WO2026006741A1 - Compositions d'adjuvant de nanoparticules lipidiques - Google Patents

Compositions d'adjuvant de nanoparticules lipidiques

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Publication number
WO2026006741A1
WO2026006741A1 PCT/US2025/035708 US2025035708W WO2026006741A1 WO 2026006741 A1 WO2026006741 A1 WO 2026006741A1 US 2025035708 W US2025035708 W US 2025035708W WO 2026006741 A1 WO2026006741 A1 WO 2026006741A1
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Prior art keywords
agonist
composition
lipid
tlr9
mpla
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PCT/US2025/035708
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English (en)
Inventor
Philip Felgner
David Huw Davies
Li Liang
Andriy V. Yeromin
Jiin Felgner
Jenny HERNANDEZ-DAVIES
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University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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Publication of WO2026006741A1 publication Critical patent/WO2026006741A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to compositions and methods that exhibit increased or maintained efficacy while exhibiting reduced toxicity or side effects, with applications in vaccines, immunotherapies, and cancer treatments.
  • Vaccinology applies principles from immunology, microbiology, infectious diseases, and epidemiology to develop vaccines targeting both established and emerging pathogens, as well as broadly applicable vaccine platforms.
  • Pathogens possess multiple components recognized by the immune system during infection, including: (1) antigens, often proteins that bind to host receptors; (2) pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS), muramyl dipeptide (MDP), CpG DNA, and polyl:C RNA; and (3) accessory microbial factors, such as toxins, quorum sensing molecules, and factors involved in microbial adhesion and persistence.
  • PAMPs pathogen-associated molecular patterns
  • LPS lipopolysaccharide
  • MDP muramyl dipeptide
  • CpG DNA CpG DNA
  • polyl:C RNA polyl:C RNA
  • accessory microbial factors such as toxins, quorum sensing molecules, and factors involved in microbial adhesion and persistence.
  • Vaccine development remains limited by the inability to consistently induce strong protective immune responses without provoking undesirable inflammatory or systemic toxicities. While various adjuvants have been incorporated into vaccine formulations to enhance immunogenicity, optimization of these formulations has largely been empirical, requiring a balance between efficacy and tolerability. Despite these efforts, no approaches have been described that successfully eliminate systemic toxic side effects while preserving or enhancing the desired adaptive immune response.
  • the present invention provides vaccine adjuvant compositions that not only enhance immune responses but also reduce or minimize associated inflammatory and systemic side effects.
  • the present invention features an adjuvant composition, such as a lipid nanoparticle (LNP) adjuvant.
  • the adjuvant composition comprises a lipid nanoparticle having a lipid bilayer that includes a plurality of cationic lipids and a plurality of structural lipids.
  • the composition further comprises at least one agonist associated with the lipid nanoparticle, which activates a pattern recognition receptor (PRR).
  • PRR pattern recognition receptor
  • the agonist e.g., at least one agonist
  • the agonist is either incorporated into or encapsulated into the lipid nanoparticle.
  • the present invention may feature an adjuvant composition
  • the TLR4 agonist is monophosphoryl lipid A (MPLA) or an MPLA analogue
  • the TLR9 agonist is a CpG oligodeoxynucleotide (CpG).
  • the present invention may feature an adjuvant composition
  • a lipid nanoparticle having a lipid bilayer comprising a plurality of ionizable cationic lipids (e.g., ALC-0315) and structural lipids (e.g., DSPC or DOPE), a toll-like receptor (TLR)-4 agonist incorporated into the lipid nanoparticle, and a TLR-9 agonist encapsulated within the lipid nanoparticle.
  • the TLR4 agonist is monophosphoryl lipid A (MPLA) or an MPLA analogue
  • the TLR9 agonist is a CpG oligodeoxynucleotide (CpG).
  • the present invention may also feature an adjuvant composition comprising an oil-in-water nanoemulsion comprising a squalene lipid core and at least one agonist which activates a pattern recognition receptor.
  • the adjuvant composition comprises an oil-in-water nanoemulsion comprising a squalene lipid core and at least two agonists.
  • the adjuvant composition comprises an oil-in-water nanoemulsion comprising a squalene lipid core and two or more agonists.
  • the agonist activates a pattern recognition receptor (PRR).
  • PRR pattern recognition receptor
  • the present invention may further feature a vaccine composition comprising an adjuvant as described herein and an antigen.
  • the adjuvant comprises a lipid nanoparticle (LNP) adjuvant or a nanoemulsion adjuvant, both as described herein.
  • the antigen may be a protein antigen, a polypeptide antigen, or an mRNA encoding the antigen.
  • the present invention features a method of inducing an immune response in a subject in need thereof, the method comprising administering a vaccine composition as described herein.
  • the vaccine composition is administered via injection.
  • the vaccine composition is administered via inhalation.
  • One of the unique and inventive technical features of the present invention is the use of lipid nanoparticles with vaccine adjuvants and antigens to produce synergistic compositions and methods that increase vaccine efficacy while reducing vaccine toxicity and/or side effects.
  • the technical feature of the present invention advantageously provides for maintenance of vaccine adjuvants within the lymphatic system of a subject into which the vaccine compositions of the present are introduced, thereby reducing systemic toxicity while maintaining efficacy.
  • None of the presently known prior references or work has the unique, inventive technical feature of the present invention.
  • typical vaccine adjuvants are squalene nanoemulsions.
  • LNP formulations also improve the immunogenicity of vaccine antigens similar to squalene nanoemulsions.
  • incorporation of MPLA into nanoemulsion-based adjuvants requires a multi-step process. Specifically, it is necessary to first prepare an MPLA-containing liposome formulated with an inert co-lipid, such as DOPG, at a defined molar ratio (e g., 1 :5 MPLA to DOPG). Upon subsequent mixing with the nanoemulsion, the MPLA and DOPG transfer to the interface of the nanoemulsion particles, enabling incorporation of MPLA into the final formulation. Surprisingly, the present invention eliminates the need for this additional liposome preformation step.
  • DOPG inert co-lipid
  • LNP cationic or ionizable lipid nanoparticle
  • inventive technical features of the present invention contributed to a surprising result. For example, it has been assumed, based on a large body of research evidence, that vaccine potency is associated with vaccine associated systemic cytokines and transient side effects. The formulations described herein show that vaccine induced acute systemic cytokines and the associated side effects are not necessary to induce a potent and efficacious immune response.
  • FIG. 1 compares the immunogenicity of the IVAX adjuvant (e.g., CpG/MPLA nano-emulsion), the DOTMA CpG/MPLA lipid nanoparticle (LNP) formulation, and the ALC CpG/MPLA LNP.
  • the H5 vaccine response was evaluated against 28 H5N1 variant hemagglutinin (HA) antigens, with each bar in the graph representing one H5N1 variant.
  • the DOTMA CpG/MPLA LNP induced a more potent antibody response at 14 days post-immunization compared to IVAX.
  • FIG. 2A and 2B shows IgG profiling of day 14 (d14) , day 28 (d28), and day (d56) serum samples on protein microarray.
  • C57BL/6 female mice were immunized intramuscularly twice with various formulations on day 0 (dO) and day 21 (d21 ) , serum samples were collected at d 14, d28, and d56 for IgG profiling against H5 variant antigens on protein microarray.
  • FIG. 2A shows IgG antibody against the immunizing H5 antigen.
  • Bars on the graph represent the following treatment groups, shown left to right for each time point (Day 14, Day 28, and Day 56): (1) Buffer control, (2) H5 antigen alone, (3) H5 + IVAX, (4) H5 + IVAX-CHOL, (5) H5 + DOTMA LNP, (6) H5 + CpG/MPLA in DOTMA LNP, (7) H5 + CpG in DOTMA LNP, (8) H5 + ALC LNP, (9) H5 + CpG in ALC LNP, and (10) H5 + CpG/MPLA in ALC LNP
  • FIG. 2B shows IgG antibodies against 28 H5N1 variant HA Ag, with each bar in the graph representing one H5N1 variant.
  • each group labeled on the graph corresponds to the ten treatment groups outlined above in FIG. 2A, shown left to right.
  • All IVAX, DOTMA, and ALC LNP formulations containing CpG or CpG/MPLA elicited strong IgG antibody responses against the immunizing H5 antigen and its variants at 28 days and 56 days post-immunization, as detected by protein microarray, whereas lower responses were observed in groups receiving empty DOTMA or ALC LNPs.
  • FIG. 3 shows total IgG midpoint titers at d21 , d28, and d56 against the vaccine antigen H5 were measured using ELISA and calculated using Sigmoidal fit. Bars on the graph represent antibody responses at the following time points, shown left to right for each treatment group: Day 14, Day 28, Day 42, and Day 56.
  • the treatment groups are as follows: (1) Buffer control, (2) H5 antigen alone, (3) H5 + IVAX, (4) H5 + IVAX-CHOL, (5) H5 + DOTMA LNP, (6) H5 + CpG/MPLA in DOTMA LNP, (7) H5 + CpG in DOTMA LNP, (8) H5 + ALC LNP, (9) H5 + CpG in ALC LNP, and (10) H5 + CpG/MPLA in ALC LNP.
  • FIG. 4 shows the total and subtype IgG midpoint titers at d28 against the vaccine antigen H5, measured using ELISA and calculated using a Sigmoidal fit.
  • the three bars represent the midpoint titers for total IgG, IgG 1 , and lgG2c, shown left to right.
  • the treatment groups are as follows: (1) Buffer control, (2) H5 antigen alone, (3) H5 + IVAX, (4) H5 + IVAX-CHOL, (5) H5 + DOTMA LNP, (6) H5 + CpG/MPLA in DOTMA LNP, (7) H5 + CpG in DOTMA LNP, (8) H5 + ALC LNP, (9) H5 + CpG in ALC LNP, and (10) H5 + CpG/MPLA in ALC LNP.
  • FIG. 5A and 5B show transient weight changes following prime (FIG. 5A) and boost (FIG. 5B) immunizations. Weight was monitored for 7 days following each immunization to assess reactogenicity.
  • FIG. 6 shows inflammatory cytokine levels three hours following prime and boost immunizations. Blood samples were collected and inflammatory cytokines were measured using LEGENDplexTM Mouse Inflammation Panel multiplex assay.
  • the innate cytokine response correlated with transient weight loss. For example, IVAX-1 and ALC CpG/MPLA LNP induced elevated cytokine and chemokine levels, while the DOTMA CpG/MPLA LNP induced minimal cytokine and chemokine responses.
  • FIG. 7A-7F shows intracellular staining of cytokines following T cell recall with H5 antigen (10 g/mL). Splenocytes were collected 14 days post-boost (Day 35). Squares indicate samples stimulated with H5 antigen; circles indicate unstimulated controls.
  • FIG. 7A shows the frequencies of IFNy -secreting Th1 cells in CD4 (CD4+/IFNy+)
  • FIG. 7B shows naive (CD62L+/CD44-), effector memory (CD62L-/CD44+), and central memory (CD62L+/CD44+) cell populations in CD4 cells
  • FIG. 7C shows the frequencies of IFNy-secreting CD4 effector memory cells (CD4+/CD62L-CD44+/IFNy+)
  • FIG. 7D shows the frequencies of IL-17A-secreting CD4 effector memory cells (OD4+/CD62L-/CD44+/IL17+)
  • FIG. 7E shows the frequencies of TNFa-secreting cells in CD4 (CD4+/TNFa+)
  • FIG. 7F shows the frequencies of TNFa-secreting CD4 effector memory cells (CD4+/CD62L-/CD44+/TNFa+).
  • IVAX-1 , IVAX with Cholesterol CpG, DOTMA, and ALC LNPs containing CpG or CpG/MPLA significantly enhanced the production of IFN-y, IL-17, and TNF-a in CD4+ T cells and CD4+ effector memory cells.
  • FIG. 8 shows virus lung titers by qPCR 4 days after challenge with H5N1 .
  • Each group is compared to PBS via Mann Mann-Whitney test, followed by Benjamini-Hochberg correction for multiple comparisons. *, p ⁇ 0.05.**, p ⁇ 0.01.
  • Mice immunized with H5 antigen formulated with IVAX-1 , IVAX with cholesterol-conjugated CpG, DOTMA LNP, or ALC LNP exhibited significantly reduced lung viral titers compared to buffer-treated controls, indicating protection against H5N1 infection.
  • FIG. 9 shows protection against SARS-CoV-2 (Wuhan strain) challenge in hamsters.
  • Hamsters immunized with SARS-CoV-2 Spike protein formulated with IVAX-1 , DOTMA LNP, or ALC LNP showed improved protection, as evidenced by reduced weight loss and significantly lower lung viral titers compared to animals that received Spike protein alone or buffer.
  • DOTMA CpG/MPLA LNP adjuvants induced lower systemic inflammatory cytokine and chemokine responses, comparable adaptive immune responses, and protective immunity relative to the IVAX reference standard.
  • compositions to be used within the methods disclosed herein Disclosed are various peptides, solvents, solutions, carriers, and/or components to be used to prepare compositions to be used within the methods disclosed herein. Also disclosed are the various steps, elements, amounts, routes of administration, symptoms, and/or treatments that are used or observed when performing the disclosed methods, as well as the methods themselves. These and other materials, steps, and/or elements are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed, that while specific reference of each various individual and collective combination and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
  • a “subject” is an individual and includes, but is not limited to, a mammal (e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig, or rodent), a fish, a bird, a reptile or an amphibian.
  • a mammal e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig, or rodent
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be included.
  • a “patient” is a subject afflicted with a disease or disorder.
  • patient includes human and veterinary subjects.
  • administering and “administration” refer to methods of providing a pharmaceutical preparation, composition, or formulation to a subject.
  • the compositions described herein can be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Such methods are well known to those skilled in the art and include, but are not limited to, administering the compositions orally, intranasally, parenterally (e.g., intravenously and subcutaneously), by intramuscular injection, by intraperitoneal injection, intrathecally, transdermally, extracorporeally, topically or the like.
  • treating refers to any indicia of success or amelioration of the progression, severity, and/or duration of a disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a patient’s physical or mental well-being.
  • the present invention features a vaccine composition, such as a lipid nanoparticle, comprising an encapsulated adjuvant and either a protein antigen or an mRNA encoding the antigen.
  • the antigens may be derived from different microorganisms, including viruses, bacteria, or parasites, thereby allowing the formulation of a single vaccine effective against multiple pathogens.
  • the antigens may be derived from tumor tissue that needs to be eliminated.
  • CpG may diffuse away from the site of delivery (e.g., an injection site) and contribute to systemic reactogenicity.
  • CpG when CpG is encapsulated within lipid nanoparticles (LNP, e.g., DOTMA LNPs), it remains localized at the injection site and within the lymphatic compartment, thereby minimizing systemic exposure.
  • LNP lipid nanoparticles
  • MPLA an amphipathic molecule
  • soluble CpG typically lacks such association and is prone to systemic diffusion. Accordingly, adjuvant formulations that retain CpG within nanoparticles and restrict it to lymphoid tissues offer a strategic advantage in promoting immune activation with reduced systemic toxicity.
  • the present invention features an adjuvant composition, such as a lipid nanoparticle (LNP) adjuvant.
  • the adjuvant composition comprises a lipid nanoparticle having a lipid bilayer that includes a plurality of cationic lipids and a plurality of structural lipids.
  • the composition further comprises at least one agonist associated with the lipid nanoparticle, which activates a pattern recognition receptor (PRR).
  • PRR pattern recognition receptor
  • the agonist e.g., at least one agonist
  • the agonist is either incorporated into or encapsulated into the lipid nanoparticle.
  • the adjuvant composition comprises a lipid nanoparticle (LNP) having a lipid bilayer that includes a plurality of cationic lipids and a plurality of structural lipids, as well as at least two agonists associated with the LNP.
  • the adjuvant composition comprises a lipid nanoparticle (LNP) having a lipid bilayer that includes a plurality of cationic lipids and a plurality of structural lipids and two or more agonists associated with the LNP.
  • the agonist activates a pattern recognition receptor (PRR).
  • PRR pattern recognition receptor
  • at least one agonist is either incorporated into or encapsulated into the lipid nanoparticle.
  • Non-limiting examples of agonists may include, but are not limited to, toll-like receptor (TLR) agonists, nucleotide oligomerization domain (NOD)-like receptor (NLR) agonists, or cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway agonists.
  • the agonist is a toll-like receptor (TLR) agonist.
  • the agonist is a TLR4 agonist, such as monophosphoryl lipid A (MPLA) or an MPLA analogue, which may be incorporated into the lipid nanoparticle.
  • the agonist is a TLR9 agonist, such as a CpG oligodeoxynucleotide (CpG), which may be encapsulated within the lipid nanoparticle.
  • CpG CpG oligodeoxynucleotide
  • TLR9 agonists may be used, as their performance can vary across species, such as between mice and humans.
  • the present invention features an adjuvant composition
  • the adjuvant composition may comprise a TLR4-agonist and a TLR9-agonist.
  • the TRL4-agonist may be incorporated into the lipid nanoparticle (e.g., within the lipid bilayer), and the TLR9-agonist is encapsulated within the lipid nanoparticle.
  • the TLR4 agonist is MPLA or an analogue thereof, and the TLR9 agonist is CpG.
  • the present invention may feature an adjuvant composition (e.g., a DOTMA CpG/MPLA LNP) comprising a lipid nanoparticle having a lipid bilayer that includes a plurality of cationic lipids (e.g., DOTMA) and structural lipids (e.g., DSPC or DOPE), a toll-like receptor 4 (TLR4) agonist incorporated into the lipid nanoparticle, and a toll-like receptor 9 (TLR9) agonist encapsulated within the lipid nanoparticle.
  • the TLR4 agonist is monophosphoryl lipid A (MPLA) or an MPLA analogue
  • the TLR9 agonist is a CpG oligodeoxynucleotide (CpG).
  • the present invention may feature an adjuvant composition (e.g., an ALC CpG/MPLA LNP) comprising a lipid nanoparticle having a lipid bilayer comprising a plurality of ionizable cationic lipids (e.g., ALC-0315) and structural lipids (e.g., DSPC or DOPE), a toll-like receptor (TLR)-4 agonist incorporated into the lipid nanoparticle, and a TLR-9 agonist encapsulated within the lipid nanoparticle.
  • the TLR4 agonist is monophosphoryl lipid A (MPLA) or an MPLA analogue
  • the TLR9 agonist is a CpG oligodeoxynucleotide (CpG).
  • the agonist is covalently associated with the lipid bilayer. In other embodiments, the agonist is non-covalently associated with the lipid bilayer. In certain embodiments, the non-covalent association involves ionic interactions, hydrophobic interactions, or a combination thereof.
  • the cationic lipids within the lipid bilayer comprise
  • the lipid nanoparticles include ionizable cationic lipids, such as [(4-hydroxybutyl)azanediyl]di(hexane-6,1-diyl) bis(2-hexyldecanoate) (ALC-0315), or other ionizable lipids.
  • the LNPs described herein may contain a plurality of cationic lipids, a plurality of ionizable cationic lipids, or a combination of both.
  • the structural lipids within the lipid bilayer may include
  • DSPC 1 .2-distearoyl-sn-glycero-3-phosphocholine
  • the lipid bilayer may further comprise phosphatidylcholines (PC), phosphatidylethanolamines (PE), cholesterol, and/or PEG-lipids.
  • PC phosphatidylcholines
  • PE phosphatidylethanolamines
  • cholesterol lipid
  • PEG-lipids PEG-lipids
  • the lipid bilayer is a disordered polymorphic lipid bilayer.
  • the adjuvants described herein exhibit greater cross-reactive potency than a control adjuvant (e.g., IVAX), while demonstrating minimal transient weight loss and no significant increase in systemic cytokines associated with reactogenicity.
  • the DOTMA CpG/MPLA formulation may bind and multimerize the vaccine antigen, enhancing immunogenic potency while reducing reactogenicity compared to a control adjuvant (e.g., IVAX).
  • ALC CpG/MPLA formulations may also induce antigen multimerization.
  • multimerization may depend on the physical properties of an antigen. LNP-induced multimerization is experimentally measurable.
  • the lipid nanoparticles (LNPs) described herein have a diameter of less than 200 nm.
  • LNPs of this size meet two desirable criteria: they are sufficiently small to permit sterile filtration (e.g., through filters with a pore size of approximately 220 nm) and fall within the optimal size range (approximately 10-200 nm) for effective drainage into lymph nodes.
  • Table 1 shows non-limiting CpG and MPLA encapsulation
  • the present invention provides a positively charged lipid nanoparticle that encapsulates 100% of the input TLR9 agonist (e.g., CpG) and 100% of the TLR4 agonist (e.g., MPLA or an analogue thereof).
  • CpG encapsulation is assessed using the Oligreen assay, a fluorescence-based method for detecting single-stranded DNA.
  • MPLA is incorporated into the lipid film during LNP preparation and achieves complete (100%) incorporation.
  • each nanoparticle includes all components necessary to stimulate an adaptive immune response.
  • the nanoparticles may remain localized within the lymphatic system and therefore cannot enter systemic circulation without first passing through the lymphatic network and draining lymph nodes, where the antigens are presented to immune cells. This configuration enables efficient antigen presentation and activation of immune responses while minimizing systemic inflammatory toxicity.
  • the LNPs described herein have a charge ratio of about 0.5 to 2. In some embodiments, the LNPs described herein have a charge ratio of about 0.5. In some embodiments, the LNPs described herein have a charge ratio of about 1. In some embodiments, the LNPs described herein have a charge ratio of about 1.5. In some embodiments, the LNPs described herein have a charge ratio of about 2.
  • the present invention after condensation with nucleic acids or other negatively charged molecules, the present invention features a lipid bilayer system that is not a pure classical bilayer system. Instead, in some embodiments, the present invention features lipid nanoparticle adjuvant compositions that are highly condensed and that form polymorphic structures with bilayer and hexagonal-2 phases.
  • Nanoemulsion Vaccine Adjuvants [0059] Nanoemulsion Vaccine Adjuvants:
  • the present invention may also feature an adjuvant composition comprising an oil-in-water nanoemulsion comprising a squalene lipid core and at least one agonist which activates a pattern recognition receptor.
  • the adjuvant composition comprises an oil-in-water nanoemulsion comprising a squalene lipid core and at least two agonists.
  • the adjuvant composition comprises an oil-in-water nanoemulsion comprising a squalene lipid core and two or more agonists.
  • the agonist activates a pattern recognition receptor (PRR).
  • PRR pattern recognition receptor
  • Non-limiting examples of agonists may include, but are not limited to, toll-like receptor (TLR) agonists, nucleotide oligomerization domain (NOD)-like receptor (NLR) agonists, or cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway agonists.
  • the agonist is a toll-like receptor (TLR) agonist.
  • the agonist is a TLR4 agonist, such as monophosphoryl lipid A (MPLA) or an MPLA analogue, which may be incorporated into the interface of an oil-in-water nanoemulsion.
  • the agonist is a TLR9 agonist, such as a CpG oligodeoxynucleotide (CpG), which may be present in soluble form or may be incorporated into the nanoemulsion interface through the inclusion of a lipophilic tail attached to the CpG.
  • the lipophilic tail comprises a cholesterol molecule or a phosphatidyl moiety.
  • the present invention may also feature an adjuvant composition comprising an oil-in-water nanoemulsion comprising a squalene lipid core and two agonists, e g., two different agonists.
  • at least one agonist is incorporated into the interface of an oil-in-water nanoemulsion.
  • the adjuvant composition may comprise a TLR4-agonist and a TLR9-agonist.
  • the TLR-4 agonist is incorporated into the interface of an oil-in-water nanoemulsion.
  • the TLR-9 agonist may be present in soluble form or may be incorporated into the nanoemulsion interface through the inclusion of a lipophilic tail (e.g., a cholesterol molecule or a phosphatidyl moiety) attached thereto.
  • a lipophilic tail e.g., a cholesterol molecule or a phosphatidyl moiety
  • the TLR4 agonist is MPLA or an analogue thereof
  • the TLR9 agonist is CpG.
  • the present invention may feature an adjuvant composition comprising: an oil-in-water nanoemulsion comprising a squalene lipid core, a toll-like receptor (TLR)-4 agonist incorporated into the interface of an oil-in-water nanoemulsion, and a TLR-9 agonist.
  • the TLR4 agonist is MPLA
  • the TLR9 agonist is CpG.
  • the TLR9 agonist comprises a lipophilic tail (e.g., a cholesterol molecule of a phosphatidyl moiety) attached thereto. In such embodiments, the presence of the lipophilic tail facilitates incorporation of the TLR9 agonist into the interface of the nanoemulsion. In the absence of the lipophilic tail, the TLR9 agonist remains in soluble form and is not incorporated into the lipid core.
  • the present invention may further feature a vaccine composition comprising an adjuvant as described herein and an antigen.
  • the adjuvant comprises a lipid nanoparticle (LNP) adjuvant or a nanoemulsion adjuvant, both as described herein.
  • the antigen may be a protein antigen, a polypeptide antigen, or an mRNA encoding the antigen.
  • the antigen is derived from a microorganism, including a virus, bacterium, or parasite.
  • the antigen is derived from a tumor cell.
  • suitable antigens include the Spike protein from SARS-CoV-2, the VP1 protein from Picornavirus, the N protein from Peribunyavirus, and the influenza hemagglutinin H1 protein.
  • the antigen is adsorbed onto a surface of the lipid bilayer.
  • the adjuvant remains localized at the site of administration.
  • the adjuvant is maintained within the lymphatic system.
  • the vaccine composition reduces side effects as compared to compositions that enter systemic circulation.
  • the present invention provides a lipid nanoparticle-based vaccine composition comprising one or more adjuvants and an antigen.
  • the lipid nanoparticle includes a cationic lipid that facilitates the formation of the nanoparticle and enables the adsorption of a protein antigen onto the nanoparticle surface.
  • the LNP may incorporate monophosphoryl lipid A (MPLA), a Toll-like receptor 4 (TLR4) agonist, into the lipid bilayer structure of the nanoparticle.
  • the nanoparticle may further comprise CpG, a Toll-like receptor 9 (TLR9) agonist, which may be encapsulated within the interior of the nanoparticle or associated externally with the nanoparticle surface.
  • MPLA monophosphoryl lipid A
  • TLR4 Toll-like receptor 4
  • TLR9 Toll-like receptor 9
  • the lipid nanoparticle contains both antigenic and adjuvant components necessary to stimulate a robust adaptive immune response. Furthermore, the positively charged nature of the nanoparticle promotes uptake by antigen-presenting cells and facilitates retention within the lymphatic system, thereby preventing direct entry into systemic circulation without first traversing the lymphatic network.
  • the vaccine compositions described herein may be formulated for intranasal administration.
  • the LNP formulations e.g., DOTMA LNP formulations
  • the vaccine compositions may be administered via other routes, including but not limited to intramuscular, intravenous, subcutaneous, or intraperitoneal administration.
  • the present invention features a method of inducing an immune response in a subject in need thereof, the method comprising administering a vaccine composition as described herein.
  • the vaccine composition is administered via injection.
  • the vaccine composition is administered via inhalation.
  • the present invention further provides a method of manufacturing an adjuvant composition
  • an adjuvant composition comprising a lipid nanoparticle having a lipid bilayer that includes a plurality of cationic lipids and structural lipids, and at least one agonist associated with the lipid nanoparticle, wherein the agonist activates a pattern recognition receptor.
  • the adjuvant composition is formulated with an antigen to produce a vaccine composition as described herein, which may be used to induce an immune response in a subject in need thereof.
  • cationic LNP combination adjuvants were formulated with either DNA (DNA lipoplex), RNA (poly l/C, RNA lipoplex), lipophylic muramyl dipeptide (MDP), or cyclic GMP/AMP (cGAMP) (Table 1). These adjuvants were extemporaneously mixed with recombinant protein antigens to produce the vaccines. The adjuvant effects of these four vaccines were compared with IVAX-1 , which was developed and well characterized by the Inventors, as well as with two benchmark adjuvants, AddaVax and Alum.
  • CpG encapsulation is assessed using the Oligreen assay, a fluorescence-based method for detecting single-stranded DNA.
  • MPLA is incorporated into the lipid film during LNP preparation and achieves complete (100%) incorporation.
  • IVAX-1 is a nanoemulsion formulation based on the squalene oil-in-water emulsion AddaVax, incorporating monophosphoryl lipid A (MPLA) and CpG oligodeoxynucleotide (ODN) 1018.
  • MPLA monophosphoryl lipid A
  • ODN CpG oligodeoxynucleotide
  • the adjuvant components are combined with antigens by extemporaneous mixing.
  • IVAX-1 was selected from an adjuvant screening study and has been shown to induce a Th1-biased immune response and generate neutralizing antibody activity.
  • Cationic Liposome/DNA Cationic liposomes and plasmid DNA individually exhibit limited immunostimulatory activity, their combination results in liposome-mediated potentiation of immune responsiveness, primarily through recognition of non-methylated CpG motifs present in bacterial plasmid DNA.
  • cationic lipid DOTMA and helper lipid DOPE are combined at an equal weight ratio to form cationic liposomes.
  • DOTMA/DOPE cationic liposomes have been reproducibly produced with an average particle size of approximately 150 nm in diameter, and can form cationic liposome/plasmid DNA complexes with similar size distributions across a range of charge ratios (0.5-2).
  • DOTMA which contains an ether linkage between the C18 alkyl chains and polar head group, provides enhanced stability, while DOPE facilitates DNA complexation and promotes the formation of fusogenic inverted hexagonal lipid phases.
  • Additional helper lipids such as cholesterol and PEG-lipids, may be incorporated to improve liposome stability and surface hydrophilicity, respectively.
  • Cationic Liposome/Poly(l: C) Polyinosinic-polycytidylic acid (poly(l:C)) is a synthetic analog of double-stranded RNA (dsRNA), a pathogen-associated molecular pattern (PAMP) commonly associated with viral infections.
  • Poly(l:C) activates the immune response through two distinct pathogen recognition receptors (PRRs): endosomal poly(l:C) activates Toll-like receptor 3 (TLR3), while cytosolic poly(l:C) activates the RIG-l/MDA-5 pathway.
  • PRRs pathogen recognition receptors
  • TLR3 Toll-like receptor 3
  • cytosolic poly(l:C) activates the RIG-l/MDA-5 pathway.
  • poly(l:C) Both signaling pathways promote Th1-biased cellular immunity through the induction of interleukin-12 (IL-12) and type I interferons (IFNs), and poly(l:C) has demonstrated potent adjuvant activity in various vaccine formulations.
  • IL-12 interleukin-12
  • IFNs type I interferons
  • poly(l:C) has demonstrated potent adjuvant activity in various vaccine formulations.
  • administration of soluble poly(l:C) has been associated with adverse effects due to the induction of pro-inflammatory cytokines.
  • Complexation of poly(l:C) with cationic liposomes to form lipid nanoparticles may mitigate these side effects.
  • the cationic liposome can potentiate the immunostimulatory effects of poly(l:C) while also protecting it from enzymatic degradation
  • Cationic Liposome/Lipophilic MDP Muramyl dipeptide (MDP) is the minimal bioactive motif derived from bacterial peptidoglycan and represents the essential structural component required for adjuvant activity in vaccines. MDP is recognized by the intracellular pattern recognition receptor NOD2.
  • L18-MDP a lipophilic derivative containing a stearoyl fatty acid moiety, exhibits enhanced activity in promoting protective immune responses against bacterial infections. Due to its limited aqueous solubility, lipophilic L18-MDP may be incorporated into the lipid bilayer of cationic liposomes during lipid film formation. The cationic liposome not only improves the solubility and incorporation efficiency of L18-MDP but also serves as a nanoparticle delivery vehicle and adjuvant potentiator.
  • Cationic liposome/Sting: 2’3’-cGAMP is a cyclic dinucleotide produced in mammalian cells by cyclic GMP-AMP synthase (cGAS) in response to the presence of double-stranded DNA in the cytoplasm.
  • Cyclic dinucleotides (CDNs), such as 2’3’-cGAMP, have been shown to enhance vaccine potency by activating innate immunity.
  • 2’3’-cGAMP binds directly to the endoplasmic reticulum-resident receptor STING (stimulator of interferon genes), initiating a signaling cascade that induces expression of interferon-p (IFN-P) and nuclear factor KB (NF-KB)-dependent pro-inflammatory cytokines.
  • IFN-P interferon-p
  • NF-KB nuclear factor KB
  • cationic liposomes may be used to encapsulate or complex divalent 2’3’-cGAMP, thereby facilitating its cytosolic delivery.
  • APCs antigen-presenting cells
  • Cationic LNP-1 is a nanoemulsion-based formulation comprising Addavax combined with CpG and MPLA. Studies conducted by the Inventors demonstrated that none of the tested cationic nanoparticle formulations outperformed IVAX-1 in terms of immunogenicity and efficacy. Notably, the prior formulations evaluated did not include the combination of CpG and MPLA. The tested formulations containing cGAMP, plasmid DNA, poly(l:C), or lipophilic MDP generated immune responses in mice that were inferior to the reference standards (Addavax and IVAX-1).
  • mice were immunized with a single H5N1 hemagglutinin (HA) protein antigen (A/Vietnam/1194/2004), and plasma samples were analyzed using an influenza protein microarray containing 28 H5N1 HA variant antigens.
  • the combination of IVAX-1 with lipophilic cholesterol-conjugated CpG further enhanced antibody levels.
  • DOTMA LNP alone exhibited weak adjuvant activity; however, encapsulation of CpG within DOTMA LNP resulted in superior antibody induction compared to IVAX-1 .
  • the addition of MPLA to the DOTMA/CpG LNP formulation yielded the highest antibody levels observed.
  • ionizable cationic LNPs containing CpG and MPLA induced antibody responses comparable to IVAX-1.
  • Weight loss following vaccination used as a sensitive indicator of reactogenicity and toxicity, revealed that buffer and H5N1 HA protein alone did not cause weight loss, while IVAX-1 induced transient weight loss, as expected.
  • DOTMA LNP formulations, with or without CpG and MPLA, did not induce significant weight loss.
  • CpG and MPLA in ionizable cationic LNPs induced substantial weight loss, with a more gradual recovery.
  • the reduced reactogenicity observed with the DOTMA LNP formulation may be attributable to differences in surface charge rather than CpG diffusion.
  • DOTMA LNP formulations which possess a positive surface charge, exhibit significantly reduced reactogenicity.
  • the surface charge may influence the trafficking of nanoparticles to the draining lymph nodes in vivo, thereby impacting both immunogenicity and reactogenicity. This is further supported by the observation that ALC LNPs, which are neutral at physiological pH yet encapsulate CpG, remain highly reactogenic, indicating that restricted CpG diffusion alone does not account for reduced systemic side effects.
  • the DOTMA/CpG/MPLA LNP formulation demonstrated potent adjuvant activity with low reactogenicity. Mice immunized with this formulation exhibited minimal weight loss and low levels of inflammatory cytokines in the blood three hours post-immunization (FIG. 6). Vaccine-induced innate cytokine levels were analyzed at this time point to assess early reactogenicity. In addition, a single dose of the DOTMA/CpG/MPLA LNP induced a strong magnitude and breadth of antibody responses (FIGs. 2-4). Plasma samples were collected on Day 28 post-boost, and antibody titers were evaluated by ELISA to assess the adaptive immune response.
  • descriptions of the inventions described herein using the phrase “comprising” includes embodiments that could be described as “consisting essentially of’ or “consisting of’, and as such the written description requirement for claiming one or more embodiments of the present invention using the phrase “consisting essentially of’ or “consisting of’ is met.

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Abstract

L'invention concerne des compositions vaccinales améliorées et des procédés qui intègrent l'utilisation de nanoparticules lipidiques pour maintenir ou améliorer l'efficacité d'un vaccin tout en réduisant la toxicité et/ou les effets secondaires du vaccin.
PCT/US2025/035708 2024-06-27 2025-06-27 Compositions d'adjuvant de nanoparticules lipidiques Pending WO2026006741A1 (fr)

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Citations (7)

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US20030054007A1 (en) * 1999-12-17 2003-03-20 Felgner Philip L. Intracellular protein delivery compositions and methods of use
US20070218077A1 (en) * 1989-03-21 2007-09-20 Vical Incorporated Lipid-Mediated Polynucleotide Administration to Deliver a Biologically Active Peptide and to Induce a Cellular Immune Response
US20090291095A1 (en) * 2008-05-23 2009-11-26 The Regents Of The University Of Michigan Nanoemulsion adjuvants
US20160038433A1 (en) * 2012-12-17 2016-02-11 Universidade De Santiago De Compostela Nanocapsules of protamine
US20210002813A1 (en) * 2014-02-25 2021-01-07 Merck Sharp & Dohme Corp. Lipid nanoparticle vaccine adjuvants and antigen delivery systems
EP4342460A1 (fr) * 2022-09-21 2024-03-27 NovoArc GmbH Nanoparticule lipidique avec charge d'acide nucléique
US20240108710A1 (en) * 2021-02-04 2024-04-04 Merck Sharp & Dohme Llc Nanoemulsion adjuvant composition for pneumococcal conjugate vaccines

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070218077A1 (en) * 1989-03-21 2007-09-20 Vical Incorporated Lipid-Mediated Polynucleotide Administration to Deliver a Biologically Active Peptide and to Induce a Cellular Immune Response
US20030054007A1 (en) * 1999-12-17 2003-03-20 Felgner Philip L. Intracellular protein delivery compositions and methods of use
US20090291095A1 (en) * 2008-05-23 2009-11-26 The Regents Of The University Of Michigan Nanoemulsion adjuvants
US20160038433A1 (en) * 2012-12-17 2016-02-11 Universidade De Santiago De Compostela Nanocapsules of protamine
US20210002813A1 (en) * 2014-02-25 2021-01-07 Merck Sharp & Dohme Corp. Lipid nanoparticle vaccine adjuvants and antigen delivery systems
US20240108710A1 (en) * 2021-02-04 2024-04-04 Merck Sharp & Dohme Llc Nanoemulsion adjuvant composition for pneumococcal conjugate vaccines
EP4342460A1 (fr) * 2022-09-21 2024-03-27 NovoArc GmbH Nanoparticule lipidique avec charge d'acide nucléique

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