Abstract: Compositions containing a nucleic acid nanostructure having a desired geometric shape and immunostimulatory agent(s) bound to its surface are provided. The nanostructures can be, for example, in the form of a 6-helix bundle, or icosahedron, or a pentagonal bipyramid. The nanostructure design allows for control of the relative position and/or stoichiometry of the immunostimulatory agent(s) bound to its surface. The immunostimulatory agent(s) displayed on the nanostructure surface are arranged with the preferred number, spacing, and 3D organization to elicit a robust immune response. The displayed antigen can be a TLR agonist, such as a TLR9 agonist. The immunostimulatory compositions may thus be useful as immunogens, vaccines, adjuvants, and the like. Methods of inducing immune responses, and for targeted induction of TLR activation are also provided.

Abstract: Immunization methods are provided. The methods typically include administering the subject an effective amount of an antigen and adjuvant to induce an immune response against an antigen, the method including two or more of (i) slow prime delivery of antigen and/or adjuvant, a (ii) temporally delayed 2nd immunization, and (iii) a robust adjuvant. Element (i) can be or include temporally extended exposure of antigen, adjuvant, or preferably the combination thereof, such as one or more of repeated administrations, infusion optionally by osmotic pump and escalating dosing. Element (ii) can include administering one or more boost doses of antigen and/or adjuvant, for example between 11 and 35 weeks after the start of the prime administration. A preferred robust adjuvant (iii) is one including non-liposome, non-micelle particles formed of a lipid, an additional adjuvant such as a TLR4 agonist, a sterol, and a saponin.

Abstract: Compositions are disclosed that include alum and a non-liposome, non-micelle particle, where the particle comprises a lipid, a sterol, a saponin, and an optional additional non-alum adjuvant, wherein the particle is optionally bound to the alum, and the use of the compositions as vaccine adjuvants and methods for eliciting immune responses.

Abstract: Compositions are disclosed that include alum and a SARS-CoV-2 Spike (S) glycoprotein variant covalently bound to the alum via at least one linker having 2-12 phosphoserine residues, where the S glycoprotein variant includes a receptor binding domain (RBD) having a mutation of at least one amino acid residue in an angiotensin-converting enzyme 2 (ACE2) receptor binding motif (RBM) relative to a wild-type RBD, where the residue is (i) hydrophobic; and (ii) within an aggregation-prone region of about 3-15 amino acid residues, and the mutation is a substitution of the hydrophobic residue with a different amino acid residue; as are compositions and vaccines including the compositions, and methods for their use.

Abstract: The present disclosure provides surprisingly useful fusion polypeptides including an immunomodulatory moiety and a metal-hydroxide binding moiety, as well as various related technologies, including methods of making and of using such fusion polypeptides.

Abstract: Compositions containing a nucleic acid nanostructure having a desired geometric shape and antigens bound to its surface are provided. The nanostructures can be, for example, in the form of a 6-helix bundle or icosahedron. The nanostructure design allows for control of the relative position and/or stoichiometry of the antigen bound to its surface. The antigens displayed on the nanostructure surface are arranged with the preferred number, spacing, and 3D organization to elicit a robust immune response. The displayed antigen can be an HIV immunogen such as eOD-GT6, eOD-GT8, or variants thereof. The compositions may thus be useful as immunogens, vaccines, immunostimulators, adjuvants, and the like. Methods of inducing immune responses, inducing protective immunity, inducing the production of neutralizing antibodies or inhibitory antibodies, inducing tolerance, and treating cancer, infectious or autoimmune diseases are also provided.

Abstract: Compositions and methods are described for inducing an immune response against an immunogen in humans. The induced immune response is obtained by administering a heterologous prime-boost combination of an in vitro transcribed (IVT) self-replicating RNA (repRNA) and an adenovirus vector. The compositions and methods can be used to provide a protective immunity against a disease, such as a viral infection or a cancer, in humans.

Abstract: A method and device for preferentially delivering a compound such as an antigen to the cytosol of an immune cell. The method comprises passing a cell suspension comprising the target immune cell through a microfluidic device and contacting the suspension with the compound(s) or payload to be delivered.

Abstract: Lipid conjugates for enhanced delivery of cargo to the lymph nodes are disclosed. The lipid conjugates typically include three domains: a lipophilic domain that binds to albumin, a polar block domain, and a cargo such as a molecular adjuvant or immunostimulatory compound (such as an oligonucleotide) or antigenic peptide. Depending on the cargo, the length and compositions of the polar block can be tailored to push the equilibrium toward albumin binding, stable micelle formation, or cell insertion. The conjugates can be administered to a subject, for example, a subject with cancer or an infection, to induce or enhance a robust immune response in the subject.

Abstract: Described are cell-based cancer vaccines and anti-cancer immunotherapies. The vaccines include isolated tumor cells activated with one or more genotoxic drugs, and, optionally, treated with one or more MK2 inhibitors. The activated cells are highly immunogenic non-proliferative cells, and may be tested for immunogenicity ex vivo for priming T cells by co-incubating the isolated activated cells with dendritic cells and T cells. The vaccines are typically administered into patient's tumor to provide an intratumoral immune activation. Immune checkpoint inhibitor(s) (ICI) may be administered before, during, or after vaccine administration. ICI may be a component of the vaccine. The vaccines confer heightened cytotoxic immune response against the cancer cells, induce tumor regression, and enhance survival from cancer. The vaccines prevent tumor recurrence and induce a long-lasting anti-tumor immunological memory.

Abstract: Lipid conjugates for enhanced delivery of cargo to the lymph nodes are disclosed. The lipid conjugates typically include three domains: a lipophilic domain that binds to albumin, a polar block domain, and a cargo such as a molecular adjuvant or immunostimulatory compound (such as an oligonucleotide) or antigenic peptide. Depending on the cargo, the length and compositions of the polar block can be tailored to push the equilibrium toward albumin binding, stable micelle formation, or cell insertion. The conjugates can be administered to a subject, for example, a subject with cancer or an infection, to induce or enhance a robust immune response in the subject.

Abstract: Compositions containing a nucleic acid nanostructure having a desired geometric shape and antigens bound to its surface are provided. The nanostructures can be, for example, in the form of a 6-helix bundle or icosahedron. The nanostructure design allows for control of the relative position and/or stoichiometry of the antigen bound to its surface. The antigens displayed on the nanostructure surface are arranged with the preferred number, spacing, and 3D organization to elicit a robust immune response. The displayed antigen can be an HIV immunogen such as eOD-GT6, eOD-GT8, or variants thereof. The compositions may thus be useful as immunogens, vaccines, immunostimulators, adjuvants, and the like. Methods of inducing immune responses, inducing protective immunity, inducing the production of neutralizing antibodies or inhibitory antibodies, inducing tolerance, and treating cancer, infectious or autoimmune diseases are also provided.

Abstract: The present invention provides for an ex vivo delivery platform of rapidly inserting lipid-conjugated molecular ligands into a membrane of cells or biological entities have a lipid membrane by lipid partitioning, termed depoting, wherein the ex vivo delivery platform is a lipid-tailed biomolecule.

Abstract: Lipid conjugates for enhanced delivery of cargo to the lymph nodes are disclosed. The lipid conjugates typically include three domains: a lipophilic domain that binds to albumin, a polar block domain, and a cargo such as a molecular adjuvant or immunostimulatory compound (such as an oligonucleotide) or antigenic peptide. Depending on the cargo, the length and compositions of the polar block can be tailored to push the equilibrium toward albumin binding, stable micelle formation, or cell insertion. The conjugates can be administered to a subject, for example, a subject with cancer or an infection, to induce or enhance a robust immune response in the subject.

Abstract: Lipid conjugates for enhanced delivery of cargo to the lymph nodes are disclosed. The lipid conjugates typically include three domains: a lipophilic domain that binds to albumin, a polar block domain, and a cargo such as a molecular adjuvant or immunostimulatory compound (such as an oligonucleotide) or antigenic peptide. Depending on the cargo, the length and compositions of the polar block can be tailored to push the equilibrium toward albumin binding, stable micelle formation, or cell insertion. The conjugates can be administered to a subject, for example, a subject with cancer or an infection, to induce or enhance a robust immune response in the subject.

Abstract: A method and device for preferentially delivering a compound such as an antigen to the cytosol of an immune cell. The method comprises passing a cell suspension comprising the target immune cell through a microfluidic device and contacting the suspension with the compound(s) or payload to be delivered.

Abstract: The present invention provides, among other things, multilayer film coating compositions, coated substrates and methods thereof. In some embodiments, a structure, comprising a substrate and a multilayer film on the substrate, wherein the multilayer film comprises a release layer and one or more layer-by-layer films. In some embodiments, a structure comprising a microneedle substrate and a multilayer film coated on at least portion of the microneedle substrate, wherein the multilayer film comprises an agent for delivery.

Abstract: Protein antigens are provided. The protein antigens typically include a peptide antigen conjugated or fused to a chaperone protein to form a “chaperone-antigen” that increases lymph node uptake; improves an immune response; or a combination thereof relative to the peptide antigen alone. The immune response can be, for example, increased antigen-specific proliferation, enhanced cytokine production, stimulation of differentiation and/or effector functions, promotion of survival, rescue from exhaustion and/or anergy of T cells, or a combination thereof. Chaperon-antigens can also be used to induce tolerance and increase immune suppressive responses. In the most preferred embodiments, the peptide antigen is fused to the chaperone protein to form a fusion protein. The “chaperone-antigen” can be combined with an adjuvant to form a vaccine and administered to a subject to modulate an immune response to the antigen.

Abstract: The present invention provides a method of treating cancer with a combination of IL-2 (e.g., extended-PK IL-2), a therapeutic antibody or fragment thereof, and a cancer vaccine. The methods of the invention can be used to treat a broad range of cancer types.

Abstract: The present invention provides a method of treating cancer with a combination of IL-2 (e.g., extended-PK IL-2), a therapeutic antibody or fragment thereof, and an immune checkpoint blocker. The methods of the invention can be used to treat a broad range of cancer types.