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The current success of mRNA vaccines against COVID‐19 has highlighted the effectiveness of mRNA and DNA vaccinations. Recently, we demonstrated that a novel needle‐free pyro‐drive jet injector (PJI) effectively delivers plasmid DNA into the skin, resulting in protein expression higher than that achieved with a needle syringe. Here, we used ovalbumin (OVA) as a model antigen to investigate the potential of the PJI for vaccination against cancers. Intradermal injection of OVA‐expression plasmid DNA into mice using the PJI, but not a needle syringe, rapidly and greatly augmented OVA‐specific CD8+ T‐cell expansion in lymph node cells. Increased mRNA expression of both interferon‐γ and interleukin‐4 and an enhanced proliferative response of OVA‐specific CD8+ T cells, with fewer CD4+ T cells, were also observed. OVA‐specific in vivo killing of the target cells and OVA‐specific antibody production of both the IgG2a and IgG1 antibody subclasses were greatly augmented. Intradermal injection of OVA‐expression plasmid DNA using the PJI showed stronger prophylactic and therapeutic effects against the progression of transplantable OVA‐expressing E.G7‐OVA tumor cells. Even compared with the most frequently used adjuvants, complete Freund's adjuvant and aluminum hydroxide with OVA protein, intradermal injection of OVA‐expression plasmid DNA using the PJI showed a stronger CTL‐dependent prophylactic effect. These results suggest that the novel needle‐free PJI is a promising tool for DNA vaccination, inducing both a prophylactic and a therapeutic effect against cancers, because of prompt and strong generation of OVA‐specific CTLs and subsequently enhanced production of both the IgG2a and IgG1 antibody subclasses. The intradermal vaccination with OVA‐expression plasmid DNA using the PJI, but not a needle syringe, induces a strong antitumor immune response via enhanced generation of antigen‐specific CTLs, with subsequent killing of the target cells, and that efficient antigen‐specific antibody production is also enhanced. Notably, induction of prophylactic antitumor immunity was faster and stronger with the injection of OVA‐expression plasmid DNA using the PJI than with the injection of OVA protein combined with alum or complete Freund's adjuvant.

•First large-scale fIPV vaccination campaign using needle-free jet injectors, Pakistan 2019.•97.6% of vaccinators prefer jet injectors to needle and syringe.•99.6% of caretakers prefer jet injectors to needle and syringe.•Mean coverage over previous IPV campaign improved by 18.4%. The first large-scale vaccination campaign using needle-free jet injectors to administer fractional doses of inactivated poliovirus vaccine (fIPV) was conducted in Karachi, Pakistan, in February 2019. Data on acceptability of jet injectors were collected from 610 vaccinators and 4898 caregivers during the first four days of the campaign. Of those with prior needle and syringe experience, both vaccinators and caregivers expressed a strong preference for jet injectors (578/592 [97.6%] and 4792/4813 [99.6%], respectively), citing ease of use, appearance, and child’s response to vaccination. Among caregivers, 4638 (94.7%) stated they would be more likely to bring their child for vaccination in a future campaign that used jet injectors. Mean vaccine coverage among towns administering fIPV was 98.7% – an increase by 18.4% over the preceding campaign involving full-dose IPV. Our findings demonstrate the strong acceptability of fIPV jet injectors and highlight the potential value of this method in future mass campaigns.

Current worldwide mRNA vaccination against SARS-CoV-2 by intramuscular injection using a needled syringe has greatly protected numerous people from COVID-19. An intramuscular injection is generally well tolerated, safer and easier to perform on a large scale, whereas the skin has the benefit of the presence of numerous immune cells, such as professional antigen-presenting dendritic cells. Therefore, intradermal injection is considered superior to intramuscular injection for the induction of protective immunity, but more proficiency is required for the injection. To improve these issues, several different types of more versatile jet injectors have been developed to deliver DNAs, proteins or drugs by high jet velocity through the skin without a needle. Among them, a new needle-free pyro-drive jet injector has a unique characteristic that utilizes gunpower as a mechanical driving force, in particular, bi-phasic pyrotechnics to provoke high jet velocity and consequently the wide dispersion of the injected DNA solution in the skin. A significant amount of evidence has revealed that it is highly effective as a vaccinating tool to induce potent protective cellular and humoral immunity against cancers and infectious diseases. This is presumably explained by the fact that shear stress generated by the high jet velocity facilitates the uptake of DNA in the cells and, consequently, its protein expression. The shear stress also possibly elicits danger signals which, together with the plasmid DNA, subsequently induces the activation of innate immunity including dendritic cell maturation, leading to the establishment of adaptive immunity. This review summarizes the recent advances in needle-free jet injectors to augment the cellular and humoral immunity by intradermal injection and the possible mechanism of action.

Methotrexate (MTX) is the anchor first-line drug for the treatment of rheumatoid arthritis (RA) in the RA guidelines of the ACR, JCR and EULAR. In the guidelines, MTX is primarily administered orally as low-dose pulse therapy. However, oral MTX therapy has a large interindividual variation of drug efficacy/adverse drug reactions due to bioavailability (BA) differences and it is often associated with gastrointestinal disturbances, making some patients unable to continue oral MTX therapy. MTX subcutaneous (SC) administration involves pain at the injection site and there are regulatory issues in disposal related to medical waste. The pyro-drive jet injector (PJI) is an innovative, needle-free drug delivery system that enables targeted delivery of drugs. This study investigated the pharmacokinetics (PK) and BA of MTX via the PJI in rats. PJI-injected India ink indicated penetration into the subcutis. The AUC 0–∞ after oral (PO) administration was significantly less than that after intravenous (IV), SC, and PJI administration. Absolute BA values with PO, SC, and PJI administration were 30.6%, 99.1%, and 100.8%, respectively. The relative BA of the PJI compared with the SC group was 101.7%. The administration of MTX using the PJI may be useful in clinical practice, but further studies, such as BA or bioequivalence tests, are necessary in animal species with skin similar to human skin or in humans.

Supersonic gas-solid injection technology finds extensive use in drug particle delivery systems. However, the combined impact of particle diameter and mass flow rate on the delivery efficiency remain insufficiently explored. Within the Euler-Lagrange framework, this study utilizes the discrete phase method (DPM) for the numerical simulation of supersonic gas-particle flow in a needle-free injector. After validating the model’s accuracy with experiment results, further investigations were conducted into the influences of particle size and mass flow rate on particle behavior and flow field properties. The results indicate that the impact of larger particles on the compressible structure is stronger, while higher mass flow rate absorbs greater energy from the gas phase, reducing the gas expansion capacity, which results in lower velocity, Mach number, and higher temperature. The jet core zone is approximately x/X  = 0.3 in length. Outside core zone, the gas velocity rapidly decays and temperature rises sharply. Within the jet core zone, drug particles are accelerated and cooled, while beyond core zone, they decelerate and heat up. The strongest inter-phase interactions occur primarily in the nozzle expansion area and the jet core zone. Smaller particles reach maximum velocity upstream. This implies that in designing needle-free injectors, the nozzle-to-skin distance must match the drug particle diameter to achieve maximum penetration effectiveness. Furthermore, the particle temperature decreases with smaller sizes. As the particle diameter rises from 10 μm to 100 μm, the minimum temperatures of the particles are 145 K and 264 K, respectively, indicating the need to match the particle diameter with the minimum temperature at which the drug particles remain effective. Additionally, higher mass flow rate doses reduce injection velocity and penetration ability, necessitating the rational control of the administered dose range. These results offer significant theoretical guidance for the design and improvement of needle-free injection.

•We compared MMR vaccine administration by disposable-syringe jet injector (DSJI) and needle and syringe (N-S).•The study was conducted in 340 toddlers who had received a measles vaccine at 9 months.•On day 35, seropositivity for all three viruses was more than 97% in both the groups.•Reactogenicity by both methods was comparable.•MMR vaccination via DSJI is as immunogenic and safe as vaccination by N-S. We conducted a randomized, non-inferiority, clinical study of MMR vaccine by a disposable-syringe jet injector (DSJI) in toddlers in India in comparison with the conventional administration. MMR vaccine was administered subcutaneously by DSJI or needle-syringe (N-S) to toddlers (15–18 months) who had received a measles vaccine at 9 months. Seropositivity to measles, mumps, and rubella serum IgG antibodies was assessed 35 days after vaccination. Non-inferiority was concluded if the upper limit of the 95% CI for the difference in the percent of seropositive between groups was less than 10%. Solicited reactions were collected for 14 days after vaccination by using structured diaries. In each study group, 170 subjects received MMR vaccine. On day 35, seropositivity for measles was 97.5% [95% CI (93.8%, 99.3%)] in the DSJI group and 98.7% [95% CI (95.5%, 99.8%)] in the N-S group; for mumps, 98.8% [95% CI (95.6%, 99.8%)] and 98.7% [95% CI (95.5%, 99.8%)]; and for rubella, 98.8% [95% CI (95.6%, 99.8%)] and 100% [95% CI (97.7%, 100.0%)]; none of the differences were significant. The day 35 post-vaccination GMTs in DSJI and N-S groups were measles: 5.48 IU/ml [95% CI (3.71, 8.11)] and 5.94 IU/ml [95% CI (3.92, 9.01)], mumps: 3.83 ISR [95% CI (3.53, 4.14)] and 3.66 ISR [95% CI (3.39, 3.95)] and rubella: 95.27 IU/ml [95% CI (70.39, 128.95)] and 107.06 IU/ml [95% CI (79.02, 145.06)]; none of the differences were significant. The DSJI group reported 173 solicited local reactions and the N-S group reported 112; most were mild grade. Of the total of 156 solicited systemic adverse events, most were mild, and incidence between the two groups was similar. MMR vaccination via DSJI is as immunogenic as vaccination by N-S. Safety profile of DSJI method is similar to N-S except for injection site reactions which are more with DSJI and are well-tolerated. Registration US National Institutes of Health clinical trials identifier – NCT02253407. Clinical trial registry of India identifier – CTRI/2013/05/003702

Vaccines usually contain an adjuvant that activates innate immunity to promote the acquisition of adaptive immunity. Aluminum and lipid nanoparticles have been used for this purpose, but their accumulation or widespread circulation in the body can lead to adverse effects. In contrast, physical adjuvants, which use physical energy to transiently stress tissues, do not persist in exposed tissues or cause lasting adverse effects. Herein, we investigate the effects of intradermal injection of endotoxin-free ovalbumin (OVA) protein alone without additional adjuvants using a needle-free pyro-drive jet injector (PJI) on tumor vaccination efficacy. Intradermal injection of OVA protein alone using PJI significantly increased OVA-specific CD8+ T cell expansion in the lymph node, although lymph node swelling was much less than when aluminum hydroxide was used. The injection also induced OVA-specific killing activity and antibody production and showed strong CD8+ T cell-dependent prophylactic antitumor effects against transplanted E.G7-OVA tumors. In particular, intradermal injection of the fluorescent OVA protein significantly enhanced its uptake by XCR1+ dendritic cells, which have a strong ability to cross-present extracellular proteins in the skin and draining lymph nodes. In addition, the injection increased the expression of HMGB1, one of the potent danger signals whose expression has been reported to increase in response to shear stress. Thus, intradermal injection of OVA protein alone without any additional adjuvants using PJI induces potent CD8+ T cell-mediated antitumor immunity by enhancing its uptake into XCR1+ dendritic cells, which have a high cross-presentation capacity accompanied by an increased expression of shear stress-induced HMGB1.

Needle-free vaccine delivery systems have many potential advantages including increased vaccine compliance and decreased risk of needlestick injuries and syringe reuse. The Med-Jet® H4 is a gas-powered, auto-disabling disposable syringe jet injector. The Med-Jet family of products are currently being used in dermatology, podiatry, pain management and veterinary practices. The objectives of this study were to assess patient attitudes, time-efficiency, safety and immunogenicity of the seasonal influenza vaccine delivered by Med-Jet compared to the traditional needle-and-syringe. A total of 80 patients were randomized 2:1:1 to receive a commercial trivalent vaccine by Med-Jet or needle injection from a single-dose or multi-dose vial. Patient attitudes were assessed pre-randomization and post-immunization. Safety data were collected for 21 days post-immunization. Efficiency of vaccine administration was measured through a time-and-motion study. Humoral and cellular responses were assessed on Days 0 and 21. Overall, the participants readily accepted Med-Jet vaccination despite greater frequency of transient local reactions (eg: redness, swelling) immediately following immunization. Vaccine administration took slightly longer with the Med-Jet, but this difference decreased over time. Geometric mean hemagglutination inhibition titers, seroconversion and seroprotection rates in the Med-Jet and needle groups were equivalent for all influenza strains in the vaccine. Microneutralization responses were also essentially identical. There were no significant differences between the groups in the frequency of functional CD4 + T cells, memory subset distribution or poly-functionality. These data suggest that the Med-Jet is an acceptable means of delivering seasonal influenza vaccine. The system was attractive to subjects, rapidly learned by skilled vaccine nurses and elicited both humoral and cellular responses that were indistinguishable from those elicited with needle injection. While other studies have assessed the humoral response to jet injection of influenza vaccine, to our knowledge, this study is the first to assess the cellular aspect of this response. (ClinTrials.gov-NCT03150537).

This study examines the steady-state combustion characteristics of a green hypergolic ignition propellant. The propellant, with an ignition delay time of approximately 7.5 ms as determined by drop tests, utilized a 95% concentration hydrogen peroxide solution as the oxidizer and a solution comprising 95% tetraethylene glycol dimethyl ether and 5% NaBH 4 as the fuel. A pentad impinging-jet injector was employed for the experiments. A total of 28 combustion tests were conducted, with combustion pressures of approximately 30 and 70 bar and an oxidize-to-fuel ratio (ROF) ranging from approximately 2.5–5.5. The results indicate that an increase in both combustion pressure and ROF leads to enhanced characteristic velocity efficiency, which is likely linked to the mixing characteristics of the hypergolic propellant. The study suggests that for impinging-type injectors utilizing hypergolic propellants, designing a higher propellant momentum ratio compared to injectors for non-hypergolic propellants could be beneficial.

Background We have previously developed a candidate therapeutic HPV DNA vaccine (pBI-11) encoding mycobacteria heat shock protein 70 linked to HPV16/18 E6/E7 proteins for the control of advanced HPV-associated oropharyngeal cancer (NCT05799144). While naked DNA vaccines are readily produced, stable, and well tolerated, their potency is limited by the delivery efficiency. Here we compared three different IM delivery strategies, including intramuscular (IM) injection, either with a needle alone or with electroporation at the injection site, and a needle-free injection system (NFIS), for their ability to elicit gene expression and to improve the potency of pBI-11 DNA vaccine. Results We found that electroporation after IM injection significantly increases gene expression from a luciferase-encoding DNA construct compared to IM injection alone or NFIS. We also showed that single administration of pBI-11 DNA via electroporation-mediated delivery generates the greatest increase in HPV antigen-specific CD8 + T cell-mediated immune responses, resulting in the most potent antitumor effect compared to the other two methods. We further compared the response to three repeat immunizations via each of these different methods. We found that electroporation-mediated delivery of pBI-11 DNA generates the greatest HPV antigen-specific CD8 + T cell immune responses and therapeutic antitumor effects compared to the other two methods. Monitoring of mouse behaviors and body weight, and necropsy indicated that electroporation-mediated delivery of clinical grade pBI-11 DNA vaccine was well-tolerated and presented no evident local or systemic toxicity. Conclusions These findings provide rationale for clinical testing of pBI-11 DNA vaccine delivered by electroporation for the control of HPV16/18-associated infections and/or cancers.