Abstract
Vaccination is an essential public health measure for infectious disease prevention. The exposure of the immune system to vaccine formulations with the appropriate kinetics is critical for inducing protective immunity. In this work, faceted microneedle arrays were designed and fabricated utilizing a three-dimensional (3D)-printing technique called continuous liquid interface production (CLIP). The faceted microneedle design resulted in increased surface area as compared with the smooth square pyramidal design, ultimately leading to enhanced surface coating of model vaccine components (ovalbumin and CpG). Utilizing fluorescent tags and live-animal imaging, we evaluated in vivo cargo retention and bioavailability in mice as a function of route of delivery. Compared with subcutaneous bolus injection of the soluble components, microneedle transdermal delivery not only resulted in enhanced cargo retention in the skin but also improved immune cell activation in the draining lymph nodes. Furthermore, the microneedle vaccine induced a potent humoral immune response, with higher total IgG (Immunoglobulin G) and a more balanced IgG1/IgG2a repertoire and achieved dose sparing. Furthermore, it elicited T cell responses as characterized by functional cytotoxic CD8+ T cells and CD4+ T cells secreting Th1 (T helper type 1)-cytokines. Taken together, CLIP 3D–printed microneedles coated with vaccine components provide a useful platform for a noninvasive, self-applicable vaccination.
Vaccines play a vital role in global healthcare. Prophylactic vaccines have nearly eliminated diseases such as smallpox and measles and have the potential to curb many other common infectious diseases as well as emerging epidemics (Ebola) and pandemics (COVID-19). Vaccines are formulated to deliver target antigens to the immune system in order to generate potent and durable protective immune responses against pathogens and prevent future infections. Subunit vaccines consisting of purified antigens are a major focus of modern prophylactic vaccine development due to their much-improved safety profile than the live attenuated and inactivated vaccines (1). However, subunit vaccines are generally not as immunogenic as whole pathogen-based vaccines because of the lack of immunostimulatory components and/or inefficient detection by the immune system. The addition of immunostimulatory agents (adjuvants) (2, 3) and customized delivery vehicles (like particles and microneedles) have shown great promise in improving the efficacy of subunit vaccines (4, 5).
Effective vaccines generally need to deliver antigens and adjuvants to the right set of innate immune cells, such as dendritic cells (DCs) and macrophages, to facilitate antigen presentation, T cell priming, and the formation of memory T cells and B cells as well as antibody-secreting plasma cells (6). Accumulating evidence suggests that vaccine kinetics and location of delivery play an essential role in promoting protective immunity while keeping the adverse effects under control (7). We have previously shown that the formation of an antigen depot and sustained cargo release at the injection site, as well as an extended presence of antigen in the draining lymph nodes via nanoparticle delivery, greatly improved humoral immunity (8, 9). Furthermore, the route of vaccine administration can potentially impact the performance of a vaccine formulation. While vaccines are typically administered as bolus injections into the muscle or subcutaneous space, there is increasing interest in the intradermal (ID) route, as human skin is rich in immune cells (Langerhans cells and dermal DCs) (10). ID vaccination has demonstrated improved vaccine efficacy with dose sparing (11⇓–13); however, ID injections require trained medical personnel, are painful, and are difficult to administer, requiring development of new ID devices (14). Leveraging these learnings, we aimed to develop a subunit vaccine to provide sustained delivery of both antigens and adjuvants in the skin, utilizing microneedles for ID delivery.
Microneedles (MNs) are arrays of micrometer-sized solid needle projections that can painlessly puncture the stratum corneum and deliver therapeutics into the epidermis/dermis. MNs can be fabricated out of solid metal, silicon, or polymers and are coated with therapeutics or fabricated out of degradable materials that encapsulate therapeutics (15⇓–17). Once applied to the skin, the cargo either dissolves off the MNs, or the MN matrix material degrades and releases the cargo into the skin. Much work has been done in the field, characterizing methods for MN drug delivery through either developing methods for coating solid microneedles with cargo (18⇓⇓–21) or evaluating degradable polymer matrices for transdermal drug delivery (22⇓⇓⇓–26)….
