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Thermostable Dry Powder Live Attenuated Influenza Vaccine for Nasal Delivery

Background
Ongoing disease and death associated with seasonal influenza and the threat of an influenza pandemic are two of the highest priority issues for global public health. Vaccination is a powerful tool for preventing influenza, however, current vaccines have several limitations. Inactivated influenza vaccines (IIV) given by needle injection require skilled health care workers and can lead to needle-associated injuries and infections. Liquid nasal live attenuated influenza vaccine (LAIV) is needle-free but has limitations which can result in restricted distribution of vaccine.  The limitations of IIV and LAIV are critical because unlike many other vaccines, almost everyone needs flu vaccine every year. Also, efficient rapid distribution is essential especially in a pandemic situation. An ideally distributable vaccine could be shipped without restriction, by mail for example, and self-administered.  Every step away from this ideal decreases the accessibility of the vaccine. Both IIV and liquid LAIV require strict adherence to cold chain requirements (shipping and storage at 2-8_C) which restricts distribution to facilities with monitored refrigeration.  This is expensive in the developed world and can significantly restrict distribution in the developed world, where cold chain capacity is stretched by routine EPI vaccination requirements and has little or no surge capacity for influenza vaccines or pandemic situations.
While the needle-free nasal administration LAIV is an advantage over vaccination by injection the liquid delivery format has several limitations. The FluMist? LAIV available in the US is shipped and delivered in a prefilled liquid in a glass syringe which imposes shipping requirements and increases shipping costs. More importantly vaccine by liquid nasal spray results in suboptimal vaccine deposition. The large droplets administered by liquid nasal spray devices accumulate in the nares and much the dose is wasted by dripping out of the nose does not reach the target nasopharyngeal tissues.  Also, liquid nasal sprays require an experienced vaccinator as differences in the force and speed of plunger depression results in variable droplet size and the placement of the spray tip can significantly affect vaccine deposition.    LAIV based on the Leningrad donor virus is also delivered as a liquid nasal spray. This vaccine is shipped as a lyophilized cake and requires reconstitution with a separate liquid diluent, which adds another layer of complexity to vaccine delivery. These two limitations in the distributability of liquid LAIV, cold chain requirements and inefficient liquid delivery are the gaps this project seeks to address.
Recent studies in anatomic models of nasal airways have shown dry powder nasal delivery provides markedly improved distribution and retention compared to liquid nasal spray delivery. Dry powder nasal delivery was also less sensitive to vaccinator variability and can potentially be self-administered. (CDC unpublished data) A nasal thermostable dry powder LAIV would retain the advantages of needle-free nasal delivery and improve upon them by removing cold chain restrictions and improving the consistency and efficiency of delivery and reducing the skill level needed to deliver nasal LAIV. 
Project Goal
The goal of the proposed research is to develop a thermostable dry powder LAIV for nasal delivery as a platform technology and assess immunogenicity following nasal powder vaccination in a ferret model. It is expected that this platform technology of thermostable dry powder nasal vaccine will be expanded to use for other vaccines.
Phase I Activities and Expected Deliverables
1.      Create dry powder LAIV
a.      Acquire high titer single strain LAIV bulk lot vaccine
b.      Dry LAIV into a thermostable format
c.      Process dry LAIV into a powder  with a size suitable for nasal delivery ( approximately 20 micron average particle size)
2.      Assess potency and 1 month thermostability of the dry powder LAIV
a.      Freeze aliquots of bulk lot vaccine at -70_C for potency test controls
b.      Store samples of powder vaccine at 4-8_C, 24_ and 37_C for testing
c.      Compare potency of powder vaccine at various temperatures to frozen and lyophilized LAIV potency at 1 week, 2 weeks, 1 month
d.      Test powder vaccine potency by EID50 and TCID50 compared to frozen LAIV
e.     Assess formulation and process parameters for optimum thermostability
Projected Phase II Activities
1.      Optimize formulation and process parameters
2.      Package powder into a nasal delivery device
3.      Assess potency and 1year thermostability of the optimum dry powder LAIV
a.      Freeze aliquots of bulk lot vaccine at -70_C for potency test controls
b.      Store samples of powder vaccine at 4-8_C, 24_ and 37_C for testing
c.      Store samples of powder vaccine in nasal delivery packages at 4-8_C, 24_ and 37_C for testing
d.      Test powder vaccine by EID50 and TCID50 compared to frozen LAIV
e.      Test packaged powder vaccine by EID50 and TCID50 compared to frozen LAIV
f.      Compare potency of powder vaccine at various temperatures to frozen and lyophilized LAIV potency at 1 week, 2 weeks, 1 month and then every other month for one year total storage time.
4.      Assess immune responses to and efficacy of  dry powder LAIV in the ferret model, which is the gold standard animal model for assessing the influenza vaccines
a.      Package powder into nasal powder delivery system
b.      Adapt delivery system to ferret nasal delivery if needed
c.      Vaccinate ferrets with dry powder LAIV and Liquid LAIV
d.      Assess serologic immune response
e.      Challenge with homologous influenza virus and measure viral load
 
Impact
The increased distributability of thermostable dry powder nasal LAIV could significantly improve coverage in the developed and developing world. In addition to the reduction in influenza morbidity and mortality, it is intended that this platform technology be expanded to other vaccines, increasing their accessibility and decreasing the morbidity and mortality of the respective diseases.  New thermostable vaccines could be stored and delivered at ambient temperatures, without refrigeration, deceasing energy usage and equipment costs for refrigeration and lightening loads for vaccine transport and delivery. This would be especially helpful in the developing world where hauling icepacks and coolers can make an already rough journey to a village more difficult. Thermostable vaccines can also eliminate the potentially catastrophic loss of vaccine potency that results when cold-chain methods fail, and facilitate distribution in pandemic responses, mass-vaccination campaigns, and agricultural applications. The disadvantages of liquid vaccine delivery format- increased shipping requirements and costs, suboptimal vaccine deposition, need for experienced vaccinators and onsite reconstitution are described above. A thermostable powder vaccine could be potentially be shipped by mail or hand carried by anyone and self-administered or administered by people with minimal skill level.   This is the ideal in making vaccines accessible to everyone who needs them.
Commercialization Potential
The Advisory Committee on Immunization Practices (ACIP) recommends every person over age 6 months receive annual flu vaccination, with few exceptions, which would require over 300 million doses a year. In recent seasons over 130 million doses of flu vaccine were distributed annually in the US, almost equaling the total of all other vaccines combined. Over the recent years, the global influenza vaccine market has witnessed double digit growth rate due to fear of an impending pandemic and is expected to cross USD 4 billion in 2015.  The high volume demand for influenza vaccine fosters competition which is leading to increased innovation in vaccine delivery. Vaccine manufacturers are willing to invest in improved delivery systems to increase market share by making their vaccines more acceptable and accessible to the population.  Recent licensed innovations influenza vaccine include needle-free nasal spray LAIV (MedImmune FluMist? AccuSpray syringe), intradermal delivery using minineedles (Sanofi Fluzone ID? with Soluvia? minineedles), and vaccination by jet injection (bio CSL?s Afluria? with PharmaJet Stratis? jet injector. 
 
The most likely business model for the small business developer of a formulation and process for thermostable dry powder LAIV would be to license the technology to vaccine manufacturers for fees and or royalties.

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