CA2138997C - Vaccine composition containing adjuvants - Google Patents
Vaccine composition containing adjuvants Download PDFInfo
- Publication number
- CA2138997C CA2138997C CA002138997A CA2138997A CA2138997C CA 2138997 C CA2138997 C CA 2138997C CA 002138997 A CA002138997 A CA 002138997A CA 2138997 A CA2138997 A CA 2138997A CA 2138997 C CA2138997 C CA 2138997C
- Authority
- CA
- Canada
- Prior art keywords
- composition
- mpl
- antigen
- vaccine
- vaccine composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/29—Hepatitis virus
- A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/002—Protozoa antigens
- A61K39/015—Hemosporidia antigens, e.g. Plasmodium antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/245—Herpetoviridae, e.g. herpes simplex virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/29—Hepatitis virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55505—Inorganic adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16611—Simplexvirus, e.g. human herpesvirus 1, 2
- C12N2710/16634—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2730/00—Reverse transcribing DNA viruses
- C12N2730/00011—Details
- C12N2730/10011—Hepadnaviridae
- C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
- C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention provides vaccine compositions comprising 3 De-O-acylated monophosphoryl lipid A and QS21. The vaccines compositions are potent inducers of CTL and .gamma. IFN responses.
Description
WO 94/001j3 ~ ~ J ~ '~ ~ ~ Pf.'f/EP93/01524 VACCINE COMPOSITION CONTAINING ADJUVANTS
The present invention relates to novel vaccine formulations, to methods of their production and to their use in medicine. In particular, the present invention relates to vaccines containing QS21, an Hplc purified non-toxic fraction derived from the bark of Quillaja Saponaria Molina, and 3 De-O-acylated monophosphoryl Iipid A (3 D-MPL).
3 De-O-acylated monophosphoryl lipid A is known from GB2220 211 (R.ibi). Chemically it is a mixture of 3-deacylated monophosphoryl Iipid A
with 4, 5 or 6 acylated chains and is manufactured by Ribi Immunochem Montana.
~S21 is a Hplc purified non toxic fraction of a saponin from the bark of I5 the South American tree Quillaja saponaria molina and its method of its production is disclosed (as QA21) in US patent No. 5,057,540.
The present invention is based on the surprising discovery that formulations containing combinations of QS21 and 3 D-MPL
synergistically enhance immune responses to a given antigen.
For example a vaccine formulation of the malarial antigen, RTS, S in combination with 3D-MPL and QS21 results in a powerful synergistic induction of CS protein specific cytotoxic-T lymphocyte (CTL) response in the spleen.
RTS is a hybrid protein comprising substantially al/ the C-terminal portion of the circumsporozoite (CS) protein of P.falciparum linked via four amino acids of the preS2 portion of Hepatitis B surface antigen to the ' surface (S) ,antigen of hepatitis B virus. It's full structure is disclosed in co-pending International Patent Application No. PCT/EP92/02591, published under Number WO 93/10152 claiming priority from Uk patent application No.9124390.7. When expressed in yeast RTS is produced as a lipoprotein particle, and when it is co-expressed with the S antigen from HBV it produces a mixed particle known as RTS,S. .
WO 94/00153 ~ 1 j ~ ~ ~ ~ PCT/EP93/01524 The observation that is possible to induce strong cytolytic T lymphocyte responses is significant as these responses; in certain animal models have been shown to induce protection against disease.
The present inventors have shown that the combination of the two adjuvants QS21 and 3D-MPL with the recombinant particulate antigen RTS,S results in a powerful induction of CS protein specific CTL in the spleen. QS21 also enhances induction of CTL on its own, while 3D-MPL
does not. The combination can be said to act in a synergistic way, because it has an effect that is larger than the sum of the separate effects of each adjuvant. The synergy between these two adjuvants for CTL induction is a surprising observation which has important implications for the use of recombinant molecules as vaccines for induction of CTL mediated immunity.
.:
Induction of CTL is easily seen when the target antigen is synthesised l intracellularly (e.g. in infections by viruses, intracellular bacteria, or in tumours); because peptides generated by proteolytic breakdown of the antigen can enter the appropriate processing pathway, leading to presentation in association with class I molecules on the cell membrane.
However; in general, pre-formed soluble antigen does not reach this processing and presentation pathway, and does not elicit class I restricted CTL. Therefore conventional non-living vaccines, while eliciting antibody and T helper. responses, do not generally induce CTL mediated immunity.
The combination of the two adjuvants QS21 and 3D-MPL can overcome this serious limitation of vaccines based or recombinant proteins, and induce a wider spectrum of immune responses.
CTL specific for CS protein have been shown to protect from malaria in 30: - .mouse model systems (Romero et al. Nature 341:323 ( 1989)): In human trials where volunteers were immunised using. irradiated sporozoites of P.
falciparum, and shown to be protected against subsequent malaria challenge, induction of CTL specific for CS epitopes was demonstrated- --(Malik et al. Proc. Natl. Acad. Sci. USA 88:3300 (1991)).
The ability to induce CTL specific for an antigen administered as a recombinant molecules is relevant to malaria vaccine development, since.
~l3S~v"~
_3_ the use of irradiated sporozoites would be impractical, on the grounds of production and the nature of the immune response. -In addition to malaria vaccines, the ability to induce CTL responses would benefit vaccines against herpes simplex virus, cytomegalovirus, human Immunodeficiency virus, and generally all cases where the pathogen has an intracellular life stage.
Likewise, CTL specific for known tumour antigens could be induced by a combination of a recombinant tumour antigen and the two adjuvants.
This would allow the development of anti cancer vaccines.
In certain systems; the combination of 3D-MPL and QS21 have been able to synergistically enhance interferon y production. The present inventors have demonstrated the synergistic potential of 3D-MPL and QS21 by utilising a herpes simplex antigen known as gD2t. gD2t is a soluble truncated glycoprotein D from HSV-2 and is produced in CHO cells according to the methodology Berman g~. Science 222 524-527.
IFN-y secretion is associated with protective responses against intracellular pathogens, including parasites, bacteria and viruses.
Activation of macrophages by IFN-~ enhances intracellular killing of microbes and increases expression of Fc receptors. Direct cytotoxicity may also occur, especially in,synergism with lymphotoxin (another product of ' TH1 cells). IFN-'y is also both an induces and a product of NK cells, which are major innate efI'ectors of protection. TH1 type responses, either trough IFN-y or other mechanisms, provide preferential help for IgG2a immunoglobulin isotypes.
. Glycoprotein D; is located on the viral envelope, and is also found ~in the cytoplasm of infected cells (Eisenberg R.J, g~L J. of Virol. 1980 .~. 428-435): It comprises 393 amino acids including a signal peptide and has a molecular weight of approximately 60kD. Of all the I~SV envelope glycoproteins this is probably the best characterized (Cohen g~.. J.
Virology ~Q I57-166). In vivo it is known to play a central role in viral -attachment to cell rriembranes. Moreover, glycoprotein D has been shown to be able to elict neutralizing antibodies inin vivo (Sing et al. J. Med Virology 127: 59-65). However, latent HSV2 virus can still be reactivated WO 94/00153 ~ ~ ~ ~ ~ ~ ~ PCT/EP93/01524 and induce recurrence of the disease despite the presence of high neutralizing antibodies titre in the patients sera. It is therefore apparent that the ability to induce neutralizing antibody alone is insufficient to adequately control the disease.
;.
In order to prevent recurrence of the disease, any vaccine will need to stimulate not only neutrali2ing antibody, but also cellular immunity mediated through T-cells, particularly cytotoxic T-cells.
In this instance the gD2t is HSV2 glycoprotein D of 308 amino acids which comprises amino acids 1 though 306 of the naturally occurring glycoprotein with the addition of Asparagine and Glutamine at the C
terminal end of the truncated protein. This form of the protein includes the signal peptide which is cleaved to yield a mature 283 amino acid protein. The production of such a protein in Chinese Hamster aviary cells has been described in Genentech's European patent EP-B-139 417.
The mature truncated glycoprotein D (rgD2t) or equivalent proteins secreted from mammalian cells, is preferably used in the vaccine formulations of .the present invention.
T he formulations of the present invention are very effective in inducing protective immunity in a genital herpes model in guinea pigs. Even with very low doses of antigenwf e.g. as low as 5 ~.g rgD2t) the formulations protect guinea pigs against primary infection and also stimulate specific neutralising antibody responses. The inventors, utilising formulation of the present invention, have also demonstrated Effector cell mediated - _ responses of the TH1 type in mice.
' Accordingly, the present invention provides a vaccine or pharmaceutical formulation comprising an antigen in conjunction with 3 Deacylated _ monophosphoryl lipid A and x,1521. Such a formulation is suitable for a _.
broad range of monovalent or polyvalent vaccines.
Preferably the vaccine formulations will contain an antigen or antigenic composition capable of eliciting an immune response against a human or animal pathogen, which antigen or antigenic composition is derived from HIV-1, (such as gp120 or gp160), any of Feline Immunodeficiency virus, ~.. ., , .. .. .r. . . . .. . : . ,: . ..., ; . ,.. .. , ..: ..~ ~ ... ,..:
;...
WO 94/00153 ~ ~ ~ ~ ~ ~ ~ PCT/EP93/01524 human or animal herpes viruses, such as gD or derivatives thereof or Immediate Early protein such as ICP27 from HSV 1 or HSV2, cytomegalovirus ((esp Human)(such as gB or derivatives thereof), Varicella Zoster Virus (such as gpI, II or III), or from a hepatitis virus such as hepatitis B virus for example Hepatitis B Surface antigen or a derivative thereof, hepatitis A virus, hepatitis C virus and hepatitis E
virus, or from other viral pathogens, such as Respiratory Syncytial virus, human papilloma virus or Influenza virus, or derived from bacterial pathogens such as Salmonella, Neisseria, Borrelia (for example OspA or OspB or derivatives thereof), or Chlamydia; or Bordetella for example P.69; PT ~d ~, or derived from parasites such as plasmodium or Touoplasma.
The formulations may also contain an anti-tumour antigen and be useful for immunotherapeutically treating cancers.
The formulation may also be useful for utilising with herpetic light particles 'such as described in International Patent Application No.
PCT/GB92/00824 and, International Patent Application No.
PCT/GB92/00179. -Derivatives of Hepatitis B Surface antigen are well known in the art and includes inter alia, those Fr~S l, PreS2 S antigens set forth described in European Patent applications EP-A-414 374; EP-A-0304 578, and EP 198-- ~ 474.
Inca ~urrher aspect of the present invention there is provided a vaccine as hexein described for use in medicine.
° .The ratio' of QS21 3D-MPL will typically be in the order of 1 : 10 to 10 : 1;
. ! preferably 1 : 5 to 5 : 1 and often' substantially 1 : 1. The preferred range for optimal synergy is 2.5:1 to 1:13D MPL: QS21. Typically for human ~ad~oninistratiox~ QS21 and 3D MPL will be present in a vaccine in the range 1 ~tg - 100 ~tg, preferably 10 ag - 50 ag per dose. Often the vaccine will not require any specific carrier and be formulated in an aqueous or other pharmaceutically acceptable buffer. In some cases it may be advantageous that the vaccines of the present invention will further contain alum or be presented in an oil in water emulsion, or other suitable vehicle, such as for example; liposomes, microspheres or encapsulated antigen particles.
Vaccine preparation is generally described in New Trends and Developments in Vaccines, edited by Voller et al., University Park Press, E
Baltimore, Maryland, U.S.A.19?8. Encapsulation within liposomes is described, for example, by Fullerton, U.S. Patent 4,235,8?7. Conjugation of proteins to macromolecules is disclosed, for example, by Likhite, U.S.
Patent 4,372,945 and by Armor et al., U.S. Patent 4,474,757.
The amount of protein in each vaccine dose is selected as an amount , which induces an immunoprotective response without significant, adverse side effects in typical vaccinees. Such amount will vary depending upon ;
which specific immunogen is employed and how it is presented. .
Generally, it is expected that each dose will comprise 1-1000 ~g of protein, preferably 2-100 ~.g, most preferably 4-40 ~tg. An optimal amount for a particular vaccine can be ascertained by standard studies involving i observation of appropriate immune responses in subjects. Following an initial vaccination, subjects may receive one or several booster immunisation adequately spaced. ~ .
The formulations of the present invention maybe used for both prophylatic ahd therapeutic purposes, Accordingly in one aspect, the invention provides a method of treatment comprising administering an effective amount of a vaccine of the present invention to a patient.
Ezamples ~ .
1.0 Synergy between 3D MPL and QS21 for induction of Interferon 'y secretion.
In order to test the ability of 3D MPL and QS21 based adjuvant formulations of rgD2t, to induce effector cell mediated immune responses, groups of Balb/c mice were vaccinated, and their draining lymph node cells tested for IFN-Y secretion as described below.
'.. i"'"r.::
~,; ..
t o: ' v~;.-;
y...
r'..
r N, . M
..5~ .
. . , . .,'.. . ... . ~ ~, - , " ; .' . .. . . , . . ~ . . ~ , ' . t , : ~ , f .. . ... . r , . .s ,. ; ' ..:~ ~.., .. . .. ,...~..'..., ......,'. ..., '~. .. ... ...... .. ..
.. . . ...,. ..i _ ..., -v ...., .' w'.
.S.Y.e O..bv - .. . . . ., . ,.. , . . . . . .. ,. , ..
WO 94/0013 PC'd'/EP93/01524 _7_ 1.1 rgD2t formulations This experiment compared three adjuvant formulations:
i) rgD2t in 3D-MPL
ii) rgD2t in QS21 iii) rgD2t in 3D-MPL/f1S21 These formulations were made up as follows. rgD2t was produced in CHO . .
20 cells and corresponds to the mature 1-283 amino acids of HSV-2 gD and is produced according to the methodology of Berman (supra) and EP
0139417.
* rgD2t / 3D-MPL
i 5 ~g of rgD2t/dose are incubated 1h, under agitation,at room temperature, then anixed with a 3D-MPL suspension (25 ~.g/dose). The volume is adjusted to 70 ~l/dose using a sodium chloride solution (5M, pH 6.5 t 0.5) and water for injection to obtain a final concentration of 0.15M sodium chloride. pH is kept at 6.5 t 0.5.
* rgD2t/QS21 5 ug rgD2t/dase are incubated 1h at room temperature under agitation The volume is adjusted using sodium chloride solution (5M, pH 6.5 t 0.5) and water forir~jection_to 70_1: QS21 (10 ~g/dose) is then added, pH is kept at 6.5 ~ 0:5.and sodium chloride final concentration at 0.15M.
* rgD2t/3D-MPL / faS2l.
' ' _ ._ . .
5 ~.g rgD2tJdose are. incubated 1h at room temperature under agitation.
3D-MPL (25 ~.g/dose) is added as an aqueous suspension. The final volume of 70~r'i'_s completed by addition of an aqueous solution of QS21 t 10 ug/dose) and the pH kept at 6.5 ~ 0.5 and the sodium chloride concentration at 0.15M.
WO 94/00I53 l ~ PC1'/EP93/01524 -s-1.2 IMMUUNISATION
Mice were injected into the hind footpads with 35 ulJfootpad of formulation. Thus each mouse received 70 pL. Immunisation were on days , 0, and 14. Animals were sacrificed on day 21. w 1.3 INTERFERON 'y ASSAYS
Popliteal lymph node cells from immunised mice were stimulated in vitro using rgD2t at 10, 1, 0.1, 0 ug/ml. Triplicate cultures (200 p1 volumes) were sat up in round bottom 96-well microtiter plates, using 2 x 105 responder cells and 2 x 10~ irradiated (3000 rad) syngeneic naive spleen cells. Culture medium was RPMI 1640 with 10°!o foetal calf serum. ;
Aliquots of 100 u1 of culture medium from each replicate were harvested and pooled for IFN-y determinations. Cultures were assayed at 72 hours.
For all assays, a control group using ConA (Boehringer Mannheim) at 5 ughmL was included. This was always positive. ~
Secretion of IFN-y was determined using a commercial ELISA assay manufactured by Holland Biotechnology (distributed by Gibco). Assays were carried out on 100 u1 of pooled supernatant from triplicate wells.
Secretion of IFN-y above the assay background of 50 pg/pl was observed in all three formulation groups (see Table). In addition, a synergistic effect between QS21 and 3D-MPL was observed. While each adjuvant on its own induced cells capable of secreting IFN-'y in response to rgD2t, their - combination induced more than twice the sum of individual responses.
W~ 94/00I53 ~ 1 ~ ~ ~ ~% ~ PCT/EP93/01524 _g_ 1.4 ~j.esult~
Synergy between QS21 and 3D-MPL for induction of IFN-y secretion.
Immunization: QS21/3D-MPL QS21 3D-MPL
rgD2t rgD2t rgD2t In vitro 10.0 1351 1105 515 stimulation 1.0 9I4 116 192 (~.g/mL gD2t): 0.1 335 <50 143 0.0 101 <50 139 IFN-y is expressed in pg/mL.
The table clearly shows that the combined vaccine induces IFN-y-secretion in a synergistic manner.
The present invention relates to novel vaccine formulations, to methods of their production and to their use in medicine. In particular, the present invention relates to vaccines containing QS21, an Hplc purified non-toxic fraction derived from the bark of Quillaja Saponaria Molina, and 3 De-O-acylated monophosphoryl Iipid A (3 D-MPL).
3 De-O-acylated monophosphoryl lipid A is known from GB2220 211 (R.ibi). Chemically it is a mixture of 3-deacylated monophosphoryl Iipid A
with 4, 5 or 6 acylated chains and is manufactured by Ribi Immunochem Montana.
~S21 is a Hplc purified non toxic fraction of a saponin from the bark of I5 the South American tree Quillaja saponaria molina and its method of its production is disclosed (as QA21) in US patent No. 5,057,540.
The present invention is based on the surprising discovery that formulations containing combinations of QS21 and 3 D-MPL
synergistically enhance immune responses to a given antigen.
For example a vaccine formulation of the malarial antigen, RTS, S in combination with 3D-MPL and QS21 results in a powerful synergistic induction of CS protein specific cytotoxic-T lymphocyte (CTL) response in the spleen.
RTS is a hybrid protein comprising substantially al/ the C-terminal portion of the circumsporozoite (CS) protein of P.falciparum linked via four amino acids of the preS2 portion of Hepatitis B surface antigen to the ' surface (S) ,antigen of hepatitis B virus. It's full structure is disclosed in co-pending International Patent Application No. PCT/EP92/02591, published under Number WO 93/10152 claiming priority from Uk patent application No.9124390.7. When expressed in yeast RTS is produced as a lipoprotein particle, and when it is co-expressed with the S antigen from HBV it produces a mixed particle known as RTS,S. .
WO 94/00153 ~ 1 j ~ ~ ~ ~ PCT/EP93/01524 The observation that is possible to induce strong cytolytic T lymphocyte responses is significant as these responses; in certain animal models have been shown to induce protection against disease.
The present inventors have shown that the combination of the two adjuvants QS21 and 3D-MPL with the recombinant particulate antigen RTS,S results in a powerful induction of CS protein specific CTL in the spleen. QS21 also enhances induction of CTL on its own, while 3D-MPL
does not. The combination can be said to act in a synergistic way, because it has an effect that is larger than the sum of the separate effects of each adjuvant. The synergy between these two adjuvants for CTL induction is a surprising observation which has important implications for the use of recombinant molecules as vaccines for induction of CTL mediated immunity.
.:
Induction of CTL is easily seen when the target antigen is synthesised l intracellularly (e.g. in infections by viruses, intracellular bacteria, or in tumours); because peptides generated by proteolytic breakdown of the antigen can enter the appropriate processing pathway, leading to presentation in association with class I molecules on the cell membrane.
However; in general, pre-formed soluble antigen does not reach this processing and presentation pathway, and does not elicit class I restricted CTL. Therefore conventional non-living vaccines, while eliciting antibody and T helper. responses, do not generally induce CTL mediated immunity.
The combination of the two adjuvants QS21 and 3D-MPL can overcome this serious limitation of vaccines based or recombinant proteins, and induce a wider spectrum of immune responses.
CTL specific for CS protein have been shown to protect from malaria in 30: - .mouse model systems (Romero et al. Nature 341:323 ( 1989)): In human trials where volunteers were immunised using. irradiated sporozoites of P.
falciparum, and shown to be protected against subsequent malaria challenge, induction of CTL specific for CS epitopes was demonstrated- --(Malik et al. Proc. Natl. Acad. Sci. USA 88:3300 (1991)).
The ability to induce CTL specific for an antigen administered as a recombinant molecules is relevant to malaria vaccine development, since.
~l3S~v"~
_3_ the use of irradiated sporozoites would be impractical, on the grounds of production and the nature of the immune response. -In addition to malaria vaccines, the ability to induce CTL responses would benefit vaccines against herpes simplex virus, cytomegalovirus, human Immunodeficiency virus, and generally all cases where the pathogen has an intracellular life stage.
Likewise, CTL specific for known tumour antigens could be induced by a combination of a recombinant tumour antigen and the two adjuvants.
This would allow the development of anti cancer vaccines.
In certain systems; the combination of 3D-MPL and QS21 have been able to synergistically enhance interferon y production. The present inventors have demonstrated the synergistic potential of 3D-MPL and QS21 by utilising a herpes simplex antigen known as gD2t. gD2t is a soluble truncated glycoprotein D from HSV-2 and is produced in CHO cells according to the methodology Berman g~. Science 222 524-527.
IFN-y secretion is associated with protective responses against intracellular pathogens, including parasites, bacteria and viruses.
Activation of macrophages by IFN-~ enhances intracellular killing of microbes and increases expression of Fc receptors. Direct cytotoxicity may also occur, especially in,synergism with lymphotoxin (another product of ' TH1 cells). IFN-'y is also both an induces and a product of NK cells, which are major innate efI'ectors of protection. TH1 type responses, either trough IFN-y or other mechanisms, provide preferential help for IgG2a immunoglobulin isotypes.
. Glycoprotein D; is located on the viral envelope, and is also found ~in the cytoplasm of infected cells (Eisenberg R.J, g~L J. of Virol. 1980 .~. 428-435): It comprises 393 amino acids including a signal peptide and has a molecular weight of approximately 60kD. Of all the I~SV envelope glycoproteins this is probably the best characterized (Cohen g~.. J.
Virology ~Q I57-166). In vivo it is known to play a central role in viral -attachment to cell rriembranes. Moreover, glycoprotein D has been shown to be able to elict neutralizing antibodies inin vivo (Sing et al. J. Med Virology 127: 59-65). However, latent HSV2 virus can still be reactivated WO 94/00153 ~ ~ ~ ~ ~ ~ ~ PCT/EP93/01524 and induce recurrence of the disease despite the presence of high neutralizing antibodies titre in the patients sera. It is therefore apparent that the ability to induce neutralizing antibody alone is insufficient to adequately control the disease.
;.
In order to prevent recurrence of the disease, any vaccine will need to stimulate not only neutrali2ing antibody, but also cellular immunity mediated through T-cells, particularly cytotoxic T-cells.
In this instance the gD2t is HSV2 glycoprotein D of 308 amino acids which comprises amino acids 1 though 306 of the naturally occurring glycoprotein with the addition of Asparagine and Glutamine at the C
terminal end of the truncated protein. This form of the protein includes the signal peptide which is cleaved to yield a mature 283 amino acid protein. The production of such a protein in Chinese Hamster aviary cells has been described in Genentech's European patent EP-B-139 417.
The mature truncated glycoprotein D (rgD2t) or equivalent proteins secreted from mammalian cells, is preferably used in the vaccine formulations of .the present invention.
T he formulations of the present invention are very effective in inducing protective immunity in a genital herpes model in guinea pigs. Even with very low doses of antigenwf e.g. as low as 5 ~.g rgD2t) the formulations protect guinea pigs against primary infection and also stimulate specific neutralising antibody responses. The inventors, utilising formulation of the present invention, have also demonstrated Effector cell mediated - _ responses of the TH1 type in mice.
' Accordingly, the present invention provides a vaccine or pharmaceutical formulation comprising an antigen in conjunction with 3 Deacylated _ monophosphoryl lipid A and x,1521. Such a formulation is suitable for a _.
broad range of monovalent or polyvalent vaccines.
Preferably the vaccine formulations will contain an antigen or antigenic composition capable of eliciting an immune response against a human or animal pathogen, which antigen or antigenic composition is derived from HIV-1, (such as gp120 or gp160), any of Feline Immunodeficiency virus, ~.. ., , .. .. .r. . . . .. . : . ,: . ..., ; . ,.. .. , ..: ..~ ~ ... ,..:
;...
WO 94/00153 ~ ~ ~ ~ ~ ~ ~ PCT/EP93/01524 human or animal herpes viruses, such as gD or derivatives thereof or Immediate Early protein such as ICP27 from HSV 1 or HSV2, cytomegalovirus ((esp Human)(such as gB or derivatives thereof), Varicella Zoster Virus (such as gpI, II or III), or from a hepatitis virus such as hepatitis B virus for example Hepatitis B Surface antigen or a derivative thereof, hepatitis A virus, hepatitis C virus and hepatitis E
virus, or from other viral pathogens, such as Respiratory Syncytial virus, human papilloma virus or Influenza virus, or derived from bacterial pathogens such as Salmonella, Neisseria, Borrelia (for example OspA or OspB or derivatives thereof), or Chlamydia; or Bordetella for example P.69; PT ~d ~, or derived from parasites such as plasmodium or Touoplasma.
The formulations may also contain an anti-tumour antigen and be useful for immunotherapeutically treating cancers.
The formulation may also be useful for utilising with herpetic light particles 'such as described in International Patent Application No.
PCT/GB92/00824 and, International Patent Application No.
PCT/GB92/00179. -Derivatives of Hepatitis B Surface antigen are well known in the art and includes inter alia, those Fr~S l, PreS2 S antigens set forth described in European Patent applications EP-A-414 374; EP-A-0304 578, and EP 198-- ~ 474.
Inca ~urrher aspect of the present invention there is provided a vaccine as hexein described for use in medicine.
° .The ratio' of QS21 3D-MPL will typically be in the order of 1 : 10 to 10 : 1;
. ! preferably 1 : 5 to 5 : 1 and often' substantially 1 : 1. The preferred range for optimal synergy is 2.5:1 to 1:13D MPL: QS21. Typically for human ~ad~oninistratiox~ QS21 and 3D MPL will be present in a vaccine in the range 1 ~tg - 100 ~tg, preferably 10 ag - 50 ag per dose. Often the vaccine will not require any specific carrier and be formulated in an aqueous or other pharmaceutically acceptable buffer. In some cases it may be advantageous that the vaccines of the present invention will further contain alum or be presented in an oil in water emulsion, or other suitable vehicle, such as for example; liposomes, microspheres or encapsulated antigen particles.
Vaccine preparation is generally described in New Trends and Developments in Vaccines, edited by Voller et al., University Park Press, E
Baltimore, Maryland, U.S.A.19?8. Encapsulation within liposomes is described, for example, by Fullerton, U.S. Patent 4,235,8?7. Conjugation of proteins to macromolecules is disclosed, for example, by Likhite, U.S.
Patent 4,372,945 and by Armor et al., U.S. Patent 4,474,757.
The amount of protein in each vaccine dose is selected as an amount , which induces an immunoprotective response without significant, adverse side effects in typical vaccinees. Such amount will vary depending upon ;
which specific immunogen is employed and how it is presented. .
Generally, it is expected that each dose will comprise 1-1000 ~g of protein, preferably 2-100 ~.g, most preferably 4-40 ~tg. An optimal amount for a particular vaccine can be ascertained by standard studies involving i observation of appropriate immune responses in subjects. Following an initial vaccination, subjects may receive one or several booster immunisation adequately spaced. ~ .
The formulations of the present invention maybe used for both prophylatic ahd therapeutic purposes, Accordingly in one aspect, the invention provides a method of treatment comprising administering an effective amount of a vaccine of the present invention to a patient.
Ezamples ~ .
1.0 Synergy between 3D MPL and QS21 for induction of Interferon 'y secretion.
In order to test the ability of 3D MPL and QS21 based adjuvant formulations of rgD2t, to induce effector cell mediated immune responses, groups of Balb/c mice were vaccinated, and their draining lymph node cells tested for IFN-Y secretion as described below.
'.. i"'"r.::
~,; ..
t o: ' v~;.-;
y...
r'..
r N, . M
..5~ .
. . , . .,'.. . ... . ~ ~, - , " ; .' . .. . . , . . ~ . . ~ , ' . t , : ~ , f .. . ... . r , . .s ,. ; ' ..:~ ~.., .. . .. ,...~..'..., ......,'. ..., '~. .. ... ...... .. ..
.. . . ...,. ..i _ ..., -v ...., .' w'.
.S.Y.e O..bv - .. . . . ., . ,.. , . . . . . .. ,. , ..
WO 94/0013 PC'd'/EP93/01524 _7_ 1.1 rgD2t formulations This experiment compared three adjuvant formulations:
i) rgD2t in 3D-MPL
ii) rgD2t in QS21 iii) rgD2t in 3D-MPL/f1S21 These formulations were made up as follows. rgD2t was produced in CHO . .
20 cells and corresponds to the mature 1-283 amino acids of HSV-2 gD and is produced according to the methodology of Berman (supra) and EP
0139417.
* rgD2t / 3D-MPL
i 5 ~g of rgD2t/dose are incubated 1h, under agitation,at room temperature, then anixed with a 3D-MPL suspension (25 ~.g/dose). The volume is adjusted to 70 ~l/dose using a sodium chloride solution (5M, pH 6.5 t 0.5) and water for injection to obtain a final concentration of 0.15M sodium chloride. pH is kept at 6.5 t 0.5.
* rgD2t/QS21 5 ug rgD2t/dase are incubated 1h at room temperature under agitation The volume is adjusted using sodium chloride solution (5M, pH 6.5 t 0.5) and water forir~jection_to 70_1: QS21 (10 ~g/dose) is then added, pH is kept at 6.5 ~ 0:5.and sodium chloride final concentration at 0.15M.
* rgD2t/3D-MPL / faS2l.
' ' _ ._ . .
5 ~.g rgD2tJdose are. incubated 1h at room temperature under agitation.
3D-MPL (25 ~.g/dose) is added as an aqueous suspension. The final volume of 70~r'i'_s completed by addition of an aqueous solution of QS21 t 10 ug/dose) and the pH kept at 6.5 ~ 0.5 and the sodium chloride concentration at 0.15M.
WO 94/00I53 l ~ PC1'/EP93/01524 -s-1.2 IMMUUNISATION
Mice were injected into the hind footpads with 35 ulJfootpad of formulation. Thus each mouse received 70 pL. Immunisation were on days , 0, and 14. Animals were sacrificed on day 21. w 1.3 INTERFERON 'y ASSAYS
Popliteal lymph node cells from immunised mice were stimulated in vitro using rgD2t at 10, 1, 0.1, 0 ug/ml. Triplicate cultures (200 p1 volumes) were sat up in round bottom 96-well microtiter plates, using 2 x 105 responder cells and 2 x 10~ irradiated (3000 rad) syngeneic naive spleen cells. Culture medium was RPMI 1640 with 10°!o foetal calf serum. ;
Aliquots of 100 u1 of culture medium from each replicate were harvested and pooled for IFN-y determinations. Cultures were assayed at 72 hours.
For all assays, a control group using ConA (Boehringer Mannheim) at 5 ughmL was included. This was always positive. ~
Secretion of IFN-y was determined using a commercial ELISA assay manufactured by Holland Biotechnology (distributed by Gibco). Assays were carried out on 100 u1 of pooled supernatant from triplicate wells.
Secretion of IFN-y above the assay background of 50 pg/pl was observed in all three formulation groups (see Table). In addition, a synergistic effect between QS21 and 3D-MPL was observed. While each adjuvant on its own induced cells capable of secreting IFN-'y in response to rgD2t, their - combination induced more than twice the sum of individual responses.
W~ 94/00I53 ~ 1 ~ ~ ~ ~% ~ PCT/EP93/01524 _g_ 1.4 ~j.esult~
Synergy between QS21 and 3D-MPL for induction of IFN-y secretion.
Immunization: QS21/3D-MPL QS21 3D-MPL
rgD2t rgD2t rgD2t In vitro 10.0 1351 1105 515 stimulation 1.0 9I4 116 192 (~.g/mL gD2t): 0.1 335 <50 143 0.0 101 <50 139 IFN-y is expressed in pg/mL.
The table clearly shows that the combined vaccine induces IFN-y-secretion in a synergistic manner.
2.0 Synergy Between 3D MP'L and f~S21 for the induction of CTLs In order to test the ability of RTS,S particles in 3D MPL and QS21 based adjuvant formulations to induce CTLs, groups of B10.BR mice were immunised and their spleen cells stimulated in vitro and tested in cytotoxicity-assays_on L cells expressing the CS protein.
2.1 Formulation of RTS,S particles.
RTS,S _particles were formulated in three different compositions:
1. RTS',S particles ((10~.g) with ~S21 (10~g) and 3D-MPL (25~g);
2. ~ RTS,S particles (( l0~tg) with QS21 ( 10~g);
2.1 Formulation of RTS,S particles.
RTS,S _particles were formulated in three different compositions:
1. RTS',S particles ((10~.g) with ~S21 (10~g) and 3D-MPL (25~g);
2. ~ RTS,S particles (( l0~tg) with QS21 ( 10~g);
3. RTS,S__particles ((10~g) with 3D-MPL (25~g);
. ~~_-._._ ..
The formulations were made up as follows:
PC1'/EP93/01524 Vd0 94100153 ~~.~89~'~
_ 10_ RTS, S/3 D MPL
~g of RTS, S particles/dose was incubated at room temperature under agitation then mixed with a 3D MPL aqueous suspension (25~tg/dose). , 5 The volume is then adjusted to 70 ~cl/dose using water far injections and a sodium chloride solution (5N, pH 6.5 ~ 0.5) to reach a final concentration of 0.15M sodium chloride (pH is kept at 6.5 ~ 0.5).
RTS,S /QS21 l0~tg of RTS, S particlesldose incubated 1h. at room temperature under agitation. The volume is adjusted using water for injection .and a sodium chloride solution (5N, pH 6.5 ~ 05) and completed to a final volume of 70~
1/ dose with an aqueous solution of QS21 (10~.g/dose). pH is kept at 6.5 ~
0.5 and sodium chloride final concentration at 0.15M.
RTS,S / 3 D MPL / QS21 10 ~g of RTS,S particles ! dose are incubated 1h. at room teperature under a~~~on then mixed with a 3D MPL (aqueous suspension (25~tg/dose) -The volume is then adjusted with water for injection and a sodium chloride solution (5D pH 6.5 ~ 0.5). The final volume is completed by addition of an aqueous solution of QS21 (10~g/dose). pH is kept at 6.5 ~
0.5, and sodium chloride final concentration at 0.15 M.
2.2 Immunisation of 'mice with RTS,S particles Four to six week old female mice of the strain B10.BR (H-2k) were purchased from IFFA CREDO (France). Groups of 3 animals were imrriunised by intro foot-pad injection of 35 ~.L of antigen formulation into each hind limb. The animals were boosted with a second equal dose of antigen injected two weeks later.
2.3. In vitro stimulation on anti CS CTL
Two weeks after the boost, spleen cells were harvested and stimulated in vitro using syngeneic fibroblasts transfected with the P. falciparum circumsporozoite protein gene (?G8 clone). These CS-transfectant cells -II_ have been described in the paper by Kumar, S. et al. ( 1988), Nature 334:258-260.
The cultures were established in RPMI 1640 medium supplemented with 10°l0 of heat inactivated foetal calf serum and usual additives, in w conditions well known to those of skill in the art. .
Responder cells were cultured at a concentration of 106 cells/mL in the presence of 105 CS-transfectants per mL. Ta prevent proliferation of CS-transfectant cells, these were irradiated using a dose of 2 x 104 rad. The , cultures were fed by replacing 1/2 of culture medium on day 3 and 6, and ' tested for cytolytic activity on day 7.
2.4. Cytoto~cicity assay for anti-CS CTL ' .
Responder cell cultures were harvested, washed, and mixed at ratios varying from 100:I to 0.3:1 with a constant number of 2004 target cells, m volumes of 200 ~:I: of medium in V-bottom 96-well plates.
Target cells were syngeneic fibroblast cells that had been labelled with 5lCr:
~Q ~erent types of target cells were used:
1. L cells _ -2. CS transfected L cells These are described in: Kumar, S: et al. (1988), Nature 334:258-260.
The assay was incubated for 6 hours at 37°C,-then the amount of radioactivity released into the supernatant by lysis of target cells was r:. . . 30 ' 'determinedi Cytolytic activity is expressed as °!o specific lysis:
WO 94/00153 PC1'/EP93/01524 ~~.~83~~ ' Results:
°lo Specific lysis by formulation_ Target cells: Effector: 1. RTS,S/ 2. RTS,S/ 3. RTS,S/ .
target QS21/ QS2I/ 3D-MPL
ratio 3D-MPL
CS transfected L I00 58 1? 1 cells 30 53 10 3 2? 1 0 j 0.3 2 -2 -1 L cell 100 3 - 2 5 0.3 3 1 2 Immunisation of B10.BR mice with RTS,S adjuvanted with QS21 and 3D
5 MPL (formulation #1) induced in the spleen high levels of CTL specific for the circumsporozoite component of RTS,S. Immunisation with RTS,S
. ~~_-._._ ..
The formulations were made up as follows:
PC1'/EP93/01524 Vd0 94100153 ~~.~89~'~
_ 10_ RTS, S/3 D MPL
~g of RTS, S particles/dose was incubated at room temperature under agitation then mixed with a 3D MPL aqueous suspension (25~tg/dose). , 5 The volume is then adjusted to 70 ~cl/dose using water far injections and a sodium chloride solution (5N, pH 6.5 ~ 0.5) to reach a final concentration of 0.15M sodium chloride (pH is kept at 6.5 ~ 0.5).
RTS,S /QS21 l0~tg of RTS, S particlesldose incubated 1h. at room temperature under agitation. The volume is adjusted using water for injection .and a sodium chloride solution (5N, pH 6.5 ~ 05) and completed to a final volume of 70~
1/ dose with an aqueous solution of QS21 (10~.g/dose). pH is kept at 6.5 ~
0.5 and sodium chloride final concentration at 0.15M.
RTS,S / 3 D MPL / QS21 10 ~g of RTS,S particles ! dose are incubated 1h. at room teperature under a~~~on then mixed with a 3D MPL (aqueous suspension (25~tg/dose) -The volume is then adjusted with water for injection and a sodium chloride solution (5D pH 6.5 ~ 0.5). The final volume is completed by addition of an aqueous solution of QS21 (10~g/dose). pH is kept at 6.5 ~
0.5, and sodium chloride final concentration at 0.15 M.
2.2 Immunisation of 'mice with RTS,S particles Four to six week old female mice of the strain B10.BR (H-2k) were purchased from IFFA CREDO (France). Groups of 3 animals were imrriunised by intro foot-pad injection of 35 ~.L of antigen formulation into each hind limb. The animals were boosted with a second equal dose of antigen injected two weeks later.
2.3. In vitro stimulation on anti CS CTL
Two weeks after the boost, spleen cells were harvested and stimulated in vitro using syngeneic fibroblasts transfected with the P. falciparum circumsporozoite protein gene (?G8 clone). These CS-transfectant cells -II_ have been described in the paper by Kumar, S. et al. ( 1988), Nature 334:258-260.
The cultures were established in RPMI 1640 medium supplemented with 10°l0 of heat inactivated foetal calf serum and usual additives, in w conditions well known to those of skill in the art. .
Responder cells were cultured at a concentration of 106 cells/mL in the presence of 105 CS-transfectants per mL. Ta prevent proliferation of CS-transfectant cells, these were irradiated using a dose of 2 x 104 rad. The , cultures were fed by replacing 1/2 of culture medium on day 3 and 6, and ' tested for cytolytic activity on day 7.
2.4. Cytoto~cicity assay for anti-CS CTL ' .
Responder cell cultures were harvested, washed, and mixed at ratios varying from 100:I to 0.3:1 with a constant number of 2004 target cells, m volumes of 200 ~:I: of medium in V-bottom 96-well plates.
Target cells were syngeneic fibroblast cells that had been labelled with 5lCr:
~Q ~erent types of target cells were used:
1. L cells _ -2. CS transfected L cells These are described in: Kumar, S: et al. (1988), Nature 334:258-260.
The assay was incubated for 6 hours at 37°C,-then the amount of radioactivity released into the supernatant by lysis of target cells was r:. . . 30 ' 'determinedi Cytolytic activity is expressed as °!o specific lysis:
WO 94/00153 PC1'/EP93/01524 ~~.~83~~ ' Results:
°lo Specific lysis by formulation_ Target cells: Effector: 1. RTS,S/ 2. RTS,S/ 3. RTS,S/ .
target QS21/ QS2I/ 3D-MPL
ratio 3D-MPL
CS transfected L I00 58 1? 1 cells 30 53 10 3 2? 1 0 j 0.3 2 -2 -1 L cell 100 3 - 2 5 0.3 3 1 2 Immunisation of B10.BR mice with RTS,S adjuvanted with QS21 and 3D
5 MPL (formulation #1) induced in the spleen high levels of CTL specific for the circumsporozoite component of RTS,S. Immunisation with RTS,S
4'.
particles adjuvanted with QS21 (formulation #2) also induced CTL in the spleen, but only at about 1/30th of the levels given by formulation #1.
RTS,S with 3D-1VIPL (formulation #3) did not induce CTL.
Since the target cells used in this assay do not express MHC class II
molecules, the effector cells can be assumed to be CD8+, class I restricted CTL.
3. Other formulation Hepatitis B Surface Antigen, Alum 3D-N~'L and QS2I.
The preparation of Hepatitis B Surface antigen (HBsAg) is well documented. See for example Harford et al Develop. Biol. Standard ~4 p125 (1983), Gregg ~ Biotechnology 5 p479 (198?) EP-A-0 226 846 and EP-A-299 108 and references therein.
WO 94/0a153 ~ ~ j ~~ j ~ ~ PCT/EP93/Ol~?4 - 3D-MPI~ was obtained from Ribi Immunochem, X521 was obtained from Cambridge Biotech, and Aluminium hydroxide was obtained from Superfos (Alhydrogel).
A number of different formulations were made up for studies of cell mediated immunity in mice and for studies in Rhesus monkeys.
3.1 Formulation 1 was made up in phosphate buffer (pH 6.8) to comprise the following per 60 ~1 dose.
~g HBsAg ~.g Al(OH)3 30 ~g 3D - MPL
I0 ~tg QS 21 10 mM pp43-0.15 M NaCl The formulation was made up in the following. manner. 20~g HBsAg/dose was incubated with A1(OH)3 for one hour at room temperature with I5 gentle shaking. 3D-MPL was added as an aqueous suspension, and the formulation completed by the addition of QS21, phosphate buffer and sodium chloride and incubated for one hour at room temperature. The final formulation had a pH of between fi.5 and ?.0 and used for foot pad studies in mice.
3.2 For~r~.ulation:~2 was made up in a phosphate buffer (pH6.8J to comprise-the following per 200 ~ul dose.
I wg HBsAg _ A1 (0H)3 100 ~g ~
50 ~,g 3D-MPL
~g_~. , . . QS 21 10-rriM p043-0,15 M NaCl The formulation was made up in the following manner. HBsAg and AI(OH3) were incubated together for one hour at room temperature with WO 94/00153 ~ -~ ~ ~ ~ ~ ~ PC T/EP93/0152.~
gentle shaking. The formulation was completed by the addition of Al(OH)3, 3D-MPL as an aqueous suspension and QS21, with phosphate buffer and sodium chloride solution and incubated again for thirty minutes. The pH of the formulation was kept between 6.5 and 7.0 and used for Humoral immunity studies in mice.
3.3 Formulation 3 was made up in a similar manner, in a phosphate buffer (pH6.5 - 7.0) to contain the following per 1 ml dose ~.g HB sAg 500 ~g AI (0H)3 50 ~g 3D-MPL
10~.g QS21 The formulation was used for monkey studies.
4. Conclusions The combination of the two adjuvants QS21 and 3D-MPL with the recombinant particulate antigen RTS,S resulted in a powerful induction of CS protein specific CTL in the spleen. QS21 enhances induction of CTL
on its own, while 3D-MPL does not. The combination can be said to act in a synergistic way, because it has an effect that is larger than the sum of _20 the separate effects of each adjuvant. The synergy between these two adjuvants for CTL induction is a surprising observation which supports our observation of synergy between QS2I and 3D-MPL for induction of T
_- . -' - . cells capable of secreting IFN-y in response to stimulation with the soluble -recombinant protein gD2t. This finding has important implications for the use of recombinant molecules as vaccines fox induction of CTL
_ ~ mediated immunity, since the combination of the two adjuvants QS21 and 3D-MPL can overcome this serious limitation of vaccines based on recombinant proteins, and induce a wider spectrum of immune responses ._. - = - than hitherto. ' The mouse cell mediated immunogenicity data show that QS21 based formulations of rgD2t induce a significant synergistic TH1 type T cell response (IFN-y secretion).
v . ~ 1 .',1 ~ 1 WO 94/00153 ~ '' 'J '' '~ ': pC1'/EP93/0152.~
i ..
Such TH1 type T cells have been shown to be involved in induction of delayed type hypersensitivity responses in mice. Our own data in prophylaxis of HSV disease show that concomitant induction of neutralizing antibody titers ~nd_ antigen specific DTH responses affords the best protection against herpes simplex disease.
Put together, these data suggested to us that (1S21 formulations of rgD2t may be effective in inducing a protective response against HSV disease.
The data presented show an unexpected synergistic effect between 3D
Monophosphoryl lipid A and faS2l, in inducing IFN-y secreting antigen specific T cells. Such a synergy may translate in improved ability to induce a protective response against HSV disease, and indeed these formulations are effective in protecting against disease in guinea pigs.
particles adjuvanted with QS21 (formulation #2) also induced CTL in the spleen, but only at about 1/30th of the levels given by formulation #1.
RTS,S with 3D-1VIPL (formulation #3) did not induce CTL.
Since the target cells used in this assay do not express MHC class II
molecules, the effector cells can be assumed to be CD8+, class I restricted CTL.
3. Other formulation Hepatitis B Surface Antigen, Alum 3D-N~'L and QS2I.
The preparation of Hepatitis B Surface antigen (HBsAg) is well documented. See for example Harford et al Develop. Biol. Standard ~4 p125 (1983), Gregg ~ Biotechnology 5 p479 (198?) EP-A-0 226 846 and EP-A-299 108 and references therein.
WO 94/0a153 ~ ~ j ~~ j ~ ~ PCT/EP93/Ol~?4 - 3D-MPI~ was obtained from Ribi Immunochem, X521 was obtained from Cambridge Biotech, and Aluminium hydroxide was obtained from Superfos (Alhydrogel).
A number of different formulations were made up for studies of cell mediated immunity in mice and for studies in Rhesus monkeys.
3.1 Formulation 1 was made up in phosphate buffer (pH 6.8) to comprise the following per 60 ~1 dose.
~g HBsAg ~.g Al(OH)3 30 ~g 3D - MPL
I0 ~tg QS 21 10 mM pp43-0.15 M NaCl The formulation was made up in the following. manner. 20~g HBsAg/dose was incubated with A1(OH)3 for one hour at room temperature with I5 gentle shaking. 3D-MPL was added as an aqueous suspension, and the formulation completed by the addition of QS21, phosphate buffer and sodium chloride and incubated for one hour at room temperature. The final formulation had a pH of between fi.5 and ?.0 and used for foot pad studies in mice.
3.2 For~r~.ulation:~2 was made up in a phosphate buffer (pH6.8J to comprise-the following per 200 ~ul dose.
I wg HBsAg _ A1 (0H)3 100 ~g ~
50 ~,g 3D-MPL
~g_~. , . . QS 21 10-rriM p043-0,15 M NaCl The formulation was made up in the following manner. HBsAg and AI(OH3) were incubated together for one hour at room temperature with WO 94/00153 ~ -~ ~ ~ ~ ~ ~ PC T/EP93/0152.~
gentle shaking. The formulation was completed by the addition of Al(OH)3, 3D-MPL as an aqueous suspension and QS21, with phosphate buffer and sodium chloride solution and incubated again for thirty minutes. The pH of the formulation was kept between 6.5 and 7.0 and used for Humoral immunity studies in mice.
3.3 Formulation 3 was made up in a similar manner, in a phosphate buffer (pH6.5 - 7.0) to contain the following per 1 ml dose ~.g HB sAg 500 ~g AI (0H)3 50 ~g 3D-MPL
10~.g QS21 The formulation was used for monkey studies.
4. Conclusions The combination of the two adjuvants QS21 and 3D-MPL with the recombinant particulate antigen RTS,S resulted in a powerful induction of CS protein specific CTL in the spleen. QS21 enhances induction of CTL
on its own, while 3D-MPL does not. The combination can be said to act in a synergistic way, because it has an effect that is larger than the sum of _20 the separate effects of each adjuvant. The synergy between these two adjuvants for CTL induction is a surprising observation which supports our observation of synergy between QS2I and 3D-MPL for induction of T
_- . -' - . cells capable of secreting IFN-y in response to stimulation with the soluble -recombinant protein gD2t. This finding has important implications for the use of recombinant molecules as vaccines fox induction of CTL
_ ~ mediated immunity, since the combination of the two adjuvants QS21 and 3D-MPL can overcome this serious limitation of vaccines based on recombinant proteins, and induce a wider spectrum of immune responses ._. - = - than hitherto. ' The mouse cell mediated immunogenicity data show that QS21 based formulations of rgD2t induce a significant synergistic TH1 type T cell response (IFN-y secretion).
v . ~ 1 .',1 ~ 1 WO 94/00153 ~ '' 'J '' '~ ': pC1'/EP93/0152.~
i ..
Such TH1 type T cells have been shown to be involved in induction of delayed type hypersensitivity responses in mice. Our own data in prophylaxis of HSV disease show that concomitant induction of neutralizing antibody titers ~nd_ antigen specific DTH responses affords the best protection against herpes simplex disease.
Put together, these data suggested to us that (1S21 formulations of rgD2t may be effective in inducing a protective response against HSV disease.
The data presented show an unexpected synergistic effect between 3D
Monophosphoryl lipid A and faS2l, in inducing IFN-y secreting antigen specific T cells. Such a synergy may translate in improved ability to induce a protective response against HSV disease, and indeed these formulations are effective in protecting against disease in guinea pigs.
Claims (20)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A vaccine composition comprising an antigen and/or antigenic composition, QS21 and 3 De-O-acylated monophosphoryl lipid A (3D-MPL).
2. A vaccine composition as claimed in claim 1 wherein the ratio of QS21:3D-MPL is from 1:10 to 10:1.
3. A vaccine composition as claimed in claim 1 or 2 capable of invoking a cytolytic T cell response in a mammal to the antigen or antigenic composition.
4. A vaccine composition as claimed in claim 1, 2 or 3 capable of stimulating interferon .gamma. production.
5. A vaccine composition as claimed in claim 1, 2, 3 or 4 wherein the ratio of QS21:3D-MPL is from 1:1 to 1:2.5.
6. A vaccine composition as claimed in claim 1, 2, 3, 4 or 5 comprising an antigen or antigenic composition derived from any of Human Immunodeficiency Virus, Feline Immunodeficiency Virus, Herpes Simplex Virus type 1, Herpes Simplex Virus type 2, Human cytomegalovirus, Hepatitis A, B, C or E, Respiratory Syncytial virus, human papilloma virus, Influenza virus, salmonella, Neisseria, Borrelia, Chlamydia, Bordetella, Plasmodium or Toxoplasma.
7. A vaccine composition as claimed in claim 1, 2, 3, 4 or 5 wherein the antigen is a tumour antigen.
8. Use of a vaccine composition as defined in claim 1, 2, 3, 4 or 5 in the prophylactic treatment of viral, bacterial, or parasitic infections.
9. Use of vaccine composition as defined in claim 1, 2, 3, 4, or 5 in the immunotherapeutic treatment of viral, bacterial, parasitic infections or cancer.
10. Use of a safe and effective amount of a vaccine composition as defined in claim 1, 2, 3, 4 or 5 in the treatment of a mammal suffering or susceptible to a pathogenic infection.
11. Use of a safe and effective amount of a vaccine composition as defined in claim 1, 2, 3, 4, or 5 in the treatment of a mammal suffering from cancer.
12. A process for making a vaccine composition according to claims 1 to 5 comprising admixing QS21 and 3D-MPL with an anitgen or antigenic composition.
13. A vaccine as claimed in any claims 1 to 5, additionally comprising alum, an oil in water emulsion, liposome, microsphere or encapsulated antigen particle as a vehicle.
14. A vaccine as claimed in claim 6, wherein the vehicle is alum or an oil in water emulsion.
15. Use of composition as defined in any of claims 1 to 5, 13 or 14 for the manufacture of a vaccine for the prophylactic treatment of viral, bacterial, or parasitic infections.
16. A pharmaceutical composition useful for adjuvanting an immune response comprising an adjuvanting effective combination of QS21 and 3-De-O-acylated monophosphoryl lipid A (3D-MPL).
17. The composition as claimed in claim 16 capable of invoking a cytolytic T
cell response in a mammal to an antigen.
cell response in a mammal to an antigen.
18. The composition as claimed in claim 16 capable of stimulating interferon .gamma.
production.
production.
19. The vaccine composition of claim 1 wherein the QS21 and the 3D-MPL
synergistically enhance the immune response in an animal to the antigen.
synergistically enhance the immune response in an animal to the antigen.
20. The composition of claim 16 in which the QS21 and 3D-MPL synergistically enhance the immune response in an animal to an antigen.
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9213559A GB9213559D0 (en) | 1992-06-25 | 1992-06-25 | Vaccines |
GB9213559.9 | 1992-06-25 | ||
GB929226283A GB9226283D0 (en) | 1992-12-17 | 1992-12-17 | Vaccines |
GB9226283.1 | 1992-12-17 | ||
GB9304056.6 | 1993-03-01 | ||
GB939304056A GB9304056D0 (en) | 1993-03-01 | 1993-03-01 | Vaccines |
PCT/EP1993/001524 WO1994000153A1 (en) | 1992-06-25 | 1993-06-15 | Vaccine composition containing adjuvants |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2138997A1 CA2138997A1 (en) | 1994-01-06 |
CA2138997C true CA2138997C (en) | 2003-06-03 |
Family
ID=27266263
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002138997A Expired - Lifetime CA2138997C (en) | 1992-06-25 | 1993-06-15 | Vaccine composition containing adjuvants |
Country Status (31)
Country | Link |
---|---|
US (2) | US5750110A (en) |
EP (2) | EP0761231B1 (en) |
JP (1) | JP3755890B2 (en) |
KR (1) | KR100278157B1 (en) |
CN (1) | CN1122530C (en) |
AP (1) | AP408A (en) |
AT (2) | ATE156710T1 (en) |
AU (1) | AU661404B2 (en) |
CA (1) | CA2138997C (en) |
CZ (1) | CZ282235B6 (en) |
DE (2) | DE69313134T2 (en) |
DK (2) | DK0761231T3 (en) |
ES (2) | ES2108278T3 (en) |
FI (1) | FI109767B (en) |
GR (2) | GR3025184T3 (en) |
HK (2) | HK1010097A1 (en) |
HU (1) | HU219808B (en) |
IL (1) | IL106109A (en) |
MA (1) | MA22911A1 (en) |
MX (1) | MX9303773A (en) |
MY (1) | MY109278A (en) |
NO (1) | NO317546B1 (en) |
NZ (1) | NZ253137A (en) |
PL (1) | PL170980B1 (en) |
PT (1) | PT761231E (en) |
RU (1) | RU2118164C1 (en) |
SG (2) | SG90042A1 (en) |
SI (1) | SI9300335B (en) |
SK (1) | SK279188B6 (en) |
UA (1) | UA40597C2 (en) |
WO (1) | WO1994000153A1 (en) |
Families Citing this family (460)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9105992D0 (en) * | 1991-03-21 | 1991-05-08 | Smithkline Beecham Biolog | Vaccine |
CZ282235B6 (en) * | 1992-06-25 | 1997-06-11 | Smithkline Beecham Biologicals (S.A.) | Inoculation substance, process of its preparation and use |
WO1994019013A1 (en) * | 1993-02-19 | 1994-09-01 | Smithkline Beecham Corporation | Influenza vaccine compositions containing 3-o-deacylated monophosphoryl lipid a |
US5773011A (en) * | 1993-09-27 | 1998-06-30 | Gerbu Biotechnik Gmbh | Method of preparing a synergistic immunological adjuvant formulation |
US6083513A (en) * | 1993-11-16 | 2000-07-04 | Gerbu Biotechnik Gmbh | Method for increasing the yield of antibodies in the techniques of immunology |
GB9326253D0 (en) * | 1993-12-23 | 1994-02-23 | Smithkline Beecham Biolog | Vaccines |
AUPM446594A0 (en) * | 1994-03-16 | 1994-04-14 | Csl Limited | Cytotoxic t-cell epitopes identified within epstein-barr virus |
GB9506863D0 (en) * | 1995-04-03 | 1995-05-24 | Smithkline Beecham Biolog | Vaccines |
US20010053365A1 (en) * | 1995-04-25 | 2001-12-20 | Smithkline Beecham Biologicals S.A. | Vaccines |
US6846489B1 (en) * | 1995-04-25 | 2005-01-25 | Smithkline Beecham Biologicals S.A. | Vaccines containing a saponin and a sterol |
UA56132C2 (en) * | 1995-04-25 | 2003-05-15 | Смітклайн Бічем Байолоджікалс С.А. | Vaccine composition (variants), method for stabilizing qs21 providing resistance against hydrolysis (variants), method for manufacturing vaccine |
GB9513261D0 (en) * | 1995-06-29 | 1995-09-06 | Smithkline Beecham Biolog | Vaccines |
DK0909323T3 (en) | 1996-01-04 | 2007-05-21 | Novartis Vaccines & Diagnostic | Helicobacter pylori bacterioferritin |
US7112331B2 (en) | 1996-02-09 | 2006-09-26 | Smithkline Beecham Biologicals, S.A. | Vaccines against varicella zoster virus gene 63 product |
GB9616351D0 (en) * | 1996-08-02 | 1996-09-11 | Smithkline Beecham Biolog | Vaccine composition |
US6406705B1 (en) | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
GB9706957D0 (en) * | 1997-04-05 | 1997-05-21 | Smithkline Beecham Plc | Formulation |
BR9809149A (en) * | 1997-05-20 | 2000-08-01 | Galenica Pharmaceuticals Inc | Analogs of triterpene saponin endowed with adjuvant and immunostimulatory activity |
US6080725A (en) * | 1997-05-20 | 2000-06-27 | Galenica Pharmaceuticals, Inc. | Immunostimulating and vaccine compositions employing saponin analog adjuvants and uses thereof |
GB9712347D0 (en) * | 1997-06-14 | 1997-08-13 | Smithkline Beecham Biolog | Vaccine |
US7459524B1 (en) * | 1997-10-02 | 2008-12-02 | Emergent Product Development Gaithersburg Inc. | Chlamydia protein, sequence and uses thereof |
GB9724531D0 (en) | 1997-11-19 | 1998-01-21 | Smithkline Biolog | Novel compounds |
US20080050367A1 (en) | 1998-04-07 | 2008-02-28 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
US7790856B2 (en) | 1998-04-07 | 2010-09-07 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize beta amyloid peptide |
TWI239847B (en) * | 1997-12-02 | 2005-09-21 | Elan Pharm Inc | N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease |
US7964192B1 (en) | 1997-12-02 | 2011-06-21 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidgenic disease |
SI1659178T1 (en) | 1998-02-05 | 2010-07-30 | Glaxosmithkline Biolog Sa | A process for the purification or production of a MAGE protein |
US20020147143A1 (en) | 1998-03-18 | 2002-10-10 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of lung cancer |
JP4227302B2 (en) | 1998-04-07 | 2009-02-18 | コリクサ コーポレイション | MYCOBACTERIUMUMBERBERCULOSIS antigen fusion protein and use thereof |
GB9808866D0 (en) | 1998-04-24 | 1998-06-24 | Smithkline Beecham Biolog | Novel compounds |
WO1999055875A2 (en) * | 1998-04-29 | 1999-11-04 | American Cyanamid Company | VACCINES CONTAINING RECOMBINANT PILIN AGAINST NEISSERIA GONORRHOEAE OR $i(NEISSERIA MENINGITIDIS) |
US6306404B1 (en) | 1998-07-14 | 2001-10-23 | American Cyanamid Company | Adjuvant and vaccine compositions containing monophosphoryl lipid A |
IL141044A0 (en) * | 1998-08-07 | 2002-02-10 | Univ Washington | Innunological herpes simplex virus antigens and methods for use thereof |
WO2000009075A2 (en) | 1998-08-14 | 2000-02-24 | Galenica Pharmaceuticals, Inc. | Chemically modified saponins and the use thereof as adjuvants |
US6692752B1 (en) | 1999-09-08 | 2004-02-17 | Smithkline Beecham Biologicals S.A. | Methods of treating human females susceptible to HSV infection |
GB9820525D0 (en) * | 1998-09-21 | 1998-11-11 | Allergy Therapeutics Ltd | Formulation |
US20030235557A1 (en) | 1998-09-30 | 2003-12-25 | Corixa Corporation | Compositions and methods for WT1 specific immunotherapy |
EP1588714A2 (en) * | 1998-10-16 | 2005-10-26 | GlaxoSmithKline Biologicals S.A. | Adjuvant systems and vaccines |
GB9826886D0 (en) * | 1998-12-07 | 1999-01-27 | Smithkline Beecham Biolog | Novel compounds |
US20020061848A1 (en) * | 2000-07-20 | 2002-05-23 | Ajay Bhatia | Compounds and methods for treatment and diagnosis of chlamydial infection |
EP2277892A3 (en) | 1998-12-08 | 2011-04-27 | Corixa Corporation | Compounds and methods for treatment and diagnosis of chlamydial infection |
WO2000034482A2 (en) | 1998-12-08 | 2000-06-15 | Smithkline Beecham Biologicals S.A. | Novel compounds derived from neisseria meningitidis |
US20020119158A1 (en) | 1998-12-17 | 2002-08-29 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6579973B1 (en) | 1998-12-28 | 2003-06-17 | Corixa Corporation | Compositions for the treatment and diagnosis of breast cancer and methods for their use |
DK1163343T3 (en) | 1999-03-12 | 2010-04-19 | Glaxosmithkline Biolog Sa | Neisseria meningitidis antigenic polypeptides, corresponding polynucleotides and protective antibodies |
PL355178A1 (en) | 1999-03-19 | 2004-04-05 | Smithkline Beecham Biologicals S.A. | Vaccine |
GB9909077D0 (en) * | 1999-04-20 | 1999-06-16 | Smithkline Beecham Biolog | Novel compositions |
KR20020007354A (en) | 1999-04-02 | 2002-01-26 | 길리스 스티브 | Compounds and methods for therapy and diagnosis of lung cancer |
US6558670B1 (en) | 1999-04-19 | 2003-05-06 | Smithkline Beechman Biologicals S.A. | Vaccine adjuvants |
CZ303515B6 (en) | 1999-04-19 | 2012-11-07 | Smithkline Beecham Biologicals S. A. | Adjuvant compositions |
US6635261B2 (en) | 1999-07-13 | 2003-10-21 | Wyeth Holdings Corporation | Adjuvant and vaccine compositions containing monophosphoryl lipid A |
GB9918319D0 (en) | 1999-08-03 | 1999-10-06 | Smithkline Beecham Biolog | Vaccine composition |
GB9919468D0 (en) | 1999-08-17 | 1999-10-20 | Smithkline Beecham Biolog | Vaccine |
AU1013601A (en) | 1999-10-22 | 2001-05-08 | Aventis Pasteur Limited | Method of inducing and/or enhancing an immune response to tumor antigens |
GB0000891D0 (en) * | 2000-01-14 | 2000-03-08 | Allergy Therapeutics Ltd | Formulation |
MXPA02007413A (en) * | 2000-01-31 | 2004-07-30 | Smithkline Beecham Biolog | Novel use. |
KR100848973B1 (en) | 2000-02-23 | 2008-07-30 | 글락소스미스클라인 바이오로지칼즈 에스.에이. | Tumour-specific animal proteins |
US20040002068A1 (en) | 2000-03-01 | 2004-01-01 | Corixa Corporation | Compositions and methods for the detection, diagnosis and therapy of hematological malignancies |
US6919187B2 (en) * | 2000-04-21 | 2005-07-19 | Corixa Corporation | Compounds and methods for treatment and diagnosis of chlamydial infection |
ES2303525T3 (en) | 2000-04-21 | 2008-08-16 | Corixa Corporation | COMPOUNDS AND METHODS FOR THE TREATMENT AND DIAGNOSIS OF INFECTION BY CHLAMYDIA. |
ATE346925T1 (en) | 2000-05-10 | 2006-12-15 | Sanofi Pasteur Ltd | IMMUNOGENIC POLYPEPTIDES ENCODED BY MAGE MINIGENE AND USES THEREOF |
AU6867801A (en) | 2000-06-20 | 2002-01-02 | Corixa Corp | Fusion proteins of mycobacterium tuberculosis |
AU2001273149A1 (en) | 2000-06-28 | 2002-01-08 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of lung cancer |
AP1695A (en) | 2000-06-29 | 2006-12-17 | Glaxosmithkline Biologicals Sa | Multivalent vaccine composition. |
GB0108364D0 (en) | 2001-04-03 | 2001-05-23 | Glaxosmithkline Biolog Sa | Vaccine composition |
UA79735C2 (en) | 2000-08-10 | 2007-07-25 | Глаксосмітклайн Байолоджікалз С.А. | Purification of hbv antigens for use in vaccines |
GB0022742D0 (en) | 2000-09-15 | 2000-11-01 | Smithkline Beecham Biolog | Vaccine |
ES2392943T3 (en) | 2000-10-18 | 2012-12-17 | Glaxosmithkline Biologicals S.A. | Anti-tumor vaccines |
EP1201250A1 (en) * | 2000-10-25 | 2002-05-02 | SMITHKLINE BEECHAM BIOLOGICALS s.a. | Immunogenic compositions comprising liver stage malarial antigens |
CA2881568C (en) | 2000-10-27 | 2019-09-24 | Novartis Vaccines And Diagnostics, Inc. | Nucleic acids and proteins from streptococcus groups a & b |
US6892140B1 (en) | 2000-11-27 | 2005-05-10 | Enteron, Inc. | Immunogenic cancer peptides and uses thereof |
US7700751B2 (en) | 2000-12-06 | 2010-04-20 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize β-amyloid peptide |
CA2430379A1 (en) | 2000-12-07 | 2002-06-13 | Chiron Corporation | Endogenous retroviruses up-regulated in prostate cancer |
GB0103171D0 (en) | 2001-02-08 | 2001-03-28 | Smithkline Beecham Biolog | Vaccine composition |
WO2002074336A2 (en) | 2001-02-23 | 2002-09-26 | Glaxosmithkline Biologicals S.A. | Influenza vaccine formulations for intradermal delivery |
US20030031684A1 (en) | 2001-03-30 | 2003-02-13 | Corixa Corporation | Methods for the production of 3-O-deactivated-4'-monophosphoryl lipid a (3D-MLA) |
GB0109297D0 (en) | 2001-04-12 | 2001-05-30 | Glaxosmithkline Biolog Sa | Vaccine |
US20020193295A1 (en) * | 2001-05-04 | 2002-12-19 | Emanuel Calenoff | Immunogenic peptides and uses thereof |
CA2446788A1 (en) | 2001-05-09 | 2002-11-14 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of prostate cancer |
MY134424A (en) | 2001-05-30 | 2007-12-31 | Saechsisches Serumwerk | Stable influenza virus preparations with low or no amount of thiomersal |
US20100221284A1 (en) | 2001-05-30 | 2010-09-02 | Saech-Sisches Serumwerk Dresden | Novel vaccine composition |
GB0115176D0 (en) | 2001-06-20 | 2001-08-15 | Chiron Spa | Capular polysaccharide solubilisation and combination vaccines |
US8481043B2 (en) | 2001-06-22 | 2013-07-09 | Cpex Pharmaceuticals, Inc. | Nasal immunization |
EP1417236A4 (en) | 2001-07-10 | 2010-03-17 | Corixa Corp | Compositions and methods for delivery of proteins and adjuvants encapsulated in microspheres |
GB0118249D0 (en) | 2001-07-26 | 2001-09-19 | Chiron Spa | Histidine vaccines |
GB0118367D0 (en) | 2001-07-27 | 2001-09-19 | Glaxosmithkline Biolog Sa | Novel use |
GB0121591D0 (en) | 2001-09-06 | 2001-10-24 | Chiron Spa | Hybrid and tandem expression of neisserial proteins |
US7361352B2 (en) | 2001-08-15 | 2008-04-22 | Acambis, Inc. | Influenza immunogen and vaccine |
AR045702A1 (en) | 2001-10-03 | 2005-11-09 | Chiron Corp | COMPOSITIONS OF ASSISTANTS. |
DK2224012T3 (en) | 2001-12-17 | 2013-05-13 | Corixa Corp | Compositions and Methods for Therapy and Diagnosis of Inflammatory Bowel Diseases |
US7030094B2 (en) * | 2002-02-04 | 2006-04-18 | Corixa Corporation | Immunostimulant compositions comprising an aminoalkyl glucosaminide phosphate and QS-21 |
AU2003215316A1 (en) | 2002-02-20 | 2003-09-09 | Chiron Corporation | Microparticles with adsorbed polypeptide-containing molecules |
US7351413B2 (en) | 2002-02-21 | 2008-04-01 | Lorantis, Limited | Stabilized HBc chimer particles as immunogens for chronic hepatitis |
MY139983A (en) | 2002-03-12 | 2009-11-30 | Janssen Alzheimer Immunotherap | Humanized antibodies that recognize beta amyloid peptide |
JP4662719B2 (en) | 2002-04-19 | 2011-03-30 | ザ ガバニング カウンシル オブ ザ ユニバーシティ オブ トロント | Immunological methods and compositions for the treatment of Alzheimer's disease |
EP1532161B1 (en) | 2002-06-13 | 2012-02-15 | Novartis Vaccines and Diagnostics, Inc. | Vectors for expression of hml-2 polypeptides |
CA2492598C (en) | 2002-07-18 | 2013-12-17 | University Of Washington | Rapid, efficient purification of hsv-specific t-lymphocytes and hsv antigens identified via same |
ES2575014T3 (en) | 2002-08-02 | 2016-06-23 | Glaxosmithkline Biologicals S.A. | Neisseria vaccine compositions comprising a combination of antigens |
GB0220194D0 (en) | 2002-08-30 | 2002-10-09 | Chiron Spa | Improved vesicles |
DK2353608T3 (en) | 2002-10-11 | 2020-02-10 | Novartis Vaccines And Diagnostics S R L | POLYPEPTID VACCINES FOR WIDE PROTECTION AGAINST HYPERVIRULENT MENINGOCOC LINES |
ES2594758T3 (en) | 2002-10-23 | 2016-12-22 | Glaxosmithkline Biologicals S.A. | Vaccination procedures against malaria |
WO2004046177A2 (en) | 2002-11-15 | 2004-06-03 | Chiron Srl | Unexpected surface proteins in neisseria meningitidis |
GB0227346D0 (en) | 2002-11-22 | 2002-12-31 | Chiron Spa | 741 |
WO2004061423A2 (en) | 2003-01-06 | 2004-07-22 | Wyeth | Compositions and methods for diagnosing and treating colon cancers |
EP2289546A3 (en) | 2003-01-30 | 2011-03-30 | Novartis Vaccines and Diagnostics S.r.l. | Injectable vaccines against multiple meningococcal serogroups |
GB0308198D0 (en) | 2003-04-09 | 2003-05-14 | Chiron Srl | ADP-ribosylating bacterial toxin |
TWI306458B (en) | 2003-05-30 | 2009-02-21 | Elan Pharma Int Ltd | Humanized antibodies that recognize beta amyloid peptide |
CA2528007C (en) | 2003-06-02 | 2012-03-27 | Chiron Corporation | Immunogenic compositions based on microparticles comprising adsorbed toxoid and a polysaccharide-containing antigen |
US20060035242A1 (en) | 2004-08-13 | 2006-02-16 | Michelitsch Melissa D | Prion-specific peptide reagents |
PL1660123T3 (en) | 2003-09-02 | 2013-08-30 | Glaxosmithkline Biologicals Sa | Rotavirus vaccine |
GB0323103D0 (en) | 2003-10-02 | 2003-11-05 | Chiron Srl | De-acetylated saccharides |
PT1670506E (en) | 2003-10-02 | 2013-01-28 | Novartis Ag | Liquid vaccines for multiple meningococcal serogroups |
EP1667712B1 (en) | 2003-10-02 | 2010-07-21 | GlaxoSmithKline Biologicals S.A. | B. pertussis antigens and use thereof in vaccination |
GB0323965D0 (en) * | 2003-10-13 | 2003-11-19 | Glaxosmithkline Biolog Sa | Immunogenic compositions |
ATE554106T1 (en) | 2003-12-23 | 2012-05-15 | Arbor Vita Corp | ANTIBODIES FOR ONCOGENIC STRAINS OF HPV AND METHOD OF USE THEREOF |
EP2561884B1 (en) | 2004-02-05 | 2017-01-04 | The Ohio State University Research Foundation | Chimeric VEGF peptides |
EP1722815A1 (en) | 2004-03-09 | 2006-11-22 | Chiron Corporation | Influenza virus vaccines |
EP1740217B1 (en) | 2004-04-30 | 2011-06-15 | Novartis Vaccines and Diagnostics S.r.l. | Meningococcal conjugate vaccination |
GB0500787D0 (en) | 2005-01-14 | 2005-02-23 | Chiron Srl | Integration of meningococcal conjugate vaccination |
GB0409745D0 (en) | 2004-04-30 | 2004-06-09 | Chiron Srl | Compositions including unconjugated carrier proteins |
GB0410866D0 (en) | 2004-05-14 | 2004-06-16 | Chiron Srl | Haemophilius influenzae |
GB0411411D0 (en) * | 2004-05-21 | 2004-06-23 | Glaxosmithkline Biolog Sa | Vaccines |
JP4896021B2 (en) | 2004-05-21 | 2012-03-14 | ノバルティス ヴァクシンズ アンド ダイアグノスティクス, インコーポレイテッド | Alphavirus vector for respiratory pathogen vaccine |
US20080199493A1 (en) | 2004-05-25 | 2008-08-21 | Picker Louis J | Siv and Hiv Vaccination Using Rhcmv- and Hcmv-Based Vaccine Vectors |
DE602005025342D1 (en) | 2004-05-28 | 2011-01-27 | Glaxosmithkline Biolog Sa | VACCINE COMPOSITIONS WITH VIRUSOMES AND A SAPONIN ADJUVANS |
JP2008508320A (en) | 2004-07-29 | 2008-03-21 | カイロン コーポレイション | Immunogenic composition against gram positive bacteria such as STREPTOCOCCUSAGALACTIAE |
GB0417494D0 (en) | 2004-08-05 | 2004-09-08 | Glaxosmithkline Biolog Sa | Vaccine |
GB0420634D0 (en) * | 2004-09-16 | 2004-10-20 | Glaxosmithkline Biolog Sa | Vaccines |
EP2181714A3 (en) | 2004-09-22 | 2010-06-23 | GlaxoSmithKline Biologicals S.A. | Immunogenic composition for use in vaccination against staphylococcei |
US8846051B2 (en) | 2004-10-08 | 2014-09-30 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, Centers For Disease Control And Prevention | Modulation of replicative fitness by deoptimization of synonymous codons |
GB0424092D0 (en) | 2004-10-29 | 2004-12-01 | Chiron Srl | Immunogenic bacterial vesicles with outer membrane proteins |
CA2590337C (en) | 2004-12-15 | 2017-07-11 | Neuralab Limited | Humanized amyloid beta antibodies for use in improving cognition |
JP4993750B2 (en) | 2005-01-27 | 2012-08-08 | チルドレンズ ホスピタル アンド リサーチ センター アット オークランド | Vesicular vaccine based on GNA1870 for broad protection against diseases caused by Neisseria meningitidis |
GB0502095D0 (en) | 2005-02-01 | 2005-03-09 | Chiron Srl | Conjugation of streptococcal capsular saccharides |
GB0503337D0 (en) | 2005-02-17 | 2005-03-23 | Glaxosmithkline Biolog Sa | Compositions |
EP1858920B1 (en) | 2005-02-18 | 2016-02-03 | GlaxoSmithKline Biologicals SA | Proteins and nucleic acids from meningitis/sepsis-associated escherichia coli |
AU2006216844B2 (en) | 2005-02-18 | 2012-11-08 | Novartis Vaccines And Diagnostics S.R.L. | Immunogens from uropathogenic escherichia coli |
GB0504436D0 (en) * | 2005-03-03 | 2005-04-06 | Glaxosmithkline Biolog Sa | Vaccine |
EP2392347A3 (en) | 2005-03-31 | 2012-01-18 | GlaxoSmithKline Biologicals S.A. | Vaccines against chlamydial infection |
JP5164830B2 (en) | 2005-04-29 | 2013-03-21 | グラクソスミスクライン バイオロジカルズ ソシエテ アノニム | A novel method for the prevention or treatment of Mycobacterium tuberculosis infection |
AU2006261342B2 (en) | 2005-06-15 | 2012-02-02 | The Ohio State University Research Foundation | Her-2 peptides |
GB0513421D0 (en) * | 2005-06-30 | 2005-08-03 | Glaxosmithkline Biolog Sa | Vaccines |
BRPI0613168A2 (en) | 2005-07-01 | 2010-12-21 | Forsyth Dental In Ry For Children Fa | isolated polypeptide molecule; isolated nucleic acid molecule; vector or plasmid; host cell; antibody; fusion protein; method for stimulating a specific tb immunogenic response in an individual or for preventing or reducing the severity of disease caused by tb; method for monitoring the treatment of TB disease in an individual; method of diagnosing disease caused by TB in an individual; method of distinguishing between disease caused by TB and immunity to disease caused by TB in an individual; method for detection of m infection. tuberculosis in a biological sample; composition; Diagnostic kit for the presence or absence of infection by m. tuberculosis in a person; and pharmaceutical composition |
CN101355960A (en) | 2005-10-18 | 2009-01-28 | 诺华疫苗和诊断公司 | Mucosal and systemic immunizations with alphavirus replicon particles |
US11707520B2 (en) | 2005-11-03 | 2023-07-25 | Seqirus UK Limited | Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture |
EA014028B1 (en) * | 2005-11-04 | 2010-08-30 | Новартис Вэксинс Энд Диагностикс Срл | Emulsions with free aqueous-phase surfactant as adjuvants for split influenza vaccines |
US20090304742A1 (en) | 2005-11-04 | 2009-12-10 | Novartis Vaccines And Diagnostics Srl | Influenza vaccines with reduced amount of emulsion adjuvant |
JP2009514838A (en) | 2005-11-04 | 2009-04-09 | ノバルティス ヴァクシンズ アンド ダイアグノスティクス エスアールエル | Adjuvant vaccine containing non-virion antigen prepared from influenza virus grown in cell culture |
JP2009514839A (en) | 2005-11-04 | 2009-04-09 | ノバルティス ヴァクシンズ アンド ダイアグノスティクス エスアールエル | Adjuvant influenza vaccine containing cytokine inducer |
JP5215865B2 (en) | 2005-11-22 | 2013-06-19 | ノバルティス ヴァクシンズ アンド ダイアグノスティクス インコーポレイテッド | Norovirus and sapovirus antigens |
GB0524066D0 (en) | 2005-11-25 | 2006-01-04 | Chiron Srl | 741 ii |
TWI457133B (en) * | 2005-12-13 | 2014-10-21 | Glaxosmithkline Biolog Sa | Novel composition |
GB0607088D0 (en) | 2006-04-07 | 2006-05-17 | Glaxosmithkline Biolog Sa | Vaccine |
TW201350129A (en) | 2005-12-22 | 2013-12-16 | Glaxosmithkline Biolog Sa | Streptococcus pneumoniae immunogenic composition comprising capsular saccharide conjugates, vaccine and kit comprising the same and uses thereof |
WO2007079193A2 (en) | 2005-12-30 | 2007-07-12 | Tti Ellebeau, Inc. | Iontophoretic systems, devices, and methods of delivery of active agents to biological interface |
US9259463B2 (en) | 2006-01-16 | 2016-02-16 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Chlamydia vaccine |
MX2008009280A (en) | 2006-01-17 | 2008-12-12 | Arne Forsgren | A NOVEL SURFACE EXPOSED HAEMOPHILUS INFLUENZAE PROTEIN (PROTEIN E; pE). |
KR20110110853A (en) | 2006-01-27 | 2011-10-07 | 노파르티스 파르마 아게 | Influenza vaccines containing hemagglutinin and matrix proteins |
US8063063B2 (en) | 2006-03-23 | 2011-11-22 | Novartis Ag | Immunopotentiating compounds |
EP2357184B1 (en) | 2006-03-23 | 2015-02-25 | Novartis AG | Imidazoquinoxaline compounds as immunomodulators |
CA2646349A1 (en) | 2006-03-24 | 2007-10-04 | Novartis Vaccines And Diagnostics Gmbh & Co Kg | Storage of influenza vaccines without refrigeration |
CA2647939A1 (en) | 2006-03-30 | 2007-11-08 | Embrex, Inc. | Methods and compositions for vaccination of poultry |
CA2647441C (en) | 2006-03-30 | 2021-02-23 | Glaxosmithkline Biologicals S.A. | Immunogenic composition comprising staphylococcus aureus saccharides |
US9839685B2 (en) | 2006-04-13 | 2017-12-12 | The Regents Of The University Of Michigan | Methods of inducing human immunodeficiency virus-specific immune responses in a host comprising nasally administering compositions comprising a naonemulsion and recombinant GP120 immunogen |
US10138279B2 (en) | 2006-04-13 | 2018-11-27 | Regents Of The University Of Michigan | Compositions and methods for Bacillus anthracis vaccination |
WO2009017467A1 (en) | 2007-07-27 | 2009-02-05 | Elan Pharma International Limited | Treatment of amyloidogenic diseases |
US8784810B2 (en) | 2006-04-18 | 2014-07-22 | Janssen Alzheimer Immunotherapy | Treatment of amyloidogenic diseases |
TW200806315A (en) | 2006-04-26 | 2008-02-01 | Wyeth Corp | Novel formulations which stabilize and inhibit precipitation of immunogenic compositions |
EP2390360A1 (en) | 2006-06-02 | 2011-11-30 | GlaxoSmithKline Biologicals S.A. | Method for identifying whether a patient will be responder or not to immunotherapy based on the differential expression of the IDO1 gene |
WO2008020335A2 (en) | 2006-06-09 | 2008-02-21 | Novartis Ag | Immunogenic compositions for streptococcus agalactiae |
CA2654709A1 (en) | 2006-06-12 | 2007-12-21 | Nathalie Devos | Neisseria meningitidis lipooligosaccharide vaccine |
US9364525B2 (en) | 2006-07-18 | 2016-06-14 | Glaxosmithkline Biologicals Sa | Vaccines for malaria |
GB0614460D0 (en) | 2006-07-20 | 2006-08-30 | Novartis Ag | Vaccines |
GB2453475B (en) | 2006-07-25 | 2011-01-19 | Secr Defence | Live vaccine strain |
JP2010500399A (en) | 2006-08-16 | 2010-01-07 | ノバルティス アーゲー | Immunogen from Urinary Pathogenic Escherichia coli |
US20080057079A1 (en) * | 2006-08-31 | 2008-03-06 | Baylor Research Institute | JC Virus Vaccine |
PT2097102E (en) | 2006-09-07 | 2012-08-03 | Glaxosmithkline Biolog Sa | Combination vaccine having reduced polio virus antigen quantities |
AU2007297178B2 (en) | 2006-09-11 | 2014-07-24 | Novartis Ag | Making influenza virus vaccines without using eggs |
US20090181078A1 (en) | 2006-09-26 | 2009-07-16 | Infectious Disease Research Institute | Vaccine composition containing synthetic adjuvant |
PT2068918E (en) | 2006-09-26 | 2012-08-06 | Infectious Disease Res Inst | Vaccine composition containing synthetic adjuvant |
AU2007330494B2 (en) | 2006-12-06 | 2014-03-13 | Seqirus UK Limited | Vaccines including antigen from four strains of influenza virus |
CA2896131C (en) | 2007-03-02 | 2020-04-07 | Glaxosmithkline Biologicals S.A. | Novel method and compositions |
US8486414B2 (en) | 2007-04-04 | 2013-07-16 | Infectious Disease Research Institute | Immunogenic compositions comprising Mycobacterium tuberculosis polypeptides and fusions thereof |
US8003097B2 (en) | 2007-04-18 | 2011-08-23 | Janssen Alzheimer Immunotherapy | Treatment of cerebral amyloid angiopathy |
EA200901340A1 (en) | 2007-05-02 | 2010-04-30 | Глаксосмитклайн Байолоджикалс С.А. | VACCINE |
AU2008267208B2 (en) | 2007-06-26 | 2012-01-19 | Glaxosmithkline Biologicals S.A. | Vaccine comprising streptococcus pneumoniae capsular polysaccharide conjugates |
NZ582595A (en) | 2007-06-27 | 2012-07-27 | Novartis Ag | Low-additive influenza vaccines |
GB0713880D0 (en) | 2007-07-17 | 2007-08-29 | Novartis Ag | Conjugate purification |
GB0714963D0 (en) | 2007-08-01 | 2007-09-12 | Novartis Ag | Compositions comprising antigens |
EA017887B1 (en) | 2007-08-02 | 2013-03-29 | Байондвакс Фармасьютикалз Лтд. | Multimeric multiepitope influenza vaccines |
CA2695421A1 (en) | 2007-08-03 | 2009-02-12 | President And Fellows Of Harvard College | Chlamydia antigens |
UY31285A1 (en) | 2007-08-13 | 2009-03-31 | VACCINES | |
CA2699513C (en) | 2007-09-12 | 2018-03-13 | Novartis Ag | Gas57 mutant antigens and gas57 antibodies |
BRPI0817008A2 (en) | 2007-09-17 | 2017-05-16 | Glaxosmithkline Biologicals Sa | oligonucleotide, primer or probe, primer pair, kit, methods for detecting the presence and / or amount of the unmethylated and methylated mage-a3 gene in a DNA-containing sample to diagnose cancer or cancer predisposition or cancer predisposition, to identify and / or select a suitable patient for treatment with a mage-a3 immunotherapeutic, to predict the likelihood of successful cancer treatment, to select an appropriate cancer treatment regimen, to treat cancer in a patient, to treat a patient susceptible to recurrence of a tumor expressing mage-a3, and use of a composition |
EP2045263A1 (en) | 2007-10-02 | 2009-04-08 | Universite Libre De Bruxelles | Identification and molecular characterisation of salivary metalloproteases expressed in the tick salivary glands |
JO3076B1 (en) | 2007-10-17 | 2017-03-15 | Janssen Alzheimer Immunotherap | Immunotherapy regimes dependent on apoe status |
GB0810305D0 (en) | 2008-06-05 | 2008-07-09 | Novartis Ag | Influenza vaccination |
EP2227250A4 (en) | 2007-12-03 | 2011-07-06 | Harvard College | Chlamydia antigens |
US10040825B2 (en) | 2007-12-19 | 2018-08-07 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Soluble forms of Hendra and Nipah virus F glycoprotein and uses thereof |
GB0818453D0 (en) | 2008-10-08 | 2008-11-12 | Novartis Ag | Fermentation processes for cultivating streptococci and purification processes for obtaining cps therefrom |
PL2235046T3 (en) | 2007-12-21 | 2012-12-31 | Novartis Ag | Mutant forms of streptolysin o |
PT2222710T (en) * | 2007-12-24 | 2016-11-02 | Glaxosmithkline Biologicals Sa | Recombinant rsv antigens |
EP3263591B1 (en) | 2008-02-21 | 2019-03-27 | GlaxoSmithKline Biologicals S.A. | Meningococcal fhbp polypeptides |
AU2009223613B2 (en) | 2008-03-10 | 2014-09-25 | Children's Hospital & Research Center At Oakland | Chimeric factor H binding proteins (fHBP) containing a heterologous B domain and methods of use |
WO2009127666A2 (en) * | 2008-04-15 | 2009-10-22 | Glaxosmithkline Biologicals S.A. | Method and compositions |
ES2651924T3 (en) | 2008-04-18 | 2018-01-30 | The General Hospital Corporation | Immunotherapies that use self-assembling vaccines |
AU2009248810B2 (en) | 2008-05-23 | 2013-12-05 | The Regents Of The University Of Michigan | Nanoemulsion vaccines |
WO2010006447A1 (en) * | 2008-07-18 | 2010-01-21 | Id Biomedical Corporation Of Quebec | Chimeric respiratory syncytial virus polypeptide antigens |
LT2315834T (en) | 2008-07-25 | 2018-09-10 | Glaxosmithkline Biologicals S.A. | THE TUBERCULOSIS Rv2386c PROTEIN, COMPOSITIONS AND USES THEREOF |
UA107180C2 (en) | 2008-07-25 | 2014-12-10 | Глаксосмітклайн Байолоджікалз С.А. | Rv1753c tuberculosis protein, composition containing it and administration |
US20110150926A1 (en) | 2008-08-01 | 2011-06-23 | Mohammed Alsharifi | Influenza vaccines |
GB0815872D0 (en) | 2008-09-01 | 2008-10-08 | Pasteur Institut | Novel method and compositions |
CA2738245A1 (en) | 2008-09-26 | 2010-04-01 | Nanobio Corporation | Nanoemulsion therapeutic compositions and methods of using the same |
US9067981B1 (en) | 2008-10-30 | 2015-06-30 | Janssen Sciences Ireland Uc | Hybrid amyloid-beta antibodies |
US9974844B2 (en) | 2008-11-17 | 2018-05-22 | The Regents Of The University Of Michigan | Cancer vaccine compositions and methods of using the same |
WO2010064243A1 (en) | 2008-12-03 | 2010-06-10 | Protea Vaccine Technologies Ltd. | GLUTAMYL tRNA SYNTHETASE (GtS) FRAGMENTS |
PE20142330A1 (en) | 2008-12-09 | 2015-01-14 | Pfizer Vaccines Llc | IGE CH3 PEPTIDE VACCINE |
MX2011007456A (en) | 2009-01-12 | 2011-08-03 | Novartis Ag | Cna_b domain antigens in vaccines against gram positive bacteria. |
GB0901423D0 (en) | 2009-01-29 | 2009-03-11 | Secr Defence | Treatment |
GB0901411D0 (en) | 2009-01-29 | 2009-03-11 | Secr Defence | Treatment |
US20100234283A1 (en) | 2009-02-04 | 2010-09-16 | The Ohio State University Research Foundation | Immunogenic epitopes, peptidomimetics, and anti-peptide antibodies, and methods of their use |
US8460674B2 (en) | 2009-02-07 | 2013-06-11 | University Of Washington | HSV-1 epitopes and methods for using same |
ES2608841T3 (en) | 2009-02-10 | 2017-04-17 | Seqirus UK Limited | Flu shots with reduced amounts of squalene |
CN102438650A (en) | 2009-03-06 | 2012-05-02 | 诺华有限公司 | Chlamydia antigens |
EA021100B1 (en) | 2009-03-17 | 2015-04-30 | МДхХЭЛС СА | Improved detection of gene expression |
US9044447B2 (en) | 2009-04-03 | 2015-06-02 | University Of Washington | Antigenic peptide of HSV-2 and methods for using same |
GB0906234D0 (en) | 2009-04-14 | 2009-05-20 | Secr Defence | Vaccine |
WO2010119343A2 (en) | 2009-04-14 | 2010-10-21 | Novartis Ag | Compositions for immunising against staphylococcus aureus |
CA2757620C (en) | 2009-04-30 | 2016-04-26 | Coley Pharmaceutical Group, Inc. | Pneumococcal vaccine and uses thereof |
US8668911B2 (en) | 2009-05-14 | 2014-03-11 | The Regents Of The University Of Michigan | Streptococcus vaccine compositions and methods of using the same |
HUE031051T2 (en) | 2009-06-05 | 2017-06-28 | Infectious Disease Res Inst | Synthetic glucopyranosyl lipid adjuvants and vaccine compositions containing them |
WO2010146414A1 (en) | 2009-06-15 | 2010-12-23 | National University Of Singapore | Influenza vaccine, composition, and methods of use |
EP2442827B1 (en) | 2009-06-16 | 2016-01-06 | The Regents of the University of Michigan | Nanoemulsion vaccines |
WO2010149743A2 (en) | 2009-06-24 | 2010-12-29 | Id Biomedical Corporation Of Quebec | Vaccine |
CA2766211A1 (en) | 2009-06-24 | 2010-12-29 | Glaxosmithkline Biologicals S.A. | Recombinant rsv antigens |
EP2451833B1 (en) | 2009-07-07 | 2018-01-17 | GlaxoSmithKline Biologicals SA | Conserved escherichia coli immunogens |
HRP20220756T1 (en) | 2009-07-15 | 2022-09-02 | Glaxosmithkline Biologicals S.A. | Rsv f protein compositions and methods for making same |
MX2012000734A (en) | 2009-07-16 | 2012-01-27 | Novartis Ag | Detoxified escherichia coli immunogens. |
RU2518291C2 (en) | 2009-07-30 | 2014-06-10 | Пфайзер Вэксинс ЭлЭлСи | Antigen tau-peptides and their application |
GB0913681D0 (en) | 2009-08-05 | 2009-09-16 | Glaxosmithkline Biolog Sa | Immunogenic composition |
GB0913680D0 (en) | 2009-08-05 | 2009-09-16 | Glaxosmithkline Biolog Sa | Immunogenic composition |
KR20120059572A (en) * | 2009-08-26 | 2012-06-08 | 셀렉타 바이오사이언시즈, 인크. | Compositions that induce t cell help |
JP2013502918A (en) | 2009-08-27 | 2013-01-31 | ノバルティス アーゲー | Hybrid polypeptide comprising Neisseria meningitidis fHBP sequence |
JP2013503623A (en) | 2009-09-03 | 2013-02-04 | ファイザー バクシーンズ エルエルシー | PCSK9 vaccine |
CN102695523A (en) | 2009-09-10 | 2012-09-26 | 诺华有限公司 | Combination vaccines against respiratory tract diseases |
GB0917457D0 (en) | 2009-10-06 | 2009-11-18 | Glaxosmithkline Biolog Sa | Method |
GB0917002D0 (en) | 2009-09-28 | 2009-11-11 | Novartis Vaccines Inst For Global Health Srl | Improved shigella blebs |
GB0917003D0 (en) | 2009-09-28 | 2009-11-11 | Novartis Vaccines Inst For Global Health Srl | Purification of bacterial vesicles |
US8974799B2 (en) | 2009-09-30 | 2015-03-10 | Novartis Ag | Conjugation of Staphylococcus aureus type 5 and type 8 capsular polysaccharides |
US20130022639A1 (en) | 2009-09-30 | 2013-01-24 | Novartis Ag | Expression of meningococcal fhbp polypeptides |
GB0918392D0 (en) | 2009-10-20 | 2009-12-02 | Novartis Ag | Diagnostic and therapeutic methods |
MX2012004850A (en) | 2009-10-27 | 2012-05-22 | Novartis Ag | Modified meningococcal fhbp polypeptides. |
GB0919690D0 (en) | 2009-11-10 | 2009-12-23 | Guy S And St Thomas S Nhs Foun | compositions for immunising against staphylococcus aureus |
WO2011067758A2 (en) | 2009-12-02 | 2011-06-09 | Protea Vaccine Technologies Ltd. | Immunogenic fragments and multimers from streptococcus pneumoniae proteins |
CN107412754A (en) | 2009-12-22 | 2017-12-01 | 塞尔德克斯医疗公司 | Vaccine combination |
ES2707778T3 (en) | 2009-12-30 | 2019-04-05 | Glaxosmithkline Biologicals Sa | Immunogens polysaccharides conjugated with carrier proteins of E. coli |
GB201003333D0 (en) | 2010-02-26 | 2010-04-14 | Novartis Ag | Immunogenic proteins and compositions |
GB201003920D0 (en) | 2010-03-09 | 2010-04-21 | Glaxosmithkline Biolog Sa | Method of treatment |
GB201003924D0 (en) | 2010-03-09 | 2010-04-21 | Glaxosmithkline Biolog Sa | Immunogenic composition |
WO2011110635A1 (en) | 2010-03-10 | 2011-09-15 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
WO2011119920A2 (en) | 2010-03-25 | 2011-09-29 | Oregon Health & Science University | Cmv glycoproteins and recombinant vectors |
WO2011117408A1 (en) | 2010-03-26 | 2011-09-29 | Glaxosmithkline Biologicals S.A. | Hiv vaccine |
ES2910199T3 (en) | 2010-03-30 | 2022-05-11 | Childrens Hospital & Res Center At Oakland | Factor H-binding proteins (fHbp) with altered properties and methods of using them |
GB201005625D0 (en) | 2010-04-01 | 2010-05-19 | Novartis Ag | Immunogenic proteins and compositions |
EP2556151A1 (en) | 2010-04-07 | 2013-02-13 | Novartis AG | Method for generating a parvovirus b19 virus-like particle |
KR20180099900A (en) | 2010-05-26 | 2018-09-05 | 셀렉타 바이오사이언시즈, 인크. | Dose selection of adjuvanted synthetic nanocarriers |
JP2013532008A (en) | 2010-05-28 | 2013-08-15 | テトリス オンライン インコーポレイテッド | Interactive hybrid asynchronous computer game infrastructure |
CN102933229A (en) | 2010-06-04 | 2013-02-13 | 惠氏有限责任公司 | Vaccine formulations |
CA2798837A1 (en) | 2010-06-07 | 2011-12-15 | Pfizer Inc. | Her-2 peptides and vaccines |
EP2942061A3 (en) | 2010-06-07 | 2016-01-13 | Pfizer Vaccines LLC | Ige ch3 peptide vaccine |
GB201009861D0 (en) | 2010-06-11 | 2010-07-21 | Novartis Ag | OMV vaccines |
US8658603B2 (en) | 2010-06-16 | 2014-02-25 | The Regents Of The University Of Michigan | Compositions and methods for inducing an immune response |
CN103154242B (en) | 2010-07-06 | 2015-09-30 | 诺华股份有限公司 | The immunogenic composition that norovirus is derivative and method |
US9192661B2 (en) | 2010-07-06 | 2015-11-24 | Novartis Ag | Delivery of self-replicating RNA using biodegradable polymer particles |
GB201015132D0 (en) | 2010-09-10 | 2010-10-27 | Univ Bristol | Vaccine composition |
GB201101665D0 (en) | 2011-01-31 | 2011-03-16 | Novartis Ag | Immunogenic compositions |
BR112013004582A2 (en) | 2010-09-27 | 2016-09-06 | Crucell Holland Bv | method for inducing an immune response in a subject against a parasite antigen that causes malaria |
SG188624A1 (en) | 2010-09-27 | 2013-04-30 | Glaxosmithkline Biolog Sa | Vaccine |
GB201017519D0 (en) | 2010-10-15 | 2010-12-01 | Novartis Vaccines Inst For Global Health S R L | Vaccines |
GB201101331D0 (en) | 2011-01-26 | 2011-03-09 | Glaxosmithkline Biolog Sa | Compositions and uses |
WO2012057904A1 (en) | 2010-10-27 | 2012-05-03 | Infectious Disease Research Institute | Mycobacterium tuberculosis antigens and combinations thereof having high seroreactivity |
BR112013011420A2 (en) | 2010-11-08 | 2016-08-02 | Infectious Disease Res Inst | vaccines comprising nonspecific nucleoside hydrolase polypeptides and sterol 24-c-methyl transferase (smt) for the treatment and diagnosis of leishmaniasis |
WO2012072769A1 (en) | 2010-12-01 | 2012-06-07 | Novartis Ag | Pneumococcal rrgb epitopes and clade combinations |
AU2011335551B2 (en) | 2010-12-02 | 2016-10-06 | Bionor Immuno As | Peptide scaffold design |
GB201022007D0 (en) | 2010-12-24 | 2011-02-02 | Imp Innovations Ltd | DNA-sensor |
WO2012085668A2 (en) | 2010-12-24 | 2012-06-28 | Novartis Ag | Compounds |
MX346475B (en) | 2011-01-06 | 2017-03-22 | Bionor Immuno As | Monomeric and multimeric immunogenic peptides. |
EP4159232A1 (en) | 2011-01-26 | 2023-04-05 | GlaxoSmithKline Biologicals S.A. | Rsv immunization regimen |
CA2825403C (en) | 2011-01-27 | 2023-02-21 | Gamma Vaccines Pty Limited | Vaccines comprising a combination of gamma irradiated influenza virus and a further immunogen |
CA2828068C (en) | 2011-02-22 | 2019-03-19 | Biondvax Pharmaceuticals Ltd. | Multimeric multiepitope polypeptides in improved seasonal and pandemic influenza vaccines |
US20140004142A1 (en) | 2011-03-02 | 2014-01-02 | Pfizer Inc. | Pcsk9 vaccine |
EP2691422B1 (en) | 2011-03-29 | 2019-02-06 | UAB Research Foundation | Methods and compositions for cytomegalovirus il-10 protein |
GB201106357D0 (en) | 2011-04-14 | 2011-06-01 | Pessi Antonello | Composition and uses thereof |
WO2012141984A1 (en) | 2011-04-08 | 2012-10-18 | Immune Design Corp. | Immunogenic compositions and methods of using the compositions for inducing humoral and cellular immune responses |
TW201302779A (en) | 2011-04-13 | 2013-01-16 | Glaxosmithkline Biolog Sa | Fusion proteins & combination vaccines |
HUE034673T2 (en) | 2011-05-13 | 2018-02-28 | Glaxosmithkline Biologicals Sa | Pre-fusion rsv f antigens |
EP2717909B1 (en) | 2011-06-04 | 2017-12-06 | Rochester General Hospital Research Institute | Compositions and methods related to p6 of haemophilus influenzae |
CA2832109C (en) | 2011-06-10 | 2021-07-06 | Oregon Health & Science University | Cmv glycoproteins and recombinant vectors |
CN103608030A (en) | 2011-06-21 | 2014-02-26 | 昂科发克特公司 | Compositions and methods for therapy and diagnosis of cancer |
ES2687129T3 (en) | 2011-07-25 | 2018-10-23 | Glaxosmithkline Biologicals Sa | Compositions and methods to evaluate the functional immunogenicity of parvovirus vaccines |
US20130039954A1 (en) | 2011-07-29 | 2013-02-14 | Selecta Biosciences, Inc. | Control of antibody responses to synthetic nanocarriers |
GB201113570D0 (en) | 2011-08-05 | 2011-09-21 | Glaxosmithkline Biolog Sa | Vaccine |
GB201114923D0 (en) | 2011-08-30 | 2011-10-12 | Novartis Ag | Immunogenic proteins and compositions |
GB201114919D0 (en) | 2011-08-30 | 2011-10-12 | Glaxosmithkline Biolog Sa | Method |
CA2789539A1 (en) | 2011-09-12 | 2013-03-12 | International Aids Vaccine Initiative | Immunoselection of recombinant vesicular stomatitis virus expressing hiv-1 proteins by broadly neutralizing antibodies |
US20150190501A1 (en) | 2011-09-12 | 2015-07-09 | Imperial Innovations Limited | Methods and compositions for raising an immune response to hiv |
EP2755994A2 (en) | 2011-09-14 | 2014-07-23 | Novartis AG | Escherichia coli vaccine combination |
TR201909110T4 (en) | 2011-09-14 | 2019-07-22 | Glaxosmithkline Biologicals Sa | Methods for making saccharide-protein glycoconjugates. |
SI2758432T1 (en) | 2011-09-16 | 2019-07-31 | Ucb Biopharma Sprl | Neutralising antibodies to the major exotoxins tcda and tcdb of clostridium difficile |
EP2586461A1 (en) | 2011-10-27 | 2013-05-01 | Christopher L. Parks | Viral particles derived from an enveloped virus |
WO2013074501A1 (en) | 2011-11-14 | 2013-05-23 | Crucell Holland B.V. | Heterologous prime-boost immunization using measles virus-based vaccines |
MX2014006630A (en) | 2011-12-08 | 2014-07-09 | Novartis Ag | Clostridium difficile toxin-based vaccine. |
WO2013108272A2 (en) | 2012-01-20 | 2013-07-25 | International Centre For Genetic Engineering And Biotechnology | Blood stage malaria vaccine |
RS58868B1 (en) | 2012-02-07 | 2019-08-30 | Infectious Disease Res Inst | Improved adjuvant formulations comprising tlr4 agonists and methods of using the same |
CN104321335A (en) | 2012-02-24 | 2015-01-28 | 诺华股份有限公司 | Pilus proteins and compositions |
US20130236484A1 (en) | 2012-03-08 | 2013-09-12 | Detectogen Inc. | Leishmaniasis antigen detection assays and vaccines |
ES2702278T3 (en) | 2012-04-01 | 2019-02-28 | Technion Res & Dev Foundation | Extracellular matrix metalloproteinase (emmprin) inducer peptides and binding antibodies |
BR112014024612A2 (en) | 2012-04-02 | 2021-06-08 | Univ North Carolina Chapel Hill | nucleic acid, polypeptide, glycoprotein and chimeric, dengue virus epitope, chimeric flavivirus-like particle (vlp), chimeric flavivirus, and in vitro methods to identify a neutralizing antibody and to identify an immunogenic composition against a dengue virus |
US10279026B2 (en) | 2012-04-26 | 2019-05-07 | Glaxosmithkline Biologicals Sa | Antigens and antigen combinations |
CN108671228A (en) | 2012-04-26 | 2018-10-19 | 诺华股份有限公司 | antigen and antigen combination |
EP2659908A1 (en) | 2012-05-01 | 2013-11-06 | Affiris AG | Compositions |
EP2659907A1 (en) | 2012-05-01 | 2013-11-06 | Affiris AG | Compositions |
EP2659906A1 (en) | 2012-05-01 | 2013-11-06 | Affiris AG | Compositions |
US9169304B2 (en) | 2012-05-01 | 2015-10-27 | Pfenex Inc. | Process for purifying recombinant Plasmodium falciparum circumsporozoite protein |
SI2844282T1 (en) | 2012-05-04 | 2019-08-30 | Pfizer Inc. | Prostate-associated antigens and vaccine-based immunotherapy regimens |
JP6619648B2 (en) | 2012-05-16 | 2019-12-11 | イミューン デザイン コーポレイション | Vaccine for HSV-2 |
SG10201608675YA (en) | 2012-05-22 | 2016-12-29 | Novartis Ag | Meningococcus serogroup x conjugate |
EP2666785A1 (en) | 2012-05-23 | 2013-11-27 | Affiris AG | Complement component C5a-based vaccine |
EP2859011B1 (en) | 2012-06-06 | 2019-12-11 | Bionor Immuno AS | Peptides derived from viral proteins for use as immunogens and dosage reactants |
ES2631608T3 (en) | 2012-06-27 | 2017-09-01 | International Aids Vaccine Initiative | Env-glycoprotein variant of HIV-1 |
EP4299138A2 (en) | 2012-08-03 | 2024-01-03 | Access to Advanced Health Institute | Compositions and methods for treating an active mycobacterium tuberculosis infection |
EP2703483A1 (en) | 2012-08-29 | 2014-03-05 | Affiris AG | PCSK9 peptide vaccine |
WO2014043189A1 (en) | 2012-09-14 | 2014-03-20 | The Regents Of The University Of Colorado, A Body Corporate | Conditionally replication deficient herpes viruses and use thereof in vaccines |
CA2882382A1 (en) | 2012-09-18 | 2014-03-27 | Novartis Ag | Outer membrane vesicles |
ES2672996T3 (en) | 2012-10-02 | 2018-06-19 | Glaxosmithkline Biologicals Sa | Non-linear saccharide conjugates |
AR092896A1 (en) | 2012-10-03 | 2015-05-06 | Novartis Ag | IMMUNOGENIC COMPOSITIONS |
EP2912186B1 (en) | 2012-10-24 | 2021-01-06 | Platelet Targeted Therapeutics LLC | Platelet targeted treatment |
WO2014083060A2 (en) | 2012-11-30 | 2014-06-05 | Novartis Ag | Pseudomonas antigens and antigen combinations |
CA2893435A1 (en) | 2012-12-05 | 2014-06-12 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
BR112015024860B1 (en) | 2013-03-28 | 2023-11-07 | Access To Advanced Health Institute | FUSION POLYPEPTIDE, ISOLATED POLYNUCLEOTIDE, COMPOSITION COMPRISING SAID POLYPEPTIDE, USE OF SAID COMPOSITION TO STIMULATE AN IMMUNE RESPONSE AGAINST LEISHMANIA AND IN VITRO METHOD AND DIAGNOSTIC KIT FOR DETECTING LEISHMANIA INFECTION IN A BIOLOGICAL SPECIMEN |
WO2014172637A1 (en) | 2013-04-18 | 2014-10-23 | Immune Design Corp. | Gla monotherapy for use in cancer treatment |
US20210145963A9 (en) | 2013-05-15 | 2021-05-20 | The Governors Of The University Of Alberta | E1e2 hcv vaccines and methods of use |
US9463198B2 (en) | 2013-06-04 | 2016-10-11 | Infectious Disease Research Institute | Compositions and methods for reducing or preventing metastasis |
GB201310008D0 (en) | 2013-06-05 | 2013-07-17 | Glaxosmithkline Biolog Sa | Immunogenic composition for use in therapy |
BR112015032388A8 (en) | 2013-06-26 | 2020-01-14 | Univ North Carolina Chapel Hill | glycoprotein and chimeric dengue virus, their uses, flavivirus particle, isolated nucleic acid molecule, and compositions |
US20150065381A1 (en) | 2013-09-05 | 2015-03-05 | International Aids Vaccine Initiative | Methods of identifying novel hiv-1 immunogens |
EP2873423B1 (en) | 2013-10-07 | 2017-05-31 | International Aids Vaccine Initiative | Soluble hiv-1 envelope glycoprotein trimers |
EP3063171B1 (en) | 2013-11-01 | 2019-07-24 | University Of Oslo | Albumin variants and uses thereof |
CA2929126C (en) | 2013-11-13 | 2020-01-07 | University Of Oslo | Outer membrane vesicles and uses thereof |
WO2015071763A2 (en) | 2013-11-15 | 2015-05-21 | Oslo Universitetssykehus Hf | Ctl peptide epitopes and antigen-specific t cells, methods for their discovery, and uses thereof |
WO2015092710A1 (en) | 2013-12-19 | 2015-06-25 | Glaxosmithkline Biologicals, S.A. | Contralateral co-administration of vaccines |
EP3092302A4 (en) | 2014-01-06 | 2017-06-07 | The United States of America, as Represented by the Secretary of Agriculture | Attenuated salmonella enterica |
RU2771293C2 (en) | 2014-01-21 | 2022-04-29 | Пфайзер Инк. | Immunogenic compositions containing conjugated capsule saccharide antigens and their use |
US11160855B2 (en) | 2014-01-21 | 2021-11-02 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
US10279019B2 (en) | 2014-02-11 | 2019-05-07 | Stc.Unm | PCSK9 peptide vaccine conjugated to a Qbeta carrier and methods of using the same |
TW201620927A (en) | 2014-02-24 | 2016-06-16 | 葛蘭素史密斯克藍生物品公司 | USPA2 protein constructs and uses thereof |
WO2015148648A1 (en) * | 2014-03-25 | 2015-10-01 | The Government Of The United States Of America As Represented By The Secretary Of The Army | Non-toxic adjuvant formulation comprising a monophosphoryl lipid a (mpla)-containing liposome composition and a saponin |
SI3160500T1 (en) | 2014-06-25 | 2019-11-29 | Glaxosmithkline Biologicals Sa | Clostridium difficile immunogenic composition |
TW201623329A (en) | 2014-06-30 | 2016-07-01 | 亞佛瑞司股份有限公司 | Vaccines and monoclonal antibodies targeting truncated variants of osteopontin and uses thereof |
EP3169699A4 (en) | 2014-07-18 | 2018-06-20 | The University of Washington | Cancer vaccine compositions and methods of use thereof |
WO2016012385A1 (en) | 2014-07-21 | 2016-01-28 | Sanofi Pasteur | Vaccine composition comprising ipv and cyclodextrins |
CA3212723A1 (en) | 2014-07-23 | 2016-01-28 | Peter T. Beernink | Factor h binding protein variants and methods of use thereof |
EP4112076A1 (en) | 2014-10-10 | 2023-01-04 | The Regents of The University of Michigan | Nanoemulsion compositions for preventing, suppressing or eliminating allergic and inflammatory disease |
BR112017008952A2 (en) | 2014-11-02 | 2018-01-16 | Univ North Carolina Chapel Hill | methods and compositions for recombinant dengue virus for vaccine development and diagnosis |
EP3229833A1 (en) | 2014-12-10 | 2017-10-18 | GlaxoSmithKline Biologicals SA | Method of treatment |
AU2016207820B2 (en) | 2015-01-15 | 2020-12-17 | Pfizer Inc. | Immunogenic compositions for use in pneumococcal vaccines |
MX2017010698A (en) | 2015-02-20 | 2018-04-30 | Univ Texas | Methods and compositions for attenuated chlamydia as vaccine and vector. |
JP2018507860A (en) * | 2015-02-26 | 2018-03-22 | ザヴァックス ジェネティクス ワクチン カンパニー リミテッドThevax Genetics Vaccine Co., Ltd. | Vaccine composition comprising a combination of an immunogenic protein and an adjuvant for inducing an antigen-specific T cell response |
WO2016141320A2 (en) | 2015-03-05 | 2016-09-09 | Northwestern University | Non-neuroinvasive viruses and uses thereof |
EP3270897A4 (en) | 2015-03-20 | 2018-12-05 | The Regents Of The University Of Michigan | Immunogenic compositions for use in vaccination against bordetella |
US10174292B2 (en) | 2015-03-20 | 2019-01-08 | International Aids Vaccine Initiative | Soluble HIV-1 envelope glycoprotein trimers |
EP3072901A1 (en) | 2015-03-23 | 2016-09-28 | International Aids Vaccine Initiative | Soluble hiv-1 envelope glycoprotein trimers |
KR20170129786A (en) | 2015-03-26 | 2017-11-27 | 지피앤 백신즈 피티와이 엘티디 | Streptococcal vaccine |
BR112017025316A2 (en) | 2015-05-26 | 2018-07-31 | Ohio State Innovation Foundation | swine flu virus nanoparticle-based vaccine strategy |
JP2018521016A (en) | 2015-06-03 | 2018-08-02 | アフィリス・アクチェンゲゼルシャフトAffiris Ag | IL-23-p19 vaccine |
AU2016281904B2 (en) | 2015-06-26 | 2022-08-11 | Seqirus UK Limited | Antigenically matched influenza vaccines |
RU2018104362A (en) | 2015-07-07 | 2019-08-08 | Аффирис Аг | VACCINES FOR TREATMENT AND PREVENTION OF IgE-MEDIATED DISEASES |
TWI684460B (en) | 2015-07-21 | 2020-02-11 | 美商輝瑞股份有限公司 | Immunogenic compositions comprising conjugated capsular saccharide antigens, kits comprising the same and uses thereof |
WO2017062246A1 (en) | 2015-10-05 | 2017-04-13 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Human rota virus g9p[6] strain and use as a vaccine |
GB201518668D0 (en) | 2015-10-21 | 2015-12-02 | Glaxosmithkline Biolog Sa | Immunogenic Comosition |
EP3377098A1 (en) | 2015-11-20 | 2018-09-26 | Pfizer Inc | Immunogenic compositions for use in pneumococcal vaccines |
WO2017109698A1 (en) | 2015-12-22 | 2017-06-29 | Glaxosmithkline Biologicals Sa | Immunogenic formulation |
KR20200109395A (en) | 2016-01-19 | 2020-09-22 | 화이자 인코포레이티드 | Cancer vaccines |
WO2017137085A1 (en) | 2016-02-11 | 2017-08-17 | Sanofi Pasteur | Meningitidis vaccines comprising subtilinases |
CA3017356A1 (en) | 2016-03-10 | 2017-09-14 | Aperisys, Inc. | Antigen-binding fusion proteins with modified hsp70 domains |
GEP20217232B (en) | 2016-03-14 | 2021-03-25 | I Oslo Universitetet | Engineered immunoglobulins with altered fcrn binding |
WO2017158421A1 (en) | 2016-03-14 | 2017-09-21 | University Of Oslo | Anti-viral engineered immunoglobulins |
DK3458475T3 (en) | 2016-05-16 | 2022-09-12 | Access To Advanced Health Inst | FORMULATION CONTAINING TLR AGONIST AND METHODS OF USE |
US11173207B2 (en) | 2016-05-19 | 2021-11-16 | The Regents Of The University Of Michigan | Adjuvant compositions |
WO2017205225A2 (en) | 2016-05-21 | 2017-11-30 | Infectious Disease Research Institute | Compositions and methods for treating secondary tuberculosis and nontuberculous mycobacterium infections |
IL298227A (en) | 2016-06-01 | 2023-01-01 | Access To Advanced Health Inst | Nanoalum particles containing a sizing agent |
US11780924B2 (en) | 2016-06-21 | 2023-10-10 | University Of Oslo | HLA binding vaccine moieties and uses thereof |
BR112019003462A2 (en) | 2016-08-23 | 2019-06-25 | Glaxosmithkline Biologicals Sa | fusion protein, polynucleotide, viral vector, pharmaceutical composition, use of a fusion protein, polynucleotide, viral vector or pharmaceutical composition, and method for treating or preventing viral hepatitis b infection or viral hepatitis c infection |
GB201614799D0 (en) | 2016-09-01 | 2016-10-19 | Glaxosmithkline Biologicals Sa | Compositions |
BR112019004913B1 (en) | 2016-09-16 | 2022-07-12 | Infectious Disease Research Institute | VACCINES COMPRISING MYCOBACTERIUM LEPRAE POLYPEPTIDES FOR THE PREVENTION, TREATMENT AND DIAGNOSIS OF LEPRO |
BE1024774B1 (en) | 2016-09-29 | 2018-07-02 | Glaxosmithkline Biologicals Sa | COMPOSITIONS AND METHODS OF TREATMENT |
WO2018096396A1 (en) | 2016-11-22 | 2018-05-31 | University Of Oslo | Albumin variants and uses thereof |
GB201620968D0 (en) | 2016-12-09 | 2017-01-25 | Glaxosmithkline Biologicals Sa | Adenovirus polynucleotides and polypeptides |
GB201621686D0 (en) * | 2016-12-20 | 2017-02-01 | Glaxosmithkline Biologicals Sa | Novel methods for inducing an immune response |
BR112019014833A2 (en) | 2017-01-20 | 2020-04-14 | Pfizer | immunogenic compositions for use in pneumococcal vaccines |
BR112019020209A2 (en) | 2017-03-31 | 2020-06-02 | Glaxosmithkline Intellectual Property Development Limited | IMMUNOGENIC COMPOSITION, USE OF AN IMMUNOGENIC COMPOSITION, METHOD OF TREATING OR PREVENTING A RECURRENCE OF AN ACUTE EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND COMBINATION THERAPY. |
WO2018178265A1 (en) | 2017-03-31 | 2018-10-04 | Glaxosmithkline Intellectual Property Development Limited | Immunogenic composition, use and method of treatment |
US11583578B2 (en) | 2017-04-28 | 2023-02-21 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Plasmodium falciparum recombinanr xiexumapoeozoite protein compositions and method for vaccine delivery |
JP2020530478A (en) | 2017-08-14 | 2020-10-22 | グラクソスミスクライン バイオロジカルズ ソシエテ アノニム | How to Strengthen the Immune Response |
US11123415B2 (en) | 2017-08-16 | 2021-09-21 | Ohio State Innovation Foundation | Nanoparticle compositions for Salmonella vaccines |
US20220118076A1 (en) | 2017-09-07 | 2022-04-21 | University Of Oslo | Vaccine molecules |
WO2019048936A1 (en) | 2017-09-07 | 2019-03-14 | University Of Oslo | Vaccine molecules |
WO2019051149A1 (en) | 2017-09-08 | 2019-03-14 | Infectious Disease Research Institute | Liposomal formulations comprising saponin and methods of use |
WO2019052975A1 (en) | 2017-09-13 | 2019-03-21 | Sanofi Pasteur | Human cytomegalovirus immunogenic composition |
WO2019079594A1 (en) | 2017-10-18 | 2019-04-25 | The University Of North Carolina At Chapel Hill | Methods and compositions for norovirus vaccines and diagnostics |
GB201721069D0 (en) | 2017-12-15 | 2018-01-31 | Glaxosmithkline Biologicals Sa | Hepatitis B Immunisation regimen and compositions |
GB201721068D0 (en) | 2017-12-15 | 2018-01-31 | Glaxosmithkline Biologicals Sa | Hepatitis B immunisation regimen and compositions |
US11633471B2 (en) | 2018-03-06 | 2023-04-25 | Unm Rainforest Innovations | Compositions and methods for reducing serum triglycerides |
WO2019175145A1 (en) | 2018-03-12 | 2019-09-19 | Janssen Vaccines & Prevention B.V. | Vaccines against urinary tract infections |
US11702674B2 (en) | 2018-06-12 | 2023-07-18 | Glaxosmithkline Biologicals Sa | Simian adenovirus vectors comprising the ChAd-157 fiber protein |
BR112021000965A2 (en) | 2018-08-07 | 2021-04-27 | Glaxosmithkline Biologicals S.A. | processes and vaccines |
US20210220462A1 (en) | 2018-08-23 | 2021-07-22 | Glaxosmithkline Biologicals Sa | Immunogenic proteins and compositions |
US11260119B2 (en) | 2018-08-24 | 2022-03-01 | Pfizer Inc. | Escherichia coli compositions and methods thereof |
EP3851120A4 (en) | 2018-09-11 | 2022-04-27 | Shanghai Public Health Clinical Center | Immunogen for broad-spectrum influenza vaccine and application thereof |
US20220000779A1 (en) | 2018-12-06 | 2022-01-06 | Glaxosmithkline Biologicals Sa | Immunogenic compositions |
EP3893926A1 (en) | 2018-12-12 | 2021-10-20 | Pfizer Inc. | Immunogenic multiple hetero-antigen polysaccharide-protein conjugates and uses thereof |
US20220184158A1 (en) | 2018-12-21 | 2022-06-16 | Glaxosmithkline Biologicals Sa | Methods of inducing an immune response |
GB201901608D0 (en) | 2019-02-06 | 2019-03-27 | Vib Vzw | Vaccine adjuvant conjugates |
JP7239509B6 (en) | 2019-02-22 | 2023-03-28 | ファイザー・インク | Method for purifying bacterial polysaccharides |
CN113573730A (en) | 2019-03-05 | 2021-10-29 | 葛兰素史密斯克莱生物公司 | Hepatitis B immunization protocols and compositions |
KR102574882B1 (en) | 2019-03-18 | 2023-09-04 | 얀센 파마슈티칼즈, 인코포레이티드 | Methods for producing bioconjugates of E. coli O-antigen polysaccharides, compositions thereof and methods of use thereof |
CR20210522A (en) | 2019-03-18 | 2021-12-17 | Janssen Pharmaceuticals Inc | Bioconjugates of e. coli o-antigen polysaccharides, methods of production thereof, and methods of use thereof |
WO2020208502A1 (en) | 2019-04-10 | 2020-10-15 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens, kits comprising the same and uses thereof |
US20220221455A1 (en) | 2019-04-18 | 2022-07-14 | Glaxosmithkline Biologicals Sa | Antigen binding proteins and assays |
CN114667158A (en) | 2019-08-05 | 2022-06-24 | 葛兰素史克生物有限公司 | Immunogenic compositions |
EP3777884A1 (en) | 2019-08-15 | 2021-02-17 | GlaxoSmithKline Biologicals S.A. | Immunogenic composition |
EP3799884A1 (en) | 2019-10-01 | 2021-04-07 | GlaxoSmithKline Biologicals S.A. | Immunogenic compositions |
KR20220107166A (en) | 2019-10-02 | 2022-08-02 | 얀센 백신스 앤드 프리벤션 비.브이. | Staphylococcus Peptides and Methods of Use |
IL292494A (en) | 2019-11-01 | 2022-06-01 | Pfizer | Escherichia coli compositions and methods thereof |
WO2021122551A1 (en) | 2019-12-19 | 2021-06-24 | Glaxosmithkline Biologicals Sa | S. aureus antigens and compositions thereof |
CN115038461A (en) | 2020-01-16 | 2022-09-09 | 杨森制药公司 | FimH mutants, compositions thereof, and uses thereof |
EP4093873A1 (en) | 2020-01-24 | 2022-11-30 | Aim Immunotech Inc. | Methods, compositions, and vaccines for treating a virus infection |
WO2021160887A1 (en) | 2020-02-14 | 2021-08-19 | Immunor As | Corona virus vaccine |
WO2021165847A1 (en) | 2020-02-21 | 2021-08-26 | Pfizer Inc. | Purification of saccharides |
BR112022014555A2 (en) | 2020-02-23 | 2022-09-20 | Pfizer | COMPOSITIONS OF ESCHERICHIA COLI AND METHODS THEREOF. |
WO2022029024A1 (en) | 2020-08-03 | 2022-02-10 | Glaxosmithkline Biologicals Sa | Truncated fusobacterium nucleatum fusobacterium adhesin a (fada) protein and immunogenic compositios thereof |
AU2021342797B2 (en) | 2020-09-17 | 2024-02-08 | Janssen Pharmaceuticals, Inc. | Multivalent vaccine compositions and uses thereof |
US11225508B1 (en) | 2020-09-23 | 2022-01-18 | The University Of North Carolina At Chapel Hill | Mouse-adapted SARS-CoV-2 viruses and methods of use thereof |
WO2022083760A1 (en) | 2020-10-23 | 2022-04-28 | 江苏省疾病预防控制中心(江苏省公共卫生研究院) | Fusion protein and application thereof |
IL302362A (en) | 2020-10-27 | 2023-06-01 | Pfizer | Escherichia coli compositions and methods thereof |
IL302413A (en) | 2020-11-04 | 2023-06-01 | Pfizer | Immunogenic compositions for use in pneumococcal vaccines |
JP2023549736A (en) | 2020-11-10 | 2023-11-29 | ファイザー・インク | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
US20220202923A1 (en) | 2020-12-23 | 2022-06-30 | Pfizer Inc. | E. coli fimh mutants and uses thereof |
WO2022147373A1 (en) | 2020-12-31 | 2022-07-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Antibody-guided pcsk9-mimicking immunogens lacking 9-residue sequence overlap with human proteins |
AU2022207740A1 (en) | 2021-01-12 | 2023-06-29 | Janssen Pharmaceuticals, Inc. | Fimh mutants, compositions therewith and use thereof |
EP4277654A1 (en) | 2021-01-18 | 2023-11-22 | Conserv Bioscience Limited | Coronavirus immunogenic compositions, methods and uses thereof |
WO2022178196A1 (en) | 2021-02-19 | 2022-08-25 | Sanofi Pasteur Inc. | Meningococcal b recombinant vaccine |
WO2022175423A1 (en) | 2021-02-22 | 2022-08-25 | Glaxosmithkline Biologicals Sa | Immunogenic composition, use and methods |
UY39710A (en) | 2021-04-01 | 2022-09-30 | Janssen Pharmaceuticals Inc | PRODUCTION OF E. COLI O18 BIOCONJUGATES |
US20220387576A1 (en) | 2021-05-28 | 2022-12-08 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
US20220387613A1 (en) | 2021-05-28 | 2022-12-08 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
WO2023092090A1 (en) | 2021-11-18 | 2023-05-25 | Matrivax, Inc. | Immunogenic fusion protein compositions and methods of use thereof |
WO2023135515A1 (en) | 2022-01-13 | 2023-07-20 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
WO2023161817A1 (en) | 2022-02-25 | 2023-08-31 | Pfizer Inc. | Methods for incorporating azido groups in bacterial capsular polysaccharides |
WO2023218322A1 (en) | 2022-05-11 | 2023-11-16 | Pfizer Inc. | Process for producing of vaccine formulations with preservatives |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4235877A (en) | 1979-06-27 | 1980-11-25 | Merck & Co., Inc. | Liposome particle containing viral or bacterial antigenic subunit |
US4372945A (en) | 1979-11-13 | 1983-02-08 | Likhite Vilas V | Antigen compounds |
IL61904A (en) | 1981-01-13 | 1985-07-31 | Yeda Res & Dev | Synthetic vaccine against influenza virus infections comprising a synthetic peptide and process for producing same |
NZ209308A (en) | 1983-08-30 | 1991-08-27 | Genentech Inc | Vaccine against hsv involving a truncated membrane-free derivative of a membrane-bound protein |
FI861417A0 (en) | 1985-04-15 | 1986-04-01 | Endotronics Inc | HEPATITIS B YTANTIGEN FRAMSTAELLD MED REKOMBINANT-DNA-TEKNIK, VACCIN, DIAGNOSTISKT MEDEL OCH CELLINJER SAMT FOERFARANDEN FOER FRAMSTAELLNING DAERAV. |
US4895800A (en) | 1985-11-26 | 1990-01-23 | Phillips Petroleum Company | Yeast production of hepatitis B surface antigen |
US4877611A (en) * | 1986-04-15 | 1989-10-31 | Ribi Immunochem Research Inc. | Vaccine containing tumor antigens and adjuvants |
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
EP0304578B1 (en) | 1987-06-22 | 2001-10-24 | Medeva Holdings Bv | Peptide comprising hepatitis B surface antigen |
ATE105858T1 (en) | 1987-07-17 | 1994-06-15 | Rhein Biotech Ges Fuer Biotech | DNA MOLECULES ENCODING FMDH CONTROL PART AND STRUCTURAL GENES FOR A PROTEIN WITH FMDH ACTIVITY AND THEIR APPLICATIONS. |
DE68927783T2 (en) * | 1988-05-03 | 1997-09-25 | Wang Laboratories | MICROPROCESSOR WITH EXTERNAL CONTROL MEMORY |
US4912094B1 (en) * | 1988-06-29 | 1994-02-15 | Ribi Immunochem Research Inc. | Modified lipopolysaccharides and process of preparation |
SG48175A1 (en) | 1989-07-25 | 1998-04-17 | Smithkline Beecham Biolog | Novel antigens and method for their preparation |
CA2123612C (en) | 1991-11-16 | 2002-06-25 | Michel De Wilde | Hybrid protein between cs from plasmodium and h bsag |
CZ282235B6 (en) * | 1992-06-25 | 1997-06-11 | Smithkline Beecham Biologicals (S.A.) | Inoculation substance, process of its preparation and use |
-
1993
- 1993-06-15 CZ CZ943296A patent/CZ282235B6/en not_active IP Right Cessation
- 1993-06-15 JP JP50200594A patent/JP3755890B2/en not_active Expired - Lifetime
- 1993-06-15 EP EP96203085A patent/EP0761231B1/en not_active Expired - Lifetime
- 1993-06-15 US US08/356,372 patent/US5750110A/en not_active Expired - Lifetime
- 1993-06-15 DK DK96203085T patent/DK0761231T3/en active
- 1993-06-15 SG SG9901248A patent/SG90042A1/en unknown
- 1993-06-15 SK SK1592-94A patent/SK279188B6/en not_active IP Right Cessation
- 1993-06-15 RU RU94046232A patent/RU2118164C1/en active
- 1993-06-15 CA CA002138997A patent/CA2138997C/en not_active Expired - Lifetime
- 1993-06-15 AT AT93912990T patent/ATE156710T1/en active
- 1993-06-15 AU AU43263/93A patent/AU661404B2/en not_active Expired
- 1993-06-15 UA UA95018058A patent/UA40597C2/en unknown
- 1993-06-15 SG SG1996009012A patent/SG49909A1/en unknown
- 1993-06-15 AT AT96203085T patent/ATE188613T1/en active
- 1993-06-15 HU HU9403778A patent/HU219808B/en unknown
- 1993-06-15 KR KR1019940704740A patent/KR100278157B1/en not_active IP Right Cessation
- 1993-06-15 ES ES93912990T patent/ES2108278T3/en not_active Expired - Lifetime
- 1993-06-15 ES ES96203085T patent/ES2143716T3/en not_active Expired - Lifetime
- 1993-06-15 PL PL93306722A patent/PL170980B1/en unknown
- 1993-06-15 NZ NZ253137A patent/NZ253137A/en not_active IP Right Cessation
- 1993-06-15 EP EP93912990A patent/EP0671948B1/en not_active Expired - Lifetime
- 1993-06-15 DE DE69313134T patent/DE69313134T2/en not_active Expired - Lifetime
- 1993-06-15 WO PCT/EP1993/001524 patent/WO1994000153A1/en active IP Right Grant
- 1993-06-15 DE DE69327599T patent/DE69327599T2/en not_active Expired - Lifetime
- 1993-06-15 PT PT96203085T patent/PT761231E/en unknown
- 1993-06-15 DK DK93912990.4T patent/DK0671948T3/en active
- 1993-06-22 MY MYPI93001207A patent/MY109278A/en unknown
- 1993-06-23 MX MX9303773A patent/MX9303773A/en unknown
- 1993-06-23 SI SI9300335A patent/SI9300335B/en unknown
- 1993-06-23 MA MA23212A patent/MA22911A1/en unknown
- 1993-06-23 IL IL10610993A patent/IL106109A/en not_active IP Right Cessation
- 1993-06-24 AP APAP/P/1993/000541A patent/AP408A/en active
- 1993-06-24 CN CN93107990A patent/CN1122530C/en not_active Expired - Lifetime
-
1994
- 1994-12-23 FI FI946064A patent/FI109767B/en not_active IP Right Cessation
- 1994-12-23 NO NO19945003A patent/NO317546B1/en not_active IP Right Cessation
-
1997
- 1997-08-12 US US08/909,879 patent/US7147862B1/en not_active Expired - Fee Related
- 1997-10-29 GR GR970402819T patent/GR3025184T3/en unknown
-
1998
- 1998-09-24 HK HK98110943A patent/HK1010097A1/en not_active IP Right Cessation
- 1998-09-24 HK HK99105834A patent/HK1022074A1/en not_active IP Right Cessation
-
2000
- 2000-02-23 GR GR20000400442T patent/GR3032742T3/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2138997C (en) | Vaccine composition containing adjuvants | |
US7169391B2 (en) | Vaccines | |
AU687494C (en) | Vaccines |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |