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Publications (738)
Background
Children play an important role in the transmission of influenza. The best choice of vaccine to achieve both direct and indirect protection is uncertain. The objective of the study was to test whether vaccinating children with MF59 adjuvanted trivalent influenza vaccine (aTIV) can reduce influenza in children and their extended household...
The genus Capripoxvirus in the subfamily Chordopoxvirinae, family Poxviridae, comprises sheeppox virus (SPPV), goatpox virus (GTPV), and lumpy skin disease virus (LSDV), which cause the eponymous diseases across parts of Africa, the Middle East, and Asia. These diseases cause significant economic losses and can have a devastating impact on the live...
Introduction: Seasonal influenza poses a major risk to the health of the population. Optimal strategies for influenza vaccination can help to reduce this risk.
Areas covered: Systematic evaluations of the burden of influenza are first reviewed. Key meta-analysis, randomized trials, and observational studies are critically reviewed to provide the be...
Regulatory B cells that produce IL-10 are now recognized as an important component of the immune system. We previously confirmed that IL-10 secreting CD21 ⁺ regulatory B cells (B reg cells)were present in ovine jejunal Peyer's patches (JPP)and this IL-10 production suppressed IL-12 and IFN-γ secretion. It is not known, however, whether ovine B reg...
The most promising strategy to sustainably prevent infectious diseases is vaccination. However, emerging as well as re-emerging diseases still constitute a considerable threat. Furthermore, lack of compliance and logistic constrains often result in the failure of vaccination campaigns. To overcome these hurdles, novel vaccination strategies need to...
Adjuvants are crucial components of many vaccines. They are used to improve the immunogenicity of vaccines with the aim of conferring long-term protection, to enhance the efficacy of vaccines in newborns, elderly or immunocompromised persons, and to reduce the amount of antigen or the number of doses required to elicit effective immunity. Novel com...
Maternal vaccination represents a potential strategy to protect both the mother and the offspring against life threatening infections. This protective role has mainly been associated with antibodies but the role of cell mediated immunity in particular passively transferred cytokines is not well understood. Herein, using a pertussis model we have de...
Background:
Patterns of influenza molecular viral shedding following influenza infection have been well established; predictors of viral shedding however remain uncertain.
Objectives:
We sought to determine factors associated with peak molecular viral load, duration of shedding, and viral area under the curve (AUC) in children and adult Hutterit...
Background:
An earlier cluster randomized controlled trial (RCT) of Hutterite colonies had shown that if more than 80% of children and adolescents were immunized with influenza vaccine there was a statistically significant reduction in laboratory-confirmed influenza among all unimmunized community members. We assessed the impact of this interventi...
Direct Vaccine Protective Effectiveness.
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Background:
Whether vaccinating children with intranasal live attenuated influenza vaccine (LAIV) is more effective than inactivated influenza vaccine (IIV) in providing both direct protection in vaccinated persons and herd protection in unvaccinated persons is uncertain. Hutterite colonies, where members live in close-knit, small rural communitie...
The zebrafish model system is helping researchers improve the health and welfare of people and animals and has become indispensable for advancing biomedical research. As genetic engineering is both resource intensive and time-consuming, sharing successfully developed genetically modified zebrafish lines throughout the international community is cri...
IL-10 secreting CD21+ B cells exist in sheep Peyer’s patches (PP). It’s not known however, whether all PP B cells are regulatory or whether an effector population also exists in this tissue. To further characterize the subpopulations of B cells in PP’s, highly purified B cells were negatively sorted from jejunal PP and fractionated according to co-...
Background:
Therapeutic vaccination is a novel treatment approach for chronic hepatitis B, but only had limited success so far. We hypothesized that optimized vaccination schemes have increased immunogenicity, and aimed at increasing therapeutic hepatitis B vaccine efficacy.
Methods:
Modified Vaccinia virus Ankara (MVA) expressing hepatitis B vi...
Lumpy skin disease, sheeppox and goatpox are high-impact diseases of domestic ruminants with a devastating effect on cattle, sheep and goat farming industries in endemic regions. In this article, we review the current geographical distribution, economic impact of an outbreak, epidemiology, transmission and immunity of capripoxvirus. The special foc...
Sheep and goat pox continue to be important livestock diseases that pose a major threat to the livestock industry in many regions in Africa and Asia. Currently, several live attenuated vaccines are available and used in endemic countries to control these diseases. One of these is a partially attenuated strain of lumpy skin disease virus (LSDV), KS-...
Infectious diseases continue to cause significant morbidity and mortality in both animals and humans. Indeed, every year infectious diseases cost the global economy billions of dollars in losses and are responsible for approximately one-third of all human deaths. These deaths occur from routine infections, hospital acquired infections (approximatel...
Protective efficacy against bovine herpesvirus-1 (BoHV-1) has been demonstrated to be induced by a plasmid encoding the bovine beta-defensin, BNBD3, as a fusion with a truncated version of glycoprotein D (tgD). However, in spite of the increased cell-mediated immune responses induced by this DNA vaccine, the clinical responses of BoHV-1 challenged...
Innate immunity represents the first line of defense against invading pathogens in the respiratory tract. Innate immune cells such as monocytes, macrophages, dendritic cells, NK cells, and granulocytes contain specific pathogen-recognition molecules which induce the production of cytokines and subsequently activate the adaptive immune response. c-d...
One of the impediments in the development of safe and cost effective vaccines for veterinary use has been the availability of appropriate delivery vehicle. We have chosen to develop and use bovine adenovirus (BAdV)-3 as vaccine delivery vector in cattle. Here, we describe the construction of recombinant E3 deleted BAdV-3 vectors expressing single v...
The process of virus replication in host cells is greatly influenced by the set of cytokines, chemokines and antiviral substances activated as a result of host-virus interaction. Alteration of cytokines profiles through manipulation of the innate immune system by innate immune stimulants may be helpful in inhibiting virus replication in otherwise p...
The potent adjuvant activity of the novel adjuvant, poly[di(sodiumcarboxylatoethylphenoxy)phosphazene] (PCEP), with various antigens has been reported previously. However, very little is known about its mechanisms of action. We have recently reported that intramuscular injection of PCEP induces NLRP3, an inflammasome receptor gene, and inflammatory...
Adjuvants are crucial components of vaccines. They significantly improve vaccine efficacy by modulating, enhancing, or extending the immune response and at the same time reducing the amount of antigen needed. In contrast to previously licensed adjuvants, current successful adjuvant formulations often consist of several molecules, that when combined...
Previous studies have suggested an important role of the cytokine adjuvant IL-6 in the induction of mucosal immune responses in animals, including mice. Here, we report the in vivo ability of bovine adenovirus (BAdV)-3 expressing bovine (Bo) IL-6, to influence the systemic and mucosal immune responses against bovine herpesvirus (BHV)-1 gDt in calve...
We recently reported a novel interleukin-10 (IL-10)-secreting CD21(+) B cell population in jejunal Peyer's patches (JPP) of sheep with a regulatory function (Bregs) suppressing Toll-like receptor 9 (TLR9)-induced cytokine responses. However, little is known about the development of these cells. Therefore, we investigate their existence in JPP cells...
Poly[di(sodiumcarboxylatoethylphenoxy)phosphazene] (PCEP) has shown great potential as a vaccine adjuvant, but the mechanisms that mediate its adjuvant activity have not been investigated. Previously, we had reported the potential of PCEP to induce cytokines and chemokines at the site of injection. Hence, we hypothesized that PCEP creates strong im...
Peste des petits ruminants (PPR) is a viral disease which primarily affects small ruminants, causing significant economic losses for the livestock industry in developing countries. It is endemic in Saharan and sub-Saharan Africa, the Middle East and the Indian sub-continent. The primary hosts for peste des petits ruminants virus (PPRV) are goats an...
Bovine herpesvirus-1 (BoHV-1) causes recurrent respiratory and genital infections in cattle, and predisposes them to lethal secondary infections. While modified-live and killed BoHV-1 vaccines exist, these are not without problems. Development of an effective DNA vaccine for BoHV-1 has the potential to address these issues. As a strategy to enhance...
Peste des petits ruminants (PPR) is a viral disease which primarily affects small ruminants, causing significant economic losses for the livestock industry in developing countries. It is endemic in Saharan and sub-Saharan Africa, the Middle East and the Indian sub-continent. The primary hosts for peste des petits ruminants virus (PPRV) are goats an...
Adjuvants are used in many vaccines, but their mechanisms of action are not fully understood. Studies from the past decade on adjuvant mechanisms are slowly revealing the secrets of adjuvant activity. In this review, we have summarized the recent progress in our understanding of the mechanisms of action of adjuvants. Adjuvants may act by a combinat...
Whooping cough is a respiratory illness most severe in infants and young children. While the introduction of whole-cell (wP) and acellular pertussis (aP) vaccines has greatly reduced the burden of the disease, pertussis remains a problem in neonates and adolescents. New vaccines are needed that can provide early life and long-lasting protection of...
The neonatal immune system is often considered as immature or impaired compared to the adult immune system. This higher susceptibility to infections is partly due to the skewing of the neonatal immune response towards a Th2 response. Activation and maturation of dendritic cells (DCs) play an important role in shaping the immune response, therefore,...
a b s t r a c t Five different viral diseases of livestock, lumpy skin disease (LSD), sheep pox (SPP), goat pox (GTP), Rift Valley fever (RVF) and peste des petits ruminants (PPR), circulate in the same regions of Africa, imposing a major burden on economic activity and public health. While commercial vaccines against these viruses are available, t...
Objectives:
To determined the pathogen-specific incidence of respiratory virus infection in Hutterite communities occurring over the 2008-2009 influenza season and assess temporal characteristics of respiratory illness related to infection.
Methods:
3273 participants community members enrolled in a cluster randomized trial of influenza vaccine w...
Vaccination continues to have a major impact on the health of humans and animals. Furthermore, vaccination of animals is proving to be effective in reducing transmission to humans. Understanding linkages between innate and adaptive immunity are improving formulations of new, as well as existing, vaccines, making them more effective.
The induction of innate immunity marks an important step in the process of eliciting protective immunity to vaccines. Stimulation of innate immunity may be enhanced through the use of adjuvants, compounds that are included in vaccine formulations in order to provide an additional danger signal that subsequently directs and refines both the innate a...
Adjuvants are critical components of many vaccines but their mechanisms of action are often poorly understood. Understanding the mechanisms of adjuvant activity is critical in defining how innate immunity influenced adaptive immunity. We investigated the capacity of a novel adjuvant, poly[di(sodiumcarboxylatoethylphenoxy)phosphazene] (PCEP), to ind...
VP8 is the most abundant tegument protein of bovine herpesvirus-1 (BHV-1). In the present study DNA damage binding protein 1 (DDB1) was identified as interacting partner of VP8. MALDI-TOF mass spectroscopy analysis of proteins co-immunoprecipitated with VP8 identified DDB1 as a protein interacting with VP8. The interaction between VP8 and DDB1 was...
A variety of mechanisms contribute to the viral-bacterial synergy which results in fatal secondary bacterial respiratory infections. Epidemiological investigations have implicated physical and psychological stressors as factors contributing to the incidence and severity of respiratory infections and psychological stress alters host responses to exp...
The selection of an optimal adjuvant to enhance the potency and longevity of antigen specific immune responses has always been imperative for the development of more effective and safer vaccines. A balanced type of immune enhancing ability of a new adjuvant known as polyphosphazene (PCEP) has been demonstrated in mice. In the present study we have...
We previously reported that CD21(+) B cells purified from bovine blood do not respond to CpG-ODN stimulation unless either CD14(+) monocytes or B-cell Activating Factor (BAFF), a cytokine produced by activated monocytes, are present. In this report, we present evidence that CD14(+) monocytes are critical for CpG-specific lymphocyte proliferation wi...
Despite the increase in the number of clinical trials in low and middle income countries (LMICs), there has been little serious discussion of whether First in Human (FIH; phase 0 and phase 1) clinical trials should be conducted in LMICs, and if so, under what conditions. Based on our own experience, studies and consultations, this paper aims to sti...
Hepatitis C virus (HCV) causes a chronic liver infection, which may result in cirrhosis and hepatocellular carcinoma. Impairment of the maturation process in dendritic cells (DCs) may be one of the mechanisms responsible for immune evasion of HCV. The core and NS3 proteins are among the most conserved HCV proteins and play a key role in viral clear...
Human and murine immature DCs (iDCs) are highly efficient in antigen capture and processing, while as mature cells they present antigen and are potent initiators of cell-mediated immune responses. Consequently, iDCs are logical targets for vaccine antigens. Originally discovered for their antimicrobial activity, and thought of as strictly part of t...
Interleukin-17 (IL-17) producing cells, referred to as Th17, have recently emerged as a third subset of the T helper (Th) cell family. Studies in mice have demonstrated that Th17 cells and their associated cytokines are involved in several autoimmune diseases and host defense against infection. Murine Th17 cells differentiate from naïve CD4(+) T-ce...
We investigated the efficacy of a novel microparticle (MP) based vaccine formulation consisting of pertussis toxoid (PTd), polyphosphazene (PCEP), CpG ODN 10101 and synthetic cationic innate defense regulator peptide 1002 (IDR) against Bordetella pertussis in mice. We studied whether encapsulation of these IDR-CpG ODN complexes into polyphosphazene...
Whooping cough caused by infection with Bordetella pertussis, is a serious illness in infants and young children. Mortality due to whooping cough is being reported in infants too young to be immunized as well as those who have not completed their series of vaccinations. One of the major factors that interferes with successful active immunization in...
Mutations found in previous studies of mouse adaptation of IAV.
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Amino acid changes in the HA protein of parental HK clones and their corresponding mouse adapted clones derived after 21 serial passages in the mouse lung.
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Amino acid changes in the NA protein of parental HK clones and their corresponding mouse adapted clones derived after 21 serial passages in the mouse lung.
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Number of mutations selected in each of 39 mouse adapted variants from 10 replicate mouse adaptation experiments.
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Amino acid changes in the PB2 protein of parental HK clones and their corresponding mouse adapted clones derived after 21 serial passages in the mouse lung.
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Amino acid changes in the PB1 and PA proteins of HK-wt clones and their corresponding mouse adapted variants derived after 21 serial passages in the mouse lung.
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Amino acid changes in the NP protein of parental HK clones and their corresponding mouse adapted clones derived after 21 serial passages in the mouse lung.
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List of PB2 gene Genbank accession numbers for human H5N1 and canine H3N8 isolates that possess PB2 D701N and/or PB2 D740N mutations.
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RNA polymerase activity effects of PB1, PB2, PA and NP mutations in mouse and human cells. Polymerase activity is shown for B82 mouse cells (A) and human 293T cells (B). Mouse adaptive mutations at the indicated positions are masked in gray and HK-wt is shown without mask in the table aligned with bars of activity. Influenza luciferase assays emplo...
Amino acid changes in the M1, M2, NS1, and NEP proteins of parental HK clones and mouse adapted clones derived after 21 serial passages in the mouse lung.
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List of Genbank accession numbers for nucleotide gene sequences of HK parental and mouse adapted variant clones for each genome segment with encoded proteins and nucleotide sequence length indicated.
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Blast alignment of mouse CPSF30 with human CPSF30. Amino acid sequence of mouse CPSF30 (query) is aligned above human CPSF30 sequence (Sbjct) with the consensus sequence indicated between each sequence. The F2F3 binding fragment is indicated in yellow mask showing identical amino acid sequence between human and mouse.
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Adaptive evolution is characterized by positive and parallel, or repeated selection of mutations. Mouse adaptation of influenza A virus (IAV) produces virulent mutants that demonstrate positive and parallel evolution of mutations in the hemagglutinin (HA) receptor and non-structural protein 1 (NS1) interferon antagonist genes. We now present a geno...
It is controversial whether naïve B cells are directly activated in response to TLR9 ligand, CpG ODN. Although bovine blood-derived CD21(+) B cells express TLR9 and proliferate in response to CpG in mixed-cell populations, purified bovine B cells do not proliferate significantly in response to CpG ODN, even when the B cell receptor is engaged. When...
Mucosal dendritic cell development in the newborn is poorly understood despite evidence that distinct DC subpopulations populate individual mucosal surfaces. Therefore, we investigated DC phenotype and distribution in the small intestine of newborn calves. DC phenotype was analyzed using flow cytometry and DC distribution was investigated with immu...
Influenza virus infections continue to cause production losses in the agricultural industry in addition to being a human public health concern. The primary method to control influenza is through vaccination. However, currently used killed influenza virus vaccines must be closely matched to the challenge virus. The ability of an elastase-dependent l...
A balanced or Th-1 type immune response is required for effective clearance of many pathogens such as Bordetella pertussis, the causative agent of whooping cough. Since current acellular pertussis vaccines induce limited Th-1 type immune responses, novel vaccine formulations are needed to induce protective immunity in the infant in the earliest sta...
The antigenic polysaccharide side chain of the cell wall lipopolysaccharide of Pasteurella haemolytica (serotype 4) was investigated by methylation, periodate oxidation, partial hydrolysis, and 13C and 1H nuclear magnetic resonance analysis methods and was found to be a simple unbranched linear polymer composed of a disaccharide repeating unit havi...
Host defense peptides (HDPs) contribute to immune defense through direct antimicrobial activity as well as modulation of host immune responses. While the antimicrobial activity of HDPs has been successfully exploited as topical antibiotics, their use as systemic immunomodulatory antimicrobials has been limited by their toxicity and biological insta...
Swine outbreaks of pandemic influenza A (pH1N1) suggest human introduction of the virus into herds. This study investigates a pH1N1 outbreak occurring on a swine research farm with 37 humans and 1300 swine in Alberta, Canada, from 12 June through 4 July 2009.
The staff was surveyed about symptoms, vaccinations, and livestock exposures. Clinical fin...
Adjuvants are critical components of many vaccines. The majority of existing vaccines contain a single adjuvant. Owing to their inherent limitations, no single adjuvant is capable of inducing all the protective immune responses required in the many different vaccines. Consequently, investigators are exploring the potential of using formulations wit...
Synthetic oligodeoxynucleotides (ODN) containing CpG motifs signal through TLR9 and activate innate immunity resulting in protection against a variety of parasitic, bacterial and viral pathogens in mouse models. However, few studies have demonstrated protection in humans and large animals. In the present investigations, we evaluated protection by C...
Dendritic cells (DCs) play a crucial role in the initiation of an immune response. As maturation is critical for effective antigen presentation, different methods have been used to generate mature DCs (mDCs) ex vivo. The use of a maturation cocktail (MC) consisting of IL-1β, IL-6, TNF-α, and prostaglandin E2 (PGE2) initially showed promising result...
Influenza A virus is an important respiratory pathogen of swine that causes significant morbidity and economic impact on the swine industry. Vaccination is the first choice for prevention and control of influenza infections. Live attenuated influenza vaccines (LAIV) are approved for use in humans and horses and their application provides broad prot...
Ovalbumin (OVA) was labeled with a near infra-red dye (*OVA) and formulated with the host defense peptide indolicidin (Indol), CpG oligodeoxynucleotide (ODN) 1826 (CpG) and/or poly(p-dicarboxylatophenoxy)-phosphazene (PP4). The immunogenicity of these *OVA formulations was evaluated in mice. All double and triple adjuvant combinations elicited stro...
Steatosis is an important clinical manifestation of hepatitis C virus (HCV) infection. The molecular mechanisms of HCV-associated steatosis are not well understood. Sterol regulatory element-binding protein-1c (SREBP-1c) is a key transcription factor which activates the transcription of lipogenic genes. Here we showed that the nuclear, mature SREBP...
We generated poly[di(carboxylatophenoxy)-phosphazene] (PCPP) microparticles encapsulating ovalbumin (OVA) and CpG of 0.5-2.5 μm in diameter with an encapsulation efficiency of approximately 63% and 95% respectively. In mice the microparticles generated high antigen-specific IgG, IgG1 and IgG2a titers with higher IgG2a/IgG1 ratios. Whole body in viv...
We previously demonstrated that polyphosphazenes, particularly PCEP, enhance immune responses in mice immunized subcutaneously and intranasally. The objective of the present study was to investigate the efficacy of polyphosphazenes as adjuvants when delivered through different routes of vaccine administration.
BALB/c mice were immunized through int...
Intestinal Peyer's patch (PP) regulatory CD21+ B cells (B(regs)) suppress TLR9-induced innate immune responses. However, it is not known whether TLR9 activation is regulated in PP B(regs). Here, we investigated the responses of PP B(regs) to stimulation with the TLR9 agonist CpG oligodeoxynucleotides (ODN). We observed that PP CD21+ B(regs) express...
Dendritic cells (DCs) are at the interface of innate and adaptive immune responses. Once activated via triggering of their pattern recognition receptors (PRRs), they acquire a mature state and migrate to the lymph nodes where they activate T cells and direct the immune response. Compounds that trigger PRRs are potential vaccine adjuvants, hence in...
Hepatitis C virus genotype-3a (HCV-3a) is directly linked to the development of steatosis. We previously showed that, through sterol regulatory element binding protein-1 (SREBP-1), HCV-3a core protein upregulates the promoter activity of fatty acid synthase, a major enzyme involved in de novo lipid synthesis. In this study, we investigated whether...
Toll-like receptors (TLRs) play an important role in the activation of innate and adaptive immune responses. Stimulation with multiple TLR agonists may result in synergistic, complimentary or inhibitory effects on innate immune responses. In this study, we investigated the effects of co-stimulation of sheep peripheral blood mononuclear cells (PBMC)...
The analysis of CpG ODN induced innate immune responses in different animal species has shown substantial similarities and differences in levels and types of induced cytokines profile. The objectives of these studies were to identify innate immune biomarkers activated by three classes of CpG ODNs in pigs. For this purpose, we investigated the kinet...
Polyphosphazene polyelectrolyte, a potent new mucosal adjuvant candidate, was tested for its ability to elicit protective immunity against several respiratory diseases. Groups of mice were intranasally (i.n.) vaccinated with poly[di(sodium carboxylatophenoxy)phosphazene] (PCPP) together with several vaccine antigens such as pertussis toxoid, pneumo...
Children and adolescents appear to play an important role in the transmission of influenza. Selectively vaccinating youngsters against influenza may interrupt virus transmission and protect those not immunized.
To assess whether vaccinating children and adolescents with inactivated influenza vaccine could prevent influenza in other community member...
Host defence peptides (HDPs) have a variety of potential therapeutic applications, including as vaccine adjuvants, energizing efforts for modification strategies to address their toxicity and instability. Here we compare l, d and RI-Bac2A as vaccine adjuvants. d and RI-Bac2A are equally resistant to proteolytic degradation with no increases in toxi...
Campylobacteriosis is the most commonly reported (notifiable) bacterial enteric disease in Alberta, Canada. The purpose of this study was to assess the prevalence of Campylobacter species in retail ground beef based on a survey of 60 stores (four supermarket chains, three cities) in southern Alberta. None of the 1,200 retail lean and regular ground...
Enhancement of antigen-specific immune responses could be achieved by co-delivery of antigens and adjuvants. CpG oligodeoxynucleotides (unmethylated cytosine-guanine tandems in a specific sequence; ODNs) increase innate and antigen-specific immune responses. Effective co-delivery approaches of CpG ODNs and antigens to antigen-presenting cells are n...
The US3 gene product of bovine herpesvirus-1 (BoHV-1) is a protein kinase that is expressed early during infection and capable of autophosphorylation. By examining differentially labelled US3 moieties by co-immunoprecipitation, we demonstrated that the protein kinase interacts with itself in vitro, which supports autophosphorylation by US3. Based o...
Intradermal immunization using microfabricated needles represents a potentially powerful technology, which can enhance immune responses and provide antigen sparing. Solid vaccine formulations, which can be coated onto microneedle patches suitable for simple administration, can also potentially offer improved shelf-life. However the approach is not...
