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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing DeliveryBruce G. Weniger, MD, MPH, Vaccine Technology, CDC
7th WHO/UNICEF Consultation with OPV/IPV Manufacturers and National Regulatory AuthoritiesWorld Health Organization, Geneva – 30 October 2008
page 1 of 8
7th WHO/UNICEF Consultation with OPV/IPV Manufacturers and NationalRegulatory Authorities
World Health Organization, Geneva – 30 October 2008
History of Cutaneous Administration of Inactivated Polio Vaccine and
Novel Devices for Dose-sparing Delivery
History of Cutaneous Administration of Inactivated Polio Vaccine and
Novel Devices for Dose-sparing Delivery
Bruce G. Weniger, MD, MPHVaccine Technology, CDC
Bruce G. Weniger, MD, MPHVaccine Technology, CDC
2
History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing Delivery
Nomenclature and advantages of cutaneous route
Clinical trials of intradermal polio vaccination
Traditional methods for intradermal vaccination
New devices for classical ID delivery
Promising technologies for cutaneous delivery
3
Prepositionalprefix �
Epi…Endo...Intra…Per…Trans…
Inconsistent TerminologyVarious terms for putting antigen into or onto the skin:
Noun �
…vaccination…immunization…delivery
Adjectivalroot �
…cutaneous …Cutaneous ……dermal …Dermal ……epithelialNeedle-free …Patch …Skin …Topical …
Latin origin (cutis = skin)Greek origin (derma = skin)
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Suggested UsageAdjectives
“Cutaneous” – All processes that target any part of the skin for delivery of antigen
Excludes needles or jets passing through to deposit into fat (SC) or muscle (IM)
“Intradermal” (aka “Classical Intradermal”) – A type of cutaneous vaccination in which a bolus of liquid is deposited into the dermis to raise a visible bleb
Includes the Mantoux needle method and newer techniques that achieve a similar result
Nouns“Vaccination” (per Dr. Pasteur honoring Dr. Jenner) – The 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 and policies and financing, etc.
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Proven and Theoretical Advantages of Current and Future Methods for Cutaneous Vaccination
Minimal invasivenessFewer unanticipated serious adverse events than other routes ?Local reactions easier to monitor and treat ?Less dependent on patient cooperation to administer
Relatively sure and certain delivery Exception: improper Mantoux method for classical ID
Potentially needle-free
Dose-sparing ability (documented for classical ID)
Large surface area for simultaneous vaccination of competing antigens
DisadvantagesDifficult Mantoux method Local reactions may rule out some adjuvantsHigh cost of newer patented technologies
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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing Delivery
Nomenclature and advantages of cutaneous route
Clinical trials of intradermal polio vaccination
Traditional methods for intradermal vaccination
New devices for classical ID delivery
Promising technologies for cutaneous delivery
-
History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing DeliveryBruce G. Weniger, MD, MPH, Vaccine Technology, CDC
7th WHO/UNICEF Consultation with OPV/IPV Manufacturers and National Regulatory AuthoritiesWorld Health Organization, Geneva – 30 October 2008
page 2 of 8
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Summary of Intradermal Immunogenicity Literature for Existing Conventional Vaccines of High Interest
Excellent resultsRabies (~117, already widely used ID in developing world)
Good results worth pursuingInfluenza (~2 dozen)Polio (IPV) (~1 dozen)
Mixed to poor resultsHepatitis B (~90)Measles (~15)
No dataPolysaccharide vaccines (MEN, PNU, HIB)
Exception: Gotschlich 1972 – good results for MENps-A
POLIPV Intradermal Vaccination – Early Salk Trials
� Aqueous formulation� 27 children and adults
at Watson School� 2 doses 0.1 mL ID 6
weeks apart� Results
�Type 2 (MEF-1) = 100% 4-fold rise�Types 1 (Mahoney) and
3 (Saukett): = 0%• ? excessive inactivation
� Later studied IM route with 1.0mL doses of mineral oil emulsions for adjuvant effect
Salk JE, et al. JAMA, 23 March 1953; 151:1081-1098
POLIPV Intradermal Vaccination – Later Salk Trials� Aqueous formulation� 20 children and 5 adults at Watson School and community� 3 doses 0.1 mL ID 1 week apart
�“+” = titer 1:4 �All responses with pre-existing antibody >4-fold� Types: 1=100% (25/25), 2=84% (21/25), 3=96% (24/25)
Salk JE. Pediatrics, Nov 1953;12:471-482
� Denmark - ID was standard route mid-1950s � 2.3 million persons vaccinated ID 1955-1957� 1956 survey
• 91% of population 9 months – 40 years• “Most of them” with 2 doses
� Von Magnus (1957, 1967): good immune responses in naïves
POLIPV Intradermal Vaccination – Denmark Experience
von Magnus H. Salk: Control of polio with noninfectious vaccine. In: Cellular Biology; Nucleic Acids and Viruses (Special Publications). New York: NY Academy of Sciences; 1957:96-97.
von Magnus H. Poliovaccination 1955-1967 og fremtidige poliovaccinationer. Ugeskrift for laeger 1967;129:1759-1762.
� Compared American vaccine 0.2 mL SC versus Danish vaccine 1.0 mL ID� Overall poor responses, particularly types 1 and 3� ID titres generally lower than SC
POLIPV Intradermal Vaccination – Iceland Study
Sigurdsson B, et al. Lancet 15 February 1958;1(7016):370-371
POLIPV Intradermal Vaccination – Further Studies
�3mm diam. induration and erythema indicative of CMI in
12 subjects
4-fold to 1024-fold booster:1: 17/18 2: 17/18 3: 17/18
0.1 mL ID NS
Prior-immunes:8 adults
10 children (7-10y)
Samuel,Lancet
1991;338:343-4
Type 1: 7/8 2: 8/8 3: 8/80.5 mL @0,1 m IM NS
Type 1: 0/3 2: 0/3 3: 0/3 5 mL x 2 @0,1 m PO
Seroconversions*:Type 1: 7/9 2: 8/9 3: 7/9
(mean 91%)
* Ab appearance or 4 x calculated residual maternal Ab level
0.1 mL ID NS x 2 doses @8 weeks interval
Naives: infants 6 weeks of
age
Samuel,Vaccine1992; 10:135
Immune-naïve
children�5y
Subjects
0.15 mLx2 @0,1 m ID NS
Dose / Tissue / Method
Type 1: 0/5 2: 2/5 3: 2/5 Connolly,Lancet
1958;272:333-6
Immune ResponseSource
ID=intradermal NS=needle/syringe PO=by mouth IM=intramuscular
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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing DeliveryBruce G. Weniger, MD, MPH, Vaccine Technology, CDC
7th WHO/UNICEF Consultation with OPV/IPV Manufacturers and National Regulatory AuthoritiesWorld Health Organization, Geneva – 30 October 2008
page 3 of 8
POLeIPV Intradermal Vaccination – 1998 Study
0.1 mL @0,2 m ID NS
1: 100% 2: 100% 3: 100%*0.1 mL @0,1,2 m ID NS
1: 89% 2: 74% 3: 96%**
1: 87% 2: 68% 3: 96%**
0.1 mL @0,1,2 m ID NS
Immune-naïve infants6-8w
+ maternal
Ab †
Immune-naïve infants6-8wNo
maternal
Ab †
Subjects
0.1 mL @0,2 m ID NS
Dose / Tissue / Method
1: 100% 2: 100% 3: 100%*
Nirmal,Vaccine1998;
16:928-931
N=69
Immune ResponseSource
* ns: p>0.05 ** ns: p>0.05 † ns: p>0.1Historical controls: types 1+3 eIPV ID > OPVx3, type 2 eIPV ID < OPVx5
POLeIPV Intradermal Vaccination – 2000s Studies
� WHO-sponsored trials in Cuba and Oman� Using Biojector® 2000 needle-free jet injector� Details and results to be reported by Roland Sutter
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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing Delivery
Nomenclature and advantages of cutaneous route
Clinical trials of intradermal polio vaccination
Traditional methods for intradermal vaccination
New devices for classical ID delivery
Promising technologies for cutaneous delivery
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Classical Intradermal (ID) Injection“Mantoux” method
Simultaneous invention in 1908Felix Mendel (Germany), Charles Mantoux (France)
Originally for TB skin testing and vaccinationFine-gauge needle, bevel-up, parallel into skinFluid bolus below basement membrane
AdvantagesUses existing, off-the-shelf vaccinesEnhanced immune response permits dose-sparing
DisadvantagesRequires training, skill, time, needle dangersLocal reactions from irritating ingredients
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Cutaneous Smallpox Vaccination Methods for Eradication
Multi-use nozzle jet injectors (“MUNJIs”)Invented in 1950s by U.S. militaryHigh-speed devices - 600-1,000 doses/hourUsed in mass campaigns 1950s-1990s
polio, meningitis, yellow fever, measles, influenza vaccines
Used in first half of smallpox eradication program Special intradermal nozzlesMid-1960s – early 1970sLatin America, West AfricaTens of millions of doses of smallpox vaccine
Billions of doses administered worldwide for various antigensWithdrawn for safety reasons. Replaced by DCJIs
Bifurcated needleInvented 1967 by Benjamin Rubin (Wyeth)
Royalties waived for WHO smallpox programReplaced MUNJIs for latter half of eradicationRequired higher-titer formulation
Tines hold 2.5 �L (0.0025 mL); most undelivered18
Ped-O-Jet® MUNJI Intradermal Nozzle
ID nozzle: 45 angle of injectionRecessed to create air gap between skin and orificeHundreds of millions of intradermal doses
SmallpoxYellow fever (FNV)Some BCG
Added spacer on IM nozzle also works for ID:
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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing DeliveryBruce G. Weniger, MD, MPH, Vaccine Technology, CDC
7th WHO/UNICEF Consultation with OPV/IPV Manufacturers and National Regulatory AuthoritiesWorld Health Organization, Geneva – 30 October 2008
page 4 of 8
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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing Delivery
Nomenclature and advantages of cutaneous route
Clinical trials of intradermal polio vaccination
Traditional methods for intradermal vaccination
New devices for classical ID delivery
Promising technologies for cutaneous delivery
20
Vitajet®
Injex®
Mini-Imojet®Mini-Imojet®
Biojector® 2000 Antares Pharma
Disposable-cartridge Jet Injectors (DCJIs)Overcome safety concerns for blood transfer by MUNJIs
PenJet™
Investigational devices intended for manufacturer pre-filling:Entire device 1-use disposable
J-Tip®
Entire device 1-use disposable:
IntraJect®
Others
PharmaJet™
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Investigational Intradermal Spacer on Biojector® 2000 DCJICreates 2 cm gap between nozzle and skinSame perpendicular injection and technique as for licensed IM and SC cartridgesClinical trials of intradermal delivery
Cancer, HIV, lymphoma, malaria vaccinesInfluenza (Dom. Rep.)Polio (Cuba, Oman)
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Intradermal Injection via Biojector® 2000 Jet Injector with Investigational Spacer
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Post-injection wheal of induration
Intradermal Injection via Biojector® 2000 Jet Injector with Investigational Spacer
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Vitavax™ DCJIBioject, Inc., Portland, OR (www.bioject.com)Manually-wound spring, targeted for developing countriesAutodisabling color-coded cartridges:
IM, SC, ID
investigational
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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing DeliveryBruce G. Weniger, MD, MPH, Vaccine Technology, CDC
7th WHO/UNICEF Consultation with OPV/IPV Manufacturers and National Regulatory AuthoritiesWorld Health Organization, Geneva – 30 October 2008
page 5 of 8
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BD Investigational Prefilled Intradermal SyringeSoluvia™ Micro-delivery System, Becton, DickinsonHuman version
Photos courtesy BDPhotos courtesy BD30 gauge needle
OD=0.305mm, projects 1.5 mmClinical trial of influenza
Belshe et al NEJM 2004Investigational ID GSK vaccine (6�g/strain) – good responsesControl vaccine: full dose IM of Aventis Fluzone®
Exclusive worldwide license to sanofi pasteur for many vaccine indications
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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing Delivery
Nomenclature and advantages of cutaneous route
Clinical trials of intradermal polio vaccination
Traditional methods for intradermal vaccination
New devices for classical ID delivery
Promising technologies for cutaneous delivery
27
Passive diffusion with or without enhancers
Occlusion and hydrationPlain water under occlusive patch
Bacterial exotoxinsIomai, Inc.
Heat-labile enterotoxin of E. coli (LT)Boost elderly influenza response75% protective efficacy for mod.-sev. travelers diarrhea (ICAAC 2007, ab G-1247A)
Cholera toxinOther chemicals
Acetone rubbingProtein and colloidal carriers
Bacterial flagellinColloidal carriers
Promising Methods for Cutaneous Delivery
“Transcutaneous Immunization (TCI)”Frech et al (Iomai)
Vaccine 2005;23:946-950
IOMAIpatch
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Mechanical disruption of stratum corneumStripping and Abrading
Cellophane tapeFriction by rubbing
Emery, pumiceUncoated microabrasives
OnVax™ “microenhancer array” (MEA)Becton, Dickinson
Promising Methods for Cutaneous Delivery
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Coated macrotinesLongstanding BCG device
Coated microtinesMacroflux® platform (Zosano Pharma)
Others http://www.zosano.com
Promising Methods for Cutaneous Delivery
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Hollow microneedle arraysMicroneedles (Georgia Tech)Micro-Trans™ Microneedle Array Patch (Biovalve)Easy Vax™ DNA Vaccination System (Cytopulse Sciences) Norwood Abbey/MITCorium (ex P&G)NanoPassMany others
Dissolving microneedle arraysGeorgia Tech
Carboxymethylcellulose750�m tall before insertion
TherajectMany others
McAllister et al.PNAS 2003;100:13755-60
Promising Methods for Cutaneous Delivery
before insertion after insertion Courtesy:MarkPrausnitz
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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing DeliveryBruce G. Weniger, MD, MPH, Vaccine Technology, CDC
7th WHO/UNICEF Consultation with OPV/IPV Manufacturers and National Regulatory AuthoritiesWorld Health Organization, Geneva – 30 October 2008
page 6 of 8
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Electromagnetic energyLight
Laser ablationElectricity
ThermoporationInduced current zaps holes in stratum corneum
ElectroporationElectric current promotes antigen uptake (abstr. S9)
Electro-osmosisSolvent flows carry non-charged molecules
IontophoresisField carries charged molecules
RF waves / heatSound energy
UltrasoundE-Trans®
Alza
Laser Assisted Drug DeliveryNorwood Abbey
ViaDerm™ TransPharma Medical
PassPort™ PatchAltea Therapeutics
Promising Methods for Cutaneous Delivery
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Gas-mediated kinetic depositionHelium gas blows antigen carriers into skin
PowderMed (Pfizer)RNA/DNA-coated gold beads (Particle-Mediated Epidermal Delivery)Antigens reformulated to suitable size and density (Epidermal Powder Immunization)
Microscission“Sandblast” coated aluminum oxide microcrystalsHarvard-MIT
Promising Methods for Cutaneous Delivery
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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing Delivery
Nomenclature and advantages of cutaneous routeClinical trials of intradermal polio vaccinationTraditional methods for intradermal vaccinationNew devices for classical ID deliveryPromising technologies for cutaneous delivery
Thank you.Disclaimers
Commercial products and prototypes are named and illustrated for information only. No endorsement or recommendation by the CDC or DHHS are implied or should be inferred.The findings and conclusions in this presentation are those of the author. They do not necessarily represent the views of the CDC, have not been formally disseminated by CDC, and should not be construed to represent any agency determination or policy.
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Additional Slides for Questions and Discussion
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Skin Cross-section (1.6 - 3 mm thick)
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Microphotograph courtesy: IOMAI, Inc.
Activated Langerhans cells in Epidermis 48 Hours after Cutaneous Vaccination with E. coli LT
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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing DeliveryBruce G. Weniger, MD, MPH, Vaccine Technology, CDC
7th WHO/UNICEF Consultation with OPV/IPV Manufacturers and National Regulatory AuthoritiesWorld Health Organization, Geneva – 30 October 2008
page 7 of 8
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Literature on Classical Intradermal VaccinationSmallpox Many, primary routeTuberculosis (BCG) Many, primary routeYellow Fever Primary route W. Africa 1940s/50sRabies 117Hepatitis B 90Influenza 24Polio (IPV) 16Cholera 15Measles 15Typhoid 11Tetanus 6Hepatitis A 5Diphtheria-Tetanus-Pertussis 2 (Rossier 1968, Stanfield 1972)Tick-borne encephalitis 2 (Zoulek 1984, 1986)Meningococcal A 1 (Gotschlich 1972)Tetanus-Diphtheria 1 (Wegmann 1976)Rift Valley Fever 1 (Kark 1985)Smallpox-BCG 1 (Vaughan 1973)Smallpox-Measles 1 (Budd 1967)Smallpox-Measles-Yellow Fever 1 (Meyer 1964)
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Early Tools for Cutaneous Smallpox Vaccination
A. VaccinostyleB. Rotary lancetC. Surgical
needle
Source: Fenner, et al, WHO, 1988
“Multiple Pressure”method
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Older, Alternative Cutaneous Methods
Primarily for BCG vaccineScarification“Multiple Puncture”method
Rosenthal: straight needles
Multi-tined devices“Kuchiki needle”
“Percutaneous” (PC) methodStill used in Japan and few other markets
Mono-test™, Mono-Vacc™Discouraged for both BCG and tuberculin skin testing
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Jet Injectors for ImmunizationSquirts pressurized liquid via tiny orifice (~0.15mm) into tissues1860s: Technology invented in France 1940s: Single-use devices for insulin and other drugs1950s: adapted for high-speed vaccination mass campaigns
Multi-use-nozzle jet injectors (MUNJIs)Many manufacturers
Aquapuncture device Galante et Cie.
Hypospray® single patient device, R.P. Scherer Corp.
Hypospray® MUNJI
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Intradermal nozzles or spacers on jet injectors
Multi-use-nozzle jet injectors (MUNJIs)
Disposable-cartridge jet injectors (DCJIs)
Classical Intradermal (ID) Injection
DermoJet
Med-E-JetPed-O-Jet
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1976-1977 Mass Campaigns with “Swine” Influenza Vaccine (A/New Jersey/8/76 - Hsw1Nsw1) (5 Mfgs)
Using Multi-use-nozzle Jet Injectors (MUNJIs)
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History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing DeliveryBruce G. Weniger, MD, MPH, Vaccine Technology, CDC
7th WHO/UNICEF Consultation with OPV/IPV Manufacturers and National Regulatory AuthoritiesWorld Health Organization, Geneva – 30 October 2008
page 8 of 8
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Demonstration of Motorized LectraJet® Jet Injector
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Jet-injected Intradermal Influenza Vaccination Trial, Dom. Rep.
http://clinicaltrials.gov/ct2/show/NCT00386542
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Subjects: Healthy �6-to-