EP3997108A1 - Procédés de production et d'utilisation de compositions de lipooligosaccharides et vaccins - Google Patents
Procédés de production et d'utilisation de compositions de lipooligosaccharides et vaccinsInfo
- Publication number
- EP3997108A1 EP3997108A1 EP20836204.6A EP20836204A EP3997108A1 EP 3997108 A1 EP3997108 A1 EP 3997108A1 EP 20836204 A EP20836204 A EP 20836204A EP 3997108 A1 EP3997108 A1 EP 3997108A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- gonorrhoeae
- compositions
- los
- aluminum
- vaccine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/095—Neisseria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/22—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Neisseriaceae (F)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55505—Inorganic adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
Definitions
- the present invention relates generally to compositions and methods for treating and/or preventing gonococcal infection and/or gonorrhea disease in a subject.
- the invention further relates to providing transformed microbial host cells (e.g., bacterial cells) that have been engineered to produce modified and/or non-naturally occurring Neisseria
- the invention still further relates to immunogenic compositions and vaccines that comprise, in pertinent part, Neisseria gonorrhoeae derived lipooligosaccharide(s).
- Neisseria gonorrhoeae (“N. gonorrhoeae”) is a Gram-negative bacterial pathogen that is the causative agent of the sexually transmitted disease known as gonorrhea.
- Gonorrhea is a common infection especially among sexually active 15-24 year-old individuals.
- gonococcal infection and gonorrhea disease are major public health concerns in the U.S. and globally that are exacerbated by growing multiple drug-resistance in the causative organism.
- CDC Centers for Disease Control
- WHO World Health Organization
- N. gonorrhoeae typically infects the mucosal surfaces of the genitals, rectum, throat, and in rare circumstances, the infection can spread through the bloodstream resulting in a disseminated gonococcal infection (“DGI”).
- DGI disseminated gonococcal infection
- Men infected with gonorrhea typically experience painful and/or frequent urination, off colored and purulent discharge, and inflammation of the genitals. Women typically also suffer discomfort during urination as well as inter menses bleeding, abnormal vaginal discharge, and abdominal or pelvic pain. Similar symptoms effect both sexes when the infection is localized in the eyes (conjunctivitis), throat, (painful and swollen lymph nodes), and rectum (discharge and itching).
- a percentage of men infected with the disease are asymptomatic. And some infected women fail to experience or outwardly present with any symptoms of infection. Often the symptoms experienced by women are only mild and can be mistaken for more common bladder or vaginal infections. Serious long-term complications in women suffering with N. gonorrhoeae infection include pelvic inflammatory disease, ectopic pregnancy, and infertility.
- Antibiotic treatment of gonorrhea has been complicated by the ability of the causative organism to develop resistance to antibiotics used for treatment. Resistance in N.
- gonorrhoeae to fluoroquinolones began to emerge in the U.S. in the 1990s and 2000s, and by 2007 the CDC stopped recommending fluoroquinolones for treatment. This move left the cephalosporin antibiotics as the only remaining class of antimicrobials recommended for treating the disease. Further, in 2010 the CDC’s gonorrhea treatment guidelines were again amended to reflect the concern about the growing antibiotic resistance in frequently co occurring pathogens (e.g., Chlamydia trachomatis) to thusly include oral administration of azithromycin or doxycycline in addition to third generation cephalosporins (e.g., ceftriaxone 250 mg or cefixime 400 mg).
- pathogens e.g., Chlamydia trachomatis
- N. gonorrhoeae Antimicrobial resistance in N. gonorrhoeae is not a new phenomena, it has been growing steadily since the 1940s and there have been frequent emergence of multidrug- resistant strains.
- Lewis DA “Global resistance of Neisseria gonorrhoeae ⁇ . when theory becomes reality,” Curr. Opin. Infect. Dis. , 27(1):62-67 (2014); and Bolan GA, et ai,“The Emerging Threat of Untreatable Gonococcal Infection,” N. Engl. J. Med., 366:485-487 (2012)).
- gonorrhoeae resistance to ceftriaxone increases and high-level macrolide resistance spreads, the state of treatment is precariously disposed to return to the pre antibiotics era where this common infection could not be treated and there was considerable morbidity (pelvic inflammatory disease) and infertility in women and urethral strictures and renal insufficiency in men.
- Several challenges to developing a successful gonorrhea vaccine exist in the laboratory and in the characteristics of causative organism itself. These challenges include the lack of strong correlates of protection, the lack of suitable animal models, the organism’s high antigenic variability, and the typical confinement of the gonococcal infection to mucosal surfaces. Additionally, N. gonorrhoeae interacts with innate immune cells such as
- meningococcal vaccines have not provided protection against gonococcal infection or gonorrhea and the immunogens in meningococcal vaccines have, again thus far, generally been considered unsuitable for protection against N.
- compositions e.g., immunogenic compositions and vaccines
- therapeutic methods that protect against N. gonorrhoeae infection and gonorrhea.
- Preferred compositions and methods in this regard would be administered in one or more doses as vaccines (e.g., to prevent and/or attenuate infection) or as therapeutic compositions (e.g., to treat and/or cure disease).
- Figure 1 shows an exemplary LOS molecule with a Lacto-/ ⁇ /-neotetraose (nLc4) a chain and no b chain extension.
- the nLc4 a chain consists of lactose (Lc2) and N-acetyl lactosamine (LacNAc) and extends from Hep1.
- the b chain would extend from C3 of Hep2, which is substituted by the R3 phosphoethanolamine (PEA) in the Figure.
- the N-acetyl glucosamine (GlcNAc) is the g chain, which is not extended.
- Figure 2 shows the GalNAc-nLc4 a chain and the addition of the non-reducing terminal GalNAc.
- Each sugar conforms a separate antigen: the nLc4 a chain presents four separate antigens, in order from the non-reducing terminus, nLc4, nLc3, Lc2 and b-Glc.
- Plummer FA et al.,“Epidemiologic evidence for the development of serovar-specific immunity after gonococcal infection,” J. Clin. Invest., 83:1472-1476 (1989); and Schmidt KA, et al.,“Experimental gonococcal urethritis and reinfection with homologous gonococci in male volunteers,” Sex Transm.
- the GalNAc-nLc4 a chain has a fifth antigen, the terminal GalNAc, and the b and y chains present additional antigens.
- This Figure further shows Lc2 conforms the antigen recognized by mAb 2C7 wherein binding of this mAb to Lc2 is enhanced by the presence of a parallel a-lactose b chain. N.
- gonorrhoeae strains isolated from blood cultures frequently make LOS with a-lactose b chains (Gibson BW, et al.,“Structure and heterogeneity of the oligosaccharides from the lipooligosaccharides of a pyocin-resistant Neisseria gonorrhoeae," Proc. Natl. Acad. Sci.
- Figure 3 shows the high-level organization of the Neisseria Igt operon.
- Figure 4 shows an exemplary organization of the Neisseria Igt operon as described in Braun DC and Stein DC.
- Braun DC and Stein DC “The IgtABCDE gene cluster, involved in lipooligosaccharide biosynthesis in Neisseria gonorrhoeae, contains multiple promoter sequences,” J. Bacteriol., 186(4): 1038- 1049 (2004)).
- Figure 5 shows silver-stained F62 LOS separated through SDS-PAGE.
- Figure 6 shows an assay using LOS from pyocin-selected mutants of gonococcal strain 1291 , denominated 1291a-e to charge immunofluorescent microspheres that bind antibodies specific for four of the five LOS a chain antigens, nLc4, nLc3, Lc2 and b-Glc.
- the present invention relates generally to compositions and methods for treating and/or preventing gonococcal infection and/or gonorrhea disease in a subject.
- the invention further relates to providing transformed microbial host cells (e.g ., bacterial cells) that have been engineered to produce modified and/or non-naturally occurring Neisseria
- the invention still further relates to immunogenic compositions and vaccines that comprise, in pertinent part, Neisseria gonorrhoeae derived lipooligosaccharide(s).
- the present invention further relates to methods of producing and administering immunogenic compositions and/or vaccines to prevent infection by N. gonorrhoeae in a subject. More particularly, the present invention provides methods of and compositions wherein said immunogenic compositions and/or vaccines are produced in a commensal species of Neisseria bacteria.
- compositions and methods are still further provided for preventing gonorrhea and/or associated pathological conditions caused by N. gonorrhoeae in a human subject.
- compositions e.g., vaccines, immunogenic compositions, pharmaceutical compositions comprising fusions or conjugates of LOS molecules with one or more carrier proteins.
- compositions and methods are provided for treating (e.g., lessening the severity, duration, or (re)occurrence of complications or sequelae related to a disease) caused in a subject (e.g., a human) by infection by N. gonorrhoeae.
- the present invention provides immunogenic compositions (and N. gonorrhoeae vaccines) comprising a GalNAc-nLc4 a chain and an nLc4 a chain from a strain of N.
- the invention still further provides immunogenic composition (and N.
- the immunogenic compositions optionally comprise an adjuvant.
- adjuvants comprising metallic salt(s) (e.g., an aluminum salt selected from the group comprising aluminum hydroxide, aluminum oxy hydroxide, aluminum hydroxyphosphate, aluminum hydroxyphosphate sulfate, aluminum phosphate, and/or potassium aluminum phosphate).
- N. gonorrhoeae vaccines in commensal N. gonorrhoeae species (e.g., a commensal selected from the group comprising/consisting of: N. cinerea, N. elongata, N. flavescens, N.
- the commensal species is N. lactamica.
- the commensal species of N. lactamica is transformed (i.e., genetically engineered to express) one or more genes from pathogenic N. gonorrhoeae strain F62.
- compositions of the present invention e.g., vaccines
- a host with a pathogenic bacteria especially infection of said host with a pathogenic bacteria selected from the Neisseriaceae family of Gram negative bacteria, for example, N. gonorrhoeae.
- a vaccine that confers protective immunity to infants as well as adults and whose protection is long-term.
- the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term "about” meaning within an acceptable error range for the particular value should be assumed.
- infection is intended to include the proliferation of a pathogenic organism within and/or on the tissues of a host organism and especially the proliferation of N. gonorrhoeae in a host.
- Pathogenic organisms typically include bacteria, viruses, fungi and protozoans, although growth of any microbe within and/or on the tissues of an organism are considered to fall within the term“infection.”
- gonorrhea refers to a sexually transmitted disease (“STD”) caused by infection with the N. gonorrhoeae.
- STD sexually transmitted disease
- N. gonorrhoeae infects the mucosal epithelium membranes of the reproductive tract, including the cervix (i.e., gonococcal cervicitis), uterus, and fallopian tubes in women, and the urethra in women and men (i.e., gonococcal urethritis).
- N. gonorrhoeae can also infect the mucous membranes of the mouth, throat, eyes, and rectum and in a small subset of cases lead to disseminated gonococcal infection.
- a“commensal(s)” or a“commensal micro-organism(s)” are those that microorganisms (e.g., bacteria) can colonize a host organism without causing disease.
- Commensal Neisseria are suitable for use in the invention, and these commensal Neisseria are typically selected from the group consisting of N. lactamica, N. cinerea, N. elongata, N. flavescens, N. mucosa, N.
- the“commensal” species e.g., N. lactamica does not possess a capsule.
- the term "antigen” or "immunogenic polypeptide/peptide” is a molecule capable of being bound by an antibody or T-cell receptor.
- An antigen is additionally capable of inducing a humoral immune response and/or cellular immune response leading to the production of B- and/or T-lymphocytes in a subject (e.g., a human).
- the term “immunogen” refers to an antigen that is recognized as unwanted, undesired, and/or foreign in a subject (e.g., a human).
- A“vaccine antigen” is an antigen that when included in a vaccine composition elicits protective immunity to bacterial infection.
- the vaccine is an antigen that when included in a vaccine composition elicits protective immunity to bacterial infection.
- compositions of the present invention are particularly suited to vaccination against infection of an animal (e.g., a mammal, and more particularly, a human).
- an animal e.g., a mammal, and more particularly, a human.
- adjuvant refers to an agent (e.g., metals, metal salts, mineral salt, amino acid, saccharides, oligosaccharides, polysaccharides, lipids, oils, oil in water emulsions, polynucleotides, peptides, polypeptides, proteins, and the like) that stimulates and/or enhances an immune response in a subject (e.g., a human).
- An adjuvant can stimulate and/or enhance an immune response in the absence of an immunogen (i.e., antigen) and/or can stimulate and/or enhance an immune response in the presence of an immunogen.
- a preferred adjuvant is aluminum hydroxyphosphate.
- immune response includes a response by a subject's immune system to an immunogenic composition or vaccine of the present invention.
- Immune responses include both cell-mediated immune responses (responses mediated by antigen- specific T cells and non-specific cells of the immune system) and humoral immune responses (responses mediated by antibodies present in the plasma lymph, and tissue fluids).
- the term “immune response” further encompasses both the initial responses to an immunogen as well as potential memory responses that are a result of "acquired immunity.”
- the phrase "stimulating an immune response” refers to an increase in an immune response in the subject following administration of an immunogenic composition or vaccine composition of the present invention relative to the level of immune response in the subject when a composition of the present invention has not been administered.
- the term " immunogenic composition” refers to a composition that elicits an endogenous immune response in a subject (e.g., a human).
- the endogenous immune response may result in, for example, the switching of a Th1 biased immune response to a Th2 biased immune response, the activation or enhancement of T effector cell responses and/or the reduction of T regulatory cell response, the activation of antigen- specific naive lymphocytes that may then give rise to antibody-secreting B cells or antigen- specific effector and memory T cells or both, and/or the direct activation of antibody- secreting B cells.
- the term“vaccine” or“vaccine composition” refer to an immunogenic composition as above that elicits an immune response in a subject sufficient to protect the subject from acquiring a disease for a period of time (e.g., gonorrhea).
- prophylactic and “preventive” immunogenic compositions, vaccines, or compositions are compositions designed and administered to prevent infection, disease, and/or any related sequelae caused by or associated with a pathogenic organism (e.g., N. gonorrhoeae) in a subject (e.g., a human).
- a pathogenic organism e.g., N. gonorrhoeae
- a subject e.g., a human
- administering includes any method of delivery of a pharmaceutical composition or agent (i.e., an immunogenic composition or vaccine) into a subject's system or to a particular region in or on a subject.
- a pharmaceutical composition or agent i.e., an immunogenic composition or vaccine
- immunogenic compositions and vaccines are administered intramuscularly, subcutaneously, intradermally, intranasally, orally, subcutaneously, transcutaneously, or transmucosally to a subject.
- administration or
- administrations encompass a singular and multiple instances of delivery of an agent to a subject over time such that an immunogenically effective singular delivery as well as a priming delivery (first dose or administration) and a subsequent (second, third, etc., doses or administrations) boosting delivery of an agent are encompassed.
- compositions may be administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
- the term“synergism” refers to at least two substances working together to increase the total effect, the combination is more effective than either substance alone.
- a "synergistically effective" therapeutic amount or “synergistically effective” amount of an agent or therapy is an amount which, when combined with an effective or sub-therapeutic amount of another agent or therapy, produces a greater effect than when either of the two agents are used alone.
- a synergistically effective therapeutic amount of an agent or therapy produces a greater effect when used in combination than the additive effects of each of the two agents or therapies when used alone.
- the term "greater effect” encompasses not only a reduction in symptoms of the disorder to be treated, but also an improved side effect profile, improved tolerability, improved patient compliance, improved efficacy, or any other improved clinical outcome.
- co-administration encompass administration of two or more agents to a subject so that both agents and/or their metabolites are present in the subject at the same time.
- Co administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
- Co-administered agents may be in the same formulation.
- Co- administered agents may also be in different formulations.
- a "therapeutic amount,” as used herein, encompasses the amount of a substance (e.g., the compositions of the present invention) that is sufficient to elicit or promote the desired therapeutic benefit and/or prophylactic benefit.
- a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
- a substance e.g., the compositions of the present invention
- therapeutic amount of the present compositions is sufficient to successfully prevent infection in a subject (e.g., human) with N. gonorrhoeae.
- the term "immunologically effective amount” is that amount sufficient to treat or prevent a disease and/or affect an endogenous immune response in a subject but not causing side effects or severe or excessive immune responses.
- the accurate dosage may vary depending on the antigen(s) to be administered and the desired effect to be obtained, and may be readily determined by those skilled in the art according to factors known in medicine and vaccinology, including the patients age, weight, health state, gender and sensitivity to any components of the intended administration(s), administration routes, and various administration methods.
- an“immunologically effective amount” is the amount of composition sufficient to produce the desired“immunological efficacy” desired as a clinical result (e.g ., disease/infection treatment and/or prevention) in a subject.
- An“immunologically effective amount” can be administered in one or more administrations over a set period of time, including, seconds, minutes, days, or years.
- a "sub-therapeutic amount" of a substance (e.g., the compositions of the present invention) or therapy using the substance is an amount or application less than the effective amount for that substance or therapy, but when combined with an effective or sub- therapeutic amount of another substance or therapy can produce a result desired by the physician, due to, for example, synergy in the resulting efficacious effects, or reduced side effects.
- the phrase“pharmacologically effective carrier” refers to any carrier approved for use in humans which facilitates delivery of the compositions of the instant invention without interfering with their therapeutic effect.
- the carrier preferably is an inert vehicle that exhibits no pharmacologic or therapeutic action.
- pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
- Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
- Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
- Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
- Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
- Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
- the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
- “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes, but is not limited to, polysorbates, as well as polymers, more generally, thickening agents, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. Exemplary pharmaceutical formulation methods and methods of producing pharmaceuticals useful in certain embodiments are described in U.S. 20030211046A1 ; U.S. 20030004182A1 ; U.S. 2002060356384; U.S. 20020015728A1 ; U.S. 6,511 ,660; U.S. 6,406,745; U.S. 6,346,269; U.S. 6,039,977; U.S.
- phrases "pharmaceutically acceptable” further denotes those substances, compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in the administration of the immunogenic compositions and vaccines of the present invention in subjects (e.g., humans) without excessive toxicity, irritation, allergic response,
- the term "subject" refers to an animal, such as a mammal, for example, a human.
- the subject is a mammal, and in particularly preferred embodiments, the subject is human.
- in vitro refers to an event that takes places outside of a subject's body.
- an in vitro assay encompasses any assay run outside of a subject.
- In vitro assays encompass cell-based assays in which cells alive or dead are employed.
- In vitro assays also encompass cell-free assays in which no intact cells are employed.
- in vivo refers to an event that takes place in a subject's body.
- a subject is understood to include both laboratory animals (e.g., mice, rats, monkeys, dogs, and the like) as well humans as in conducting human clinic trials or approved experimental uses.
- sample refers to any sample suitable for testing or assaying according to the methods of the present invention or to routine analytic and/or diagnostic techniques for determining disease and/or the identity of cultured
- sample is not limited to bacterial cultures, but can also be used to describe collected fluids, exudates, tissues, cell, and/or collected microorganisms, viruses, prions, or any portion or subunit thereof of the aforementioned, that are suitably obtained, processed, transported and stored using various standard procedures.
- the samples can be stored in suitable storage or transportation devices, refrigerated, frozen, desiccated, diluted, cultured, divided, passaged, separated, mixed with various additives, mounted on slides, subjected to common molecular or immunological techniques (e.g., amplification, sequencing, immunoprecipitation, and the like) or physicochemical techniques (e.g., spectroscopy, electrophoresis, chromatography, microscopy, nuclear magnetic resonance, and the like).
- common molecular or immunological techniques e.g., amplification, sequencing, immunoprecipitation, and the like
- physicochemical techniques e.g., spectroscopy, electrophoresis, chromatography, microscopy, nuclear magnetic resonance, and the like.
- the present invention relates generally to compositions and methods for treating and/or preventing gonococcal infection and/or gonorrhea disease in a subject.
- the invention further relates to providing transformed microbial host cells (e.g., bacterial cells) that have been engineered to produce modified and/or non-naturally occurring Neisseria
- the invention still further relates to immunogenic compositions and vaccines that comprise, in pertinent part,
- transformed microbial host cells are alternatively described as being LOS production systems and/or the component cells and cell cultures thereof.
- N. gonorrhoeae lipooligosaccharide is an antigenically complex triantennary glycolipid molecule comprising three glycose antennae designated as a, b, and g chains. While the present invention is not limited to any particular mechanisms, sequences, or structures whether antigenic or not, a general structure for N. gonorrhoeae
- lipooligosaccharide is discussed, for example, by Schneider H., et ai, and thusly
- Fig.1 and Fig 2. show potential antigenic
- compositions and lipooligosaccharide structures contemplated by the present invention and are discussed more fully herein.
- compositions of the present invention comprise immunogenic, and more preferably vaccinal (i.e., as a prophylactic or therapeutic vaccine), LOS molecules
- Lipid A comprising one or more a, b, or g chains, and a Lipid A moiety and optionally one or more additional constituents such, but not limited to, adjuvants, enteric coatings, and/or antigens.
- compositions of the present invention comprise LOS molecules further comprising an a chain and a Lipid A moiety. In certain other embodiments, the compositions of the present invention comprise LOS molecules further comprising a b chain. In still further embodiments, the compositions of the present invention comprise LOS molecules further comprising a g chain. More typical embodiments, the compositions comprise one each of a, b, and g chains, and a Lipid A moiety.
- the immunogenic, and more preferably vaccinal LOS compositions of the present invention comprise GalNAc-nLc4 and nLc4 a chains. Accordingly, some embodiments provide LOS molecules having GalNAc-nLc4 a chains as well as molecules having nLc4 a chains.
- the final compositions of the invention i.e., those formulated and intended for administration, are preferably formulated to encompass LOS molecules having: 1 ) GalNAc-nLc4 a chain(s); or 2) nLc4 a chain(s); or 3) combination products having a ratio of both GalNAc-nLc4 a chain(s) and nLc4 a chain(s).
- Suitable ratios when a combined product is desired, comprise both GalNAc-nLc4 a chains and nLc4 a chains formulated, respectively, in ratios from: 0.0001 :99.9999, 0.001:99.999, 0.01 :99.99, 0.1 :99.9,... 0.5:99.50,... 1 :99,... 5:95,... 10:90,... 25:75,... 50:50, and likewise from,
- N. gonorrhoeae strain F62 uniquely makes LOS with both nLc4 and GalNAc-nLc4 a chains.
- Fig. 5 See, Schneider H, et al.,“Stability of expression of Neisseria gonorrhoeae lipooligosaccharides. Infect Immun., 54(3):924-927 (1986)).
- silver stained LOS from strain F62 is shown in an SDS-PAGE gel.
- F62 IgtC is OOF, but its polyG tract optimally splits the promoter, so that the downstream IgtD, which is IF, is re-promoted and strongly expressed.
- F62 makes two LOS molecules, one with nLc4 a chains (faster migrating) and one with GalNAc-nLc4 a chains (slower migrating).
- nLc4 a chains faster migrating
- GalNAc-nLc4 a chains slower migrat
- engineered LOS production systems e.g ., engineered bacteria
- F62 LOS molecules with nLc4 and GalNAc-nLc4 a chains.
- the LOS production systems of the present invention are selected from harmless commensal Neisseria species (e.g., N. Iactamica).
- N. Iactamica a suitable strain N. Iactamica is engineered to stably express immunogenic (i.e., vaccinal) LOS nLc4 and GalNAc-nLc4 a chain glycoforms as contemplated by the present invention; wherein the particular glycoforms are the same as, or substantially similar to, those in strain F62.
- compositions of the present invention are produced in prokaryotic host cells, and more particularly, in bacterial host cells.
- certain compositions of the present invention may be produced in eukaryotic cells (e.g., fungi, yeast, etc.) instead of, or in addition to, being produced in prokaryotic cells.
- a bacteria host is selected from one or more bacterial species of known commensal species of Neisseria. There are 10 identified species of Neisseria, wherein eight of these are classified as human commensal organisms that are generally nonpathogenic in healthy non-immunocompromised individuals. While production of the compositions of the present invention is possible directly in N. gonorrhoeae, in preferred embodiments, other cells are utilized as LOS production systems mainly because N. gonorrhoeae is a BSL2 bacterium and it grows poorly in liquid media.
- the bacterial LOS production system is selected from a species of commensal Neisseria, including, but not limited to: N. cinerea, N. elongata, N. flavescens, N. lactamica, N. mucosa, N. polysaccharea, N. sicca, and N. subflava, with N. perflava and N. flava considered biovars of N. subflava.
- the bacterial host of choice i.e., the LOS production system
- the bacterial host comprises N. lactamica.
- N. lactamica like N. gonorrhoeae, is a Gram-negative diplococcic bacteria.
- N. lactamica however is a strictly commensal species that colonizes the human nasopharynx. It is especially common in young children and forms part of normal healthy placental microbiome. Colonization with N. lactamica very rarely leads to invasive disease, and then only in severely immunocompromised individuals. Genetically engineering a strain of Neisseria commensal to express the relevant LOS antigens of the present invention (e.g., N.
- gonorrhoeae F62 LOS provides a solution to the difficulty of growing large volumes of gonococci necessary for commercial scale vaccine production.
- N. lactamica Production in N. lactamica is contemplated to have several additional advantages over other potential LOS production systems.
- the endotoxin moiety of N. lactamica can be further attenuated by deleting the IptA gene.
- N. lactamica can also be grown in liquid culture for large scale production and most strains of the bacteria make LOS with nLc4 a chains while lacking IgtD.
- Kim JJ, et ai “Neisseria lactamica and Neisseria meningitidis share lipooligosaccharide epitopes but lack common capsular and class 1 , 2 and 3 protein epitopes,” Infect. Immun., 57(2):602-608 (1989); and Stein DC, et ai,“Sequence-based predictions of lipooligosaccharide diversity in the Neisseriaceae and their implication in pathogenicity,” PLoS One 6(4):e18923
- N. lactamica is colistin-resistant, grows well on gonococcal selective medium, and is characterized by its ability to produce acid from glucose, maltose, and lactose as well as for its ability to produce beta-galactosidase.
- N. lactamica is the only species of Neisseria that produces beta-galactosidase and acid from lactose; however, one lactose-negative strain of N. lactamica is known to exist.
- Neisseria While growth media requirements are generally similar for the various species of Neisseria (e.g., Mueller Hinton medium, Thayer-Martin medium, American Type Culture Collection (“ATCC”) Medium 814:GC Agar/Broth Medium, or Columbia Blood Media 693), the respective species have slightly different nutritional profiles that can be used for differentiation and identification.
- a growth media is preferentially supplied as a liquid broth that is supplemented (e.g., with minerals, amino acids, peptones, hemoglobin, sugars, salts, and/or antibiotics, and the like) that is held under a CO2 enriched atmosphere (e.g., 3-7% CO2) at or near 37°C to preferentially sustain the particular species of bacteria (e.g., N. lactamica).
- a CO2 enriched atmosphere e.g., 3-7% CO2
- N. lactamica ST640 Wellcome Trust Sanger Institute, Hinxton, UK
- N. lactamica Y92-1009 K. Anish, et al.,“Neisseria lactamica Y92-1009 complete genome sequence,” Standards in Genomic Sci., 12(41): 1-9 (2017)); and N. lactamica Hollis et al., Strains ATCC 23970, 23971 , 23972 / NCTC 10617, 10618, 10616 (American Type Culture Collection (“ATCC”), Manassas, VA and National Collection of Type Cultures (“NCTC”), Public Health England, Salisbury, UK).
- ATCC American Type Culture Collection
- NCTC National Collection of Type Cultures
- the cells are from a suitable strain of the species N. lactamica, and more preferably, the strain has been engineered and/or selected to exhibit: 1) low lipid phosphate substitutions; 2) low inflammatory profile; 3) good growth in liquid media; and 4) sufficient genetic mutability to be engineered to express high levels of immunogenic gonococcal lipooligosaccharides (e.g., N. gonorrhoeae strain F62 GalNAc- nLc4 and nLc4 a chains).
- immunogenic gonococcal lipooligosaccharides e.g., N. gonorrhoeae strain F62 GalNAc- nLc4 and nLc4 a chains.
- the strain has been engineered to contain a deletion of a portion, or substantially a deletion of all, of IptA gene and/or corresponding operon.
- the LOS production system cells comprise AlptA strains of a Neisseria commensal, and more preferably, comprise a AlptA strain of N. lactamica, N. cinerea, or N. flavescens.
- factors that contribute to the cells of LOS production systems being deemed to have suitably low lipid phosphate substitutions and/or low inflammatory profiles include, but are not limited to, a lack of (or intended reduction therein) of pyrophosphorylation and/or
- lipid phosphates preferably are from 1-3 phosphates, and more preferably two phosphates.
- Neisseria species e.g., N. lactamica
- TNF-a released from 104 of the human monocytic leukemia cell line, THP-1 , after incubation for 18 h with 100 ng/mL of LOS.
- Fowler Ml, et al. “Comparison of the Inflammatory Responses of Human Meningeal Cells following Challenge with Neisseria lactamica and with Neisseria meningitidis," Infect.
- the present invention further contemplates that LOS productions systems (e.g., bacterial host cells) are selected, or subsequently modified, to exhibit good growth characteristics in liquid growth media, for example, from 30-60 min. generation times, and preferably about a 45 min. generation time.
- LOS productions systems e.g., bacterial host cells
- the present invention provides one or more stably transformed commensal Neisseria species.
- the commensal strain comprises N. lactamica, and further comprise a functional IgtA-E operon integrated into the strain for the reliable, safe, and efficient production of LOS antigens of interest.
- the invention provides stably transformed Neisseria commensal species used to make LOS molecules comprising F62 nLc4 and GalNAC-nLc4 a chains.
- Transforming i.e., genetically engineering
- a commensal Neisseria species is preferentially done using one or more of the various primers and methods described in: 1) Cheng H, et al.,“Human lipooligosaccharide IgG that prevents endemic meningococcal disease recognizes and internal lacto-/ ⁇ /-neotetraose structure,” J. Biol. Chem., 286:43622- 43633 (2011); 2) Braun and Stein DC“The IgtABCDE gene cluster, involved in lipooligosaccharide biosynthesis in Neisseria gonorrhoeae, contains multiple promoter sequences,” J. Bacteriol., 186:1038-1049 (2004); 3) Song W, et a/.,“Role of
- One contemplated aspect of these engineering methods involves the amplification of the Igt gene cluster from a N. gonorrhoeae strain (e.g., F62) and modification of the IgtA, IgtC and IgtD coding sequences.
- a further contemplated aspect of these engineering methods involves providing fixed polyguanine tracts that resist slip, produced by replacing every third guanine nucleotide with an alternative nucleotide thus preferentially, avoiding, or minimizing, subsequent changes to the translated protein products so that IgtA, IgtC and IgtD are phase invariant (e.g., GGGGGGGGG becomes GGCGGAGGT).
- a still further aspect of these engineering methods is the internal promoter found in IgtC is modified to promote ⁇ e.g., strongly promote) IgtD expression.
- the final amplicon is introduced into the commensal Neisseria specie(s) (e.g., N. lactamica) using the spot transformation method described by JS Gun and DC Stein.
- JS Gun and DC Stein “Gunn JS and Stein DC,“Use of a non-selectable transformation technique to construct a multiple restriction modification deficient mutant of Neisseria gonorrhoeae,” Mol. Gen. Genet., 251(5):509-517 (1996).
- the Gunn and Stein method permits introduction of DNA sequence alterations into the neisserial chromosome without having to use antibiotic selection.
- LOS production strains with defined chromosomal changes can be constructed without regard to potential polarity effects caused by the insertion of antibiotic resistance cassettes, the availability of antibiotic resistance cassettes, and/or the common problems associated with using antibiotic resistant organisms for production.
- neisserial LOS The reactogenicity of neisserial LOS is mediated in part by the addition of PEA to the lipoidal moiety and is catalyzed by LptA.
- the LOS lipid A of pathogenic Neisseria is substituted with 2-3 P and 1-2 PEA; where phosphorylation correlates with the inflammatory potential of both LOS and bacteria.
- Lipid A of some N. lactamica strains is highly phosphorylated and moderately inflammatory.
- the present invention contemplates using high mass resolution mass spectrometry to discriminate phosphoforms of lipid A from the spectra of various N.
- lactamica strains as part of LOS production system selection. (See, John CM., et al.,“Lack of Lipid A Pyrophosphorylation and Functional LptA Reduces Inflammation by Neisseria Commensals,” Infect. Immun., 80(11):4014-4026 (2012)).
- LOS biosynthesis is regulated primarily by the IgtA-E operon that consists of five genes promoted by upstream and internal promoters. (See, Fig. 3). The size of the operon depicted in Fig. 3 is about 5.8 kb.
- IgtE and IgtB encode galactosyl transferases that complete the nLc4 basal lactose and terminal LacNAc, respectively, they are invariant.
- polyG homopolymeric guanine
- these genes slip in and out of frame and the enzymes they encode (glycosyl transferases) may or may not be functional.
- These slip-strand mispairings result in the production of a different LOS chemotypes.
- the positioning of the polyG tract between two halves of a Pribnow box of an internal promoter found in IgtC can also effect LOS biosynthesis.
- Fig. 4 as compared to Fig. 3, provides a more detailed representation of an exemplary organization of the Neisseria Igt operon described in Braun DC and Stein DC. More particularly, the diagram in Fig. 4 was derived from the DNA sequence of the Igt gene cluster originally published by Gotschlich under NCBI accession number U14554. The sequence numbers given in Fig. 4 correspond to those described in that accession. The features identified in Fig.
- the immunogenic compositions i.e., F62 LOS comprising GalNAc-nLc4 and nLc4 a chains
- F62 LOS comprising GalNAc-nLc4 and nLc4 a chains
- a modification See, Apicella MA, Griffiss JMcL and Schneider H,“Isolation and characterization of lipopolysaccharides, lipooligosaccharides, and lipid A,” Methods
- the present invention is not limited to any particular mechanism(s) or mode(s) of action, it is contemplated that protective LOS immune responses vary between males and females (i.e., gender-specific protective LOS IgG induction during gonococcal infection).
- the present invention provides vaccine compositions that are substantially as effective for preventing (or treating) gonococcal infections and/or gonorrhea in both men and women.
- a vaccine product is provided that is tailored to the immunological responses and gonorrhea disease pathogenesis in either a male or a female.
- IgtA, IgtC and IgtD were amplified from gonococci scraped from diagnostic slides of urethral exudates and their polyguanine tracts sequenced.
- LgtA, which encodes the glucosaminyl transferase that initiates the nLc4 LacNAc is in-frame (IF) in bacteria from the male urethra while IgtC is out of frame (OOF).
- the present invention thus contemplates providing effective gonococcal LOS vaccines that induce IgG that binds the nLc4 a chains made by gonococci in the male urethra (i.e., urethral discharge) to protect women, and also binds the GalNAc-nLc4 a chains made by gonococci shed from the female cervix to protect men.
- the immunogenic, and more preferably vaccinal, compositions of the present invention comprise both GalNAc-nLc4 and nLc4 a chains. Accordingly, certain embodiments provide LOS molecules comprising GalNAc-nLc4 a chains as well as nLc4 a chains.
- the present invention provides methods that use multiplexed indirect immunofluorescent assays based on the LUMINEX ® (ThermoFisher Scientific, Waltham, MA) platform for LOS IgG profiling.
- LUMINEX ® ThermoFisher Scientific, Waltham, MA
- This particular assay uses LOS from pyocin-selected mutants of gonococcal strain 1291 , denominated 1291a-e (Fig.
- FIG. 6 shows a SDS-PAGE of LOS made by the 1291 mutants, wherein the columns read left to right represent mutants: 1291 , 1291a, 1291 b, 1291c, 1291d, and 1291e, respectively.
- the 1291 mutants make LOS with a single glycose deletion in the a chain. (See, Fig. 6).
- 1291wt makes nLc4 a chains, but not GalNAc-nLc4 a chains
- 1291a makes nLc3 a chains (nLc3 is lacto-/ ⁇ /-neotriaose, without the nLc4 terminal Gal)
- 1291b makes Gb3 a chains (not made by gonococci within urethral discharge PMNs) (McLaughlin SE, 2012, supra)]
- 1291 c makes Lc2 a chains (lactose, Fig.
- the invention contemplates IgG that binds 291wt LOS represents the total IgG that binds any of the 1291wt antigens.
- IgG binding to 1291a (nLc3) LOS was subtracted from 1291wt LOS IgG.
- IgG binding to 1291c (Lc2) LOS was subtracted from 1291a LOS IgG.
- Table 2 shows the accuracy of the assays used in this aspect of the invention.
- Concentrations of IgG, in pg/rnL, specific for the nLc4 terminal Gal (nLc4-nLc3), the internal GlcNAc of the nLc4 LacNAc (nLc3-Lc2) and the antigens of the lactose a chain and basal PEA-diheptoside glycolipid and g chain GlcNAc sum to the concentrations bound by the native 1291wt LOS (nLc4) - .28.54 v. 28.62 and 21.37 v. 21.37.
- Table 2 also shows the induction of LOS IgG antibodies during acute gonococcal infection. Concentrations of the four specificities in the sera of infected contacts who were seen within seven days of exposure, before an immune response would have produced new antibodies, were less than those in the sera of infected contacts seen after seven days. While the present invention is not limited to any particular theories related to infection or epidemiology, it is contemplated that these data support to the hypothesis that early treatment contributes to recidivism by preventing induction of protective antibodies.
- Still further embodiments of the present invention include IgG specific for the GalNAc-nLc4 and mAb 2C7 antigens by conjugating 1291e, F62 and 15253 LOS to the microspheres, and incorporating them in the assay.
- N. gonorrhoeae strain F62 makes LOS molecules with nLc4 and GalNAc-nLc4 a chains in nearly equal abundance
- 15253 makes LOS with truncated and parallel b-lactose a chains and a-lactose b chains; it strongly binds mAb 2C7.
- the concentrations of IgG bound by 1291wt LOS (nLc4) are subtracted from those bound to F62 LOS, as described above.
- mAb 2C7-like IgG are quantified in two ways: 1 ) by subtracting concentrations that bind 1291e LOS (b-Glc a chain and basal antigens) from those that bind 1291c LOS (Lc2); and 2) by subtracting concentrations that bind 1291e LOS from those that bind 15253 LOS. Since the a and b chains of 15253 LOS are truncated at lactose (Fig. 2), they will not bind the distal nLc3, nLc4 and GalNAc-nLc4 a chains.
- the immunogenic and/or vaccinal compositions of the present invention optionally further comprise one or more adjuvants or adjuvant systems as a means of enhancing the immune response or immunomodulatory effects of the
- compositions of the present invention can be associated (e.g., chemically linked) to the adjuvant(s) by a coordinate, covalent, hydrophilic, or hydrophobic bonds.
- the association can optionally proceed through an activated moiety or chemical group on the adjuvant or the immunogenic composition and, at least in part, through a fluoride, phosphate, sulfate, carbonate group, or like chemically reactive group or moiety, or through one or more linker molecules.
- the compositions of the present invention are absorbed to the chosen adjuvant(s); while in other embodiments, the compositions are adsorbed to the adjuvant(s).
- the present invention is not intended to be limited however by the method of association between the compositions and the chosen adjuvant(s) and/or adjuvant system(s).
- Suitable adjuvants include, but are not limited to, aluminum salts, 3D- MPL, oil in water emulsions including, but not limited, to AS03, AF03, AF04, MF-59, and QS21.
- Suitable oil in water emulsions can be comprised a-tocopherol, squalene, and polysorbates, TWEEN ® (e.g., 20, 80, etc., Sigma Aldrich, St. Louis, MO), SPAN ® (e.g., 20, 60, 80, 85, etc., Sigma-Aldrich), and the like.
- the adjuvant comprises one or more metallic adjuvants such as an aluminum adjuvant comprising aluminum hydroxide, aluminum oxy hydroxide, aluminum hydroxyphosphate, aluminum hydroxyphosphate sulfate, aluminum phosphate, or alum (potassium aluminum phosphate) or combinations thereof.
- metallic adjuvants such as an aluminum adjuvant comprising aluminum hydroxide, aluminum oxy hydroxide, aluminum hydroxyphosphate, aluminum hydroxyphosphate sulfate, aluminum phosphate, or alum (potassium aluminum phosphate) or combinations thereof.
- aluminum adjuvant comprising aluminum hydroxide, aluminum oxy hydroxide, aluminum hydroxyphosphate, aluminum hydroxyphosphate sulfate, aluminum phosphate, or alum (potassium aluminum phosphate) or combinations thereof.
- other metallic salts have been used to adsorb antigens, including salts of zinc, calcium, cerium, chromium, iron, and beryllium. And these metal salts find use in some embodiments.
- compositions of the present invention but it is not required.
- the skilled artisan will select a suitable adjuvant/adjuvant system based on consideration of various factors including, but not limited to, the desired immune response in the recipient, potential antigen/adjuvant interactions, and potential issues related to immunogenicity ⁇ e.g., potency, Th1/2 bias), ease of formulation (e.g., adsorption state, charge), purification, final product distribution and storage, regulatory acceptability, and the like.
- the final product might lack the desired stability due to the emulsion’s hydrophobic nature.
- one or more nonionic surfactant emulsifiers such as TWEEN® 80 and/or SPAN® 85, are used to prepare stable emulsions; wherein, the two phases are prepared separately then mixed to make the emulsion. Desired homogeneity in these products (e.g., sub-micron particle sizes) for example, ⁇ 0.2 microns, preferably, 40- 80 nm (0.04-0.08 microns, is obtained by using standard methods, including,
- products comprising squalene adjuvants are stored cold (or refrigerated) to retard oxidation of the squalene.
- the stability of products comprising emulsions can be monitored by standard methods, such as, Light Scatter (DLS), gel-electrophoresis, and/or ELISA.
- the potency of adsorbed and non-adsorbed LOS can be compared by producing a series of charged aluminum surfaces ranging from positively charged aluminum hydroxide adjuvant to negatively charged aluminum phosphate.
- Aluminum hydroxide adjuvant can be treated with increasing amounts of phosphate ion to decrease the surface charge of the adjuvant. Phosphate in solution can exchange with surface hydroxyls of aluminum hydroxide adjuvant due to higher affinity for aluminum causing the change in surface charge.
- Phosphate in solution can exchange with surface hydroxyls of aluminum hydroxide adjuvant due to higher affinity for aluminum causing the change in surface charge.
- various formulations are prepared with each of these adjuvant surfaces and the adsorption stability is monitored over time under accelerated conditions (e.g., elevated temperature) using standard methods, including, but not limited to, DLS, gel-electrophoresis, and/or ELISA.
- Product formulations e.g., immunogenic compositions and vaccines
- Aluminum containing adjuvants typically cannot be sterilized using standard methods due to the particle size of the adjuvant being greater than 0.2 pm.
- Materials used to prepare vaccines with aluminum containing adjuvants are thus preferentially sterilized prior to adjuvantation and subsequently handled aseptically during final formulation and filling processes.
- LOS antigens are dissolved in 20 mM succinate, 130 mM NaCI, and adjusted to a of about pH 6.5 and further prepared according to the methods described herein and known in the art.
- isolated gonococcal LOS is provided in an aggregated state when reconstituted (e.g., as micelles).
- Micelle formations can be reduced by adding about 0.02% of a polysorbate-type nonionic surfactant (e.g., polysorbate 20).
- Micellar formulated LOS molecules are then formulated (e.g., conjugated, aggregated, and the like) with one or more suitable protein carriers to achieve the desired level of immunogenicity.
- the bulk product is purified in buffered saline at from about pH 5 to about pH 9.
- the pH stability of the bulk product is determined using common methods such as DLS, gel-electrophoresis, ELISA, and endotoxin activity assays.
- the final product e.g., immunogenic composition and/or vaccine
- the pH of the bulk/final product is adjusted with one or more agents generally regarded as safe (i.e., GRAS) such as salts and sugars or sugar alcohols (e.g., sodium chloride, sucrose, sorbitol, mannitol, and the like) or surfactants (e.g., polysorbate 80, TRITONTM x-100 (Sigma-Aldrich), or deoxycholic acid (“DOC”) and the like) and amino acids.
- agents generally regarded as safe i.e., GRAS
- salts and sugars or sugar alcohols e.g., sodium chloride, sucrose, sorbitol, mannitol, and the like
- surfactants e.g., polysorbate 80, TRITONTM x-100 (Sigma-Aldrich), or deoxycholic acid (“DOC”) and the like
- DOC deoxycholic acid
- the buffing agent comprises DOC.
- Amino acids are also suitable for use as stabilizers in certain formulations.
- lysine, histidine, glycine, arginine, proline, aspartic acid as well as poly-lysine, and combinations thereof, are further contemplated for use in certain embodiments.
- Poly-lysine can also bind the endotoxin portion of the LOS molecule and can reduce or minimize potential reactogenicity.
- the final/bulk product formulations are stored under various temperature conditions (e.g., 25°, 37°, to 45°C) and subsequently monitored over time using common methods such as DLS, gel-electrophoresis, ELISA, and endotoxin activity. It is contemplated that high temperature storage accelerates antigen degradation thus aiding proper stabilizer selection. Similarly, DLS analysis is used to detect antigen aggregation, while gel electrophoresis and ELISA are used to monitor antigen stability.
- the potency of final or candidate products is generally determined using one or more in vivo and/or in vitro methods.
- the present invention contemplates in vivo testing in mice wherein test animals are administered either an adsorbed or non-adsorbed formulation at one or more relevant times (e.g., days 0 and 14). Sera is collected from the animals (e.g., day 28) and the resulting immune responses evaluated using standard ELISA techniques.
- mice receive high, medium, or low doses of final products or candidate formulations comprising either an aluminum or oil in water emulsion adjuvant, wherein a prime dose of the composition is delivered on day 0, and a booster dose on day 14.
- Sera is collected on day 28 and analyzed for antibody response and any Th1/Th2 bias according to standard protocols. It is contemplated that aluminum adjuvanted product will produce a Th2 biased response while emulsion adjuvanted systems will produce a more Th1 biased response.
- the immune response to final products or candidate formulations produced in N. lactamica is compared to LOS antigens produced in N. gonorrhoeae strain F62.
- N. gonorrhoeae strain F62 For example, in one embodiments C57BL/6 mice are
- a vaccine formulated with LOS produced from either N. lactamica or N.
- gonorrhoeae on days 0 and 14. Sera is collected on day 28 and the resulting immune responses are evaluated by ELISA and confirmed by multiplex assays.
- compositions of the present invention may be prepared by means standard in the art.
- a number of standard text are known in the art regarding preparation and formulation considerations. (See e.g., Remington’s Pharmaceutical Sciences).
- compositions e.g., immunogenic compositions and vaccines
- the compositions are sterile and, optionally, preservative-free (e.g., mercurial and/or organomercurial compounds such as thimerosal).
- preservative-free e.g., mercurial and/or organomercurial compounds such as thimerosal
- the compositions are sterile, optionally preservative-free, and formulated in a single-use or unit- dose formats.
- the sterile formulations contain one or more preservatives, stabilizers, sugars, or sugar alcohols.
- compositions of the present invention provide immunogenic compositions and vaccines for use in a subject (e.g., a human) in order to confer a medicinal or therapeutic benefit (e.g. , treating or preventing infection with N. gonorrhoeae and/or gonorrhea disease) in the subject upon administration of an effective dose of the one or more of compositions described herein.
- a subject e.g., a human
- a medicinal or therapeutic benefit e.g. , treating or preventing infection with N. gonorrhoeae and/or gonorrhea disease
- Methods of administering the compounds of the invention may be by metered dose by one or more injection devices.
- the compositions may be filled in unit dosage forms suitable for single administration of a precise dosage.
- the concentration of one or more of the component antigens, or other constituents, provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0.5%, 0.4%, 0.3%, 0.2%, 0.1 %, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01 %, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001 % w/w, w/v or v/v.
- the concentration of one or more of the component antigens, or other constituents, of the present invention is greater than 90%, 80%, 70%,
- the concentration of one or more of the component antigens, or other constituents, of the present invention is in the range from approximately 0.0001 % to approximately 50%, approximately 0.001 % to approximately 40%, approximately 0.01 % to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1 % to approximately 21 %, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1 % to approximately
- the concentration of one or more of the component antigens, or other constituents, of the present invention is in the range from approximately 0.001 % to approximately 10%, approximately 0.01 % to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1 %, approximately 0.1 % to approximately 0.9% w/w, w/v or v/v.
- the amount of one or more of the component antigens, or other constituents, of the present invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g,
- the amount of one or more of the component antigens, or other constituents, of the present invention is more than 0.0001 g, 0.0002 g, 0.0003 g,
- Other embodiments provide, amounts of one or more of the component antigens, or other constituents, of the present invention in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, 1-3 g, or 1-10 g.
- the target dose may be administered in a single dose.
- the target dose may be administered in about or more than about 1 , 2, or 3, or more, doses.
- compositions of the present invention may be administered in one dose or multiple dosages. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the particular compositions used, the purpose of the use, the target cells or tissues infected, and the subject being treated. Single or multiple administrations (e.g., about or more than about 1 , 2, 3, or more doses) over the course of from 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10, or 50, or more, minutes, hours, days, weeks, or months.
- one or more doses of the composition is/are administered (e.g., intramuscularly, subcutaneously, and the like) as prescribed by a physician or as otherwise deemed necessary for maintaining health. Administration can be carried out with the dose level and pattern being selected by the treating physician. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimens is often necessary. Dosing for compositions of the present invention may be found by routine experimentation considering the instant disclosure and one’s skill in the art.
- a suitable pharmaceutical preparation may also include, optionally, in addition to one or more compounds of the present invention, other agents, including, but not limited to, excipients, diluents, stabilizers, formulating agents (e.g., gels and thickeners), antioxidants, chelating agents, preservatives, sterile aqueous solutions, buffers, sugars, and the like, as are generally known and accepted.
- agents including, but not limited to, excipients, diluents, stabilizers, formulating agents (e.g., gels and thickeners), antioxidants, chelating agents, preservatives, sterile aqueous solutions, buffers, sugars, and the like, as are generally known and accepted.
- Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and combinations thereof.
- Exemplary preservatives include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
- Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
- Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate.
- EDTA ethylenediaminetetraacetic acid
- citric acid monohydrate disodium edetate
- dipotassium edetate dipotassium edetate
- edetic acid fumaric acid, malic acid
- phosphoric acid sodium edetate
- tartaric acid tartaric acid
- trisodium edetate trisodium edetate.
- antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
- Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
- Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
- Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
- Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, and potassium metabisulfite.
- the preservative is an antioxidant.
- the preservative is a chelating agent.
- Exemplary buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, trimethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic
- one or more additional small molecule drug and/or biological agents may be preferentially combined with the one or more compounds of the present invention to achieve a beneficial, or even synergistic, outcome in the subject.
- Certain compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other one or more additional agents/drug substances, immunogenic compositions, and/or vaccines against other STDs available now or as they become available (e.gr., T. pallidum, C. tachomatis, HPV- 6, 11 , 16, 18, 31 , 33, 45, 52, and 58, HSV- 2, AIDS, and the like).
- compositions of present invention are administered in a manner consistent with vaccine formulations, and in such amounts as will be therapeutically effective and/or immunogenic.
- the quantity to be administered depends on the subject to be treated, including the capacity of the individual's immune system to synthesize antibodies and the degree of protection desired. Precise amounts of active ingredient required to be
- administered depend on the judgment of the practitioner. Typically, from about 0.1 , to 1 , to 5, to 10, to 20, to 30, to 40, to 50, to 60, to 70, to 80, to 90, to 100 ng, pg, or mg may be administered per vaccination or administration.
- Suitable regimes for initial administration and booster shots are also variable, but are typified by an initial administration followed by subsequent inoculations or other
- administrations from 1 , 2, 3, 4, 5, . . . 10, . . . 20, . . . 35, . . . 55, . . . 100, . . . 1 ,000, . . . 10,000, or more, units of time (e.g., minutes, hours, days, weeks, etc.) pass between the first administration of a composition and subsequent administration(s) to a subject.
- units of time e.g., minutes, hours, days, weeks, etc.
- administrations are constant (e.g., of equal duration). In still other embodiments, the interval(s) between any two or more administrations are varied (e.g., not of equal duration). Varied intervals can be either random or repeating and formulaic.
- compositions and methods of the present invention are immunogenic and/or prophylactic and are administered to a subject to treat and more preferably prevent infection with and/or disease caused N. gonorrhoeae. Accordingly, the present invention specifically contemplates providing a first administration of the
- an administration schedule can proceed with administrations occurring every 1 , 2, 3, 4, 5, 6, 7,
- a first administration of the present immunogenic compositions/vaccines is followed by a subsequent booster administration.
- a single dose of the present compositions will normally be in the range of from about .001 ml_ to about 5.0 ml_ of the composition; preferably the single dose is about 0.03 ml_ to about 0.05 ml_.
- Griffiss JMcL, et al. “Relationship of dose to the reactogenicity and immunogenicity of meningococcal polysaccharide vaccines in adults.”
- Military Med. 150 (10): 529-533 (1985) See, e.g., Griffiss JMcL, et al.,“Relationship of dose to the reactogenicity and immunogenicity of meningococcal polysaccharide vaccines in adults.”
- Military Med. 150 (1010): 529-533 (1985)).
- doses higher or lower than these amounts can be used if desired and the skilled administering physician or healthcare consultant (e.g., nurse, nurse practitioner, pharmacist, and the like) will be able to readily adjust dosing amounts and frequencies to obtain the desired results.
- physicians can use standard tests to determine the efficacy of the various embodiments of the inventive compositions and methods. However, in addition to these standard tests, the physician may also consider quality of life, comfort, hygiene related issues, and prevention of disease transmission in evaluating efficacy of a particular treatment regime and adjust specific administration schedules.
- Exemplary routes of administration to the subject can be through the eyes
- suitable routes of administration include, for example, oral or transmucosal administration as well as parenteral delivery (e.g., intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration).
- parenteral delivery e.g., intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration.
- a sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3- butanediol, using physiological saline, aqueous solutions such as Ringers solution, U.S.P., isotonic sodium chloride solution, and non-aqueous solutions, such as vegetable oils, high fatty acid esters (e.g., ethyl oleic acid, etc.), alcohols (e.g., ethanol, benzyl alcohol, propylene glycol and glycerin, etc.).
- a sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3- butanediol, using physiological saline, aqueous solutions such as Ringers solution, U.S.
- the injectable preparation(s) may be supplemented with pharmaceutical carriers, which are exemplified by a stabilizer for preventing degeneration (e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), or reagents, and techniques, for facilitating solidification/semi-solidification of the preparation(s) (e.g., foam drying, freeze-foam drying, spray drying (atomization), spray- freeze-drying, evaporative drying, percolative drying, vacuum drying, lyophilization, micropelleting, prilling, and variations thereof, etc.), an emulsifier(s), an excipient(s), a buffering agent for pH adjustment, and a preservative for inhibiting contamination, including but not limited to, microbial growth (e.g., phenylmercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benz
- Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- compositions and methods of the present invention are suitable for delivery using intradermal delivery devices (i.e., short singular or plural needle arrays) such as those described in U.S. 4,886,499; U.S.5,190,521 ; U.S. 5,328,483; U.S. 5,527,288; U.S.
- compositions formulated for intradermal delivery may be administered by devices that limit the effective penetration of a needle into the skin, such as those described in PCT publication WO99/34850 and functional equivalents thereof.
- jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum coraeum and produces a jet which reaches the dermis are suitable. Jet injection devices are described, for example, in U.S. 5,480,381; U.S.
- compositions for oral administration are typically liquid or in solid dosage forms.
- Compositions for oral administration may include protease inhibitors, including organic acids such as citric acid, in order to inhibit pancreatic and brush border proteases.
- Compositions for oral administration may additionally include absorption enhancers, such as acylcarnitine and lauroylcarnitine, to facilitate the uptake of the peptide through the lumen of the intestine into the systemic circulation by a paracellular transport mechanism.
- Compositions for oral administration may additionally include detergents to improve the solubility of the peptides and excipients and to decrease interactions with intestinal mucus.
- Solid form compositions for oral administration may typically comprise an enteric coating which further protects the peptides from stomach proteases and permits passage of the tablet or capsule into the small intestine.
- the solid form composition may additionally comprise a subcoat such as a non-ionic polymer. Examples of preparation of such orally available formulations are disclosed in U.S. 5,912,014; U.S. 6,086,918; and U.S. 6,673,574. The disclosure of each of these documents is hereby incorporated herein by reference in its entirety.
- the compositions are presented as capsules, tablets, pills, powders, or granules.
- the active ingredients e.g., LOS antigens and/or adjuvant(s)
- the active ingredients are mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as sodium citrate or dicalcium phosphate and
- the dosage form may comprise buffering agents.
- Solid compositions of a similar type may be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
- Solid compositions of a similar type may be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
- the active ingredient may be admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- the dosage forms may comprise buffering agents.
- opacifying agents may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- embedding compositions which can be used include polymeric substances and waxes.
- exemplary techniques and reagents for solidification/semi solidification of the compositions in particular embodiments may be found in, for example, U.S. 5,307,640; U.S. 5,897,852; U.S. 6,106,836; U.S. 6,458,363; U.S. 7,836,606; U.S.
- EP 1 140 152B1 EP 1 794 524B1 ; WO 2003/072016; WO 2004/073652; WO 2006/008006; FR 1054443; and FR 1056961 , each of which is incorporated herein by reference in its entirety.
- compositions and vaccines of the present invention are preferably supplied in finely divided form along with a surfactant and propellant.
- the surfactant must, of course, be nontoxic, and preferably soluble in the propellant.
- Representatives of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
- Mixed esters, such as mixed or natural glycerides may be employed.
- a carrier can also be included, as desired, such as the inclusion of lecithin for intranasal delivery.
- Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
- a vaccine of the invention may be prepared, packaged, and/or sold in a formulation suitable for buccal administration.
- Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may, for example, comprise about 0.1% to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients.
- formulations suitable for administration to buccal mucosa may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
- Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 pm to about 200 pm, and may further comprise one or more of the additional ingredients (constituents).
- compositions whether biologically, or more particularly immunologically active (i.e., immunogens, antigens, adjuvants, and the like) or conversely inert (e.g., excipients, diluents, buffers, and the like) are selected such that they do not deleteriously react (e.g., acutely diminish stability or immunological efficacy and the like) with other constituents of the composition or produce untoward or adverse reactions in a subject.
- immunologically active i.e., immunogens, antigens, adjuvants, and the like
- inert e.g., excipients, diluents, buffers, and the like
- preferred embodiments of the present invention are formulated and administered systemically or locally.
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Abstract
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US201962871472P | 2019-07-08 | 2019-07-08 | |
US201962872973P | 2019-07-11 | 2019-07-11 | |
PCT/US2020/041272 WO2021007365A1 (fr) | 2019-07-08 | 2020-07-08 | Procédés de production et d'utilisation de compositions de lipooligosaccharides et vaccins |
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EP (1) | EP3997108A4 (fr) |
JP (1) | JP2022541757A (fr) |
AU (1) | AU2020309556A1 (fr) |
CA (1) | CA3147314A1 (fr) |
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US5545553A (en) * | 1994-09-26 | 1996-08-13 | The Rockefeller University | Glycosyltransferases for biosynthesis of oligosaccharides, and genes encoding them |
US6610306B2 (en) * | 1998-10-22 | 2003-08-26 | The University Of Montana | OMP85 protein of neisseria meningitidis, compositions containing the same and methods of use thereof |
US7261901B2 (en) * | 2001-01-31 | 2007-08-28 | University Of Iowa Research Foundation | Vaccine and compositions for the prevention and treatment of neisserial infections |
US7250172B2 (en) * | 2001-01-31 | 2007-07-31 | University Of Iowa Research Foundation | Vaccine and compositions for the prevention and treatment of neisserial infections |
GB0819633D0 (en) * | 2008-10-25 | 2008-12-03 | Isis Innovation | Composition |
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