Nanoparticle vaccine adjuvant and methods of use thereof

Inventors

Irvine, Darrell J. • Silva, Murillo • Crotty, Shane • Kato, Yu

Assignees

La Jolla Institute for Allergy and Immunology • Massachusetts Institute of Technology

Abstract

Non-liposome, non-micelle particles formed of a lipid, an additional adjuvant such as a TLR4 agonist, a sterol, and a saponin are provided. The particles are porous, cage-like nanoparticles, also referred to as nanocages, and are typically between about 30 nm and about 60 nm. In some embodiments, the nanocages include or are administered in combination with an antigen. The particles can increase immune responses and are particularly useful as adjuvants in vaccine applications and related methods of treatment. Preferred lipids, additional adjuvants including TLR4 agonists, sterols, and saponins, methods of making the nanocages, and method of using them are also provided.

Core Innovation

The invention relates to porous or perforated non-liposome, non-micelle nanoparticles that form cage-like structures and function as vaccine adjuvants. The nanoparticles comprise a phospholipid, a sterol, a saponin, and a TLR4 agonist lipopolysaccharide (LPS) or a lipid A derivative thereof, and the formulation is based on detergent-assisted self-assembly to produce porous or perforated nanocage-like particles.

In the reported embodiments, the TLR4 agonist is MPLA or related lipid A forms, including 3D-MPLA, and the saponin includes Quil-A or QS-21, also referred to as Q-21. The sterol can be cholesterol, and the phospholipid can be DPPC. The nanoparticle can be prepared to incorporate antigen within the nanocage or be administered with separate antigen, including free antigen, alongside the nanocage adjuvant concept.

The described non-liposome, non-micelle nanocage platform is characterized as increasing TLR4 activation and improving antigen-specific immune readouts. In the reported comparisons, MPLA-containing saponin nanocages show substantially higher antigen-specific humoral responses together with germinal center activity, T follicular helper (Tfh) function, plasmablast frequency, and pro-inflammatory cytokine production.

Additional reported effects include antigen drainage to lymph nodes, lymph node permeability, enhanced B-cell antigen uptake, dendritic cell activation, and broader lymph node or follicle distribution of antigen compared with saponin-only nanoparticles and other adjuvants.

Claims Coverage

The document includes two independent claims. Across the independent claims, the main inventive features are the porous or perforated non-liposome, non-micelle cage-like nanoparticle architecture together with a defined combination of a phospholipid, sterol, saponin, and a TLR4 agonist LPS or lipid A derivative; one claim further specifies an explicit component set as phospholipid, cholesterol, QS-21, and MPLA.

Overall claim coverage is directed to porous or perforated, cage-like, non-liposome and non-micelle nanoparticles that combine a phospholipid, sterol, a saponin, and a TLR4 agonist LPS or lipid A derivative, with the goal of an adjuvant composition based on these defined structural and ingredient limitations.

Stated Advantages

Documented Applications