaemia), Fx versus RRR p = 0.0455. ** Parasitaemia measured at D28 after the challenge.
The strength of the study was unable to detect a superiority of the "dose fraction administered later" group compared to the "0, 1, 2 months" group, and the difference between the two groups is not statistically significant. (Fx group EV increase over RRR group = 57.0%, [-7.9-88.3], p = 0.0741,
Fisher). However, the analysis of the difference in the survival time of the group "dose fraction administered later" compared to the group "0, 1, 2 months", which takes into account the delay of appearance of the infection in the group " fraction of dose administered later ", has a statistical significance (p = 0.0455, Mantel-Haensze test).
In addition, the analysis compared the results of the "Subsequent dose fraction" arm of the study against pooled data for 95 subjects studied in five completed 0, 1, 2 month RTS, S / AS01 trials. to date (data not shown), indicates that the results obtained in this study are very unlikely to be random (p = 0.0045, Fisher's test).

权利要求:
Claims (39)
[1]
claims
A method of inducing an immune response in humans by administering to the subject a first immunogenic composition comprising one or more antigens and a first adjuvant, followed by a second immunogenic composition comprising one or more antigens and a second adjuvant, the first and second compositions having at least one antigen in common, the first and second adjuvants comprising a TLR agonist and / or an immunologically active saponin and having at least one of these two components in common and the second adjuvant containing a smaller amount of the component in common than the first adjuvant, and / or • the antigen in common being RTS, S and the second composition containing a lower amount of RTS, S than the first composition, provided that the first and the second composition does not both include RTS, S and QS21 and 3D-MPL associated with an oil-in-water emulsion.
[2]
2. Method according to claim 1, the first adjuvant and the second adjuvant consisting of the same components.
[3]
3. Method according to any one of the preceding claims, the first adjuvant and the second adjuvant consisting of the same components in the same relative proportions.
[4]
4. A method according to any one of the preceding claims, the second adjuvant containing a lower amount of the common component than the first adjuvant.
[5]
5. Method according to any one of the preceding claims, the amount of the common component present in the second adjuvant being at least 10% lower, for example at least 25% lower, for example at least two times lower, by for example at least three times lower, for example at least four times lower, for example at least five times lower, for example at least six times lower, for example at least seven times lower, for example at least eight times lower, for example at least nine times lower, for example at least ten times lower, for example at least 15 times lower, for example at least 20 times lower than the amount present in the first adjuvant.
[6]
6. Method according to any one of the preceding claims, the amount of the common component present in the second adjuvant being between 2 and 50 times lower, for example between 2 and 20 times lower, for example between 2 and 15 times more low, for example between 2 and 10 times lower, for example between 3 and 7 times lower, for example between 4 and 6 times lower than the amount present in the first adjuvant.
[7]
The method of any one of the preceding claims, the first and second adjuvant comprising a TLR agonist, and the TLR agonist being a TLR4 agonist, e.g., 3D-MPL.
[8]
The method of any one of the preceding claims, wherein the first and second adjuvants comprise an immunologically active saponin, for example QS21, and optionally a sterol.
[9]
The method of any of the preceding claims, the first and second adjuvant comprising 3D-MPL and QS21 in a liposomal preparation.
[10]
10. Method according to claim 9, the first adjuvant comprising between 25 and 75, for example 50 micrograms, of 3D-MPL and between 25 and 75, for example 50 micrograms of QS21 and the second adjuvant comprising between 5 and 15, for example 10 micrograms of 3D-MPL and between 5 and 15, for example 10 micrograms of QS21.
[11]
11. The method of claim 9, the first adjuvant comprising between 12.5 and 37.5, for example 25 micrograms, 3D-MPL and between 12.5 and 37.5, for example 25 micrograms of QS21 and the second adjuvant comprising between 2.5 and 7.5, for example 5 micrograms of 3D-MPL and between 2.5 and 7.5, for example 5 micrograms of QS21.
[12]
12. Method according to any one of the preceding claims, the first adjuvant and / or the second adjuvant not comprising aluminum.
[13]
13. A method according to any one of the preceding claims, the second composition containing an amount of the antigen in common lower than the first composition.
[14]
14. Method according to any one of the preceding claims, the amount of the antigen in common present in the second composition being at least 10% lower, for example at least 25% lower, for example at least twice as low for example at least three times lower, for example at least four times lower, for example at least five times lower, for example at least six times lower, for example at least seven times lower, for example at least eight times lower, for example at least nine times lower, for example at least ten times lower, for example at least 15 times lower, for example at least 20 times lower than the amount present in the first composition.
[15]
15. Method according to any one of the preceding claims, the amount of the antigen in common present in the second composition being between 2 and 50 times lower, for example between 2 and 20 times lower, for example between 2 and 15 1 times lower, for example between 2 and 10 times lower, for example between 3 and 7 times lower, for example between 4 and 6 times lower than the amount present in the first composition.
[16]
16. A method according to any one of the preceding claims, the antigens contained in the first and second composition being all identical.
[17]
17. A method according to any one of the preceding claims, the antigen in common being a Plasmodium antigen, for example a P. falciparum or P. vivax antigen.
[18]
18. A method according to any one of the preceding claims, wherein the antigen in common is the circumsporozoite protein or an immunogenic fragment or a variant thereof.
[19]
19. A method according to any one of the preceding claims, the antigen in common being selected from the group consisting of: RTS, CSV-S, RTS, S and CSV-S, S and mixed particles comprising RTS and CSV-S .
[20]
20. Method according to any one of the preceding claims, the delay between the administration of the first composition and the administration of the second composition being between 1 and 24 months, for example between 1 and 18 months, for example between 1 and 12 months, for example between 2 and 10 months, for example between 3 and 9 months, for example between 4 and 8 months.
[21]
21. A method according to any one of the preceding claims, the first immunogenic composition being administered twice before administration of the second immunogenic composition.
[22]
22. Method according to any one of the preceding claims, the second composition being administered one or more times after its first administration.
[23]
23. A method according to any one of the preceding claims, the human subject being over 18 years old at the time of administration of the first composition.
[24]
24. The method according to claim 1, the human subject being less than five years old at the time of administration of the first composition.
[25]
25. The method as claimed in claim 1, the second administration being carried out intradermally.
[26]
26. Immunogenic composition for use in a method for inducing an immune response in humans, the method of administering to the subject a first immunogenic composition comprising one or more antigens and a first adjuvant, then a second immunogenic composition comprising one or more antigens and a second adjuvant, the first and second compositions having at least one antigen in common, the first and second adjuvants comprising a TLR agonist and / or an immunologically active saponin and having at least one of these antigens; two components in common and • the second adjuvant containing a smaller amount of the common component than the first adjuvant, and / or • the antigen in common being RTS, S and the second composition containing a lower amount of RTS, S that the first composition, provided that the first and second composition do not both include the RTS, S and QS21 and the e 3D-MPL associated with an oil-in-water emulsion.
[27]
27. The immunogenic composition of claim 26 comprising one or more of the features of any one of claims 2 to 25.
[28]
28. Use of a second immunogenic composition comprising one or more antigens and a second adjuvant in the manufacture of a medicament for inducing an immune response in humans, said subject having already received a first immunogenic composition comprising one or more antigens and a first adjuvant, the first and second compositions having at least one antigen in common, the first and second adjuvants comprising a TLR agonist and / or an immunologically active saponin and having at least one of these two components. common • the second adjuvant containing a smaller amount of the common component than the first adjuvant, and / or • the antigen in common being RTS, S and the second composition containing a lower amount of RTS, S than the first composition , provided that the first and second compositions do not both include RTS, S and QS21 and 3D-MPL associated with an oil emulsion. s water.
[29]
Use according to claim 28 comprising one or more of the features of any one of claims 2 to 25.
[30]
30. A method of inducing an immune response in humans comprising administering to the subject a first immunogenic composition comprising one or more antigens and a first adjuvant, and then a second immunogenic composition comprising one or more antigens and a second adjuvant, the first and second compositions having at least one antigen in common, the first and second adjuvants comprising 3D-MPL and QS21 in a liposomal preparation in the same relative proportions, the second composition containing a lower amount of antigen and / or or a lower amount of adjuvant than the first composition.
[31]
31. The method of claim 30 comprising one or more of the features of any one of claims 2 to 25.
[32]
32. A method for inducing in humans an immune response against malaria and comprising administering to the subject a first immunogenic composition comprising RTS, S and a first adjuvant, then a second immunogenic composition comprising RTS, S and a second adjuvant, the first and second adjuvant comprising a TLR4 agonist and / or an immunologically active saponin in the same relative proportions, the second composition containing a lower amount of adjuvant than the first composition, provided that the first composition does not comprise not all RTS, S and QS21 and 3D-MPL associated with an oil-in-water emulsion.
[33]
33. The method of claim 32 comprising one or more of the features of any one of claims 2 to 25.
[34]
34. A method for inducing in humans an immune response against malaria and administering to the subject a first immunogenic composition comprising RTS, S and a first adjuvant, then a second immunogenic composition comprising RTS, S and a second adjuvant, the first and second adjuvants consisting of 3D-MPL and QS21 in a liposomal preparation in the same relative proportions, the second composition containing a lower amount of antigen and / or a lower amount of adjuvant than the first composition.
[35]
The method of claim 34 comprising one or more of the features of any one of claims 2 to 25.
[36]
36. A method of inducing an immune response in humans comprising administering to the subject a first immunogenic composition comprising RTS, S and an adjuvant, followed by a second immunogenic composition comprising RTS, S, the adjuvant comprising an agonist of TLR and / or an immunologically active saponin, the second immunogenic composition not comprising an adjuvant.
[37]
The method of claim 36, the adjuvant comprising one or more of the features of any one of claims 7 to 9 or 12.
[38]
38. The method of claim 36 or 37 comprising one or more of the features of any one of claims 13 to 25.
[39]
39. A method according to any one of claims 36 to 38, the first and second composition comprising both 25 micrograms of RTS, S or 50 micrograms of RTS, S.

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AU2015239025B2|2018-01-25|

EA037405B1|2021-03-25|

JP2017511327A|2017-04-20|

EA201691638A1|2017-04-28|

JP2017511324A|2017-04-20|

KR20160132115A|2016-11-16|

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US10688168B2|2020-06-23|

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WO2015150568A1|2015-10-08|

MX2016012932A|2016-12-07|

JP6655549B2|2020-02-26|

EP3125930B1|2020-12-02|

US20170112914A1|2017-04-27|

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法律状态:
2018-03-07| FG| Patent granted|Effective date: 20160930 |

2018-03-07| MM| Lapsed because of non-payment of the annual fee|Effective date: 20170331 |

2019-12-19| MM| Lapsed because of non-payment of the annual fee|Effective date: 20190430 |

优先权:

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GBGB1405921.6A|GB201405921D0|2014-04-02|2014-04-02|Novel methods for inducing an immune response|

GB1405921.6|2014-04-02|

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