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WO 2012/085872 A2 28 June 2012 (28.06.2012) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/085872 A2 28 June 2012 (28.06.2012) P O P C T (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, A61K 39/085 (2006.01) C07K 16/12 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, PCT/IB201 1/055883 MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (22) International Filing Date: OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, 2 1 December 201 1 (21 .12.201 1) SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/426,476 22 December 2010 (22. 12.2010) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant (for all designated States except US): WYETH DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LLC [US/US]; Five Giralda Farms, Madison, New Jersey LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 07940 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and (75) Inventors/ Applicants (for US only): KHANDKE, Lak- Declarations under Rule 4.17 : shmi [US/US]; Pfizer Inc. 401 North Middletown Road, — as to the identity of the inventor (Rule 4.1 7(Ϊ)) Building 140-4th Floor, Pearl River, New York 10965 (US). NONOYAMA, Akihisa [US/US]; 1657 Legendary — as to applicant's entitlement to apply for and be granted a Lane, Morrisville, North Carolina 27560 (US). HODGE, patent (Rule 4.1 7(H)) Tamara Shafer [US/US]; Pfizer Global Research and De — as to the applicant's entitlement to claim the priority of the velopment, 700 Chesterfield Parkway West, Chesterfield, earlier application (Rule 4.1 7(in)) Missouri 63017 (US). NEMA, Sandeep [US/US]; Pfizer Global Research and Development, 700 Chesterfield Park — of inventorship (Rule 4.17(iv)) way West, Chesterfield, Missouri 63017 (US). Published: (74) Agent: POKRAS, Bruce, A.; Pfizer Inc., Five Giralda — without international search report and to be republished Farms, Madison, NJ 07940 (US). upon receipt of that report (Rule 48.2(g)) (81) Designated States (unless otherwise indicated, for every — with sequence listing part of description (Rule 5.2(a)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, < l 00 ©00 o (54) Title: STABLE IMMUNOGENIC COMPOSITIONS OF STAPHYLOCOCCUS AUREUS ANTIGENS (57) Abstract: The present invention is directed towards a lyophilized or reconstituted multi- antigen or multicomponent immuno - genie composition comprising at least one antigen isolated from a staphylococcal bacterium, and methods of making the same. STABLE IMMUNOGENIC COMPOSITIONS OF STAPHYLOCOCCUS AUREUS ANTIGENS Background of the Invention [0001] Humans are the natural reservoirs for Staphylococcus aureus (S. aureus). Healthy individuals can be colonized by S. aureus on the skin, in the nares and the throat either persistently (10-35%), intermittently (20-75%) or be in a non-carriage state (5-70%o) with no associated disease. See Vandenbergh et al, J. Clin. Micro. 37:3 133-3 140 (1999). Disease subsequently occurs when individuals become immunocompromised due to breaches in immune barriers, such as during surgery, placement of indwelling catheters or other devices, trauma, or wounds. The resulting S. aureus infection can cause a wide range of diseases that range from mild skin infections to endocarditis, osteomyelitis, bacteremia, sepsis, and other forms of disease with accompanying high mortality rates. The large human reservoir enhances opportunity for evolution and spread of adapted pathogenic clonal types. [0002] Invasive staphylococcal infections from the Gram positive cocci S. aureus and S. epidermidis are of particular concern because they are an increasing public health problem worldwide. Specifically, S. aureus is responsible for the majority of hospital-acquired (nosocomial) infections, and its prevalence in community- onset infections is increasing. For example, the incidence of invasive methicillin- resistant S. aureus (MRSA) was estimated at 31.8 per 100,000 persons, including 18,650 deaths in the United States in 2005. See Klevens R.M. et al, JAMA, 298:1763-71 (2007). [0003] Staphylococcal diseases have seen a dramatic increase in the last 20 years; this increase parallels the use of intravascular devices and invasive procedures. The rise in disease incidence is made more troubling because of the parallel rise of antibiotic resistance; therefore, there is an urgent need for immunogenic compositions for use in vaccines or to elicit polyclonal or monoclonal antibodies to confer passive immunity as a means to prevent or treat staphylococcal infection and associated diseases. [0004] Clumping factor A (ClfA) is an S. aureus cell wall-associated adhesin that mediates staphylococcal binding to fibrinogen and platelets. It is expressed on the cell surface of the bacterium, where it is thought to promote pathogenesis by binding to the fibrinogen and fibrin that is deposited at the site of tissue damage. ClfA is well conserved, and even the most diverse form (-85% identity) exhibits extensive cross-reactivity to both monoclonal and polyclonal antibodies. Thus, ClfA is a reasonable candidate for a component of a vaccine against S. aureus. However, given the structural instability of ClfA, a formulation of ClfA is problematic since it can readily degrade over time in storage. [0005] Full-length ClfA comprises several regions and domains: an N-terminal secretory domain ("S" domain); followed by a ligand-binding A region, which contains three domains (Nl, N2, which contains an EF-hand motif, and N3); followed by an R region, which contains serine-aspartate dipeptide repeats; followed by a cell wall-binding region ("W" region) containing an LPXTG motif; a hydrophobic membrane-spanning domain ("M" region); and a charged C- terminus ("C" region) containing positively charged amino acids. The N l region contains a protease-sensitive site. Much of the instability of ClfA is attributed to the clipping of ClfA at Nl, which results in fragments containing N l and N2N3. The structure and function of ClfA is disclosed in U.S. Patent Application Publication No. 20070087014A1 (Pavliak et al, April 19, 2007), which is incorporated herein by reference in its entirety. [0006] Staphylococcal microorganisms capable of causing invasive disease generally also are capable of producing a capsule polysaccharide (CP) that encapsulates the bacterium and enhances its resistance to clearance by the host innate immune system. The CP serves to cloak the bacterial cell in a protective capsule that renders the bacteria resistant to phagocytosis and intracellular killing. Bacteria lacking a capsule are more susceptible to phagocytosis. Capsular polysaccharides are frequently an important virulence factor for many bacterial pathogens, including Haemophilus influenzae, Streptococcus pneumoniae and Group B streptococci. [0007] Most clinical isolates of S. aureus are encapsulated with either serotypes 5 or 8. Type 5 (CP5) and type 8 (CP8) capsular polysaccharides have similar tri- saccharide repeating units comprised of N-acetyl mannosaminuronic acid, N-acetyl L-fucosamine, and N-acetyl D-fucosamine. See Fournier, J.M. et al., Infect. Immun. 45:97-93 (1984) and Moreau, M., et al, Carbohydrate Res. 201 :285-297 (1990). The two CPs, which have the same sugars, but differ in the sugar linkages and in sites of O-acetylation, each produce serologically distinct patterns of immunoreactivity. [0008] The S. aureus MntC protein (also known as Protein 305, P305, P305A, and ORF305) is a component of a manganese ABC transporter. This protein is expressed in vivo. S. aureus uses manganese as a cofactor for an enzyme that enhances the survival of S. aureus in neutraphils. MntC is, therefore, important for the in vivo survival of S. aureus during infection. Like ClfA, this protein is also unstable in solution. However, unlike ClfA, which can aggregate, or clip via hydrolysis, the primary mechanism of MntC degradation is deamidation when subject to basic pH and/or temperature around room temperature (about 25°C) or higher. [0009] Accordingly, there is an urgent need not only for vaccines against S. aureus infection, but in particular for vaccines with enhanced antigen stability. Summary of the Invention [0010] The present invention is directed towards a lyophilized or reconstituted multi-antigen or multicomponent immunogenic composition comprising at least one antigen isolated from a staphylococcal bacterium. The antigens, which are polypeptides and polysaccharides, may be obtained, inter alia, directly from the bacterium using isolation procedures known to those skilled in the art, or they may be produced using synthetic protocols, or they may be recombinantly produced using genetic engineering procedures also known to those skilled in the art, or through a combination of any of the foregoing. In certain embodiments, a lyophilized or reconstituted immunogenic composition of the invention comprises an isolated S. aureus clumping factor A (ClfA). In certain embodiments, a lyophilized or reconstituted immunogenic composition of the invention comprises three or more antigens selected from an isolated S. aureus clumping factor A (ClfA) polypeptide, an isolated S. aureus clumping factor B (ClfB) polypeptide, an isolated S.
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