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1.
Mol Cell Probes ; 64: 101833, 2022 08.
Article in English | MEDLINE | ID: mdl-35691598

ABSTRACT

DNA-based immunization has been previously shown to be an efficient approach to induce robust immunity against infectious diseases in animals and humans. The advantages of DNA vaccines are simplicity of their construction and production, low cost, high stability, and ability to elicit a full spectrum of immune responses to target antigens. The goals of this study were (i) to assess the antibody immune response to rabies virus glycoproteins (rGPs) in rabbits and guinea pigs after intramuscular immunization with pTargeT and pVAC2-mcs mammalian expression vectors encoding either the wild-type (WT) or codon-optimized (cOPT) rGP genes; and (ii) to prepare in-house rabbit anti-rGP polyclonal antibody reagents suitable for in Single Radial Immunodiffusion (SRID) and Indirect Fluorescent Antibody (IFA) assays. The maximum antibody responses against rabies virus in rabbits and guinea pigs were observed after immunization series with 500 µg/dose of pVAC2-mcs vector encoding either the WT or cOPT rGP genes adjuvanted with Emulsigen-D. No significant difference in the anti-rabies virus neutralizing antibody titers was observed in rabbits immunized with the WT and cOPT rGPs. The in-house rabbit anti-rGP polyclonal antibody reagents reacted comparable to the current reference reagents in SRID and IFA assays. The results of the study demonstrated that the DNA immunization of animals with the WT or cOPT rGPs is a promising approach to either induction of high anti-rabies virus neutralizing antibody titers in vivo or for production of polyclonal antibody reagents against rabies.


Subject(s)
Rabies virus , Vaccines, DNA , Animals , Antibodies, Neutralizing , Antibodies, Viral , DNA , Glycoproteins/genetics , Guinea Pigs , Immunity, Humoral , Indicators and Reagents , Mammals/genetics , Plasmids/genetics , Rabbits , Rabies virus/genetics , Vaccines, DNA/genetics
2.
Clin Infect Dis ; 73(2): e304-e311, 2021 07 15.
Article in English | MEDLINE | ID: mdl-32556176

ABSTRACT

BACKGROUND: Patients on dialysis are hyporesponsive to the hepatitis B virus vaccines (HBVv). We examined intradermal (ID) HBVv Sci-B-Vac, with topical Toll-like receptor 7 (TLR7) agonist imiquimod pretreatment in dialysis patients. METHODS: We enrolled and prospectively followed adult patients on dialysis between January 2016 and September 2018. Eligible patients were randomly allocated (1:1:1) into 1 treatment group, topical imiquimod cream followed by ID HBVv (IMQ + ID); and 2 control groups: topical aqueous cream (placebo) followed by ID HBVv (AQ + ID) or topical aqueous cream followed by intramuscular HBVv (AQ + IM). The primary endpoint was the seroprotection rate (hepatitis B surface antibody ≥10 mIU/mL) at 52 weeks. RESULTS: Ninety-four patients were enrolled, among which 57.4% were previous nonresponders. Seroprotection rate was significantly better at week 52 for the IMQ + ID group with 96.9% compared to 74.2% and 48.4% for AQ + ID and AQ + IM groups, respectively (P < .0001). The geometric mean concentration was significantly higher at week 52 for the IMQ + ID group: 1135 (95% confidence interval [CI], 579.4-2218.2) mIU/mL, compared to 86.9 (95% CI, 18.5-409.3) mIU/mL and 7.2 (2.0-26.5) mIU/mL for the AQ + ID and AQ + IM groups, respectively (P < .0001). IMQ + ID vaccination (odds ratio, 3.70 [95% CI, 1.16-11.81]; P = .027) was the only factor independently associated with higher 52-week seroprotection rate. Adverse reaction was infrequent. CONCLUSIONS: Pretreatment with topical imiquimod before ID HBVv Sci-B-Vac was safe with favorable seroprotection in dialysis patients. CLINICAL TRIALS REGISTRATION: NCT02621112.


Subject(s)
Hepatitis B , Toll-Like Receptor 7 , Adult , Hepatitis B Vaccines , Humans , Imiquimod , Injections, Intradermal , Injections, Intramuscular , Renal Dialysis , Vaccination
3.
Nanomedicine ; 32: 102321, 2021 02.
Article in English | MEDLINE | ID: mdl-33184020

ABSTRACT

Ultra-small 1-2 nm gold nanoparticles (NP) were conjugated with a poorly-soluble peptide auto-antigen, associated with type 1 diabetes, to modify the peptide pharmacokinetics, following its intradermal delivery. Peptide distribution was characterized, in vivo, after delivery using either conventional intradermal injection or a hollow microneedle device. The poorly-soluble peptide was effectively presented in distant lymph nodes (LN), spleen and draining LN when conjugated to the nanoparticles, whereas peptide alone was only presented in the draining LN. By contrast, nanoparticle conjugation to a highly-soluble peptide did not enhance in vivo distribution. Transfer of both free peptide and peptide-NPs from the skin to LN was reduced in mice lacking lymphoid homing receptor CCR7, suggesting that both are actively transported by migrating dendritic cells to LN. Collectively, these data demonstrate that intradermally administered ultra-small gold nanoparticles can widen the distribution of poorly-soluble auto-antigenic peptides to multiple lymphoid organs, thus enhancing their use as potential therapeutics.


Subject(s)
Antigens/metabolism , Gold/chemistry , Metal Nanoparticles/chemistry , Peptides/pharmacology , Amino Acid Sequence , Animals , Cell Proliferation , Dendritic Cells/drug effects , Injections, Intradermal , Mice, Inbred C57BL , Mice, Transgenic , Needles , Peptides/chemistry , Peptides/pharmacokinetics , Phenotype , Skin/drug effects , Solubility , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
4.
J Immunol ; 195(1): 386-92, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-26026065

ABSTRACT

Assessment of immune responses in lymph nodes (LNs) is routine in animals, but rarely done in humans. We have applied minimally invasive ultrasound-guided fine-needle aspiration of the LN to a before-and-after study of the immune response to intradermally delivered Ag in healthy volunteers (n = 25). By comparison with PBMCs from the same individual, LN cells (LNCs) were characterized by reduced numbers of effector memory cells, especially CD8(+) TEMRA cells (3.37 ± 1.93 in LNCs versus 22.53 ± 7.65 in PBMCs; p = 0.01) and a marked increased in CD69 expression (27.67 ± 7.49 versus 3.49 ± 2.62%, LNCs and PBMCs, respectively; p < 0.0001). At baseline, there was a striking absence of IFN-γ ELISPOT responses to recall Ags (purified protein derivative, Tetanus toxoid, or flu/EBV/CMV viral mix) in LN, despite strong responses in the peripheral blood. However, 48 h after tuberculin purified protein derivative administration in the ipsilateral forearm resulting in a positive skin reaction, a clear increase in IFN-γ ELISPOT counts was seen in the draining LN but not in PBMCs. This response was lost by 5 d. These data suggest that the low levels of effector memory cells in the LN may explain the low background of baseline ELISPOT responses in LNs as compared with PBMCs, and the appearance of a response after 48 h is likely to represent migration of effector memory cells from the skin to the LN. Hence, it appears that the combination of intradermal Ag administration and draining LN sampling can be used as a sensitive method to probe the effector memory T cell repertoire in the skin.


Subject(s)
Biopsy, Fine-Needle/methods , Leukocytes, Mononuclear/immunology , Lymph Nodes/immunology , T-Lymphocytes/immunology , Adolescent , Adult , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/immunology , Antigens, Viral/administration & dosage , Biopsy, Fine-Needle/instrumentation , Cell Movement , Enzyme-Linked Immunospot Assay , Female , Humans , Immunologic Memory , Immunophenotyping , Injections, Intradermal , Interferon-gamma/biosynthesis , Lectins, C-Type/immunology , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Lymph Nodes/cytology , Lymph Nodes/drug effects , Lymphocyte Activation , Male , Middle Aged , Skin/drug effects , Skin/immunology , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , Tetanus Toxoid/administration & dosage , Tuberculin/administration & dosage
5.
J Infect Dis ; 211(9): 1447-50, 2015 May 01.
Article in English | MEDLINE | ID: mdl-25391313

ABSTRACT

Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost.


Subject(s)
Poliovirus Vaccine, Inactivated/immunology , Animals , Antibodies, Viral/blood , Dose-Response Relationship, Immunologic , Female , Injections, Intradermal/instrumentation , Poliovirus Vaccine, Inactivated/administration & dosage , Poliovirus Vaccine, Inactivated/economics , Rats , Rats, Wistar
6.
J Infect Dis ; 211(12): 1969-76, 2015 Jun 15.
Article in English | MEDLINE | ID: mdl-25567841

ABSTRACT

BACKGROUND: Inactivated polio vaccine (IPV) is necessary for global polio eradication because oral polio vaccine can rarely cause poliomyelitis as it mutates and may fail to provide adequate immunity in immunocompromised populations. However, IPV is unaffordable for many developing countries. Intradermal IPV shows promise as a means to decrease the effective dose and cost of IPV, but prior studies, all using 20% of the standard dose used in intramuscular IPV, resulted in inferior antibody titers. METHODS: We randomly assigned 231 adults with well-controlled human immunodeficiency virus infection at a ratio of 2:2:2:1 to receive 40% of the standard dose of IPV intradermally, 20% of the standard dose intradermally, the full standard dose intramuscularly, or 40% of the standard dose intramuscularly. Intradermal vaccination was done using the NanoPass MicronJet600 microneedle device. RESULTS: Baseline immunity was 87%, 90%, and 66% against poliovirus serotypes 1, 2, and 3, respectively. After vaccination, antibody titers increased a median of 64-fold. Vaccine response to 40% of the standard dose administered intradermally was comparable to that of the standard dose of IPV administered intramuscularly and resulted in higher (although not significantly) antibody titers. Intradermal administration had higher a incidence of local side effects (redness and itching) but a similar incidence of systemic side effects and was preferred by study participants over intramuscular administration. CONCLUSIONS: A 60% reduction in the standard IPV dose without reduction in antibody titers is possible through intradermal administration.


Subject(s)
HIV Infections/immunology , Immunization, Secondary/methods , Poliomyelitis/immunology , Poliomyelitis/prevention & control , Poliovirus Vaccine, Inactivated/immunology , Adult , Antibodies, Viral/blood , Female , Humans , Injections, Intradermal , Injections, Intramuscular , Male , Middle Aged , Poliovirus Vaccine, Inactivated/administration & dosage , Treatment Outcome , Young Adult
7.
iScience ; 26(4): 106335, 2023 Apr 21.
Article in English | MEDLINE | ID: mdl-36968065

ABSTRACT

Intradermal delivery of self-replicating RNA (srRNA) is a promising vaccine platform. We have developed an srRNA that functions optimally at around 33°C (skin temperature) and is inactivated at or above 37°C (core body temperature) as a safety switch. This temperature-controllable srRNA (c-srRNA), when tested as an intradermal vaccine against SARS-CoV-2, functions when injected naked without lipid nanoparticles. Unlike most currently available vaccines, c-srRNA vaccines predominantly elicit cellular immunity with little or no antibody production. Interestingly, c-srRNA-vaccinated mice produced antigen-specific antibodies upon subsequent stimulation with antigen protein. Antigen-specific antibodies were also produced when B cell stimulation using antigen protein was followed by c-srRNA booster vaccination. We have thus designed a pan-coronavirus booster vaccine that incorporates both spike-receptor-binding domains as viral surface proteins and evolutionarily conserved nucleoproteins as viral internal proteins, from both severe acute respiratory syndrome coronavirus 2 and Middle East respiratory syndrome coronavirus. c-srRNA may provide a route to activate cellular immunity against a wide variety of pathogens.

8.
PLoS One ; 17(1): e0261641, 2022.
Article in English | MEDLINE | ID: mdl-35100279

ABSTRACT

BACKGROUND: Peripheral venous cannulation is one of the most common procedures in medicine. It is associated with noticeable pain and apprehension, although in most cases it is performed without any anesthesia due to lack of a painless, cost-effective option, which would provide rapid local anesthesia with subsequent significant reduction in the experienced pain. We conducted an open-label placebo-controlled clinical trial to evaluate the efficacy and safety of a 2% lidocaine injection using the commercially available microneedle device MinronJet600 (NanoPass Technologies Ltd, Israel) to achieve rapid local anesthesia prior to peripheral venous cannulation. METHODS: One hundred and two subjects were randomly allocated into two groups. In the first group, 100µL of lidocaine hydrochloride (2%) was injected intradermally to subjects using the MicronJet600 device in the left arm (MJ-Lido) and 100µL of saline was injected intradermally using the device in the right arm (MJ-Saline). In the second group, 100µL of lidocaine hydrochloride (2%) was injected using the MicronJet600 device into the left arm (MJ-Lido), with no injection into the right arm of subjects (No pretreatment). In both groups the intradermal injection was performed at the cannulation site prior to insertion of a 18G cannula into a median cubital vein in both arms. As a primary variable, a score of cannulation-induced pain was indicated by subjects using a 100-point visual analog scale immediately after cannulation. As a secondary variable, subjects in Group 2 also indicated their preference to receive the anaesthetic injection with MicronJet600 in the future by using the 5-point Likert scale. Also, as a secondary variable, the duration of skin numbness after lidocaine injection was indicated by performing a superficial pin-prick with a 27G needle at 15, 30 and 45 minutes, at distances of 1, 2 and 3 centimeters from the injection site. RESULTS: A significant pain reduction (11.0-fold) was achieved due to the lidocaine injection compared to the cannulation without any pretreatment (p< 0.005). After the lidocaine injection the anesthesia was effective up to 2 centimeters from the injection site and remained for up to 30 minutes. Eighty percent of subjects from the second group preferred cannulation after the lidocaine injection over cannulation without any pretreatment. No significant side effects were identified. CONCLUSION: Intradermal injection of anaesthetic with Micronjet600 was found to be a safe and effective option for providing rapid local anesthesia for peripheral intravenous cannulation. TRIAL REGIATRATION: The clinical trial was registered, before the patient enrollment began, in the Research Registry publicly accessible database (registration identifier: researchregistry4662). Also, the trial was registered in ClinicalTrials.gov (registration identifier: NCT05108714) after its completion.


Subject(s)
Anesthesia, Local/instrumentation , Anesthetics, Local/administration & dosage , Lidocaine/administration & dosage , Adolescent , Adult , Anesthesia, Local/methods , Female , Humans , Injections, Intradermal , Male , Middle Aged , Pain Measurement/methods , Placebo Effect , Young Adult
9.
bioRxiv ; 2022 Sep 06.
Article in English | MEDLINE | ID: mdl-36263074

ABSTRACT

Intradermal delivery of self-replicating RNA (srRNA) is a promising vaccine platform. Considering that human skin temperature is around 33°C, lower than core body temperature of 37°C, we have developed an srRNA that functions optimally at skin temperature and is inactivated at or above 37°C as a safety switch. This temperature- c ontrollable srRNA (c-srRNA), when tested as an intradermal vaccine against SARS-CoV-2, functions when injected naked without lipid nanoparticles. Unlike most currently available vaccines, c-srRNA vaccines predominantly elicit cellular immunity with little or no antibody production. Interestingly, c-srRNA-vaccinated mice produced antigen-specific antibodies upon subsequent stimulation with antigen protein. Antigen-specific antibodies were also produced when B-cell stimulation using antigen protein was followed by c-srRNA booster vaccination. Using c-srRNA, we have designed a pan-coronavirus booster vaccine that incorporates both spike receptor binding domains as viral surface proteins and evolutionarily conserved nucleoproteins as viral non-surface proteins, from both SARS-CoV-2 and MERS-CoV. It can thereby potentially immunize against SARS-CoV-2, SARS-CoV, MERS-CoV, and their variants. c-srRNA may provide a route to activate cellular immunity against a wide variety of pathogens.

10.
Mol Ther Nucleic Acids ; 11: 382-392, 2018 Jun 01.
Article in English | MEDLINE | ID: mdl-29858073

ABSTRACT

In recent years, synthetic mRNA-based applications to produce desired exogenous proteins in cells have been gaining importance. However, systemic delivery of synthetic mRNA can result in unspecific uptake into undesired cells or organs and, thereby, fail to target desired cells. Thus, local and targeted delivery of synthetic mRNA becomes increasingly important to reach the desired cell types and tissues. In this study, intradermal delivery of synthetic mRNA using a hollow microneedle injection-based method was evaluated. Furthermore, an ex vivo porcine skin model was established to analyze synthetic mRNA-mediated protein expression in the skin following intradermal delivery. Using this model, highly efficient delivery of synthetic mRNA was demonstrated, which resulted in detection of high levels of secretable humanized Gaussia luciferase (hGLuc) protein encoded by the microinjected synthetic mRNA. Interestingly, synthetic mRNA injected without transfection reagent was also able to enter the cells and resulted in protein expression. The established ex vivo porcine skin model can be used to evaluate the successful production of desired proteins after intradermal delivery of synthetic mRNAs before starting with in vivo experiments. Furthermore, the use of microneedles enables patient-friendly, painless, and efficient delivery of synthetic mRNAs into the dermis; thus, this method could be applied for local treatment of different skin diseases as well as for vaccination and immunotherapy.

11.
Sci Adv ; 4(9): eaas9930, 2018 09.
Article in English | MEDLINE | ID: mdl-30221194

ABSTRACT

Adjuvants are key to shaping the immune response to vaccination, but to date, no adjuvant suitable for human use has been developed for intradermal vaccines. These vaccines could be self-administered and sent through the mail as they do not require long needles or technical expertise in immunization. In the event of a pandemic outbreak, this approach could alleviate the congregation of patients in health centers and thus reduce the potential of these centers to enhance the spread of lethal infection. A reliable and potent vaccine system for self-administration would provide an effective countermeasure for delivery through existing product distribution infrastructure. We report results from preclinical and clinical trials that demonstrate the feasibility of an adjuvanted, intradermal vaccine that induced single shot protection in ferrets and seroprotection in humans against one of the more lethal strains of pandemic flu, Indonesia H5N1. In the human trial, the vaccine was safe and clinical responses were above approvable endpoints for a protective flu vaccine. Inclusion of a modern TLR4 (Toll-like receptor 4) agonist-based adjuvant was critical to the development of the response in the intradermal groups. In humans, this is the first report of a safe and effective intradermal adjuvant, GLA-AF (aqueous formulation of glucopyranosyl lipid adjuvant), and provides a future path for developing a vaccine-device combination for distribution by mail and self-administration in case of a pandemic.


Subject(s)
1,2-Dipalmitoylphosphatidylcholine/immunology , Adjuvants, Immunologic/pharmacology , Influenza Vaccines/pharmacology , Lipid A/analogs & derivatives , 1,2-Dipalmitoylphosphatidylcholine/adverse effects , 1,2-Dipalmitoylphosphatidylcholine/pharmacology , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/adverse effects , Adult , Animals , Drug Combinations , Female , Ferrets , Guinea Pigs , Humans , Influenza A Virus, H5N1 Subtype/genetics , Influenza A Virus, H5N1 Subtype/immunology , Influenza A Virus, H5N1 Subtype/pathogenicity , Influenza Vaccines/administration & dosage , Influenza Vaccines/adverse effects , Injections, Intradermal , Lipid A/adverse effects , Lipid A/immunology , Lipid A/pharmacology , Male , Mice, Inbred C57BL , Toll-Like Receptor 4/agonists
12.
Mol Ther Nucleic Acids ; 11: 475-484, 2018 Jun 01.
Article in English | MEDLINE | ID: mdl-29858082

ABSTRACT

Elastin is one of the most important and abundant extracellular matrix (ECM) proteins that provide elasticity and resilience to tissues and organs, including vascular walls, ligaments, skin, and lung. Besides hereditary diseases, such as Williams-Beuren syndrome (WBS), which results in reduced elastin synthesis, injuries, aging, or acquired diseases can lead to the degradation of existing elastin fibers. Thus, the de novo synthesis of elastin is required in several medical conditions to restore the elasticity of affected tissues. Here, we applied synthetic modified mRNA encoding tropoelastin (TE) for the de novo synthesis of elastin and determined the mRNA-mediated elastin synthesis in cells, as well as ex vivo in porcine skin. EA.hy926 cells, human fibroblasts, and mesenchymal stem cells (MSCs) isolated from a patient with WBS were transfected with 2.5 µg TE mRNA. After 24 hr, the production of elastin was analyzed by Fastin assay and dot blot analyses. Compared with untreated cells, significantly enhanced elastin amounts were detected in TE mRNA transfected cells. The delivered synthetic TE mRNA was even able to significantly increase the elastin production in elastin-deficient MSCs. In porcine skin, approximately 20% higher elastin amount was detected after the intradermal delivery of synthetic mRNA by microinjection. In this study, we demonstrated the successful applicability of synthetic TE encoding mRNA to produce elastin in elastin-deficient cells as well as in skin. Thus, this auspicious mRNA-based integration-free method has a huge potential in the field of regenerative medicine to induce de novo elastin synthesis, e.g., in skin, blood vessels, or alveoli.

13.
Diabetes Technol Ther ; 18(9): 525-31, 2016 09.
Article in English | MEDLINE | ID: mdl-27500713

ABSTRACT

BACKGROUND: Currently available short-acting insulin analogs have slower absorption compared with endogenous insulin occasionally resulting in immediate postprandial hyperglycemia. Intradermal (ID) injection facilitates faster drug absorption and may result in improved insulin pharmacokinetics. METHODS: Seventeen patients with type 2 diabetes were included in this single-center, pilot, open-label crossover study. Patients received 0.2 U/kg Insulin aspart ID injections using a MicronJet (MJ) needle and subcutaneous (SC) injections, using a conventional needle in a crossover design. Thirteen patients were studied under fasting conditions and four before a standard meal test. The pharmacokinetic/pharmacodynamic (PK/PD) profile, as well as the safety and tolerability of injections, was compared. RESULTS: Fourteen patients completed the study per-protocol. ID versus SC injection demonstrated significantly shorter Tmax (median 35 vs. 87.5 min [P < 0.001]), while the Cmax did not significantly differ (median 80 vs. 55 µU/mL [P = 0.085]). Median insulin area under the curve (AUC; 360 min) did not differ between the groups (9914 vs. 10,936 µU/mL/min [p = 0.077]), yet 0-60 min insulin AUC was higher with ID versus SC injection (mean ± SD 3821 ± 1429 vs. 2534 ± 737 µU/mL/min [p = 0.01]) and 4-6 h AUC was lower with ID versus SC injection (mean ± SD 2054 ± 858 vs. 2929 ± 1412 µU/mL/min [p = 0.02]). The relative bioavailability of the ID versus the SC insulin (AUCID/AUCSC) was similar (median 0.91 [95% confidence interval 0.73-1.27]). CONCLUSIONS: ID insulin injection delivered through an MJ needle demonstrated superior PK profile compared with conventional SC administration, including shorter Tmax and higher early and lower late exposure in patients with type 2 diabetes. This may help achieve better insulin coverage of meals and lower postprandial glucose excursions.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/pharmacokinetics , Insulin Aspart/pharmacokinetics , Adult , Aged , Cross-Over Studies , Female , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Injections, Intradermal , Insulin Aspart/administration & dosage , Insulin Aspart/therapeutic use , Male , Middle Aged , Pilot Projects , Treatment Outcome
14.
Vaccine ; 34(44): 5262-5272, 2016 10 17.
Article in English | MEDLINE | ID: mdl-27667332

ABSTRACT

BACKGROUND: Influenza remains a significant problem in elderly despite widespread vaccination coverage. This randomized, phase-I study in elderly compared different strategies of improving vaccine immunogenicity. METHODS: A total of 370 healthy participants (⩾65years) were randomized equally 1:1:1:1:1:1 to six influenza vaccine treatments (approximately 60-63 participants per treatment arm) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5, 15, and 45µg HA antigen/strain administered intradermally (ID) by MicronJet600™ microneedle device (NanoPass Technologies) or intramuscularly (IM), and three comparator registered seasonal vaccines; Inflexal V™ (Janssen) and MF59 adjuvanted Fluad™ (Novartis) administered IM and Intanza™ (Sanofi Pasteur) administered ID via Soluvia™ prefilled microinjection system (BD). Serological evaluations were performed at days 22 and 90 and safety followed-up for 6months. RESULTS: Intradermal delivery of virosomal vaccine using MicronJet600™ resulted in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V™ administered intramuscularly across most of the parameters and strains, as well as in some of the readouts and strains as compared with the 45µg dose of virosomal vaccine formulation. Of 370 participants, 300 (81.1%) reported ⩾1 adverse event (AE); more participants reported solicited local AEs (72.2%) than solicited systemic AEs (12.2%). CONCLUSIONS: Intradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45µg) virosomal vaccine did not demonstrate any benefit on vaccine's immunogenicity over 15µg commercial presentation. All treatments were generally safe and well-tolerated.


Subject(s)
Aging/immunology , Immunogenicity, Vaccine , Influenza Vaccines/administration & dosage , Influenza, Human/prevention & control , Adjuvants, Immunologic , Aged , Aged, 80 and over , Antibodies, Viral/blood , Dose-Response Relationship, Immunologic , Drug Administration Routes , Female , Humans , Influenza Vaccines/adverse effects , Influenza Vaccines/immunology , Influenza, Human/immunology , Injections, Intradermal , Injections, Intramuscular , Male , Vaccines, Virosome/administration & dosage , Vaccines, Virosome/adverse effects , Vaccines, Virosome/immunology
16.
PLoS One ; 11(11): e0166038, 2016.
Article in English | MEDLINE | ID: mdl-27824918

ABSTRACT

Live-attenuated oral rotavirus (RV) vaccines have lower efficacy in low income countries, and additionally are associated with a rare but severe adverse event, intussusception. We have been pursuing the development of an inactivated rotavirus vaccine (IRV) using the human rotavirus strain CDC-9 (G1P[8]) through parenteral immunization and previously demonstrated dose sparing and enhanced immunogenicity of intradermal (ID) unadjuvanted IRV using a coated microneedle patch in comparison with intramuscular (IM) administration in mice. The aim of this study was to evaluate the immune response and protection against RV infection and diarrhea conferred by the administration of the ID unadjuvanted IRV using the microneedle device MicronJet600® in neonatal gnotobiotic (Gn) piglets challenged with virulent Wa G1P[8] human RV. Three doses of 5 µg IRV when administered intradermally and 5 µg IRV formulated with aluminum hydroxide [Al(OH)3] when administered intramuscularly induced comparable rotavirus-specific antibody titers of IgA, IgG, IgG avidity index and neutralizing activity in sera of neonatal piglets. Both IRV vaccination regimens protected against RV antigen shedding in stools, and reduced the cumulative diarrhea scores in the piglets. This study demonstrated that the ID and IM administrations of IRV are immunogenic and protective against RV-induced diarrhea in neonatal piglets. Our findings highlight the potential value of an adjuvant sparing effect of the IRV ID delivery route.


Subject(s)
Germ-Free Life/immunology , Rotavirus Infections/veterinary , Rotavirus Vaccines/therapeutic use , Rotavirus/immunology , Swine Diseases/prevention & control , Animals , Animals, Newborn/immunology , Antibodies, Viral/immunology , Injections, Intradermal/veterinary , Microinjections/methods , Microinjections/veterinary , Rotavirus Infections/immunology , Rotavirus Infections/prevention & control , Rotavirus Vaccines/administration & dosage , Rotavirus Vaccines/immunology , Swine/immunology , Swine/virology , Swine Diseases/immunology , Swine Diseases/virology
17.
Lancet Infect Dis ; 16(8): 915-22, 2016 08.
Article in English | MEDLINE | ID: mdl-27061887

ABSTRACT

BACKGROUND: The licensed live, attenuated varicella-zoster virus vaccine prevents herpes zoster in adults older than 50 years. We aimed to determine whether intradermal administration of zoster vaccine could enhance vaccine immunogenicity compared with conventional needle subcutaneous administration. METHODS: In this randomised, dose-ranging study, adults aged 50 years or older who had a history of varicella or who had resided in a country with endemic varicella-zoster virus infection for 30 years or more were eligible. Participants received the approved full or a 1/3 dose of zoster vaccine given subcutaneously or one of four intradermal doses (full, 1/3, 1/10, or 1/27 dose) using the MicronJet600 device. The two subcutaneous doses and the four intradermal doses were randomised (1·5:1:1:1:1:1) by computer generated sequence with randomisation stratified by age (50-59 years or 60 years or older). The primary immunogenicity endpoint was the change from baseline in IgG antibody to varicella-zoster virus-specific glycoproteins (gpELISA) measured at 6 weeks. All patients were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, number NCT01385566. FINDINGS: Between Sept 2, 2011, and Jan 13, 2012, 224 participants were enrolled from three clinics in the USA and 223 were randomly assigned: 52 to receive the full dose subcutaneous zoster vaccine, 34 to receive the 1/3 dose subcutaneous zoster vaccine, 34 to receive the full dose intradermal zoster vaccine, 35 to receive the 1/3 dose intradermal zoster vaccine, 34 to receive the 1/10 dose intradermal zoster vaccine, and 34 to receive the 1/27 dose intradermal zoster vaccine. Full dose zoster vaccine given subcutaneously resulted in a gpELISA geometric mean fold-rise (GMFR) of 1·74 (90% CI 1·48-2·04) at 6 weeks post-vaccination compared with intradermal administration which resulted in a significantly higher gpELISA GMFR of 3·25 (2·68-3·94; p<0·0001), which also remained high at 18 months. An apparent dose-response relation was observed with intradermal administration (1/3 dose subcutaneous GMFR 1·64 [90% CI 1·36-1·99], 1/3 dose intradermal 2·58 (2·13-3·13), 1/10 dose intradermal 2·22 [1·83-2·69], and 1/27 dose intradermal 1·64 [1·35-2·00]). Each partial dose of zoster vaccine given intradermaly had a gpELISA GMFR comparable to that of full dose zoster vaccine given subcutaneously. Transient erythema and induration were more common after intradermal administration (31% erythema for full subcutaneous dose and 77% for intradermal dose). INTERPRETATION: Intradermal zoster vaccine showed a greater increase in varicella-zoster virus gpELISA antibody compared with subcutaneous zoster vaccine at comparable doses. Larger and longer studies of intradermal administration of live, attenuated zoster vaccine are needed to provide convincing evidence of improved cell mediated immunity. FUNDING: Merck & Co Inc.


Subject(s)
Dose-Response Relationship, Immunologic , Herpes Zoster Vaccine/administration & dosage , Herpes Zoster/prevention & control , Injections, Intramuscular/methods , Injections, Subcutaneous/methods , Aged , Chickenpox/immunology , Erythema/etiology , Herpes Zoster/immunology , Herpes Zoster Vaccine/immunology , Herpesvirus 3, Human/immunology , Humans , Immunization Schedule , Middle Aged , United States , Vaccination , Vaccines, Attenuated
18.
Hum Vaccin Immunother ; 11(4): 991-7, 2015.
Article in English | MEDLINE | ID: mdl-25745830

ABSTRACT

Intradermal immunization has become a forefront of vaccine improvement, both scientifically and commercially. Newer technologies are being developed to address the need to reduce the dose required for vaccination and to improve the reliability and ease of injection, which have been major hurdles in expanding the number of approved vaccines using this route of administration. In this review, 7 y of clinical experience with a novel intradermal delivery device, the MicronJet600, which is a registered hollow microneedle that simplifies the delivery of liquid vaccines, are summarized. This device has demonstrated both significant dose-sparing and superior immunogenicity in various vaccine categories, as well as in diverse subject populations and age groups. These studies have shown that intradermal delivery using this device is safe, effective, and preferred by the subjects. Comparison with other intradermal devices and potential new applications for intradermal delivery that could be pursued in the future are also discussed.


Subject(s)
Influenza Vaccines/administration & dosage , Injections, Intradermal/methods , Vaccination/methods , Vaccination/trends , Humans
19.
Vaccine ; 32(34): 4249-52, 2014 Jul 23.
Article in English | MEDLINE | ID: mdl-24930715

ABSTRACT

The skin provides the largest immune barrier to infection and is a readily accessible site for vaccination, although intradermal (ID) injection can be challenging. The MicronJet™ microneedle is a novel device that consistently injects antigens very close to the skin's dendritic cells. A dose-sparing ID injection study was conducted in 280 healthy adult volunteers using trivalent virosomal adjuvanted influenza vaccine. ID injection of 3 µg using the MicronJet™ was well tolerated and showed a statistically higher geometric mean fold rise than the same dose ID using a conventional needle (Mantoux technique) for the H1N1 and B strains or a 15 µg intramuscular (IM) injection for the H3N2 strain. Thus, the immune response appears to partially depend on the delivery device and route of injection. The MicronJet™ may allow dose-sparing, yet give a superior response in influenza vaccination and warrants further clinical evaluation.


Subject(s)
Influenza Vaccines/administration & dosage , Injections, Intradermal/instrumentation , Needles , Adult , Antibodies, Viral/blood , Dose-Response Relationship, Immunologic , Humans , Influenza A Virus, H1N1 Subtype , Influenza B virus , Vaccines, Virosome/administration & dosage
20.
Hum Vaccin Immunother ; 10(6): 1701-10, 2014.
Article in English | MEDLINE | ID: mdl-24732325

ABSTRACT

UNLABELLED: Strategies to optimize responses to seasonal influenza vaccination in older adults include the use of adjuvants, higher antigen doses, and intradermal delivery. In this study adults aged ≥65 years (n = 450) received a single dose of 1 of 2 non-adjuvanted trivalent influenza vaccine (TIV) formulations administered intradermally (ID), both containing 6 µg of A/H1N1 and B, differing in A/H3N2 content (6 µg or 12 µg), or a single dose of 1 of 8 TIV formulations administered intramuscularly (IM) all containing 15 µg of A/H1N1 and B, differing in A/H3N2 hemagglutinin (HA) content (15 µg or 30 µg) and/or in MF59(®) adjuvant content (0%, 25%, 50%, or 100% of the standard dose). This paper focuses on the comparisons of low-dose non-adjuvanted ID, full-dose non-adjuvanted IM and full-dose MF59-adjuvanted IM formulations (n = 270). At day 22 post-vaccination, at least one European licensure immunogenicity criterion was met by all groups against all 3 strains; however, all three criteria were met against all 3 vaccine strains by the low-dose non-adjuvanted ID and the full-dose MF59-adjuvanted IM groups only. The full-dose MF59-adjuvanted IM group elicited significantly higher immune response vs. the low-dose non-adjuvanted ID formulations for most comparisons. The full-dose MF59 adjuvanted IM groups were associated with increased pain at the site of injection (P<0.01) compared to the ID groups, and the low-dose non-adjuvanted ID groups were associated with increased erythema, induration, and swelling at the injection site (P<0.0001) and unsolicited AEs compared with the IM groups. There were no differences between IM and ID groups in the frequencies of subjects experiencing solicited systemic reactions. Overall, while MF59 adjuvantation increased pain at the site of injection, and intradermal delivery increased unsolicited adverse events, erythema, induration, and swelling at the injection site, both strategies of vaccination strongly enhanced the immunogenicity of seasonal influenza vaccine in older adults compared with conventional non-adjuvanted intramuscular delivery. TRIAL REGISTRATION: http://www.clinicaltrials.gov: NCT00848848.


Subject(s)
Adjuvants, Immunologic/adverse effects , Dose-Response Relationship, Immunologic , Influenza Vaccines/adverse effects , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Polysorbates/adverse effects , Squalene/adverse effects , Adjuvants, Immunologic/administration & dosage , Aged , Aged, 80 and over , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H3N2 Subtype/immunology , Influenza B virus/immunology , Influenza Vaccines/administration & dosage , Injections, Intradermal , Injections, Intramuscular , Male , Polysorbates/administration & dosage , Squalene/administration & dosage
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