Safety and dose-sparing effect of Japanese encephalitis vaccine administered by microneedle patch in uninfected, healthy adults (MNA-J): a randomised, partly blinded, active-controlled, phase 1 trial.

BACKGROUND: It is unclear whether microneedle vaccinations of Japanese encephalitis virus can induce sufficient neutralising antibodies and reduce the amount of vaccine needed. We aimed to assess the safety and dose-sparing effect of a microneedle vaccine patch against Japanese encephalitis in healthy individuals who are naive to both the vaccine and natural infection. METHODS: The MNA-J study was a randomised, partly blinded, active-controlled, phase 1 clinical trial at Hokkaido University (Sapporo, Japan) that enrolled healthy adults aged 20-34 years with no history of Japanese encephalitis vaccination nor of infection as confirmed by seronegativity. We excluded individuals who had been infected with or vaccinated against Japanese encephalitis. Eligible participants were randomly assigned (1:1:1) to one of three groups to receive inactivated Japanese encephalitis vaccine administered twice, 3 weeks apart, by either 2·5 µg per injection by subcutaneous injection, 0·63 µg per patch by high-dose microneedle array (MNA-25%), or 0·25 µg per patch by low-dose microneedle array (MNA-10%). The randomisation sequence, using stratification by cohort and blocks of six, was computer-generated by a statistician who was unaware of group assignment. After administration, the remaining amount of unadministered vaccine was measured by ELISA and calculated as the delivered amount of vaccine. The primary outcome was the neutralising antibody titre at day 42 after first immunisation. Successful seroconversion was defined as post-vaccination titres of 1·3 (log10) or higher in individuals whose pre-vaccination titres had been less than 1 (log10). This study is registered with the Japan Registry of Clinical Trials (s011190004). FINDINGS: Between Aug 31 and Sept 2, 2019, 39 participants were enrolled and each was randomly assigned to a group (n=13 per group). No serious adverse events were observed. All participants in the microneedle array groups had a localised erythematous reaction. The amount of vaccine delivered by microneedle array to each participant was 0·63-1·15 µg (50-92%) of the full 1·26 µg for the MNA-25% group and 0·25-0·41 µg (51-84%) of the full 0·50 µg for the MNA-10% group. All participants demonstrated seroconversion at day 42, and the mean titres (log10) were 2·55 for MNA-25%, 2·04 for MNA-10%, and 2·08 for subcutaneous injection. INTERPRETATION: A microneedle patch of the Japanese encephalitis vaccine is safe, well tolerated, and immunogenically effective. The dose-sparing effect suggests a significant potential to reduce the amount of immunogens needed. However, improved delivery is needed to make it more tolerable and user friendly. FUNDING: FUJIFILM.

Possible role of epiregulin from dermal fibroblasts in the keratinocyte hyperproliferation of psoriasis.

Psoriasis, an immune-mediated inflammatory disease, is characterized by keratinocyte hyperproliferation. Tumor necrosis factor (TNF)-α, interleukin (IL)-23, and IL-17A play critical roles in the pathogenesis of psoriasis. IL-17A secreted by T-helper 17 acts more directly against keratinocytes than TNF-α or IL-23 do. Regarding the receptors of cytokines, fibroblasts also express receptors against IL-17A and TNF-α, and induce the production of growth factors. Epiregulin (EREG), an epidermal growth factor receptor ligand, is produced by both keratinocytes and fibroblasts. EREG enhances keratinocyte proliferation and differentiation. We hypothesized that fibroblasts stimulated with IL-17A and/or TNF-α may play a role in epidermal hyperproliferation through the production of epidermal growth factors in psoriasis. The mRNA expression of EREG was found to be significantly upregulated by co-stimulation with IL-17A and TNF-α (mean, 49.2-fold). Furthermore, the stimulation with TNF-α alone, but not IL-17A alone, induced significant increases. Immunofluorescent staining demonstrated that the protein expression level of EREG was also increased in fibroblasts stimulated with these cytokines. Stimulation with EREG significantly enhanced keratinocyte proliferation in vitro. In human psoriatic patients' skin, immunofluorescence staining of EREG showed significantly high intensity in the dermis of lesional skin. In conclusion, cytokine stimulation with TNF-α and IL-17A induces the overexpression of EREG from dermal fibroblasts in the lesional skin of psoriasis, and plays a role in epidermal hyperproliferation.

Serum Krebs von den Lungen-6 levels in psoriatic patients under treatment with biologics.

During biologic treatments, attention should be paid to adverse reactions, particularly infectious diseases. Furthermore, drug-induced interstitial lung disease is also known to be associated with biologic therapies. We retrospectively reviewed serum Krebs von den Lungen-6 (KL-6) levels in psoriatic patients who underwent treatment with seven different biologics. A total of 67 patients who received 80 biologic treatments were evaluated. The 31 anti-tumor necrosis factor (TNF)-α treatments consisted of 17 infliximab (IFX) and 14 adalimumab. The 23 anti-interleukin (IL)-23 treatments consisted of 14 ustekinumab and nine guselkumab. The 26 anti-IL-17 treatments consisted of nine secukinumab, six ixekizumab and 11 brodalumab. The IFX showed significantly increased mean serum KL-6 (170.9%), but none of the other treatments showed significant increases. Thirteen of the 17 (75.6%) patients in the IFX and 17 of the 31 (54.8%) patients in the total anti-TNF-α group demonstrated at least a 25% increase in serum KL-6. Levels exceeding the cut-off (500 U/mL) were detected in three patients before treatment and in seven patients after treatment. This study showed that anti-IL-17 and anti-IL-23 treatments have no significant impact on serum KL-6 level. In addition to the influence of IFX, a significantly large number of patients in the IFX group had a history of methotrexate administration associated with psoriatic arthritis, which might have influenced the KL-6 level. None of the patients with elevated serum KL-6 showed pulmonary changes by computed tomography and/or X ray.