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Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Opportunities and challenges in delivering influenza vaccine by microneedle patch Erica Jacoby a , Courtney Jarrahian a , Harry F. Hull b , Darin Zehrung a,∗ a b
PATH, PO Box 900922, Seattle, WA 98109, USA HF Hull & Associates, 1200 Riverside Dr., Reno, NV 89503, USA
a r t i c l e Article history: Available online xxx Keywords: Vaccines Vaccine delivery Microneedle Public health Influenza Immunization safety
i n f o
a b s t r a c t Introduction: Simple and efficacious delivery methods for influenza vaccines are needed to improve health outcomes and manage possible pandemics both in the United States and globally. One approach to meeting these needs is the microneedle patch (MNP), a small array of micron-scale needles that is applied to the skin like a bandage. Methods: To inform additional technical developments and the eventual introduction of MNPs for influenza vaccination, we interviewed key opinion leaders in the United States for insights into the opportunities and challenges associated with this technology, particularly its potential for self-administration. Results: All interviewees expressed high support for administration of influenza vaccine in MNPs by health care providers and for self-administration in groups supervised by a provider. Self-administration via prescription and over-the-counter purchase of MNPs received lower levels of support. Interviewees also highlighted priorities that should be considered in the ongoing development of an influenza vaccine MNP, such as confirming efficacy and ensuring safety for self-administration. For patient and health care provider acceptability, important attributes are ease of use, short wear times, and an easily accessible application site. Discussion and conclusions: Stakeholders agreed that using MNPs can help increase coverage, facilitate easy and safe delivery, reduce the cost of vaccination, and decrease the global morbidity and mortality associated with influenza. Another opportunity for this delivery method is the potential for selfadministration. The prospect of reduced provider training requirements, increased thermostability, and high patient and provider acceptability makes it an attractive option for use in remote and low-resource settings worldwide. However, in addition to the technological challenges associated with producing the patch, developers must be mindful of cost considerations and key product attributes or requirements, such as usability, wear time, and proper disposal, that can affect how the product will be received in the marketplace. © 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Worldwide, influenza causes approximately five million cases of serious illness and 250,000–500,000 deaths each year [1]. If a highly virulent pandemic strain were to emerge in today’s interconnected world, it would have the potential to kill more than 60 million people, with a disproportionate number of deaths occurring in low-income countries [2].
Abbreviations: KOLs, key opinion leaders; MNP, microneedle patch; OTC, over-the-counter. ∗ Corresponding author. Tel.: +1 2062853500. E-mail address: [email protected] (D. Zehrung).
In the United States, annual estimates of influenza-associated deaths between 1976 and 2007 ranged from more than 3000 to 49,000, depending on the characteristics of the circulating virus strains [3]. Despite recommendations that all persons 6 months of age and older be vaccinated annually, only 31% of healthy adults aged 18–49 years, 57% of healthy children aged 6 months to 17 years, and 66% of adults aged 65 and older received a seasonal influenza vaccine during the 2012–2013 season [4]. While many factors influence the decision to be vaccinated, simple and efficacious delivery methods for influenza vaccines could improve vaccination rates and health outcomes, and could help manage possible pandemics in the United States and globally, especially because the influenza vaccine must be administered every year. An alternative delivery method is using microneedles, which are less than one millimeter long and allow administration of
http://dx.doi.org/10.1016/j.vaccine.2015.03.062 0264-410X/© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Jacoby E, et al. Opportunities and challenges in delivering influenza vaccine by microneedle patch. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.03.062
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FluMist® , superior efficacy and cost-effectiveness [32–34]. However, neither vaccine is licensed for all age groups, and both are priced higher than other influenza vaccines, factors which have likely decreased their adoption rate. [32,35,36]. Research on both FluMist® and Fluzone Intradermal® indicated that selfadministration would be feasible, but neither is currently licensed for this [37–39]. In order to inform additional technical developments and the eventual introduction of MNPs for influenza vaccination, we interviewed key opinion leaders (KOLs) in the United States for insights into the opportunities and challenges associated with this technology, particularly its potential for self-administration. 2. Materials and methods
Fig. 1. A dissolvable microneedle patch currently in development. Photo credit: Georgia Institute of Technology.
vaccines or drugs into the epidermis and dermis of the skin (Fig. 1), rather than intramuscularly, the typical route. Intradermal delivery of influenza vaccine by microneedles can lead to longer-lasting and more-robust antibody responses than intramuscular vaccination in mice, suggesting the possibility of improved efficacy [5–17]. Clinical studies comparing intramuscular delivery of influenza vaccine to intradermal delivery in liquid form through hollow minineedles and microneedles have shown a superior immune response in the elderly when an equal dose is administered intradermally, and equivalent immune responses in younger adults with administration of a reduced dose [18–24]. With the emergence of microfabrication manufacturing technology over the past several decades, microneedles have been developed by academic laboratories and pharmaceutical companies [25]. There are four basic types of microneedles: (1) solid microneedles used for skin pretreatment rather than direct drug delivery, (2) solid drug-coated microneedles, (3) polymer microneedles that contain the drug and release it when they dissolve, and (4) hollow microneedles for liquid delivery into the skin [26]. When microneedles are fabricated in arrays on a backing that can be applied to the skin like a bandage, the device is called a microneedle patch (MNP) [25]. Unlike hollow microneedles, which deliver liquid vaccine, MNPs require vaccine reformulation into a solid format and offer the potential for improved vaccine thermostability (which could reduce or eliminate the requirement for storage in the cold chain), reduced packaging volume, and decreased sharps waste. Solid-coated MNPs and dissolvablepolymer MNPs are being developed for delivery of influenza vaccine [27]. Although further research is needed to determine whether solid MNP delivery of influenza vaccine will allow for the use of reduced antigen doses or improve the efficacy of vaccine in humans, there are also other potential advantages of MNP delivery of influenza vaccine, for example improved patient acceptability and the possibility of self-administration, which would allow for health care provider-supervised group vaccination or unsupervised patient self-administration as a prescribed or over-the-counter (OTC) product. The history of commercialization efforts for other new influenza vaccines provides important lessons for the introduction and market potential of new vaccination methods. In recent years, intranasally delivered, live attenuated influenza vaccine, FluMist® , and a prefilled, hollow microneedle delivery system, Fluzone Intradermal® , have become available [28]. Each has significant advantages over intramuscular delivery of influenza vaccine, including increased acceptability [29–31], and in the case of
We invited 69 KOLs nationwide with expertise in different areas of influenza vaccination to participate in interviews about influenza vaccine delivery by MNP. Many were current or past representatives of liaison organizations for the United States Public Health Service’s Advisory Committee on Immunization Practices or were current or former members of that committee. Questionnaires about the perceived benefits of MNP influenza vaccination in different delivery situations were developed, sent to external experts for review, and finalized in an iterative process. Each participating KOL received two questionnaires in advance of a telephone interview. The first was a uniform set of nine questions for all interviewees, and the second was a set of questions tailored to the interviewee’s area of expertise. In addition to the questionnaires, each interviewee received an information sheet on MNPs for influenza vaccination and potential scenarios of use. Researchers used the questionnaires to conduct a structured telephone interview lasting 30–60 min with each interviewee. The interview questions required both quantitative and qualitative answers and highlighted the following areas: priority policy issues; impact on coverage rates; acceptability to health care providers and patients; and the importance of various product attributes, including wear time, dissolvable versus coated MNP technology, and thermostability. Interviewees also were asked to list the top three issues that should be considered in the introduction of a vaccine delivery technology with the long-term goal of self-administration. These answers were analyzed for the terms or phrases used most frequently, which are listed as major findings in the presentation of results. The PATH Research Determination Committee ruled that this activity was not a human subjects research study, and, therefore, no ethics committee review was conducted. Interviewees were informed that their names would not be used in any report or dissemination of results. 3. Results Twenty-five KOLs agreed to be interviewed (response rate of 36%), including 10 policymakers, seven health care providers, three waste management employees, two state immunization program representatives, two regulatory experts, and one purchasing specialist. 3.1. Support for different delivery scenarios Results of the quantitative questions asking interviewees to indicate the level of support their organizations would likely express for use of the MNP for influenza vaccination in each of four scenarios are presented in Fig. 2. Not all interviewees answered all questions; the number responding to each question is given in figure legends.
Please cite this article in press as: Jacoby E, et al. Opportunities and challenges in delivering influenza vaccine by microneedle patch. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.03.062
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All interviewees who ranked the scenarios expressed support for administration of the patch by health care providers, with 77%, on a scale ranging from 1 (highest support) to 7 (highest opposition), assigning this scenario a rating of 1 and the remaining percentage assigning a rating of 2 (Fig. 2). For supervised group self-administration, support was also high, with 90% of interviewees selecting a positive score of 1, 2, or 3 and the remaining 10% selecting the neutral score of 4. Several interviewees noted that group self-administration could increase efficiency in some locations, for example, for groups of about 10 persons in the workplace or at colleges but not in public clinics due to perceived challenges in scheduling and communicating with diverse patient populations. Self-administration via prescription received positive scores from 79% of interviewees. Five percent of interviewees provided a neutral response, and 16% gave a negative score to this scenario. Those who were less enthusiastic about MNP vaccination in this setting commented that it requires an additional step for patients—purchasing the product at a pharmacy after obtaining the prescription from a physician—as well as uncompensated work for physicians. OTC purchase for self-administration received approval from 45% of interviewees, a neutral score from 20%, and a negative response from 35%—a number of whom commented on cost and/or reimbursement issues. They noted that insured patients receive influenza vaccine at no cost, that there is currently no reimbursement mechanism for OTC purchase, and that those at highest risk are often the least likely to be able to pay. For a question asking for the relative ranking of four delivery scenarios based on their perceived benefit to United States public health, interviewees were instructed to answer as experts in their fields rather than as representatives of their organizations. Fig. 3 shows that no scenario received a majority of number 1 rankings; rather, 20–30% of interviewees ranked each individual scenario as number 1. While more than half of the interviewees ranked OTC administration as the lowest option for public health benefit, 30% ranked it as the highest.
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3.2. Key elements to consider for successful introduction of MNP influenza vaccination Each interviewee listed the top three issues that should be considered for the introduction of a vaccine delivery technology that includes the long-term goal of self-administration. The topics mentioned most frequently are presented below, along with qualitative comments on these topics from the common and tailored questionnaires. 3.2.1. Efficacy and safety Interviewees who expressed favorable views of the MNP commented that their approval assumed that the efficacy and safety of this delivery method would be equivalent to that of existing vaccine delivery methods, with some suggesting that a direct comparison of efficacy with FluMist® would be useful. Some noted that an improved safety profile might be necessary for unsupervised self-administration because influenza vaccines have been associated with anaphylaxis, syncope, and other serious adverse events following immunization. Interviewees also noted that the demonstration of efficacy and safety comparable to existing presentations will be needed for regulatory approval, as well as subsequent recommendations by professional bodies, incorporation into clinical practices, insurance reimbursement, and finally, acceptance and uptake by patients. 3.2.2. Ease of use Many interviewees expressed enthusiasm for the MNP as a potentially easy-to-use delivery technology that could save time for health care providers administering vaccines. In order to avoid user errors and to encourage compliance, particularly for self-administration, interviewees emphasized that the delivery technology and application procedures should be as simple as possible. Many noted that errors have occurred with other selfadministered products.
Fig. 2. Perceived support from health care organizations for administration of influenza vaccine microneedle patches in different scenarios. Distribution of interviewees scoring microneedle patch influenza vaccination scenarios on a scale of 1–7, wherein 1 is highest support, 4 is neutral, and 7 is highest opposition. Interviewees were asked to indicate the support they expected from the organizations they represented. Number of interviewees scoring each scenario (not all respondents scored all scenarios): health care professional administration: 22; supervised group self-administration: 21; prescription self-administration: 19; over-the-counter selfadministration: 20.
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Fig. 3. Perceived public health benefit of administration of influenza vaccine microneedle patches in different scenarios. Distribution of interviewees ranking microneedle patch influenza vaccination scenarios on a 1–4 scale, where 1 is highest support and 4 is lowest. Interviewees were asked to rank scenarios in order of most beneficial to least beneficial for US public health, considering the potential for increasing coverage. They were not asked specifically to represent their organization’s viewpoint. Number of interviewees ranking the scenarios (not all interviewees ranked all scenarios): health care professional administration: 19; supervised group self-administration: 18; prescription self-administration: 18; over-the-counter self-administration: 17.
3.2.3. Cost and reimbursement Interviewees noted that although cost is a key driver affecting the vaccines offered in clinics, a slightly higher cost for the influenza vaccine MNP may be acceptable. They also commented that reimbursement rates to providers for vaccine administration are already very low, so there is limited ability to offset increased vaccine cost through administration efficiencies. Concerns were also expressed that reimbursement for administration fees might be cut or eliminated, reducing the incentives for medical care providers, pharmacies, and commercial vaccinators to provide influenza immunization services. Commercial vaccinators and public health programs could potentially achieve savings from reduced cold chain requirements and increased throughput rates when using MNPs at off-site mass clinics. In the absence of superior vaccine efficacy for MNP delivery, most interviewees indicated that the cost of the vaccine and the reimbursement rates would be dominant factors in providers choosing to offer the vaccine. A requirement for self-payment could adversely affect immunization rates, particularly among retirees, children, and chronically ill or low-income patients. Reimbursement for OTC purchase could be problematic for both insurance companies and government immunization programs. 3.2.4. Education Currently, education on influenza vaccination is provided primarily by government agencies, not vaccine manufacturers. Many interviewees reported that the education of and marketing to health care providers as well as to the general public by vaccine manufacturers would be essential for the successful introduction and uptake of the influenza vaccine MNP. Education efforts should also reinforce the importance of receiving an annual influenza vaccination. In addition, health care providers and the public will need information about how to use and dispose of the MNP, as well as how to manage possible adverse events following immunization.
3.2.5. Acceptability Interviewees noted that a needle-free patch technology would be highly acceptable to health care providers and patients, especially children and their parents. Needle phobia was regularly mentioned as a barrier to vaccine uptake, as were the drawbacks of nasally applied FluMist® . Interviewees also commented on the public’s general familiarity with patch-delivery technology, ranging from bandages to birth control products. High levels of acceptability of the MNP could, therefore, result in higher coverage rates and/or a larger market segment. The versatility of the MNP delivery method was also attractive as it can be used in all the settings described in the four administration scenarios, ranging from a physician’s office to the patient’s workplace or home. 3.2.6. Wear time and application site When asked about potential MNP wear times between 10 s and 10 min, interviewees recommended short wear times, stating that this would increase compliance, reduce administrative burden, and prevent errors such as early removal. They also noted that longer wear times could reduce throughput at clinics, increase the complexity of administration (requiring providers to check back in with each patient), and require more health care provider time for supervision. The placement of MNPs at sites other than the deltoid (e.g., forearm) should be validated and is a consideration both for self-administration and for ensuring high throughput in clinics. Placement at sites that do not require clothing to be removed would facilitate group vaccinations at the workplace and in clinics and would improve acceptability. 3.2.7. Documentation and reporting Although vaccine registries already exist or are being developed by all states, they are not equally robust. Ensuring that a patient’s immunization status is available to medical care providers and for measuring immunization coverage is an important consideration for self-administration, especially for OTC delivery. Lack of
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documentation in the OTC scenario was seen as a particular issue for health care providers (who usually are required to be vaccinated by their employers) and for people at higher risk of developing influenza-related complications.
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3.3.1. Sharps and waste disposal Interviewees strongly preferred MNPs with dissolvable microneedles to solid needles coated with vaccine because the latter will produce sharps waste and are a potential hazard if not disposed of properly. Also, patients could remove and dispose of dissolvable MNPs themselves. Some respondents pointed out that a new technology would require following state-by-state requirements, as each state has its own laws and regulations that fit within the federal policy for sharps and dangerous waste. California could serve as a good model due to its conservative disposal policies.
packaging will decrease space requirements for transport and storage, thus reducing cold chain impact. Finally, if a dissolvable MNP is used, needlestick injuries and sharps waste could be eliminated. While experts expressed enthusiasm for this new product, challenges were noted. Important next steps after technical development is completed will include clinical studies that generate data demonstrating the product’s safety and effectiveness for the intended population and studies on self-administration. An interviewee with regulatory expertise also noted that there is currently no formal guidance or precedent for supervised group self-administration of a vaccine in the United States. Oral typhoid vaccine has been approved for self-administered at home, but this involves taking a capsule rather than applying a patch to the skin [40]. Clearly the complexities of an OTC influenza vaccine for self-administration will require a careful, stepwise program of introduction. Among the additional challenges identified by interviewees, concerns about cost and reimbursement were foremost. As noted in the introduction, the intranasal influenza vaccine was more expensive than the injected vaccine when introduced, and this caused decreased acceptability when insurance reimbursement was less than the cost of the vaccine [35]. Interviewees indicated that if the efficacy via MNP is similar to that of existing vaccines, cost would be a major factor in whether providers choose to offer the vaccine. Development by insurers of novel reimbursement mechanisms for OTC purchases of vaccines or automatic annual renewal of prescriptions for MNPs sent by mail to patients could facilitate self-administration scenarios. Although our study was conducted with stakeholders in the United States and concerned the possible use of MNPs in this country, the potential for reduced provider training requirements, increased thermostability, and high patient and provider acceptability makes it an attractive option for eventual use in remote and low-resource settings worldwide.
4. Discussion
5. Conclusions
Interviewees with expertise in influenza vaccination indicated a high level of support for MNP delivery of this vaccine, identified a number of opportunities for the introduction of MNPs, and made valuable suggestions for refining the target product profile of this technology, which is currently in development. Overall, results indicated that the easy-to-use, needle-free patch could increase acceptance among providers and patients (particularly children), leading to increased coverage—a major public health goal. The limitation of our survey is the low number of KOLs interviewed. However, these individuals represented a variety of organizations, and the interviews were comprehensive. While most interviewees were in favor of self-administration with the MNP, delivery by health care professionals received even higher support. Responses on the potential for public health benefit from different administration scenarios trended toward bimodal distributions, possibly indicating that some interviewees were more concerned with professional administration of vaccine and others were more concerned with getting vaccine quickly to the largest number of people. Since MNP technology is still in development, opportunities exist to create a device with a short wear time, and interviewees advocated for this, as it would likely reduce errors and increase acceptability by patients and providers. Interviewees also believed that demonstrated efficacy and safety at an accessible administration site, such as the forearm, could also improve patient flow at clinics and pharmacies. Further, a thermostable product would alleviate pressure on the cold chain, which is especially important for vaccines that are seasonal and for all vaccines distributed in lowresource settings with limited or no electricity. Minimal, efficient
The MNP is a promising approach to influenza vaccination, as evidenced by the input received from KOLs with expertise in various areas of immunization. MNPs could help to increase coverage, facilitate easy and safe delivery, reduce the cost of vaccination, and decrease the global morbidity and mortality associated with influenza. A majority of interviewees agreed that MNPs have potential for self-administration, either by individuals or in supervised groups. In addition to the technological challenges associated with producing the patch, developers must be mindful of cost considerations and key product attributes, such as usability, wear time, and sharps disposal, which can affect how the product will be received in the marketplace. These marketplace factors will determine whether an innovative and novel technology such as an MNP achieves its potential and is successfully introduced with broad uptake in the influenza vaccine market.
3.3. Thermostability The cold chain is a temperature-controlled supply chain from the manufacturer to the point of vaccine delivery. The cold chain for influenza vaccines requires maintenance of temperatures in the range of 2–8 ◦ C. Interviewees felt that a thermostable MNP would have a positive effect by reducing the large amounts of vaccine that typically are present for limited periods of time in the cold chain. Thermostability would also reduce storage and shipping costs and eliminate the risk of spoilage during power outages or during transport to offsite vaccination clinics. For self-administration of MNPs at home, thermostability also was noted as a critical attribute. Another advantage of MNPs that do not require refrigeration would be the possibility of administration by medical specialists such as cardiologists, who often do not have refrigerators in their offices but could offer a thermostable vaccine to patients who come to them for reasons other than vaccination.
Conflicts of interest The authors have no conflicts of interest to report. Acknowledgments This work was supported by Award Number U01EB012495 from the National Institute of Biomedical Imaging and Bioengineering. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Biomedical Imaging and Bioengineering or the National Institute of Health.
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The authors thank Mark Prausnitz, James Norman, and Sebastien Henry at the Georgia Institute of Technology and Savitha Swaminathan, Amy Wales, Marjorie Murray, Jillian Zemanek, Nate Schmidt, Patricia Logan, and Tessa James at PATH for their assistance in the development of this article.
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine. 2015.03.062.
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Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Opportunities and challenges in delivering influenza vaccine by microneedle patch Erica Jacoby a , Courtney Jarrahian a , Harry F. Hull b , Darin Zehrung a,∗ a b
PATH, PO Box 900922, Seattle, WA 98109, USA HF Hull & Associates, 1200 Riverside Dr., Reno, NV 89503, USA
a r t i c l e Article history: Available online xxx Keywords: Vaccines Vaccine delivery Microneedle Public health Influenza Immunization safety
i n f o
a b s t r a c t Introduction: Simple and efficacious delivery methods for influenza vaccines are needed to improve health outcomes and manage possible pandemics both in the United States and globally. One approach to meeting these needs is the microneedle patch (MNP), a small array of micron-scale needles that is applied to the skin like a bandage. Methods: To inform additional technical developments and the eventual introduction of MNPs for influenza vaccination, we interviewed key opinion leaders in the United States for insights into the opportunities and challenges associated with this technology, particularly its potential for self-administration. Results: All interviewees expressed high support for administration of influenza vaccine in MNPs by health care providers and for self-administration in groups supervised by a provider. Self-administration via prescription and over-the-counter purchase of MNPs received lower levels of support. Interviewees also highlighted priorities that should be considered in the ongoing development of an influenza vaccine MNP, such as confirming efficacy and ensuring safety for self-administration. For patient and health care provider acceptability, important attributes are ease of use, short wear times, and an easily accessible application site. Discussion and conclusions: Stakeholders agreed that using MNPs can help increase coverage, facilitate easy and safe delivery, reduce the cost of vaccination, and decrease the global morbidity and mortality associated with influenza. Another opportunity for this delivery method is the potential for selfadministration. The prospect of reduced provider training requirements, increased thermostability, and high patient and provider acceptability makes it an attractive option for use in remote and low-resource settings worldwide. However, in addition to the technological challenges associated with producing the patch, developers must be mindful of cost considerations and key product attributes or requirements, such as usability, wear time, and proper disposal, that can affect how the product will be received in the marketplace. © 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Worldwide, influenza causes approximately five million cases of serious illness and 250,000–500,000 deaths each year [1]. If a highly virulent pandemic strain were to emerge in today’s interconnected world, it would have the potential to kill more than 60 million people, with a disproportionate number of deaths occurring in low-income countries [2].
Abbreviations: KOLs, key opinion leaders; MNP, microneedle patch; OTC, over-the-counter. ∗ Corresponding author. Tel.: +1 2062853500. E-mail address: [email protected] (D. Zehrung).
In the United States, annual estimates of influenza-associated deaths between 1976 and 2007 ranged from more than 3000 to 49,000, depending on the characteristics of the circulating virus strains [3]. Despite recommendations that all persons 6 months of age and older be vaccinated annually, only 31% of healthy adults aged 18–49 years, 57% of healthy children aged 6 months to 17 years, and 66% of adults aged 65 and older received a seasonal influenza vaccine during the 2012–2013 season [4]. While many factors influence the decision to be vaccinated, simple and efficacious delivery methods for influenza vaccines could improve vaccination rates and health outcomes, and could help manage possible pandemics in the United States and globally, especially because the influenza vaccine must be administered every year. An alternative delivery method is using microneedles, which are less than one millimeter long and allow administration of
http://dx.doi.org/10.1016/j.vaccine.2015.03.062 0264-410X/© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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FluMist® , superior efficacy and cost-effectiveness [32–34]. However, neither vaccine is licensed for all age groups, and both are priced higher than other influenza vaccines, factors which have likely decreased their adoption rate. [32,35,36]. Research on both FluMist® and Fluzone Intradermal® indicated that selfadministration would be feasible, but neither is currently licensed for this [37–39]. In order to inform additional technical developments and the eventual introduction of MNPs for influenza vaccination, we interviewed key opinion leaders (KOLs) in the United States for insights into the opportunities and challenges associated with this technology, particularly its potential for self-administration. 2. Materials and methods
Fig. 1. A dissolvable microneedle patch currently in development. Photo credit: Georgia Institute of Technology.
vaccines or drugs into the epidermis and dermis of the skin (Fig. 1), rather than intramuscularly, the typical route. Intradermal delivery of influenza vaccine by microneedles can lead to longer-lasting and more-robust antibody responses than intramuscular vaccination in mice, suggesting the possibility of improved efficacy [5–17]. Clinical studies comparing intramuscular delivery of influenza vaccine to intradermal delivery in liquid form through hollow minineedles and microneedles have shown a superior immune response in the elderly when an equal dose is administered intradermally, and equivalent immune responses in younger adults with administration of a reduced dose [18–24]. With the emergence of microfabrication manufacturing technology over the past several decades, microneedles have been developed by academic laboratories and pharmaceutical companies [25]. There are four basic types of microneedles: (1) solid microneedles used for skin pretreatment rather than direct drug delivery, (2) solid drug-coated microneedles, (3) polymer microneedles that contain the drug and release it when they dissolve, and (4) hollow microneedles for liquid delivery into the skin [26]. When microneedles are fabricated in arrays on a backing that can be applied to the skin like a bandage, the device is called a microneedle patch (MNP) [25]. Unlike hollow microneedles, which deliver liquid vaccine, MNPs require vaccine reformulation into a solid format and offer the potential for improved vaccine thermostability (which could reduce or eliminate the requirement for storage in the cold chain), reduced packaging volume, and decreased sharps waste. Solid-coated MNPs and dissolvablepolymer MNPs are being developed for delivery of influenza vaccine [27]. Although further research is needed to determine whether solid MNP delivery of influenza vaccine will allow for the use of reduced antigen doses or improve the efficacy of vaccine in humans, there are also other potential advantages of MNP delivery of influenza vaccine, for example improved patient acceptability and the possibility of self-administration, which would allow for health care provider-supervised group vaccination or unsupervised patient self-administration as a prescribed or over-the-counter (OTC) product. The history of commercialization efforts for other new influenza vaccines provides important lessons for the introduction and market potential of new vaccination methods. In recent years, intranasally delivered, live attenuated influenza vaccine, FluMist® , and a prefilled, hollow microneedle delivery system, Fluzone Intradermal® , have become available [28]. Each has significant advantages over intramuscular delivery of influenza vaccine, including increased acceptability [29–31], and in the case of
We invited 69 KOLs nationwide with expertise in different areas of influenza vaccination to participate in interviews about influenza vaccine delivery by MNP. Many were current or past representatives of liaison organizations for the United States Public Health Service’s Advisory Committee on Immunization Practices or were current or former members of that committee. Questionnaires about the perceived benefits of MNP influenza vaccination in different delivery situations were developed, sent to external experts for review, and finalized in an iterative process. Each participating KOL received two questionnaires in advance of a telephone interview. The first was a uniform set of nine questions for all interviewees, and the second was a set of questions tailored to the interviewee’s area of expertise. In addition to the questionnaires, each interviewee received an information sheet on MNPs for influenza vaccination and potential scenarios of use. Researchers used the questionnaires to conduct a structured telephone interview lasting 30–60 min with each interviewee. The interview questions required both quantitative and qualitative answers and highlighted the following areas: priority policy issues; impact on coverage rates; acceptability to health care providers and patients; and the importance of various product attributes, including wear time, dissolvable versus coated MNP technology, and thermostability. Interviewees also were asked to list the top three issues that should be considered in the introduction of a vaccine delivery technology with the long-term goal of self-administration. These answers were analyzed for the terms or phrases used most frequently, which are listed as major findings in the presentation of results. The PATH Research Determination Committee ruled that this activity was not a human subjects research study, and, therefore, no ethics committee review was conducted. Interviewees were informed that their names would not be used in any report or dissemination of results. 3. Results Twenty-five KOLs agreed to be interviewed (response rate of 36%), including 10 policymakers, seven health care providers, three waste management employees, two state immunization program representatives, two regulatory experts, and one purchasing specialist. 3.1. Support for different delivery scenarios Results of the quantitative questions asking interviewees to indicate the level of support their organizations would likely express for use of the MNP for influenza vaccination in each of four scenarios are presented in Fig. 2. Not all interviewees answered all questions; the number responding to each question is given in figure legends.
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All interviewees who ranked the scenarios expressed support for administration of the patch by health care providers, with 77%, on a scale ranging from 1 (highest support) to 7 (highest opposition), assigning this scenario a rating of 1 and the remaining percentage assigning a rating of 2 (Fig. 2). For supervised group self-administration, support was also high, with 90% of interviewees selecting a positive score of 1, 2, or 3 and the remaining 10% selecting the neutral score of 4. Several interviewees noted that group self-administration could increase efficiency in some locations, for example, for groups of about 10 persons in the workplace or at colleges but not in public clinics due to perceived challenges in scheduling and communicating with diverse patient populations. Self-administration via prescription received positive scores from 79% of interviewees. Five percent of interviewees provided a neutral response, and 16% gave a negative score to this scenario. Those who were less enthusiastic about MNP vaccination in this setting commented that it requires an additional step for patients—purchasing the product at a pharmacy after obtaining the prescription from a physician—as well as uncompensated work for physicians. OTC purchase for self-administration received approval from 45% of interviewees, a neutral score from 20%, and a negative response from 35%—a number of whom commented on cost and/or reimbursement issues. They noted that insured patients receive influenza vaccine at no cost, that there is currently no reimbursement mechanism for OTC purchase, and that those at highest risk are often the least likely to be able to pay. For a question asking for the relative ranking of four delivery scenarios based on their perceived benefit to United States public health, interviewees were instructed to answer as experts in their fields rather than as representatives of their organizations. Fig. 3 shows that no scenario received a majority of number 1 rankings; rather, 20–30% of interviewees ranked each individual scenario as number 1. While more than half of the interviewees ranked OTC administration as the lowest option for public health benefit, 30% ranked it as the highest.
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3.2. Key elements to consider for successful introduction of MNP influenza vaccination Each interviewee listed the top three issues that should be considered for the introduction of a vaccine delivery technology that includes the long-term goal of self-administration. The topics mentioned most frequently are presented below, along with qualitative comments on these topics from the common and tailored questionnaires. 3.2.1. Efficacy and safety Interviewees who expressed favorable views of the MNP commented that their approval assumed that the efficacy and safety of this delivery method would be equivalent to that of existing vaccine delivery methods, with some suggesting that a direct comparison of efficacy with FluMist® would be useful. Some noted that an improved safety profile might be necessary for unsupervised self-administration because influenza vaccines have been associated with anaphylaxis, syncope, and other serious adverse events following immunization. Interviewees also noted that the demonstration of efficacy and safety comparable to existing presentations will be needed for regulatory approval, as well as subsequent recommendations by professional bodies, incorporation into clinical practices, insurance reimbursement, and finally, acceptance and uptake by patients. 3.2.2. Ease of use Many interviewees expressed enthusiasm for the MNP as a potentially easy-to-use delivery technology that could save time for health care providers administering vaccines. In order to avoid user errors and to encourage compliance, particularly for self-administration, interviewees emphasized that the delivery technology and application procedures should be as simple as possible. Many noted that errors have occurred with other selfadministered products.
Fig. 2. Perceived support from health care organizations for administration of influenza vaccine microneedle patches in different scenarios. Distribution of interviewees scoring microneedle patch influenza vaccination scenarios on a scale of 1–7, wherein 1 is highest support, 4 is neutral, and 7 is highest opposition. Interviewees were asked to indicate the support they expected from the organizations they represented. Number of interviewees scoring each scenario (not all respondents scored all scenarios): health care professional administration: 22; supervised group self-administration: 21; prescription self-administration: 19; over-the-counter selfadministration: 20.
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Fig. 3. Perceived public health benefit of administration of influenza vaccine microneedle patches in different scenarios. Distribution of interviewees ranking microneedle patch influenza vaccination scenarios on a 1–4 scale, where 1 is highest support and 4 is lowest. Interviewees were asked to rank scenarios in order of most beneficial to least beneficial for US public health, considering the potential for increasing coverage. They were not asked specifically to represent their organization’s viewpoint. Number of interviewees ranking the scenarios (not all interviewees ranked all scenarios): health care professional administration: 19; supervised group self-administration: 18; prescription self-administration: 18; over-the-counter self-administration: 17.
3.2.3. Cost and reimbursement Interviewees noted that although cost is a key driver affecting the vaccines offered in clinics, a slightly higher cost for the influenza vaccine MNP may be acceptable. They also commented that reimbursement rates to providers for vaccine administration are already very low, so there is limited ability to offset increased vaccine cost through administration efficiencies. Concerns were also expressed that reimbursement for administration fees might be cut or eliminated, reducing the incentives for medical care providers, pharmacies, and commercial vaccinators to provide influenza immunization services. Commercial vaccinators and public health programs could potentially achieve savings from reduced cold chain requirements and increased throughput rates when using MNPs at off-site mass clinics. In the absence of superior vaccine efficacy for MNP delivery, most interviewees indicated that the cost of the vaccine and the reimbursement rates would be dominant factors in providers choosing to offer the vaccine. A requirement for self-payment could adversely affect immunization rates, particularly among retirees, children, and chronically ill or low-income patients. Reimbursement for OTC purchase could be problematic for both insurance companies and government immunization programs. 3.2.4. Education Currently, education on influenza vaccination is provided primarily by government agencies, not vaccine manufacturers. Many interviewees reported that the education of and marketing to health care providers as well as to the general public by vaccine manufacturers would be essential for the successful introduction and uptake of the influenza vaccine MNP. Education efforts should also reinforce the importance of receiving an annual influenza vaccination. In addition, health care providers and the public will need information about how to use and dispose of the MNP, as well as how to manage possible adverse events following immunization.
3.2.5. Acceptability Interviewees noted that a needle-free patch technology would be highly acceptable to health care providers and patients, especially children and their parents. Needle phobia was regularly mentioned as a barrier to vaccine uptake, as were the drawbacks of nasally applied FluMist® . Interviewees also commented on the public’s general familiarity with patch-delivery technology, ranging from bandages to birth control products. High levels of acceptability of the MNP could, therefore, result in higher coverage rates and/or a larger market segment. The versatility of the MNP delivery method was also attractive as it can be used in all the settings described in the four administration scenarios, ranging from a physician’s office to the patient’s workplace or home. 3.2.6. Wear time and application site When asked about potential MNP wear times between 10 s and 10 min, interviewees recommended short wear times, stating that this would increase compliance, reduce administrative burden, and prevent errors such as early removal. They also noted that longer wear times could reduce throughput at clinics, increase the complexity of administration (requiring providers to check back in with each patient), and require more health care provider time for supervision. The placement of MNPs at sites other than the deltoid (e.g., forearm) should be validated and is a consideration both for self-administration and for ensuring high throughput in clinics. Placement at sites that do not require clothing to be removed would facilitate group vaccinations at the workplace and in clinics and would improve acceptability. 3.2.7. Documentation and reporting Although vaccine registries already exist or are being developed by all states, they are not equally robust. Ensuring that a patient’s immunization status is available to medical care providers and for measuring immunization coverage is an important consideration for self-administration, especially for OTC delivery. Lack of
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documentation in the OTC scenario was seen as a particular issue for health care providers (who usually are required to be vaccinated by their employers) and for people at higher risk of developing influenza-related complications.
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3.3.1. Sharps and waste disposal Interviewees strongly preferred MNPs with dissolvable microneedles to solid needles coated with vaccine because the latter will produce sharps waste and are a potential hazard if not disposed of properly. Also, patients could remove and dispose of dissolvable MNPs themselves. Some respondents pointed out that a new technology would require following state-by-state requirements, as each state has its own laws and regulations that fit within the federal policy for sharps and dangerous waste. California could serve as a good model due to its conservative disposal policies.
packaging will decrease space requirements for transport and storage, thus reducing cold chain impact. Finally, if a dissolvable MNP is used, needlestick injuries and sharps waste could be eliminated. While experts expressed enthusiasm for this new product, challenges were noted. Important next steps after technical development is completed will include clinical studies that generate data demonstrating the product’s safety and effectiveness for the intended population and studies on self-administration. An interviewee with regulatory expertise also noted that there is currently no formal guidance or precedent for supervised group self-administration of a vaccine in the United States. Oral typhoid vaccine has been approved for self-administered at home, but this involves taking a capsule rather than applying a patch to the skin [40]. Clearly the complexities of an OTC influenza vaccine for self-administration will require a careful, stepwise program of introduction. Among the additional challenges identified by interviewees, concerns about cost and reimbursement were foremost. As noted in the introduction, the intranasal influenza vaccine was more expensive than the injected vaccine when introduced, and this caused decreased acceptability when insurance reimbursement was less than the cost of the vaccine [35]. Interviewees indicated that if the efficacy via MNP is similar to that of existing vaccines, cost would be a major factor in whether providers choose to offer the vaccine. Development by insurers of novel reimbursement mechanisms for OTC purchases of vaccines or automatic annual renewal of prescriptions for MNPs sent by mail to patients could facilitate self-administration scenarios. Although our study was conducted with stakeholders in the United States and concerned the possible use of MNPs in this country, the potential for reduced provider training requirements, increased thermostability, and high patient and provider acceptability makes it an attractive option for eventual use in remote and low-resource settings worldwide.
4. Discussion
5. Conclusions
Interviewees with expertise in influenza vaccination indicated a high level of support for MNP delivery of this vaccine, identified a number of opportunities for the introduction of MNPs, and made valuable suggestions for refining the target product profile of this technology, which is currently in development. Overall, results indicated that the easy-to-use, needle-free patch could increase acceptance among providers and patients (particularly children), leading to increased coverage—a major public health goal. The limitation of our survey is the low number of KOLs interviewed. However, these individuals represented a variety of organizations, and the interviews were comprehensive. While most interviewees were in favor of self-administration with the MNP, delivery by health care professionals received even higher support. Responses on the potential for public health benefit from different administration scenarios trended toward bimodal distributions, possibly indicating that some interviewees were more concerned with professional administration of vaccine and others were more concerned with getting vaccine quickly to the largest number of people. Since MNP technology is still in development, opportunities exist to create a device with a short wear time, and interviewees advocated for this, as it would likely reduce errors and increase acceptability by patients and providers. Interviewees also believed that demonstrated efficacy and safety at an accessible administration site, such as the forearm, could also improve patient flow at clinics and pharmacies. Further, a thermostable product would alleviate pressure on the cold chain, which is especially important for vaccines that are seasonal and for all vaccines distributed in lowresource settings with limited or no electricity. Minimal, efficient
The MNP is a promising approach to influenza vaccination, as evidenced by the input received from KOLs with expertise in various areas of immunization. MNPs could help to increase coverage, facilitate easy and safe delivery, reduce the cost of vaccination, and decrease the global morbidity and mortality associated with influenza. A majority of interviewees agreed that MNPs have potential for self-administration, either by individuals or in supervised groups. In addition to the technological challenges associated with producing the patch, developers must be mindful of cost considerations and key product attributes, such as usability, wear time, and sharps disposal, which can affect how the product will be received in the marketplace. These marketplace factors will determine whether an innovative and novel technology such as an MNP achieves its potential and is successfully introduced with broad uptake in the influenza vaccine market.
3.3. Thermostability The cold chain is a temperature-controlled supply chain from the manufacturer to the point of vaccine delivery. The cold chain for influenza vaccines requires maintenance of temperatures in the range of 2–8 ◦ C. Interviewees felt that a thermostable MNP would have a positive effect by reducing the large amounts of vaccine that typically are present for limited periods of time in the cold chain. Thermostability would also reduce storage and shipping costs and eliminate the risk of spoilage during power outages or during transport to offsite vaccination clinics. For self-administration of MNPs at home, thermostability also was noted as a critical attribute. Another advantage of MNPs that do not require refrigeration would be the possibility of administration by medical specialists such as cardiologists, who often do not have refrigerators in their offices but could offer a thermostable vaccine to patients who come to them for reasons other than vaccination.
Conflicts of interest The authors have no conflicts of interest to report. Acknowledgments This work was supported by Award Number U01EB012495 from the National Institute of Biomedical Imaging and Bioengineering. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Biomedical Imaging and Bioengineering or the National Institute of Health.
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The authors thank Mark Prausnitz, James Norman, and Sebastien Henry at the Georgia Institute of Technology and Savitha Swaminathan, Amy Wales, Marjorie Murray, Jillian Zemanek, Nate Schmidt, Patricia Logan, and Tessa James at PATH for their assistance in the development of this article.
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine. 2015.03.062.
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Please cite this article in press as: Jacoby E, et al. Opportunities and challenges in delivering influenza vaccine by microneedle patch. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.03.062
