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Skin immunization against rotavirus using microneedles

Skin immunization against rotavirus using microneedles. Dr. Baoming Jiang Centers for Disease Control & Prevention Atlanta, USA bxj4@cdc.gov San Antonio, TX 8 October 2014. Rotavirus. •. Most common cause of severe. diarrhea in children. •. All children infected by age 5. •.

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Skin immunization against rotavirus using microneedles

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  1. Skin immunization against rotavirus using microneedles • Dr. Baoming Jiang • Centers for Disease Control & Prevention • Atlanta, USA • bxj4@cdc.gov • San Antonio, TX • 8 October 2014

  2. Rotavirus • • • Most common cause of severe • diarrhea in children • • • All children infected by age 5 • • • First infections symptomatic • • • Natural immunity • • • Various strains/serotypes in circulation • • • Improvements in sanitation • don • ’ • t prevent infection

  3. Rotavirus Mortality by Country~453,000 deaths, 2008 • < 10 deaths per 100,000 • 10 to 50 deaths per 100,000 • 50 to 100 deaths per 100,000 • 100 to 1000 deaths per 100,000

  4. G1 G3 G1P[8] P[8] G2 G4 Single human rotavirus strain Five bovine-human reassortant rotavirus strains Two Live Oral Rotavirus VaccinesRotaTeq is Pentavalent & Rotarix is Monovalent RotaTeq Rotarix

  5. Rotavirus Vaccines in US •  Feb 2006 – RotaTeq licensed by FDA •  Feb 2006 – RotaTeq recommended by ACIP •  April 2008 – Rotarix licensed by FDA •  June 2008 – Rotarix recommended by ACIP

  6. Vaccine Introduced 2006

  7. Rotarix • RotaTeq • Mali • Ghana • Kenya • Malawi • South Africa GAVI Co-Sponsored Trials in Africa and Asia • Slide: K Neuzil, PATH

  8. Current Status of Rotavirus Vaccine Introduction

  9. Rotavirus Vaccine Experience to Date Borrowed from: http://dannybrown.me/wp-content/uploads/2011/01/success_baby.jpg (Courtsey of U Parashar)

  10. Issues of safety ORVs- (real or implied) remain! Post-Licensure Data • Intussusception cases /100,000 vaccinees • Source: www.cdc.gov/vaccines/acip/meetings • Other safety issues: PCV, antigenemia, AGE

  11. US$4,687.50 * 4,100 doses of polio and measles vaccines. Rural hospital storage, Mozambique. 625 dosesof rotavirus vaccine.District vaccine store, Brazil. RV Vaccines Need a Separate Cold ChainCost and Volume Comparison with Existing Vaccines US$635.50 Courtesy: Darin Zehrung *Older photo—improvements in packaging volume have been achieved.

  12. Rotarix* & RotaTeq† Efficacy vs Social Economic Status ▲China* ▲Bangladesh* • Nelson & Glass, Lancet 2010

  13. Risk Factors for Lower Performance • Of Live Oral Rotavirus Vaccine • Factors that lower viral titer • Breast milk • Maternal antibodies • Stomach acid • Prior exposure • Factors that impair immune response • Malnutrition - Zn, Vit A • Interfering microbes- viruses and bacteria • Other infections- HIV, malaria, TBC • Others: Novel & diverse strains • Host genetic diversity

  14. Studies to improve efficacy of ORVs • Transplacentally transferred maternal serum Ab - Change schedule: time & no. of doses - S. Africa, Pakistan, Bangladesh, India • High levels of Ab in breast milk - Withhold breast feeding at time of vaccination - S. Africa, India, Pakistan, Bangladesh, Nicaragua • ● Add Nutritional supplements - zinc, vitamin A, probiotics, etc. - India, Pakistan • Increase Rotarix titer ? • Search for RV vaccine -- OPV interference - South Africa, Bangladesh • None has led to major improvement !

  15. Inactivated Rotavirus vaccine (IRV) Efficacy ▪ Not subject to interference/gut enteropathy seen with oral vaccines ▪ more effective for infants in low income countries Safety ▪ No stigma of ORVs - intussusception, PCVs ▪ No vaccine-acquired disease or new reassortant virulent strain Combination vaccines – ease delivery, lower administration cost, increase vaccine coverage Technology well established/tested (e.g., IPV, HAV) Would represent insurance against problems with ORVs • IRV could be a Game Changer!

  16. CDC-9 as a monovalent IRV candidate • ffu/ml G1P8 G2P4 G1P8

  17. IRV: Strain & dose matter ! • -------------- --------------------------------------------------------------------------------- • Homotypic Heterotypic • 1. Three doses induce cross neut. antibodies to human strains & reassortant G1 strain • 2. Little cross reactivity with animal strain or reassortant P8 strain • Jiang et al, Human Vaccines & Immunotherapeutics 2013

  18. Proof of concept for IRV in gnotobiotic piglets • Vaccine • Neutralizing antibody (post dose 3) • Placebo • Wang et al Vaccine 2010

  19. Skin Immunization • ● One of the earliest known route of vaccination -- smallpox, TB • ● Immunology: rich in APC – Langerhans cells & dermal DC • ● No hypodermic needle, no disposal of sharp waste • ● No pain • ● Combination vaccines, mass vaccination campaigns • ● No need for additional cold chain

  20. Smallpox Delivery Techniques Early Tools for Breaking the Skin • Vaccinostyle • Rotary lancet • Surgical needle “Multiple Pressure” method Source: Fenner, et al, WHO, 1988

  21. Skin immunization uses fractional doses and enhances antibody response in mice • Before • coating • After • coating • 0 10 28 • Days Post Inoculation • Dose sparing: 10% MN = 100% IM • Moon et al, Vaccine, 2013 (in collaboration with M. Prausnitz)

  22. NanoPass developed MicronJet™, an intradermal (ID) microneedles device Used for ID delivery of vaccines and large molecules First true (~0.5mm) microneedle device ever registered with FDA Microneedles are barely visible to the naked eye Clinically shown to be almost painless and non-intimidating Applicable for adults and pediatrics (i.e., IPV) • NanoPass MicronJet™ • Dose sparing effect established • NanoPass • Intanza • Courtesy: Yotam Levin

  23. ID & IM immunization induces comparable IgG & IgA • titers in gnotobiotic piglets • 1st Vax • 2nd Vax • 3rd Vax • 1st Vax • 2nd Vax • 3rd Vax • ID: 5 ug Ag; IM: 5 ug Ag + 600 ug Al(OH)3; Control: diluent • Jiang (unpublished data)

  24. IRV induces protection against oral challenge in piglets • Placebo (ID) • IRV (ID) • IRV (IM) • RV antigen in stool (OD value) • Day after oral challenge • RV shedding in stool was measured by EIA • Jiang (unpublished data)

  25. CDC IRV Program – Current status Established technology (cell substrate, methods, assays, etc.) Strains developed, characterized CDC-9 G1P8 Inactivation method Heat process – simple, robust, maintain structural integrity Formalin procedure  Process development, formulation, stability  Pre-clinical studies Proof of concept for serum antibody in macaques Proof of concept for IRV by IM immunization in mice, guinea pigs & piglets Proof of concept for IRV by skin immunization in mice & piglets  IP protection (strains & inactivation method)  Partnerships (CMO, manufacturers, NGO, etc)

  26. Discovery to Market: IRV Pre-clinical Studies Clinical trials

  27. Public Support & Public-Private Partnerships • ▪ 2011 Winner - CDC’s inaugural innovation Fund Challenge • ▪ 2011 Excellence in Technology Transfer Award - SE Federal Laboratory Consortium • ▪ 2012 Excellence in Technology Transfer Award - Federal Laboratory Consortium • ▪ 2013 CDC SBIR Phase I Award • ▪ 2014 CDC SBIR Phase II Award ▪ cGMP MVB production complete (CMO) ▪ SBIR contracts (CMO) • Phase I: Optimization of rotavirus vaccine production (complete) • USP & DSP process development • Assay development • Phase II: Preparation of IRV pilot lots for phase I clinical trials • Validation of processes, scale-up, inactivation & formulation • Toxicity study in animals • cGMP production of pilot vaccine lots

  28. CDC Commercial Partners • # Company

  29. In partnerships with several vaccine manufacturers Pathways Forward • Early Phase (5~7 yrs): Develop stand-alone IRV (IM & ID) • Demonstrate safety, efficacy, and value • Determine if IRV is more effective than ORV • Late Phase (3-5 yrs): Combine IRV with multivalent vaccine • (e.g., DTaP, IPV) for IM administration (established vaccine Co.) • Adds competitive value to multivalent vaccine • Avoids administration & delivery costs • Opens up product to global market Or Combine with target vaccine (e.g., IPV) for ID administration (Biotech Co.)

  30. IPV • OPV • IPV then OPV • The global move to IPV ! Countries Currently Using IPV in National Immunization Programs • Courtesy: Cara Burns

  31. Acknowledgments • CDC • Yuhuan Wang • Sung-Sil Moon • Daniel Velasquez • Houping Wang • Mathew Esona • Jennifer Hull • Charles Humphrey • Lauren Snipes • Larry Westerman • Umesh Parashar • Jon Gentsch • Roger Glass • Outside CDC • Linda Saif • Anastasia Vlasova • Marli Azevedo • Mark Prausnitz • Chris Edens • Yotam Levin • Penelope Dennehy • Harry Keyserling • Jean-Francois Saluzzo • Stan Cryz • Harry Greenberg • Vic Van Cleave

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