A Regimen Compression Strategy for Commercial Vaccines Leveraging an Injectable Hydrogel Depot Technology for Sustained Vaccine Exposure

Abstract

Equitable global access to vaccines requires overcoming challenges associated with complex immunization schedules and their associated economic burdens that hinder delivery in under‐resourced environments. The rabies vaccine, for example, requires multiple immunizations for effective protection and each dose is cost prohibitive, and therefore inaccessibility disproportionately impacts low‐ and middle‐income countries. In this work, an injectable hydrogel depot technology for sustained delivery of commercial inactivated rabies virus vaccines is developed. In a mouse model, it is shown that a single immunization of a hydrogel‐based rabies vaccine elicited comparable antibody titers to a standard prime‐boost bolus regimen of a commercial rabies vaccine, despite these hydrogel vaccines comprising only half of the total dose delivered in the bolus control. Moreover, these hydrogel‐based vaccines elicited similar antigen‐specific T‐cell responses and neutralizing antibody responses compared to the bolus vaccine. Notably, it is demonstrated that while the addition of a potent clinical Toll‐like receptor 4 (TLR4) agonist adjuvant to the gels slightly improved binding antibody responses, inclusion of this adjuvant to the inactivated virion vaccine is detrimental to neutralizing responses. Taken together, these results suggest that these hydrogels can enable an effective regimen compression and dose‐sparing strategy for improving global access to vaccines.

Synthetic Evolution of a Supramolecular Harpooning Mechanism to Immobilize Vesicles at Antifouling Interfaces

“…Lastly, this approach may be employed to immobilize vesicles for delivering lipids or vaccines from intricate interfaces like nanofibers. [33]…”

“…In fact, all life forms on Earth are based on cells, thus vesicles are considered early precursors of protocells. [1] Apart from natural vesicles, there are various other types, such as liposomes, [2][3][4][5][6] polymersomes, [7,8] quatsomes, [9] dendrimersomes, [10][11][12][13][14][15][16][17] and ionic combisomes [18] with numerous applications in various fields, including the development of synthetic cells, [19] diagnostics, [20][21][22] cancer research, [20,23,24] regenerative medicine, [25][26][27][28] drug delivery, [29][30][31][32] vaccines, [33] antimicrobials, [34] food applications, [35] biotechnology, [36][37][38] and pollutant removal. [39,40] In their free and unbound form, vesicles can function as information carriers between cells or as delivery vehicles.…”

“…In this way, these systems, resembling "polymerized lipids", leverage a multitude of simultaneous, very weak attractive interactions that collectively firmly insert into membranes. This approach has been expanded to generate new amphiphiles that can be used either to develop injectable hydrogels containing vesicles for immunotherapy and regenerative medicine, [29] or polymer nanoparticle hydrogel-based vaccines, [33] as well as a means to generate a new family of vesicles termed i-combisomes that can fuse with living bacteria. [18] However, when considering the immobilization of vesicles directly onto solid surfaces, maintaining the integrity of vesicles is more challenging due to interfacial interactions.…”

Targeting enhanced neutralizing antibody responses via increased germinal center activity: early-phase vaccine trials with novel clinical designs

“…The only difference is the number of administrations. Alternative strategies have used constant slow-release strategies driven by osmotic pumps or hydrogel-based technologies [6].…”

“…We are not aware of licensed or investigational products or devices intended for prolonged administration into the IM space. In preclinical models, an alternate strategy for sustained antigen exposure involves the use of implantable subcutaneous osmotic pumps or deposition of long-acting gels [6]; however, these devices have not yet been evaluated for this purpose in clinical trials. If higher rates of somatic hypermutation are observed with sustained antigen exposure administered intramuscularly via dose escalation in people, pulsed or continuous subcutaneous administration delivered devices such as pumps or patches represent a plausible mechanism for delivery of sustained antigens in clinical applications.…”