New adjuvant/delivery strategies that could enable protein and peptide vaccines to elicit both potent cellular and humoral immunity would be highly complementary to existing approaches in HIV vaccine development. In this Core, we will supply and further develop two classes of potent novel adjuvants recently developed in the Irvine lab to support the subunit vaccine studies of projects 1 and 2 in studying human immune responses to HIV immunogens in BLT humanized mice: stabilized lipid nanocapsules (SLNCs) and membrane-targeted micelles (MTMs). SLNCs are a lipid nanocapsule system for delivery of protein or peptide antigens together with molecular danger signals such as TLR agonists (TLRa), which retain entrapped antigen/TLRa much more effectively than traditional liposomes, leading to enhanced antigen/adjuvant delivery to dendritic cells and sustained accumulation of antigen in draining lymph nodes following vaccination. The second adjuvant system, membrane-targeted micelles (MTM), is based on the conjugation of molecular adjuvants or peptide antigen cargos to a micelle-forming lipid tail. These amphiphilic molecules self-assemble to form nanoparticles -15 nm in diameter in water, but also dynamically dis-assemble to anchor their lipid tails in the membrane on contact with cells. MTMs dramatically target TLRa or peptides to lymph nodes, forming intranodal vaccine depots following s.c. injection, and driving strongly enhanced immune responses to co-administered protein antigens. We will provide these potent adjuvants on demand for BLT humanized mouse immunization studies for projects 1 and 2. In addition, we will further develop these adjuvants to maximize the effectiveness in BLT mice while designing for negligible toxicity/reactogenicity, to ensure their relevance for human vaccine development. Results from these studies will further the BLT humanized mouse model as a tool for vaccine development, by identifying effective adjuvants and routes of administration for vaccine delivery, and provide new adjuvants applicable to diverse subunit vaccines beyond HIV.

RELEVANCE (See instructions): The development of novel vaccine adjuvants for promoting humoral and cellular responses is a pressing need for HIV vaccine development. This Core will both provide and develop novel adjuvants that support the studies of HIV vaccines in humanized mice of projects 1 and 2, which may be broadly applicable to human vaccines.