Title: Opportunities and challenges in delivering influenza vaccine by microneedle patch

Running title: Delivering influenza vaccine by microneedle patch

Darin Zehrung1, Courtney Jarrahian1, Erica Jacoby1, Harry Hull

1 PATH, PO Box 900922, Seattle, WA 98109 USA.

Keywords: vaccines, vaccine delivery, microneedle, public health, influenza, immunization safety

The authors declare that there are no conflicts of interest or financial disclosures to mention.

1

Abbreviations and Acronyms

AEFIs adverse events following immunization

ID intradermal

IM intramuscular

KOLs key opinion leaders

LAIV live attenuated influenza vaccine

MNP microneedle patch

OTC over-the-counter

TIV trivalent, inactivated influenza vaccine

US United States

2

Abstract

Simple and efficacious delivery methods for influenza vaccines are needed to improve health outcomes

and to manage possible pandemics 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. Because MNPs do not require a conventional needle and syringe, training requirements

for providers can be reduced, making it an attractive option for use in both low-and high-income

countries. To inform additional technical developments and the eventual introduction of MNPs for

influenza vaccination, we interviewed 24 key opinion leaders in the United States for insights into the

opportunities and challenges associated with this technology, particularly its potential for self-

administration. All interviewees expressed high support for administration of MNPs by health care

providers and for supervised self-administration. Self-administration via prescription or over-the-

counter purchase received lower levels of support, although even the latter received approval or a

neutral score from a majority of interviewees. Interviewees also listed issues that should be considered

in the ongoing development of the MNP, such as confirming it as efficacious as existing influenza

vaccines 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. All

agreed that MNPs could help to increase coverage, facilitate easy and safe delivery scenarios, reduce the

cost of vaccination, and decrease the global morbidity and mortality associated with influenza.

3

Introduction

Influenza burden

Worldwide, influenza causes 250,000 to 500,000 deaths and approximately 5 million cases of serious

illness 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,2 with a disproportionate number of deaths

occurring in low-income countries.

In the United States (US), annual estimates of influenza-associated deaths between 1976 and 2007

ranged from more than 3,000 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 29 percent of healthy adults aged 18-49 years, 52 percent of healthy children aged 6 months to 17

years, and 65 percent of adults aged 65 and older received a seasonal influenza vaccine in the US during

the 2011–2012 season.4 Low rates are also seen in people with compromised immune systems, a

population vulnerable to influenza-related complications. Simple and efficacious delivery methods for

influenza vaccines are needed to improve health outcomes and to manage possible pandemics in the US

and globally, especially because the influenza vaccine must be administered every year.

Microneedle patch

One approach to meeting these needs is a microneedle patch, which allows administration of vaccines

or drugs into the epidermis and dermis of the skin via needles less than one millimeter long. Studies in

mice have demonstrated that intradermal (ID) vaccination prompts a flood of cytokines in the dermis,

which has been correlated with recruitment of specialized cells that speed up the immune response.5

4

Microneedle delivery of influenza vaccine can lead to longer lasting and more robust antibody responses

in mice,6-12 suggesting the possibility of improved efficacy.

Microneedles were developed several decades ago for drug delivery and became the focus of research

by academic laboratories and pharmaceutical companies starting in the 1990s with the emergence of

microfabrication manufacturing technology.13 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.14 The technology is used to deliver drugs and

biotherapeutics, and studies are being conducted with vaccines. Examples of hollow minineedles and

microneedles mounted on a syringe include Fluzone Intradermal®, which consists of a single minineedle

on a prefilled syringe, and the Nanopass MicronJet®, a device with a row of hollow microneedles

mounted on a hub compatible with standard syringes.15 Clinical studies comparing intramuscular (IM)

delivery of influenza vaccine to ID delivery in liquid form through hollow minineedles and microneedles

have shown an equivalent immune response.16-20

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).13 Solid coated MNPs and dissolvable polymer MNPs are

being developed for delivery of influenza vaccine.21 Although further research is needed to determine

whether solid MNP delivery of influenza vaccine will allow use of reduced antigen doses or improve

vaccine efficacy in humans, the potential advantages for MNP delivery of influenza vaccine include

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.

5

Previous introductions of new influenza vaccine delivery methods

Commercialization efforts for other new influenza vaccines have shown that new vaccination methods

that are technologically superior to existing products are not guaranteed success on the market. For

example, the live attenuated influenza vaccine (LAIV) FluMist® has significant advantages over trivalent,

inactivated influenza vaccine (TIV). It is administered intranasally without a needle and syringe,

potentially making it more acceptable to consumers and useful for mass administration. Research

indicated that self-administration would be feasible.22,23 While studies showed lower serum antibody

levels after self-vaccination compared to expert-vaccination of LAIV, vaccine efficacy was higher for LAIV

compared with TIV, presumably because of live-virus induced cell-mediated immunity and a mucosal

immune response.24 LAIV provided superior protection against influenza in children25 and was more cost

effective than TIV for adult vaccination.26

However, because of concern over adverse events following immunization (AEFIs), FluMist® is licensed

and recommended only for children over 2 years of age and is contraindicated for immune-

compromised patients. Consequently, TIV is still needed for the youngest children, so that even

pediatricians preferring LAIV need to stock TIV. The initial frozen formulation for LAIV was difficult for

some providers to store and was eventually replaced with a refrigerator-stable formulation.24 While the

transmission of live vaccine virus or requirement for stringent storage requirements should not be issues

with MNPs, FluMist’s® story highlights how unanticipated issues can adversely affect the market

introduction of a vaccine or an integrated vaccine delivery device.

In 2011, an ID influenza vaccine delivered by an injection device with a single hollow minineedle was

approved and became available in the US (Sanofi-Pasteur’s Fluzone Intradermal®).27 This prefilled

injection device contains 9 micrograms of hemagglutinin antigen per virus strain, compared with 15

6

micrograms in a full-dose IM vaccine, and safety and immunogenicity have been shown to be

comparable.28

Research suggests that Fluzone Intradermal® has the potential to increase influenza vaccination

coverage due to higher rates of patient acceptability of ID delivery compared with other routes, mainly

because it avoids injection with a hypodermic needle. The minineedle is 1.5 millimeters in length and

reduces blood vessel and nerve injuries in recipients.29 A study of more than 350 US patients and their

providers found that 99 percent of patients and all providers were satisfied with ID administration, with

patients reporting less pre-injection anxiety and post-injection pain compared with IM administration,

both immediately and 7 days after vaccination.30 In a different study of acceptance by patients over 60

years of age in Belgium, 98 percent of more than 800 participants stated that they were either very

satisfied or satisfied with physician-administered ID vaccine.31 Furthermore, 88 percent of the general

practitioners in this study expressed a preference for the ID vaccine over IM influenza vaccine. Another

study reported on results of acceptability questionnaires completed in two European randomized

clinical trials by more than 2,000 adults and 2,800 elderly adults who received ID vaccination.32 Although

injection-site reactions were more frequent with ID vaccinations than with IM administration, more than

96 percent of participants rated injection-site reactions after ID or IM vaccination as either ‘totally

acceptable’ or ‘very acceptable.’

In regard to self-administration of ID influenza vaccine, a randomized clinical trial in Canada comparing

self-administration with nurse administration showed that 93 percent of those administering their own

vaccine were successful on the first attempt, and 70 percent of all trial participants said they would

prefer ID over IM vaccinations in the future, if given the choice.33 However, Fluzone Intradermal® is not

currently licensed for self-administration.

7

Fluzone Intradermal® is priced higher than IM vaccine (list price of US$15 versus US$10 per dose),34 and

the 2012–2013 flu season was the first time it was fully available in the US. It remains to be seen how

the higher price will affect uptake, and whether the new vaccine delivery option will help to increase

coverage.

In order to inform additional technical developments and the eventual introduction of MNPs for

influenza vaccination, we interviewed key opinion leaders (KOLs) in the US for insights into the

opportunities and challenges associated with this technology, particularly its potential for self-

administration.

Results

Out of 69 KOLs contacted, 24 agreed to be interviewed (response rate of 35 percent), including

policymakers, health care providers, waste management employees, state immunization program

representatives, regulatory experts, and purchasing specialists.

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 Figure 1. Not all interviewees answered all questions; the number responding to each

question is given in figure legends.

All interviewees expressed support for administration of the patch by health care providers, with 77

percent assigning this scenario a rating of 1 and the remainder a rating of 2 on the 1 to 7 scale of

support (Figure 1). For supervised self-administration, support was also high, with 90 percent of

interviewees selecting a score of 1, 2, or 3 and 10 percent the neutral score of 4. Several interviewees

8

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 communication with diverse patient populations.

Self-administration via prescription received scores of 1 to 4 (high support through neutral) from 84

percent of interviewees. Those who were less enthusiastic about MNP vaccination in this setting

commented that it requires an additional step for patients—obtaining the prescription from a physician

and then purchasing the product at a pharmacy. They also expressed concern that physicians would not

receive income for counseling patients and providing the prescription.

OTC purchase with self-administration received approval or a neutral score from 65 percent of

interviewees. A number of whom commented on cost issues, noting that most vaccines are provided

without cost to patients, 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 the question on ranking the four delivery scenarios for benefit to US public health (Figure 2), no

scenario received a majority of number 1 rankings; rather, 20 to 30 percent of interviewees ranked each

scenario as number 1. Administration by a health care professional was ranked number 4 (lowest) by

nearly as many interviewees as ranked it number 1 (highest). While more than half of the interviewees

ranked OTC administration lowest, 30 percent ranked it highest for public health benefit.

Key elements to consider for successful introduction of MNP influenza vaccination

In response to a question in the common questionnaire, each interviewee listed the top three issues

that should be considered for the introduction of a vaccine delivery technology with the long-term goal

of self-administration. The topics mentioned most frequently are presented below, along with

qualitative remarks on these topics from the common and tailored questionnaires.

9

Efficacy and safety

Interviewees who expressed favorable views on the MNP for influenza vaccine commented that their

approval assumed that the efficacy and safety of this delivery method would be equivalent to that of

existing vaccines, with some interviewees suggesting that a direct comparison of efficacy with FluMist®

would be useful. While many were enthusiastic about the possibility of improved vaccine efficacy, they

also noted that an improved safety profile might be necessary for unsupervised self-administration.

Some interviewees commented that influenza vaccines have been associated with anaphylaxis, syncope,

and other serious AEFIs. Those who were most concerned about AEFIs generally favored the use of

MNPs in clinics or self-administration only with supervision. Interviewees also noted that demonstration

of efficacy and safety comparable to existing presentations will be needed for regulatory approval,

subsequent recommendations by professional bodies, incorporation into clinical practices, insurance

reimbursement, and, finally, acceptance and uptake by patients.

Ease of use

Many interviewees expressed enthusiasm for the MNP as a potentially simple, easy-to-use delivery

technology that could save time for health care workers administering vaccines. In order to avoid user

errors that would adversely affect safety or efficacy 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 the errors that have occurred with other self-administered

products.

Cost and reimbursement

Interviewees noted that although cost is a key driver affecting the vaccines offered in clinics, a slightly

higher cost for a delivery technology such as the MNP for influenza vaccine may be acceptable.

10

Interviewees commented that reimbursement rates for vaccine administration are already very low, so

there is limited ability to offset increased vaccine cost through administration efficiencies.

Reimbursement must therefore cover a number of clinical tasks in addition to the actual delivery of the

vaccine, including vaccine ordering, storage, and patient counseling.

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. However, commercial vaccinators and public health programs could

potentially achieve additional savings from reduced cold chain requirements and increased throughput

rates when using MNPs at off-site mass clinics. Reimbursement for OTC purchase could be problematic

for both insurance companies and government immunization programs.

Self-payment could adversely affect immunization rates, particularly among retirees, children, and

chronically ill or low-income patients. 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 a dominant

factor in providers choosing to offer the vaccine.

Education

Currently, education on flu 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 the general public by vaccine manufacturers would be essential for successful

introduction and uptake of the MNP. Education efforts should also reinforce the importance of 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 AEFIs, if they were to arise.

Acceptability

11

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 publics’ 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.

Wear time and application site

When asked about potential MNP wear times between 10 seconds and 10 minutes, interviewees

supported short wear times, stating that this would increase compliance, reduce administrative burden,

and prevent errors, such as early removal. Many interviewees felt that patients should be supervised for

the duration of the MNPs wear time unless patient errors were unlikely to have a negative impact on

safety and efficacy. 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.

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, as well as improve acceptability.

Documentation and reporting

12

Although vaccine registries already exist or are being developed by all states, they are not equally

robust. There is a general trend toward improving documentation and reporting, which is especially

important for OTC delivery. Some state registries require providers to record every individual

vaccinated. 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 purchase. Lack of documentation in the OTC scenario was seen as a particular issue for people at

higher risk of developing influenza-related complications and for health care providers (the latter usually

are required to be vaccinated by their employers).

Thermostability

Interviewees felt that a thermostable MNP would reduce the impact of large amounts of vaccine that

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. In regard to OTC provision of MNPs, some interviewees commented on experiences

with Zostavax®—a vaccine against shingles—that patients purchase at pharmacies and transport to a

physician’s office for administration. Zostavax® must be stored at freezing temperatures at all times, so

transporting it out of the cold chain can result in loss of immunogenicity, which stakeholders believed

was a problem for this vaccine.35 Therefore, thermostability was noted as a critical attribute for self-

administration of MNPs at home. Another advantage of MNPs that do not require refrigeration would

be the possibility of administration by medical specialists, who often do not have refrigerators but could

offer a thermostable vaccine to patients who come to them for reasons other than vaccination.

Sharps and waste disposal

Interviewees strongly preferred MNPs with dissolvable microneedles to solid needles coated with

vaccine because the latter would result in sharps waste and are a potential hazard, if not disposed of

13

properly. Patients could also remove and dispose of dissolvable MNPs themselves. Some respondents

pointed out that a new technology would require a state-by-state implementation plan, as each state

has its own laws and regulations that fit within federal policy for sharps and dangerous waste. California

could serve as a good benchmark due to its conservative disposal policies.

Discussion

Interviewees with expertise in influenza vaccination indicated a high level of support for MNP delivery of

influenza 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.

Interviewees also provided advice that can inform programmatic strategies for MNP influenza

vaccination, such as educating health care providers and the public about the importance of universal

influenza vaccination when introducing the new technology. The major limitation of our survey is the

somewhat low number of KOLs interviewed. However, the KOLs represented a variety of organizations

and the interviews were comprehensive.

A major opportunity for this delivery method is the potential for self-administration, either by

individuals or in supervised groups. Overall, 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. As noted earlier, the coverage gap in the US for healthy adults is large, and there is an

opportunity for addressing this via supervised group administration of MNPs in workplace or college

settings. Individual self-administration could reduce pressure on clinics, particularly since influenza

vaccinations are seasonal. MNPs may also help to increase throughput in clinics and during workplace

group administration. For coverage in the event of a pandemic, MNPs could facilitate mass

immunization. If MNPs require lower amounts of antigen, they may also help to increase the number of

doses produced from limited quantities of vaccine virus.

14

While a large majority of interviewees supported self-administration with the MNP, administration by

health care professionals received universally strong support among the KOLs interviewed. When asked

if their organizations would support administration by a health care professional, all interviewees chose

the two highest scores out of seven; no other scenario received support this high. Responses were less

strongly positive as administration moved farther away from supervision by health care professionals, as

seen in Figure 1. However, even OTC purchase and self-administration had 65 percent of responses with

positive or neutral scores.

Responses on the potential for different administration scenarios to provide public health benefit were

somewhat different from those about organizational support. About 30 percent of interviewees gave

administration by health care professionals a ranking of number 1, but the same proportion gave OTC

self-administration a number 1 ranking (Figure 2). The graphs for these two scenarios appear to trend

toward bimodal distributions, possibly indicating one group more concerned with professional

administration of vaccine and another more concerned with getting vaccine quickly to the largest

number of people.

Although our study was conducted with stakeholders in the US and concerned potential use of MNPs in

this country, we noted that many features of this technology are relevant for immunization programs in

low-income countries. Because MNPs do not require a conventional needle and syringe, training

requirements for providers could be reduced, and this, along with the potential for high patient and

provider acceptability, makes it an attractive option for use in remote and low-resource settings

worldwide.

Interviewees pointed out that since MNP technology is still in development, opportunities exist to create

a device with a short wear time, which would likely reduce errors and increase acceptability by patients

and providers. Demonstrated efficacy and safety at an accessible administration site, such as the

15

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 low-resource settings with limited or no electricity. Minimal, efficient

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. Next steps after

technical development is completed will be clinical studies that generate data demonstrating the

product’s safety and effectiveness for the intended population, in parallel with or followed by data for

self-administration. An interviewee with regulatory expertise also noted that there is currently no formal

guidance or precedent for supervised self-administration of a vaccine. 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.36 Clearly, the complexities of an OTC influenza vaccine for self-administration will require a

careful, stepwise program of introduction.

Both medical care providers and public health experts expressed concerns over documentation of

immunizations by MNPs. Record-keeping is important for coverage estimates and is especially needed

for populations at higher risk of influenza complications and for health care providers required to have

influenza vaccination by their employers.

Among the additional challenges identified by interviewees, concerns about cost and reimbursement

were foremost. As noted in the introduction, LAIV was more expensive than TIV when introduced,37 and

this decreased acceptability when insurance reimbursement was less than the cost of the vaccine.

Interviewees indicated that, if the efficacy via MNP is similar to that of existing vaccines, cost would be a

major factor in providers choosing to offer the vaccine. While there are potential cost savings associated

with faster throughput of patients and reduced cold chain storage and transport requirements, current

16

Medicare reimbursement rates for vaccine administration are on the order of $25.38 This would

presumably be the upper limit of the increase in cost that could be accommodated by the system

without an increase in the total cost of vaccination—far less than the $100 per dose typical of recently

introduced vaccines. However, reimbursement policies for both the vaccine and its administration could

change with health care reform in the US, potentially making cost considerations less important.

Once the necessary clinical studies for safety, efficacy, and self-administration are completed, all

interviewees said the organizations they represented would be highly likely to approve administration of

the patch by health care providers. Many also saw advantages in self-administration, with or without

supervision. The responses of interviewees to quantitative questions in this study—those that gauge

support for the four MNP scenarios of use—reflected the perceived response of the organizations they

represented. Interviewees’ personal opinions, while not formally analyzed in this study, were often

more positive, a result indicating that the technology is desirable but that programmatic challenges

must be considered during product development.

Summary

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 scenarios, reduce the cost of vaccination, and decrease the global morbidity and

mortality associated with influenza. In addition to the technological challenges associated with

producing the patch, developers must be mindful of cost considerations and key product attributes

shared by stakeholders such as usability, wear time, and sharps disposal that can affect how the product

will be received in the US marketplace. These marketplace factors will determine whether a

technologically superior MNP achieves its potential and is successfully introduced with broad uptake in

the US influenza vaccine market.

17

Materials and Methods

We identified KOLs with expertise in different areas of influenza vaccination. Many were current or past

representatives of liaison organizations for the US 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 to 60 minutes with each

interviewee. The common questionnaire included questions requiring both quantitative and qualitative

answers. The tailored questionnaire included between three and thirteen qualitative questions,

depending on the interviewee’s area of expertise.

The first question requiring quantitative answers in the common questionnaire asked how supportive

the organization represented by the interviewee would be of MNP for influenza vaccination in different

scenarios. Interviewees were asked to score the following scenarios for level of support: (1) delivery by

health care professionals; (2) self-administration by groups of people under the supervision of a health

care professional; (3) self-administration by prescription; and (4) self-administration via OTC purchase.

The last scenario was qualified as follows: the MNP would have had several years on the market as a

prescription product, with no AEFIs beyond that expected with current influenza vaccinations. For each

scenario, interviewees were asked to select a number from 1 to 7 to indicate perceived support by their

18

organization or institution, where 1 was highest support, 4 was neutral, and 7 was highest opposition.

Follow-up questions asked the interviewee to explain his/her selected level of support.

The second quantitative question asked interviewees to rank the four scenarios in order of most to least

beneficial for US public health, considering the potential for increasing coverage for influenza

vaccination. For this question, interviewees were not instructed to speak for their organizations; the

answers were to reflect their expertise in the field.

Interviewees were also 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 interview questions requiring qualitative answers 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. Answers to these questions informed the discussion 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.

Acknowledgements

This work was supported with funding from the National Institute of Biomedical Imaging and

Bioengineering and through a sub agreement with Georgia Institute of Technology. The authors would

like to thank Mark Prausnitz, James Norman and Sebastien Henry at Georgia Institute of Technology, as

19

well as Savitha Swaminathan, Amy Wales, Marjorie Murray, and Patricia Logan at PATH for their

assistance in the development of this article.

20

References

1. World Health Organization. Influenza (seasonal) fact sheet [Internet]. Geneva: World Health

Organization; 2009. Available from: http://www.who.int/mediacentre/factsheets/fs211/en/.

2. Murray CJ, Lopez AD, Chin B, Feehan D, Hill KH. Estimation of potential global pandemic influenza

mortality on the basis of vital registry data from the 1918-20 pandemic: a quantitative analysis.

Lancet 2006; 368(9554): 2211–8.

3. Centers for Disease Control and Prevention. Estimates of deaths associated with seasonal

influenza—United States, 1976-2007. MMWR Morb Mortal Wkly Rep 2010; 59(33): 1057–62.

4. Centers for Disease Control and Prevention. Flu vaccination coverage, United States, 2011-12

influenza season [Internet]. Atlanta, GA: Centers for Disease Control and Prevention; 2012.

Available from: http://www.cdc.gov/flu/professionals/vaccination/coverage_1112estimates.htm.

5. del Pilar MM, Weldon WC, Zarnitsyn VG, Koutsonanos DG, Akbari H, Skountzou I, Jacob J,

Prausnitz MR, Compans RW. Local response to microneedle-based influenza immunization in the

skin. M Bio 2012; 3(2): e00012.

6. Koutsonanos DG, Vassilieva EV, Stavropoulou A, Zarnitsyn VG, Esser ES, Taherbhai MT, Prausnitz

MR, Compans RW, Skountzou I. Delivery of subunit influenza vaccine to skin with microneedles

improves immunogenicity and long-lived protection. Sci Rep 2012; 2: 357.

7. Koutsonanos DG, del Pilar MM, Zarnitsyn VG, Jacob J, Prausnitz MR, Compans RW, Skountzou I.

Serological memory and long-term protection to novel H1N1 influenza virus after skin vaccination.

J Infect Dis 2011; 204(4): 582–91.

21

8. Martin MP, Seth S, Koutsonanos DG, Jacob J, Compans RW, Skountzou I. Adjuvanted influenza

vaccine administered intradermally elicits robust long-term immune responses that confer

protection from lethal challenge. PLoS One 2010; 5(5): e10897.

9. Weldon WC, Martin MP, Zarnitsyn V, Wang B, Koutsonanos D, Skountzou I, Prausnitz MR,

Compans RW. Microneedle vaccination with stabilized recombinant influenza virus hemagglutinin

induces improved protective immunity. Clin Vaccine Immunol 2011; 18(4): 647–54.

10. Quan FS, Kim YC, Vunnava A, Yoo DG, Song JM, Prausnitz MR, Compans RW, Kang SM. Intradermal

vaccination with influenza virus-like particles by using microneedles induces protection superior to

that with intramuscular immunization. J Virol 2010; 84(15): 7760–9.

11. Song JM, Kim YC, Lipatov AS, Pearton M, Davis CT, Yoo DG, Park KM, Chen LM, Quan FS, Birchall JC,

et al. Microneedle delivery of H5N1 influenza virus-like particles to the skin induces long-lasting B-

and T-cell responses in mice. Clin Vaccine Immunol 2010; 17(9): 1381–9.

12. Kim YC, Song JM, Lipatov AS, Choi SO, Lee JW, Donis RO, Compans RW, Kang SM, Prausnitz MR.

Increased immunogenicity of avian influenza DNA vaccine delivered to the skin using a

microneedle patch. Eur J Pharm Biopharm 2012; 81(2): 239–47.

13. Prausnitz MR, Mikszta JA, Cormier M, Andrianov AK. Microneedle-based vaccines. Curr Top

Microbiol Immunol 2009; 333: 369–93.

14. Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev

2012; 64(14): 1547–68.

22

15. Hung IF, Levin Y, To KK, Chan KH, Zhang AJ, Li P, Li C, Xu T, Wong TY, Yuen KY. Dose sparing

intradermal trivalent influenza (2010/2011) vaccination overcomes reduced immunogenicity of

the 2009 H1N1 strain. Vaccine 2012; 30(45): 6427–35.

16. Gorse GJ, Falsey AR, Fling JA, Poling TL, Strout CB, Tsang PH. Intradermally-administered influenza

virus vaccine is safe and immunogenic in healthy adults 18-64 years of age. Vaccine 2013; 31(19):

2358–65.

17. Frenck RW Jr, Belshe R, Brady RC, Winokur PL, Campbell JD, Treanor J, Hay CM, Dekker CL, Walter

EB Jr, Cate TR, et al. Comparison of the immunogenicity and safety of a split-virion, inactivated,

trivalent influenza vaccine (Fluzone®) administered by intradermal and intramuscular route in

healthy adults. Vaccine 2011; 29(34): 5666–74.

18. Van Damme P, Oosterhuis-Kafeja F, Van der WM, Almagor Y, Sharon O, Levin Y. Safety and efficacy

of a novel microneedle device for dose sparing intradermal influenza vaccination in healthy adults.

Vaccine 2009; 27(3): 454–9.

19. Van Damme P, Arnou R, Kafeja F, Fiquet A, Richard P, Thomas S, Meghlaoui G, Samson SI, Ledesma

E. Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using

two serological techniques: a randomised comparative study. BMC Infect Dis 2010; 10: 134.

20. Sullivan SP, Koutsonanos DG, del Pilar MM, Lee JW, Zarnitsyn V, Choi SO, Murthy N, Compans RW,

Skountzou I, Prausnitz MR. Dissolving polymer microneedle patches for influenza vaccination. Nat

Med 2010; 16(8): 915–20.

21. Nichol KL, Mendelman PM, Mallon KP, Jackson LA, Gorse GJ, Belshe RB, Glezen WP, Wittes J.

Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a

randomized controlled trial. JAMA 1999; 282(2): 137–44.

23

22. Ambrose CS, Wu X. The safety and effectiveness of self-administration of intranasal live

attenuated influenza vaccine in adults. Vaccine 2013; 31(6): 857–60.

23. Carter NJ, Curran MP. Live attenuated influenza vaccine (FluMist®; Fluenz™): a review of its use in

the prevention of seasonal influenza in children and adults. Drugs 2011; 71(12): 1591–622.

24. Belshe RB, Ambrose CS, Yi T. Safety and efficacy of live attenuated influenza vaccine in children 2-7

years of age. Vaccine 2008; 26 Suppl 4: D10–6.

25. Luce BR, Nichol KL, Belshe RB, Frick KD, Li SX, Boscoe A, Rousculp MD, Mahadevia PJ. Cost-

effectiveness of live attenuated influenza vaccine versus inactivated influenza vaccine among

children aged 24-59 months in the United States. Vaccine 2008; 26(23): 2841–8.

26. Ansaldi F, de Florentiis D, Durando P, Icardi G. Fluzone(®) intradermal vaccine: a promising new

chance to increase the acceptability of influenza vaccination in adults. Expert Rev Vaccines 2012;

11(1): 17–25.

27. Arnou R, Eavis P, Pardo JR, Ambrozaitis A, Kazek MP, Weber F. Immunogenicity, large scale safety

and lot consistency of an intradermal influenza vaccine in adults aged 18-60 years: randomized,

controlled, phase III trial. Hum Vaccin 2010; 6(4): 346–54.

28. Foy JE, Hendriksz T, Malouf P, Tobin A. Acceptability of fluzone intradermal vaccine to patients and

vaccine administrators. J Am Osteopath Assoc 2013; 113(2): 134–43.

29. Dhont PA, Albert A, Brenders P, Podwapinska A, Pollet A, Scheveneels D, Tihon F, Verheyden I,

Victor J, Samson SI. Acceptability of Intanza® 15 mug intradermal influenza vaccine in Belgium

during the 2010-2011 influenza season. Adv Ther 2012; 29(6): 562–77.

24

30. Reygrobellet C, Viala-Danten M, Meunier J, Weber F, Nguyen VH. Perception and acceptance of

intradermal influenza vaccination: Patient reported outcomes from phase 3 clinical trials. Hum

Vaccin 2010; 6(4): 336–45.

31. Coleman BL, McGeer AJ, Halperin SA, Landley JM, Shamout Y, Taddio A, Shah V, McNeil SA. A

randomized control trial comparing immunogenicity, safety, and preference for self- versus nurse-

administered intradermal influenza vaccine. Vaccine 2012; 30(44): 6287–93.

32. Roos R. FDA approves Sanofi's intradermal flu vaccine [Internet]. Minneapolis, MN: University of

Minnesota; 2011. Available from:

http://www.cidrap.umn.edu/cidrap/content/influenza/general/news/may1011intradermal.html.

33. Immunization Action Coalition. Zoster (shingles) [Internet]. St. Paul, MN: Immunization Action

Coalition; 2011. Available from: http://www.immunize.org/askexperts/experts_zos.asp.

34. Cryz SJ Jr. Patient compliance in the use of Vivotif Berna® vaccine, typhoid vaccine, live oral Ty21a.

J Travel Med 1998; 5(1): 14–7.

35. Nichol KL, Mallon KP, Mendelman PM. Cost benefit of influenza vaccination in healthy, working

adults: an economic analysis based on the results of a clinical trial of trivalent live attenuated

influenza virus vaccine. Vaccine 2003; 21(17–18): 2207–17.

36. Centers for Medicare & Medicaid Services. Physician Fee Schedule Search [Internet]. Baltimore,

MD: Centers for Medicare & Medicaid Services; 2013. Available from:

http://www.cms.gov/apps/physician-fee-schedule/license-agreement.aspx.

25

Figure Legends

Figure 1.

1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7Health care worker

adminsupervised self Prescription self OTC

0

2

4

6

8

10

12

14

16

18

Scenarios, with scoring of 1 to 7

Num

ber o

f res

pond

ents

Title: Perceived support from health care organizations for administration of influenza vaccine

microneedle patches in different scenarios.

Legend: Distribution of interviewees scoring microneedle patch influenza vaccination scenarios on a

scale of 1 to 7, where 1 is highest support, 4 is neutral, and 7 is highest opposition. Interviewees were

asked to indicate the support they expected from the organization they represented. Number of

interviewees scoring each scenario (not all respondents scored all scenarios): health care professional:

26

22; supervised group self-administration: 21; prescription self-administration: 19; over-the-counter self-

administration: 20.

Figure 2.

1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

Healthcare pro-fessional

Supervised group Prescription Over the counter

0

2

4

6

8

10

12

Scenarios, with ranking of 1 to 4

Num

ber o

f Res

pond

ents

Title: Perceived public health benefit of administration of influenza vaccine microneedle patches in

different scenarios.

Legend: Distribution of interviewees ranking microneedle patch influenza vaccination scenarios on a 1 to

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 United States 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

27

professional administration: 19; supervised group self-administration: 18; prescription self-

administration: 18; over-the-counter self-administration: 17.

28