Intradermal delivery:Intradermal delivery:the challenges, g

the pros and cons

R Chi Chi MD MSRu-Chien Chi MD MSUniversity of Washington

S ttl WASeattle, WAApril 8, 2008

Potential advantages of intradermal-delivery

Improve vaccine efficacy Dose-sparing strategy during shortage Dose-sparing strategy during shortage

Example: seasonal influenza vaccine Reduced cost

Example: rabies vaccineExample: rabies vaccine Overcome poor-response (e.g. elderly or

immunocompromised)immunocompromised)Example: hepatitis B vaccine

Potential disadvantages of intradermal delivery

Skin holds limited volume--optimal dose is not known.not known.

ID injection technique requires skill and time--leakage SQ injection needle dangersleakage, SQ injection, needle dangers.

Injection site reactions--discoloration, swelling, itching.

A Randomized Open Label Phase IIA Randomized, Open-Label, Phase II Clinical Trial Comparing Safety,

Reactogenicity, & Immunogenicity of Trivalent Influenza Vaccine by y

Intradermal (ID) or Intramuscular (IM) Vaccination Among Healthy ElderlyVaccination Among Healthy Elderly

Objectives Compare efficacy of influenza vaccine given by

intradermal (ID) and intramuscular (IM) route in h lth ld lhealthy elderly.

Evaluate reactogenicity and safety of influenza vaccine given by intradermal (ID) route, at volumes up to 0 3 mlup to 0.3 ml.

Compare differences in priming by intradermal (ID) Compare differences in priming by intradermal (ID) and intramuscular (IM) routes.

Methods

Design: Single center (Seattle VA Hospital), phase II, randomized, open-label clinical trial.

Participants: 258 healthy veterans/partners aged ≥65 yrsyrs.

Intervention: Full dose IM or 60% IM or ID vaccination with trivalent inactivated influenza vaccine (TIV).

Data collection: Pre and post vaccination blood Data collection: Pre- and post-vaccination blood specimens and safety diary.

Measurements: HAI antibody titers and adverse eventscores.

Study flowchart

Route Dosage Volume September/October

October/November

November/DecemberOctober

Visit 1 November

Visit 2 December

Visit 3 IM 15 µg 0.5 ml Blood draw,

vaccinationBlood draw, exit studyvaccination exit study

IM 9 µg 0.3 ml Blood draw, vaccination

Blood draw, standard flu shot

Blood draw, exit study

IM exit study

ID 9 µg 0.3 ml Blood draw, vaccination

Blood draw, standard flu shot

Blood draw, exit study

IM exit study

ID 4.5 µg 0.15 ml twice

Blood draw, vaccination

Blood draw, standard flu shot

Blood draw, exit studytwice IM exit study

Injection routes

Mosby's Drug Guide for Nurses, 5th edition

ID t h iID techniqueDay 0 (20 mins)

ID technique

D 1 D 3Day 1 Day 3

Day 5 Day 7

Baseline characteristics0.5 ml IM, %

(n=65)0.3 ml IM, %

(n=64)0.3 ml ID, %

(n=63)2 X 0.15 ml

ID, %(n=65)(n=65)

Age, yrs (s.d.) 75.6 (6.8) 75.2 (7.7) 73.6 (6.3) 74.7 (6.3)Male, n (%) 54 (83.1) 53 (82.8) 52 (82.5) 54 (83.1)Male, n (%) 54 (83.1) 53 (82.8) 52 (82.5) 54 (83.1)White race 56 (86.2) 60 (93.8) 55 (87.3) 53 (81.5)Chronic 41 (63.1) 40 (63.5) 34 (54.0) 44 (67.7)conditionsHeart disease 19 (29.2) 18 (28.1) 15 (23.8) 23 (35.4)Lung disease 6 (9.2) 9 (14.1) 5 (7.9) 7 (10.8)Diabetes 16 (24.6) 9 (14.1) 6 (9.5) 15 (23.1)Fl shot 63 (96 9) 59 (92 2) 61 (96 8) 62 (95 4)Flu shot (2006)

63 (96.9) 59 (92.2) 61 (96.8) 62 (95.4)

Severity scales for solicited adverse eventsAdverse Event

Grade I Grade II Grade III

Redness ≤8 cm >8 cm ≤15 cm >15 cm to whole arm

Swelling ≤8 cm >8 cm ≤15 cm >15 cm to wholeSwelling ≤8 cm >8 cm ≤15 cm >15 cm to whole arm

Arm motion Easily tolerated Interferes with Interferes with anyArm motion limitation

Easily tolerated Interferes with normal activities

Interferes with any arm motion

Fatigue, l i

Easily tolerated Interferes with l ti iti

Severe, i it timyalgia,

itching, painnormal activities incapacitating

Fever Oral T ≥ 38 0°C Oral T ≥ 39 0°C Oral T ≥ 40 0°CFever Oral T ≥ 38.0 C <39°C

Oral T ≥ 39.0 C <40°C

Oral T ≥ 40.0 C

Intradermal influenza vaccination:Local symptomsLocal symptoms

0.5 ml IM, %

0.3 ml IM, %

0.3 ml ID, 2 X 0.15 ml ID %%

(n=65)%

(n=64)%

(n=63)

ID, %(n=65)

R dRedness

Any 14.1 10.9 71.4* 80.0*

Grade II-III 0 0 4.8 6.2

Swelling

Any 20.3 6.3 58.7* 67.7*

Grade II-III 0 0 3.2 4.6

Itching

Any 6.3 7.9 23.8† 29.2*

Grade II-III 0 0 0 3.1

* P≤0.002 †P<0.015, comparing to 0.3 ml IM

Intradermal influenza vaccination:Local and systemic symptoms

0.5 ml IM, %(n=65)

0.3 ml IM, %(n=64)

0.3 ml ID, %(n=63)

2 X 0.15 ml ID, %(n=65)(n=65)

Local pain 10.9 17.2 11.1 21.5Arm motion 1 6 1 6 0 0Arm motion limitation

1.6 1.6 0 0

Fever 0 1.6 0 6.1Chills 3.2 3.2 1.6 10.7Myalgia 11.0 10.9 8.0 23.1Headache 15.6 9.4 6.4 21.6Nausea 6.3 4.7 3.2 4.6

Leakage

0.5 ml IM, %(n=65)

0.3 ml IM, %(n=64)

0.3 ml ID, %(n=63)

2 X 0.15 ml ID, %( ) ( ) ( )(n=65)

Leakage 0 1.6 7.9* 10.8†

*P=0.09, † P= 0.03, comparing to 0.3 ml IM.

Serious adverse events ID Group Event Onset Vaccine

1Vaccine

2Days s/p vaccine

006 0.3 ml ID

Anemia, arrythmia

10/01/07 09/05/07 10/16/07 26

075 0 15 ml Small bowel 10/06/07 9/17/07 10/16/07 19075 0.15 ml X 2 ID

Small bowel obstruction

10/06/07 9/17/07 10/16/07 19

094 0.3 ml IM

Acute coronary d

10/15/07 09/19/07 10/17/07 26IM syndrome

105 0.15 ml X 2 ID

S/p fall 9/20/07 9/19/07 10/16/07 1

224 0.15 ml X 2 ID

Nausea & vomiting

12/12/07 10/17/07 11/15/07 56

239 0 3 ml Appendicitis 11/11/07 10/22/07 11/19/07 20239 0.3 ml IM

Appendicitis 11/11/07 10/22/07 11/19/07 20

Proportion of subjects achieving serum HAI antibody titer ≥40 againstHAI antibody titer ≥40 against A/Soloman Islands/3/2006 (H1N1)

100%

60%

80%

40%Day 0Day 28Day 56

0%

20%Day 56

0%0.5 ml IM 0.3 ml IM 0.3 ml ID 0.15 ml ID X

2

Proportion of subjects achieving serum HAI antibody titer ≥40 againstHAI antibody titer ≥40 against A/Wisconsin/67/2005 (H3N2)

100%

60%

80%

40%Day 0Day 28Day 56

0%

20%Day 56

0%0.5 ml IM 0.3 ml IM 0.3 ml ID 0.15 ml ID X

2

Proportion of subjects achieving serum HAI antibody titer ≥40 againstHAI antibody titer ≥40 against B/Malaysia/2506/2004

100%

60%

80%

40%Day 0Day 28Day 56

0%

20%Day 56

0%0.5 ml IM 0.3 ml IM 0.3 ml ID 0.15 ml ID X

2

Challenges to ID vaccination Studies that control for dose of vaccine,

number of shots, so to compare only varying p y y groute.

Determine optimal dose, volume, vaccination p , ,schedule.

Refine the intradermal technique (needle and Refine the intradermal technique (needle and syringe requires skill).

Understand the immunology of ID vaccination Understand the immunology of ID vaccination. Acceptability (pain, skin reaction).

Acknowledgements

Seattle VA HospitalSusan Bigda, RNTeresita Cornell

PATHJeff Huentelman, BAKathy Neuzil MD MPH

Vanderbilt UniversityMarie Griffin, MD MPHMichael Rock PhDTeresita Cornell

Janice Enzmann, RN, BSNAngie MonacoJulie Nicholas RN BSN

Kathy Neuzil, MD MPHKim Kelly, MPA, CCRPDarin Zehrung, BA

Michael Rock, PhD

Julie Nicholas, RN, BSN Gigi Rostomily, RN Funding

VA Career Development AwardUSAID

Prevaccination seropositivity(HAI ≥ 1:10)(HAI ≥ 1:10)

90%90%

100%Fig 1: H1N1 Fig 2: H3N2

50%60%70%80%

0.5 ml IM 60%70%80%90%

20%30%40%50%

0.3 ml IM0.3 ml ID0.15ml X 2 ID

20%30%40%50%

0%10%

All Age 65-74 yrs >75 yrs 0%10%

All Age 65-74 yrs >75 yrs80% B

50%

60%

70%

80%

0 5 ml IM

B

Fig 3: B

20%

30%

40%0.5 ml IM0.3 ml IM0.3 ml ID0.15ml X 2 ID

0%

10%

All Age 65-74 yrs >75 yrs