The present invention provides novel scaffolded HIV-1 vaccine immunogens. Some of the scaffolded immunogens contain a soluble gp140 trimer linked to the N-terminus of the nanoparticle subunit and a T-helper epitope that is fused via a short peptide spacer to the C-terminus of the nanoparticle subunit. Some other immunogens of the invention contain a soluble gp140 trimer protein that is linked to a stable nanoparticle via a short peptide spacer that is a T-helper epitope. Some of the scaffolded immunogens contain a gp140 trimer immunogen presented on a nanoparticle platform formed with I3-01 protein, E2p, or variants of protein 1VLW. Also provided in the invention are nucleic acids that encode the various vaccine immunogens described herein, and expression vectors and host cells harboring the nucleic acids. The invention further provides methods of using the scaffolded HIV-1 vaccine immunogens for preventing or treating HIV infections.

The present invention provides novel scaffolded HIV-1 vaccine immunogens. Some of the scaffolded immunogens contain a soluble gp140 trimer linked to the N-terminus of the nanoparticle subunit and a T-helper epitope that is fused via a short peptide spacer to the C-terminus of the nanoparticle subunit. Some other immunogens of the invention contain a soluble gp140 trimer protein that is linked to a stable nanoparticle via a short peptide spacer that is a T-helper epitope. Some of the scaffolded immunogens contain a gp140 trimer immunogen presented on a nanoparticle platform formed with I3-01 protein, E2p, or variants of protein 1VLW. Also provided in the invention are nucleic acids that encode the various vaccine immunogens described herein, and expression vectors and host cells harboring the nucleic acids. The invention further provides methods of using the scaffolded HIV-1 vaccine immunogens for preventing or treating HIV infections.

The invention relates to germline-targeting designs, stabilization designs, and/or combinations thereof, of proteins designed with modified surfaces helpful for immunization regimens, other protein modifications and/or development of nanoparticles, methods of making and using the same, and to (a) germline-targeting priming or boosting/shepherding immunogens to initiate or guide maturation of VRC01-class responses (b) PCT64/PG9-germline-targeting designs (c) BG18-germline-targeting designs or boosting/shepherding immunogens to initiate or guide maturation of BG18-like responses, and/or (d) trimer stabilization and presentation in a membrane-bound format.

The invention relates to germline-targeting designs, stabilization designs, and/or combinations thereof, of proteins designed with modified surfaces helpful for immunization regimens, other protein modifications and/or development of nanoparticles, methods of making and using the same, and to (a) germline-targeting priming or boosting/shepherding immunogens to initiate or guide maturation of VRC01-class responses (b) PCT64/PG9-germline-targeting designs (c) BG18-germline-targeting designs or boosting/shepherding immunogens to initiate or guide maturation of BG18-like responses, and/or (d) trimer stabilization and presentation in a membrane-bound format.

Compounds, compositions and methods are provided for the inhibition of ENPP1. Aspects of the subject methods include contacting a sample with a cell impermeable ENPP1 inhibitor to inhibit cGAMP hydrolysis activity of ENPP 1. Also provided are vaccine compositions and methods relate thereto. Aspects of the methods include administering to a subject an effective amount of a cell impermeable ENPP1 inhibitor to inhibit the hydrolysis of cGAMP in combination with a vaccine.

Compounds, compositions and methods are provided for the inhibition of ENPP1. Aspects of the subject methods include contacting a sample with a cell impermeable ENPP1 inhibitor to inhibit cGAMP hydrolysis activity of ENPP 1. Also provided are vaccine compositions and methods relate thereto. Aspects of the methods include administering to a subject an effective amount of a cell impermeable ENPP1 inhibitor to inhibit the hydrolysis of cGAMP in combination with a vaccine.

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.

Methods and compositions are provided for delivery of a polynucleotide encoding a gene of interest, typically an antigen, to a dendritic cell (DC). The virus envelope comprises a DC-SIGN specific targeting molecule. The methods and related compositions can be used to treat patients suffering from a wide range of conditions, including infection, such as HIV/AIDS, and various types of cancers.

Methods and compositions are provided for delivery of a polynucleotide encoding a gene of interest, typically an antigen, to a dendritic cell (DC). The virus envelope comprises a DC-SIGN specific targeting molecule. The methods and related compositions can be used to treat patients suffering from a wide range of conditions, including infection, such as HIV/AIDS, and various types of cancers.

The present invention relates to methods and compositions for the stimulation of immune responses. Specifically, the present invention provides methods of inducing an immune response to human immunodeficiency virus (HIV) in a subject (e.g., a human subject) and compositions useful in such methods (e.g., a nanoemulsion comprising HIV or antigenic portion thereof).