US20090010959A1 - Pneumococcal Polysaccharide Conjugate Vaccine - Google Patents
Pneumococcal Polysaccharide Conjugate Vaccine Download PDFInfo
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- US20090010959A1 US20090010959A1 US12/097,303 US9730306A US2009010959A1 US 20090010959 A1 US20090010959 A1 US 20090010959A1 US 9730306 A US9730306 A US 9730306A US 2009010959 A1 US2009010959 A1 US 2009010959A1
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Definitions
- the present invention relates to an improved Streptococcus pneumoniae vaccine.
- the B-cells to the carrier protein predominate, there are not enough Th-cells available to provide the necessary help for the B-cells specific to the polysaccharide.
- the observed immunological effects have been inconsistent, with the total amount of carrier protein in some instances increasing the immune response, and in other cases diminishing the immune response.
- Streptococcus pneumoniae is a Gram-positive bacterium responsible for considerable morbidity and mortality (particularly in the young and aged), causing invasive diseases such as pneumonia, bacteraemia and meningitis, and diseases associated with colonisation, such as acute Otitis media.
- the rate of pneumococcal pneumonia in the US for persons over 60 years of age is estimated to be 3 to 8 per 100,000. In 20% of cases this leads to bacteraemia, and other manifestations such as meningitis, with a mortality rate close to 30% even with antibiotic treatment.
- Pneumococcus is encapsulated with a chemically linked polysaccharide which confers serotype specificity.
- a chemically linked polysaccharide which confers serotype specificity.
- serotypes of pneumococci There are 90 known serotypes of pneumococci, and the capsule is the principle virulence determinant for pneumococci, as the capsule not only protects the inner surface of the bacteria from complement, but is itself poorly immunogenic.
- Polysaccharides are T-independent antigens, and can not be processed or presented on MHC molecules to interact with T-cells. They can however, stimulate the immune system through an alternate mechanism which involves cross-linking of surface receptors on B cells.
- Streptococcus pneumoniae is the most common cause of invasive bacterial disease and Otitis media in infants and young children. Likewise, the elderly mount poor responses to pneumococcal vaccines [Roghmann et al., (1987), J. Gerontol. 42:265-270], hence the increased incidence of bacterial pneumonia in this population [Verghese and Berk, (1983) Medicine (Baltimore) 62:271-285].
- IPD Invasive pneumococcal disease
- COPD chronic obstructive pulmonary disease
- airflow obstruction chronic bronchitis, bronchiolitis or small airways disease and emphysema
- Patients suffer exacerbations of their condition that are usually associated with increased breathlessness, and often have increased cough that may be productive of mucus or purulent sputum (Wilson, Eur Respir J 2001 17:995-1007).
- COPD is defined physiologically by the presence of irreversible or partially reversible airway obstruction in patients with chronic bronchitis and/or emphysema (Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am J Respir Crit.
- FIG. 1 Bar chart showing 11 valent conjugate immunogenicity in elderly Rhesus monkeys.
- the lighter bars represent the GMC after two inoculations with 11 valent conjugate in aluminium phosphate adjuvant.
- the darker bars represent the GMC after two inoculations with 11 valent conjugate in adjuvant C.
- FIG. 2 Bar chart showing memory B cells for PS3 after inoculation with the 11 valent conjugate in adjuvant C or aluminium phosphate adjuvant.
- FIG. 3 Bar chart showing anti polysaccharide 19F immunogenicity in Balb/C mice for the 4-valent plain polysaccharides and the 4-valent dPly conjugates.
- FIG. 4 Bar chart showing anti polysaccharide 22F immunogenicity in Balb/C mice for the 4-valent plain polysaccharides and the 4-valent PhtD conjugates.
- FIG. 5 Bar chart showing anti-22F IgG response in Balb/c mice
- FIG. 6 Bar chart showing anti-22F opsono-phagocytosis titres in Balb/c mice.
- FIG. 7 Bar chart comparing IgG responses induced in young C57B1 mice after immunisation with 13 Valent conjugate vaccine formulated in different adjuvants.
- FIG. 8 Bar chart showing the protective efficacy of different vaccine combinations in a monkey pneumonia model.
- FIG. 9 Bar chart showing anti PhtD IgG response in Balb/c mice after immunisation with 22F-PhtD or 22F-AH-PhtD conjugates.
- FIG. 10 Protection against type 4 pneumococcal challenge in mice after immunisation with 22F-PhtD or 22F-AH-PhtD.
- the present invention provides an improved Streptococcus pneumoniae vaccine comprising 10 or more (e.g. 11, 12, 13, 14, or 15 or more) capsular saccharides from different S. pneumoniae serotypes conjugated to 2 or more carrier proteins, wherein the vaccine comprises serotype 19F capsular saccharide conjugated to diphtheria toxoid or CRM197, and wherein the vaccine optionally further comprises protein D from Haemophilus influenzae as free protein or as a further carrier protein or both.
- 10 or more e.g. 11, 12, 13, 14, or 15 or more
- capsular saccharides from different S. pneumoniae serotypes conjugated to 2 or more carrier proteins
- the vaccine comprises serotype 19F capsular saccharide conjugated to diphtheria toxoid or CRM197
- the vaccine optionally further comprises protein D from Haemophilus influenzae as free protein or as a further carrier protein or both.
- “immunizing a human host against exacerbations of COPD” or “treatment or prevention of exacerbations of COPD” or “reduction in severity of COPD exacerbations” refers to a reduction in incidence or rate of COPD exacerbations (for instance a reduction in rate of 0.1, 0.5, 1, 2, 5, 10, 20% or more) or a reduction in severity of COPD exacerbations as defined above, for instance within a patient group immunized with the compositions or vaccines of the invention.
- the Streptococcus pneumoniae vaccine of the present invention will comprise capsular saccharide antigens (preferably conjugated), wherein the saccharides are derived from at least ten serotypes of S. pneumoniae .
- the number of S. pneumoniae capsular saccharides can range from 10 different serotypes (or “V”, valences) to 23 different serotypes (23V). In one embodiment there are 10, 11, 12, 13, 14 or 15 different serotypes.
- the vaccine may comprise conjugated S. pneumoniae saccharides and unconjugated S. pneumoniae saccharides.
- the total number of saccharide serotypes is less than or equal to 23.
- the invention may comprise 10 conjugated serotypes and 13 unconjugated saccharides.
- the vaccine may comprise 11, 12, 13, 14, 15 or 16 conjugated saccharides and 12, 11, 10, 9, 8 or 7, respectively, unconjugated saccharides.
- the multivalent pneumococcal vaccine of the invention will be selected from the following serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F, although it is appreciated that one or two other serotypes could be substituted depending on the age of the recipient receiving the vaccine and the geographical location where the vaccine will be administered, e.g. serotype 6A may be included on the list.
- an 10-valent vaccine may comprise polysaccharides from serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F.
- An 11-valent vaccine may also include saccharides from serotype 3.
- a 12 or 13-valent paediatric (infant) vaccine may also include the 10 or 11 valent formulation supplemented with serotypes 6A and 19A, or 6A and 22F, or 19A and 22F, or 6A and 15B, or 19A and 15B, or 22F and 15B, whereas a 13-valent elderly vaccine may include the 11 valent formulation supplemented with serotypes 19A and 22F, 8 and 12F, or 8 and 15B, or 8 and 19A, or 8 and 22F, or 12F and 15B, or 12F and 19A, or 12F and 22F, or 15B and 19A, or 15B and 22F.
- a 14 valent pediatric vaccine may include the 10 valent formulation described above supplemented with serotypes 3, 6A, 19A and 22F; serotypes 6A, 8, 19A and 22F; serotypes 6A, 12F, 19A and 22F; serotypes 6A, 15B, 19A and 22F; serotypes 3, 8, 19A and 22F; serotypes 3, 12F, 19A and 22F; serotypes 3, 15B, 19A and 22F; serotypes 3, 6A, 8 and 22F; serotypes 3, 6A, 12F and 22F; or serotypes 3, 6A, 15B and 22F.
- composition in one embodiment includes capsular saccharides derived from serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (preferably conjugated).
- at least 11 saccharide antigens are included, for example capsular saccharides derived from serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F.
- a vaccine may comprise capsular saccharides derived from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F or capsular saccharides derived from serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F and 23F, although further saccharide antigens, for example 23 valent (such as serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F), are also contemplated by the invention.
- 23 valent such as serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F
- the vaccine of the present invention may comprise protein D (PD) from Haemophilus influenzae (see e.g. EP 0594610).
- Haemophilus influenzae is a key causative organism of otitis media, and the present inventors have shown that including this protein in a Streptococcus pneumoniae vaccine will provide a level of protection against Haemophilus influenzae related otitis media (reference POET publication).
- the vaccine composition comprises protein D.
- PD is present as a carrier protein for one or more of the saccharides.
- protein D could be present in the vaccine composition as a free protein.
- protein D is present both as a carrier protein and as free protein.
- Protein D may be used as a full length protein or as a fragment (WO0056360).
- protein D is present as a carrier protein for the majority of the saccharides, for example 6, 7, 8, 9 or more of the saccharides may be conjugated to protein D.
- protein D may also be present as free protein.
- the vaccine of the present invention comprises two or more different types of carrier protein.
- Each type of carrier protein may act as carrier for more than one saccharide, which saccharides may be the same or different.
- saccharides may be the same or different.
- serotypes 3 and 4 may be conjugated to the same carrier protein, either to the same molecule of carrier protein or to different molecules of the same carrier protein.
- two or more different saccharides may be conjugated to the same carrier protein, either to the same molecule of carrier protein or to different molecules of the same carrier protein.
- Each Streptococcus pneumoniae capsular saccharide may be conjugated to a carrier protein independently selected from the group consisting of TT, DT, CRM197, fragment C of TT, PhtD, PhtDE fusions (particularly those described in WO 01/98334 and WO 03/54007), detoxified pneumolysin and protein D, other than saccharide from serotype 19F which is always conjugated to DT or CRM 197, preferably DT.
- a carrier protein independently selected from the group consisting of TT, DT, CRM197, fragment C of TT, PhtD, PhtDE fusions (particularly those described in WO 01/98334 and WO 03/54007), detoxified pneumolysin and protein D, other than saccharide from serotype 19F which is always conjugated to DT or CRM 197, preferably DT.
- the saccharides could be conjugated to the same molecule of the protein carrier (carrier molecules having 2 more different saccharides conjugated to it) [see for instance WO 04/083251].
- the saccharides may each be separately conjugated to different molecules of the protein carrier (each molecule of protein carrier only having one type of saccharide conjugated to it).
- the carrier protein conjugated to one or more of the S. pneumoniae capsular saccharides in the conjugates present in the immunogenic compositions of the invention is optionally a member of the polyhistidine triad family (Pht) proteins, fragments or fusion proteins thereof.
- the PhtA, PhtB, PhtD or PhtE proteins may have an amino acid sequence sharing 80%, 85%, 90%, 95%, 98%, 99% or 100% identity with a sequence disclosed in WO 00/37105 or WO 00/39299 (e.g. with amino acid sequence 1-838 or 21-838 of SEQ ID NO: 4 of WO 00/37105 for PhtD).
- fusion proteins are composed of full length or fragments of 2, 3 or 4 of PhtA, PhtB, PhtD, PhtE.
- fusion proteins are PhtA/B, PhtA/D, PhtA/E, PhtB/A, PhtB/D, PhtB/E. PhtD/A. PhtD/B, PhtD/E, PhtE/A, PhtE/B and PhtE/D, wherein the proteins are linked with the first mentioned at the N-terminus (see for example WO01/98334).
- each fragment optionally contains one or more histidine triad motif(s) and/or coiled coil regions of such polypeptides.
- a histidine triad motif is the portion of polypeptide that has the sequence HxxHxH where H is histidine and x is an amino acid other than histidine.
- a coiled coil region is a region predicted by “Coils” algorithm Lupus, A et al (1991) Science 252; 1162-1164.
- the or each fragment includes one or more histidine triad motif as well as at least one coiled coil region.
- the or each fragment contains exactly or at least 2, 3, 4 or 5 histidine triad motifs (optionally, with native Pht sequence between the 2 or more triads, or intra-triad sequence that is more than 50, 60, 70, 80, 90 or 100% identical to a native pneumococcal intra-triad Pht sequence—e.g. the intra-triad sequence shown in SEQ ID NO: 4 of WO 00/37105 for PhtD).
- the or each fragment contains exactly or at least 2, 3 or 4 coiled coil regions.
- a Pht protein disclosed herein includes the full length protein with the signal sequence attached, the mature full length protein with the signal peptide (for example 20 amino acids at N-terminus) removed, naturally occurring variants of Pht protein and immunogenic fragments of Pht protein (e.g. fragments as described above or polypeptides comprising at least 15 or 20 contiguous amino acids from an amino acid sequence in WO00/37105 or WO00/39299 wherein said polypeptide is capable of eliciting an immune response specific for said amino acid sequence in WO00/37105 or WO00/39299).
- PhtD includes the full length protein with the signal sequence attached, the mature full length protein with the signal peptide (for example 20 amino acids at N-terminus) removed, naturally occurring variants of PhtD and immunogenic fragments of PhtD (e.g. fragments as described above or polypeptides comprising at least 15 or 20 contiguous amino acids from a PhtD amino acid sequence in WO00/37105 or WO00/39299 wherein said polypeptide is capable of eliciting an immune response specific for said PhtD amino acid sequence in WO00/37105 or WO00/39299 (e.g. SEQ ID NO: 4 of WO 00/37105 for PhtD).
- the saccharides could be conjugated to the same molecule of the protein carrier (carrier molecules having 2 more different saccharides conjugated to it) [see for instance WO 04/083251].
- the saccharides may each be separately conjugated to different molecules of the protein carrier (each molecule of protein carrier only having one type of saccharide conjugated to it).
- carrier proteins which may be used in the present invention are DT (Diphtheria toxoid), TT (tetanus toxid) or fragment C of TT, DT CRM197 (a DT mutant) other DT point mutants, such as CRM176, CRM228, CRM 45 (Uchida et al J. Biol. Chem.
- meningitidis serogroup B EP0372501
- PorB from N. meningitidis
- PD Haemophilus influenzae protein D—see, e.g., EP 0 594 610 B), or immunologically functional equivalents thereof, synthetic peptides (EP0378881, EP0427347), heat shock proteins (WO 93/17712, WO 94/03208), pertussis proteins (WO 98/58668, EP0471177), cytokines, lymphokines, growth factors or hormones (WO 91/01146), artificial proteins comprising multiple human CD4+ T cell epitopes from various pathogen derived antigens (Falugi et al (2001) Eur J Immunol 31; 3816-3824) such as N19 protein (Baraldoi et al (2004) Infect Immun 72; 4884-7) pneumococcal surface protein PspA (WO 02/091998), iron uptake proteins (WO 01/72337), toxin A or B of C. diff
- the remaining saccharide serotypes of the immunogenic composition may all be conjugated to one or more carrier proteins that are not DT (i.e. only 19F is conjugated to DT), or may be split between one or more carrier proteins that are not DT and DT itself.
- 19F is conjugated to DT or CRM 197 and all of the remaining serotypes are conjugated to PD.
- 19F is conjugated to DT or CRM 197, and the remaining serotypes are split between PD, and TT or DT or CRM 197.
- 19F is conjugated to DT or CRM 197 and no more than one saccharide is conjugated to TT.
- said one saccharide is 18C or 12F.
- 19F is conjugated to DT or CRM 197 and no more than two saccharides are conjugated to TT. In a further embodiment, 19F is conjugated to DT or CRM 197, and the remaining serotypes are split between PD, TT and DT or CRM 197. In a further embodiment, 19F is conjugated to DT or CRM 197, and the remaining serotypes are split between PD, TT and pneumolysin. In a further embodiment, 19F is conjugated to DT or CRM 197, and the remaining serotypes are split between PD, TT and CRM 197.
- 19F is conjugated to DT or CRM197 and the remaining serotypes are split between PD, TT, pneumolysin and optionally PhtD or PhtD/E fusion protein.
- 19F is conjugated to DT or CRM197, 19A is conjugated to pneumolysin or TT, one (two or three) further saccharide(s) is conjugated to TT, one further saccharide is conjugated to PhtD or PhtD/E and all further saccharides are conjugated to PD.
- 19F is conjugated to DT or CRM197
- 19A is conjugated to pneumolysin
- one (two or three) further saccharide(s) is conjugated to TT
- one further saccharide is conjugated to pneumolysin
- 2 further saccharides are conjugated to PhtD or PhtD/E and all further saccharides are conjugated to PD.
- the immunogenic composition of the invention comprises protein D from Haemophilus influenzae .
- PD is not one of the carrier proteins used to conjugate any saccharides other than 19F, for example 19F is conjugated to DT whilst the other serotypes are conjugated to one or more different carrier proteins which are not PD, then PD will be present in the vaccine composition as free protein. If PD is one of the carrier proteins used to conjugate saccharides other than 19F, then PD may optionally be present in the vaccine composition as free protein.
- saccharide throughout this specification may indicate polysaccharide or oligosaccharide and includes both.
- Polysaccharides are isolated from bacteria and may be sized to some degree by known methods (see for example EP497524 and EP497525) and preferably by microfluidisation. Polysaccharides can be sized in order to reduce viscosity in polysaccharide samples and/or to improve filterability for conjugated products. Oligosaccharides have a low number of repeat units (typically 5-30 repeat units) and are typically hydrolysed polysaccharides
- Capsular polysaccharides of Streptococcus pneumoniae comprise repeating oligosaccharide units which may contain up to 8 sugar residues.
- oligosaccharide units for the key Streptococcus pneumoniae serotypes see JONES, Christopher. Vaccines based on the cell surface carbohydrates of pathogenic bacteria. An. Acad. Bras. Ciênc ., June 2005, vol. 77, no. 2, p. 293-324. ISSN 0001-3765.
- a capsular saccharide antigen may be a full length polysaccharide, however in others it may be one oligosaccharide unit, or a shorter than native length saccharide chain of repeating oligosaccharide units.
- all of the saccharides present in the vaccine are polysaccharides.
- Full length polysaccharides may be “sized” i.e. their size may be reduced by various methods such as acid hydrolysis treatment, hydrogen peroxide treatment, sizing by Emulsiflex® followed by a hydrogen peroxide treatment to generate oligosaccharide fragments or microfluidization.
- the inventors have also noted that the focus of the art has been to use oligosaccharides for ease of conjugate production.
- a conjugate having high immunogenicity which is filterable 2) the ratio of polysaccharide to protein in the conjugate can be altered such that the ratio of polysaccharide to protein (w/w) in the conjugate may be increased (which can have an effect on the carrier suppression effect), 3) immunogenic conjugates prone to hydrolysis may be stabilised by the use of larger saccharides for conjugation.
- the use of larger polysaccharides can result in more cross-linking with the conjugate carrier and may lessen the liberation of free saccharide from the conjugate.
- conjugate vaccines described in the prior art tend to depolymerise the polysaccharides prior to conjugation in order to improve conjugation.
- the present inventors have found that saccharide conjugate vaccines retaining a larger size of saccharide can provide a good immune response against pneumococcal disease.
- the immunogenic composition of the invention may thus comprise one or more saccharide conjugates wherein the average size (e.g. weight-average molecular weight; M w ) of each saccharide before conjugation is above 80 kDa, 100kDa, 200 kDa, 300 kDa, 400 kDa, 500 kDa or 1000 kDa.
- one or more saccharide conjugates of the invention should have an average size of saccharide pre-conjugation of 50-1600, 80-1400, 100-1000, 150-500, or 200-400 kDa (note that where average size is M w , ‘kDa’ units should be replaced herein with ‘ ⁇ 10 3 ’).
- the conjugate post conjugation should be readily filterable through a 0.2 micron filter such that a yield of more than 50, 60, 70, 80, 90 or 95% is obtained post filtration compared with the pre filtration sample.
- “native polysaccharide” refers to a saccharide that has not been subjected to a process (e.g. post-purification), the purpose of which is to reduce the size of the saccharide.
- a polysaccharide can become slightly reduced in size during normal purification procedures.
- Such a saccharide is still native. Only if the polysaccharide has been subjected to sizing techniques would the polysaccharide not be considered native.
- “sized by a factor up to ⁇ 2” means that the saccharide is subject to a process intended to reduce the size of the saccharide but to retain a size more than half the size of the native polysaccharide.
- ⁇ 3, ⁇ 4 etc. are to be interpreted in the same way i.e. the saccharide is subject to a process intended to reduce the size of the polysaccharide but to retain a size more than a third, a quarter etc. the size of the native polysaccharide.
- the immunogenic composition comprises Streptococcus pneumoniae saccharides from at least 10 serotypes conjugated to a carrier protein, wherein at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or each S. pneumoniae saccharide is native polysaccharide.
- the immunogenic composition comprises Streptococcus pneumoniae saccharides from at least 10 serotypes conjugated to a carrier protein, wherein at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or each S. pneumoniae saccharide is sized by a factor up to ⁇ 2, ⁇ 3, ⁇ 4, ⁇ 5, ⁇ 6, ⁇ 7, ⁇ 8, ⁇ 9 or ⁇ 10.
- the majority of the saccharides, for example 6, 7, 8 or more of the saccharides are sized by a factor up to ⁇ 2, ⁇ 3, ⁇ 4, ⁇ 5, ⁇ 6, ⁇ 7, ⁇ 8, ⁇ 9 or ⁇ 10.
- the molecular weight or average molecular weight (or size) of a saccharide herein refers to the weight-average molecular weight (M w ) of the saccharide measured prior to conjugation and is measured by MALLS.
- MALLS technique is well known in the art and is typically carried out as described in example 2.
- two columns (TSKG6000 and 5000PWxl) may be used in combination and the saccharides are eluted in water. Saccharides are detected using a light scattering detector (for instance Wyatt Dawn DSP equipped with a 10 mW argon laser at 488 nm) and an inferometric refractometer (for instance Wyatt Otilab DSP equipped with a P100 cell and a red filter at 498 nm).
- a light scattering detector for instance Wyatt Dawn DSP equipped with a 10 mW argon laser at 488 nm
- an inferometric refractometer for instance Wyatt Otilab DSP equipped with a P100 cell and a red filter at 498 nm.
- the S. pneumoniae saccharides are native polysaccharides or native polysaccharides which have been reduced in size during a normal extraction process.
- the S. pneumoniae saccharides are sized by mechanical cleavage, for instance by microfluidisation or sonication.
- Microfluidisation and sonication have the advantage of decreasing the size of the larger native polysaccharides sufficiently to provide a filterable conjugate. Sizing is by a factor of no more than ⁇ 20, ⁇ 10, ⁇ 8, ⁇ 6, ⁇ 5, ⁇ 4, ⁇ 3 or ⁇ 2.
- the immunogenic composition comprises S. pneumoniae conjugates that are made from a mixture of native polysaccharides and saccharides that are sized by a factor of no more than ⁇ 20.
- the majority of the saccharides for example 6, 7, 8 or more of the saccharides are sized by a factor of up to ⁇ 2, ⁇ 3, ⁇ 4, ⁇ 5 or ⁇ 6.
- the Streptococcus pneumoniae saccharide is conjugated to the carrier protein via a linker, for instance a bifunctional linker.
- the linker is optionally heterobifunctional or homobifunctional, having for example a reactive amino group and a reactive carboxylic acid group, 2 reactive amino groups or two reactive carboxylic acid groups.
- the linker has for example between 4 and 20, 4 and 12, 5 and 10 carbon atoms.
- a possible linker is ADH.
- Other linkers include B-propionamido (WO 00/10599), nitrophenyl-ethylamine (Gever et al (1979) Med. Microbiol. Immunol. 165; 171-288), haloalkyl halides (U.S. Pat. No.
- ADH is used as a linker for conjugating saccharide from serotype 18C. In an embodiment, ADH is used as a linker for conjugating saccharide from serotype 22F.
- the saccharide conjugates present in the immunogenic compositions of the invention may be prepared by any known coupling technique.
- the conjugation method may rely on activation of the saccharide with 1-cyano-4-dimethylamino pyridinium tetrafluoroborate (CDAP) to form a cyanate ester.
- CDAP 1-cyano-4-dimethylamino pyridinium tetrafluoroborate
- the activated saccharide may thus be coupled directly or via a spacer (linker) group to an amino group on the carrier protein.
- the spacer could be cystamine or cysteamine to give a thiolated polysaccharide which could be coupled to the carrier via a thioether linkage obtained after reaction with a maleimide-activated carrier protein (for example using GMBS) or a haloacetylated carrier protein (for example using iodoacetimide [e.g. ethyl iodoacetimide HCl] or N-succinimidyl bromoacetate or SIAB, or SIA, or SBAP).
- a maleimide-activated carrier protein for example using GMBS
- a haloacetylated carrier protein for example using iodoacetimide [e.g. ethyl iodoacetimide HCl] or N-succinimidyl bromoacetate or SIAB, or SIA, or SBAP).
- the cyanate ester (optionally made by CDAP chemistry) is coupled with hexane diamine or ADH and the amino-derivatised saccharide is conjugated to the carrier protein using carbodiimide (e.g. EDAC or EDC) chemistry via a carboxyl group on the protein carrier.
- carbodiimide e.g. EDAC or EDC
- Conjugation may involve a carbonyl linker which may be formed by reaction of a free hydroxyl group of the saccharide with CDI (Bethell et al J. Biol. Chem. 1979, 254; 2572-4, Hearn et al J. Chromatogr. 1981. 218; 509-18) followed by reaction of with a protein to form a carbamate linkage.
- CDI Carbonyl linker
- This may involve reduction of the anomeric terminus to a primary hydroxyl group, optional protection/deprotection of the primary hydroxyl group′ reaction of the primary hydroxyl group with CDI to form a CDI carbamate intermediate and coupling the CDI carbamate intermediate with an amino group on a protein.
- the conjugates can also be prepared by direct reductive amination methods as described in U.S. Pat. No. 4,365,170 (Jennings) and U.S. Pat. No. 4,673,574 (Anderson). Other methods are described in EP-0-161-188, EP-208375 and EP-0-477508.
- a further method involves the coupling of a cyanogen bromide (or CDAP) activated saccharide derivatised with adipic acid dihydrazide (ADH) to the protein carrier by Carbodiimide condensation (Chu C. et al Infect. Immunity, 1983 245 256), for example using EDAC.
- CDAP cyanogen bromide
- ADH adipic acid dihydrazide
- a hydroxyl group (preferably an activated hydroxyl group for example a hydroxyl group activated to make a cyanate ester [e.g. with CDAP]) on a saccharide is linked to an amino or carboxylic group on a protein either directly or indirectly (through a linker).
- a linker is present, a hydroxyl group on a saccharide is preferably linked to an amino group on a linker, for example by using CDAP conjugation.
- a further amino group in the linker for example ADH may be conjugated to a carboxylic acid group on a protein, for example by using carbodiimide chemistry, for example by using EDAC.
- the pneumococcal capsular saccharide(s) is conjugated to the linker first before the linker is conjugated to the carrier protein.
- the linker may be conjugated to the carrier before conjugation to the saccharide.
- a combination of techniques may also be used, with some saccharide-protein conjugates being prepared by CDAP, and some by reductive amination.
- Carboxyl for instance via aspartic acid or glutamic acid. In one embodiment this group is linked to amino groups on saccharides directly or to an amino group on a linker with carbodiimide chemistry e.g. with EDAC.
- Amino group for instance via lysine. In one embodiment this group is linked to carboxyl groups on saccharides directly or to a carboxyl group on a linker with carbodiimide chemistry e.g. with EDAC.
- this group is linked to hydroxyl groups activated with CDAP or CNBr on saccharides directly or to such groups on a linker; to saccharides or linkers having an aldehyde group; to saccharides or linkers having a succinimide ester group.
- E) Imidazolyl group (for instance via histidine). In one embodiment this group is activated/modified with bis diazobenzidine.
- Aldehyde groups can be generated after different treatments known in the art such as: periodate, acid hydrolysis, hydrogen peroxide, etc.
- protein carrier chemical group that may be generally used for coupling with a saccharide are amino groups (for instance on lysine residues), COOH groups (for instance on aspartic and glutamic acid residues) and SH groups (if accessible) (for instance on cysteine residues.
- the ratio of carrier protein to S. pneumoniae saccharide is between 1:5 and 5:1; e.g. between 1:0.5-4:1, 1:1-3.5:1, 1.2:1-3:1, 1.5:1-2.5:1; e.g. between 1:2 and 2.5:1; 1:1 and 2:1 (w/w).
- the majority of the conjugates, for example 6, 7, 8, 9 or more of the conjugates have a ratio of carrier protein to saccharide that is greater than 1:1, for example 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1 or 1.6:1.
- At least one S. pneumoniae saccharide is conjugated to a carrier protein via a linker using CDAP and EDAC.
- CDAP and EDAC may be conjugated to a protein via a linker (for example those with two hydrazino groups at its ends such as ADH) using CDAP and EDAC as described above.
- CDAP may be used to conjugate the saccharide to a linker and EDAC may then be used to conjugate the linker to a protein or, alternatively EDAC may be used first to conjugate the linker to the protein, after which CDAP may be used to conjugate the linker to the saccharide.
- the immunogenic composition of the invention may comprise a dose of each saccharide conjugate between 0.1 and 20 ⁇ g, 1 and 10 ⁇ g or 1 and 3 ⁇ g of saccharide.
- the immunogenic composition of the invention contains each S. pneumoniae capsular saccharide at a dose of between 0.1-20 ⁇ g; 0.5-10 ⁇ g; 0.5-5 ⁇ g or 1-3 ⁇ g of saccharide.
- capsular saccharides may be present at different dosages, for example some capsular saccharides may be present at a dose of exactly 1 ⁇ g or some capsular saccharides may be present at a dose of exactly 3 ⁇ g.
- saccharides from serotypes 3, 18C and 19F (or 4, 18C and 19F) are present at a higher dose than other saccharides.
- serotypes 3, 18C and 19F are present at a dose of around or exactly 3 ⁇ g whilst other saccharides in the immunogenic composition are present at a dose of around or exactly 1 ⁇ g.
- At least one of the S. pneumoniae capsular saccharides is directly conjugated to a carrier protein (e.g. using one of the chemistries described above).
- a carrier protein e.g. using one of the chemistries described above.
- the at least one of the S. pneumoniae capsular saccharides is directly conjugated by CDAP.
- the majority of the capsular saccharides for example 5, 6, 7, 8, 9 or more are directly linked to the carrier protein by CDAP (see WO 95/08348 and WO 96/29094)
- the immunogenic composition may comprise Streptococcus pneumoniae proteins, herein termed Streptococcus pneumoniae proteins of the invention. Such proteins may be used as carrier proteins, or may be present as free proteins, or may be present both as carrier proteins and as free proteins.
- Streptococcus pneumoniae proteins of the invention are either surface exposed, at least during part of the life cycle of the pneumococcus, or are proteins which are secreted or released by the pneumococcus.
- the proteins of the invention are selected from the following categories, such as proteins having a Type II Signal sequence motif of LXXC (where X is any amino acid, e.g., the polyhistidine triad family (PhtX)), choline binding proteins (CbpX), proteins having a Type I Signal sequence motif (e.g., Sp101), proteins having a LPXTG motif (where X is any amino acid, e.g., Sp128, Sp130), and toxins (e.g., Ply).
- Preferred examples within these categories (or motifs) are the following proteins, or immunologically functional equivalents thereof.
- the immunogenic composition of the invention comprises at least 1 protein selected from the group consisting of the Poly Histidine Triad family (PhtX), Choline Binding Protein family (CbpX), CbpX truncates, Lytx family, LytX truncates, CbpX truncate-LytX truncate chimeric proteins (or fusions), pneumolysin (Ply), PspA, PsaA, Sp128, Sp101, Sp130, Sp125 and Sp133.
- PhtX Poly Histidine Triad family
- CbpX Choline Binding Protein family
- CbpX truncates CbpX truncates
- Lytx family Lytx family
- LytX truncates CbpX truncate-LytX truncate chimeric proteins (or fusions)
- pneumolysin Ply
- PspA PsaA
- Sp128, Sp101 Sp130
- the immunogenic composition comprises 2 or more proteins selected from the group consisting of the Poly Histidine Triad family (PhtX), Choline Binding Protein family (CbpX), CbpX truncates, Lytx family, LytX truncates, CbpX truncate-LytX truncate chimeric proteins (or fusions), pneumolysin (Ply), PspA, PsaA, and Sp128.
- PhtX Poly Histidine Triad family
- CbpX Choline Binding Protein family
- CbpX Choline Binding Protein family
- CbpX truncates CbpX truncates
- Lytx family Lytx family
- LytX truncates CbpX truncate-LytX truncate chimeric proteins (or fusions)
- pneumolysin Ply
- PspA PsaA
- Sp128 Sp128
- the immunogenic composition comprises 2 or more proteins selected from the group consisting of the Poly Histidine Triad family (PhtX), Choline Binding Protein family (CbpX), CbpX truncates, LytX family, LytX truncates, CbpX truncate-LytX truncate chimeric proteins (or fusions), pneumolysin (Ply), and Sp128.
- PhtX Poly Histidine Triad family
- CbpX Choline Binding Protein family
- CbpX Choline Binding Protein family
- CbpX truncates CbpX truncates
- LytX family LytX family
- LytX truncates CbpX truncate-LytX truncate chimeric proteins (or fusions)
- pneumolysin Ply
- Sp128 Sp128.
- the Pht (Poly Histidine Triad) family comprises proteins PhtA, PhtB, PhtD, and PhtE.
- the family is characterized by a lipidation sequence, two domains separated by a proline-rich region and several histidine triads, possibly involved in metal or nucleoside binding or enzymatic activity, (3-5) coiled-coil regions, a conserved N-terminus and a heterogeneous C terminus. It is present in all strains of pneumococci tested. Homologous proteins have also been found in other Streptococci and Neisseria .
- the Pht protein of the invention is PhtD.
- phrases Pht A, B, D, and E refer to proteins having sequences disclosed in the citations below as well as naturally-occurring (and man-made) variants thereof that have a sequence homology that is at least 90% identical to the referenced proteins. Preferably it is at least 95% identical and most preferably it is 97% identical.
- PhtA is disclosed in WO 98/18930, and is also referred to Sp36. As noted above, it is a protein from the polyhistidine triad family and has the type II signal motif of LXXC.
- PhtD is disclosed in WO 00/37105, and is also referred to Sp036D. As noted above, it also is a protein from the polyhistidine triad family and has the type II LXXC signal motif.
- PhtB is disclosed in WO 00/37105, and is also referred to Sp036B. Another member of the PhtB family is the C3-Degrading Polypeptide, as disclosed in WO 00/17370.
- This protein also is from the polyhistidine triad family and has the type II LXXC signal motif.
- a preferred immunologically functional equivalent is the protein Sp42 disclosed in WO 98/18930.
- a PhtB truncate (approximately 79 kD) is disclosed in WO99/15675 which is also considered a member of the PhtX family.
- PhtE is disclosed in WO00/30299 and is referred to as BVH-3.
- any Pht protein is referred to herein, it is meant that immunogenic fragments or fusions thereof of the Pht protein can be used.
- a reference to PhtX includes immunogenic fragments or fusions thereof from any Pht protein.
- a reference to PhtD or PhtB is also a reference to PhtDE or PhtBE fusions as found, for example, in WO0198334.
- Pneumolysin is a multifunctional toxin with a distinct cytolytic (hemolytic) and complement activation activities (Rubins et al., Am. Respi. Cit Care Med, 153:1339-1346 (1996)).
- the toxin is not secreted by pneumococci, but it is released upon lysis of pneumococci under the influence of autolysin. Its effects include e.g., the stimulation of the production of inflammatory cytokines by human monocytes, the inhibition of the beating of cilia on human respiratory epithelial, and the decrease of bactericidal activity and migration of neutrophils.
- the most obvious effect of pneumolysin is in the lysis of red blood cells, which involves binding to cholesterol.
- Detoxification of ply can be conducted by chemical means, e.g., subject to formalin or glutaraldehyde treatment or a combination of both (WO 04081515, PCT/EP2005/010258). Such methods are well known in the art for various toxins. Alternatively, ply can be genetically detoxified. Thus, the invention encompasses derivatives of pneumococcal proteins which may be, for example, mutated proteins.
- mutated is used herein to mean a molecule which has undergone deletion, addition or substitution of one or more amino acids using well known techniques for site directed mutagenesis or any other conventional method.
- a mutant ply protein may be altered so that it is biologically inactive whilst still maintaining its immunogenic epitopes, see, for example, WO90/06951, Berry et al. (Infect Immun, 67:981-985 (1999)) and WO99/03884.
- Choline Binding Protein family members of that family were originally identified as pneumococcal proteins that could be purified by choline-affininty chromatography. All of the choline-binding proteins are non-covalently bound to phosphorylcholine moieties of cell wall teichoic acid and membrane-associated lipoteichoic acid. Structurally, they have several regions in common over the entire family, although the exact nature of the proteins (amino acid sequence, length, etc.) can vary.
- choline binding proteins comprise an N terminal region (N), conserved repeat regions (R1 and/or R2), a proline rich region (P) and a conserved choline binding region (C), made up of multiple repeats, that comprises approximately one half of the protein.
- CbpX Choline Binding Protein family
- CbpA is disclosed in WO97/41151.
- CbpD and CbpG are disclosed in WO00/29434.
- PspC is disclosed in WO97/09994.
- PbcA is disclosed in WO98/21337.5
- psA is a Choline binding protein disclosed in WO 98/39450.
- the Choline Binding Proteins are selected from the group consisting of CbpA, PbcA, SpsA and PspC.
- CbpX truncates wherein “CbpX” is defined above and “truncates” refers to CbpX proteins lacking 50% or more of the Choline binding region (C).
- truncates refers to CbpX proteins lacking 50% or more of the Choline binding region (C).
- C Choline binding region
- the such protein truncates lack the entire choline binding region. More preferably, the such protein truncates lack (i) the choline binding region and (ii) a portion of the N-terminal half of the protein as well, yet retain at least one repeat region (R1 or R2). More preferably still, the truncate has 2 repeat regions (R1 and R2).
- NR1xR2 and R1xR2 as illustrated in WO99/51266 or WO99/51188, however, other choline binding proteins lacking a similar choline binding region are also contemplated within the scope of this invention.
- the LytX family is membrane associated proteins associated with cell lysis.
- the N-terminal domain comprises choline binding domain(s), however the LytX family does not have all the features found in the CbpA family noted above and thus for the present invention, the LytX family is considered distinct from the CbpX family.
- the C-terminal domain contains the catalytic domain of the LytX protein family.
- the family comprises LytA, B and C.
- LytA is disclosed in Ronda et al., Eur J Biochem, 164:621-624 (1987).
- LytB is disclosed in WO 98/18930, and is also referred to as Sp46.
- LytC is also disclosed in WO 98/18930, and is also referred to as Sp91.
- a preferred member of that family is LytC.
- LytX truncates wherein “LytX” is defined above and “truncates” refers to LytX proteins lacking 50% or more of the Choline binding region. Preferably such proteins lack the entire choline binding region.
- CbpX is selected from the group consisting of CbpA, PbcA, SpsA and PspC. More preferably still, it is CbpA.
- LytX is LytC (also referred to as Sp91).
- Another embodiment of the present invention is a PspA or PsaA truncates lacking the choline binding domain (C) and expressed as a fusion protein with LytX.
- LytX is LytC.
- PsaA and PspA both are know in the art.
- PsaA and transmembrane deletion variants thereof have been described by Berry & Paton, Infect Immun 1996 December; 64(12):5255-62.
- PspA and transmembrane deletion variants thereof have been disclosed in, for example, U.S. Pat. No. 5,804,193, WO 92/14488, and WO 99/53940.
- Sp128 and Sp130 are disclosed in WO00/76540.
- Sp125 is an example of a pneumococcal surface protein with the Cell Wall Anchored motif of LPXTG (where X is any amino acid). Any protein within this class of pneumococcal surface protein with this motif has been found to be useful within the context of this invention, and is therefore considered a further protein of the invention.
- Sp125 itself is disclosed in WO 98/18930, and is also known as ZmpB—a zinc metalloproteinase.
- Sp101 is disclosed in WO 98/06734 (where it has the reference # y85993). It is characterized by a Type I signal sequence.
- Sp133 is disclosed in WO 98/06734 (where it has the reference # y85992). It is also characterized by a Type I signal sequence.
- Moraxella catarrhalis protein antigens which can be included in a combination vaccine (especially for the prevention of otitis media) are: OMP106 [WO 97/41731 (Antex) & WO 96/34960 (PMC)]; OMP21 or fragments thereof (WO 00/8910); LbpA &/or LbpB [WO 98/55606 (PMC)]; TbpA &/or TbpB [WO 97/13785 & WO 97/32980 (PMC)]; CopB [Helminen M E, et al., (1993) Infect. Immun.
- non-typeable Haemophilus influenzae antigens or fragments thereof which can be included in a combination vaccine (especially for the prevention of otitis media) include: Fimbrin protein [(U.S. Pat. No. 5,766,608—Ohio State Research Foundation)] and fusions comprising peptides therefrom [eg LB1(f) peptide fusions; U.S. Pat. No.
- the proteins of the invention may also be beneficially combined.
- the immunogenic composition comprises all of the proteins from within the following combinations, either as carrier proteins or as free proteins or a mixture of the two.
- both proteins may be used as carrier proteins, or both proteins may be present as free proteins, or both may be present as carrier and as free protein, or one may be present as a carrier protein and a free protein whilst the other is present only as a carrier protein or only as a free protein, or one may be present as a carrier protein and the other as a free protein.
- Preferred combinations include, but are not limited to, PhtD+NR1xR2, PhtD+NR1xR2-Sp91Cterm chimeric or fusion proteins, PhtD+Ply, PhtD+Sp128, PhtD+PsaA, PhtD+PspA, PhtA+NR1xR2, PhtA+NR1xR2-Sp91Cterm chimeric or fusion proteins, PhtA+Ply, PhtA+Sp128, PhtA+PsaA, PhtA+PspA, NRIxR2+LytC, NR1xR2+PspA, NR1xR2+PsaA, NR1xR2+Sp128, R1xR2+LytC, R1xR2+PspA, R1xR2+PsaA, R1xR2+Sp128, R1xR2+PhtD, R1xR2+PhtA.
- NR1xR2 (or R1xR2) is from CbpA or PspC. More preferably it is from CbpA.
- Other combinations include 3 protein combinations such as PhtD+NR1xR2+Ply, and PhtA+NR1xR2+PhtD.
- the vaccine composition comprises detoxified pneumolysin and PhtD or PhtDE as carrier proteins.
- the vaccine composition comprises detoxified pneumolysin and PhtD or PhtDE as free proteins.
- the present invention further provides a vaccine containing the immunogenic compositions of the invention and a pharmaceutically acceptable excipient.
- the vaccines of the present invention may be adjuvanted, particularly when intended for use in an elderly population but also for use in infant populations.
- Suitable adjuvants include an aluminum salt such as aluminum hydroxide gel or aluminum phosphate or alum, but may also be a salt of calcium, magnesium, iron or zinc, or may be an insoluble suspension of acylated tyrosine, or acylated sugars, cationically or anionically derivatized saccharides, or polyphosphazenes.
- the adjuvant be selected to be a preferential inducer of a TH1 type of response.
- Th1-type cytokines tend to favour the induction of cell mediated immune responses to a given antigen, whilst high levels of Th2-type cytokines tend to favour the induction of humoral immune responses to the antigen.
- Th1 and Th2-type immune response are not absolute. In reality an individual will support an immune response which is described as being predominantly Th1 or predominantly Th2.
- TH1 and TH2 cells different patterns of lymphokine secretion lead to different functional properties. (Annual Review of Immunology, 7, p145-173).
- Th1-type responses are associated with the production of the INF- ⁇ and IL-2 cytokines by T-lymphocytes.
- Suitable adjuvant systems which promote a predominantly Th1 response include: Monophosphoryl lipid A or a derivative thereof, particularly 3-de-O-acylated monophosphoryl lipid A (3D-MPL) (for its preparation see GB 2220211 A); and a combination of monophosphoryl lipid A, preferably 3-de-O-acylated monophosphoryl lipid A, together with either an aluminum salt (for instance aluminum phosphate or aluminum hydroxide) or an oil-in-water emulsion.
- Monophosphoryl lipid A or a derivative thereof, particularly 3-de-O-acylated monophosphoryl lipid A (3D-MPL) for its preparation see GB 2220211 A
- a combination of monophosphoryl lipid A preferably 3-de-O-acylated monophosphoryl lipid A, together with either an aluminum salt (for instance aluminum phosphate or aluminum hydroxide) or an oil-in-water emulsion.
- antigen and 3D-MPL are contained in the same particulate structures, allowing for more efficient delivery of antigenic and immunostimulatory signals.
- An enhanced system involves the combination of a monophosphoryl lipid A and a saponin derivative, particularly the combination of QS21 and 3D-MPL as disclosed in WO 94/00153, or a less reactogenic composition where the QS21 is quenched with cholesterol as disclosed in WO 96/33739.
- a particularly potent adjuvant formulation involving QS21, 3D-MPL and tocopherol in an oil in water emulsion is described in WO 95/17210.
- the immunogenic composition additionally comprises a saponin, which may be QS21.
- the formulation may also comprise an oil in water emulsion and tocopherol (WO 95/17210).
- Unmethylated CpG containing oligonucleotides (WO 96/02555) and other immunomodulatory oligonucleotides (WO0226757 and WO03507822) are also preferential inducers of a TH1 response and are suitable for use in the present invention.
- Particular adjuvants are those selected from the group of metal Salts, oil in water emulsions, Toll like receptors agonist, (in particular Toll like receptor 2 agonist, Toll like receptor 3 agonist, Toll like receptor 4 agonist, Toll like receptor 7 agonist, Toll like receptor 8 agonist and Toll like receptor 9 agonist), saponins or combinations thereof.
- An adjuvant that can be used with the vaccine compositions of the invention are bleb or outer membrane vesicle preparations from Gram negative bacterial strains such as those taught by WO02/09746—particularly N. meningitidis blebs.
- Adjuvant properties of blebs can be improved by retaining LOS (lipooligosacccharide) on its surface (e.g. through extraction with low concentrations of detergent [for instanct 0-0.1% deoxycholate]).
- LOS can be detoxified through the msbB( ⁇ ) or htrB( ⁇ ) mutations discussed in WO02/09746.
- Adjuvant properties can also be improved by retaining PorB (and optionally removing PorA) from meningococcal blebs. Adjuvant properties can also be improved by truncating the outer core saccharide structure of LOS on meningococcal blebs—for instance via the IgtB( ⁇ ) mutation discussed in WO2004/014417. Alternatively, the aforementioned LOS (e.g. isolated from a msbB( ⁇ ) and/or IgtB( ⁇ ) strain) can be purified and used as an adjuvant in the compositions of the invention.
- LOS e.g. isolated from a msbB( ⁇ ) and/or IgtB( ⁇ ) strain
- a further adjuvant which may be used with the compositions of the invention may be selected from the group: a saponin, lipid A or a derivative thereof, an immunostimulatory oligonucleotide, an alkyl glucosaminide phosphate, an oil in water emulsion or combinations thereof.
- a further preferred adjuvant is a metal salt in combination with another adjuvant. It is preferred that the adjuvant is a Toll like receptor agonist in particular an agonist of a Toll like receptor 2, 3, 4, 7, 8 or 9, or a saponin, in particular Qs21. It is further preferred that the adjuvant system comprises two or more adjuvants from the above list.
- the combinations preferably contain a saponin (in particular Qs21) adjuvant and/or a Toll like receptor 9 agonist such as a CpG containing immunostimulatory oligonucleotide.
- a saponin (in particular QS21) and a Toll like receptor 4 agonist such as monophosphoryl lipid A or its 3 deacylated derivative, 3 D-MPL, or a saponin (in particular QS21) and a Toll like receptor 4 ligand such as an alkyl glucosaminide phosphate.
- Particularly preferred adjuvants are combinations of 3D-MPL and QS21 (EP 0 671 948 B1), oil in water emulsions comprising 3D-MPL and QS21 (WO 95/17210, WO 98/56414), or 3D-MPL formulated with other carriers (EP 0 689 454 B1).
- Other preferred adjuvant systems comprise a combination of 3 D MPL, QS21 and a CpG oligonucleotide as described in U.S. Pat. No. 6,558,670, U.S. Pat. No. 6,544,518.
- the adjuvant is (or comprises) a Toll like receptor (TLR) 4 ligand, preferably an agonist such as a lipid A derivative particularly monophosphoryl lipid A or more particularly 3 Deacylated monophoshoryl lipid A (3 D-MPL).
- TLR Toll like receptor
- 3D-MPL is available from GlaxoSmithKiine Biologicals North America and primarily promotes CD4+ T cell responses with an IFN-g (Th1) phenotype. It can be produced according to the methods disclosed in GB 2 220 211 A. Chemically it is a mixture of 3-deacylated monophosphoryl lipid A with 3, 4, 5 or 6 acylated chains. Preferably in the compositions of the present invention small particle 3 D-MPL is used. Small particle 3 D-MPL has a particle size such that it may be sterile-filtered through a 0.22 ⁇ m filter. Such preparations are described in International Patent Application No. WO 94/21292. Synthetic derivatives of lipid A are known and thought to be TLR 4 agonists including, but not limited to:
- TLR4 ligands which may be used are alkyl Glucosaminide phosphates (AGPs) such as those disclosed in WO9850399 or U.S. Pat. No. 6,303,347 (processes for preparation of AGPs are also disclosed), or pharmaceutically acceptable salts of AGPs as disclosed in U.S. Pat. No. 6,764,840.
- AGPs alkyl Glucosaminide phosphates
- Some AGPs are TLR4 agonists, and some are TLR4 antagonists. Both are thought to be useful as adjuvants.
- Quil A is a saponin preparation isolated from the South American tree Quilaja Saponaria Molina and was first described as having adjuvant activity by Dalsgaard et al. in 1974 (“Saponin adjuvants”, Archiv. für diedorf Virusforschung, Vol. 44, Springer Verlag, Berlin, p243-254). Purified fragments of Quil A have been isolated by HPLC which retain adjuvant activity without the toxicity associated with Quil A (EP 0 362 278), for example QS7 and QS21 (also known as QA7 and QA21).
- QS-21 is a natural saponin derived from the bark of Quillaja saponaria Molina which induces CD8+ cytotoxic T cells (CTLs), Th1 cells and a predominant IgG2a antibody response and is a preferred saponin in the context of the present invention.
- CTLs cytotoxic T cells
- Th1 cells Th1 cells
- IgG2a antibody response is a preferred saponin in the context of the present invention.
- the saponins forming part of the present invention may be separate in the form of micelles, mixed micelles (preferentially, but not exclusively with bile salts) or may be in the form of ISCOM matrices (EP 0 109 942 B1), liposomes or related colloidal structures such as worm-like or ring-like multimeric complexes or lipidic/layered structures and lamellae when formulated with cholesterol and lipid, or in the form of an oil in water emulsion (for example as in WO 95/17210).
- the saponins may preferably be associated with a metallic salt, such as aluminium hydroxide or aluminium phosphate (WO 98/15287).
- the saponin is presented in the form of a liposome, ISCOM or an oil in water emulsion.
- An enhanced system involves the combination of a monophosphoryl lipid A (or detoxified lipid A) and a saponin derivative, particularly the combination of QS21 and 3D-MPL as disclosed in WO 94/00153, or a less reactogenic composition where the QS21 is quenched with cholesterol as disclosed in WO 96/33739.
- a particularly potent adjuvant formulation involving tocopherol with or without QS21 and/or 3D-MPL in an oil in water emulsion is described in WO 95/17210.
- the immunogenic composition additionally comprises a saponin, which may be QS21.
- Immunostimulatory oligonucleotides or any other Toll-like receptor (TLR) 9 agonist may also be used.
- the preferred oligonucleotides for use in adjuvants or vaccines of the present invention are CpG containing oligonucleotides, preferably containing two or more dinucleotide CpG motifs separated by at least three, more preferably at least six or more nucleotides.
- a CpG motif is a Cytosine nucleotide followed by a Guanine nucleotide.
- the CpG oligonucleotides of the present invention are typically deoxynucleotides.
- the internucleotide in the oligonucleotide is phosphorodithioate, or more preferably a phosphorothioate bond, although phosphodiester and other internucleotide bonds are within the scope of the invention.
- oligonucleotides with mixed internucleotide linkages are included within the scope of the invention. Methods for producing phosphorothioate oligonucleotides or phosphorodithioate are described in U.S. Pat. No. 5,666,153, U.S. Pat. No. 5,278,302 and WO95/26204.
- oligonucleotides have the following sequences.
- the sequences preferably contain phosphorothioate modified internucleotide linkages.
- OLIGO 1 (SEQ ID NO:1): TCC ATG ACG TTC CTG ACG TT (CpG 1826)
- OLIGO 2 (SEQ ID NO:2): TCT CCC AGC GTG CGC CAT (CpG 1758)
- OLIGO 3 (SEQ ID NO:3): ACC GAT GAC GTC GCC GGT GAC GGC ACC ACG
- OLIGO 4 (SEQ ID NO:4): TCG TCG TTT TGT CGT TTT GTC GTT (CpG 2006)
- OLIGO 5 (SEQ ID NO:5): TCC ATG ACG TTC CTG ATG CT (CpG 1668)
- OLIGO 6 (SEQ ID NO:6): TCG ACG TTT TCG GCG CGC GCC G (CpG 5456)
- Alternative CpG oligonucleotides may comprise the preferred sequences above in that they have inconsequential deletions or additions thereto.
- the CpG oligonucleotides utilised in the present invention may be synthesized by any method known in the art (for example see EP 468520). Conveniently, such oligonucleotides may be synthesized utilising an automated synthesizer.
- the adjuvant may be an oil in water emulsion or may comprise an oil in water emulsion in combination with other adjuvants.
- the oil phase of the emulsion system preferably comprises a metabolisable oil.
- the meaning of the term metabolisable oil is well known in the art. Metabolisable can be defined as “being capable of being transformed by metabolism” (Dorland's Illustrated Medical Dictionary, W. B. Sanders Company, 25 th edition (1974)).
- the oil may be any vegetable oil, fish, oil, animal or synthetic oil, which is not toxic to the recipient and is capable of being transformed by metabolism. Nuts, seeds, and grains are common sources of vegetable oils. Synthetic oils are also part of this invention and can include commercially available oils such as NEOBEE® and others.
- Squalene (2,6,10,15,19,23-Hexamethyl-2,6,10,14,18,22-tetracosahexaene) is an unsaturated oil which is found in large quantities in shark-liver oil, and in lower quantities in olive oil, wheat germ oil, rice bran oil, and yeast, and is a particularly preferred oil for use in this invention.
- Squalene is a metabolisable oil by virtue of the fact that it is an intermediate in the biosynthesis of cholesterol (Merck index, 10 th Edition, entry no. 8619).
- Tocols e.g. vitamin E
- Tocols used in the oil emulsions (preferably oil in water emulsions) of the invention may be formulated as described in EP 0 382 271 B1, in that the tocols may be dispersions of tocol droplets, optionally comprising an emulsifier, of preferably less than 1 micron in diameter. Alternatively, the tocols may be used in combination with another oil, to form the oil phase of an oil emulsion. Examples of oil emulsions which may be used in combination with the tocol are described herein, such as the metabolisable oils described above.
- Oil in water emulsion adjuvants per se have been suggested to be useful as adjuvant compositions (EP 0 399 843B), also combinations of oil in water emulsions and other active agents have been described as adjuvants for vaccines (WO 95/17210; WO 98/56414; WO 99/12565; WO 99/11241).
- Other oil emulsion adjuvants have been described, such as water in oil emulsions (U.S. Pat. No. 5,422,109; EP 0 480 982 B2) and water in oil in water emulsions (U.S. Pat. No. 5,424,067; EP 0 480 981 B). All of which form preferred oil emulsion systems (in particular when incorporating tocols) to form adjuvants and compositions of the present invention.
- the oil emulsion (for instance oil in water emulsions) further comprises an emulsifier such as TWEEN 80 and/or a sterol such as cholesterol.
- emulsifier such as TWEEN 80 and/or a sterol such as cholesterol.
- a preferred oil emulsion (preferably oil-in-water emulsion) comprises a metabolisible, non-toxic oil, such as squalane, squalene or a tocopherol such as alpha tocopherol (and preferably both squalene and alpha tocopherol) and optionally an emulsifier (or surfactant) such as Tween 80.
- a sterol (preferably cholesterol) may also be included.
- the method of producing oil in water emulsions is well known to the man skilled in the art.
- the method comprises mixing the tocol-containing oil phase with a surfactant such as a PBS/TWEEN80TM solution, followed by homogenisation using a homogenizer, it would be clear to a man skilled in the art that a method comprising passing the mixture twice through a syringe needle would be suitable for homogenising small volumes of liquid.
- a surfactant such as a PBS/TWEEN80TM solution
- a homogenizer emulsification process in microfluidiser (M110S Microfluidics machine, maximum of 50 passes, for a period of 2 minutes at maximum pressure input of 6 bar (output pressure of about 850 bar)) could be adapted by the man skilled in the art to produce smaller or larger volumes of emulsion.
- the adaptation could be achieved by routine experimentation comprising the measurement of the resultant emulsion until a preparation was achieved with oil droplets of the required diameter.
- the oil and emulsifier should be in an aqueous carrier.
- the aqueous carrier may be, for example, phosphate buffered saline.
- the size of the oil droplets found within the stable oil in water emulsion are preferably less than 1 micron, may be in the range of substantially 30-600 nm, preferably substantially around 30-500 nm in diameter, and most preferably substantially 150-500 nm in diameter, and in particular about 150 nm in diameter as measured by photon correlation spectroscopy.
- 80% of the oil droplets by number should be within the preferred ranges, more preferably more than 90% and most preferably more than 95% of the oil droplets by number are within the defined size ranges.
- the amounts of the components present in the oil emulsions of the present invention are conventionally in the range of from 0.5-20% or 2 to 10% oil (of the total dose volume), such as squalene; and when present, from 2 to 10% alpha tocopherol; and from 0.3 to 3% surfactant, such as polyoxyethylene sorbitan monooleate.
- oil preferably squalene
- tocol preferably ⁇ -tocopherol
- An emulsifier such as Tween80 or Span 85 may also be present at a level of about 1%. In some cases it may be advantageous that the vaccines of the present invention will further contain a stabiliser.
- the adjuvant of the invention may additionally comprise further immunostimulants, such as LPS or derivatives thereof, and/or saponins.
- further immunostimulants are described herein and in “Vaccine Design—The Subunit and Adjuvant Approach” 1995, Pharmaceutical Biotechnology, Volume 6, Eds. Powell, M. F., and Newman, M. J., Plenum Press, New York and London, ISBN 0-306-44867-X.
- the adjuvant and immunogenic compositions according to the invention comprise a saponin (preferably QS21) and/or an LPS derivative (preferably 3D-MPL) in an oil emulsion described above, optionally with a sterol (preferably cholesterol).
- a sterol preferably cholesterol
- the oil emulsion preferably oil in water emulsion
- Adjuvants comprising an oil-in-water emulsion, a sterol and a saponin are described in WO 99/12565.
- the saponin (preferably QS21) and/or LPS derivative (preferably 3D-MPL) will be present in a human dose of immunogenic composition in the range of 1 ⁇ g-200 ⁇ g, such as 10-100 ⁇ g, preferably 10 ⁇ g-50 ⁇ g per dose.
- the oil emulsion preferably oil in water emulsion
- the oil emulsion will comprise from 2 to 10% metabolisible oil.
- it will comprise from 2 to 10% squalene, from 2 to 10% alpha tocopherol and from 0.3 to 3% (preferably 0.4-2%) emulsifier (preferably tween 80 [polyoxyethylene sorbitan monooleate]).
- the ratio of squalene:alpha tocopherol is equal to or less than 1 as this provides a more stable emulsion.
- Span 85 (Sorbitan trioleate) may also be present at a level of 0.5 to 1% in the emulsions used in the invention.
- the immunogenic compositions and vaccines of the present invention will further contain a stabiliser, for example other emulsifiers/surfactants, including caprylic acid (merck index 10 th Edition, entry no. 1739), of which Tricaprylin is particularly preferred.
- squalene and a saponin are included, it is of benefit to also include a sterol (preferably cholesterol) to the formulation as this allows a reduction in the total level of oil in the emulsion. This leads to a reduced cost of manufacture, improvement of the overall comfort of the vaccination, and also qualitative and quantitative improvements of the resultant immune responses, such as improved IFN- ⁇ production.
- a sterol preferably cholesterol
- the adjuvant system of the present invention typically comprises a ratio of metabolisable oil:saponin (w/w) in the range of 200:1 to 300:1, also the present invention can be used in a “low oil” form the preferred range of which is 1:1 to 200:1, preferably 20:1 to 100:1, and most preferably substantially 48:1, this vaccine retains the beneficial adjuvant properties of all of the components, with a much reduced reactogenicity profile.
- the particularly preferred embodiments have a ratio of squalene:QS21 (w/w) in the range of 1:1 to 250:1, also a preferred range is 20:1 to 200:1, preferably 20:1 to 100:1, and most preferably substantially 48:1.
- a sterol most preferably cholesterol is also included present at a ratio of saponin:sterol as described herein.
- the emulsion systems of the present invention preferably have a small oil droplet size in the sub-micron range. Most preferably the oil droplet sizes will be in the range 120 to 750 nm, and most preferably from 120-600 nm in diameter.
- a particularly potent adjuvant formulation involves a saponin (preferably QS21), an LPS derivative (preferably 3D-MPL) and an oil emulsion (preferably squalene and alpha tocopherol in an oil in water emulsion) as described in WO 95/17210 or in WO 99/12565 (in particular adjuvant formulation 11 in Example 2, Table 1).
- a saponin preferably QS21
- an LPS derivative preferably 3D-MPL
- an oil emulsion preferably squalene and alpha tocopherol in an oil in water emulsion
- TLR 2 agonist examples include peptidoglycan or lipoprotein.
- Imidazoquinolines such as Imiquimod and Resiquimod are known TLR7 agonists.
- Single stranded RNA is also a known TLR agonist (TLR8 in humans and TLR7 in mice), whereas double stranded RNA and poly IC (polyinosinic-polycytidylic acid—a commercial synthetic mimetic of viral RNA).
- TLR 3 agonists 3D-MPL is an example of a TLR4 agonist whilst CPG is an example of a TLR9 agonist.
- the immunogenic composition may comprise an antigen and an immunostimulant adsorbed onto a metal salt.
- Aluminium based vaccine formulations wherein the antigen and the immunostimulant 3-de-O-acylated monophosphoryl lipid A (3D-MPL), are adsorbed onto the same particle are described in EP 0 576 478 B1, EP 0 689 454 B1, and EP 0 633 784 B1.
- antigen is first adsorbed onto the aluminium salt followed by the adsorption of the immunostimulant 3D-MPL onto the same aluminium salt particles.
- Such processes first involve the suspension of 3D-MPL by sonication in a water bath until the particles reach a size of between 80 and 500 nm.
- the antigen is typically adsorbed onto aluminium salt for one hour at room temperature under agitation.
- the 3D-MPL suspension is then added to the adsorbed antigen and the formulation is incubated at room temperature for 1 hour, and then kept at 4° C. until use.
- the immunostimulant and the antigen are on separate metal particles, as described in EP 1126876.
- the improved process comprises the adsorption of immunostimulant, onto a metallic salt particle, followed by the adsorption of the antigen onto another metallic salt particle, followed by the mixing of the discrete metallic particles to form a vaccine.
- the adjuvant for use in the present invention may be an adjuvant composition comprising an immunostimulant, adsorbed onto a metallic salt particle, characterised in that the metallic salt particle is substantially free of other antigen.
- vaccines are provided by the present invention and are characterised in that the immunostimulant is adsorbed onto particles of metallic salt which are substantially free from other antigen, and in that the particles of metallic salt which are adsorbed to the antigen are substantially free of other immunostimulant.
- the present invention provides an adjuvant formulation comprising immunostimulant which has been adsorbed onto a particle of a metallic salt, characterised in the composition is substantially free of other antigen.
- this adjuvant formulation can be an intermediate which, if such an adjuvant is used, is required for the manufacture of a vaccine.
- a process for the manufacture of a vaccine comprising admixing an adjuvant composition which is one or more immunostimulants adsorbed onto a metal particle with an antigen.
- the antigen has been pre-adsorbed onto a metallic salt.
- Said metallic salt may be identical or similar to the metallic salt which is adsorbed onto the immunostimulant.
- the metal salt is an aluminium salt, for example Aluminium phosphate or Aluminium hydroxide.
- the present invention further provides for a vaccine composition comprising immunostimulant adsorbed onto a first particle of a metallic salt, and antigen adsorbed onto a metallic salt, characterised in that first and second particles of metallic salt are separate particles.
- LPS or LOS derivatives or mutations or lipid A derivatives described herein are designed to be less toxic (e.g. 3D-MPL) than native lipopolysaccharides and are interchangeable equivalents with respect to any uses of these moieties described herein. They may be TLR4 ligands as described above. Other such derivatives are described in WO020786737, WO9850399, WO01 34617, WO0212258, WO03065806.
- the adjuvant used for the compositions of the invention comprises a liposome carrier (made by known techniques from a phospholipids (such as dioleoyl phosphatidyl choline [DOPC]) and optionally a sterol [such as cholesterol]).
- a liposome carrier made by known techniques from a phospholipids (such as dioleoyl phosphatidyl choline [DOPC]) and optionally a sterol [such as cholesterol]).
- lipid A derivatives such as 3D-MPL—see above] and/or saponins (such as QS21—see above).
- the adjuvant comprises (per 0.5 mL dose) 0.1-10 mg, 0.2-7, 0.3-5, 0.4-2, or 0.5-1 mg (e.g.
- phospholipid for instance DOPC
- 0.025-2.5, 0.05-1.5, 0.075-0.75, 0.1-0.3, or 0.125-0.25 mg e.g. 0.2-0.3, 0.1-0.15, 0.25 or 0.125 mg
- sterol for instance cholesterol
- 5-60, 10-50, or 20-30 ⁇ g e.g. 5-15, 40-50, 10, 20, 30, 40 or 50 ⁇ g
- lipid A derivative for instance 3D-MPL
- 5-60, 10-50, or 20-30 ⁇ g e.g. 5-15, 40-50, 10, 20, 30, 40 or 50 ⁇ g
- saponin for instance QS21
- the vaccine composition comprising this adjuvant comprises saccharide conjugates derived from at least all the following serotypes: 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F (and may also comprise one or more from serotypes 3, 6A, 19A, and 22F), wherein the GMC antibody titre induced against one or more (or all) the vaccine components 4, 6B, 9V, 14, 18C, 19F and 23F is not significantly inferior to that induced by the Prevnar® vaccine in human vaccinees.
- the adjuvant used for the compositions of the invention comprises an oil in water emulsion made from a metabolisable oil (such as squalene), an emulsifier (such as Tween 80) and optionally a tocol (such as alpha tocopherol).
- a metabolisable oil such as squalene
- an emulsifier such as Tween 80
- a tocol such as alpha tocopherol
- the adjuvant comprises (per 0.5 mL dose) 0.5-15, 1-13, 2-11, 4-8, or 5-6 mg (e.g. 2-3, 5-6, or 10-11 mg) metabolisable oil (such as squalene), 0.1-10, 0.3-8, 0.6-6, 0.9-5, 1-4, or 2-3 mg (e.g.
- emulsifier such as Tween 80
- emulsifier such as Tween 80
- tocol such as alpha tocopherol
- This adjuvant may optionally further comprise 5-60, 10-50, or 20-30 ⁇ g (e.g. 5-15, 40-50, 10, 20, 30, 40 or 50 ⁇ g) lipid A derivative (for instance 3D-MPL).
- 5-60, 10-50, or 20-30 ⁇ g e.g. 5-15, 40-50, 10, 20, 30, 40 or 50 ⁇ g
- lipid A derivative for instance 3D-MPL.
- the GMC antibody titre induced against one or more (or all) the vaccine components 4, 6B, 9V, 14, 18C, 19F and 23F is not significantly inferior to that induced by the Prevnar® vaccine in human vaccinees.
- This adjuvant may optionally contain 0.025-2.5, 0.05-1.5, 0.075-0.75, 0.1-0.3, or 0.125-0.25 mg (e.g. 0.2-0.3, 0.1-0.15, 0.25 or 0.125 mg) sterol (for instance cholesterol), 5-60, 10-50, or 20-30 ⁇ g (e.g. 5-15, 40-50, 10, 20, 30, 40 or 50 ⁇ g) lipid A derivative (for instance 3D-MPL), and 5-60, 10-50, or 20-30 ⁇ g (e.g. 5-15, 40-50, 10, 20, 30, 40 or 50 ⁇ g) saponin (for instance QS21).
- sterol for instance cholesterol
- 5-60, 10-50, or 20-30 ⁇ g e.g. 5-15, 40-50, 10, 20, 30, 40 or 50 ⁇ g
- saponin for instance QS21
- the vaccine composition comprising this adjuvant comprises saccharide conjugates derived from at least all the following serotypes: 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F (and may also comprise one or more from serotypes 3, 6A, 19A, and 22F), wherein the GMC antibody titre induced against one or more (or all) the vaccine components 4, 6B, 9V, 14, 18C, 19F and 23F is not significantly inferior to that induced by the Prevnar® vaccine in human vaccinees.
- the adjuvant used for the compositions of the invention comprises aluminium phosphate and a lipid A derivative (such as 3D-MPL).
- This adjuvant may comprise (per 0.5 mL dose) 100-750, 200-500, or 300-400 ⁇ g Al as aluminium phosphate, and 5-60, 10-50, or 20-30 ⁇ g (e.g. 5-15, 40-50, 10, 20, 30, 40 or 50 ⁇ g) lipid A derivative (for instance 3D-MPL).
- the vaccine composition comprising this adjuvant comprises saccharide conjugates derived from at least all the following serotypes: 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F (and may also comprise one or more from serotypes 3, 6A, 19A, and 22F), wherein the GMC antibody titre induced against one or more (or all) the vaccine components 4, 6B, 9V, 14, 18C, 19F and 23F is not significantly inferior to that induced by the Prevnar® vaccine in human vaccinees.
- the vaccine preparations containing immunogenic compositions of the present invention may be used to protect or treat a mammal susceptible to infection, by means of administering said vaccine via systemic or mucosal route.
- These administrations may include injection via the intramuscular, intraperitoneal, intradermal or subcutaneous routes; or via mucosal administration to the oral/alimentary, respiratory, genitourinary tracts.
- Intranasal administration of vaccines for the treatment of pneumonia or otitis media is preferred (as nasopharyngeal carriage of pneumococci can be more effectively prevented, thus attenuating infection at its earliest stage).
- the vaccine of the invention may be administered as a single dose, components thereof may also be co-administered together at the same time or at different times (for instance pneumococcal saccharide conjugates could be administered separately, at the same time or 1-2 weeks after the administration of the any bacterial protein component of the vaccine for optimal coordination of the immune responses with respect to each other).
- the optional Th1 adjuvant may be present in any or all of the different administrations.
- 2 different routes of administration may be used.
- saccharides or saccharide conjugates may be administered IM (or ID) and bacterial proteins may be administered IN (or ID).
- the vaccines of the invention may be administered IM for priming doses and IN for booster doses.
- the content of protein antigens in the vaccine will typically be in the range 1-100 ⁇ g, preferably 5-50 ⁇ g, most typically in the range 5-25 ⁇ g. Following an initial vaccination, subjects may receive one or several booster immunizations adequately spaced.
- Vaccine preparation is generally described in Vaccine Design (“The subunit and adjuvant approach” (eds Powell M. F. & Newman M. J.) (1995) Plenum Press New York). Encapsulation within liposomes is described by Fullerton, U.S. Pat. No. 4,235,877.
- the vaccines of the present invention may be stored in solution or lyophilized.
- the solution is lyophilized in the presence of a sugar such as sucrose or lactose. It is still further preferable that they are lyophilized and extemporaneously reconstituted prior to use. Lyophilizing may result in a more stable composition (vaccine) and may possibly lead to higher antibody titers in the presence of 3D-MPL and in the absence of an aluminum based adjuvant.
- a vaccine kit comprising a vial containing an immunogenic composition of the invention, optionally in lyophilised form, and further comprising a vial containing an adjuvant as described herein. It is envisioned that in this aspect of the invention, the adjuvant will be used to reconstitute the lyophilised immunogenic composition.
- the vaccines of the present invention may be administered by any route, administration of the described vaccines into the skin (ID) forms one embodiment of the present invention.
- Human skin comprises an outer “horny” cuticle, called the stratum corneum, which overlays the epidermis. Underneath this epidermis is a layer called the dermis, which in turn overlays the subcutaneous tissue.
- the dermis which in turn overlays the subcutaneous tissue.
- Intradermal vaccination with the vaccines described herein forms a preferred feature of the present invention.
- the conventional technique of intradermal injection comprises steps of cleaning the skin, and then stretching with one hand, and with the bevel of a narrow gauge needle (26-31 gauge) facing upwards the needle is inserted at an angle of between 10-15°.
- the barrel of the needle is lowered and further advanced whilst providing a slight pressure to elevate it under the skin.
- the liquid is then injected very slowly thereby forming a bleb or bump on the skin surface, followed by slow withdrawal of the needle.
- Alternative methods of intradermal administration of the vaccine preparations may include conventional syringes and needles, or devices designed for ballistic delivery of solid vaccines (WO 99/27961), or transdermal patches (WO 97/48440; WO 98/28037); or applied to the surface of the skin (transdermal or transcutaneous delivery WO 98/20734; WO 98/28037).
- the vaccine is in a low liquid volume, particularly a volume of between about 0.05 ml and 0.2 ml.
- the content of antigens in the skin or intradermal vaccines of the present invention may be similar to conventional doses as found in intramuscular vaccines (see above). However, it is a feature of skin or intradermal vaccines that the formulations may be “low dose”. Accordingly the protein antigens in “low dose” vaccines are preferably present in as little as 0.1 to 10 ⁇ g, preferably 0.1 to 5 ⁇ g per dose; and the saccharide (preferably conjugated) antigens may be present in the range of 0.01-1 ⁇ g, and preferably between 0.01 to 0.5 ⁇ g of saccharide per dose.
- the term “intradermal delivery” means delivery of the vaccine to the region of the dermis in the skin.
- the vaccine will not necessarily be located exclusively in the dermis.
- the dermis is the layer in the skin located between about 1.0 and about 2.0 mm from the surface in human skin, but there is a certain amount of variation between individuals and in different parts of the body. In general, it can be expected to reach the dermis by going 1.5 mm below the surface of the skin.
- the dermis is located between the stratum corneum and the epidermis at the surface and the subcutaneous layer below.
- the vaccine may ultimately be located solely or primarily within the dermis, or it may ultimately be distributed within the epidermis and the dermis.
- the present invention further provides an improved vaccine for the prevention or amelioration of Otitis media caused by Haemophilus influenzae by the addition of Haemophilus influenzae proteins, for example protein D in free or conjugated form.
- the present invention further provides an improved vaccine for the prevention or amelioration of pneumococcal infection in infants (e.g., Otitis media), by relying on the addition of one or two pneumococcal proteins as free or conjugated protein to the S. pneumoniae conjugate compositions of the invention.
- Said pneumococcal free proteins may be the same or different to any S. pneumoniae proteins used as carrier proteins.
- One or more Moraxella catarrhalis protein antigens can also be included in the combination vaccine in a free or conjugated form.
- the present invention is an improved method to elicit a (protective) immune response against Otitis media in infants.
- the present invention is an improved method to elicit a (protective) immune response in infants (defined as 0-2 years old in the context of the present invention) by administering a safe and effective amount of the vaccine of the invention [a paediatric vaccine].
- Further embodiments of the present invention include the provision of the antigenic S. pneumoniae conjugate compositions of the invention for use in medicine and the use of the S. pneumoniae conjugates of the invention in the manufacture of a medicament for the prevention (or treatment) of pneumococcal disease.
- the present invention is an improved method to elicit a (protective) immune response in the elderly population (in the context of the present invention a patient is considered elderly if they are 50 years or over in age, typically over 55 years and more generally over 60 years) by administering a safe and effective amount of the vaccine of the invention, preferably in conjunction with one or two S. pneumoniae proteins present as free or conjugated protein, which free S. pneumoniae proteins may be the same or different as any S. pneumoniae proteins used as carrier proteins.
- a further aspect of the invention is a method of immunising a human host against disease caused by S. pneumoniae and optionally Haemophilus influenzae infection comprising administering to the host an immunoprotective dose of the immunogenic composition or vaccine or kit of the invention.
- a further aspect of the invention is an immunogenic composition of the invention for use in the treatment or prevention of disease caused by S. pneumoniae and optionally Heemophilus influenzae infection.
- a further aspect of the invention is use of the immunogenic composition or vaccine or kit of the invention in the manufacture of a medicament for the treatment or prevention of diseases caused by S. pneumoniae and optionally Haemophilus influenzae infection.
- Embodiments herein relating to “vaccine compositions” of the invention are also applicable to embodiments relating to “immunogenic compositions” of the invention, and vice versa.
- Protein D is highly conserved among H. influenzae of all serotypes and non-typeable strains.
- the vector pHIC348 containing the DNA sequence encoding the entire protein D gene has been obtained from Dr. A. Forsgren, Department of Medical Microbiology, University of Lund, Malmo General Hospital, Malmö, Sweden.
- the DNA sequence of protein D has been published by Janson et al. (1991) Infect. Immun. 59: 119-125.
- the expression vector pMG1 is a derivative of pBR322 (Gross et al., 1985) in which bacteriophage ⁇ derived control elements for transcription and translation of foreign inserted genes were introduced (Shatzman et al., 1983). In addition, the Ampicillin resistance gene was exchanged with the Kanamycin resistance gene.
- the E. coli strain AR58 was generated by transduction of N99 with a P1 phage stock previously grown on an SA500 derivative (galE::TN10, lambdaKil ⁇ cl857 ⁇ H1).
- N99 and SA500 are E. coli K12 strains derived from Dr. Martin Rosenberg's laboratory at the National Institute of Health.
- the DNA encoding the protein has been cloned into the expression vector pMG 1.
- This plasmid utilises signals from lambdaphage DNA to drive the transcription and translation of inserted foreign genes.
- the vector contains the promoter PL, operator OL and two utilisation sites (NutL and NutR) to relieve transcriptional polarity effects when N protein is provided (Gross et al., 1985).
- Vectors containing the PL promoter are introduced into an E. coli lysogenic host to stabilise the plasmid DNA. Lysogenic host strains contain replication-defective lambdaphage DNA integrated into the genome (Shatzman et al., 1983).
- the chromosomal lambdaphage DNA directs the synthesis of the cl repressor protein which binds to the OL repressor of the vector and prevents binding of RNA polymerase to the PL promoter and thereby transcription of the inserted gene.
- the cl gene of the expression strain AR58 contains a temperature sensitive mutant so that PL directed transcription can be regulated by temperature shift, i.e. an increase in culture temperature inactivates the repressor and synthesis of the foreign protein is initiated. This expression system allows controlled synthesis of foreign proteins especially of those that may be toxic to the cell (Shimataka & Rosenberg, 1981).
- the AR58 lysogenic E. coli strain used for the production of the protein D carrier is a derivative of the standard NIH E. coli K12 strain N99 (F ⁇ su ⁇ galK2, lacZ ⁇ thr ⁇ ). It contains a defective lysogenic lambdaphage (galE::TN10, lambdaKil c1857 ⁇ H1). The Kil ⁇ phenotype prevents the shut off of host macromolecular synthesis. The c1857 mutation confers a temperature sensitive lesion to the cl repressor. The ⁇ H1 deletion removes the lambdaphage right operon and the hosts bio, uvr3, and chIA loci.
- the AR58 strain was generated by transduction of N99 with a P1 phage stock previously grown on an SA500 derivative (gaIE::TN10, lambdaKil ⁇ cl857 ⁇ H1).
- the introduction of the defective lysogen into N99 was selected with tetracycline by virtue of the presence of a TN10 transposon coding for tetracyclin resistance in the adjacent galE gene.
- the pMG 1 vector which contains the gene encoding the non-structural S1 protein of Influenzae virus was used to construct pMGMDPPrD.
- the protein D gene was amplified by PCR from the pHIC348 vector (Janson et al. 1991 Infect. Immun. 59:119-125) with PCR primers containing NcoI and XbaI restriction sites at the 5′ and 3′ ends, respectively.
- the NcoI/XbaI fragment was then introduced into pMGNS1 between NcoI and XbaI thus creating a fusion protein containing the N-terminal 81 amino acids of the NS1 protein followed by the PD protein.
- This vector was labelled pMGNS1 PrD.
- the protein D does not contain a leader peptide or the N-terminal cysteine to which lipid chains are normally attached. The protein is therefore neither excreted into the periplasm nor lipidated and remains in the cytoplasm in a soluble form.
- the final construct pMG-MDPPrD was introduced into the AR58 host strain by heat shock at 37° C. Plasmid containing bacteria were selected in the presence of Kanamycin. Presence of the protein D encoding DNA insert was demonstrated by digestion of isolated plasmid DNA with selected endonucleases.
- the recombinant E. coli strain is referred to as ECD4.
- the host strain AR58 contains a temperature-sensitive cl gene in the genome which blocks expression from lambda P L at low temperature by binding to OL Once the temperature is elevated cl is released from O L and protein D is expressed.
- the extraction from harvested cells and the purification of protein D was performed as follows.
- the cell culture homogenate is clarified by centrifugation and cell debris is removed by filtration.
- the filtered lysate is applied to a cation exchange chromatography column (SP Sepharose Fast Flow).
- SP Sepharose Fast Flow SP Sepharose Fast Flow
- PD binds to the gel matrix by ionic interaction and is eluted by a step increase of the ionic strength of the elution buffer.
- impurities are retained on an anionic exchange matrix (Q Sepharose Fast Flow).
- PD does not bind onto the gel and can be collected in the flow through.
- the protein D containing ultrafiltration retentate is finally passed through a 0.2 ⁇ m membrane.
- the extraction from harvested cells and the purification of protein D was performed as follows.
- the harvested broth is cooled and directly passed twice through a high pressure homogenizer at a Pressure of around 800 bars.
- the cell culture homogenate is diluted and applied to a cation exchange chromatography column (SP Sepharose Big beads).
- PD binds to the gel matrix by ionic interaction and is eluted by a step increase of the ionic strength of the elution buffer and filtrated.
- impurities are retained on an anionic exchange matrix (Q Sepharose Fast Flow).
- PD does not bind onto the gel and can be collected in the flow through.
- the protein D containing ultrafiltration retentate is finally passed through a 0.2 ⁇ m membrane.
- PhtD protein is a member of the pneumococcal histidine-triad (Pht) protein family characterized by the presence of histidine-triads (HXXHXH motif).
- PhtD is a 838 aa-molecule and carries 5 histidine triads (see MedImmune WO00/37105 SEQ ID NO: 4 for amino acid sequence and SEQ ID NO: 5 for DNA sequence).
- PhtD also contains a proline-rich region in the middle (amino acid position 348-380). PhtD has a 20 aa-N-terminal signal sequence with a LXXC motif.
- the gene sequence of the mature Medimmune PhtD protein was transferred recombinantly to E. coli using the in-house pTCMP14 vector carrying the p ⁇ promoter.
- the E. coli host strain is AR58, which carries the cI857 thermosensitive repressor, allowing heat-induction of the promotor.
- Polymerase chain reaction was realized to amplify the phtD gene from a MedImmune plasmid (carrying the phtD gene from Streptococcus pneumoniae strain Norway 4 (serotype 4)-SEQ ID NO: 5 as described in WO 00/37105).
- Primers specific for the phtD gene only, were used to amplify the phtD gene in two fragments.
- Primers carry either the NdeI and KpnI or the KpnI and XbaI restriction sites. These primers do not hybridize with any nucleotide from the vector but only with phtD specific gene sequences. An artificial ATG start codon was inserted using the first primer carrying the NdeI restriction site.
- the generated PCR products were then inserted into the pGEM-T cloning vector (Promega), and the DNA sequence was confirmed, Subcloning of the fragments in the TCMP14 expression vector was ten realized using standard techniques and the vector was transformed into AR58 E. coli.
- Pneumococcal pneumolysin was prepared and detoxified as described in WO2004/08 1515 and WO2006/032499.
- the activation and coupling conditions are specific for each polysaccharide. These are given in Table 1. Sized polysaccharide (except for PS5, 6B and 23F) was dissolved in NaCl 2M, NaCl 0.2M or in water for injection (WFI). The optimal polysaccharide concentration was evaluated for all the serotypes. All serotypes except serotype 18C were conjugated directly to the carrier protein as detailed below. Two alternative serotype 22F conjugates were made; one conjugated directly, one through an ADH linker.
- CDAP(CDAP/PS ratio 0.5-1.5 mg/mg PS) was added to the polysaccharide solution. 1.5 minute later, 0.2 M-0.3 M NaOH was added to obtain the specific activation pH. The activation of the polysaccharide was performed at this pH during 3 minutes at 25° C.
- Purified protein protein D, PhtD, pneumolysin or DT
- the quantity depends on the initial PS/carrier protein ratio was added to the activated polysaccharide and the coupling reaction was performed at the specific pH for up to 2 hour (depending upon serotype) under pH regulation.
- Polysaccharide serotype 18C was microfluidized before conjugation.
- purified TT was diluted at 25 mg/ml in 0.2M NaCl and the ADH spacer was added in order to reach a final concentration of 0.2M.
- the pH was adjusted to 6.2.
- EDAC 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide
- the reaction of condensation was stopped by increasing pH up to 9.0 for at least 30 minutes at 25° C.
- Derivatized TT was then diafiltrated (10 kDa CO membrane) in order to remove residual ADH and EDAC reagent.
- CDAP solution 100 mg/ml freshly prepared in 50/50 v/v acetonitrile/NFI was added to reach the appropriate CDAP/PS ratio.
- the pH was raised up to the activation pH 9.0 by the addition of 0.3M NaOH and was stabilised at this pH until addition of TT AH .
- TT AH (20 mg/ml in 0.2 M NaCl) was added to reach a ratio TT AH /PS of 2; the pH was regulated to the coupling pH 9.0. The solution was left one hour under pH regulation.
- the pH was adjusted to the quenching pH (pH 9.0).
- the solution was stirred for 30 min at 25° C., and then left overnight at 2-8° C. with continuous slow stirring.
- Activation and coupling are performed at 25° C. under continuous stirring in a temperature-controlled waterbath.
- Microfluidized PS22F was diluted to obtain a final PS concentration of 6 mg/ml in 0.2M NaCl and the solution was adjusted at pH 6.05 ⁇ 0.2 with 0.1N HCl.
- CDAP solution 100 mg/ml freshly prepared in acetonitrile/WFI, 50/50 was added to reach the appropriate CDAP/PS ratio (1.5/1 ww).
- the pH was raised up to the activation pH 9.00 ⁇ 0.05 by the addition of 0.5M NaOH and was stabilised at this pH until addition of ADH.
- ADH was added to reach the appropriate ADH/PS ratio (8.9/1 w/w); the pH was regulated to coupling pH 9.0. The solution was left for 1 hour under pH regulation.
- the PS AH derivative was concentrated and diafiltrated.
- PhtD at 10 mg/ml in 0.2M NaCl was added to the PS22F AH derivative in order to reach a PhtD/PS22F AH ratio of 4/1 (w/w).
- the pH was adjusted to 5.0 ⁇ 0.05 with HCl.
- the EDAC solution (20 mg/ml in 0.1 M Tris-HCl pH 7.5) was added manually in 10 min (250 ⁇ l/min) to reach 1 mg EDAC/mg PS22F AH .
- the resulting solution was incubated for 150 min (though 60 mins was also used) at 25° C. under stirring and pH regulation.
- the solution was neutralized by addition of 1 M Tris-HCl pH 7.5 ( 1/10 of the final volume) and let 30 min at 25° C.
- the conjugate Prior to the elution on Sephacryl S400HR, the conjugate was clarified using a 5 ⁇ m Minisart filter.
- the resulting conjugate has a final PhtD/PS ratio of 4.1 (w/w), a free PS content below 1% and an antigenicity ( ⁇ -PS/ ⁇ -PS) of 36.3% and anti-PhtD antigenicity of 7.4%.
- the conjugates were purified by gel filtration using a Sephacryl S400HR gel filtration column equilibrated with 0.15M NaCl (S500HR for 18C) to remove small molecules (including DMAP) and unconjugated PS and protein. Based on the different molecular sizes of the reaction components, PS-PD, PS-TT, PS-PhtD, PS-pneumolysin or PS-DT conjugates are eluted first, followed by free PS, then by free PD or free DT and finally DMAP and other salts (NaCl, glycine).
- Fractions containing conjugates are detected by UV 280 nm . Fractions are pooled according to their Kd, sterile filtered (0.22 ⁇ m) and stored at +2-8° C. The PS/Protein ratios in the conjugate preparations were determined.
- pHa, c, q corresponds to the pH for activation, coupling and quenching, respectively
- the free polysaccharide content of conjugates kept at 4° C. or stored 7 days at 37° C. was determined on the supernatant obtained after incubation with ⁇ -carrier protein antibodies and saturated ammonium sulfate, followed by a centrifugation.
- the antigenicity on the same conjugates was analyzed in a sandwich-type ELISA wherein the capture and the detection of antibodies were ⁇ -PS and ⁇ -Protein respectively.
- Unconjugated carrier protein can be separated from the conjugate during the purification step.
- the protein conjugates can be adsorbed onto aluminium phosphate and pooled to form the final vaccine.
- Immunogenic conjugates have been produced, that have since been shown to be components of a promising vaccine.
- a 10 valent vaccine was made by mixing serotype 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F conjugates (e.g. at a dose of 1, 3, 1, 1, 1, 1, 1, 1, 3, 3, 1 ⁇ g of saccharide, respectively per human dose).
- An 11 valent vaccine was made by further adding the serotype 3 conjugate from Table 5 (e.g. at 1 ⁇ g of saccharide per human dose).
- a 13 valent vaccine was made by further adding the serotypes 19A and 22F conjugates above (with 22F either directly linked to PhtD, or alternatively through an ADH linker) [e.g. at a dose of 3 ⁇ g each of saccharide per human dose].
- a 14 valent vaccine may be made by further adding the serotype 6A conjugate above [e.g. at a dose of 1 ⁇ g of saccharide per human dose.
- Infanrix-hexa is a combination of Pediarix and Hib mixed before administration.
- a clinical diagnosis of AOM was based on either the visual appearance of the tympanic membrane (i.e. redness, bulging, loss of light reflex) or the presence of middle ear fluid effusion (as demonstrated by simple or pneumatic otoscopy or by microscopy).
- ear pain had to be present: ear pain, ear discharge, hearing loss, fever, lethargy, irritability, anorexia, vomiting, or diarrhea.
- ENT specialist confirmed the clinical diagnosis, a specimen of middle ear fluid was collected by tympanocentesis for bacteriological testing.
- AOM episode For subjects with repeated sick visits, a new AOM episode was considered to have started if more than 30 days had elapsed since the beginning of the previous episode. In addition, an AOM episode was considered to be a new bacterial episode if the isolated bacterium/serotype differed from the previous isolate whatever the interval between the two consecutive episodes.
- Table 3 presents the protective efficacy of the 11 Pn-PD vaccine and both 7-valent vaccines previously tested in Finland (Eskola et al N Engi J Med 2001; 344: 403-409 and Kilpi et al Clin Infect Dis 2003 37:1155-64) against any episode of AOM and AOM caused by different pneumococcal serotypes, H. influenzae , NTHi and M. catarrhalis .
- Statistically significant and clinically relevant reduction by 33.6% of the overall AOM disease burden was achieved with 11 Pn-PD, irrespective of the etiology (table 3).
- the overall efficacy against AOM episodes due to any of the 11 pneumococcal serotypes contained in the 11 PN-PD vaccine was 57.6% (table 3).
- the 22F inhibition ELISA method was essentially based on an assay proposed in 2001 by Concepcion and Frasch and was reported by Henckaerts et al., 2006, Clinical and Vaccine Immunology 13:356-360. Briefly, purified pneumococcal polysaccharides were mixed with methylated human serum albumin and adsorbed onto Nunc MaxisorpTM (Roskilde, D K) high binding microtitre plates overnight at 4° C. The plates were blocked with 10% fetal bovine serum (FBS) in PBS for 1 hour at room temperature with agitation.
- FBS fetal bovine serum
- Serum samples were diluted in PBS containing 10% FBS, 10 ⁇ g/mL cell-wall polysaccharide (SSI) and 2 ⁇ g/mL of pneumococcal polysaccharide of serotype 22F (ATCC), and further diluted on the microtitre plates with the same buffer.
- An internal reference calibrated against the standard serum 89-SF using the serotype-specific IgG concentrations in 89-SF was treated in the same way and included on every plate. After washing, the bound antibodies were detected using peroxidase-conjugated anti-human IgG monoclonal antibody (Stratech Scientific Ltd., Soham, UK) diluted in 10% FBS (in PBS), and incubated for 1 hour at room temperature with agitation.
- the color was developed using ready-to-use single component tetramethylbenzidine peroxidase enzyme immunoassay substrate kit (BioRad, Hercules, Calif., US) in the dark at room temperature. The reaction was stopped with H2SO4 0.18 M, and the optical density was read at 450 nm. Serotype-specific IgG concentrations (in ⁇ g/mL) in the samples were calculated by referencing optical density points within defined limits to the internal reference serum curve, which was modelized by a 4-parameter logistic log equation calculated with SoftMax ProTM (Molecular Devices, Sunnyvale, Calif.) software. The cut-off for the ELISA was 0.05 ⁇ g/mL IgG for all serotypes taking into account the limit of detection and the limit of quantification.
- Table 10 shows 22F-ELISA antibody concentrations and percentages of subjects reaching the 0.2 ⁇ g/mL threshold before and after 23-valent plain polysaccharide booster vaccination.
- opsonophagocytic activity was shown to be clearly improved for antibodies induced with these 19F-DT formulations as demonstrated by higher seropositivity rates (opsonophagocytic titers ⁇ 1:8) and OPA GMTs one month following primary vaccination (Table 9).
- opsonophagocytic activity of 19F antibodies remained significantly better for children primed with 19F-DT formulations (Table 11).
- Table 12 presents immunogenicity data following a 11Pn-PD booster dose in toddlers previously primed with 19F-DT or 19F-PD conjugates compared to a 4 th consecutive dose of Prevnar®. Given the breakthrough cases reported after the introduction of Prevnar® in the US, the improved opsonophagocytic activity against serotype 19F when conjugated to the DT carrier protein may be an advantage for the candidate vaccine.
- Table 13 provides ELISA and OPA data for the 19F-DT conjugate with respect to the cross-reactive serotype 19A. It was found that 19F-DT induces low but significant OPA activity against 19A.
- GSK formulated an 11-valent polysaccharide (PS) conjugate vaccine with a novel adjuvant Adjuvant C—see below.
- the 11-valent PS conjugates were each composed of the following conjugates PS1-PD, PS3-PD, PS4-PD, PS5-PD, PS7F-PD, PS9V-PD, PS14-PD, PS18C-PD, PS19F-PD, PS23F-DT and PS6B-DT.
- Anti-PS ELISA IgG levels and opsono-phagocytosis titres were dosed in sera collected at day 42.
- Anti-PS3 memory B cell frequencies were measured by Elispot from peripheral blood cells collected at day 42.
- Adjuvant C significantly improved the immunogenicity of 11-valent PS conjugates versus conjugates with AIPO4 in elderly monkeys.
- the novel adjuvant enhanced the IgG responses to PS ( FIG. 1 ) and the opsono-phagocytosis antibody titres (Table 14).
- the principle of the assay relies on the fact that memory B cells mature into plasma cells in vitro following cultivation with CpG for 5 days. In vitro generated antigen-specific plasma cells can be easily detected and therefore be enumerated using the B-cell elispot assay. The number of specific plasma cells mirrors the frequency of memory B cells at the onset of the culture.
- in vitro generated plasma cells are incubated in culture plates coated with antigen.
- Antigen-specific plasma cells form antibody/antigen spots, which are detected by conventional immuno-enzymatic procedure and enumerated as memory B cells.
- Polysaccharides have been used to coat culture plates in order to enumerate respective memory B cells. Results are expressed as a frequency of PS specific memory B cells within a million of memory B cells.
- Adjuvant C may be able to alleviate the known problem of PS3 boostability (see 5th International Symposium on Pneumococci and Pneumococcal Diseases, Apr. 2-6 2006, Alice Springs, Central Australia.
- mice Groups of 40 female Balb/c mice (4-weeks old) were immunized IM at days 0, 14 and 28 with 50 ⁇ l of either 4-valent plain PS or 4-valent dPly-conjugated PS, both admixed with Adjuvant C.
- Both vaccine formulations were composed of 0.1 ⁇ g (quantity of saccharide) of each of the following PS: PS8, PS12F, PS19F and PS22F.
- Anti-PS ELISA IgG levels were dosed in sera collected at day 42.
- the anti-PS19F response shown as an example in FIG. 3 , was strongly enhanced in mice given 4-valent dPly conjugates compared to mice immunized with the plain PS. The same improvement was observed for the anti-PS8, 12F and 22F IgG responses (data not shown).
- mice Groups of 40 female Balb/c mice (4-weeks old) were immunized IM at days 0, 14 and 28 with 50 ⁇ l of either 4-valent plain PS or 4-valent PhtD-conjugated PS, both admixed with Adjuvant C.
- Both vaccine formulations were composed of 0.1 ⁇ g (quantity of saccharide) of each of the following PS: PS8, PS12F, PS19F and PS22F.
- Anti-PS ELISA IgG levels were dosed in sera collected at day 42.
- the anti-PS22F response shown as an example in FIG. 4 , was strongly enhanced in mice given 4-valent PhtD conjugates compared to mice immunized with the plain PS. The same improvement was observed for the anti-PS8, 12F and 19F IgG responses (data not shown).
- mice Groups of 30 old C57Bl mice (>69-weeks old) were immunized IM at days 0, 14 and 28 with 50 ⁇ l of either 11-valent PS conjugates or 13-valent PS conjugates, both admixed with Adjuvant C (see below).
- the 11-valent vaccine formulation was composed of 0.1 ⁇ g saccharide of each of the following conjugates: PS1-PD, PS3-PD, PS4-PD, PS5-PD, PS6B-PD, PS7F-PD, PS9V-PD, PS14-PD, PS18C-TT, PS19F-DT and PS23F-PD (see Table 1 and comment on 11 valent vaccine discussed under Table 2).
- the 13-valent vaccine formulation contained in addition 0.1 ⁇ g of PS19A-dPly and PS22F-PhtD conjugates (see Table 1 and comment on 13 valent vaccine discussed under Table 2 [using directly-conjugated 22F]).
- Anti-PS19A and 22F ELISA IgG levels were dosed in individual sera collected at day 42.
- the ELISA IgG response generated to the other PS was measured in pooled sera.
- 19A-dPly and 22F-PhtD administered within the 13-valent conjugate vaccine formulation were shown immunogenic in old C57BI mice (Table 15). The immune response induced against the other PS was not negatively impacted in mice given the 13-valent formulation compared to those immunized with the 11-valent formulation.
- mice Groups of 30 young Balb/c mice (4-weeks old) were immunized IM at days 0, 14 and 28 with 50 ⁇ l of either 11-valent PS conjugates or 13-valent PS conjugates, both admixed with Adjuvant C (see below).
- the 11-valent vaccine formulation was composed of 0.1 ⁇ g saccharide of each of the following conjugates: PS1-PD, PS3-PD, PS4-PD, PS5-PD, PS6B-PD, PS7F-PD, PS9V-PD, PS14-PD, PS18C-Tf, PS19F-DT and PS23F-PD (see Table 1 and comment on 11 valent vaccine discussed under Table 2).
- the 13-valent vaccine formulation contained in addition 0.1 ⁇ g of PS19A-dPly and PS22F-PhtD conjugates (see Table 1 and comment on 13 valent vaccine discussed under Table 2 [using directly-conjugated 22F]).
- Anti-PS19A and 22F ELISA IgG levels were dosed in individual sera collected at day 42.
- the ELISA IgG response generated to the other PS was measured in pooled sera.
- 19A-dPly and 22F-PhtD administered within the 13-valent conjugate vaccine formulation were shown immunogenic in young Balb/c mice (Table 16). The immune response induced against the other PS was not negatively impacted in mice given the 13-valent formulation compared to those immunized with the 11-valent formulation.
- the 11-valent vaccine formulation was composed of 0.25 ⁇ g saccharide of each of the following conjugates: PS1-PD, PS3-PD, PS4-PD, PS5-PD, PS6B-PD, PS7F-PD, PS9V-PD, PS14-PD, PS18C-TT, PS19F-DT and PS23F-PD (see Table 1 and comment on 11 valent vaccine discussed under Table 2).
- the 13-valent vaccine formulation contained in addition 0.1 ⁇ g of PS19A-dPly and PS22F-PhtD conjugates (see Table 1 and comment on 13 valent vaccine discussed under Table 2 [using directly-conjugated 22F]).
- Anti-PS19A and 22F ELISA IgG levels were dosed in individual sera collected at day 42.
- the ELISA IgG response generated to the other PS was measured in pooled sera.
- the saccharides are also formulated with two liposome
- mice Groups of 30 female Balb/c mice were immunised by the intramuscular (IM) route at days 0, 14 and 28 with 13-valent PS formulations containing PS 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F and 23F (dose: 0.3 ⁇ g saccharide/PS for P ⁇ 4, 18C, 19A, 19F and 22F and 0.1 ⁇ g saccharide/PS for the other PS).
- IM intramuscular
- PS 18C was conjugated to Tetanus Toxoid, 19F to Diphteria Toxoid, 19A to formol-detoxified Ply, 22F to PhtD and the other PS to PD.
- Two formulations constituted of either 22F-PhtD prepared by direct CDAP chemistry or 22F-AH-PhtD (ADH-derivitized PS), were compared. See Example 2, Table 1 and comment under Table 2 for characteristics of 13 valent vaccine made either with 22F directly conjugated or via an ADH spacer.
- the vaccine formulations were supplemented with adjuvant C.
- Anti-PS22F ELISA IgG levels and opsono-phagocytosis titres were measured in sera collected at day 42.
- 22F-AH-PhtD was shown much more immunogenic than 22F-PhtD in terms of both IgG levels ( FIG. 5 ) and opsono-phagocytic titres ( FIG. 6 ).
- Groups of 40 female Balb/c mice were immunised by the IM route at days 0, 14 and 28 with 13-valent PS formulations containing PS 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F and 23F (dose: 0.3 ⁇ g/PS for P ⁇ 4, 18C, 19A, 19F and 22F and 0.1 ⁇ g/PS for the other PS).
- PS 18C was conjugated to Tetanus Toxoid, 19F to Diphteria Toxoid, 19A to formol-detoxified Ply, 22F to PhtD and the other PS to PD. See Example 2, Table 1 and comment under Table 2 for characteristics of 13 valent vaccine made with 22F directly conjugated.
- Anti-PS, Ply, PhtD and PD ELISA IgG levels were measured in sera collected at day 42 and pooled per group. The following ratio was calculated for each antigen:IgG level induced with the new adjuvant tested/IgG level induced with AIPO 4 .
- 11-valent PS conjugates i.e. 1 ⁇ g of PS 1, 3, 5, 6B, 7F, 9V, 14 and 23F, and 3 ⁇ g of PS 4, 18C and 19F
- PS 18C was conjugated to Tetanus Toxoid, 19F to Diphteria Toxoid and the other PS to PD. See Example 2, Table 1 and comment under Table 2 for characteristics of 11 valent vaccine. All formulations were supplemented with adjuvant C.
- Type 19F pneumococci (5.10 8 cfu) were inoculated in the right lung at day 42. Colonies were counted in broncho-alveolar lavages collected at days 1, 3 and 7 post-challenge. The results were expressed as the number of animals per group either dead, lung colonized or cleared at day 7 after challenge.
- mice Groups of 20 female OF1 mice were immunised by the intramuscular route at days 0 and 14 with 3 ⁇ g of either 22F-PhtD (prepared by direct CDAP chemistry) or 22F-AH-PhtD (ADH-derivitized PS), or the adjuvant alone. Both monovalent 22F conjugates were made by the processes of Example 2 (see also Table 1 and Table 2). Each formulation was supplemented with adjuvant C.
- Anti-PhtD ELISA IgG levels were measured in sera collected at day 27.
- mice were challenged intranasally with 5.10 6 cfu of type 4 pneumococci at day 28 (i.e. a pneumococcal serotype not potentially covered by the PS present in the vaccine formulation tested). The mortality induced was monitored until day 8 post-challenge.
- 22F-AH-PhtD induced a significantly higher anti-PhtD IgG response and better protection against type 4 challenge than 22F-PhtD.
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RU2600838C1 (ru) * | 2015-06-08 | 2016-10-27 | Андрей Дмитриевич Протасов | Способ усиления активности факторов неспецифической защиты у пациентов с хронической обструктивной болезнью легких |
MY187461A (en) * | 2015-06-08 | 2021-09-23 | Serum Inst Of India Private Ltd | Methods for improving the adsorption of polysaccharide-protein conjugates and multivalent vaccine formulation obtained thereof |
KR20160146240A (ko) | 2015-06-12 | 2016-12-21 | 전관구 | 염기성 계면활성제를 이용한 산화은나노 및 은나노 제조 방법 |
HUE053272T2 (hu) * | 2015-06-23 | 2021-06-28 | Biological E Ltd | Multivalens konjugált pneumococcus vakcina |
CN108367063A (zh) * | 2015-07-21 | 2018-08-03 | 辉瑞公司 | 包含缀合的荚膜糖抗原的免疫原性组合物及其试剂盒和用途 |
GB201518684D0 (en) * | 2015-10-21 | 2015-12-02 | Glaxosmithkline Biolog Sa | Vaccine |
GB201522068D0 (en) | 2015-12-15 | 2016-01-27 | Glaxosmithkline Biolog Sa | Dried composition |
EP3493840B1 (en) | 2016-08-05 | 2022-08-24 | Sanofi Pasteur Inc. | Multivalent pneumococcal polysaccharide-protein conjugate composition |
BR112019001971A2 (pt) | 2016-08-05 | 2019-05-07 | Sanofi Pasteur, Inc. | composição conjugada de polissacarídeo-proteína pneumocócica multivalente |
CN109890413B (zh) | 2016-09-02 | 2024-04-16 | 赛诺菲巴斯德股份有限公司 | 脑膜炎奈瑟氏菌疫苗 |
CN109982715A (zh) * | 2016-09-27 | 2019-07-05 | 免疫疫苗技术有限公司 | 利用低剂量体积b细胞表位组合物以在受试人中诱导抗体免疫应答的方法 |
EP3518965A1 (en) * | 2016-09-30 | 2019-08-07 | Biological E Limited | Multivalent pneumococcal vaccine compositions comprising polysaccharide-protein conjugates |
CN108144052A (zh) * | 2016-12-02 | 2018-06-12 | 武汉博沃生物科技有限公司 | 肺炎链球菌多糖-蛋白质缀合物及其制取方法和用途 |
EP3562838A2 (en) | 2016-12-28 | 2019-11-06 | Henriques Normark, Birgitta | Microparticles from streptococcus pneumoniae as vaccine antigens |
US11951165B2 (en) | 2016-12-30 | 2024-04-09 | Vaxcyte, Inc. | Conjugated vaccine carrier proteins |
JP7186166B2 (ja) * | 2016-12-30 | 2022-12-08 | バックスサイト・インコーポレイテッド | 非天然アミノ酸とのポリペプチド抗原接合体 |
MX2019008564A (es) * | 2017-01-20 | 2019-09-19 | Pfizer | Composiciones inmunogenicas para su uso en vacunas neumococicas. |
CN110225757A (zh) | 2017-01-31 | 2019-09-10 | 默沙东公司 | 由肺炎链球菌血清型19f生产荚膜多糖蛋白缀合物的方法 |
US11400162B2 (en) | 2017-02-24 | 2022-08-02 | Merck Sharp & Dohme Llc | Processes for the formulation of pneumococcal polysaccharides for conjugation to a carrier protein |
US10259865B2 (en) | 2017-03-15 | 2019-04-16 | Adma Biologics, Inc. | Anti-pneumococcal hyperimmune globulin for the treatment and prevention of pneumococcal infection |
CN107929728A (zh) * | 2017-04-19 | 2018-04-20 | 武汉博沃生物科技有限公司 | 一种肺炎球菌蛋白疫苗及其制备方法 |
WO2018227177A1 (en) | 2017-06-10 | 2018-12-13 | Inventprise, Llc | Multivalent conjugate vaccines with bivalent or multivalent conjugate polysaccharides that provide improved immunogenicity and avidity |
US10729763B2 (en) | 2017-06-10 | 2020-08-04 | Inventprise, Llc | Mixtures of polysaccharide-protein pegylated compounds |
WO2019043245A1 (en) * | 2017-09-04 | 2019-03-07 | London School Of Hygiene And Tropical Medicine | MICROBIAL CELLS EXPRESSING STREPTOCOCCAL SERROTYPES |
MX2020002556A (es) | 2017-09-07 | 2020-07-13 | Merck Sharp & Dohme | Polisacaridos neumococicos y su uso en conjugados de polisacarido inmunogenico con proteina transportadora. |
US11395849B2 (en) | 2017-09-07 | 2022-07-26 | Merck Sharp & Dohme Llc | Pneumococcal polysaccharides and their use in immunogenic polysaccharide-carrier protein conjugates |
JP2020533299A (ja) * | 2017-09-07 | 2020-11-19 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | キャリアタンパク質へのコンジュゲーションのための肺炎球菌多糖の製剤方法 |
CN111683678B (zh) | 2017-12-06 | 2024-01-26 | 默沙东有限责任公司 | 包含肺炎链球菌多糖蛋白缀合物的组合物及其使用方法 |
KR102486891B1 (ko) | 2018-02-05 | 2023-01-10 | 사노피 파스퇴르 인코포레이티드 | 다가 폐렴구균성 다당류-단백질 접합체 조성물 |
WO2019152921A1 (en) | 2018-02-05 | 2019-08-08 | Sanofi Pasteur Inc. | Multivalent pneumococcal polysaccharide-protein conjugate composition |
CA3096358A1 (en) | 2018-04-18 | 2019-10-24 | Sk Bioscience Co., Ltd. | Streptococcus pneumoniae capsular polysaccharide and immunogenic conjugate thereof |
CN112074293A (zh) * | 2018-04-30 | 2020-12-11 | 默沙东公司 | 生产肺炎链球菌荚膜多糖载体蛋白缀合物的方法 |
KR20210002641A (ko) | 2018-04-30 | 2021-01-08 | 머크 샤프 앤드 돔 코포레이션 | 디메틸술폭시드 중의 동결건조된 돌연변이체 디프테리아 독소의 균질 용액을 제공하는 방법 |
JP2021522285A (ja) * | 2018-04-30 | 2021-08-30 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | リオスフィアから肺炎連鎖球菌莢膜多糖類キャリアタンパク質コンジュゲートを生産する方法 |
CN108524926B (zh) * | 2018-06-29 | 2021-06-29 | 康希诺生物股份公司 | 一种多价肺炎球菌结合疫苗的制剂组合及其应用 |
AU2019299836A1 (en) * | 2018-07-04 | 2021-02-25 | Vaxcyte, Inc. | Improvements in immunogenic conjugates |
KR20210093854A (ko) * | 2018-09-12 | 2021-07-28 | 아피니백스, 인크. | 다가 폐렴구균 백신 |
TWI788610B (zh) | 2018-12-19 | 2023-01-01 | 美商默沙東有限責任公司 | 包含肺炎鏈球菌多醣-蛋白質結合物之組合物及其使用方法 |
KR20210010412A (ko) * | 2019-07-18 | 2021-01-27 | (주)셀트리온 | 다가 폐렴구균 다당류-단백질 접합체를 포함하는 면역원성 조성물 |
AU2020347951B2 (en) | 2019-09-18 | 2023-11-02 | Alcon Inc. | Wet-packed soft hydrogel ocular inserts |
WO2021146681A1 (en) * | 2020-01-17 | 2021-07-22 | Inventprise, Llc | Multivalent streptococcus vaccines |
KR20210117663A (ko) | 2020-03-20 | 2021-09-29 | 주식회사 보고 | 수직형 침지식 dpf 세척장치 |
CN116121106A (zh) * | 2021-07-08 | 2023-05-16 | 成都生物制品研究所有限责任公司 | 肺炎链球菌无动物源冻干保护剂 |
KR20240055283A (ko) | 2022-10-20 | 2024-04-29 | 우남철 | Dpf용 순환펌프 연결구 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5695768A (en) * | 1995-06-07 | 1997-12-09 | Alberta Research Council | Immunostimulating activity of Streptococcus pneumoniae serotype 8 oligosaccharides |
US5785973A (en) * | 1988-02-01 | 1998-07-28 | Praxis Biologics, Inc. | Synthetic peptides representing a T-cell epitope as a carrier molecule for conjugate vaccines |
US5965714A (en) * | 1997-10-02 | 1999-10-12 | Connaught Laboratories, Inc. | Method for the covalent attachment of polysaccharides to protein molecules |
Family Cites Families (177)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4057685A (en) | 1972-02-02 | 1977-11-08 | Abbott Laboratories | Chemically modified endotoxin immunizing agent |
US4235877A (en) | 1979-06-27 | 1980-11-25 | Merck & Co., Inc. | Liposome particle containing viral or bacterial antigenic subunit |
EP0027888B1 (en) | 1979-09-21 | 1986-04-16 | Hitachi, Ltd. | Semiconductor switch |
BE889979A (fr) | 1981-08-14 | 1982-02-15 | Smith Kline Rit | Procede de preparation de polysaccharides bacteriens capsulaires antigeniques purifies, produits obtenus et leur utilisation |
US4673574A (en) | 1981-08-31 | 1987-06-16 | Anderson Porter W | Immunogenic conjugates |
US4619828A (en) | 1982-07-06 | 1986-10-28 | Connaught Laboratories, Inc. | Polysaccharide exotoxoid conjugate vaccines |
SE8205892D0 (sv) | 1982-10-18 | 1982-10-18 | Bror Morein | Immunogent membranproteinkomplex, sett for framstellning och anvendning derav som immunstimulerande medel och sasom vaccin |
US4459286A (en) | 1983-01-31 | 1984-07-10 | Merck & Co., Inc. | Coupled H. influenzae type B vaccine |
US4695624A (en) | 1984-05-10 | 1987-09-22 | Merck & Co., Inc. | Covalently-modified polyanionic bacterial polysaccharides, stable covalent conjugates of such polysaccharides and immunogenic proteins with bigeneric spacers, and methods of preparing such polysaccharides and conjugates and of confirming covalency |
US4808700A (en) | 1984-07-09 | 1989-02-28 | Praxis Biologics, Inc. | Immunogenic conjugates of non-toxic E. coli LT-B enterotoxin subunit and capsular polymers |
US4596556A (en) | 1985-03-25 | 1986-06-24 | Bioject, Inc. | Hypodermic injection apparatus |
US4709017A (en) | 1985-06-07 | 1987-11-24 | President And Fellows Of Harvard College | Modified toxic vaccines |
IT1187753B (it) | 1985-07-05 | 1987-12-23 | Sclavo Spa | Coniugati glicoproteici ad attivita' immunogenica trivalente |
US5173294A (en) | 1986-11-18 | 1992-12-22 | Research Foundation Of State University Of New York | Dna probe for the identification of haemophilus influenzae |
US4950740A (en) | 1987-03-17 | 1990-08-21 | Cetus Corporation | Recombinant diphtheria vaccines |
AU614755B2 (en) | 1987-06-05 | 1991-09-12 | United States of America, as represented by the Secretary, U.S. Department of Commerce, The | Autocrine motility factors in cancer diagnosis and management |
US4941880A (en) | 1987-06-19 | 1990-07-17 | Bioject, Inc. | Pre-filled ampule and non-invasive hypodermic injection device assembly |
US4940460A (en) | 1987-06-19 | 1990-07-10 | Bioject, Inc. | Patient-fillable and non-invasive hypodermic injection device assembly |
US4790824A (en) | 1987-06-19 | 1988-12-13 | Bioject, Inc. | Non-invasive hypodermic injection device |
US5339163A (en) | 1988-03-16 | 1994-08-16 | Canon Kabushiki Kaisha | Automatic exposure control device using plural image plane detection areas |
US5278302A (en) | 1988-05-26 | 1994-01-11 | University Patents, Inc. | Polynucleotide phosphorodithioates |
US4912094B1 (en) | 1988-06-29 | 1994-02-15 | Ribi Immunochem Research Inc. | Modified lipopolysaccharides and process of preparation |
DE3841091A1 (de) | 1988-12-07 | 1990-06-13 | Behringwerke Ag | Synthetische antigene, verfahren zu ihrer herstellung und ihre verwendung |
WO1990006951A1 (en) | 1988-12-16 | 1990-06-28 | De Staat Der Nederlanden Vertegenwoordigd Door De Minister Van Welzijn, Volksgezondheid En Cultuur | Pneumolysin mutants and pneumococcal vaccines made therefrom |
EP0378881B1 (en) | 1989-01-17 | 1993-06-09 | ENIRICERCHE S.p.A. | Synthetic peptides and their use as universal carriers for the preparation of immunogenic conjugates suitable for the development of synthetic vaccines |
EP0382271B1 (en) | 1989-02-04 | 1994-12-21 | Akzo Nobel N.V. | Tocols as adjuvant in vaccine |
WO1990014837A1 (en) | 1989-05-25 | 1990-12-13 | Chiron Corporation | Adjuvant formulation comprising a submicron oil droplet emulsion |
FR2649013B1 (fr) | 1989-07-03 | 1991-10-25 | Seppic Sa | Vaccins et vecteurs de principes actifs fluides contenant une huile metabolisable |
FR2649012B1 (fr) | 1989-07-03 | 1991-10-25 | Seppic Sa | Emulsions multiphasiques injectables |
EP0482068A1 (en) | 1989-07-14 | 1992-04-29 | American Cyanamid Company | Cytokine and hormone carriers for conjugate vaccines |
US5064413A (en) | 1989-11-09 | 1991-11-12 | Bioject, Inc. | Needleless hypodermic injection device |
US5312335A (en) | 1989-11-09 | 1994-05-17 | Bioject Inc. | Needleless hypodermic injection device |
IT1237764B (it) | 1989-11-10 | 1993-06-17 | Eniricerche Spa | Peptidi sintetici utili come carriers universali per la preparazione di coniugati immunogenici e loro impiego per lo sviluppo di vaccini sintetici. |
SE466259B (sv) | 1990-05-31 | 1992-01-20 | Arne Forsgren | Protein d - ett igd-bindande protein fraan haemophilus influenzae, samt anvaendning av detta foer analys, vacciner och uppreningsaendamaal |
EP0468520A3 (en) | 1990-07-27 | 1992-07-01 | Mitsui Toatsu Chemicals, Inc. | Immunostimulatory remedies containing palindromic dna sequences |
DE69113564T2 (de) | 1990-08-13 | 1996-05-30 | American Cyanamid Co | Faser-Hemagglutinin von Bordetella pertussis als Träger für konjugierten Impfstoff. |
US5153312A (en) | 1990-09-28 | 1992-10-06 | American Cyanamid Company | Oligosaccharide conjugate vaccines |
CA2059693C (en) | 1991-01-28 | 2003-08-19 | Peter J. Kniskern | Polysaccharide antigens from streptococcus pneumoniae |
CA2059692C (en) * | 1991-01-28 | 2004-11-16 | Peter J. Kniskern | Pneumoccoccal polysaccharide conjugate vaccine |
US6592876B1 (en) | 1993-04-20 | 2003-07-15 | Uab Research Foundation | Pneumococcal genes, portions thereof, expression products therefrom, and uses of such genes, portions and products |
EP0786521A1 (en) | 1991-02-15 | 1997-07-30 | Uab Research Foundation | Nucleic acid encoding PspA |
US5476929A (en) | 1991-02-15 | 1995-12-19 | Uab Research Foundation | Structural gene of pneumococcal protein |
GB9105992D0 (en) | 1991-03-21 | 1991-05-08 | Smithkline Beecham Biolog | Vaccine |
US5552146A (en) | 1991-08-15 | 1996-09-03 | Board Of Regents, The University Of Texas System | Methods and compositions relating to useful antigens of Moraxella catarrhalis |
GB9118204D0 (en) | 1991-08-23 | 1991-10-09 | Weston Terence E | Needle-less injector |
NZ249704A (en) | 1992-02-11 | 1996-11-26 | Jackson H M Found Military Med | A two carrier immunogenic construct comprising a 70+ kd molecule conjugated to at least 1 t-dependent antigen, preparation, compositions containing the construct |
IT1262896B (it) | 1992-03-06 | 1996-07-22 | Composti coniugati formati da proteine heat shock (hsp) e oligo-poli- saccaridi, loro uso per la produzione di vaccini. | |
MY111880A (en) | 1992-03-27 | 2001-02-28 | Smithkline Beecham Biologicals S A | Hepatitis vaccines containing 3-0 deacylated monophosphoryl lipid a |
AU4230493A (en) | 1992-05-06 | 1993-11-29 | President And Fellows Of Harvard College | Diphtheria toxin receptor-binding region |
EP0652758B1 (en) | 1992-06-18 | 2000-01-05 | The President And Fellows Of Harvard College | Diphtheria toxin vaccines |
KR100278157B1 (ko) | 1992-06-25 | 2001-01-15 | 장 스테판느 | 보조약을 함유하는 백신 조성물 |
US5383851A (en) | 1992-07-24 | 1995-01-24 | Bioject Inc. | Needleless hypodermic injection device |
IL102687A (en) | 1992-07-30 | 1997-06-10 | Yeda Res & Dev | Conjugates of poorly immunogenic antigens and synthetic pepide carriers and vaccines comprising them |
US5569189A (en) | 1992-09-28 | 1996-10-29 | Equidyne Systems, Inc. | hypodermic jet injector |
US5334144A (en) | 1992-10-30 | 1994-08-02 | Becton, Dickinson And Company | Single use disposable needleless injector |
GB9224584D0 (en) | 1992-11-23 | 1993-01-13 | Connaught Lab | Use of outer membrane protein d15 and its peptides as vaccine against haempohilus influenzae diseases |
DK0812593T4 (da) | 1993-03-23 | 2008-05-13 | Smithkline Beecham Biolog | Vaccinepræparater indeholdende 3-O-deacyleret monophosphoryllipid-A |
PT699076E (pt) | 1993-05-18 | 2003-03-31 | Univ Ohio State Res Found | Vacina contra a otite media |
ATE254475T1 (de) | 1993-09-22 | 2003-12-15 | Jackson H M Found Military Med | Verfahren zur aktivierung von löslichem kohlenhydraten durch verwendung von neuen cyanylierungsreagenzien, zur herstellung von immunogenischen konstrukten |
SK281944B6 (sk) | 1993-11-17 | 2001-09-11 | Laboratoires Om S. A. | Beta(1->6)glukozamínové disacharidy, spôsob ich prípravy, farmaceutický prostriedok, ktorý ich obsahuje, a ich použitie |
GB9326253D0 (en) | 1993-12-23 | 1994-02-23 | Smithkline Beecham Biolog | Vaccines |
WO1995024176A1 (en) | 1994-03-07 | 1995-09-14 | Bioject, Inc. | Ampule filling device |
US5466220A (en) | 1994-03-08 | 1995-11-14 | Bioject, Inc. | Drug vial mixing and transfer device |
WO1995026204A1 (en) | 1994-03-25 | 1995-10-05 | Isis Pharmaceuticals, Inc. | Immune stimulation by phosphorothioate oligonucleotide analogs |
US6455673B1 (en) | 1994-06-08 | 2002-09-24 | President And Fellows Of Harvard College | Multi-mutant diphtheria toxin vaccines |
US5917017A (en) | 1994-06-08 | 1999-06-29 | President And Fellows Of Harvard College | Diphtheria toxin vaccines bearing a mutated R domain |
EP0772619B2 (en) | 1994-07-15 | 2010-12-08 | The University of Iowa Research Foundation | Immunomodulatory oligonucleotides |
US5565204A (en) | 1994-08-24 | 1996-10-15 | American Cyanamid Company | Pneumococcal polysaccharide-recombinant pneumolysin conjugate vaccines for immunization against pneumococcal infections |
US5599302A (en) | 1995-01-09 | 1997-02-04 | Medi-Ject Corporation | Medical injection system and method, gas spring thereof and launching device using gas spring |
ES2200059T3 (es) | 1995-03-22 | 2004-03-01 | Henry M. Jackson Foundation For The Advancement Of Military Medicine | Produccion de construcciones inmunogenicas usando carbohidratos solubles activados mediante reactivos cianilados organicos. |
GB9620795D0 (en) | 1996-10-05 | 1996-11-20 | Smithkline Beecham Plc | Vaccines |
UA56132C2 (uk) | 1995-04-25 | 2003-05-15 | Смітклайн Бічем Байолоджікалс С.А. | Композиція вакцини (варіанти), спосіб стабілізації qs21 відносно гідролізу (варіанти), спосіб приготування композиції вакцини |
US6440425B1 (en) | 1995-05-01 | 2002-08-27 | Aventis Pasteur Limited | High molecular weight major outer membrane protein of moraxella |
US5730723A (en) | 1995-10-10 | 1998-03-24 | Visionary Medical Products Corporation, Inc. | Gas pressured needle-less injection device and method |
US5843464A (en) | 1995-06-02 | 1998-12-01 | The Ohio State University | Synthetic chimeric fimbrin peptides |
GB9513074D0 (en) | 1995-06-27 | 1995-08-30 | Cortecs Ltd | Novel anigen |
US5666153A (en) | 1995-10-03 | 1997-09-09 | Virtual Shopping, Inc. | Retractable teleconferencing apparatus |
US6290970B1 (en) | 1995-10-11 | 2001-09-18 | Aventis Pasteur Limited | Transferrin receptor protein of Moraxella |
US5893397A (en) | 1996-01-12 | 1999-04-13 | Bioject Inc. | Medication vial/syringe liquid-transfer apparatus |
US6090576A (en) | 1996-03-08 | 2000-07-18 | Connaught Laboratories Limited | DNA encoding a transferrin receptor of Moraxella |
GB9607549D0 (en) | 1996-04-11 | 1996-06-12 | Weston Medical Ltd | Spring-powered dispensing device |
CA2253252A1 (en) | 1996-05-01 | 1997-11-06 | The Rockefeller University | Choline binding proteins for anti-pneumococcal vaccines |
US7341727B1 (en) | 1996-05-03 | 2008-03-11 | Emergent Product Development Gaithersburg Inc. | M. catarrhalis outer membrane protein-106 polypeptide, methods of eliciting an immune response comprising same |
AU3399197A (en) | 1996-06-18 | 1998-01-07 | Alza Corporation | Device for enhancing transdermal agent delivery or sampling |
EP0956289A4 (en) | 1996-08-16 | 2004-10-13 | Smithkline Beecham Corp | NOVEL PROKARYOTA POLYNUCLEOTIDES AND POLYPEPTIDES AND USES THEREOF |
DE69737125T3 (de) | 1996-10-31 | 2015-02-26 | Human Genome Sciences, Inc. | Streptococcus pneumoniae-Antigene und Impfstoffe |
AU5355398A (en) | 1996-11-12 | 1998-06-03 | Regents Of The University Of Minnesota | C3 binding protein of (streptococcus pneumoniae) |
US5980898A (en) | 1996-11-14 | 1999-11-09 | The United States Of America As Represented By The U.S. Army Medical Research & Material Command | Adjuvant for transcutaneous immunization |
DE69720057T2 (de) | 1996-12-20 | 2003-09-25 | Alza Corp | Vorrichtung und verfahren zur erhöhung des transdermalen wirkstoffeflusses |
DE19708537A1 (de) | 1997-03-03 | 1998-09-10 | Biotechnolog Forschung Gmbh | Neues Oberflächenprotein (SpsA-Protein) von Streptococcus pneumoniae etc. |
US6299881B1 (en) | 1997-03-24 | 2001-10-09 | Henry M. Jackson Foundation For The Advancement Of Military Medicine | Uronium salts for activating hydroxyls, carboxyls, and polysaccharides, and conjugate vaccines, immunogens, and other useful immunological reagents produced using uronium salts |
US6764840B2 (en) | 1997-05-08 | 2004-07-20 | Corixa Corporation | Aminoalkyl glucosaminide phosphate compounds and their use as adjuvants and immunoeffectors |
US6113918A (en) | 1997-05-08 | 2000-09-05 | Ribi Immunochem Research, Inc. | Aminoalkyl glucosamine phosphate compounds and their use as adjuvants and immunoeffectors |
US6303347B1 (en) | 1997-05-08 | 2001-10-16 | Corixa Corporation | Aminoalkyl glucosaminide phosphate compounds and their use as adjuvants and immunoeffectors |
FR2763244B1 (fr) * | 1997-05-14 | 2003-08-01 | Pasteur Merieux Serums Vacc | Composition vaccinale multivalente a porteur mixte |
US5993412A (en) | 1997-05-19 | 1999-11-30 | Bioject, Inc. | Injection apparatus |
EP1000144B1 (en) | 1997-06-03 | 2007-12-12 | Sanofi Pasteur Limited | Lactoferrin receptor gene of moraxella |
GB9711990D0 (en) | 1997-06-11 | 1997-08-06 | Smithkline Beecham Biolog | Vaccine |
GB9713156D0 (en) | 1997-06-20 | 1997-08-27 | Microbiological Res Authority | Vaccines |
JP2001510031A (ja) | 1997-07-21 | 2001-07-31 | ノース・アメリカン・ヴァクシン・インコーポレーテッド | ワクチンとしての修飾された免疫原ニューモリシン組成物 |
GB9718901D0 (en) | 1997-09-05 | 1997-11-12 | Smithkline Beecham Biolog | Vaccine |
WO1999011241A1 (en) | 1997-09-05 | 1999-03-11 | Smithkline Beecham Biologicals S.A. | Oil in water emulsions containing saponins |
JP2001517449A (ja) | 1997-09-24 | 2001-10-09 | リージェンツ・オブ・ザ・ユニバーシティ・オブ・ミネソタ | ストレプトコッカス・ニューモニア由来のヒト補体c3分解プロテイナーゼ |
US6224880B1 (en) * | 1997-09-24 | 2001-05-01 | Merck & Co., Inc. | Immunization against Streptococcus pneumoniae using conjugated and unconjugated pneumoccocal polysaccharide vaccines |
AU756828B2 (en) | 1997-12-02 | 2003-01-23 | Powderject Vaccines, Inc. | Transdermal delivery of particulate vaccine compositions |
IT1298087B1 (it) | 1998-01-08 | 1999-12-20 | Fiderm S R L | Dispositivo per il controllo della profondita' di penetrazione di un ago, in particolare applicabile ad una siringa per iniezioni |
US7018637B2 (en) | 1998-02-23 | 2006-03-28 | Aventis Pasteur, Inc | Multi-oligosaccharide glycoconjugate bacterial meningitis vaccines |
KR100638503B1 (ko) | 1998-04-07 | 2006-10-26 | 세인트 쥬드 칠드런즈 리써치 호스피탈 | N-말단 콜린 결합 단백질 a 절두물의 아미노산을 포함하는 폴리펩티드, 이로부터 유도된 백신 및 이를 포함하는 약제학적 조성물 |
KR20060126844A (ko) | 1998-04-07 | 2006-12-08 | 메디뮨 인코포레이티드 | 백신용 폐렴 구균의 콜린 결합성 단백질의 유도체 |
EP1073450A4 (en) | 1998-04-23 | 2003-04-23 | Uab Research Foundation | PNEUMOCOCCAL SURFACE PROTEIN C (PSPC), EPITOPIC REGIONS, SELECTION OF CORRESPONDING STRES AND USES |
AU7924598A (en) | 1998-06-08 | 1999-12-30 | Sca Emballage France | Fast flattening packaging |
GB9812613D0 (en) | 1998-06-11 | 1998-08-12 | Smithkline Beecham Biolog | Vaccine |
DK1091928T3 (da) | 1998-06-30 | 2007-07-23 | Om Pharma | Nye acylerede pseudodipeptider, fremgangsmåde til disses fremstilling og sammensætninger, som indeholder dem |
AU771330B2 (en) | 1998-08-19 | 2004-03-18 | Baxter Healthcare Sa | Immunogenic beta-propionamido-linked polysaccharide protein conjugate useful as a vaccine produced using an N-acryloylated polysaccharide |
GB9818548D0 (en) | 1998-08-25 | 1998-10-21 | Microbiological Res Authority | Treatment of mucas hypersecretion |
IL142017A0 (en) | 1998-09-24 | 2002-03-10 | Univ Minnesota | Human complement c3-degrading polypeptide from streptococcus pneumoniae |
US6541616B1 (en) | 1998-10-01 | 2003-04-01 | Antex Biologics Inc. | Moraxella catarrhalis protein, gene sequence and uses thereof |
ATE357252T1 (de) | 1998-10-16 | 2007-04-15 | Glaxosmithkline Biolog Sa | Adjuvanzsysteme und impfstoffe |
GB2359228A (en) | 1998-11-17 | 2001-08-15 | Schlumberger Technology Corp | Transmitting information over a communication link |
AU2027400A (en) | 1998-11-19 | 2000-06-05 | St. Jude Children's Research Hospital | Identification and characterization of novel pneumococcal choline binding proteins, cbpg and cbpd, and diagnostic and therapeutic uses thereof |
DK1140157T3 (da) | 1998-12-21 | 2009-06-08 | Medimmune Inc | Streptococcus pneumoniae-proteiner og immunogene fragmenter til vacciner |
WO2000039299A2 (en) | 1998-12-23 | 2000-07-06 | Shire Biochem Inc. | Streptococcus antigens |
EP1034792A1 (en) | 1999-03-11 | 2000-09-13 | Pasteur Merieux Serums Et Vaccins | Intranasal delivery of pneumococcal polysaccharide vaccines |
PL203917B1 (pl) | 1999-03-19 | 2009-11-30 | Glaxosmithkline Biolog Sa | Kompozycja immunogenna, sposób jej wytwarzania oraz zastosowanie |
AU781027B2 (en) | 1999-04-09 | 2005-04-28 | Department Of Health & Human Services | Recombinant toxin a protein carrier for polysaccharide conjugate vaccines |
US6558670B1 (en) | 1999-04-19 | 2003-05-06 | Smithkline Beechman Biologicals S.A. | Vaccine adjuvants |
CZ303515B6 (cs) | 1999-04-19 | 2012-11-07 | Smithkline Beecham Biologicals S. A. | Adjuvantní prostredek |
ATE500843T1 (de) | 1999-06-10 | 2011-03-15 | Medimmune Llc | Streptococcus pneumoniae proteine und impfstoffe |
US6319224B1 (en) | 1999-08-20 | 2001-11-20 | Bioject Medical Technologies Inc. | Intradermal injection system for injecting DNA-based injectables into humans |
US6494865B1 (en) | 1999-10-14 | 2002-12-17 | Becton Dickinson And Company | Intradermal delivery device including a needle assembly |
US20040191834A1 (en) * | 1999-10-28 | 2004-09-30 | Laferriere Craig Antony Joseph | Novel method |
AU1581400A (en) | 1999-12-22 | 2001-07-03 | Om Pharma | Acyl pseudopeptides bearing a functionalised auxiliary spacer |
FR2806304B1 (fr) * | 2000-03-17 | 2002-05-10 | Aventis Pasteur | Conjugues polysaccharidiques du pneumocoque a usage vaccinal contre le tetanos et la diphterie |
GB0007432D0 (en) | 2000-03-27 | 2000-05-17 | Microbiological Res Authority | Proteins for use as carriers in conjugate vaccines |
KR100927767B1 (ko) | 2000-06-20 | 2009-11-20 | 아이디 바이오메디칼 코포레이션 | 스트렙토코커스 항원 |
PE20020126A1 (es) * | 2000-06-29 | 2002-04-27 | Smithkline Beecham Biolog | Composicion de vacuna |
GB0108364D0 (en) * | 2001-04-03 | 2001-05-23 | Glaxosmithkline Biolog Sa | Vaccine composition |
GB0103170D0 (en) | 2001-02-08 | 2001-03-28 | Smithkline Beecham Biolog | Vaccine composition |
JP4843181B2 (ja) | 2000-08-04 | 2011-12-21 | コリクサ コーポレイション | 免疫エフェクター化合物 |
GB0022742D0 (en) | 2000-09-15 | 2000-11-01 | Smithkline Beecham Biolog | Vaccine |
DE60132471T2 (de) | 2000-09-26 | 2009-01-15 | Idera Pharmaceuticals, Inc., Cambridge | Modulation der immunostimulatorischen aktivität von immunostimulierenden oligonukleotidanaloga durch positionelle chemische veränderungen |
WO2002078673A1 (fr) | 2001-03-29 | 2002-10-10 | Takeda Chemical Industries, Ltd. | Procede de production d'un medicament sous forme de granules fins |
US20030031684A1 (en) | 2001-03-30 | 2003-02-13 | Corixa Corporation | Methods for the production of 3-O-deactivated-4'-monophosphoryl lipid a (3D-MLA) |
AU2002309706A1 (en) | 2001-05-11 | 2002-11-25 | Aventis Pasteur, Inc. | Novel meningitis conjugate vaccine |
FR2827199B1 (fr) | 2001-07-10 | 2004-07-09 | Centre Nat Rech Scient | Procede et machine de fabrication ex situ de reseaux de biopuces basse et moyennes integration |
GB0123580D0 (en) | 2001-10-01 | 2001-11-21 | Glaxosmithkline Biolog Sa | Vaccine |
WO2003035836A2 (en) | 2001-10-24 | 2003-05-01 | Hybridon Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5' ends |
GB0130215D0 (en) * | 2001-12-18 | 2002-02-06 | Glaxosmithkline Biolog Sa | Vaccine |
WO2003054007A2 (en) | 2001-12-20 | 2003-07-03 | Shire Biochem Inc. | Streptococcus antigens |
HUP0500539A2 (en) | 2002-02-04 | 2006-09-28 | Corixa Corp | New immunoeffector 2-deoxi-2-amino-3-d glucopyranose derivatives |
GB0213622D0 (en) * | 2002-06-13 | 2002-07-24 | Glaxosmithkline Biolog Sa | Vaccine Corporation |
US20040096461A1 (en) | 2002-07-30 | 2004-05-20 | Baxter Healthcare Corporation | Chimeric multivalent polysaccharide conjugate vaccines |
PT2255826E (pt) | 2002-08-02 | 2016-06-08 | Glaxosmithkline Biologicals Sa | Composições de vacina de neisseria compreendendo uma combinação de antigénios |
GB0220198D0 (en) * | 2002-08-30 | 2002-10-09 | Chiron Spa | Modified saccharides,conjugates thereof and their manufacture |
JP3754420B2 (ja) | 2003-02-04 | 2006-03-15 | 三洋電機株式会社 | 二次電池用電極板及びその製造方法並びにこの電極板を用いた二次電池 |
DE602004010376T2 (de) | 2003-03-13 | 2008-10-23 | Glaxosmithkline Biologicals S.A. | Verfahren zur reinigung von bakteriellem cytolysin |
WO2004083251A2 (en) | 2003-03-17 | 2004-09-30 | Wyeth Holdings Corporation | Mutant cholera holotoxin as an adjuvant and an antigen carrier protein |
EP2851088A1 (en) | 2003-06-23 | 2015-03-25 | Baxter International Inc. | Vaccines against group Y Neisseria meningitidis and meningoccal combinations thereof |
US8048432B2 (en) * | 2003-08-06 | 2011-11-01 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Polysaccharide-protein conjugate vaccines |
GB0323103D0 (en) * | 2003-10-02 | 2003-11-05 | Chiron Srl | De-acetylated saccharides |
GB0408977D0 (en) * | 2004-04-22 | 2004-05-26 | Chiron Srl | Immunising against meningococcal serogroup Y using proteins |
RU2379052C2 (ru) | 2004-04-30 | 2010-01-20 | Чирон С.Р.Л. | Вакцинация менингококковыми конъюгатами |
ATE464066T1 (de) | 2004-05-11 | 2010-04-15 | Staat Der Nederlanden Vert Doo | Neisseria meningitidis igtb los als adjuvans |
GB0421083D0 (en) | 2004-09-22 | 2004-10-27 | Glaxosmithkline Biolog Sa | Purification process |
GB0502096D0 (en) | 2005-02-01 | 2005-03-09 | Chiron Srl | Purification of streptococcal capsular polysaccharide |
US20070184072A1 (en) | 2005-04-08 | 2007-08-09 | Wyeth | Multivalent pneumococcal polysaccharide-protein conjugate composition |
US7955605B2 (en) * | 2005-04-08 | 2011-06-07 | Wyeth Llc | Multivalent pneumococcal polysaccharide-protein conjugate composition |
KR20150061019A (ko) * | 2005-04-08 | 2015-06-03 | 와이어쓰 엘엘씨 | 다가 폐렴구균 다당류-단백질 접합체 조성물 |
CA2611960C (en) | 2005-06-27 | 2015-05-05 | Glaxosmithkline Biologicals S.A. | Immunogenic compositions comprising n.meningitidis capsular saccharide conjugates |
JP5135220B2 (ja) | 2005-09-01 | 2013-02-06 | 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 ゲーエムベーハー アンド カンパニー カーゲー | 血清群c髄膜炎菌を含む複数ワクチン接種 |
US20090035326A1 (en) | 2005-11-01 | 2009-02-05 | Novartis Ag | Compositions with antigens adsorbed to calcium phosphate |
TWI457133B (zh) * | 2005-12-13 | 2014-10-21 | Glaxosmithkline Biolog Sa | 新穎組合物 |
AR058707A1 (es) * | 2005-12-22 | 2008-02-20 | Glaxosmithkline Biolog Sa | Vacuna, procedimiento para fabricarla y su uso |
GB0607088D0 (en) * | 2006-04-07 | 2006-05-17 | Glaxosmithkline Biolog Sa | Vaccine |
ES2540059T3 (es) | 2006-04-26 | 2015-07-08 | Micell Technologies, Inc. | Recubrimientos que contienen múltiples fármacos |
EA200901578A1 (ru) | 2007-06-26 | 2010-08-30 | Глаксосмитклайн Байолоджикалс С.А. | Вакцина, содержащая конъюгаты капсульных полисахаридов streptococcus pneumoniae |
CN102257127B (zh) | 2008-12-18 | 2014-01-01 | 惠氏有限责任公司 | 使用二氧化碳控制肺炎链球菌多糖分子量的方法 |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5785973A (en) * | 1988-02-01 | 1998-07-28 | Praxis Biologics, Inc. | Synthetic peptides representing a T-cell epitope as a carrier molecule for conjugate vaccines |
US5695768A (en) * | 1995-06-07 | 1997-12-09 | Alberta Research Council | Immunostimulating activity of Streptococcus pneumoniae serotype 8 oligosaccharides |
US5965714A (en) * | 1997-10-02 | 1999-10-12 | Connaught Laboratories, Inc. | Method for the covalent attachment of polysaccharides to protein molecules |
Cited By (57)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030180316A1 (en) * | 2000-06-29 | 2003-09-25 | Dominique Boutriau | Multivalent vaccine composition |
US9981045B2 (en) | 2005-04-08 | 2018-05-29 | Wyeth Llc | Multivalent pneumococcal polysaccharide-protein conjugate composition |
US11191830B2 (en) | 2005-04-08 | 2021-12-07 | Wyeth Llc | Process for preparing pneumococcal polysaccharide-protein conjugates |
US10716848B2 (en) | 2005-04-08 | 2020-07-21 | Wyeth Llc | Process for preparing pneumococcal polysaccharide-protein conjugates |
US11969474B2 (en) | 2005-04-08 | 2024-04-30 | Wyeth Llc | Multivalent pneumococcal polysaccharide-protein conjugate composition |
US10780160B2 (en) | 2005-04-08 | 2020-09-22 | Wyeth Llc | Process for preparing pneumococcal polysaccharide-protein conjugates |
US8883163B2 (en) | 2005-06-27 | 2014-11-11 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
US8398983B2 (en) | 2005-06-27 | 2013-03-19 | Glaxosmithkline Biologicals, S.A. | Immunogenic composition |
US20090136541A1 (en) * | 2005-06-27 | 2009-05-28 | Ralph Leon Biemans | Immunogenic composition |
US11241495B2 (en) | 2005-06-27 | 2022-02-08 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
US20080199490A1 (en) * | 2005-06-27 | 2008-08-21 | Glaxosmithkline Biologicals S.A. | Immunogenic Composition |
US10166287B2 (en) | 2005-06-27 | 2019-01-01 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
US10245317B2 (en) | 2005-06-27 | 2019-04-02 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
US20090252759A1 (en) * | 2005-06-27 | 2009-10-08 | Ralph Leon Biemans | Immunogenic composition |
US8431136B2 (en) | 2005-06-27 | 2013-04-30 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
US9358279B2 (en) | 2005-06-27 | 2016-06-07 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
US9931397B2 (en) | 2005-06-27 | 2018-04-03 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
US9789179B2 (en) | 2005-06-27 | 2017-10-17 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
US9486515B2 (en) * | 2005-06-27 | 2016-11-08 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
US20080193476A1 (en) * | 2005-06-27 | 2008-08-14 | Ralph Leon Biemans | Immunogenic Composition |
US10646564B2 (en) | 2005-12-22 | 2020-05-12 | Glaxosmithkline Biologicals S.A. | Vaccine |
US9884113B2 (en) | 2005-12-22 | 2018-02-06 | Glaxosmithkline Biologicals, Sa | Pneumoccal polysacchride conjugate vaccine |
US20090017072A1 (en) * | 2005-12-22 | 2009-01-15 | Glaxosmithkline Biologicals S.A. | Vaccine |
US11400147B2 (en) | 2005-12-22 | 2022-08-02 | Glaxosmithkline Biologicals Sa | Pneumococcal capsular saccharide conjugate vaccine |
US20090017059A1 (en) * | 2005-12-22 | 2009-01-15 | Glaxosmithkline Biologicals S.A. | Vaccine Comprising Streptococcus Pneumoniae Capsular Polysaccharide Conjugates |
US10279033B2 (en) | 2005-12-22 | 2019-05-07 | Glaxosmithkline Biologicals Sa | Vaccine comprising Streptococcus pneumoniae capsular polysaccharide conjugates |
US20110002962A1 (en) * | 2006-08-17 | 2011-01-06 | The Uab Research Foundation | Immunogenic PcpA Polypeptides and Uses Thereof |
US9610339B2 (en) | 2007-06-26 | 2017-04-04 | Glaxosmithkline Biologicals, S.A. | Vaccine comprising Streptococcus pneumoniae capsular polysaccharide conjugates |
US9610340B2 (en) | 2007-06-26 | 2017-04-04 | Glaxosmithkline Biologicals, S.A. | Vaccine comprising Streptococcus pneumoniae capsular polysaccharide conjugates |
WO2010141312A2 (en) | 2009-06-01 | 2010-12-09 | Wake Forest University Health Sciences | Flagellin fusion proteins and conjugates comprising pneumococcus antigens and methods of using the same |
WO2010141312A3 (en) * | 2009-06-01 | 2011-01-27 | Wake Forest University Health Sciences | Flagellin fusion proteins and conjugates comprising pneumococcus antigens and methods of using the same |
US20120301502A1 (en) * | 2010-02-09 | 2012-11-29 | Caulfield Michael J | 15-valent pneumococcal polysaccharide-protein conjugate vaccine composition |
AU2011216095B2 (en) * | 2010-02-09 | 2013-07-18 | Merck Sharp & Dohme Llc | 15-valent pneumococcal polysaccharide-protein conjugate vaccine composition |
WO2011100151A1 (en) * | 2010-02-09 | 2011-08-18 | Merck Sharp & Dohme Corp. | 15-valent pneumococcal polysaccharide-protein conjugate vaccine composition |
WO2011110241A1 (en) * | 2010-03-09 | 2011-09-15 | Glaxosmithkline Biologicals S.A. | Immunogenic composition comprising s. pneumoniae polysaccharides conjugated to carrier proteins |
AU2010348155B2 (en) * | 2010-03-09 | 2014-03-06 | Glaxosmithkline Biologicals S.A. | Immunogenic composition comprising S. pneumoniae polysaccharides conjugated to carrier proteins |
US20140072622A1 (en) * | 2011-05-17 | 2014-03-13 | Glaxosmithkline Biologicals S.A. | Vaccine against streptococcus pneumoniae |
US11510875B2 (en) * | 2012-02-07 | 2022-11-29 | Access To Advanced Health Institute | Adjuvant formulations comprising TLR4 agonists and methods of using the same |
WO2013131983A1 (en) * | 2012-03-07 | 2013-09-12 | Novartis Ag | Adjuvanted formulations of streptococcus pneumoniae antigens |
US20150132339A1 (en) * | 2012-03-07 | 2015-05-14 | Novartis Ag | Adjuvanted formulations of streptococcus pneumoniae antigens |
JP2015510872A (ja) * | 2012-03-07 | 2015-04-13 | ノバルティス アーゲー | Streptococcuspneumoniae抗原の増強された製剤 |
CN104519910A (zh) * | 2012-03-07 | 2015-04-15 | 诺华股份有限公司 | 肺炎链球菌抗原的含佐剂制剂 |
US10034949B2 (en) | 2012-06-20 | 2018-07-31 | Sk Chemicals Co., Ltd. | Polyvalent pneumococcal polysaccharide-protein conjugate composition |
US10058607B2 (en) | 2012-06-20 | 2018-08-28 | Sk Chemicals Co., Ltd. | Polyvalent pneumococcal polysaccharide-protein conjugate composition |
US9561268B2 (en) | 2012-10-17 | 2017-02-07 | Glaxosmithkline Biologicals, S.A. | Immunogenic composition |
US9981029B2 (en) | 2012-12-11 | 2018-05-29 | Sk Chemical Co., Ltd. | Multivalent pneumococcal polysaccharide-protein conjugate composition |
EP2932979A4 (en) * | 2012-12-11 | 2016-06-01 | Sk Chemicals Co Ltd | COMPOSITION OF A POLYSACCHARIDE-MULTIVALENT PNEUMOCOCCAL PROTEIN CONJUGATE |
CN104837505A (zh) * | 2012-12-11 | 2015-08-12 | Sk化学公司 | 多价肺炎球菌多糖-蛋白结合组合物 |
RU2771293C2 (ru) * | 2014-01-21 | 2022-04-29 | Пфайзер Инк. | Иммуногенные композиции, содержащие конъюгированные капсульные сахаридные антигены, и их применение |
RU2774075C1 (ru) * | 2014-01-21 | 2022-06-15 | Пфайзер Инк. | Иммуногенные композиции, содержащие конъюгированные капсульные сахаридные антигены, и их применение |
US11027005B2 (en) | 2016-10-20 | 2021-06-08 | Km Biologics Co., Ltd. | Method for producing Hib conjugate vaccine using PRP with lowered molecular weight |
TWI749085B (zh) * | 2016-10-20 | 2021-12-11 | 日商Km生物醫藥股份有限公司 | 使用低分子化PRP之Hib接合型疫苗之製造方法 |
KR102083973B1 (ko) * | 2016-10-28 | 2020-04-23 | 주식회사 엘지화학 | 향상된 IgG 역가를 갖는 다가면역원성 조성물 및 이의 용도 |
KR20180046893A (ko) * | 2016-10-28 | 2018-05-09 | 주식회사 엘지화학 | 향상된 IgG 역가를 갖는 다가면역원성 조성물 및 이의 용도 |
WO2018080213A1 (ko) * | 2016-10-28 | 2018-05-03 | 주식회사 엘지화학 | 향상된 IgG 역가를 갖는 다가면역원성 조성물 및 이의 용도 |
US11246918B2 (en) | 2017-02-03 | 2022-02-15 | Eva Barbara Schadeck | Haemophilus influenzae saccharide-carrier conjugate compositions and uses thereof |
EP3789494A1 (en) | 2019-09-06 | 2021-03-10 | Serum Institute of India Private Limited | Method for obtaining purified bacterial polysaccharides |
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