A V D Conventional needle-syringe – Why not? S P , P ...

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”)


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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)


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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)


http://Bit.ly/Vaccines6thChap61a

Bruce

Typewritten Text

https://www.blsmeetings.net/NucleicAcidDeliveryDevices/index.cfm

https://www.blsmeetings.net/NucleicAcidDeliveryDevices/index.cfm

Bruce

Typewritten Text

http://videocast.nih.gov/summary.asp?live=16059&bhcp=1

http://videocast.nih.gov/summary.asp?live=16059&bhcp=1



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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


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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



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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



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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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☐ Oral ingestion (drops, capsules, dissolving films)

✔Cutaneous delivery into/onto skin■ Jet injection by “DSJIs”■ Intranasal sprays■ Pulmonary inhalation■ Ballistic/kinetic delivery


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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



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☐ Oral ingestion (drops, capsules, dissolving films)

✔Cutaneous delivery into/onto skin✔Jet injection by “DSJIs”■ Intranasal sprays■ Pulmonary inhalation■ Ballistic/kinetic delivery


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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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☐ Oral ingestion (liquid drops, dissolving films, capsules)

✔Cutaneous delivery into/onto skin✔Jet injection by “DSJIs”✔Intranasal sprays■ Pulmonary inhalation■ Ballistic/kinetic delivery


http://www.optinose.no



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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



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☐ 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

A V D Conventional needle-syringe – Why not? S P , P ...

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