1. Inactivated Influenza Vaccine Administration via Microneedle Patch; a Novel Vaccine Delivery System Karen Mask, RN, BSN MPH Candidate April 11, 2014

2. Background  Seasonal influenza leads to significant morbidity & mortality each year.  Worldwide:  3 to 5 million cases of severe illness  250,000 to 500,000 deaths per year (WHO, 2009)  United States:  >220,000 hospitalizations  36,000 deaths per year (Thompson, 2004)  Vaccination is the most effective way of preventing influenza.  CDC recommends annual flu vaccine for everyone 6 months and older

3. Background  Despite recommendations, early season vaccination coverage was only 39.5% for 2013-2014 flu season (CDC, 2013) http://www.cdc.gov/flu/fluvaxview/nifs-estimates-nov2013.htm

4. Background  Barriers to flu vaccination  Needle phobia  Access to vaccine  Vaccine acceptability  Need for trained personnel to administer vaccine  Lack of financial and physical space resources

5. Background  Microneedle patches  Micron-scale (10 -6 m) needles, minimally invasive, eliminate sharps waste, painless http://drugdelivery.chbe.gatech.edu/gallery_microneedles.html

6. Background  Microneedle patch product administration http://drugdelivery.chbe.gatech.edu/Images/Image_gallery/Full/patch-application.jpg

7. Background Microneedle patch pre-clinical studies  Mice model microneedle study (Zhu et al, 2009)  Vaccinated with H1N1 and H3N2 strains via microneedle patch  Protected when challenged with lethal flu dose  Rabies, BCG, HPV vaccine studies  Favorable safety profile to date  Acceptability study (Norman et al, 2014)  increased intent to vaccinate with microneedle patches (from 44% to 65%)  majority preference to self-vaccinate (64%)

8. Rationale  Flu vaccination is highly effective in preventing disease but barriers to vaccination limit the protective impact of influenza vaccination programs.  Microneedle patch delivery system has potential to greatly impact acceptability and ease of delivery of inactivated flu vaccine.  Painless, simple administration  Effect more profound in pandemic flu situation  Potential to expand beyond influenza vaccine.  Reduction in influenza related morbidity & mortality

9. Internship  The Hope Clinic of the Emory Vaccine Center; Emory University  National Institutes of Health (NIH) funded Vaccine Treatment and Evaluation Unit (VTEU)  Preceptor – Dr. Nadine Rouphael  Assistant Professor Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine

10. Special Project  A Phase I Study of the Safety, Reactogenicity, Acceptability and Immunogenicity of Inactivated Influenza Vaccine Delivered by Microneedle Patch or by Hypodermic Needle (working title - in development)  Microneedle technology – Dr. Mark Prausnitz  Clinical trial development and execution – Drs. Nadine Rouphael and Mark Mulligan  Sponsored by: National Institute of Biomedical Imaging and Bioengineering (NIBIB)

11. Objectives  Project Development  Establish collaborative working group  Microneedle team develop concept  Clinical team develop clinical trial protocol  Secure Investigational New Drug (IND) approval  Secure Institutional Review Board (IRB) approvals  Complete clinical trial preparation  Clinical Trial  Evaluate safety and reactogenicity of study product  Evaluate immunogenicity of study product  Compare immunogenicity of staff vs. self administration

12. Methods  Literature search  Morbidity & mortality of influenza, microneedle development and testing, public health programs and roadblocks  CDC Ecological Framework  Individual factors (needle phobia)   Relationship factors (family members decline vaccine)   Community factors (herd immunity)   Societal factors (policy)  Policy analysis  Vaccination recommendations vs. requirements

13. Methods  Financial management  Grant funding coverage and restrictions  Program planning & evaluation  Clinical trial design: subject recruitment, blinding, statistical significance  Results analysis – safety, reactogenicity, immunogenicity

14. Results  Established collaborative working group  Microneedle development team at Georgia Tech led by Dr. Mark Prausnitz  Clinical trial development team at Emory University led by Dr. Nadine Rouphael  Team conference calls and in-person development meetings  Microneedle patch concept developed by Georgia Tech  Delivered to Emory University for study protocol development

15. Results  Emory clinical trial team developed draft study design and protocol  Delivered to Georgia Tech for review and pre-IND submission  Progress towards securing IND / IRB approvals  Pre-IND meeting held; study team incorporating FDA comments in protocol and preparing FDA response  Working on final IND submissions  Complete clinical trial preparation – Fall 2014/Spring 2015  Clinical trial – Spring/Summer 2015

16. Results - Timeline Pre-June 2013Winter 2015 Spring 2015Summer 2014 Fall 2014Summer 2013Spring 2014 Concept Development Protocol Development IND Application Clinic Preparations Clinical Trial Collaborative Group

17. Discussion  Microneedle technology is very early in development  A project of this scope takes several years to develop, implement and analyze the results  Front end of the project is primarily administrative, but critical to achieving accurate, reliable, and generalizable data  As a first-in-humans trial, this protocol will need to be replicated and/or expanded to ensure results are accurate and generalizable.

18. Implications  Improved acceptability of annual influenza vaccination  Pain reduction, improved access to vaccine, potential for self-vaccination  Increased compliance to annual influenza vaccination recommendations  Potential decreased influenza morbidity and mortality through improved immunogenicity of intradermal vaccination  Targets antigen-presenting Langerhans and dermal dendritic cells.

19. Implications  Potential for improved and expanded global vaccination program (provided methods are generalizable to other vaccines)  Improved access to vaccine  Improved vaccine stability and less stringent cold chain requirements  Decreased reliance on administration by trained personnel  Increased acceptability  Expansion of collaborative partnerships across concentration areas such as engineering and healthcare

20. MPH Core Competencies Strengthened  Monitoring health status to identify and solve community health problems  Mobilizing community partnerships and action to identify and solve health problems  Evaluating effectiveness, accessibility and quality of personal and population-based health services  Conducting research for new insights and innovative solutions to health problems

21. Concentration Competencies Strengthened  Identify & understand the historical context of epidemiology, epidemiologic terminology, study designs & methodology  Demonstrate communication skills key to public health workforce participation and advocacy  Effectively manage public health programs and projects  Demonstrate the principles of problem solving and crisis management

22. Lessons Learned  Challenges associated with Intellectual Property  Challenges in collaborative partnerships between academic institutions  Research funding environment  Interactions with governmental agencies and regulatory consultant groups

23. Thank You  Dr. Nadine Rouphael – Emory University  The clinical research team at the Hope Clinic of the Emory Vaccine Center.  Dr. Mark Prausnitz and the microneedle development team at the Georgia Institute of Technology  Dr. John Lednicky – University of Florida

24. References Centers for Disease Control and Prevention. (2013). National early season flu vaccination coverage, United States. Retrieved March 30, 2014 from http://www.cdc.gov/flu/fluvaxview/nifs-estimates-nov2013.htm http://www.cdc.gov/flu/fluvaxview/nifs-estimates-nov2013.htm Norman, J.J., Arya, J.M., McClain, M.A., Frew, P.M., Meltzer, M.I., & Prausnitz, M.R. (2014). Microneedle patches: Usability and acceptability for self- vaccination against influenza. Vaccine, 32(16), 1856-1862. Thompson, W.W. (2004). Influenza-associated hospitalizations in the United States. Journal of the American Medical Association, 292(11), 1333- 1340. World Health Organization. (2009, April). Influenza (Seasonal). WHO Fact Sheet, 211. Zhu, Q., Zarnitsyn, V.G., Ye, L., Wen, Z, Gao, Y., Pan, L., Skountzou, I., et al. (2009). Immunization by vaccine-coated microneedle arrays protects against lethal influenza challenge. Proceedings of the National Academy of Sciences of the United States of America, 106(19), 7968- 7973.

25. Questions http://drugdelivery.chbe.gatech.edu/Images/Image_gallery/Full/microneedle-patch2.jpg