Devices and methods for enhancing the immunogenicity of intradermal vaccination

Abstract

Devices and methods are described for utilizing occlusive dressings in combination with topical medicaments to enhance the efficacy of vaccines. The occlusive dressing delivers a defined dose of a topical medicament that enhances the immune system responsiveness of the vaccine to the vaccination site and provides a barrier that maintains the topical medicament layer on the skin for a desired period of time while also providing a port through which the immunization composition can be administered. In some embodiments, the occlusive dressing comprises a wound dressing used to cover the injection site after vaccination.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 419,895, filed November 9, 2016. These and all other extrinsic materials referenced herein are incorporated by reference in their entirety. In the event of inconsistent usages between this document and those references, the definitions provided herein are considered controlling. TECHNICAL FIELD

[0002] The field of the application is devices and methods for enhancing the efficacy of intradermally administered vaccines, particularly influenza vaccines. BACKGROUND

[0003] The background description includes information that can be useful in understanding the present application. It is not admitted that any information provided herein is prior art or related to the presently claimed application, nor that any publication or patent application or patent cited herein is prior art.

[0004] Annual epidemics of influenza (flu) result in a significant disease burden and excessive mortality due to global complications. Vaccination against influenza is considered the most effective way to reduce the disease burden and mortality due to flu and to prevent further epidemics in humans. Several formulations of influenza vaccines are currently available for use, including inactivated whole virus vaccines, "split" virus or subunit vaccines without virions, recombinant hemagglutinin (HA) vaccines, and live attenuated influenza virus vaccines (Centers for Disease Control and Prevention 2013). All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In the event of inconsistent usages between this document and those references, the definitions provided herein are considered controlling, and the definitions in the cited references are not to be applied.

[0005] Commercial influenza vaccines can have low immunogenicity and can not respond to rapidly emerging influenza strains within a short time frame. The poor immunogenicity of commercial vaccines is well known and particularly impacts the elderly and young children. Meta-analysis estimates the overall efficacy of these vaccines to be approximately 70% (Osterholm et al., 2012). These issues limit the benefit of influenza vaccines for elderly and young populations, which have a high risk of hospitalization for influenza infection and its complications, and most need vaccine protection.

[0006] Recently, attempts have been made to improve vaccine immunogenicity, including intradermal route vaccination (Huang 2012a; Huang 2012b) and administration of new vaccine adjuvants that function by recruiting pattern recognition receptors (PRRs) in the innate immune system, including Toll-like receptors (TLRs), retinoic acid-inducible gene-like receptors, and NOD-like receptors (Kasturi et al., 2011; Pashine et al., 2005; Demento et al., 2009). For example, imiquimod is a synthetic agonist of Toll-like receptor 7 that is used as an immune response modifier and is currently used to treat genital warts, superficial basal cell carcinoma, and actinic keratosis. In a mouse model, the immunogenicity of an influenza vaccine was enhanced by administration of imiquimod cream, and the local immune enhancement indicated that imiquimod could potentially be used as a vaccine adjuvant to improve immunogenicity (Zhang et al., 2014). In a clinical trial in older subjects, pre-treatment with topical imiquimod significantly accelerated, enhanced, and prolonged the immunogenicity of influenza vaccination relative to the vaccine-only group, with early and better seroconversion rates maintained through 1 year, and fewer people hospitalized for influenza or pneumonia (Hung et al., 2014). In a phase 2b / 3 trial, in young, healthy individuals, local administration of imiquimod prior to intradermal trivalent influenza vaccine significantly improved immunogenicity against vaccine influenza strains and increased immunogenicity against non-vaccine strains (Hung et al., 2016). However, conducting such pre-treatment, as well as vaccination, is inconvenient in a clinical setting and compromises the use of the method. This is especially true in mass vaccination programs, and is further complicated when additional benefits are achieved by maintaining the pre-treatment drug at or near the injection site for an extended period of time after immunization.

[0007] Thus, there remains a need for safe and convenient devices and methods for enhancing the efficacy of intradermal vaccination. SUMMARY

[0008] The present inventive subject matter provides devices, systems, and methods in which a closed dressing for delivery of a topical medicament is provided that enhances the effect of an immunological composition delivered by injection. The closed dressing includes a barrier that covers the applied topical medicament and a central aperture through which an immunological injection is administered. The topical medicament can be applied to the surface of the skin prior to application of the closed dressing, or to the skin-facing surface of the closed dressing. The closed dressing can be in a layered configuration, and include a frame layer and a barrier layer. In some embodiments, the closed dressing can include a portion that covers the central aperture after administration of the injection. The closed dressing can include a wound dressing placed to cover the injection site after immunization. In some embodiments, the closed dressing can be held in place by a separate wound dressing. Embodiments of the inventive concept can include a measuring device for aliquoting a desired amount of the topical medicament. Such a measuring device can be used to administer or apply the topical medicament.

[0009] The various objects, features, aspects and advantages of the present subject matter will become more apparent from the following detailed description, along with the accompanying drawings in which like reference numerals represent like parts. BRIEF DESCRIPTION OF DRAWINGS

[0010] Figure 1 Figure 1 A front view of a device (i.e. Vaccine-Grid TM ) of the present subject matter is schematically depicted.

[0011] Figure 2 Figure 2 A cross-section of the device shown in Figure 1 is schematically depicted, showing the layered construction.

[0012] Figure 3 Figure 3 An exploded view of the device of Figure 1 is schematically depicted. All four layers are aligned to the center of the device.

[0013] Figure 4 Figure 4 A procedure for using the device of the present subject matter in an immunization method is depicted.

[0014] Figure 5A and 5B Figure 5A and Figure 5B An alternative embodiment of the device is schematically depicted, having attached "wing" portions that can be used as a dressing or bandage. Figure 5A A front view of the device is schematically depicted. Figure 5B An exploded view of the device is schematically depicted.

[0015] Figure 6 Figure 6 The positioning of the adhesive layer in the device of the present subject matter as shown in Figure 5A and 5B is depicted.

[0016] Figure 7 Figure 7 A procedure for using the device of the present subject matter with a dressing is depicted.

[0017] Figures 8A to 8D Figure 8A An alternative embodiment of the device of the present subject matter is shown, configured for use with an external bandage. Figure 8B An exploded view of such a device is shown. Figure 8C and 8D The steps of a method for using such a device with an external bandage are schematically depicted. ​​​​​​​​

[0018] Figure 9 : Figure 9 Embodiments of measuring and application tools for use with other devices of the inventive concept are depicted.

[0019] Figure 10A and 10B : Figure 10A A method of use is schematically depicted using an applicator as shown in Figure 9 A method of use is schematically depicted using an applicator as shown in Figure 10B Photographs (I to VI) showing a stepwise series of use of an applicator of the inventive concept with a closure film are provided.

[0020] Figure 11A and 11B : Figure 11A and 11B Embodiments of kits of the inventive concept are depicted. Figure 11A Kits comprising instructions for use of a simplified version of a device of the inventive concept are depicted. Figure 11B Kits comprising instructions for use of a local medicament measuring device and applicator and for use of a vaccine-enhancing device of the inventive concept are depicted. DETAILED DESCRIPTION

[0021] The inventive subject matter provides devices, systems, and methods in which a closure device or dressing comprising an access feature is provided that applies a desired amount of an immune-enhancing agent (e.g., a toll-like receptor 7 agonist, and / or a toll-like receptor 9) to a skin area that receives an intradermal vaccination. After a suitable period of time, the access feature is used (e.g., by a hole being punched or removed) to allow access to the area of the skin surface for delivery of the intradermal vaccination. In some embodiments, a portion of the closure device (e.g., a "wing") can be deflected to provide a dressing over the access feature after the immunization. In other embodiments, the dressing can be provided as a separate item. After another suitable period of time (e.g., a period of time suitable to provide an enhanced immunity post- enhancement), the device can be removed. The closure device can be configured to provide the immune-enhancing agent to the site of the immunization, to an area surrounding the site of the immunization, or both. In some embodiments, the device is self-adhesive to the skin surface. In other embodiments, the closure device can be applied and / or affixed to the skin surface using a second device (e.g., a bandage or dressing).

[0022] In some embodiments, numerical values expressed in describing and claiming certain embodiments of the present application are to be understood as being modified in some instances by the term "about." Accordingly, in some embodiments, numerical parameters expressly recited in the written description and claims are approximations that can depend upon the specific embodiment in which the skills are practiced. In some embodiments, numerical values are approximations that can depend upon the accuracy of measurement as taught or are the permissible variation in the respective testing measurement techniques. While the exact amounts required will vary depending on the specific embodiments, the numerical values presented in some embodiments of the present application can include some error resulting from the standard deviation found in their respective testing measurements.

[0023] As used in the description of the application and the following claims, the terms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Also, as used in the description of the application, the term "in" includes "in" and "on" unless the context clearly dictates otherwise. The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of the elements of the present application, the inventive subject matter is intended to be interpreted to include all possible combinations of the elements introduced across all embodiments. Thus, if one embodiment introduces elements A, B and C, and a second embodiment introduces elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C or D, even if not explicitly disclosed.

[0024] As used herein, and unless the context dictates otherwise, the term "coupled to" is intended to include both direct coupling (in which two elements that are coupled to each other contact each other directly) and indirect coupling (in which at least one additional element is located between the two elements). Therefore, the term "coupled to" and "coupled with" are used synonymously.

[0025] It will be appreciated that the disclosed technology provides a number of advantageous technical effects, including providing methods and devices for increasing the efficacy of intradermal vaccination in a safe, convenient and easy to use manner in a clinical setting, particularly mass vaccination programs. In some embodiments, intradermal vaccination can be performed prior to or after topical application of an immunopotentiating drug to the skin. It will also be appreciated that in the methods and devices of the inventive concept, the injection site can be separated from the topical composition and thus can remain sterile during or after the intradermal injection procedure. In addition, the topical compositions including the immunopotentiating drug can be protected from clothing and the environment, such that they remain in place for an extended period of time after injection until the desired immunogenicity is achieved.

[0026] While the discussion in this application can focus on vaccination against influenza, the inventors contemplate that the devices and methods of the inventive concept can be used with any vaccine composition suitable for subcutaneous, intradermal, subdermal, intramuscular, and / or intravenous use. Such vaccine compositions can be against pathogens, such as viruses, bacteria, fungi, and / or parasites. Suitable viral vaccines can be against influenza virus, hepatitis virus (such as hepatitis A and / or hepatitis B), and / or viruses that cause respiratory infections. In preferred embodiments, the viral vaccine is against influenza virus. In some embodiments, the vaccine composition administered can be against a disease not caused by a separate pathogen. For example, the devices and methods of the inventive concept can be applied to therapeutic vaccines used in the treatment of cancer. The devices and methods of the inventive concept can also be used to apply pharmaceutical preparations for treating diseases that respond and / or require immunomodulation. Such diseases include allergic reactions, multiple sclerosis, and Alzheimer's disease.

[0027] The following discussion provides many exemplary embodiments of the inventive subject matter. Although each embodiment represents a single combination of the inventive elements, the inventive subject matter contemplates all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter also contemplates other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

[0028] The present invention provides a closed device and method that enhances the immune effect. This is achieved by providing a closed device that simplifies safe and effective local administration of a composition comprising an immune-enhancing drug at or near (e.g., around) the site of vaccine injection. Such an immune-enhancing agent can be an aluminum-based salt, such as alum, aluminum phosphate, and / or aluminum hydroxide. In some embodiments, the immune-enhancing agent can be an organic compound, such as squalene. In some embodiments, a suitable immune-enhancing agent can be a toll-like receptor agonist, such as a toll-like receptor 7 agonist and / or a toll-like receptor 9 agonist. In preferred embodiments, the immune-enhancing agent can be imiquimod. To avoid potential infection during injection and to allow time for tissue penetration, the local composition is preferably applied at and / or around the vaccination site for a period of time (e.g., 1 to 2 hours) before the vaccine is injected, and it can be necessary to avoid the effects of clothing, accidental contact, and other environmental factors during this period.

[0029] In practice, this method is time-consuming and prone to error. Suitable application can require an additional step of cleaning the site of residual local composition before injection, and can suffer from lack of compliance (even from medical professionals). For example, early removal of the local composition comprising the immune-enhancing agent (e.g., due to limited personnel in a clinical setting) can compromise the immune-enhancing effect on immunogenicity.

[0030] In some embodiments of the inventive concept, the applicator can deliver a fixed or selectable volume of a topical preparation (e.g., a cream, powder, paste, ointment, lotion, liquid, suspension, foam, and / or gel) onto at least a portion of the inventive concept device that subsequently contacts the skin surface at which immunization is desired. Alternatively, the skin at or around the desired immunization site of the individual to be immunized can be provided with such a volume of topical preparation. The volume of the topical preparation can be selected to provide sufficient coverage at and / or around the immunization site in order to enhance the immune response to the immunogen provided. It will be appreciated that the volume of the topical preparation can be varied to accommodate the nature of the vaccine and / or the characteristics of the individual to be immunized (e.g., age, sex, size, body composition, underlying health conditions, previous disease states, etc.). In some embodiments, the topical preparation can be provided as part of the device, e.g., as a pre-applied layer that contacts the skin at the time of application. In such embodiments, the dosage of the topical preparation can be controlled or adjusted by selecting a device of appropriate size. Alternatively, in some embodiments, the topical preparation can be provided as a pre-filled dose or bolus that is extruded onto the applicator and / or onto the area of the skin of the subject to be immunized. In some embodiments, such an applicator can be sized to provide a desired amount of the topical preparation, and / or can include indicia that allow the user to select a desired amount of the topical preparation.

[0031] The devices and methods of the inventive concept can utilize or support the use of a preparation comprising a toll-like receptor 7 agonist and / or a toll-like receptor 9 agonist as an immune enhancer. Suitable toll-like receptor agonists include imidazoquinoline derivatives (e.g., imiquimod and / or resiquimod), guanosine analogs (e.g., loxoribine), pyrimidine analogs (e.g., bromo-pyrimidine), phosphonic acid derivatives, and 8-oxoadenine derivatives and their carboxylate esters. In preferred embodiments, the immune enhancer is imiquimod, which can be provided as a topically-applied lotion, cream, or gel. Such an immune enhancer can be provided in an applicator used in conjunction with the inventive concept device, or can be incorporated into one or more skin-contacting portions of the provided device.

[0032] Topical compositions suitable for use with the inventive concept occlusive devices can include an immune-enhancing drug (such as imiquimod) that can be applied to an area at and / or near the vaccination site. In some embodiments of the inventive concept, the occlusive device provides or is equipped with a dispensing or measuring device that includes a reservoir sized to include a suitable amount of the topical composition (e.g., 1 cm to 10 cm x 1 cm to 10 cm) that surrounds the desired vaccination site after application to the individual to be vaccinated. The reservoir area for the topical composition can have an area that covers greater than 1 cm 2 , for example up to 8 cm 2or larger area shapes. Such reservoirs can have any suitable configuration. For example, such reservoirs can be circular, oval, square, rectangular, polygonal, and / or irregular. Such reservoirs can have a minimum dimension of about 1 cm and a maximum dimension of up to 8 cm. The reservoirs can be made of any suitable material that is non-reactive with the immunopotentiating drug stored therein, e.g., a polymer such as polyethylene, polypropylene, or silicone. In some embodiments the reservoirs can include additional features to enhance the stability of the immunopotentiating drug, e.g., impermeability to oxygen, ability to block UV and / or visible light, etc.

[0033] Embodiments of the inventive concept can include an adhesive-bearing portion that allows the occlusive device to adhere to the skin during use. In some embodiments, the adhesive-bearing portion is coupled to the reservoir. In other embodiments, the adhesive-bearing portion is provided as a separate piece, e.g., as a tape or bandage that is applied to the reservoir when in use. The adhesive-bearing portion can be made of any suitable flexible and supportive material, such as a polymeric sheet, a polymeric mesh, a woven fabric (natural or synthetic), or a nonwoven fabric (natural or synthetic). In preferred embodiments, at least a portion of the adhesive-bearing portion allows free passage of air (i.e., is breathable) in order to promote comfort and skin integrity when the device is in use. The adhesive-bearing portion can include a surface that is applied to the skin when in use. At least a portion of this skin-facing surface can include a pharmaceutically compatible adhesive that provides a transient bond to the skin surface. Such transient bond should be stable for 5 minutes up to 48 hours after application to the skin. In some embodiments, the occlusive device can be provided with a removable (e.g., peelable) covering that protects the adhesive prior to application.

[0034] Some embodiments of the inventive concept incorporate a bandage or dressing that can be used to cover the puncture caused by vaccination. Such a bandage or dressing can be coupled to or provided by a portion of the device. For example, a device of the inventive concept can include tabs or wings that can be folded to act as a bandage or dressing. In other embodiments, a bandage or dressing can be provided as a separate item that is applied after immunization. Such a bandage or dressing can include an adhesive portion, and an absorbent portion, as well as a backing. The backing can be made of any suitable flexible material, such as a polymeric sheet, a polymeric mesh, a woven fabric, a nonwoven fabric, or the like. The absorbent portion can be coupled to the backing and include a material that is suitable for absorbing and / or containing blood and other bodily fluids. Suitable absorbent materials include fabrics, wool, and / or gels made of natural or synthetic materials. In some embodiments, the absorbent material can include a medicament that provides pain control (such as a topical analgesic or anesthetic) and / or promotes healing (such as an antibiotic). The adhesive portion can be an adhesive layer coupled to the backing. Such an adhesive layer can be provided as an adhesive compound applied to at least a portion of the backing or as a layer of a material that incorporates such an adhesive compound and is coupled to the backing.

[0035] Some embodiments of the inventive concept can include a dispensing or measuring device that is suitable for storing and dispensing a topical composition. Such a device can be provided as a reservoir that is sized to hold at least a volume of a topical composition that is suitable for a single use. For example, such a reservoir can be reversibly sealed using a polymeric film or sheet that is reversibly affixed to an opening of the reservoir. Such a dispensing device can include an applicator that facilitates moving the topical composition from the reservoir and applying it to the skin of a subject in need of immunization or to a skin-contacting surface of a device of the inventive concept. In some embodiments, such an applicator can include a marker (e.g., a visible line or similar indicia along its length) that allows for gauging or measuring the amount of topical composition present on the applicator.

[0036] Examples of closure devices of the inventive concept are shown in Figure 1 FIGS. 1-3. As shown, the closure device provides a closure dressing that protects and maintains a drug layer on the skin that enhances the immune response to an injected vaccine. The closure device provides a through hole through which a vaccination can be administered. Figure 1The example shown in FIG. 1 provides a frame (120) that supports a film (140) for protecting a medicament layer. The frame (120) can be constructed from any suitable paper (e.g., paperboard, fiberboard, etc.) or polymer (e.g., polyethylene, polypropylene, nylon, silicone, etc.) and have a sufficient thickness to support the film (140) and other elements of the closure device while being pliant enough to be applied to a skin surface. The film can serve as a barrier layer during use of the closure device. In some embodiments, the frame (120) can include or support one or more tabs (130) that can be used to improve adhesion to a skin surface. The film can be made from a suitable polymeric material (e.g., polyethylene, polypropylene, nylon, silicone, etc.) that provides an environmental barrier (e.g., moisture resistance, etc.) and, in preferred embodiments, is transparent or translucent. The frame (120) can support a through-hole cover (110) for covering a through-hole that extends through the closure device. Such a through-hole can be created by aligning holes in different portions of the closure device.

[0037] In some embodiments, the closure devices of the present inventive concept are constructed in a layered or stratified manner. Referring to FIG. 2, a cross-sectional view of a closure device is shown. As shown, the closure device is constructed from a plurality of layers including a through-hole cover 110, a frame 120, a film (140), and a backing (150). Each of these layers can be constructed from different materials. The layers of the closure device can be connected by any suitable means. For example, the layers can be connected using an adhesive, by melting, by welding (e.g., ultrasonic welding), by crimping or folding, and / or by using connectors (e.g., sutures, stabilizers, etc.). In some embodiments, the connection between two or more layers can be easily broken without the use of tools (e.g., “peelable” layers), allowing one or more layers to be removed or broken away from the main body of the closure device. Such a layered construction facilitates the manufacture of the closure device. Figure 2 As can be seen, it depicts a closure device such as Figure 1 A cross-sectional view of a closure device is shown in FIG. 2. As shown, the closure device is constructed from a plurality of layers including a through-hole cover 110, a frame 120, a film (140), and a backing (150). Each of these layers can be constructed from different materials. The layers of the closure device can be connected by any suitable means. For example, the layers can be connected using an adhesive, by melting, by welding (e.g., ultrasonic welding), by crimping or folding, and / or by using connectors (e.g., sutures, stabilizers, etc.). In some embodiments, the connection between two or more layers can be easily broken without the use of tools (e.g., “peelable” layers), allowing one or more layers to be removed or broken away from the main body of the closure device. Such a layered construction facilitates the manufacture of the closure device.

[0038] Figure 3 Provided are Figure 1An exploded view of the closure device is shown in FIG. 1. As shown, the through-hole cover (110) is centered over the frame hole (125), which is at least approximately centered on the frame (120). The frame hole (125) can be defined by a ring or similarly shaped portion extending from the inner edge of the frame (120). The remaining open space between the edges of the frame (120) defines the frame cutout (127) through which the membrane (140) can be seen. As shown, the membrane (140) includes a membrane hole (145) that is centered with the frame hole (125). The backing (150) similarly includes a backing hole (155) that is centered with the frame hole (125) and the membrane hole (145). This alignment of the holes in the assembled closure device provides a through-hole through which vaccination can be administered.

[0039] In some embodiments, the backing (150) can include an adhesive on the side facing away from the membrane (140) that facilitates adhesion of the closure device to the skin during use. In such embodiments, the adhesive can be covered by a removable or peelable membrane. In other embodiments, the backing (150) can be removed prior to use to expose the surface of the membrane (140) facing away from the frame (120). In such embodiments, the membrane (140) can include an adhesive interposed between the membrane (140) and the backing (150) that facilitates affixing the closure device to the skin of the patient to be immunized. Alternatively, the membrane (120) can be constructed of a material having sufficient traction to adhere to the skin without the need for an adhesive.

[0040] In some embodiments of the inventive concept, the closure device can be provided with a drug that enhances the immune response to the vaccination that has been incorporated into the closure device. For example, such a closure device can include a layer of drug interposed between the membrane (140) and the backing (150) such that removal of the backing exposes the drug. Alternatively, the backing (150) can include a layer of drug applied to the surface facing away from the membrane (140). Such a layer can be covered with a removable barrier during storage, which is removed when the closure device is applied to the patient. In other embodiments, the drug is provided in a separate container or applicator.

[0041] Figure 4 The use of a closure device such as Figures 1 to 3The method of applying the closure device is shown in the figure. From left to right, the backing (1) is removed from the bottom surface of the closure device and then applied to the appropriate immunization area, wherein the through-hole cap is oriented away from the skin (2). In this case, the upper arm is shown, but other sites are suitable. The closure device of the present invention can be supplied in various sizes (e.g., 4cm × 4cm to 10cm × 10cm) and configurations (e.g., square, rectangular, circular, oval, etc.) suitable for different immunization sites and / or different patient body sizes. In some embodiments, a drug that enhances the immune response to the vaccine composition is applied to the skin before the closure device is applied. In other embodiments, such drug is incorporated into the closure device and applied to the skin at the time of application. The closure device may remain in the appropriate position on the skin for a period of time sufficient to allow the drug to provide the desired enhancement of the vaccine administration (e.g., from 30 seconds to 48 hours), or alternatively, the vaccine may be administered immediately.

[0042] To administer the vaccine, the perforation cap (3) is removed to expose the skin area (4) to which immunization will be administered. At this point, a local analgesic may be applied to the exposed area, if necessary. In some embodiments, the lower surface of the perforation cap may include a local anesthetic, such that the anesthetic is applied to the immunized area during device administration. Finally, immunization is administered (e.g., via microneedle, intradermal, subcutaneous, or intramuscular injection). After vaccine administration, the occlusive device may remain in place for a period suitable for enhancing the immune response to the injection (e.g., 5 minutes to 48 hours). In some embodiments, a portion of the occlusive device may be removed. For example, the frame may be removed while the membrane remains in place on the patient. Alternatively, if the occlusive device has been administered for a period sufficient to enhance vaccine efficacy prior to vaccine administration, it may be removed substantially immediately after administration.

[0043] Vaccination inevitably leaves skin trauma, which may result in bleeding or infection. Therefore, some embodiments of the present invention incorporate or support the use of wound dressings. Figure 5A One embodiment of the inventive concept is depicted, wherein the closure device includes a wound dressing (560). Other portions of the closure device may be connected to... Figure 1 This is similar to those closure devices that include a frame (520), a through-hole cap (510), and a membrane (540). In some embodiments, one or more connectors (530) help to hold the closure device in place during use. During use of the closure device, the membrane (540) can act as a barrier layer. A wound dressing (560) can be attached to, or extend from, the outer edge of the frame (520), the membrane (540), or any part thereof of the closure device that remains on the skin during use. Figure 5B Provided Figure 5AAn exploded view of the device in (560). As shown, the wound dressing (560) can include a dressing protection film (565) that is removed prior to application of the dressing. The wound dressing (560) can include an adhesive layer that is covered by the dressing protection film (565) during storage. As shown, the through-hole cover (510) is positioned to occlude the through-hole created by the superposition of the hole in the frame (520), film (540), and backing (550) during storage. In the embodiment shown, the wound dressing (560) is attached to the outer edge of the frame (520) along one edge, which allows the wound dressing (560) to be deflected over the through-hole after immunization.

[0044] As noted above, the closure devices of the present inventive concept can include one or more adhesive layers, strips, or patches that facilitate positioning and use of the device. Such adhesive layers, strips, or patches can be covered by a removable film that provides protection during storage and prior to use. Figure 6 An example of the positioning of such adhesive portions in the closure device shown in Figure 5A and 5B The upper panel shows a “front” view of the closure device (i.e., oriented away from the skin during use), where removal of the peelable film exposes an adhesive layer for securing the wound dressing (610). The lower panel shows a “back” view of the closure device (i.e., oriented toward the skin during use), where removal of the peelable film exposes an adhesive layer (620) that facilitates securing the closure device to the surface of the skin.

[0045] Figure 7 Depictions of the use of the closure devices of the present inventive concept incorporating wound dressings, such as Figure 5A and 5BThe method of using the closure device is illustrated. From left to right, the peelable film (1) is removed from the back of the closure device (2), and then applied to the skin so that the through-hole is oriented over the desired immunization site. As described above, a drug that enhances the immune response to the vaccine to be administered can be placed on the skin prior to application of the closure device. Alternatively, such a drug can be incorporated into the closure device so that it is administered to the skin upon placement. In some embodiments, as described above, the closure device can be left in place for a period of time to allow the drug to take effect. To administer the vaccine, the through-hole cover is removed (3), and optionally a local anesthetic is administered to the vaccination site (4). As described above, in some embodiments, a local anesthetic can be provided on the skin-facing surface of the through-hole cover. After removal of the through-hole cover, the vaccine can be injected (5). After injection, the wound dressing can be prepared for use by removing the film that protects the wound-facing surface (6). The wound dressing can then be placed over the wound created by vaccination by folding, for example, at or near the area where the wound dressing is connected to the device body (7, 8). The adhesive layer applied to at least a portion of the skin-facing surface of the wound dressing can be used to hold the wound dressing in place until the device is removed (e.g., after a period of time sufficient to allow the drug to have a vaccine-enhancing effect, as described above).

[0046] Figure 8A An alternative, simplified closure device of the inventive concept is depicted. Such a simplified closure device is suitable for use with a separate wound dressing or bandage, and can be manufactured at low cost. As shown, the closure device includes a frame (820) that can support one or more tabs (830), and also includes a film (840) and a backing (not shown in this view). The film (840) can serve as a barrier layer during use of the closure device. Alignment of the holes in these layers provides a through-hole (860). Figure 8B An exploded view of the simplified closure device is provided, and shows the arrangement of the frame (820), film (840), and backing (850) portions. As described above, such a closure device can incorporate a drug that enhances the immune response to a vaccine composition, which is positioned so as to be in contact with the skin during use (e.g., on the skin-facing surface of the backing or film). In other embodiments, such a drug is provided from a separate source prior to application of the closure device.

[0047] Figure 8C The use of a simplified closure device such as Figure 8A and 8BThe method of the closure device is depicted. From left to right, the protective film (1) is removed from the device, and the closure device is oriented on the skin and affixed to the skin such that the through-hole is over the desired vaccination site (2). Prior to vaccination, a local anesthetic can be applied to at least a portion of the area of skin exposed by the through-hole (3). As described above, a drug that enhances the immune response to the vaccination can be applied to the skin at the time of application of the closure device (e.g., when the drug is provided with the closure device) or prior to application of the closure device. The closure device can then be held in place for a period of time that allows the drug to enter the tissue at or near the vaccination site. Alternatively, the vaccination can be performed substantially immediately, and the closure device is then maintained in place (as described above). The vaccination can be accomplished by injection (4). In Figure 8D An additional optional step is shown in which, after injection (4), a wound dressing (870) is applied over the wound created by the injection. Such a wound dressing can advantageously aid in maintaining the closure device in place after the vaccination. As described above, in some embodiments, a portion of the closure device (e.g., the frame) can be removed during use, while leaving the remaining portion (e.g., the film) in contact with the skin.

[0048] As described above, in some embodiments, a topical drug is provided as part of the closure device, which is used to enhance the immune response to the vaccine composition. In other embodiments, the drug is provided as a separate part. In such embodiments, it is advantageous to be able to dispense a predetermined or desired portion or dose of the drug, rather than relying on the health care professional's estimate of the amount to apply. Figure 9Examples of such measuring or portioning devices are depicted. Such measuring devices can have a laminar configuration. As shown, the measuring device has a base (930) with a reservoir (940) that can be created by pressing into a portion of the base. Alternatively, the reservoir (940) can be a distinct feature that is connected to the base (930) by, for example, gluing, melting, or welding. In some embodiments, the reservoir can be used as part of a repository for a portion of topical medicament (950) that can be retained in the measuring device until use. In other embodiments, the reservoir provides a defined volume into which a portion of medicament is introduced prior to use. The base (930) can be made of any suitable material, such as a metal foil or a polymer sheet. The base (930) can be connected to a plate (920) that provides structural support. The plate (920) includes a plate aperture (925) that is aligned with the reservoir (940). The reservoir (940) is sealed by a removable film (910) that can be removably attached to the plate (920). The removable film (910), plate (920), and base (930) can be connected by any suitable method, including the use of adhesives, melting, welding, and fastening devices.

[0049] Figure 10 depicts the use of the measuring device shown in Figure 9 with a method of separately supplying topical medicament. From left to right, the removable film is peeled away to expose the reservoir (1). A dispenser of topical medicament (960) is used to place a portion of medicament in the reservoir (2), which provides a defined volume that represents the desired unit dose of topical medicament. It should be understood that the reservoir can have any suitable shape, including a hemispherical, ovoid, or polygonal volume. The volume of these shapes can be readily calculated from known geometric formulas. To dispense the topical medicament, a health care professional can apply pressure to the protruding portion of the reservoir until it exerts (3). The exposed portion of topical medicament can then be applied to a skin surface (4). The flat surface of the measuring device can be used to spread the topical medicament and avoid contamination of the health care professional's hands. Figure 9

[0050] In some embodiments, the measuring device can be used independently of the closure device of the inventive concept. As shown in Figure 11, a health care professional can use the measuring device to apply a portion of topical medicament to a skin surface (1). The health care professional can then use the measuring device to apply a portion of topical medicament to a skin surface (2). The health care professional can then use the measuring device to apply a portion of topical medicament to a skin surface (3). The health care professional can then use the measuring device to apply a portion of topical medicament to a skin surface (4). The health care professional can then use the measuring device to apply a portion of topical medicament to a skin surface (5). The health care professional can then use the measuring device to apply a portion of topical medicament to a skin surface (6). Figure 10B ​The reservoir portion of the measuring device can be filled with topical medicament (I) to provide the desired unit dose. By everting the reservoir portion of the measuring device, the unit dose can be exposed for administration (II). The exposed topical medicament is then applied to the skin surface at or near the intended vaccination site (III) and distributed over the skin (IV). This provides a treated vaccination site (V), which can be protected (VI) by the application of a dressing or film to maintain the topical medicament at the vaccination site for a desired period of time (e.g., up to 48 hours). In some vaccination protocols, this period of time can be performed before, after, or both before and after administration of the vaccine to the patient.

[0051] In some embodiments, the closure device of the inventive concept as described above can be provided as part of a kit. Such a kit can include instructions for use, and can also include a measuring device and / or a supply of topical medicament. In some embodiments, the kit can include two or more devices and / or measuring devices. The kit packaging can include indicia suitable for product identification and / or tracking (e.g., 1- and 2-dimensional bar codes). Such packaging can also include a storage device such as an RFID chip that can store and transmit information related to the packaging and / or its contents, such as package content, date of manufacture, expiration date, etc. In some embodiments, the packaging for the devices of the inventive concept can include an indicator that provides an indication of exposure to water or moisture, extreme temperatures, and other conditions that can adversely affect the contents of the packaging. Figure 11A A picture of such a kit is shown, along with instructions for use of a simple form of the closure device. Figure 11B A picture of such a kit is shown, along with instructions for use of a simple form of the closure device.

[0052] In a typical vaccination method of the inventive concept, when vaccination is performed using a closure device as described above, the protective layer is first removed from the skin-facing surface of the closure device. In some embodiments, the exposed surface can include a topical formulation of an immune-enhancing drug that was deposited during manufacture and exposed by removal of the protective layer. In other embodiments, the clinician can apply a topical formulation of an immune-enhancing drug after removal of the protective layer. For example, a suitable amount of 5% imiquimod cream (e.g., cream containing 12.5 mg of imiquimod in 250 mg of cream) can be evenly applied to the skin-facing surface of the closure device. The closure device is then placed on the skin of the patient where the vaccine is to be administered. In another embodiment, the imiquimod cream can be applied directly to the skin of the person to be vaccinated. After a suitable period of time (e.g., about 5 minutes), the through-hole cover of the closure device is removed. The exposed skin can be disinfected (e.g., using 75% alcohol), and the influenza vaccine can then be administered intradermally to the patient through the exposed through-hole. In some embodiments, the skin-facing surface of the through-hole cover can include a topical formulation of a local anesthetic, such as lidocaine. Alternatively, as an optional step prior to intradermal injection, a local anesthetic can be applied to the skin at the vaccination site to reduce pain, either by injection or pressure gun.

[0053] The skin-facing surface area of the closure device can provide a consistent amount of an immune-enhancing drug compound that is uniformly and consistently provided to the skin of the patient in each treatment. The use of the closure device of the inventive concept simplifies the disinfection of the skin at the injection site, and as a result, the time required for vaccine administration can be reduced, thereby increasing the efficiency of the vaccination procedure. The method can also allow the vaccination-enhancing drug to remain on the skin for a defined period of time. The following examples show how a vaccination-enhancing drug such as imiquimod can be used with the device to enhance the efficacy of influenza and other vaccinations.

[0054] In a vaccination using a closure device of 2 cm x 2 cm size, the protective layer on the skin-facing surface of the closure device is first removed. About 0.2 mL of 5% imiquimod cream (containing 12.5 mg of imiquimod in 250 mg of cream or gel) is evenly applied to the exposed surface of the closure device. The closure device is then placed on the arm of the patient with the vertical axis aligned with the arm. After a suitable period of time (e.g., about 5 minutes), the through-hole cover is removed. The exposed skin is then disinfected, and the influenza vaccine is administered intradermally through the exposed through-hole.

[0055] As shown above, in some embodiments, the closure device includes "wing" protrusions or appendages that incorporate an elastoplast-like wound dressing or bandage to facilitate the vaccination process. The vaccination procedure described above can be used to perform the vaccination. After the intradermal injection is completed and the 'air pocket' or bubble of inoculant formed under the skin has been absorbed, the protective layer can be removed to expose the bandage portion extending from the device body. This bandage "wing" can be folded over the device body to cover and protect the injection site.

[0056] It will be apparent to those skilled in the art that numerous improvements and modifications can be made to the application described herein without departing from the inventive concept. Therefore, except as it can be limited by the scope of the following claims, the application is not limited to the details shown. In addition, all terminology used herein is to be interpreted in an inclusive, and not an exclusive, sense. Specifically, the terms "comprise" and "comprising" should be interpreted as referring to elements, components, or steps in a non-exclusive sense, indicating that the referenced elements, components, or steps can be present, or utilized, or combined with other elements, components, or steps not expressly referenced. When a claim recites a selection from A, B, C... and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.

Claims

1. A closure device for administering a medicament, comprising: a frame layer comprising a first central aperture; a barrier layer having a first surface affixed to a first surface of the frame layer, comprising a second central aperture substantially coaxial with the first central aperture; and a cover portion affixed to a second surface of the frame layer, wherein the cover portion has a first position in which the first central aperture is closed by the cover portion and a second position in which at least a portion of the first central aperture is not closed by the cover portion, wherein the first central aperture is centrally aligned with the second central aperture to provide a through aperture through which a vaccination is administered; and wherein at least a portion of a surface of the barrier layer opposite the first surface of the barrier layer comprises an immune-enhancing medicament.

2. The closure device of claim 1, wherein the cover portion is removable.

3. The closure device of claim 1 or 2, further comprising a foldable extension affixed to a peripheral portion of the frame layer, wherein the foldable extension is configured to be folded such that at least a portion of the foldable extension closes the first central aperture.

4. The closure device of claim 1, wherein the immune-enhancing medicament comprises squalene.

5. The closure device of claim 1, wherein the immune-enhancing medicament comprises a toll-like receptor agonist.

6. The closure device of claim 1, wherein the immune-enhancing medicament comprises imiquimod.

7. The closure device of claim 1 or 2, further comprising a wound dressing, wherein an edge of the wound dressing is connected to a periphery of the frame layer.

8. The closure device of claim 1 or 2, wherein the cover portion comprises a local anesthetic.

9. A kit comprising: a closure device according to any one of claims 1 to 8; and an administration device, wherein the administration device is configured to retain a fixed amount of a flowable composition.

10. The kit of claim 9, further comprising a topical pharmaceutical compound formulated as the flowable composition.

11. The kit of claim 10, wherein the topical pharmaceutical compound comprises an immune-enhancing compound.

12. The kit of any one of claims 9 to 11, wherein the fixed amount is between 100 µL and 4 mL.

13. The kit of any one of claims 9 to 11, wherein the flowable composition is selected from a lotion, a gel, a suspension, a cream, and a powder.

14. The kit of any one of claims 9 to 11, wherein the fixed amount in a single workpiece ensures precise measurement and uniform distribution of the combined functionality of creams, lotions, gels, suspensions, and powders. ​

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