Inconsistent Terminology Suggested Usage À · History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing Delivery Bruce G. Weniger, MD, MPH,

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

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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

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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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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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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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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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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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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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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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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


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Coated macrotinesLongstanding BCG device

Coated microtinesMacroflux® platform (Zosano Pharma)

Others http://www.zosano.com


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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


before insertion after insertion Courtesy:MarkPrausnitz



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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


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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


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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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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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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-

Documents

Inconsistent Terminology Suggested Usage À · History of Cutaneous Administration of Inactivated Polio Vaccine and Novel Devices for Dose-sparing Delivery Bruce G. Weniger, MD, MPH,