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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