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`1. History of intradermal vaccination
`
`The discovery of the principles of vaccination is often described
`as one of the most important developments in public health.
`The practice of inoculating small amounts of material from sick
`patients, such as powdered smallpox scabs or pus, into the nose
`or skin of healthy individuals to prevent disease was widespread
`across parts of Africa, Asia and the Ottoman empire, before inoc-
`ulation into the skin – variolation – was introduced to Europe in
`1721. Inoculated patients would generally develop a milder form of
`the disease than that occurring naturally. However, the risk of death
`from smallpox remained. It was not until 1796 that the first vacci-
`nation was carried out as practiced today by Edward Jenner in the
`United Kingdom based on his observation that milkmaids who had
`contracted cowpox through contact with cowpox pustules were not
`getting smallpox. Initially Jenner’s findings were not well received
`and it took 44 years for variolation to be forbidden by an Act of Par-
`liament and a further 13 years for vaccination against smallpox to
`be made compulsory in Britain in 1853 [1].
`The next important development was made by the French
`physician Charles Mantoux in 1910 when he published his clinical
`research on the intradermal injection of tuberculin as a diagnostic
`skin test for tuberculosis disease [2]. Not only was this technique
`used for tuberculosis diagnosis, but it formed the basis for intra-
`dermal (ID) injection of vaccines, a technique still used today for
`vaccines such as rabies and BCG [3,4].
`In 1967 the WHO launched a global programme to eradicate
`smallpox which, 150 years after Jenner’s discovery, was still affect-
`ing 10–15 million people each year. Eradication of the disease was
`finally confirmed by the World Health Assembly in 1980 [5] A major
`contribution to this achievement was the development of the bifur-
`cated needle by Benjamin A. Rubin. This needle was specifically
`designed to ensure the delivery of about 2 ␮l, but sufficient, quan-
`tity of this very potent vaccine into the dermis. It helped healthcare
`workers to correctly deliver vaccine to the most efficient site for
`immunization against smallpox. Vaccination was done by dipping
`the bifurcated needle into the vial of vaccine to pick up a minute
`drop of vaccine solution between the needle’s two prongs, then by
`jabbing the skin – typically in the deltoid region – several times
`with a brisk movement perpendicularly to the skin surface [6].
`The first renewed interest in intradermal immunization using
`a needle and syringe injection system in controlled clinical trials
`was reported by Tuft in 1930 [7]. This study reported an equiv-
`alent immune response and an improved adverse event profile
`with a smaller dose of typhoid vaccine when injected intrader-
`mally relative to subcutaneous injection [8]. Subsequently to these
`reports several studies aiming to evaluate the efficiency and util-
`ity of intradermal delivery route such as vaccine dose reduction
`were conducted using different commercially available vaccines
`including influenza [9–11], measles [12,13], cholera [14], rabies
`[15,16], hepatitis B [17–20], polio virus [21–24] aiming to evalu-
`ate the optimal route of immunization for preventive vaccination.
`In spite of the large number of published clinical trials compar-
`ing post-immunization humoral immune responses, the evaluation
`of the benefit and utility of intradermal delivery suffers from the
`absence of a consistent clinical design and standardized investi-
`gational method permitting an efficient side-by-side comparison
`and meta-analysis. The vaccine antigen concentration/immune
`response curve has rarely been thoroughly evaluated to detect and
`characterize the minimal, maximal and optimal antigen concen-
`trations in various population segments which correspond to the
`clinical indication of investigated vaccine. Nevertheless, vaccines
`can be generally categorized into three groups: (i) those for which
`intradermal delivery induces better responses than by intramus-
`cular or subcutaneous injection; (ii) vaccines for which conflicting
`
`results has been observed in separate clinical trials; and (iii) vaccine
`remaining to be investigated such as combo vaccines, meningococ-
`cal. Potential benefits of the intradermal delivery route as measured
`by post-immunization immune response depend upon the type
`of vaccine. For example, it is well documented that the immune
`response after intradermal administration of one-tenth of an intra-
`muscular dose is equivalent to the full dose given intramuscularly
`for rabies and hepatitis B vaccines, but not for trivalent influenza
`vaccine [25–29]. One confounding factors leading to mixed clini-
`cal study results with trivalent influenza vaccine is the priming by
`previous natural infection; primed adult subjects produce equiv-
`alent immune response with reduced dose of antigen delivered
`by intramuscular as well as intradermal delivery routes [29,30]. In
`contrast, intradermal influenza vaccination in elderly subjects (15
`and 21 ␮g of haemagluttinin/strain/0.1 ml dose) induced a humoral
`immune response superior to the IM control against all three strains
`[31]. Clinical studies in subjects with chronic medical conditions
`such as kidney failure, with or without haemodialysis, suggest
`that intradermal delivery of hepatitis B vaccine induces a better
`immune response than intramuscular injection [27,28,32]. Meta-
`analysis of clinical trials evaluating rabies vaccine prepared on
`diploid cells indicated that the persistence of specific humoral anti-
`bodies is at least equivalent to that observed with intramuscular
`delivery; the same results are observed with hepatitis B vaccine
`[25,33]. The local skin reactivity usually observed at the injection
`site after intradermal vaccine inoculation reflects the physiological
`local inflammatory response due to immune response induction
`and is characterized by spontaneously reversible redness at the
`injection site for a maximum period of 2 days without local seque-
`lae. Systemic adverse event profiles are equivalent whatever the
`delivery route.
`
`2. Current situation and future needs of innovative vaccine
`delivery systems
`
`An ideal vaccine is safe, cost-effective, and efficient after a sin-
`gle dose [34]. The way in which a vaccine is delivered can have
`considerable bearing on these factors through its influence on the
`efficiency of the procedure, the dose required, compliance, and
`safety. For vaccination to succeed holistically in contributing to
`public health, vaccine delivery systems must allow efficient deliv-
`ery without compromising product stability during storage and
`transport and without negatively influencing patient perception.
`To be considered safe, new delivery systems should reduce the risk
`of injury and infection of healthcare workers, and prevent illicit re-
`use. A delivery system combining all these qualities would facilitate
`the vaccination of greater portion of the population.
`Currently licensed vaccines are delivered via one of five
`main administration routes: intramuscular for the majority of
`vaccines including hepatitis A and B, rabies,
`influenza and
`diphtheria–tetanus–pertussis-based combination vaccines; subcu-
`taneous for vaccines such as measles, mumps and rubella, and
`yellow fever; intradermal for BCG and rabies; intranasal for live
`attenuated influenza vaccine, and oral for poliomyelitis, cholera,
`rotavirus and typhoid fever. With the rare exception of jet injectors,
`intramuscular, subcutaneous, and intradermal routes are accessed
`using needles. These techniques, whilst having proven efficacy in
`terms of achieving the required immune response, have some draw-
`backs relating to safety and patient compliance [35,36]. The invasive
`nature of the parenteral injection procedure and the potential for
`inappropriate reuse of equipment exposes patients to the risk of
`transmission of blood borne pathogens. Additionally, the use and
`disposal of equipment is associated with the risk of needle-stick
`injury. The introduction of safer devices engineered to prevent nee-
`dle re-use and reduce the risk of needle stick infections is likely
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`to lessen these concerns. However, the perceived or real pain and
`trauma sometimes associated with needle-based vaccination can
`be barriers to vaccination uptake, particularly by needle-phobic
`individuals [37,38]. These drawbacks, and the development of new
`types of vaccines, are some of the reasons driving the pharmaceu-
`tical industry and public health organizations to search for new
`delivery methods that are safe, cost-effective and efficient.
`While the majority of vaccines in clinical development are envi-
`sioned as needle and syringe products, a number of research groups
`and vaccine manufacturers are exploring the advantages of new
`parenteral delivery systems as well as of mucosal and transcu-
`taneous delivery [39]. Mucosal delivery is currently only used
`for live attenuated vaccines against poliomyelitis, typhoid fever
`(oral), rotavirus and influenza (nasal) [40,41]. Mucosally adminis-
`tered vaccines have a number of benefits. They eliminate the risk
`of transmission of blood borne diseases and needle stick injury.
`They can potentially be given by personnel with little medical
`training, which provides significant practical and cost benefits, par-
`ticularly in the context of large-scale immunisation programmes
`in the developing world [42]. This route can also, in theory, elicit
`both mucosal and humoral immunity, offering advantages against
`diseases contracted via mucosal surfaces [43]. However, there
`are also a number of drawbacks. The live attenuated viruses in
`oral poliomyelitis vaccine (OPV) can revert to virulence, causing
`vaccine-associated paralytic poliomyelitis (VAPP) in the vaccinated
`child or their close contacts, particularly in the immuno-depressed
`subjects [44]. This has resulted in a shift from the use of OPV
`to the use of injectable poliomyelitis vaccine containing inacti-
`vated virus, especially in countries that have eliminated naturally
`occurring polio [45]. Oral vaccines have to overcome problems
`associated with poor absorption or degradation within the diges-
`tive system that may require the concomitant administration of
`antacids [46]. Finally, to date no mucosal vaccine adjuvant is
`available with the required safety and efficacy [44]. Such safety
`issues were encountered with an intranasal adjuvant-containing
`influenza vaccine that was associated with the occurrence of facial
`palsy [47].
`
`3. Skin physiology and immunology
`
`3.1. Skin anatomy
`
`An increasing understanding of skin physiology means that this
`organ is now recognized as a potentially excellent site for vacci-
`nation. It is easily accessible and has both cellular and humoral
`immune system components. The skin is comprised of three
`primary layers from outside to inside: epidermis, dermis and
`hypodermis (Fig. 1). Vaccine delivery into these layers is known,
`respectively as transdermal, intradermal and subcutaneous vacci-
`nation.
`The epidermis is the outermost layer of the skin and acts as a
`physical barrier, preventing chemicals and micro-organisms from
`entering the body and stopping excess body water loss. This layer
`is generally 50–200 ␮m thick, depending on the body region and
`has four sublayers: the outermost stratum corneum, below which
`is the stratum granulosum, the stratum of Malpighii or spinosum,
`and finally the stratum basale (or germinativium). Keratinocytes
`constitute approximately 90% of the epidermis; the remaining cells
`are melanocytes and Langerhans dendritic cells. While Langerhans
`cells account for only about 1% of cells, they cover nearly 20% of
`the surface area due to their horizontal orientation and long pro-
`trusions [48]. The epidermis does not have its own blood supply;
`cells in lower levels receive nutrients via diffusion from blood cap-
`illaries in the dermis. Cells form within the stratum basale and
`migrate through to the stratum corneum where they are sloughed
`off. During this process, which lasts approximately 30 days, cells
`become keratinised. It is the stratum corneum with its layer of ker-
`atinised cells that is so important in the skin’s role as a physical
`barrier. The stratum corneum is also the greatest barrier to effec-
`tive transdermal vaccine delivery. To be effective, it is critical that
`the vaccine be delivered to the Langerhans cells. This implies that
`a transdermal delivery method must include a system to disrupt,
`either physically or chemically, the stratum corneum, allowing anti-
`gens to pass through this layer and onto the Langerhans cells for
`antigen presentation.
`
`Fig. 1. Skin anatomy. Skin thickness was measured by 20 MHz ultrasound echography in usual body sites for vaccine delivery [55].
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`The dermis lies beneath the epidermis and is comprised of col-
`lagen, elastin and reticular fibres. It is a tough, flexible and very
`elastic layer between 1.5 and 3 mm thick, arranged into two sub-
`layers: the papillary dermis and the reticular dermis. The papillary
`dermis is the upper and the thinner of the two and consists of
`loosely arranged connective tissue. The reticular dermis consists
`of a network of horizontally running collagen fibres, connective
`tissue, and a very dense network of capillary blood and lymphatic
`vessels in which dermal dendritic cells, monocytes, polymorphonu-
`clear lymphocytes and mast cells circulate. Lymphatic vessels drain
`the dermis to satellite lymph nodes. Fibroblasts are the most abun-
`dant type of cells in the dermis. Endothelial cells forming the wall of
`blood and lymphatic channels play a key role in the inflammatory
`and immune cells as well as fluid movements in dermis. Endothelial
`cell contribute to various physiological effects in the skin including
`vasodilation increased permeability, increased vasomotion, pro-
`duction of cytokines converting adherent leukocytes into mobile
`cells, angiogenesis and trafficking of antigen presenting cells, T and
`B effector cells [49].
`The hypodermis, or subcutaneous tissue, is a layer of loose con-
`nective tissue and elastin located immediately beneath the dermis.
`The arteries and veins that drain the skin dermis issue from the
`vascular plexus located in subcutaneous tissue. When entering the
`skin dermal arteries form a dense network of capillary loops in the
`papillary dermis layer. Numerous lymphatic vessels draining the
`skin dermis pass through the hypodermis before reaching draining
`lymph nodes. The hypodermis is the main tissue for fat storage.
`Anatomical variations of skin according to body site, gender,
`age and ethnic origin are important parameters to consider for
`dermal vaccination. For example, skin thickness – an essential
`parameter for intradermal vaccination – is known to vary signif-
`icantly between different parts of the body [50–54]. In a recent
`study designed specifically to investigate skin thickness at the usual
`areas for intradermal vaccination (deltoid, suprascapular, upper
`abdomen and thigh) in groups of people of different age, sex and
`ethnic origin, skin was found to be on average 1.5 mm thick at the
`thigh and between 1.8 mm and 2.7 mm at the other body sites,
`with no major differences between the different population sub-
`groups considered [55]. Indeed skin thickness was found to vary
`less between people of different body mass index, age, gender and
`ethnic origin than it did between different body sites on people
`with the same demographic characteristics [55]. The average thick-
`ness of the skin appears to remain relatively unchanged in the age
`range of 18–70 years [56]. Skin is thinner in women than in men
`
`by 0.06–0.2 mm, but minimal skin thickness in women is greater
`than 1.5 mm in all cases [55–58]. The absence of a significant effect
`of the ethnic origin on the skin thickness at deltoid, and supras-
`capular body sites has also been reported in studies in US [54]
`and Japan [59]. This consistency in skin thickness across people
`with different demographic profiles represents a major advantage
`over classic intramuscular vaccination as, to correctly perform an
`intramuscular vaccination, it is important to select the appropriate
`needle length based on considerations of the muscle mass of the
`injection site, the amount of subcutaneous fat, and the weight of
`the patient [52,60].
`
`3.2. Skin and immune response
`
`The skin generates both innate (antigen non-specific response
`without immunological memory) and adaptive immune responses
`(antigen specific response with immunological memory), Table 1.
`While the adaptive response is primordial in generating a response
`to vaccination and generally becomes more effective with each
`successive encounter with an antigen [63], innate immune mech-
`anisms also play a key role as they are activated first in response to
`pathogen invasion or contact with foreign antigens. The key group
`of immune cells involved in the skin’s innate immune response is
`dendritic leukocytes: Langerhans cells in the epidermis and dermal
`dendritic cells in the dermis [63–68].
`In 1868 Paul Langerhans, driven by the interest in the anatomy
`of skin nerves, identified a population of dendritically shaped
`cells in the suprabasal region of the epidermis after impregnat-
`ing human skin with gold salt [65]. These cells are known as
`antigen-presenting cells, called Langerhans cells after their discov-
`erer. Although substantial numbers of dendritic leukocytes reside
`and circulate in the skin, only some of them are Langerhans cells,
`the majority being phenotypically different from Langerhans cells
`and generically called dermal dendritic cells [64]. Both Langerhans
`cells and dermal dendritic cells are bone marrow-derived leuko-
`cytes highly specialized in antigen-presenting properties. These
`cells, in association with macrophages recruited from circulating
`blood and infiltrating dermis tissue, are the gatekeepers of the
`immune systems. Compelling evidence exists that Langerhans cells
`and dermal dendritic cells, as members of the family of antigen-
`presenting cells play a pivotal role in the induction of adaptive
`immune response against pathogens and any other antigens and
`haptens which compromise the host homeostasis. The immuno-
`genic potential of antigen-presenting cells from both epidermis and
`
`Table 1
`Innate and adaptive skin immune system
`
`Functional components of skin immune system
`
`Cells of the skin immune system
`
`Innate
`Reactive oxygens
`Ligands Toll receptors
`Heat shock proteins
`Cytokines: IL-1, IL-6, TNF␣
`Chimiokines: CC, CXC
`Adhesion molecules
`Neuropeptides
`Eicosanoids
`Immune tolerance: T regulator, IL-10, TGF␤
`
`Adaptive
`Antigen recognition and presentation
`Cytokines: IL-1, IL-6, TNF␣
`IL-2, IL-12, IL-18, INF␣
`Chimiokines: CC, CXC
`Adhesion molecules
`T and B lymphocyte responses with high affinity effectors
`
`Resident
`
`Recruited
`
`Recirculating
`
`Keratinocytes
`Endothelial cells
`Langerhans cells
`
`Monocytes
`Granulocytes
`
`Natural killer cells
`Dendritic cells
`
`Mast cells
`Macrophages
`T lymphocytes
`Dendritic cells
`
`Mast cells
`Epitheloid cells
`T lymphocytes
`B lymphocytes
`
`Pro-monocytes
`
`T lymphocytes
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`dermis tissues is regulated by cell surface receptors triggered by lig-
`ands secreted or presented by other somatic cells, or alternatively,
`by microbial products (danger or competence signals) [66]. Dan-
`ger signals are represented for example by DNA rich in CpG repeats
`in bacteria, or other Toll-like receptor ligands [66,67]. Many of the
`receptor structures that sense such signals are essential compo-
`nents of the innate immune system. They are used to recognize
`molecular patterns demarking infectious nonself, as well as normal
`and abnormal self. The response to danger signals leads to tissue
`perturbation as evidenced by increased secretion of GM-CSF, TNF-
`␣, IL-1 by keratinocytes and other skin cells. The antigen-presenting
`cells that pick up the antigen, process it, and re-express part of it as
`peptide/MHC complex on the surface are also profoundly affected
`by danger signals or danger signal-induced cytokine. The alter-
`ations of Langerhans cells and dermal dendritic cells include the
`increased expression of MHC antigens, co-stimulatory molecules,
`and cytokines such as IL-1␤, IL-6, IL-12, as well as the enhanced
`emigration of these cells from the skin to the paracortical area
`of draining lymph nodes. At this site, the skin-derived dendritic
`cells provide the activation stimuli to na¨ıve resting T cells sur-
`rounding them. This occurs in an antigen-specific fashion and
`thus results in the expansion of the respective clone(s) to mature
`into extremely potent immuno-stimulatory cells that controls the
`development of adaptive immunity [68]. Some evidence also exists
`that dermal dendritic cells that have not received such compe-
`tence signals are not stimulatory, but actively down regulate or
`prevent potentially harmful immune responses by tolerizing T cells
`or by inducing T cells with suppressive properties (regulatory T
`cells) [69,70]. Several studies have indicated that protein or pep-
`tide delivery through the epidermis can lead to production of
`specific IgE due to a Th2-regulated response as well as immune
`tolerance status by regulatory T-cells [71–75]. As a consequence,
`in addition to the immuno-surveillance activity, the skin immune
`system secures the homeostasis of the skin integument by prevent-
`ing the development of exaggerated, tissue destructive immune
`responses against per se innocuous moieties such as auto-antigens,
`allergens and haptens. Interestingly, a clinical study in healthy
`adults evaluating epidermal delivery of live-attenuated measles
`vaccine through disrupted stratum corneum relative to intra-
`muscular route strongly suggests that resident antigen-presenting
`cells in epidermis were unable to boost the antibody response
`[76].
`
`3.3. Skin immune response and sun exposure
`
`It has been suggested that sun exposure may affect local
`or systemic immune responses through release of inflammatory
`mediators [80]. The question may be raised whether such effects
`may particularly influence responses to intradermal immunization.
`UV radiation below 290 nm is absorbed by the ozone layer in the
`stratosphere and does not reach the Earth’s surface. The UVB wave-
`lengths range from 280 to 315 nm and from 315 to 400 nm for UVA.
`Solar UV radiation is 95–98% UVA and 25% UVB. The most obvious
`clinical effects of the sun exposure are sunburn and tanning, but
`include more complex biological effects such as DNA photo dam-
`age, immunosuppression and vitamin D synthesis. These biological
`effects are radiation dose-dependent and the amount of UV radia-
`tion penetrating the epidermis and dermis is the critical factor. For
`instance, the stratum corneum of the epidermis is able to dissipate
`90% of UVB radiation, and no more than 10% of UVB reaches the
`dermal-epidermal junction area. In addition, melanin present in
`high concentration in the epidermis acts as UV radiation filter. The
`biological effects of UVB on the skin immune response was actively
`investigated, the main changes being the depletion of Langerhans
`cells, the increased recruitment of macrophages in skin dermis and
`
`the release of pro-inflammatory cytokines such as TNF-␣, IL-10,
`TGF-␤, ␣-MSH and CGRP [77–80].
`
`4. Clinical experience, techniques and devices for
`intradermal vaccination
`
`Considerable clinical research has been conducted to compare
`the intradermal route with other routes of vaccine delivery (Table 2)
`and into new techniques for intradermal delivery to eliminate some
`of the problems associated with the methods currently available.
`This section will describe the available techniques, as well as those
`in clinical research or earlier development.
`
`4.1. Current methods
`
`4.1.1. Mantoux injection technique
`The standard intradermal
`injection technique consists of
`stretching the surface of the skin and inserting the tip of a 27G,
`3/8 in. short bevel needle attached to a plastic 1 ml disposable
`syringe. The needle is inserted bevel upwards, almost parallel to
`the skin surface and vaccine is injected slowly into the uppermost
`layer of the skin [81]. If placed properly, there is considerable resis-
`tance to injection and a raised papule immediately appears which
`can cause pain during injection. The correct placing of the needle-
`tip in the dermis is critical to avoid fluid injection difficulties due
`to inelastic skin or age-related anatomic changes [53,58,61,62,81].
`This technique, introduced by Charles Mantoux over 95 years ago as
`a diagnostic skin test for tuberculosis disease [2] has not been pur-
`sued for the vast majority of vaccines due to its inherent difficulties.
`This technique is associated with a poor consistency of the injected
`volume, due in part to the difficulty of performing it correctly, but
`also to the unavoidable leakage of vaccine from the injection site,
`fluid wastage when filling disposable syringes and when purging
`the needle of air, and the large dead volume of the assembled dis-
`posable needle and syringe [82–84]. In many cases, intradermal
`vaccination according to Mantoux has proved to be comparably
`immunogenic to the comparator even at a reduced dose, due to the
`skin’s ability to generate a strong immune response [3,27,85–91].
`This comparable efficacy at lower doses suggests that intradermal
`injection can have considerable benefits over other injection tech-
`niques when mass vaccination is necessary, as the reduced dose
`means improvement of vaccine availability and of health economic
`ratios if an injection system that is easier to practice becomes avail-
`able.
`
`4.1.2. Bifurcated needle
`While working for Wyeth Laboratories in 1965, Benjamin Rubin
`developed his two-pronged needle for smallpox vaccination by skin
`scarification by grinding the eyelet of a sewing machine needle into
`a fork shape. This was the first example in modern medical history
`of a device specifically designed to deliver vaccine intradermally.
`The small space between the two tines was able to hold about 2 ␮l of
`vaccine solution but only part of this volume that was actually intro-
`duced into the skin and precise control of dose delivery accuracy
`was not possible. The needle was jabbed into the papillary dermis
`skin layer, yielding a spot of blood. Bifurcated needles with features
`for protecting health-care workers against needle-stick injuries are
`commercially available.
`
`4.1.3. Multipuncture
`The percutaneous BCG delivery using single or multipunc-
`ture devices was introduced by Sol Roy Rosenthal in 1939, and
`developed worldwide by the Merieux Institute [92–94]. The mul-
`tipuncture unit is a cylinder-like device with small needles, 1 mm
`length, which should be pressed firmly against the skin, within the
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`area where the vaccine dose is spread on the skin surface. In con-
`trast with the intradermal technique, the percutaneous method
`does not allow a precise estimation of the dose injected in the
`epidermis or dermis skin layers. As a consequence, the num-
`ber of live attenuated bacilli given per delivery is highly variable
`[95–97].
`
`4.1.4. Needle-free jet injection
`Needle-free jet injection uses a gas to force a liquid or powder
`vaccine through the skin, delivering it intradermally, intramus-
`cularly or subcutaneously [98,99]. These devices can either be
`multidose or monodose. The latter are based either on entirely dis-
`posable devices or on a re-usable system with single dose cartridges
`[99]. This technology has been available since the 1940s and was
`used for several mass vaccination programmes [98–101]. However,
`when an outbreak of hepatitis B linked to the use of multidose
`jet injectors revealed the risk of contamination by the aspiration
`of small amounts of blood into the nozzle during the vaccination
`procedure, their use was discontinued by the WHO and health
`authorities around the world [101]. Recent research has focused
`on improved devices with single-use nozzles to remedy this prob-
`lem [102] and on developing standardised single-dose cartridges
`that could potentially make monodose injectors financially viable
`for mass vaccination [99].
`Studies have shown that vaccination via jet injection can elicit
`an immune response comparable to or better than other delivery
`methods. A comparison of jet injection with the standard needle-
`based techniques for five vaccines found that for four of them,
`jet injection had equivalent, if not improved efficacy [97,98,104].
`Successful intramuscular or subcutaneous jet injection has been
`demonstrated with a wide range of vaccine technologies includ-
`ing DNA coated nanoparticles [105], naked DNA [106], inactivated
`virus, polysaccharide–protein conjugates, toxoids, and whole cell
`vaccines [103]. In one study with tetanus toxoid vaccine, jet injec-
`
`tion was found to be less immunogenic than the standard needle
`and syringe technique in subjects younger than 40 years, although
`the techniques gave equivalent results in those aged over 40 [102].
`In this study the jet injector delivered the vaccine into the deep
`subcutaneous layer.
`In contrast to needle-based vaccination, jet injection results in a
`wide distribution of vaccine in the dermis, hypodermis and muscle,
`depending on jet injector settings and individual body character-
`istics. This distribution effect means that jet injection may face
`some problems when used to specifically deliver a precise dose
`of vaccine into the dermis, but is thought to lead to the increased
`immune responses observed [102,108]. It is also possible that the
`larger immune responses are a result of increased inflammation
`with jet injectors, leading to the recruitment of more immune cells
`to the injection site [107,108]. Indeed, while it has been suggested
`that jet injection results in less tissue damage than with needles
`as the injected liquid follows the path of least resistance [109] a
`number of studies refute this finding that jet injection (whether
`intradermal, intramuscular or subcutaneous) causes more adverse
`events including swelling, erythema, induration, haematoma and
`pain [98,103,110,111]. In a comparison of DNA vaccine delivered
`either by intramuscular injection or by intradermal jet injection, or
`a combination of the two, jet injection caused approximately twice
`as many adverse events. Despite this, the majority of subjects in this
`study stated that they preferred the jet injection to needle injection
`at the time of injection [106].
`Jet injection with single use nozzles or single dose cartridges
`removes the risk of needle stick injuries after vaccine delivery and
`associated risk of blood borne transmission of diseases through
`contamination. In addition, the nature of jet injection is such that a
`large number of vaccines (in excess of 600 per hour) can potentially
`be treated in a short period of time [102]. This makes jet injectors an
`attractive technology for mass parenteral vaccination programmes.
`It has indeed been used in a number of mass campaigns for small-
`
`Table 2
`New technologies targeting vaccine delivery into the skin
`
`Technology
`
`Prefilled microinjection
`system
`
`Non-prefilled microinjection
`needle
`
`Company
`
`BD Medical Pharmaceutical Systems/Sanofi Pasteur
`
`BD Medical Pharmaceutical Systems/Oncovax
`
`Nanopass, Micro-Pyremidal Needle
`Georgia Institute of Technology
`Debiotec
`
`Topical Patch with cholera toxin adjuvant
`
`Iomai Corporation
`
`Topical Patch
`
`Transdermal with electroporation
`
`Solid microneedle array
`
`Vaxin, Inc.
`Ichor Medical Systems, TriGrid
`
`Cyto Pulse: Derma Vax, Easy Vax
`Inovio, MedPulser DNA Delivery System
`
`Genetronics Biomedical Corporation
`Alza Corporation, Macroflux
`
`Biovalve, Micro-Trans
`Epidermal Powder Immunization
`
`Jet injector (Powder)
`
`PowderMed
`
`Jet injector (liquid)
`Skin abrasion
`Skin permeation by low frequency (20 kHz)
`ultrasound associated with topical patch
`Nanoparticle and microparticle
`formulation
`
`Bioject
`BD Technology, Microenhancer Array
`Sonics & Materials, Newtown, CT
`
`Chiron
`Various
`
`Vaccine (development phase)
`
`Trivalent inactivated seasonal
`influenza (clinical phase 3)
`Cancer vaccine (clinical phase 2)
`
`Flu (clinical phase 1)
`Pre-clinical
`Pre-clinical
`
`Trivalent inactivated seasonal
`influenza (clinical phase 2) Travelers’
`diarrhea (clinical phase 2)
`
`Pre-clinical
`