Chimeric NOD2 Mincle Agonists as Vaccine Adjuvants

There is a need for improved vaccine adjuvants to augment
vaccine
efficacy. One way to address this is by targeting multiple immune
cell pathogen recognition receptors (PRRs) using chimeric pathogen-associated
molecular patterns (PAMPs). Conjugation of the PAMPs will ensure codelivery
of the immunostimulatory molecules to the same cell, enhancing adjuvant
activity. The macrophage inducible C-type lectin (Mincle) is a promising
PRR for adjuvant development; however, no effective chimeric Mincle
adjuvants have been prepared. We addressed this by synthesizing Mincle
adjuvant conjugates, MDP-C18Brar and MDP-C18Brar-dilipid, which contain
PAMPs recognized by Mincle and the nucleotide-binding oligomerization
domain 2 (NOD2). The two PAMPs are joined by a pH-sensitive oxyamine
linker which, upon acidification at lysosomal pH, hydrolyzed to release
the NOD2 ligands. The conjugates elicited the production of Th1 and
Th17 promoting cytokines in vitro, and when using
OVA as a model antigen, exhibited enhanced T-cell-mediated immune
responses and reduced toxicity in vivo, compared
to the coadministration of the adjuvants.