Modulation of injectable hydrogel properties for slow co‐delivery of influenza subunit vaccine components enhance the potency of humoral immunity

Abstract

Vaccines are critical for combating infectious diseases across the globe. Influenza, for example, kills roughly 500,000 people annually worldwide, despite annual vaccination campaigns. Efficacious vaccines must elicit a robust and durable antibody response, and poor efficacy often arises from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune system's natural response to extended pathogen exposure during infection by designing an easily administered slow‐delivery influenza vaccine platform. We utilized an injectable and self‐healing polymer‐nanoparticle (PNP) hydrogel platform to prolong the co‐delivery of vaccine components to the immune system. We demonstrated that these hydrogels exhibit unique dynamic physical characteristics whereby physicochemically distinct influenza hemagglutinin antigen and a toll‐like receptor 7/8 agonist adjuvant could be co‐delivered over prolonged timeframes that were tunable through simple alteration of the gel formulation. We show a relationship between hydrogel physical properties and the resulting immune response to immunization. When administered in mice, hydrogel‐based vaccines demonstrated enhancements in the magnitude and duration of humoral immune responses compared to alum, a widely used clinical adjuvant system. We found stiffer hydrogel formulations exhibited slower release and resulted in the greatest improvements to the antibody response while also enabling significant adjuvant dose sparing. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of influenza subunit vaccines.

Yield‐Stress and Creep Control Depot Formation and Persistence of Injectable Hydrogels Following Subcutaneous Administration

“…Half-lives for cargo release calculated by fitting fluorescent decay curves to a single-phase exponential decay model. Half-lives are comparable to those predicted from Ritger-Peppas diffusional release kinetics with caliper dimensions and D = 2 um 2 sec −1 [53,54]. Values reported are means ± SE of n = 4 per group.…”

“…These normalized fluorescence intensity values between day 0 and day 5 for each mouse (n = 4) were fit to single phase exponential decay models and half-lives of cargo retention were acquired and averaged using GraphPad Prism. [53,54] Values reported are means ± SE of n = 4 per group.…”

Injectable polymer-nanoparticle hydrogel for the sustained intravitreal delivery of bimatoprost

“…[18] We first sought to investigate a PNP hydrogel formulation comprising 2 wt% HPMC-C12 and 10 wt% PEG-PLA NPs, denoted PNP-2-10, based on prior work showing this formulation enables the slowest release rate for various molecular cargo. [13d, 19] We loaded these materials with bimatoprost and evaluated the drug-loaded materials both in vitro and in vivo in New Zealand white rabbits.…”

Gelation and yielding behavior of polymer–nanoparticle hydrogels

“…Fluorescein isothiocyanate was coupled to HPMC‐C 12 according to literature protocols, 4 , 24 and included as the wt% of total polymer added to each hydrogel. Alexa 647 was coupled to the PEG–PLA nanoparticles using copper‐free click chemistry according to previously published protocols, 36 and included as the wt% of total nanoparticles added to each hydrogel. Gels were sealed between a glass slide and a coverslip with a 1 mm gap using an epoxy adhesive and imaged using a confocal LSM780 microscope.…”