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1.
AAPS PharmSciTech ; 23(4): 103, 2022 Apr 05.
Article in English | MEDLINE | ID: covidwho-1779704

ABSTRACT

Vaccination has produced a great improvement to the global health by decreasing/eradicating many infectious diseases responsible for significant morbidity and mortality. Thanks to vaccines, many infections affecting childhood have been greatly decreased or even eradicated (smallpox, measles, and polio). That is why great efforts are made to achieve mass vaccination against COVID-19. However, developed vaccines face many challenges with regard to their safety and stability. Moreover, needle phobia could prevent a significant proportion of the population from receiving vaccines. In this context, microneedles (MNs) could potentially present a solution to address these challenges. MNs represent single dose administration systems that do not need reconstitution or cold-chain storage. Being self-administered, pain-free, and capable of producing superior immunogenicity makes them a more attractive alternative. This review explores microneedles' types, safety, and efficacy in vaccine delivery. Preclinical and clinical studies for microneedle-based vaccines are discussed and patent examples are included.


Subject(s)
COVID-19 , Vaccines , Administration, Cutaneous , Child , Drug Delivery Systems , Humans , Needles , Technology , Vaccination
2.
Antiviral Res ; 198: 105246, 2022 02.
Article in English | MEDLINE | ID: covidwho-1639070

ABSTRACT

The utility of remdesivir treatment in COVID-19 patients is currently limited by the necessity to administer this antiviral intravenously, which has generally limited its use to hospitalized patients. Here, we tested a novel, subcutaneous formulation of remdesivir in the rhesus macaque model of SARS-CoV-2 infection that was previously used to establish the efficacy of remdesivir against this virus in vivo. Compared to vehicle-treated animals, macaques treated with subcutaneous remdesivir from 12 h through 6 days post inoculation showed reduced signs of respiratory disease, a reduction of virus replication in the lower respiratory tract, and an absence of interstitial pneumonia. Thus, early subcutaneous administration of remdesivir can protect from lower respiratory tract disease caused by SARS-CoV-2.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Lung Diseases, Interstitial/prevention & control , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/therapeutic use , Administration, Cutaneous , Alanine/administration & dosage , Alanine/pharmacokinetics , Alanine/therapeutic use , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Disease Models, Animal , Female , Lung/pathology , Lung/virology , Macaca mulatta , Male , Viral Load/drug effects , Virus Replication/drug effects
3.
Nature ; 601(7894): 617-622, 2022 01.
Article in English | MEDLINE | ID: covidwho-1528018

ABSTRACT

T cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T cell epitopes derived from various viral proteins1,2, combined with the Toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG, aiming to induce profound SARS-CoV-2 T cell immunity to combat COVID-19. Here we conducted a phase I open-label trial, recruiting 36 participants aged 18-80 years, who received a single subcutaneous CoVac-1 vaccination. The primary end point was safety analysed until day 56. Immunogenicity in terms of CoVac-1-induced T cell response was analysed as the main secondary end point until day 28 and in the follow-up until month 3. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study participants, whereas systemic reactogenicity was absent or mild. SARS-CoV-2-specific T cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T helper 1 CD4+ and CD8+ T cells. CoVac-1-induced IFNγ T cell responses persisted in the follow-up analyses and surpassed those detected after SARS-CoV-2 infection as well as after vaccination with approved vaccines. Furthermore, vaccine-induced T cell responses were unaffected by current SARS-CoV-2 variants of concern. Together, CoVac-1 showed a favourable safety profile and induced broad, potent and variant of concern-independent T cell responses, supporting the presently ongoing evaluation in a phase II trial for patients with B cell or antibody deficiency.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Vaccines, Subunit/immunology , Administration, Cutaneous , Adolescent , Adult , Aged , Aged, 80 and over , CD8-Positive T-Lymphocytes/immunology , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , Clinical Trials, Phase II as Topic , Female , Granuloma/immunology , Humans , Immunogenicity, Vaccine , Interferon-gamma/immunology , Male , Middle Aged , T-Lymphocytes, Helper-Inducer/immunology , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/adverse effects , Young Adult
4.
Sci Adv ; 7(45): eabj0611, 2021 11 05.
Article in English | MEDLINE | ID: covidwho-1515256

ABSTRACT

This work reports a suction-based cutaneous delivery method for in vivo DNA transfection. Following intradermal Mantoux injection of plasmid DNA in a rat model, a moderate negative pressure is applied to the injection site, a technique similar to Chinese báguàn and Middle Eastern hijama cupping therapies. Strong GFP expression was demonstrated with pEGFP-N1 plasmids where fluorescence was observed as early as 1 hour after dosing. Modeling indicates a strong correlation between focal strain/stress and expression patterns. The absence of visible and/or histological tissue injury contrasts with current in vivo transfection systems such as electroporation. Specific utility was demonstrated with a synthetic SARS-CoV-2 DNA vaccine, which generated host humoral immune response in rats with notable antibody production. This method enables an easy-to-use, cost-effective, and highly scalable platform for both laboratorial transfection needs and clinical applications for nucleic acid­based therapeutics and vaccines.


Subject(s)
COVID-19 Vaccines , COVID-19 , DNA , SARS-CoV-2 , Skin/immunology , Transfection , Vaccines, DNA , Administration, Cutaneous , Animals , COVID-19/genetics , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , COVID-19 Vaccines/pharmacology , DNA/genetics , DNA/immunology , DNA/pharmacology , Male , Rats , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Suction , Vaccines, DNA/genetics , Vaccines, DNA/immunology , Vaccines, DNA/pharmacology
5.
Acc Chem Res ; 54(23): 4262-4271, 2021 12 07.
Article in English | MEDLINE | ID: covidwho-1510542

ABSTRACT

Over the past two decades, research on mRNA-based therapies has exploded, mainly because of the inherent advantages of mRNA, including a low integration probability, transient expression, and simple and rapid in vitro transcription production approaches. In addition, thanks to improved stability and reduced immunogenicity by advanced strategies, the application of mRNA has expanded from protein replacement therapy to vaccination, gene editing and other fields, showing great promise for clinical application. Recently, with the successive launch of two mRNA-based COVID-19 vaccines, mRNA technology has attracted an enormous amount of attention from scientific researchers as well as pharmaceutical companies. Because of the large molecular weight, hydrophilicity, and highly negative charge densities of mRNA, it is difficult to overcome the intracellular delivery barriers. Therefore, various delivery vehicles have been developed to achieve more effective mRNA delivery. In general, conventional mRNA administration methods are based on injection strategies, including intravenous, intramuscular, intradermal, and subcutaneous injections. Although these routes circumvent the absorption barriers to some extent, they bring about injection-related concerns such as safety issues, pain, low compliance, and difficulty in repeated dosing, increasing the need to explore alternative strategies for noninvasive delivery. The ideal noninvasive delivery systems are featured with easy to use, low risks of infection, and good patient compliance. At the same time, they allow patients to self-administer, reducing reliance on professional healthcare workers and interference with bodily functions and daily life. In particular, the noninvasive mucosal delivery of mRNA vaccines can induce mucosal immune responses, which are important for resisting pathogens infected through mucosal routes.Because of the potential clinical benefits mentioned above, we detailed the existing strategies for the noninvasive delivery of mRNA in this review, including delivery via the nasal, pulmonary, vaginal, and transdermal routes. First, we discussed the unique strengths and biological hindrances of each route on the basis of physiology. Next, we comprehensively summarized the research progress reported so far and analyzed the technologies and delivery vehicles used, hoping to provide some references for further explorations. Among these noninvasive routes, nasal and pulmonary delivery are the earliest and most intensively studied areas, mostly owing to their favorable physiological structures: the nasal or pulmonary mucosa is easily accessible, highly permeable and highly vascularized. In contrast, the development of vaginal mRNA delivery is relatively less reported, and the current research mainly focused on some local applications. In addition, microneedles have also been investigated to overcome skin barriers for mRNA delivery in recent years, making microneedle-based delivery an emerging alternative pathway. In summary, a variety of mRNA formulations and delivery strategies have been developed for noninvasive mRNA delivery, skillfully combining appropriate vehicles or physical technologies to enhance effectiveness. We surmise that continuous advances and technological innovations in the development of mRNA noninvasive delivery will accelerate the translation from experimental research to clinical application.


Subject(s)
Drug Delivery Systems/methods , /chemistry , Administration, Cutaneous , Administration, Inhalation , Animals , COVID-19/prevention & control , COVID-19/virology , Humans , SARS-CoV-2/isolation & purification , /immunology
6.
Theranostics ; 11(20): 10012-10029, 2021.
Article in English | MEDLINE | ID: covidwho-1512995

ABSTRACT

Various living organisms have proven to influence human health significantly, either in a commensal or pathogenic manner. Harnessing the creatures may remarkably improve human healthcare and cure the intractable illness that is challenged using traditional drugs or surgical approaches. However, issues including limited biocompatibility, poor biosafety, inconvenience for personal handling, and low patient compliance greatly hinder the biomedical and clinical applications of living organisms when adopting them for disease treatment. Microneedle arrays (MNAs), emerging as a promising candidate of biomedical devices with the functional diversity and minimal invasion, have exhibited great potential in the treatment of a broad spectrum of diseases, which is expected to improve organism-based therapies. In this review, we systemically summarize the technologies employed for the integration of MNAs with specific living organisms including diverse viruses, bacteria, mammal cells and so on. Moreover, their applications such as vaccination, anti-infection, tumor therapy and tissue repairing are well illustrated. Challenges faced by current strategies, and the perspectives of integrating more living organisms, adopting smarter materials, and developing more advanced technologies in MNAs for future personalized and point-of-care medicine, are also discussed. It is believed that the combination of living organisms with functional MNAs would hold great promise in the near future due to the advantages of both biological and artificial species.


Subject(s)
Biological Therapy/methods , Drug Delivery Systems/instrumentation , Drug Delivery Systems/methods , Administration, Cutaneous , Bacteria , Biological Therapy/trends , Cells , Immunotherapy/methods , Immunotherapy/trends , Needles , Skin/drug effects , Vaccination/methods , Vaccination/trends , Viruses
8.
Adv Drug Deliv Rev ; 179: 113997, 2021 12.
Article in English | MEDLINE | ID: covidwho-1458710

ABSTRACT

The recent advancement and prevalence of wearable technologies and their ability to make digital measurements of vital signs and wellness parameters have triggered a new paradigm in the management of diseases. Drug delivery as a function of stimuli or response from wearable, closed-loop systems can offer real-time on-demand or preprogrammed drug delivery capability and offer total management of disease states. Here we review the key opportunities in this space for development of closed-loop systems, given the advent of digital wearable technologies. Particular considerations and focus are given to closed-loop systems combined with transdermal drug delivery technologies.


Subject(s)
Administration, Cutaneous , Drug Delivery Systems , Wearable Electronic Devices/trends , Animals , Equipment Design , Humans , Skin
12.
Regul Toxicol Pharmacol ; 124: 104978, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1283630

ABSTRACT

An in vivo pharmacokinetic study was conducted using consumer antiseptic wash containing 0.13% benzalkonium chloride (BAC) to assess the effect of dermal absorption on long-term systemic exposure to BAC. The objective of the study was to determine blood levels of BAC under maximal use conditions. Subjects were enlisted to wash their hands 60 s with soap containing 0.13% BAC 30 times per day over an 8-9 h time period for 5 consecutive days. The test product with the highest absorption potential was selected based on market share and results from in vitro permeation testing. Blood plasma was collected from subjects on 32 occasions over the 6-day study period. Plasma samples were analyzed for the C12 and C14 homologs of BAC using LC-MS/MS with a lower limit of quantitation (LLOQ) of 106.9 and 32.6 ng/L, respectively. For the 32 subjects, C12 homolog was detected above the LLOQ in only four of 1,024 plasma samples at 117.8-191.7 ng/L, and C14 homolog was detected in only one sample at 59.5 ng/L. Consequently, systemic exposure to BAC in antimicrobial soap is very low and below the level of concern identified by the U.S. Food and Drug Administration (500 ng/L) even under maximal use conditions.


Subject(s)
Benzalkonium Compounds/pharmacokinetics , Hand Disinfection/methods , Soaps/pharmacokinetics , Administration, Cutaneous , Adult , Benzalkonium Compounds/administration & dosage , Female , Humans , Male , Middle Aged , Pilot Projects , Skin Absorption , Soaps/administration & dosage , Soaps/chemistry , Young Adult
15.
J Cosmet Dermatol ; 20(8): 2378-2379, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1269752
16.
Dermatol Clin ; 39(4): 653-673, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1252657

ABSTRACT

In 2021, we entered a new phase of the COVID-19 pandemic. As mass vaccinations are underway and more vaccines are approved, it is important to recognize cutaneous adverse events. We review the dermatologic manifestations of COVID-19 vaccines as reported in clinical trial data and summarize additional observational reports of skin reactions to COVID-19 vaccines. Early-onset local injection reactions were the most common cutaneous side effects observed in clinical trials; delayed injection reactions were the most common cutaneous side effect reported outside of clinical trials. Understanding the landscape of cutaneous manifestations to COVID-19 vaccines is key to providing appropriate vaccine guidance.


Subject(s)
Adverse Drug Reaction Reporting Systems/statistics & numerical data , COVID-19 Vaccines/adverse effects , Drug Eruptions/etiology , Drug-Related Side Effects and Adverse Reactions/diagnosis , Registries , Administration, Cutaneous , Drug Eruptions/epidemiology , Humans
17.
Drug Deliv Transl Res ; 11(4): 1498-1508, 2021 08.
Article in English | MEDLINE | ID: covidwho-1237565

ABSTRACT

Transdermal drug delivery systems (TDDS) have many advantages and represent an excellent alternative to oral delivery and hypodermic injections. TDDS are more convenient and less invasive tools for disease and viral infection treatment, prevention, detection, and surveillance. The emerging development of microneedles for TDDS has facilitated improved skin barrier penetration for the delivery of macromolecules or hydrophilic drugs. Microneedle TDDS patches can be fabricated to deliver virus vaccines and potentially provide a viable alternative vaccine modality that offers improved immunogenicity, thermostability, simplicity, safety, and compliance as well as sharp-waste reduction, increased cost-effectiveness, and the capacity for self-administration, which could improve vaccine distribution. These advantages make TDDS-based vaccine delivery an especially well-suited option for treatment of widespread viral infectious diseases including pandemics. Because microneedle-based bioassays employ transdermal extraction of interstitial fluid or blood, they can be used as a minimally invasive approach for surveying disease markers and providing point-of-care (POC) diagnostics. For cutaneous viral infections, TDDS can provide localized treatment with high specificity and less systemic toxicity. In summary, TDDS, especially those that employ microneedles, possess special attributes that can be leveraged to reduce morbidity and mortality from viral infectious diseases. In this regard, they may have considerable positive impact as a modality for improving global health. In this article, we introduce the possible role and summarize the current literature regarding TDDS applications for fighting common cutaneous or systemic viral infectious diseases, including herpes simplex, varicella or herpes zoster, warts, influenza, measles, and COVID-19.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , Drug Delivery Systems/methods , Microinjections/methods , Administration, Cutaneous , Animals , Antiviral Agents/immunology , Antiviral Agents/metabolism , COVID-19/immunology , COVID-19/metabolism , Communicable Diseases/drug therapy , Communicable Diseases/immunology , Communicable Diseases/metabolism , Drug Delivery Systems/trends , Humans , Microinjections/trends
18.
Dermatitis ; 32(3): 133-139, 2021.
Article in English | MEDLINE | ID: covidwho-1183048

ABSTRACT

We are entering a new stage of the severe acute respiratory syndrome coronavirus 2 pandemic with the initiation of large-scale vaccination programs globally. In these circumstances, even rare adverse effects of vaccines may be encountered more often, if millions of people are to be vaccinated in a short period. Vaccination has the potential for causing cutaneous adverse effects. Thus, it is paramount that dermatologists worldwide are acquainted with the possible skin reaction patterns to the coming vaccines. Herein, we conduct a review to discuss the most frequent cutaneous adverse effects of vaccines and their management, with a particular focus on the expected adverse reactions for the coming severe acute respiratory syndrome coronavirus 2 vaccines, such as local reactions, as well as immediate- and delayed-type hypersensitivity reactions, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrosis, serum sickness-like reactions, and vasculitides. We also discuss the yet unanswered questions on vaccines for which we may soon be asked to provide an expert opinion.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Drug Eruptions/etiology , Drug-Related Side Effects and Adverse Reactions/diagnosis , Administration, Cutaneous , Adverse Drug Reaction Reporting Systems/standards , Humans
19.
Adv Drug Deliv Rev ; 171: 164-186, 2021 04.
Article in English | MEDLINE | ID: covidwho-1062195

ABSTRACT

The COVID-19 pandemic is a serious threat to global health and the global economy. The ongoing race to develop a safe and efficacious vaccine to prevent infection by SARS-CoV-2, the causative agent for COVID-19, highlights the importance of vaccination to combat infectious pathogens. The highly accessible cutaneous microenvironment is an ideal target for vaccination since the skin harbors a high density of antigen-presenting cells and immune accessory cells with broad innate immune functions. Microarray patches (MAPs) are an attractive intracutaneous biocargo delivery system that enables safe, reproducible, and controlled administration of vaccine components (antigens, with or without adjuvants) to defined skin microenvironments. This review describes the structure of the SARS-CoV-2 virus and relevant antigenic targets for vaccination, summarizes key concepts of skin immunobiology in the context of prophylactic immunization, and presents an overview of MAP-mediated cutaneous vaccine delivery. Concluding remarks on MAP-based skin immunization are provided to contribute to the rational development of safe and effective MAP-delivered vaccines against emerging infectious diseases, including COVID-19.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Drug Development/trends , SARS-CoV-2/immunology , Skin/immunology , Transdermal Patch/trends , Administration, Cutaneous , COVID-19/metabolism , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/metabolism , Drug Development/methods , Humans , Immunity, Innate/drug effects , Immunity, Innate/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Skin/drug effects , Skin/metabolism
20.
JAMA Dermatol ; 156(12): 1333-1343, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1008230

ABSTRACT

Importance: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced disease severity in moderate to severe atopic dermatitis (AD) in 2 phase 3 monotherapy studies. Objective: To assess the efficacy and safety of 4 mg and 2 mg of baricitinib in combination with background topical corticosteroid (TCS) therapy in adults with moderate to severe AD who previously had an inadequate response to TCS therapy. Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial, BREEZE-AD7 (Study of Baricitinib [LY3009104] in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis) was conducted from November 16, 2018, to August 22, 2019, at 68 centers across 10 countries in Asia, Australia, Europe, and South America. Patients 18 years or older with moderate to severe AD and an inadequate response to TCSs were included. After completing the study, patients were followed up for up to 4 weeks or enrolled in a long-term extension study. Interventions: Patients were randomly assigned (1:1:1) to receive 2 mg of baricitinib once daily (n = 109), 4 mg of baricitinib once daily (n = 111), or placebo (n = 109) for 16 weeks. The use of low-to-moderate potency TCSs was allowed. Main Outcomes and Measures: The primary end point was the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear), with a 2-point or greater improvement from baseline at week 16. Results: Among 329 patients (mean [SD] age, 33.8 [12.4] years; 216 [66%] male), at week 16, a vIGA-AD score of 0 (clear) or 1 (almost clear) was achieved by 34 patients (31%) receiving 4 mg of baricitinib and 26 (24%) receiving 2 mg of baricitinib compared with 16 (15%) receiving placebo (odds ratio vs placebo, 2.8 [95% CI, 1.4-5.6]; P = .004 for the 4-mg group; 1.9 [95% CI, 0.9-3.9]; P = .08 for the 2-mg group). Treatment-emergent adverse events were reported in 64 of 111 patients (58%) in the 4-mg group, 61 of 109 patients (56%) in the 2-mg group, and 41 of 108 patients (38%) in the placebo group. Serious adverse events were reported in 4 patients (4%) in the 4-mg group, 2 (2%) in the 2-mg group, and 4 (4%) in the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and folliculitis. Conclusions and Relevance: A dose of 4 mg of baricitinib in combination with background TCS therapy significantly improved the signs and symptoms of moderate to severe AD, with a safety profile consistent with previous studies of baricitinib in AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03733301.


Subject(s)
Azetidines/administration & dosage , Dermatitis, Atopic/drug therapy , Glucocorticoids/administration & dosage , Purines/administration & dosage , Pyrazoles/administration & dosage , Sulfonamides/administration & dosage , Administration, Cutaneous , Administration, Oral , Adult , Azetidines/adverse effects , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/immunology , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Female , Folliculitis/chemically induced , Folliculitis/epidemiology , Folliculitis/immunology , Glucocorticoids/adverse effects , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Male , Middle Aged , Nasopharyngitis/chemically induced , Nasopharyngitis/epidemiology , Nasopharyngitis/immunology , Purines/adverse effects , Pyrazoles/adverse effects , Respiratory Tract Infections/chemically induced , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/immunology , Severity of Illness Index , Signal Transduction/drug effects , Signal Transduction/immunology , Sulfonamides/adverse effects , Young Adult
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