Drug Discovery, Development & Delivery

Needle-free Injection – Eradicating Diseases to Improve Global Health

vaccine delivery into certain tissue IM and SC Needle-free Injections Needle-free injection technology has depths of the body, whether it be (0.5mL Disposable Syringe) evolved significantly over the last 50 intramuscular (into the muscle, see years and is now accepted in many 1. Prepare the Injector routine immunisation settings as a safe Figure 1), subcutaneous (below the and effective vaccine delivery method. dermis level), or intradermal injection Disposable syringe jet injectors are now (directly into the dermis level, see being used for the delivery of vaccines Figure 2). Additionally, the needle-free to eradicate polio, MMR, and influenza, syringe is auto-disabling, eliminating and are showing promising results in the possibility of reuse, and calibrated vaccine clinical trials for the Zika virus for a specific vaccine volume, either and HPV. The devices are fast, safe, 0.5mL or 0.1mL dose. While needle and easy to use, with most providers injection is largely dependent upon trained in less than 20 minutes. the provider’s technique, which can have a wide variation in terms Figure 3a Delivering vaccines without a of accuracy and injection speeds, needle addresses a host of issues needle-free injection uses a simple 2. Fill Syringe surrounding needles. For example, point-and-click approach, resulting there are about 800,000 needle stick in consistent delivery every time. injuries annually in the US1 and this is an even larger issue internationally. As shown in Figures 3a-3d and Accidental needle sticks have been an 4a–4e, the needle-free injectors ongoing safety issue for providers and are easy to use, employing a simple patients, accounting for 33,800 new four-step process, and most users HIV infections, 1.7 million hepatitis are self or web-based trained in less B infections and 315,000 hepatitis C than 20 minutes. 2 infections annually. In addition, as Figure 3b many as 500 million used needles are added to trash dumps and landfills 3. Load Injector every year, with 75 million of those needles potentially infected with blood-borne illnesses.2 No needle means no needle-trash, reduction of needle stick injuries and the potential Figure 1: The 0.5mL PharmaJet® Stratis® Injector for improved acceptability, coverage delivers vaccines to the intramuscular and efficiency of vaccine delivery. (IM) and subcutaneous (SC) depths.

How Needle-free Injectors Work Figure 3c The spring-powered injectors use a narrow stream of fluid that goes 4. Give Injection through the skin in about 1/10 of a second. There is no power or electricity needed. Needle-free Figure 2: The 0.1mL PharmaJet® Tropis® Injector injectors are precisely designed for delivers vaccines to the intradermal (ID) depth.

Figure 3d

The workflow using the PharmaJet intramuscular/subcutaneous needle- free device (Stratis) is comparable to needle-syringe (See YouTube video: https://www.youtube.com/ watch?v=0ag-v7bv960).

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ID Needle-free Injections (0.1mL support the global demand, and this schedule. These countries include Disposable Syringe) shortage is anticipated to continue Argentina, Bolivia, Brazil, Chile, for years to come.3,4 As part of its Colombia, Cuba, Ecuador, El Salvador, 1. Prepare the Injector Global Polio Eradication Initiative Honduras, Nicaragua, Paraguay, Peru, (GPEI), the World Health Organization Uruguay and Venezuela.”10 has been working closely with PATH and the Gates Foundation to While the clinical studies provided clinically evaluate alternate delivery a workable solution for the supply options and technologies, including shortage, they also recognised the fractional dose needle-free delivery, ongoing difficulty of administering to address increases in demand and vaccines intradermally with the 5 Figure 4a vaccine supply shortages. Mantoux technique using a needle and 2. Fill Syringe syringe. Administration can be slow, Multiple clinical studies evaluated technically difficult, inconsistent, the effectiveness of one full dose of and painful (see Figures 6a and 6b). polio vaccine (0.5mL) administered Additionally, many healthcare workers intramuscularly vs. two fractional are not familiar with the intradermal doses (0.1mL) administered intra- technique, making it unsuitable for dermally, with either a needle and house-to-house campaigns, and the syringe or a needle-free injection inconsistent delivery is less than ideal Figure 4b device (PharmaJet® Tropis®). As for mass immunisations. Conversely, 3. Load Injector summarised in Figure 5, the studies the PharmaJet Needle-free Injector found that two fractional doses of is easy-to-use and requires minimal intradermal IPV (fIPV) (2 doses x 0.1mL) training (see Figures 6c and 6d). were superior to one full dose (0.5mL) Healthcare workers that have used administered intramuscularly6, the device found that they quickly thus using 60% less vaccine.7 This became proficient in providing means 2–3x more children can be consistent and rapid injections.11 Figure 4c vaccinated with the same amount of 4. Give Injection vaccine. Comparing Needles to Needle-free for Intradermal Injections

Mantoux Technique (Needle)

Figure 4d Deltoid Injection Figure 6a Figure 6b

Needle-free Technique

Figure 5. IPV Fractional dose immunogenicity8

Fractional dose polio vaccine Figure 4e Lateral Thigh Injection delivery has been endorsed by the WHO and the Indian Ministry of The workflow using the Pharma- Health, as it also provides a more Figure 6c Figure 6d Jet intradermal needle-free device cost-effective option. Specifically, Figure 6: Comparison of Mantoux technique with needle (a and b) to Needle-free technique (c and d) (Tropis) is 25% faster than a needle- the WHO Strategic Advisory Group syringe (See YouTube video: https://www. of Experts (SAGE) recommends that The needle-free injector’s simple youtube.com/watch?v=prwEHS3KN_8). countries adopt a two fractional point-and-click design ensures dose IPV schedule in the routine consistent and accurate intradermal Protecting Every Last Child: Fractional immunisation and outbreak response. 9 injection. Additionally, the preparation Dose Delivery and Polio Eradication The Technical Advisory Group on and administration time is 50–70% Polio is a crippling and potentially Vaccine-preventable Diseases less than needle and syringe, making fatal infectious disease, mainly (TAG) and Pan American Health it an ideal choice for vaccination affecting children under five years Organization (PAHO) endorsement campaigns.12 And, because there is old, and there is no cure. The move states that “countries that administer no needle, healthcare workers can from oral polio vaccine (OPV) to more than 100,000 doses of IPV work fast and not have to worry injectable polio vaccine (IPV) to each year and have the capability to about needle sticks. The PharmaJet eliminate “wild” types of polio has adequately train health care workers needle-free device is currently being created a worldwide shortage. It is and supervise implementation used as part of the polio eradication estimated that less than half the should immediately begin to prepare effort in Bangladesh, Cuba, Gambia amount of polio vaccine is available to to implement a fractional dose IPV and Pakistan.

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MMR Vaccine Delivered to a traditional needle and syringe one study showed that only about without a Needle delivery. This was the first definitive 20% of healthy working-age adults Measles is a leading cause of childhood non-inferiority study to measure aged 18–49 years receive an annual deaths globally, with 3 million cases the immune responses to all three flu shot.20,21,22 diagnosed and nearly 1 million deaths influenza viruses induced after each year. The WHO estimates that administration of a seasonal flu During the 2016–17 influenza season global immunisation coverage for vaccine by a jet injection device as the PharmaJet Stratis® needle-free measles containing vaccine in 2013 compared to a needle and syringe. injection system was used in multiple was 84%, with many countries still The study also found that 89 per cent workplace health influenza clinics. well below the recommended 95% of the people receiving the needle- There were 35 vaccinations events, level required to interrupt endemic free injection reported they would which included employees from measles transmission. For example, choose a needle-free injection over BP Oil, Cargill, Denver International in India, the coverage averages only needle and syringe for their next Airport, Ernst & Young, Morgan 66%, with rates below 50% in many injection.18 Stanley, Terumo BCT, TriNet, and parts of the country.13 Xerox, among others. Surveys were Patient and Provider Feedback completed by patients and caregivers A recently completed Phase IV – using Needle-free to Increase to collect feedback regarding the clinical study, supported by the Gates Compliance and Productivity acceptability and usability of the Foundation and PATH, included 300+ The Centers for Disease Control device, whether it should be an children aged 15-18 months over a and Prevention (CDC) recommends option for next year, and the potential 12-month period. The objective of annual flu shots for all adults, yet to increase influenza immunisation the study was to demonstrate the only around 43% of them receive coverage at a particular site.23 non-inferiority of seropositivity of the yearly vaccination; many citing MMR vaccine administered using a fear of needles as a reason for Patient Surveys the needle-free injector to MMR non-compliance. Needle-free devices Overall, 1018 surveys were completed vaccine administered by needle and provide an option for the one in four by working individuals, 18-64 years of syringe for all three components adults who have a fear of needles.17,19 age, who received a needle-free flu of the vaccine. Secondarily, there shot at one of the influenza vaccination was an objective to assess and More than half of adults aged events. Figure 7 shows results for each compare the safety of MMR vaccine 20–64 years who are employed are of the three key questions regarding administered by needle-free jet affected by the flu, resulting in about satisfaction, likelihood of choosing a injector vs. needle and syringe. 111 million lost working days every needle-free injection next year, and The results showed comparable year. Workplace health influenza likelihood of recommending a needle- non-inferiority performance and immunisation programmes are an free injection. In summary (see Figure safety to that of the traditional needle important factor to consider for 7a-c): and syringe.14 Needle-free injection addressing decreased productivity, is being used to administer the when a simple flu shot could • The majority of patients (97%) MMR vaccine TRESIVAC NF (needle- decrease work absenteeism and were satisfied with the needle- free) in Cambodia and India. significantly reduce the spread of free shot influenza to others. According to the • 95% of patients responded that Needle-free Flu Shots US National Institute for Occupational they would choose needle-free Influenza is one of the most common Safety and Health (NIOSH), the cost again next year preventable infectious diseases. In associated with sick days and lost • 95% said they were likely to the US alone, approximately 10-20% productivity is approximately $7 recommend the needle-free of the population contracts influenza billion in the US annually. Despite option to friends and family each year, which accounts for about the potential benefits of vaccination, 226,000 hospitalisations and 36,000 How satisfied were you with today’s needle-free flu shot? deaths annually.15 While morbidity and mortality affect mostly the young and old, all age groups are affected. The US Department of Health and Human Services (HHS) has established a Healthy People 2020 campaign that includes the goal of 70 per cent flu Figure 7a: Satisfaction with needle-free injection vaccination compliance by the year For next year’s flu vaccination, will you choose to receive your flu shot with a 2020, versus 43 per cent in 2016.16,17 needle-free injection?

In 2014, The Lancet published a study that demonstrated that the delivery of an influenza vaccine with the PharmaJet needle-free jet injector compared favourably Figure 7b: Likelihood of choosing a needle-free injection next year

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How likely are you to recommend a needle-free flu shot to your family and friends? Future Vaccines NIH Clinical Trial for Needle-free Zika Vaccine Shows Promise There are now more than 30,000 diagnosed Zika cases in every state but Alaska, with most of those in the US territory of Puerto Rico. Because it is now known that Zika can be Figure 7c: Likelihood of recommending a needle-free injection to family or friends. transmitted through mosquitoes, blood Figure 7: Patient survey results regarding: a) satisfaction with the needle-free injection they just received; and sex, that number is expected to b) likelihood of choosing a needle-free injection next year; and c) likelihood of recommending a needle- rise. The National Institute of Allergy free injection to family or friends. and Infectious Diseases (NIAID) within Healthcare Provider Surveys • 91% said they were satisfied with the National Institutes of Health (NIH) ease of use is using the Stratis 0.5mL needle-free Combining surveys from providers • 87% would like the option of device in a DNA vaccine clinical trial at these flu clinics and those from needle-free next year for a Zika vaccine, and the results are previous seasons, there were a • 82% said they would be likely to promising. DNA vaccines are a rapidly total of 67 healthcare providers that recommend needle-free flu shots developing field. Unlike traditional completed the survey, including to their colleagues vaccines, like for flu or measles, that contract nurses, pharmacists and • 45% thought that offering a contain whole viruses, DNA vaccines occupational health nurses. (24) In needle-free option could increase contain just a tiny piece of a virus’s summary (see Figure 8a-d): flu vaccinations by more than 10% genetic code, making them safe and at their facility. easy to work with. For these vaccines to work, the DNA vaccine must get How satisfied were you with the ease of use? directly into the cells. For that purpose, a new delivery method was needed.25 Various pre-clinical and clinical preliminary studies have shown that the performance of nucleic acid-based vaccines (DNA and RNA) when injected with needle-free injectors have been superior to needle-syringe delivery and Figure 8a: Satisfaction with ease of use at least equivalent to other delivery For next year’s flu vaccinations, would you like the option of needle-free shots at methods.26 your facility? The NIH announced the start of the Phase II Zika vaccine trial in March 2017, which consists of two studies in the US, Central and South America. Part A will further evaluate the vaccine’s safety and ability to stimulate an immune Figure 8b: Wanting the option of needle-free shots in their facility response in participants, and assess the optimal dose for administration. How likely are you to recommend needle-free flu shot to your colleagues? Part B will attempt to determine if the vaccine can effectively prevent disease caused by Zika infection. "A safe and effective vaccine is urgently needed to prevent the often-devastating birth defects that can result from Zika virus infection during pregnancy," says NIAID Figure 8c: Likelihood of recommending to colleagues Director, Dr Anthony S. Fauci. "Evidence How much could your flu vaccinations increase next year by offering the option of a also is accumulating that Zika can needle-free flu shot? cause a variety of health problems in adults as well."27

Needle-free Providing a More Comfortable Experience – HPV Vaccine Human papillomavirus or HPV is the main cause of cervical cancer Figure 8d: How much vaccination could be increased by offering needle-free affecting 530,000 women annually Figure 8: Healthcare provider survey results regarding: a) satisfaction with ease of use; b) needle-free and an additional 10 million women option for next year c) likelihood to recommend to colleagues; and d) how much vaccination could be increased by offering needle-free are impacted by a long pre-invasive

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disease called cervical intraepithelial Demand Update, September 2016, Unicef non-inferiority trial, McAllister, L et al, neoplasis (CIN). Current standard Supply Division; https://www.unicef.org/ Lancet 2014: 384:674-81 supply/files/Inactivated_Polio_Vaccine_ 19. Survey of the prevalence of immunization therapy for CIN 2/3 varies between (IPV)_-_september_2016.pdf non-compliance due to needle fears countries and regions and often 5. To help end polio, intradermal delivery takes in children and adults. Taddio A, Ipp M, involves surgical removal of the affected center stage, Vaccine and Pharmaceutical Thivakaran S, et al. Vaccine 2012: 30: 4807- Technologies News and Updates – PATH, 4812 Web. tissue. These invasive procedures are May 2016, http://www.path.org/newsletters/ 20. Centers for Disease Control and Prevention associated with bleeding, infection, vaccine-technologies-newsletter.php Website, Frequently Asked Flu Questions cervical stenosis, scarring and, most 6. Immunogenicity to poliovirus type 2016-2017 Influenza Season. Accessed importantly, pre-term deliveries in 2 following two doses of fractional October 2016 (http://www.cdc.gov/flu/about/ intradermal inactivated poliovirus vaccine: season/flu-season-2016-2017.htm subsequent pregnancies. As a result, A novel dose sparing immunization 21. Lee BY, et al, Economics of Employer- there is a significant need for an schedule. Anand A., et al. Vaccine, 2017 May sponsored workplace vaccination to prevent effective therapeutic vaccine to treat 19:35(22):2993-2998; https://www.ncbi.nlm. pandemic and seasonal influenza. Vaccine, nih.gov/pubmed/28434691 existing HPV infection and associated 2010, Vol. 28 (37), pp 5952-5959 7. Early priming with inactivated poliovirus 22. US Centers for Disease Control and pre-malignancies and malignancies vaccine (IPV) and intradermal fractional dose Prevention Website, National Institute of of the cervix and thereby prevent the IPV administered by a microneedle device: Occupational Safety and Health Activities: development of cervical cancer caused A randomized controlled trial, Anand A., et Surveillance Tracking Influenza Cases and 28,29 al., Vaccine. 2017 May 19;35(22):2993-2998. Preventive Measures. Accessed 2017. https:// by human papillomavirus. doi: 10.1016/j.vaccine.2017.03.008. Epub 2017 www.cdc.gov/niosh/topics/flu/surveillance. Apr 20. html In late 2016, Vaccibody AS 8. Use of fractional dose IPV in routine 23. Needle-free jet injection in workplace announced the results of the Phase immunization programmes: Considerations influenza clinics, Miller, T, et al., for decision-making, WHO Polio Global ONdrugDELIVERY, May 2017, Issue No. 75, I clinical trial of their VB10.16 HPV Eradication Initiative, March 2017; pp. 18-21, http://www.ondrugdelivery.com/ vaccine delivered with the Stratis http://www.who.int/immunization/ publications/75/PharmaJet.pdf needle-free jet injector. Martin Bonde, diseases/poliomyelitis/endgame_ 24. Doc. #61-10194, Third Party Review – objective2/inactivated_polio_vaccine/ Stratis PMS Health Care Provider. Internal the CEO of Vaccibody AS noted, “While fIPV_considerations_for_decision-making_ PharmaJet Document, 2015. other DNA vaccines developed for this March2017.pdf?ua=1 25. The Zika Virus, Nov. 6, 2016, CBS 60 indication require delivery with in vivo 9. Weekly epidemiological record, World Health Minutes,( http://www.cbsnbews.com/ electroporation, which is quite painful Organization, June 2, 2017, page 309, http:// news/60-minutes-zika-in-the-united- apps.who.int/iris/bitstream/10665/255611/1/ states-mosquito-disease/) for the patients, VB10.16 is delivered WER9222.pdf?ua=1 26. Safety and immunogenicity of a mRNA by needle-free injection, which we 10. Ad hoc Virtual TAG Meeting 20176, 10, March rabies vaccine in healthy adults: an open- believe improves patient compliance 2017, Washington D.C., USA, p. 7; http://www. label, non-randomised, prospective, tremendously and will be a significant who.int/immunization/sage/meetings/2017/ first-in-human phase 1 clinical trial. april/6_2017_TAG_Ad-hoc_Meeting_Report_ Alberer M et al. Lancet. 2017 Jul 25. pii: asset in further development of this EN.pdf S0140-6736(17)31665-3. product.”29 Given that multiple vaccine 11. PharmaJet Inc., Doc. #60-10214-001A 27. Zika vaccine trial site in Peru led by Fogarty doses are required for the HPV vaccine, Cambodia Healthcare Worker Interview trainee, Global Health Matters, May/June Video 2017, Volume 16, Issue 3 improved compliance with needle- 12. Intradermal Administration of Fractional 28. Vaccibody announces positive results from free is an important advantage over Dose of Inactivated Poliovirus Vaccine the phase 1 part of the clinical trial, press traditional methods. (fIPV) Using Tropis® Intradermal Needle release, August 25, 2016, www.vaccibody. Free Injection System, Karachi Pakistan, com/news Community Based Polio Vaccination 29. Vaccibody announces positive results from In March 2017, Vaccibody AS Campaign, December 2016; Ali Faisal the 12-month analysis of the Phase 1 part announced the start of their Phase Saleem, Mach Ondrej, Muhammad Tahir of the clinical trial VB C-01 in patients with IIa clinical study: an exploratory, Yousafzai, Attaullah Baig, Roland Sutter, high-grade cervical dysplasia, press release, Anita KM Zaidi, Aga Khan University, Karachi June 21, 2017 open-label, multi-centre study with Pakistan, WHO, Geneva, Switzerland VB10.16 immunotherapy for the 13. Serum Institute of India website, Health FAQ treatment of high-grade cervical – Measles, http://www.seruminstitute.com/ intraepithelial neoplasia (CIN 2/3) content/faq_measles.htm 14. Effect of jet injection on infectivity of caused by human papillomavirus 16 measles, mumps, and rubella vaccine (HPV 16). The vaccine is also being in a bench model, Coughlin, MM, et al., Erin delivered with the Stratis needle-free Vaccine (2015), http://dx.doi.org/10.1016/j. Spiegel injection system.29 vaccine.2015.07.013 Norwalk MP, et al, Improving Influenza Dr Erin Spiegel is the Regulatory Affairs Vaccination Rates in the Workplace. Am J Manager at PharmaJet, Inc., a medical 1. United States. Centers for Disease Control Preventive Med, 2010, Vol 38 pp 237-246 device company developing needle-free and Prevention. National Institute for Healthy People 2020, Office of Disease injection technologies. Erin specialises Occupational Safety and Health. Preventing Prevention and Health promotion (ODPHP), Needlestick Injuries in Health Care Settings. in regulatory strategy for medical HealthyPeople.gov. Immunization and devices, drugs, and biologics. She spent N.p.n.d. Web. http://www.cdc.gov/niosh/ Infectious Diseases IID-12.12. https://www. the first half of her career developing docs/2000-108/pdfs/2000-108.pdf healthypeople.gov/2020/topics-objectives/ vaccines and biologics and has expertise 2. Health-care waste, World Health topic/immunization-and-infectious- in genetic engineering, virology and Organization Fact sheet No 253, November diseases/objectives Updated March 23, 2015; http://www.who.int/mediacentre/ 2016v molecular biology. Erin received her factsheets/fs253/en/ 17. Flu Vaccination Coverage, United States PhD in biophysics and genetics from 3. IPV introduction and RI strengthening, 2316-2017 Influenza Season, CDC, https:// the University of Colorado and her BS WHO; http://www.who.int/immunization/ www.cdc.gov/flu/fluvaxview/coverage- in animal science from the University of diseases/poliomyelitis/endgame_objective2/ 1617estimates.htm Nebraska-Lincoln. inactivated_polio_vaccine/en/ 18. Needle-free jet injection for administration 4. Inactivated Polio Vaccine Supply and of influenza vaccine: a randomized Email: [email protected]

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