research on n vaccine delivery methods focus on influenza · research on new vaccine delivery...

RESEARCH ON NEW VACCINE DELIVERY METHODS: FOCUS ON INFLUENZABruce G. Weniger, MD, MPH (Associate Editor, Vaccine)

Second WHO Consultation on Global Action Plan for Influenza Vaccines (GAP-II), 12-14 July 2011, Geneva, Switzerland

of 15Slides 1-77, plus 12 backups

RESEARCH ON

NEW VACCINE DELIVERYMETHODS:

FOCUS ON INFLUENZA

1 of 77

Second WHO Consultation on Global Action Plan for Influenza Vaccines (GAP-II)

World Health Organization12-14 July 2011, Geneva, Switzerland

Bruce G. Weniger, MD, MPHAssociate Editor, (Elsevier)Former Lead, Vaccine Technology, 2 of 77

World Health Organization, 2006WHO/IVB/06.13WHO/CDS/EPR/GIP/2006.1

3 of 77

U.S. Department of Health and Human Services (HHS)November 2005Appendix F, p. F-39

U.S. Centers for Disease Control and Prevention2006

4 of 77

NEW DELIVERY METHODS: INFLUENZA

Cutaneous, including Classic Intradermal (ID) Improving on Dr. Mantoux’s ID Method Mechanical Disruption of Stratum Corneum Coated Microtines Hollow Microneedles Dissolving Microneedles

5 of 77

g Other (Kinetic, Electromagnetic, Chemical, Sonic)

Jet Injection Intranasal Spray Pulmonary Inhalation of Wet/Dry Aerosols Oral Ingestion Issues; Relative Pros and Cons

Cutaneous VaccinationPutting Antigen Into or Onto the Skin

Prepositionalprefix _

o Epi…E d

Noun o…vaccination

i i ti

Adjectivalroot

o…cutaneous …C t

Terminological Tower of Babel in medical literature

6 of 77

o Endo...o Intra…o Per…o Trans…

o…immunizationo…delivery

o Cutaneous …o…dermal …oDermal …o…epithelialoNeedle-free …o Patch …o Skin …o Topical …

Latin origin (cutis = skin)Greek origin (derma = skin)

Common usage to distinguish: Epidermal (into epidermis)Intradermal (into dermis) Transcutaneous (diffusion

after “topical” application)




Cutaneous VaccinationSuggested Nomenclature Adjectives

“Cutaneous” – All processes that target any part of the skin for delivery of antigen Excludes needles or jets 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

7 of 77

q pthe dermis to raise a visible bleb Includes Mantoux needle method and new techniques of similar result

Nouns “Vaccination” (per Dr. Pasteur to honor 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.

Anatomy of the Skin, in Cross-section (1.6 - 3 mm thick)

< Basement membrane

Painless if onlyto epidermis

Stratum corneum principal barrier to antigen

8 of 77

Subcutaneous (SC) fat layer

Simultaneous invention in 1908 Felix Mendel (Germany), Charles Mantoux (France)

Originally for TB skin testing and vaccination Fine-gauge needle, bevel-up, parallel into skin Fluid bolus below basement membrane

Advantages Uses existing, off-the-shelf vaccines

Classical Intradermal VaccinationThe “Mantoux” Method

9 of 77

g Enhanced immune response often permits dose-sparing

Disadvantages Requires training, skill, time, needle dangers Local reactions from irritating ingredients Painful

Smallpox Many, primary route Tuberculosis (BCG) Many, primary route Yellow Fever Primary route W. Africa 1940s/50s Rabies ≥117 Hepatitis B ≥90 Influenza ≥28 Polio (IPV) 16 Cholera 15

Classical Intradermal VaccinationLong-established Literature

10 of 77

Measles 15 Typhoid 11 Tetanus 6 Hepatitis A 5 Diphtheria-Tetanus-Pertussis 2 (Rossier 1968, Stanfield 1972) Tick-borne encephalitis 2 (Zoulek 1984, 1986) Meningococcal A 1 (Gotschlich 1972) Meningococcal A-C-Y-W135 1 (Sanofi Pasteur, 2006, unpublished) 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)

Excellent results Rabies (already widely used ID in developing world)

Good results worth pursuing Influenza (24 in 1937-1979; 32 in 2003-2010, sig. ClinicalTrials.gov)

Polio (IPV) ( 18)

Classical Intradermal VaccinationOverview of Literature

11 of 77

Polio (IPV) (~18)

Little but promising data Polysaccharide vaccines (MEN, PNU, HIB) Gotschlich 1972 – MENps-A good results

Sanofi Pasteur 2002 (unpublished) – MENps-ACYW135 (Menomune®) good results

Mixed to poor results Hepatitis B (~90)

Measles (~15)

Majority of reports ID immune response >= SC/IM☜Francis T, et al, J Exper Med 1937;65:251-9Van Gelder D, et al, Naval Med Bull 1947:47:197-206☜Weller TH, et al, Proc Soc Exp Biol Med 1948;67:96-101Bruyn H, et al, J Immunol 1949;62:1-11Bruyn H et al Am J Dis Child 1949 77 149 163

Classical Intradermal VaccinationInfluenza ID by Needle, 1930s-1970s

12 of 77

Bruyn H, et al, Am J Dis Child, 1949;77:149-163☜Hilleman M, et al, JAMA 1958;166:1134-40Kirkham L, et al, J Iowa Med Soc 1958;45:593-8Sanger M, et al, Ann Allergy 1959;17:173-8Saslaw S, et al, Am J Med Sci 1964;248:273-284Clark M, et al, J Lab Clin Med 1965;66:34-41Davies JW, et al, Can J Public Health 1969;60:104-108 (JI)Marks M, et al, Am Rev Resp Dis 1971;103:579-581Brown H, et al, J Infect Dis 1977;136(suppl2):s466-s471Halperin W, et al, AJPH 1979;69(12):1247-1251




Minority of Reports: ID Less than SC, or Uncertain

Boger W, et al, JAMA 1957;165:1687-1689

Elderly: SC 500 CCA 79% seroconv > ID 50 CCA 36% (ID lower)

Saslaw S et al Am J Med Sci 1963;245:387-398

Classical Intradermal VaccinationInfluenza ID by Needle, ‘30s-’70s (cont.)

13 of 77

Saslaw S, et al, Am J Med Sci 1963;245:387-398

Non-naïve elderly 4-fold: SC 1.0 mL 60-78% > ID 0.1 mL 39-56% (ID lower)

Sigel M, et al, JAMA 1975;165:1860-1861

Mixed ages, various doses, 4-fold increase: SC 78%, 88%, 77% > ID 45%, 74%, 62% (ID lower) Hutchinson P, et al, Can Dis Wk Rep 1977;3-28:110

ID 0.1 mL seroconversion: A/New Jersey/8/76 - 11/17, A/Victoria/3/75 - 22/26 (uncontrolled)

Question:Does ID make a difference for dose-sparing?

Bruyn H, et al, J Immunol 1949;62:1-11

Adult GMTs: ID 0.1 mL > SC 1.0 mL Child GMTs: ID 0.2 mL > SC 0.2 mL

Classical Intradermal VaccinationInfluenza ID by Needle, 1930s-1970s

14 of 77

McCarroll J, et al, N Engl J Med 1958;259:618-621

Adults: “small doses” ID equivalent to “small doses” SC

Stille W, et al, J Clin Lab Med 1959:53:751-754

Dose ranging, equal ID vs. SC: small antigen mass - ID > SC large antigen mass - SC > ID

Klein M, et al, J Peds 1961;58:312-314

2m-5y children, same dose ID vs. SC: No difference in seroconversion or GMTs

Recent Reports: ID equivalent to IM

Belshe RB, et al, NEJM 2004;351:2286-94

ID: investigational GSK, 6 μg/strain (60% sparing) Using 1.5mm, 30-gauge, BD ID microneedle syringe

IM control: Fluzone® (Aventis), 15 μg/strain, 2001-2002 Adults 18-81 years 1 dose

Classical Intradermal VaccinationInfluenza ID by Needle, 2004-Present

15 of 77

Adults 18 81 years, 1 dose Exception: Elderly, H3N2 GMT and SC: ID < IM

Kenney RT, et al, NEJM 2004;351:2295-301

Fluvirin® (Evans/Chiron), 2003-04 0.1 mL ID vs. 0.5 mL IM

Adults 19-41 years, 1 dose

Chiu SS, et al, Pediatrics 2007;119:1076-1082

Fluarix® (GSK), 2005-06 0.1 mL ID vs. 0.5 mL IM Children 3-17 years, 1 dose (3 - <9 with prior vaccination)


Avian H5N1 - ID (3 or 9 μg) vs. IM (15 or 45 μg) ID and IM doses <45 μg not immunogenic, even after 3rd dose at

8 months

16 of 77

Source: Patel, et al. Vaccine, 2010;28:3025-3029

Classical Intradermal VaccinationInfluenza ID by Needle, 2004-Present Seasonal 2006 ID vs. IM, one dose assessed at day 28 ID < IM in both naive and non-naive subjects Satisfies EMEA/CHMP registration requirements

17 of 77Source: Auewarakul P, et al. Vaccine, 2007;25:659-663

Comparing Equal Doses by ID and IM Routes Belshe, et al, Vaccine 2007;25:37-38 Adults 18-49 years of age, 3-year-retrospective naïves Equal doses of Fluzone® INF (2006-2007) by both routes ID: 3 μg, 6 μg (0.1 mL x 2), 9 μg (0.1 mL x 3) IM: 3 μg, 6 μg, 9 μg, 15 μg (full)


18 of 77

Immune response: ID >= IM at all equivalent doses Local reactions: ID > IM





✔ Cutaneous, including Classic Intradermal (ID) Improving on Dr. Mantoux’s ID Method Mechanical Disruption of Stratum Corneum Coated Microtines Hollow Microneedles Dissolving Microneedles

19 of 77



Soluvia™ Microinjection System (BD)30 gauge needle OD=0.305mm, projects 1.5 mm Exclusive worldwide license to sanofi

pasteur for commercial use 2009: EU approved Intanza® and

Improving on Dr. Mantoux’s MethodReinventing the Wheal

20 of 77

2009: EU-approved Intanza® and IDflu® influenza vaccines

2011: U.S. FDA approved Fluzone Intradermal®

Improving on Dr. Mantoux’s MethodReinventing the WhealSoluvia™ Microinjection System (BD)

21 of 77

Sanofi Pasteur intradermal influenza vaccines Modest or no dose-sparing from conventional IM 15 μg HA / strain / 0.5 mL volume

EU market - Intanza® and IDflu®

9 μg / strain / 0.1 mL (18-59 years) (40% sparing) 15 μg / strain / 0.1 mL (>=60 years) (0% sparing)

US market - Fluzone Intradermal® 9 μg / strain / 0.1 mL (18-64 years age) (40% sparing)

Intradermal Injection Adaptor SID Technologies, LLC, Newtown, PA Foolproof tool to perform classical

Mantoux injection using conventional tuberculin/insulin syringe

Applications: BCG dose sparing RAB

Improving on Dr. Mantoux’s MethodReinventing the Wheal

22 of 77

Applications: BCG, dose-sparing RAB, IPV, INF, etc. CDC SBIR contract Nurse ergonomics

compared to Mantoux Animal model injections

PATH support Rabies, IPV clinical trials India


✔ Cutaneous, including Classic Intradermal (ID)✔ Improving on Dr. Mantoux’s ID Method Mechanical Disruption of Stratum Corneum Coated Microtines Hollow Microneedles Dissolving Microneedles

23 of 77



Cutaneous VaccinationMechanical Disruption of Stratum Corneum Remove or reduce top layer of

dead skin (stratum corneum) Principal barrier to antigen entry

Methods to abrade and strip Peeling cellophane tape

24 of 77

Friction by rubbing Emery, pumice

Uncoated microabrasives Cyanoacrylate “super glue”

OnVax™ microenhancerarray (MEA), BD




Cutaneous VaccinationMechanical Disruption of Stratum Corneum Intercell AG acquired “Transcutaneous

Immunization” platform from Iomai (US Army/WRAIR spinoff)

Uses heat-labile LT toxin as adjuvant (or antigen) Preparation device pulls sandpaper across skin prior

to applying vaccine-impregnated patch Travelers diarrhea vaccine

25 of 77

Randomized, placebo-controlled trials Phase II (723 travelers from Europe to India) Phase III (n=2036 European travelers to Mexico and

Guatemala) Both trial endpoints not met No reduced incidence ETEC and/or all-cause diarrhea

Confirmed consistent induction of protective antibodies against the LT-toxin

December 2010: Suspended TD patch, but will pursue other patch-based vaccines

Influenza Earlier study (see next slide)

Cutaneous VaccinationMechanical Disruption of Stratum Corneum Iomai, US Army/WRAIR spinoff (now

owned by Intercell AG) Patch platform using heat-labile LT

toxin as adjuvant (or antigen) Patch applied over injection site of

conventional INF vaccination by needleB d i fl i ld l

26 of 77

Boosted influenza response in elderly

“Transcutaneous Immunization (TCI)” Frech SA, et al Vaccine 2005;23:946-950


✔ Cutaneous, including Classic Intradermal (ID)✔ Improving on Dr. Mantoux’s ID Method✔ Mechanical Disruption of Stratum Corneum Coated Microtines Hollow Microneedles Dissolving Microneedles

27 of 77



Cutaneous VaccinationCoated Microtines Vaccine or drug coated on

microtine arrays elutes and diffuses upon insertion

Georgia Tech/Emory Mice protected from influenza

Georgia Institute of Technology

28 of 77

Mice protected from influenza challenge Weldon WC, et al, Clin Vacc

Immunol 2011;18:647-654

Zosano Pharma Macroflux™ patch, others

No human vaccine trials reported

Zosano Pharma


✔ Cutaneous, including Classic Intradermal (ID)✔ Improving on Dr. Mantoux’s ID Method✔ Mechanical Disruption of Stratum Corneum✔ Coated Microtines Hollow Microneedles Dissolving Microneedles

29 of 77



Cutaneous VaccinationHollow Microneedles Nanopass MicronJet™ ~250 μm-tall array of four

microneedles Luer-slip interface attaches to

conventional syringe

30 of 77

y g Van Damme et al found 3 μg or

6 μg influenza HA into skin yielded similar HAI titers as 15 μg IM Vaccine 2009;27:454-459

Several clinical trials for influenza NCT00558649, NCT01049490,

NCT01304563





✔ Cutaneous, including Classic Intradermal (ID)✔ Improving on Dr. Mantoux’s ID Method✔ Mechanical Disruption of Stratum Corneum✔ Coated Microtines✔ Hollow Microneedles Dissolving Microneedles

31 of 77



Cutaneous VaccinationDissolving Microneedles Vaccine antigen or drug formulated within solid, dissolvable

matrix Commonly carboxymethylcellulose

Several groups pursuing Georgia Tech Tines 750 μm tall before insertion; dissolve within minutes

Mi d tib d d ll l d h ll t ti

32 of 77

Mice: good antibody and cellular responses and challenge protection Sullivan SP, et al, Nature Med 2010;16:915-920

before insertion after insertion

Photos courtesy:Mark Prausnitz


✔ Cutaneous, including Classic Intradermal (ID)✔ Improving on Dr. Mantoux’s ID Method✔ Mechanical Disruption of Stratum Corneum✔ Coated Microtines✔ Hollow Microneedles✔ Dissolving Microneedles

33 of 77



Cutaneous VaccinationOther Mechanisms Kinetic deposition of propelled microparticles Pfizer’s PowderMed

“Particle-mediated Epidermal Delivery” (PMED™) (DNA on beads) “Epidermal Powder Immunization” (EPI) (protein antigens) 15μg HA via EPI induced similar seroconversion and GMT as 15 μg IM

Three 2006 human influenza studies at Clinical Trials.gov unpublished as of mid-2011

Pfizer PowderMed system

Pfizer PowderMed system

34 of 77

Electromagnetic energy Laser light ablation

Norwood Abbey’s LAD Thermoporation to burn pores

Altea Therapeutics PassPort™ TransPharma Medical ViaDerm™

Iontophoresis current to carry charged drug or solution J&J Alza’s E-trans®

Chemical enhancers Sound energy



35 of 77

g✔ Other (Kinetic, Electromagnetic, Chemical, Sonic)


Jet InjectionWhat is It? Squirts pressurized liquid Through orifice (~0.15 mm) Like child’s water pistol

1860s: Invented in France 1940s: Single-user device

Aquapuncture device Galante et Cie.

36 of 77

1940s: Single user device Insulin and other drugs

1950s: Adapted by U.S. Army for high-speed vaccination sessions Multi-use-nozzle jet injectors

(“MUNJIs”)

Hypospray®, R.P. Scherer Corp.

Ped-O-Jet® MUNJI




Jet InjectionMUNJI Use in Mass Campaigns

1950s Salk inactivated

polio vaccine (IM)

1960s – 1970s “Swine flu” 1976

Salk polio vaccine mass campaign, 1955+

37 of 77

Swine flu 1976 Many other

vaccines: MEA, MENps, POLIPV, SMA, YEL, inter alia

Intradermal nozzle for smallpox (SMA) eradication

“Swine flu” campaign 1976

Davies JW, et al, Can J Public Health 1969;60:104-108 Monovalent: A2/Australia/54 (600 CCA/mL) Same antigen quantity compared ID vs. SC Conclusion: “intradermal … superior to subcutaneous… at same dosage”

MethodRoute and dose (n=)

HAI titer 4-fold rise

Post HAI GMT-1

(post/pre)

Jet InjectionTrial of Influenza Vaccination ID vs. SC

38 of 77

Jet Injection

ID 0.1 mL60 CCA (64)

37 (58%) 114.0 † (3.3x)

SC 0.1 mL60 CCA (91)

29 (32%) 77.6 (2.3x)

SC 0.5 mL300 CCA (85)

50 (59%) † 140.4 † (4.0x)

Needle-syringe

SC 0.5 mL300 CCA (77)

31 (40%) † 75.8 † (2.5x)

† p<0.05 for Jet injection vs. needle-syringe

Jet InjectionSafety Concerns for MUNJIs

Since 1970s – Growing body of evidence for cross-contamination between vaccinees Bench laboratory assays Animal transmission models Outbreak investigation

39 of 77

Epidemiologic studies Human trials assaying “next ejectates”

1997 – Withdrawn from use by U.S. military

2000s – WHO and CDC recommend against use

No high-speed devices remain available for mass campaigns

CDC bench/primate studies, 1980s

PATH human trial using PCR

MUNJIs (C, D and similar withdrawn from use for safety)

A. Aquapuncture device, Galante et Compagnie

B. Hypospray®

C. Ped-O-Jet®

Jet InjectionNew Generation of Disposable-syringe Jet Injectors (DSJIs) Comes to Market

40 of 7740

JD. Med-E-Jet®

E. MadaJet®

F. GentleJet®

DSJIs since 1990s (inter alia)G. Medi-Jector® VISION®

H. J-Tip®

I. Injex®

J. Vitajet™K. LectraJet® HSL. LectraJet® M3M. ZetaJet™N. PharmaJet®

Jet InjectionBoth MUNJIs and DSJIs ID-capable Special intradermal nozzle Ped-O-Jet® MUNJI Recessed orifice: air gap weakens stream Ejects at 45°

S DSJI i f i

41 of 77

Spacer on DSJI syringe for air gap Biojector® 2000 with ID spacer

Dedicated ID device and syringe PharmaJet®

Reduced force profile Unique device-syringe interface

prevents mis-mating with SC or IM devices

Biojector® 2000

PharmaJetPharmaJet®®

(new model to replace)(new model to replace)

Jet InjectionBioject’s ZetaJet™ DSJI

Pioneering DSJI manufacturer 1990s: Biojector® 2000, Vitajet™ www.bioject.com

Mid-2000s: ZetaJet™ CDC SBIR R&D contracts, other funding, PATH assistance L t f d l i t k t

42 of 77

Low-cost for developing-country markets Spring powered Built-in hand crank No separate cocking/reset station

Break-off vial adapter Auto-disabling by plunger lock

510(k) clearance, 2 April 2009 (K090003) SC/IM; ID still investigational

Clinical trial HIV/DNA vaccine, Sweden

http://www.bioject.com




Jet InjectionBioject’s ID Pen Injector Metal-spring powered Manual compression Single-use autodisable

syringes

43 of 77

y g 0.05 or 0.1 mL intradermal

volumes PATH-WHO agreement for

R&D studies (Feb 2011)

Jet InjectionDCI’s LectraJet® M3 Developing DSJI technology since 1990s Marketed veterinary LectraVet® www.dantonioconsultants.com

CDC SBIR R&D contracts 510(k) clearance 0.5 mL SC/IM

44 of 77

24 December 2009 (K090959) Metal-spring powered Separate cocking device/storage box

Clinical trial seasonal influenza DSJI (n=30) vs. needle-syringe (n=30) J. Simon, et al, Univ. Maryland, 2010 Seroconversion, seroprotection similar HAI titer fold increases trended higher

LectraJet® M3

Jet InjectionDCI’s LectraJet® HS High-Speed device for mass campaigns Same 600-1000/hour as Ped-O-Jet Novel fingers-free, rapid loading and unloading Same cartridges as for manual M3 model

Metal spring compressed by internal motor

45 of 77

Rechargeable, replaceable battery pack >3,000 injections per charge

Battery-charging – AC mains, vehicle, solar Backup manual spring compression possible Electronic injection counters Investigational U.S. military expressing interest

Jet InjectionDCI’s LectraJet® HS Video Demonstration

46 of 77http://www.dantonioconsultants.com/videos.htm

Jet InjectionPharmaJet®

www.pharmajet.com Rapid R&D-to-market pace 510(k) clearance 0.5 mL SC/IM 26 Feb. 2009 (K081532)B il ANVISA l

NonNon--investigational seasonal investigational seasonal influenza vaccination, influenza vaccination, 10 Sept 2009,10 Sept 2009,King SooperKing Soopersupermarket,supermarket,Denver, CODenver, CO

47 of 77

Brazil ANVISA clearance Nov. 2009 (80102519021)

EU (CE mark) January 2010 Modest but growing US sales

2009; overseas sales 2010 Coincided with pandemic

influenza campaign of 2009

Jet InjectionIPV Polio Vaccination by DSJI

Polio eradication switch from cheap OPV to expensive IPV (10x cost) Pre-eradication: overcome decreased immune

responses to OPV in remaining hot zones Post-eradication: avoid reversion to virulence from

live virus in OPV

Biojector® 2000 with

investigational ID spacer

48 of 77

Deliver ID by licensed, needle-free jet injectors Avoid difficult Mantoux method for ID route Avoid dangers and drawbacks of needle-syringes

WHO trials of IPV by dose-sparing ID route 80% dose reduction: 0.5 mL to 0.1 mL

Mohammed AJ, et al, NEJM 2010;362:2351-2359 Resik S, et al, JID, 2010201:1344-1352

Roland Sutter, WHO point person

PharmaJetPharmaJet®® IDID

http://www.dantonioconsultants.com

http://www.dantonioconsultants.com/videos.htm

http://www.pharmajet.com




Jet InjectionPharmaJet Intradermal Program CDC SBIR R&D contracts since 2009 FDA “510(k)” clearance in 2011 Dengue vaccine (DEN) Primate study completed

49 of 77

y p Human trial begun 2010

Other clinical trials Rabies (RAB) ID (India) Polio (IPV) ID (Oman, India,

Netherlands) Eradication requires switch from OPV

HPV vaccine (Hong Kong)



50 of 77


✔ Jet Injection Intranasal Spray Pulmonary Inhalation of Wet/Dry Aerosols Oral Ingestion Issues; Relative Pros and Cons

Instranasal SprayBD’s Accuspray™ Nasal Spray System

Becton Dickinson’s syringe for prefilled packaging Produces large droplets for

l d

51 of 77

nasal deposition Medimmune’s FluMist® live

attenuated influenza vaccine (LAIV) Successful and widespread market

use since 2003

Instranasal SprayNasalFlu® Influenza Vaccine

Berna Biotech (formerly Swiss Serum and Vaccine Institute) Contained heat-labile E. coli

LT toxin adjuvant (Escherigen®)

52 of 77

j ( g )Withdrawn in 2001 for safety 84-fold risk of Bell’s palsy

affecting 7th “facial” cranial nerve passing near nose ? Toxicity of LT adjuvant

Instranasal SprayOptiNose™ Nasal Delivery Device Bi-directional deposition to nose only Dry powder or liquid aerosol delivery

53 of 77Video demonstration (http://www.optinose.no)

Percentage of subjects with

Instranasal SprayOptiNose™ Nasal Delivery Device

After 2 doses OptiNose™ … … titers equivalent with nasal drops … better than simple oral or nasal sprays All methods similar on HAI seroprotection

k O tiMi t™

54 of 77

Percentage of subjects withHAI titers ≥40 (seroprotection) a.k.a. OptiMist™

Bakke et al, Scand J Immunol 2006;63:223-231

http://www.optinose.no




Intranasal DropsSimple Instillation

TIV (7.5 μg HA/strain) + 3/10/30 μg LTK63 adjuvant + “Biovector” lipid nanoparticle carrier B

Guangdong

HAI GMT A/Panama/H3N2

55 of 77

j p p Control: 15 μg HA/strain + MF59 adjuvant IM 2 doses, 1 week apart

Delivery: simple instillation from dropper Modest antibody responses; partial CHMP criteria Peak seroconversion rate at 6 weeks H3N2: 27% (IM=67%) B: 67% (IM=80%)

Peak seroprotection rates at 6 weeks H3N2: 27% (IM=73%) B: 73% (IM=87%)

Peak fold-rise at 6 weeks H3N2: 2.2 (IM=6.4) B: 5.8 (IM=20)

Microneut.

A/Duck/Sing./97

HAI GMT B



56 of 77


✔ Jet Injection✔ Intranasal Spray Pulmonary Inhalation of Wet/Dry Aerosols Oral Ingestion Issues; Relative Pros and Cons

Intranasal SpraysDry Powder Measles Vaccine Inhalers Grand Challenge in Global Health #3 “Needle-free Delivery” “Needle-free Delivery of Stable Respirable Powder Vaccine“ Objective 2: “Design and fabricate one or two inexpensive, single-dose

devices to deliver microparticles to the respiratory tract”

Antigen: freeze/spray-dried with sugar stabilizers

57 of 77

g / p y g E.g., measles antigen by Aktiv-Dry LLC

Two Inhalation delivery devices Aktiv-Dry’s PuffHaler™ BD’s Solovent™

Both devices protected rhesus macaques with Aktiv-Dry’s spray-dried live measles virus vaccine See: Lin W-H, PNAS 2011;108:2987-2992

Pulmonary InhalationBD Solovent™ Dry Powder Delivery Inhalers Powder capsule only component

needing cold-chain storage Luer-lock fits onto regular syringe Good IgG, IgA, influenza HAI

responses in rats compared to IM delivery

i l i i b i d

58 of 77

Particle sizings can be increased (>50μm) to target nose, not lung

Huang, et al. Vaccine 2004;23:794-780

AirwayDeposition5-10 µmDeep

Lung(Alveoli)<5 µm

NasalPassages>50 µm

Pulmonary InhalationAktiv-Dry PuffHaler™ Only internal dose capsule need require

cold-chain storage Detachable reservoir avoids cross-

contamination from aerosolizer system

59 of 77

Pulmonary InhalationAktiv-Dry PuffHaler™

60 of 77

Video demonstrationhttp://www.aktiv-dry.com/puffhaler.html

http://www.aktiv-dry.com/puffhaler.html




DP-4 Dry Powder Insufflator™ for murine studies

Pulmonary InhalationInfluenza Study Mice - Univ. Gröningen

Vaccine 2011;29:4345-4352

J Controlled Release 2010;144:127-133

61 of 77

Whole inactivated Influenza A/HIR virus in wet and dry aerosols Freeze- and spray-dried with inulin cryoprotectant IM controls: A/PR/8 split virus

Delivery by model DP-4 Dry Powder Insufflator™ (PennCentury™) to intubated BALB/c mice

Two doses of 5 μg HA to lungs at 2-week intervals Controls: 5μ IM once

Similar to IM controls: Antibody (IgA higher with powder – not shown) Virus grams per lung tissue upon A/PR/8 challenge

Wet aerosol

Dryaerosol

Subunitcontrol

IgG1

IgG2a

IgG1

IgG2a

IgG1

IgG2a

Twincer® powder inhaler for human applications 23%-37% particle sizes <5μm No human trials yet reportedAmorij, et al. Lancet Infection 2010;10:699-711

Pulmonary InhalationInhaler for Human Use - Univ. Gröningen

62 of 77

j, ;

Pulmonary InhalationWet Aerosol Measles Vaccine Inhaler Method Pioneered by Sabin Requires electrical nebulizer

Measles Aerosol Project Since 2002: WHO, CDC,

American Red Cross

63 of 77

American Red Cross Gates Foundation funding Goal: Develop and license at

least one device for a currently-licensed measles vaccine for the developing world

Caveat: Cross-contamination with respiratory pathogens?



64 of 77


✔ Jet Injection✔ Intranasal Spray✔ Pulmonary Inhalation of Wet/Dry Aerosols Oral Ingestion Relative Pros and Cons; Issues to Consider

Oral IngestionFew Human Studies for Influenza Generally poor results 2 – 10 doses, split or whole vaccines, 24, 140, 150 μg HA/strain No detectable IgG Secretory IgA up, then down after further doses (? tolerance)

Lazzell V, et al, J Biol Stand 1984;12:315-321 Bergmann KC, et al. Int Arch Allergy Appl Immunol 1986;80:1070109

65 of 77

g gy pp Moldoveanu Z, et al, Vaccine 1995;13:1006-1012 Avtushenko, SS, et al, J Biotechnol 1996;44:21-28

Bakke et al., Scand J. Immunol, 2006;63:223-231 Spray of conventional A/H1N1/New Caledonia/20/99 (Chiron Behring) As control arm for Optinose™/OptiMist™ intranasal spray device Sprayed into mouth with conventional device Good proportions with HAI seroprotection (≥40) in serum Diminished virus-specific IgA antibodies detected in nasal secretions and saliva

compared to nasal routes (OptiMist™, spray, drops)



66 of 77


✔ Jet Injection✔ Intranasal Spray✔ Pulmonary Inhalation of Wet/Dry Aerosols✔ Oral Ingestion Issues; Relative Pros and Cons




Needle-free delivery methods more desirable for developing countries Avoid dangers / drawbacks of conventional needle-syringe Inadvertent or intentional reuse of unsterile equipment

Issues; Relative Pros and ConsGeneral

67 of 77

Unsafe disposal of medical sharps posing threat to community

Some end-user-fillable methods that can use existing, off-the-shelf vaccines advantageous for lower cost, sooner availability E.g., jet injection, some hollow microneedles BD invented end-user-fillable Soluvia™ – ? useful for

economical ID rabies filled from multi-dose vials

EMEA/FDA criteria may not be relevant for novel non-parenteral routes/antigens Hemagglutination inhibition (HAI) assay primarily validated

on basis of inactivated antigen delivered by needle into fat or muscle

Issues; Relative Pros and ConsGeneral

68 of 77

or muscle Newer antigens delivered to other tissues may induce

cellular or other mechanisms for protection not predicted by HAI titer

Potentially effective vaccines may be falsely rejected (type II β error ?) using HAI performance alone

Phase III field efficacy trials may be required to tease out and validate new immunologic correlates of protection for new routes

Issues; Relative Pros and ConsCutaneous Advantages Minimal invasiveness Easier to monitor and treat local adverse reactions ? Visualizable Amenable to local, topical treatments

Fewer unanticipated serious adverse events than other

69 of 77

Fewer unanticipated serious adverse events than other routes ? Oral - e.g., intussusception (Rotashield®, Wyeth) Intranasal - e.g., Bell’s palsy (Nasalflu®, Berna) Pulmonary – allergic reaction ? IM/SC injection - e.g., abscess, nerve injury, hematoma

Issues; Relative Pros and ConsCutaneous Advantages - 2 Dose-sparing ability (in many, but not all

cases) Enhanced or equivalent immune response for

many antigens compared to IM and SCP l l i i h

70 of 77

Protect larger populations with scarce or expensive vaccines

Large surface area for simultaneous but separate vaccination of competing antigens In contrast to oral & intranasal & respiratory

routes ? Separate vaccines may compete at same delivery

site or draining lymph node

Issues; Relative Pros and Cons Cutaneous Advantages - 3 Less dependent on patient cooperation Think: squirming, uncooperative children, unable to

swallow capsules or actuate inhalers

Relatively sure and certain delivery Next to gold standard: needle IM or SC

71 of 77

Next to gold standard: needle IM or SC

The ideal delivery method a “patch” (“Band-Aid®”, “plaster”) Painless upon delivery to epidermis Containing dissolving micro needles or coated microtines Extremely space-efficient for cold chain volume demand Inexpensive disposal as non-hazardous waste No complex delivery device to buy, transport, maintain,

break, lose

Issues; Relative Pros and Cons Cutaneous Disadvantages

Conventional Mantoux ID injection tedious and difficult to perform consistently

Some adjuvants may be too irritating to tolerate in the skin

72 of 77

the skin Live antigens requiring growth may not do so well in

skin Technologies (patches, kinetic devices) not using

existing off-the-shelf vaccines will require extensive and expensive formulation efforts




Issues; Relative Pros and Cons Intranasal Spray Advantages

Needle-free Relatively quick delivery Proven method for administering LAIV

73 of 77

Proven method for administering LAIV Wide patient acceptance

Issues; Relative Pros and Cons Intranasal Spray Disadvantages

Less certainty of delivery/antigenicity in some situations Sneezing after administration Mucoid or purulent

hi i i “ i ”)

74 of 77

rhinitis (“11 sign”) Pivotal FluMist LAIV trials

limited to “healthy children” Was chronic/acute rhinitis

excluded ? Is LAIV effective in such

conditions common in developing world ?

Issues; Relative Pros and Cons Pulmonary Inhalation Advantages

Needle-free

May takes advantage of immune system cells ideally located for

75 of 77

system cells ideally located for antigen sampling

May induces both systemic and mucosal immune responses

Issues; Relative Pros and Cons Pulmonary Inhalation Disadvantages Highly invasive - targets organ essential for survival Disposable tubing and masks (auto-disabling ?) may

increase per-dose costs Respiratory pathogens may cross-contaminate if dose pathways

reused

76 of 77

reused

May require patient cooperation (? Infants, children) Different anatomies an obstacle in development and

predictable and consistent dosing Animal models to humans Human-to-human variation

Health workers constantly exposed to stray antigen Some methods tedious (30 seconds per dose)


✔ Cutaneous, including Classic Intradermal (ID)✔ Improving on Dr. Mantoux’s ID Method✔ Mechanical Disruption of Stratum Corneum✔ Coated Microtines✔ Hollow Microneedles✔ Dissolving Microneedles✔ Other (Kinetic, Electromagnetic, Chemical, Sonic)

✔ Jet Injection

77 of 77

✔ Jet Injection✔ Intranasal Spray✔ Pulmonary Inhalation of Wet/Dry Aerosols✔ Oral Ingestion✔ Issues; Relative Pros and Cons

Thank you

End of presentation

Backup /supplemental slides followfor further information and discussion

78 of 77




Majority of reports ID immune response >= SC/IMKirkham L, et al, J Iowa Med Soc 1958;45:593-598

Outbreak attack rates: ID 40 CCA = 10% (v.e. 75%) SC 200 CCA = 10% (v.e. 75%) unvaccinated = 33% (referent)

Sanger M et al Ann Allergy 1959;17:173-178

Classical Intradermal VaccinationInfluenza ID by Needle, ‘30s-’70s (cont.)

79 of 77

Sanger M, et al, Ann Allergy 1959;17:173 178 Adult 4-fold rise: ID 20 CCA 41% ~= SC 200 CCA 45%

Saslaw S, et al, Am J Med Sci 1964;248:273-284 Non-naïve elderly 4-fold: ID 0.1 mL ~= SC 1.0 or 0.5 mL > SC 0.25 mL

Clark M, et al, J Lab Clin Med 1965;66:34-41 ID 0.1 mL x2 = SC 1.0 mL x2

Marks M, et al, Am Rev Resp Dis 1971;103:579-581 4-fold rises: Adults ID 160 CCA 86%; Children SC 400 CCA 86%

Brown H, et al, J Infect Dis 1977;136(suppl2):s466-s471 0.1 mL ID equivalent antibody titers to 0.5 mL IM

Halperin W, et al, AJPH, 1979;69(12):1247-1251

Bivalent: A/NewJersey/76 + A/Victoria/75 Age: 18-24 years, 1 dose (“swine flu” campaign cancelled) Different antigen quantity: ID and SC

AntigenRoute and dose

4-fold rise †

HAI 40 †

HAI GMT-1 †

Local reactions

13/64 23/56

Classical Intradermal Vaccination

80 of 77

A/New Jersey/8/76Hsw1Nsw1

ID 0.1 mL nr 13/64 (20%)* 22.71* 23/56

(41%)*

SC 0.5 mL nr 12/60 (20%)* 25.19* 13/56

(23%)*

A/Victoria/3/75 H3N2

ID 0.1 mL 17/31 (55%)*

18/33 (55%)* 28.94* ditto

SC 0.5 mL 11/28 (39%)*

11/33 (33%)* 39.12* ditto

* No significant differences between ID and SC nr = not reported

† Analyses limited to subjects with pre-vaccine titers <10

Herbert FA, et al, JID, 1979;140(2):234-238

Bivalent: A/NewJersey/76 + A/Victoria/75 Age: 17-82 years, 1 dose Different antigen quantity: ID and SC

AntigenRoute and dose (n=)

4-fold rise HAI 40

Post HAI GMT-1

(post/pre)Local

reactions

ID 0.1 mL 30 53 127 %


81 of 77

A/New Jersey/8/76Hsw1Nsw1 ‡

40 CCA (70)30

(43%) † (76%)127

(3.26x) 26%

SC 0.5 mL200 CCA (70)

41(59%) †

62(89%)

196 (7.00x) 12%

A/Victoria/3/75 H3N2

ID 0.1 mL40 CCA (70)

30(43%)*

58(83%)

106 (2.86x) ditto

SC 0.5 mL200 CCA (70)

24 (34%)*

56(80%)

98(2.72x)

ditto

* No significant differences between ID and SC† p<0.05 ‡ 50 year olds had high pre-titers

Phillips et al, JID, 1970;122:26-32

Lilly 1968 season monovalent: A2/Aichi/2/68 ID vs. SC vs. intranasal (IN) Different antigen quantity: ID and SC

Route and HAI 40 HAI “Significant”


82 of 77

Route and dose n 4-fold rise

0 HAI GMT-1

Significant local reactions

ID 0.1 mL80 CCA 34 27 (79%)* 18 (53%) 26.7 7/35 (20%)

SC 0.5 mL400 CCA 71 63 (89%)* 53 (75%) 46.7 15/80 (19%)

IN 0.5 mL400 CCA 33 24 (73%)* 13 (39%) 18.8 1/34 (3%)

* no significant differences

Cutaneous VaccinationMechanical Disruption of Stratum Corneum Van Kampen, et al, Vaccine 2005;23:1029-36 Shaved human abdominal skin, then 30 toothbrush strokes, applied liquid

vaccine and occlusive patch Adenovirus vector expressing hemagglutinin of influenza strain A/PR/8/34

(H1N1) [uncontrolled]

Intranasal drops Immune responses

83 of 77

83

Skin4.8x109 vp Skin

4.8x1010 vp

Skin4.8x1011 vp

p5x108 vp Skin: Modest to good immune

responses at highest doses Intranasal: best

Local reactions Skin: mild erythema, rash, itching Nose: mild irritation

Generally equivalent to or better than needle-syringe Antigen-presenting dendritic (Langerhans) cells in skin ?

Jet InjectionClinical Evidence

Live vaccines Bacille Calmette-Guérin Measles Mumps Measles-Mumps-Rubella

Inactivated vaccines Botulism Cholera Diphtheria-Tetanus-Pertussis Hepatitis A

84 of 77

Often more local reactions than needle-syringe (alum?)Source: Weniger, Papania, Chap. 61, In: Vaccines, 5th Ed., 2008, Elsevier/Saunders, pp.1357-92.

Measles-Mumps-Rubella Measles-Smallpox (vaccinia) Rubella Smallpox (vaccinia) Yellow fever

Routes IM, ID (MUNJIs, one DCJI) SC (DCJIs, investigationals)

Hepatitis B Influenza Japanese encephalitis Meningococcus A, C Plague Polio (IPV) Tetanus, Tetanus-Diphtheria Tularemia-Typhoid Typhoid, Typhoid-Paratyphoid Investigationals: HIV, DNA, cancer, etc.




Influenzavaccineproductinsert -1962

85 of 77

http://clinicaltrials.gov/ct2/show/NCT00386542

Jet InjectionPediatric ID Influenza Vaccination Trial, Dom. Rep.

86 of 77

Jet InjectionPharmaJet® SC and IM “DSJI” Injectors Metal-spring powered Separate cocking

station Color coded

87 of 77

Blue Thicker-skinned adults

Green and Violet (not shown) thinner-skinned

children and elderly

Jet InjectionPharmaJet® Collaborations R&D CDC for intradermal system PATH for technical, bench, regulatory, country-access U.S. Army for investigational smallpox vaccine

88 of 77

Netherlands Vaccine Institute for IPV

Clinical trials of SC/IM injectors PATH and/or WHO and local institutions Measles-Mumps-Rubella (MMR) vaccine SC (Brazil) 582 Brazilian infants aged 12 - 18 months

Yellow fever vaccine (YEL) trial (Brazil) DTP-HIB or DTP-HIB-HBV vaccines (Brazil)

Intranasal DropsSimple Instillation

89 of 77

MEM71-reassortant inactivated split-virus antigen. Nasal instillation of drops 0.01, 0.1, 1.0, or 10 μg virus + 10 μg ISCOMATRIX™

adjuvant No IM/SC controls Challenged with 104.5 pfu infectious MEM71 virus Caveats: some antigen swallowed? Only Ag reaching

lower respiratory tract successful?

10 μg dose

http://clinicaltrials.gov/ct2/show/NCT00386542

research on n vaccine delivery methods focus on influenza · research on new vaccine delivery...

Documents