Microneedle delivery of an M2e-TLR5 ligand fusion protein to skin confers broadly cross-protective influenza immunity

Abstract

Influenza vaccines with broad cross-protection are urgently needed to prevent an emerging influenza pandemic. A fusion protein of the TLR5-agonist domains from flagellin and multiple repeats of the conserved extracellular domain of the influenza matrix protein 2 (M2e) was constructed, purified and evaluated as such a vaccine. A painless vaccination method suitable for possible self-administration using coated microneedle arrays was investigated for skin-targeted delivery of the fusion protein in a mouse model. The results demonstrate that microneedle immunization induced strong humoral as well as mucosal antibody responses and conferred complete protection against homo- and heterosubtypic lethal virus challenges. Protective efficacy with microneedles was found to be significantly better than that seen with conventional intramuscular injection, and comparable to that observed with intranasal immunization. Because of its advantages for administration, safety and storage, microneedle delivery of M2e-flagellin fusion protein is a promising approach for an easy-to-administer universal influenza vaccine.

Cutaneous vaccination with coated microneedles prevents development of airway allergy

“…To apply MNs, a previously described protocol was used [15]. Briefly, mice were first anesthetized under an isoflurane and air mixture, and their back-skin was treated with an electric hair-trimmer.…”

“…The objective was to test if this could reduce or prevent asthma development during the three years of treatment and two years post-treatment. After immunotherapy a significantly fewer number of children experienced asthma or used asthma medication, and this effect sustained for two years after end of treatment [15]. The trial also demonstrated that allergic rhinoconjunctivitis symptoms were also significantly reduced.…”

“…MNs are micrometer-sized needles, which can deliver the drug or antigen/allergen into the skin by rupturing the stratum corneum (topmost layer of the skin) and they can activate the immune response effectively [15, 22]. They have been widely explored in the development of infectious diseases vaccines [15, 22, 23]. For the very first time, we demonstrate here their efficacy to deliver the allergen in to the skin for primary protection against allergy progression in mice.…”

Effect of vaccine administration modality on immunogenicity and efficacy

“…Different types of microneedles can be made for vaccine delivery, including solid and dissolvable microneedles[113], coated microneedles[114], and hollow microneedles[115]. …”

Microneedle patch delivery to the skin of virus-like particles containing heterologous M2e extracellular domains of influenza virus induces broad heterosubtypic cross-protection

“…Therefore, several strategies have been attempted to improve its immunogenicity including fusion of M2e peptides with carrier proteins or vehicles formulated in adjuvants such as cholera toxin subunits and flagellin [8-11]. Despite their ability to stimulate immune responses, these adjuvants would not be approved for human use because of potential toxicity.…”