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

Abstract

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.

Microneedle‐Mediated Transcutaneous Immunization: Potential in Nucleic Acid Vaccination

“…No risks of reuse Limited mechanical strength Limited loading capacity Limited dose accuracy Strong hygroscopicity Influenza [40] Tuberculosis [ 43,63] Subcutaneous tumor [64] Melanoma [65] Prostate cancer [66] Cervical cancer [67] HBV infection [68] COVID-19 [69] Japanese encephalitis [70] Tetanus [71] Hollow MNs Large loading capacity Controlled and accurate drug release…”

Opportunities and challenges for commercializing microarray patches for vaccination from a MAP developer’s perspective

“…Additionally, the immunogenicity benefits of MAPs in humans have to date only be shown with protein-based vaccines, such as influenza 9 and an inactivated Japanese encephalitis virus vaccine. 20 In both of these cases, delivery of the vaccine by MAP resulted in enhanced immune responses compared with N&S injection. However, whether a similar effect will be seen with other vaccine types such as nucleic acids, live attenuated viruses or live virus vectors remains to be seen.…”

Local Response and Barrier Recovery in Elderly Skin Following the Application of High-Density Microarray Patches

“…As a function of this targeted vaccine delivery, our group and other researchers have demonstrated that enhanced immune responses with lower doses of vaccine are achievable as compared to traditional needle-based vaccination methods [8,9]. Previous studies have demonstrated the broad utility of the HD-MAP delivery platform, which has shown promising results against the dengue virus [10][11][12], influenza [13,14], West Nile virus, Chikungunya virus [15], Japanese encephalitis [16], and poliovirus [17,18]. Recently, pre-clinical studies using the HD-MAP have shown promising results producing broadly high titre neutralizing antibody responses against the SARS-CoV-2 ancestral virus and variants of concerns [19].…”