Importantly, traditional covalently cross-linked hydrogels are often not appropriate for vaccine applications, as they cannot be easily administered and have limitations in their delivery kinetics for diverse cargo. (28) Therefore, there is a significant need for the development of new controlled delivery approaches that allow for the sustained exposure of vaccine components to the immune system. (9,10,12,13,16−27) However, many previously reported sustained-release technologies are limited by several factors: (i) the inability to deliver chemically diverse cargo, (ii) restricted time frame tunability for prolonged release, and/or (iii) low yielding and, oftentimes, challenging multistep syntheses. (15) These studies and others demonstrate that the kinetics of antigen presentation to the immune system dramatically influences the adaptive immune response. (10,11) It has been reported that the mechanisms of traditional adjuvant systems such as aluminum hydroxide (alum) rely on increased antigen persistence in the body, (12−14) a feature that was recently exploited further through engineering antigens that adhere more strongly to alum particles, thereby providing sustained antigen delivery to lymph nodes and improving the humoral response.
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(9) Similarly, sustained release of a stabilized HIV antigen from a microneedle patch led to increased serum titers and bone marrow plasma cells in mice. (6−8) Recent work demonstrates that slow delivery of an HIV vaccine using surgically implantable osmotic pumps in nonhuman primates resulted in higher neutralizing titers. (5) The sustained release of soluble antigen provides essential signals to germinal centers (GCs) in the lymph nodes-the structures responsible for the affinity maturation of B cells-leading to high-affinity antibody production and generation of humoral immune memory. (5) Conversely, the short-term presentation of subunit vaccines from a single bolus administration persists for only 1–2 days.
(5) With regards to temporal dynamics, natural infections expose the immune system to antigen and inflammatory signals for 1–2 weeks. (1−4) To elicit a durable, protective antibody response, vaccines must interact with the appropriate cell types at the right time and place while also providing the necessary cues to guide the immune system. Unfortunately, vaccines against many infectious diseases have proven to be difficult to develop for various reasons ranging from poor antigen immunogenicity, poor breadth of protection against rapidly mutating antigenic targets, or poor durability of immune protection. Vaccines are critical for combating infectious diseases across the globe. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of subunit vaccines. This strengthened germinal center response promoted greater antibody affinity maturation, resulting in a more than 1000-fold increase in antigen-specific antibody affinity in comparison to bolus immunization. We report that the creation of a local inflammatory niche within the hydrogel, coupled with sustained exposure of vaccine cargo, enhanced the magnitude and duration of germinal center responses in the lymph nodes. When administered in mice, hydrogel-based sustained vaccine exposure enhanced the magnitude, duration, and quality of the humoral immune response compared to standard PBS bolus administration of the same model vaccine. We demonstrated that these hydrogels exhibit unique delivery characteristics, whereby physicochemically distinct compounds (such as antigen and adjuvant) could be codelivered over the course of weeks. We utilized an injectable and self-healing polymer–nanoparticle (PNP) hydrogel platform to prolong the codelivery of vaccine components 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 vaccine platform. Failure of a vaccine to elicit such a response arises in part from inappropriate temporal control over antigen and adjuvant presentation to the immune system.
Vaccines aim to elicit a robust, yet targeted, immune response.
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