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. MethodsThe 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 (log 10 ) or higher in individuals whose pre-vaccination titres had been less than 1 (log 10 ). This study is registered with the Japan Registry of Clinical Trials (s011190004). FindingsBetween 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 (log 10 ) 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.

To more sensitively detect OA changes in subchondral trabecular bone structure, a focus on osteoporotic changes in the lateral joint and the medial-lateral ratio would be useful. Detectability of early OA remains unknown, but based on a strong correlation with the degree of OA progression, trabecular structural analysis of subchondral bone may be a useful parameter to evaluate OA severity and evaluate treatment.

We analyzed the microstructure and degree of mineralization of the subchondral trabecular bone in hip osteoarthritis (OA) using synchrotron radiation computed tomography (SRCT) to identify the relationship between bone structure and bone turnover. Subchondral bone samples were extracted from femoral heads of 10 terminal-staged hip OA patients. The SRCT scan was performed at 30 keV energy and 5.9 mm voxel size. Trabecular bone structure, bone cyst volume, and the degree of trabecular bone mineralization were measured, and correlations between bone structure and the degree of mineralization were analyzed. In addition, the trabecular bone was divided into the area immediately surrounding the bone cyst and the remaining area, and they were compared. The average cyst volume fraction in the whole region was 31.8%, and the bone volume fraction in the bone region was 55.6%. Cyst volume was the only structural parameter that had a significant correlation with the degree of mineralization. The degree of mineralization was diminished when the bone cyst was larger (r ¼ À0.81, p ¼ 0.004). The trabecular bone immediately surrounding the bone cyst had a lower degree of mineralization when compared with the remaining trabecular bone (p ¼ 0.008). In the bone sclerosis of OA subchondral bone, there are many large and small bone cysts, which are expected to play a significant part in the high bone turnover of OA. ß

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