Transdermal vaccination route using biodegradable microneedles is a rapidly progressing field of research and applications. The fear of painful needles is one of the primary reasons most people avoid getting vaccinated. Therefore, developing an alternative pain-free method of vaccination using microneedles has been a significant research area. Microneedles comprise arrays of micron-sized needles that offer a pain-free method of delivering actives across the skin. Apart from being pain-free, microneedles provide various advantages over conventional vaccination routes such as intramuscular and subcutaneous. Microneedle vaccines induce a robust immune response as the needles ranging from 50 to 900 μm in length can efficiently deliver the vaccine to the epidermis and the dermis region, which contains many Langerhans and dendritic cells. The microneedle array looks like band-aid patches and offers the advantages of avoiding cold-chain storage and self-administration flexibility. The slow release of vaccine antigens is an important advantage of using microneedles. The vaccine antigens in the microneedles can be in solution or suspension form, encapsulated in nano or microparticles, and nucleic acid-based. The use of microneedles to deliver particle-based vaccines is gaining importance because of the combined advantages of particulate vaccine and pain-free immunization. The future of microneedle-based vaccines looks promising however, addressing some limitations such as dosing inadequacy, stability and sterility will lead to successful use of microneedles for vaccine delivery. This review illustrates the recent research in the field of microneedle-based vaccination.

Neisseria gonorrhoeae is a strict human pathogen responsible for more than 100 million new sexually transmitted infections worldwide each year. Due to the global emergence of antibiotic resistance, the Center for Disease control (CDC) recently listed N. gonorrhoeae as an urgent threat to public health. No vaccine is available in spite of the huge disease burden and the possibility of untreatable gonorrhea. The aim of this study is to investigate the immunogenicity of a novel whole-cell-based inactivated gonococcal microparticle vaccine formulation loaded in dissolvable microneedles for transdermal administration. The nanotechnology-based vaccine formulation consists of inactivated whole-cell gonococci strain CDC-F62, spray dried and encapsulated into biodegradable cross-linked albumin matrix with sustained slow antigen release. The dry vaccine nanoparticles were then loaded in a dissolvable microneedle skin patch for transdermal delivery. The efficacy of the whole-cell microparticles vaccine formulation loaded in microneedles was assessed in vitro using dendritic cells and macrophages as well as in vivo mouse model. Antibody titers were measured using an enzyme immunosorbent assay (ELISA) and antigen-specific T lymphocytes were assessed in spleens and lymph nodes. Here we report that whole-cell-based gonococcal microparticle vaccine loaded in dissolvable microneedles for transdermal administration induced significant increase in antigen-specific IgG antibody titers and antigen-specific CD4 and CD8 T lymphocytes in mice compared to gonococcal antigens in solution or empty microneedles. Significant increase in antigen-specific IgG antibody levels was observed at the end of week 2 in groups that received the vaccine compared to the group receiving empty nanoparticles. The advantages of using formalin-fixed whole-cell gonococci that all immunogenic epitopes are covered and preserved from degradation. The spherical shaped micro and nanoparticles are biological mimics of gonococci, therefore present to the immune system as invaders but without the ability to suppress adaptive immunity. In conclusion, the transdermal delivery of microparticles vaccine via a microneedle patch was shown to be an effective system for vaccine delivery. The novel gonorrhea nanovaccine is cheap to produce in a stable dry powder and can be delivered in microneedle skin patch obviating the need for needle use or the cold chain.

Currently, most vaccines available on the market are for parental use; however, this may not be the best option on several occasions. Mucosal routes of administration such as intranasal, sublingual, and buccal generate great interest due to the benefits they offer. These range from increasing patient compliance to inducing a more effective immune response than that achieved through conventional routes. Due to the activation of the common mucosal immune system, it is possible to generate an effective systemic and local immune response, which is not achieved through parenteral administration. Protection against pathogens that use mucosal entry routes is provided by an effective induction of mucosal immunity. Mucosal delivery systems are being developed, such as films and microneedles, which have proven to be effective, safe, and easy to administer. These systems have multiple advantages over commonly used injections, which are simple to manufacture, stable at room temperature, painless for the patient since they do not require puncture. Therefore, these delivery systems do not require to be administered by medical personnel; in fact, they could be self-administered.

Significance: Needleless delivery into the skin would overcome a major barrier to efficient clinical utilization of advanced therapies such as nanomaterials and macromolecules. This study demonstrates that controlled skin stretching (in porcine, rat, and mouse models) using a patch comprising a hypobaric chamber, to open the skin appendages, can increase the permeability of the tissue and provide a means to enable direct delivery of advanced therapies directly into the skin without the use of a needle or injection system. This technology can facilitate the self-administration of therapeutics including vaccines, RNA, and antigens, thus improving the translation of these products into effective clinical use.

The emergence of drug-resistant gonorrhea infections worldwide combined with the lack of a vaccine is alarming. We prepared a novel microparticulate (MP) vaccine formulation using whole-cell inactivated Neisseria gonorrhoeae as the vaccine antigen, with Alum and AddaVax™ as vaccine adjuvants. The adjuvanted vaccine MP formulation was assessed for in vitro immunostimulatory activity, autophagy, and antigen presentation ability. The data shows that the adjuvanted gonococci vaccine MP enhanced autophagy induction in antigen presenting cells (APCs) compared to gonococci vaccine MP without adjuvants, which is important for enhancing antigen presentation. In addition, the adjuvanted vaccine formulation increased the surface expression of antigen presenting molecules MHCI and MHCII as well as co-stimulatory molecules CD40 and CD86 on the surface of dendritic cells. In addition, the gonococci vaccine microparticles at lower doses did not significantly increase the expression of the death receptor CD95 in APCs, which when elevated leads to suboptimal antigen presentation and reduced immune responses. The adjuvanted whole-cell inactivated gonococci microparticle vaccine formulation enhanced antigen uptake, processing, and antigen presentation.