Iwata Hiroaki, Kakita Kosuke, Imafuku Keisuke, Takashima Shota, Haga Naoya, Yamaguchi Yasuyuki, Taguchi Kenji, Oyamada Takayoshi
Department of Dermatology, Faculty of Medicine and Graduate School of Medicine Hokkaido University, Sapporo, Japan.
FUJIFILM Corporation, Tokyo, Japan.
Lancet Microbe. 2022 Feb;3(2):e96-e104. doi: 10.1016/S2666-5247(21)00269-X. Epub 2021 Dec 16.
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.
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 (log) or higher in individuals whose pre-vaccination titres had been less than 1 (log). This study is registered with the Japan Registry of Clinical Trials (s011190004).
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 (log) were 2·55 for MNA-25%, 2·04 for MNA-10%, and 2·08 for subcutaneous injection.
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.
FUJIFILM.
目前尚不清楚日本脑炎病毒微针疫苗能否诱导产生足够的中和抗体并减少所需疫苗剂量。我们旨在评估微针疫苗贴片在未接种过疫苗且未自然感染过日本脑炎的健康个体中预防日本脑炎的安全性和减量效果。
MNA-J研究是一项在北海道大学（日本札幌）进行的随机、部分盲法、活性对照1期临床试验，纳入20-34岁无日本脑炎疫苗接种史及感染史（血清学阴性确认）的健康成年人。我们排除了曾感染或接种过日本脑炎疫苗的个体。符合条件的参与者被随机分配（1:1:1）至三组之一，接受皮下注射灭活日本脑炎疫苗，每3周注射一次，每次2.5μg；或高剂量微针阵列（MNA-25%）每片0.63μg；或低剂量微针阵列（MNA-10%）每片0.25μg。随机分组序列采用按队列分层和6个一组的区组设计，由一名不知分组情况的统计学家通过计算机生成。给药后，通过酶联免疫吸附测定法测量剩余未给药疫苗量，并计算为疫苗给药量。主要结局是首次免疫后42天的中和抗体滴度。成功血清转化定义为接种前滴度低于1（log）的个体接种后滴度达到1.3（log）或更高。本研究已在日本临床试验注册中心注册（s011190004）。
2019年8月31日至9月2日，39名参与者入组并随机分配至各组（每组n = 13）。未观察到严重不良事件。微针阵列组所有参与者均出现局部红斑反应。微针阵列组向每位参与者递送的疫苗量，MNA-25%组为全量1.26μg的0.63 - 1.15μg（50 - 92%），MNA-10%组为全量0.50μg的0.25 - 0.41μg（51 - 84%）。所有参与者在42天时均出现血清转化，MNA-25%组平均滴度（log）为2.55，MNA-10%组为2.04，皮下注射组为2.08。
日本脑炎疫苗微针贴片安全、耐受性良好且具有免疫原性效果。减量效果表明在减少所需免疫原剂量方面具有显著潜力。然而，需要改进递送方式以使其更易于耐受且使用方便。
富士胶片公司。
