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TRANSCRIPT
Chair’s Overview: Alternative Vaccine Delivery Systems – Past, Present, & FutureBruce G. Weniger , MD, MPH, International Professor, Chiang Mai University
Workshop: Nucleic Acid Delivery Devices for HIV Vaccines, NIAID, National Institutes of Health, Bethesda, MD, USA, 21 May 2015
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Workshop: Nucleic Acid Delivery Devices for HIV VaccinesNIAID, National Institutes of Health, Bethesda, MD, USA, 21 May 2015
Overview:ALTERNATIVE VACCINE DELIVERY
SYSTEMS – PAST, PRESENT, & FUTURE
Bruce G. Weniger, MD, MPHInternational Professor, Research Institute for Health SciencesChiang Mai University
http://Bit.ly/Vaccines6thChap61a
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■ Advantages of N-S□ Sure and certain delivery, compared to:
▶ Oral drops spit out/vomited, nasal doses blocked/sneezed out, skin patches misapplied/removed, jet-injectors fail penetration, etc.
Alternative Vaccine Delivery Systems Conventional needle-syringe – Why not?
■ Disadvantages of N-S□ Iatrogenic disease from unsterile
reuse/needlesticks□ Expensive needle shields to protect
occupational health□ Needle phobia in children/adults□ Slow to fill and deliver in mass
campaigns□ May not target most immunogenic
tissue□ Prefills challenge cold-chain volume
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■ Overlapping, non-exclusive categories□ BY TARGET TISSUE FOR DEPOSITION
□ BY MECHANICAL DEVICE
□ BY ANTIGEN FORMULATION
□ BY ADJUVANTATION METHOD
Alternative Vaccine Delivery Systems The challenge of taxonomic classification
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■ BY TARGET TISSUE FOR DEPOSITION
□ Mucosal surface (“oral”, “intranasal”, other orifices)
□ Muscle (“intramuscular”, IM)
□ Fat (“subcutaneous”, SC)
□ Skin (“cutaneous”, and its many synonyms)
□ Lung (“respiratory”)
Alternative Vaccine Delivery Systems The challenge of taxonomic classification
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■ BY MECHANICAL DEVICE□ Needles
▶ hypodermic, intradermal
▶ Macro-needles, mini-needles, micro-needles
▶ Hollow lumens, solid, dissolving
□ Dispettes for oral instillation/ingestion □ Intranasal insufflators (large-droplet sprayers)□ Aerosol generators (small droplets/powders for
inhalation by mask/spray (or rooms: Soviet violations of 1975 BWC)
□ Jet injectors□ Ballistic/kinetic delivery (“shooting” into tissue)
Alternative Vaccine Delivery Systems The challenge of taxonomic classification
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■ BY ANTIGEN FORMULATION
□ Liquid□ Aerosol (dry powder, liquid droplets)□ Solid▶ Traditional capsule/tablet▶ Depot for slow dissolution▶ Coated non-dissolving microparticle (often
gold)▶ Milled antigen in microparticle form
□ Gas (none described to date)
Alternative Vaccine Delivery Systems The challenge of taxonomic classification
Chair’s Overview: Alternative Vaccine Delivery Systems – Past, Present, & FutureBruce G. Weniger , MD, MPH, International Professor, Chiang Mai University
Workshop: Nucleic Acid Delivery Devices for HIV Vaccines, NIAID, National Institutes of Health, Bethesda, MD, USA, 21 May 2015
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■ BY ADJUVANTATION METHOD
□ Electroporation▶ Needle electrodes▶ Iontophoresis
□ Thermoporation▶ Heat induced by electromagnetic radiation
□ Chemicals▶ Enterotoxigenic E. Coli LT toxin▶ Cholera B-subunit toxin
□ Ultrasound
Alternative Vaccine Delivery Systems The challenge of taxonomic classification
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☐ Conventional needle injection (IM, SC)
☐ Oral ingestion (drops, capsules, dissolving films)▶ Oral polio, rotavirus, adenovirus, cholera, typhoid
■ Cutaneous delivery into/onto skin■ Jet injection by “DSJIs”■ Intranasal sprays■ Pulmonary inhalation■ Ballistic/kinetic delivery
Alternative Vaccine Delivery Systems A classification system, with examples
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<= “Sub-cutaneous” (SC) fat layer
<= Basement membrane
Painless if only to epidermis
Stratum corneummain barrier to antigen
Cutaneous VaccinationAnatomy of skin (1.6 – 3 mm thick)
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Cutaneous VaccinationNon-standardized nomenclature
Prepositionalprefix _
o Epi…o Endo...o Intra…o Per…o Trans…
Noun o…vaccinationo…immunizationo…delivery
Adjectivalroot
o…cutaneous …o Cutaneous …o…dermal …oDermal …o…epithelialoNeedle-free …o Patch …o Skin …o Topical …
Latin origin (cutis = skin)Greek origin (derma = skin)
Terminological Tower of Babel in medical literature
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■ Adjectives□ “Cutaneous” – All processes that target any part of the skin for
delivery of antigen▶ Excludes needles, jets, depots passing through into fat (SC) or muscle (IM)
□ “Intradermal” (a.k.a. “Classical Intradermal”) – A type of cutaneous vaccination in which a bolus of liquid is deposited into the dermis to raise a visible bleb▶ Includes Mantoux needle method and new techniques of similar result
■ Nouns□ “Vaccination” (per Pasteur’s homage to Dr. Jenner) – The
mechanical, physical process of introducing foreign substances into the body to stimulate an immune response
□ “Immunization” – The broad field of manipulating the immune system to confer disease protection, including related programs,policies, financing, etc.
Cutaneous VaccinationSuggested nomenclature
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■ Smallpox ■ Tuberculosis (BCG)■ Yellow Fever■ Rabies ■Hepatitis B ■ Influenza ■ Polio (IPV)■ Cholera ■Measles ■ Typhoid■ Tetanus
■Hepatitis A■Diphtheria-Tetanus-Pertussis■ Tick-borne encephalitis■Meningococcal A■Meningococcal A-C-Y-W135■ Tetanus-Diphtheria■ Rift Valley Fever■ Smallpox-BCG■ Smallpox-Measles■ Smallpox-Measles-Yellow Fever
Cutaneous VaccinationAntigens routinely delivered or once studied
Chair’s Overview: Alternative Vaccine Delivery Systems – Past, Present, & FutureBruce G. Weniger , MD, MPH, International Professor, Chiang Mai University
Workshop: Nucleic Acid Delivery Devices for HIV Vaccines, NIAID, National Institutes of Health, Bethesda, MD, USA, 21 May 2015
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■ Felix Mendel (1892-1925), Germany■ Charles Mantoux (1877-1947), France
Cutaneous VaccinationClassical “intradermal” injection
La Presse Médicale1910;2:10-15
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■ Mantoux method□ Fine-gauge needle, bevel-up, inserted parallel into skin
■ New adapter for “foolproof” Mantoux injection□ SID Technologies, West Pharmaceuticals, PATH
Cutaneous Vaccination“Classical” intradermal injection 2
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■ Instruments to break skin for smallpox vaccine□ A. Vaccinostyle□ B. Rotary lancet□ C. Surgical
needle▶ Multiple-pressure
method□ Bifurcated needle
Cutaneous VaccinationMechanical disruption of stratum corneum
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Cutaneous VaccinationMechanical disruption of stratum corneum 2■ Remove or reduce top layer of
dead skin (stratum corneum)□ Principal barrier to antigen entry
■ Various methods□ Peeling cellophane tape□ Cyanoacrylate “super glue”□ Microscopic projections□ Sandpaper friction□ Others
OnVax™ microenhancer array, BD
Transcutaneous Immunization (TCI)
patch platform, (Valneva, f.k.a. Intercell, Iomai)
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■ Becton Dickinson Soluvia™□ 30 ga., OD=0.305 mm, 1.5 mm projection□ Licensed to Sanofi Pasteur
▶ 2009: Intanza®/IDflu® (EU)▶ 2011: Fluzone® ID (USA)
■ Nanopass MicronJet™□ 450 μm tall array □ Luer-slip fitting for syringe□ Marketed U.S., elsewhere
■ 3M Hollow Microstructured Transdermal System™ (hMTS)
□ Large volumes by reservoir & spring
Cutaneous VaccinationHollow minineedles (≥1mm), microneedles (<1,000 μm)
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Cutaneous VaccinationCoated and dissolving solid microneedles■ Tissue moisture elutes vaccine/drug
coated and dried onto microneedles□ Georgia Tech/Emory□ 3M Corporation
▶ Solid Microstructured Transdermal System™ (sMTS)
□ Zosano Pharma™ ▶ ZP Patch™ (formerly Macroflux®)
□ Others
]330 µm]330 µm
1 cm
■ Antigen dissolved in matrix□ Avoid “sharps” waste□ GA Tech□ Others
Chair’s Overview: Alternative Vaccine Delivery Systems – Past, Present, & FutureBruce G. Weniger , MD, MPH, International Professor, Chiang Mai University
Workshop: Nucleic Acid Delivery Devices for HIV Vaccines, NIAID, National Institutes of Health, Bethesda, MD, USA, 21 May 2015
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Cutaneous VaccinationOther techniques■ Kinetic deposition of microparticles
□ Pfizer’s PowderMed® powered by He gas▶ Particle-mediated Epidermal Delivery (PMED™)
▷ DNA on gold beads▶ Epidermal Powder Immunization (EPI™)
▷ Protein antigens
■ Electromagnetic energy □ Thermoporation burns pores by induced heat
▶ Altea Therapeutics PassPort™□ Laser light ablates stratum corneum
▶ Norwood Abbey’s LAD□ Iontophoresis carries charged drug or solution
▶ Johnson & Johnson Alza’s E-trans®
■ Chemical enhancers■ Sound energy■ Abrasive sandblasts; others
Pfizer PowderMed® system
Altea Therapeutics PassPort
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■ Clinical trials of investigational cutaneous DSJIs :□ BCG□ Dengue□ HPV□ Influenza□ Polio□ Rabies
■ Sponsors□ PATH□ WHO□ CDC□ Mfgs.
Cutaneous vaccinationDisposable-syringe jet injectors (DSJIs)
Photos: PATH/Patrick McKern; CDC
Bioject®ID-PenPharmaJet
Tropis®
Investigational ID spacer on Biojector® 2000
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☐ Conventional needle injection (IM, SC)
☐ Oral ingestion (drops, capsules, dissolving films)
✔Cutaneous delivery into/onto skin■ Jet injection by “DSJIs”■ Intranasal sprays■ Pulmonary inhalation■ Ballistic/kinetic delivery
Alternative Vaccine Delivery Systems A classification system, with examples
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Jet InjectionWhat is it?■ Squirts pressurized liquid □ Through orifice (~0.15 mm Ø)□ Like child’s water pistol
■ 1860s: Invented in France
■ 1940s: Single-user devices□ Insulin and other drugs
■ 1950s: Multi-use-nozzle jet injectors (“MUNJIs”)□ Adapted by U.S. Army for high-
speed mass vaccination□ 600-1000 injections per
operator per hour
Aquapuncture device Galante et Cie.
Hypospray®, R.P. Scherer Corp.
Ped-O-Jet® MUNJI
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JI immune response = or occasionally > needle-syringe(Antigen-presenting dendritic (Langerhans) cells in skin ?)
Jet injection local reactions usually > needle-syringe Mostly reported as “tolerable”
■ Live vaccines□ Bacille Calmette-Guérin□ Measles□ Mumps□ Measles-Mumps-Rubella□ Measles-Smallpox (vaccinia)□ Rubella□ Smallpox (vaccinia)□ Yellow fever
■ Routes□ IM, ID (MUNJIs, one DSJI)□ SC (DSJIs, investigationals)
■ Inactivated vaccines□ Botulism□ Cholera□ Diphtheria-Tetanus-Pertussis□ Hepatitis A□ Hepatitis B□ Influenza (including ‘76 “swine”)□ Japanese encephalitis□ Meningococcus A, C□ Plague□ Polio (IPV)□ Tetanus, Tetanus-Diphtheria□ Tularemia-Typhoid□ Typhoid, Typhoid-Paratyphoid□ Investigationals: HIV, DNA,
cancer, etc.
Jet InjectionClinical Evidence
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■ Multi-use-nozzle jet injectors(MUNJIs) used since 1950s□ Administered billions of vaccine doses
for polio, smallpox, influenza, yellow fever, BCG, etc.
□ Cross-contamination risk realized□ Public health use contraindicated by
WHO, CDC in 1990s
■ A new generation of safe, disposable-syringe jet injectors(DSJIs) developed since 1990s□ Avoid bloodborne-pathogen cross-
contamination risk of MUNJIs
Jet InjectionUnsafe MUNJIs now resolved with DSJIs
Ped-O-Jet®
PharmaJetStratis®
Biojector®
2000
LectraJet® M3 & HS
Chair’s Overview: Alternative Vaccine Delivery Systems – Past, Present, & FutureBruce G. Weniger , MD, MPH, International Professor, Chiang Mai University
Workshop: Nucleic Acid Delivery Devices for HIV Vaccines, NIAID, National Institutes of Health, Bethesda, MD, USA, 21 May 2015
Page 5
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☐ Conventional needle injection (IM, SC)
☐ Oral ingestion (drops, capsules, dissolving films)
✔Cutaneous delivery into/onto skin✔Jet injection by “DSJIs”■ Intranasal sprays■ Pulmonary inhalation■ Ballistic/kinetic delivery
Alternative Vaccine Delivery Systems A classification system, with examples
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■ Variolation of smallpox virus□ Viable variola (smallpox) virus□ Powdered, dried pustules or
scabs from patients blown or stuffed on cotton into the nose
□ China, perhaps as early as 10th
Century, and at least by 17th
Intranasal SpraysOriginal method for immunization delivery
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■ Becton Dickinson’s prefilled Accuspray™ syringe for intranasal deposition of large droplets
■ Delivers Medimmune’s FluMist®live attenuated influenza vaccine□ Successful use in U.S. since 2003
Intranasal SpraysBD’s Accuspray™ Nasal Spray System
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■ Berna Biotech (formerly Swiss Serum and Vaccine Institute)
■ Contained ETEC LT toxin adjuvant (Escherigen®)
■ Withdrawn from Swiss market in 2001 for safety□ 84-fold risk of Bell’s palsy
affecting 7th “facial” cranial nerve passing near nose
□ ? LT toxicity ?
Intranasal SpraysNasalFlu® Influenza Vaccine
29http://www.optinose.no
■ Bi-directional deposition to nose only■ Dry powder or liquid aerosol delivery■ No announced applications for vaccines
□ Fluticasone□ Oxytocin□ Sumatriptan
Intranasal SpraysOptiNose™ Nasal Delivery Device
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☐ Conventional needle injection (IM, SC)
☐ Oral ingestion (liquid drops, dissolving films, capsules)
✔Cutaneous delivery into/onto skin✔Jet injection by “DSJIs”✔Intranasal sprays■ Pulmonary inhalation■ Ballistic/kinetic delivery
Alternative Vaccine Delivery Systems A classification system, with examples
Chair’s Overview: Alternative Vaccine Delivery Systems – Past, Present, & FutureBruce G. Weniger , MD, MPH, International Professor, Chiang Mai University
Workshop: Nucleic Acid Delivery Devices for HIV Vaccines, NIAID, National Institutes of Health, Bethesda, MD, USA, 21 May 2015
Page 6
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■ Liquid off-the-shelf antigen□ Classical Mexican Device
▶ 1980s: Pioneered by Albert Sabin□ Measles Aerosol Project Device
▶ 2002: WHO, CDC, Amer R.C.□ Nebulizer requires electricity
■ Powdered/dry antigen□ Aktiv-Dry’s PuffHaler™
□ BD’s Solovent™
Pulmonary inhalationWet and dry aerosol measles virus delivery
Classical Mexican Device
WHO Measles Aerosol
Project Device
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Twincer® (Univ. Gröningen) 23%-37% particle sizes <5μm No human trials yet reported
Amorij, et al. Lancet Infection 2010;10:699-711
Pulmonary inhalationInhaler for self-administration
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Alternative Vaccine Delivery Systems A classification system, with examples☐ Conventional needle injection (IM, SC)
☐ Oral ingestion (liquid drops, dissolving films, capsules)
✔Cutaneous delivery into/onto skin✔Jet injection by “DSJIs”✔Intranasal sprays✔Pulmonary inhalation■ Ballistic/kinetic delivery
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■ Pfizer’s PowderMed® technology□ Supersonic delivery carried by helium gas
▶ Particle-mediated Epidermal Delivery (PMED™)▷ DNA antigen coated on gold beads
▶ Epidermal Powder Immunization (EPI™)▷ Protein antigens milled to appropriate size and density
□ Not actively pursued▶ Clinical trials: long-term (permanent?) cosmetic skin scarring
Ballistic/kinetic deliveryPropelled microparticles
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■ Glide SDI® (Solid Dose Injector, “Bioneedle”)□ Antigen admixed in solid slow-dissolvable□ Pointed for injection intact into fat under skin□ Spring-powered applicator device□ No human trials with an API to date
Ballistic/kinetic deliverySolid antigen for subcutaneous dissolution
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Ballistic/kinetic deliveryTattoo technology■ Rapidly-piercing needle delivers
liquid antigen into dermis■ Pokorna D, et al., Genetic Vaccines
and Therapy 2008;6:4.▶ Mouse model▶ Commercial tattoo device (Rotary 12000
PL, Bortech Tattoogrosshandel, Wuppertal, Germany)
□ 50 μg of HPV-16 DNA antigen via 60,900 punctures (7 needle-array x 145 Hz speed x 30 replicates x 2 sec. each)
□ “The tattoo procedure was well tolerated, however local trauma involving minor swelling and reddening of the skin was observed.”
●
■ Would pain, and time, and cost of disposables be acceptable and practical ?
Unrelated photo of humantattooing with 6-needle array
Chair’s Overview: Alternative Vaccine Delivery Systems – Past, Present, & FutureBruce G. Weniger , MD, MPH, International Professor, Chiang Mai University
Workshop: Nucleic Acid Delivery Devices for HIV Vaccines, NIAID, National Institutes of Health, Bethesda, MD, USA, 21 May 2015
Page 7
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☐ Conventional needle injection (IM, SC)
☐ Oral ingestion (liquid drops, capsules, dissolving films
✔ Cutaneous delivery into/onto skin✔ Jet injection by “DSJIs”✔ Intranasal sprays✔ Pulmonary inhalation✔ Ballistic/kinetic delivery
Thank you
Overview:ALTERNATIVE VACCINE DELIVERY
SYSTEMS – PAST, PRESENT, & FUTURE