Sustained delivery of a HIV subunit vaccine using silk microneedle skin patches

Abstract

Abstract Many broadly neutralizing antibodies (bNAbs) against HIV exhibit high degrees of somatic hypermutation, suggesting that immunization approaches promoting germinal center (GC) stimulation and affinity maturation may be critical for an HIV vaccine. To this end, we recently demonstrated that sustained exposure of draining lymph nodes (LNs) to env immunogens through repeated injections over 2 weeks enhanced env capture on follicular dendritic cell networks in LNs, with Tfh expansion and GC induction. To obtain similar sustained vaccine kinetics for mass immunization, we developed a submicron-scale dissolving silk microneedle array (MN) for dermal vaccine delivery. We utilized silk protein to encapsulate an HIV envelope trimer (BG505 SOSIP variants) with adjuvants supported by a poly acrylic acid (PAA) base. Upon dermal application, rapid PAA dissolution is followed by silk beta sheet-dependent sustained release of encapsulated vaccine with minimal local inflammation. Antigenicity of SOSIP was maintained in silk as determined by binding to structure-sensitive bNAbs- PGT151, PGT145, PGT121 and VRCO1 without binding to non-bNAb 14e. Following immunization in mice, skin and draining LNs were subjected to lipid clearance using organic solvents and imaged by confocal microscopy. We observed SOSIP and silk co-retention at the skin site of microneedle application after one week. MN delivery resulted in higher SOSIP retention and increased SOSIP-specific T follicular helper cells in the GCs of vaccine draining LNs on day 14 post prime, and increased anti-SOSIP IgG titers on day 28 post prime compared to intradermal injections. Taken together, these results suggest the potential of silk MNs in modulating release of HIV subunit vaccine.