Influenza Vaccination by Classical Intradermal (ID) Route, Influenza Vaccination by Classical Intradermal (ID) Route,

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1 Influenza Vaccination by Classical Intradermal (ID) Route, Meeting on Fondation Mérieux, Les Pensières, Veyrier-du-Lac (Annecy), France 7-9 April 2008 Bruce G. Weniger, MD, MPH Vaccine Technology Immunization Safety Office, CDC Influenza Vaccination by Classical Intradermal (ID) Route, Pandemic preparedness research agendas Traditional classical ID delivery methods Future classical ID delivery methods Historical clinical trials s-1970s Recent clinical trials 2000s 2 page 1

2 U.S. Department of Health and Human Services (HHS), Appendix F, p. F-39 page 2

3 Influenza Vaccination by Classical Intradermal (ID) Route Influenza vaccine product insert 1962 Swine Influenza Mass Vaccination Campaigns Using MUNJI Jet Injectors, Intramuscular delivery with IM nozzle A/New Jersey/8/76 Hsw1Nsw1 50-dose 25 ml vials monovalent and bivalent formulations with seasonal strain ~80m doses distributed Doses delivered uncertain At least tens of millions page 3

4 Influenza Vaccination by Classical Intradermal (ID) Route, Pandemic preparedness research agendas Traditional classical ID delivery methods Future classical ID delivery methods Historical clinical trials s-1970s Recent clinical trials 2000s 7 Classical Intradermal (ID) Injection Deposit liquid bolus under basement membrane Create visible wheal or bleb Mantoux method by needle-syringe Jet Injectors with intradermal nozzles or spacers Multi-use-nozzle jet injectors (MUNJIs) DermoJet 8 Ped-O-Jet Med-E-Jet page 4

5 Influenza Vaccination by Classical Intradermal (ID) Route, Pandemic preparedness research agendas Traditional classical ID delivery methods Future classical ID delivery methods Historical clinical trials s-1970s Recent clinical trials 2000s 9 Intradermal Injection via Biojector 2000 Jet Injector with Investigational Spacer page 5

6 Intradermal Injection via Biojector 2000 Jet Injector with Investigational Spacer Post-injection wheal of induration Investigational Prefilled Intradermal Syringe Soluvia Micro-delivery System, Becton, Dickinson and Co.) 30 gauge microneedle -syringe OD=0.305mm, projects 1.5 mm Limitations Filling line capacity (pre-filled only end-users cannot fill this model) Exclusive license to sanofi pasteur (unrevealed terms) page 6

7 Influenza Vaccination by Classical Intradermal (ID) Route, Pandemic preparedness research agendas Traditional classical ID delivery methods Future classical ID delivery methods Historical clinical trials s-1970s Recent clinical trials 2000s 13 Intradermal Influenza Vaccination by Needle, 1930s-1970s Literature Majority of Reports: ID Greater than or Equivalent to SC Francis T, et al, J Exper Med 1937;65: ID and SC routes: no substantial difference in immunogenicity Van Gelder D, et al, Naval Med Bull 1947:47: GMTs: ID 0.1 ml x1 > ID 0.1 ml x2 > SC 1.0 ml x1 Weller TH, et al, Proc Soc Exp Biol Med 1948;67: NEJM 2005: Similar findings [good ID response] as Belshe, Kenney 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 (same dosage) Bruyn H, et al, Am J Dis Child, 1949;77: Child GMTs: ID 0.1 ml x2 > (ID 0.1 ml x1 / SC 0.5 ml x1) Hilleman M, et al, JAMA 1958;166: Adults: ID 0.1 ml vs. SC 1.0 ml equivalent immunogenicity page 7

8 Intradermal Influenza Vaccination by Needle, 1930s-1970s literature - continued ID Greater than or Equivalent to SC/IM Kirkham L, et al, J Iowa Med Soc 1958;45: 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: Adult 4-fold rise: ID 20 CCA 41% ~= SC 200 CCA 45% Saslaw S, et al, Am J Med Sci 1964;248: 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: fold rises: Adults ID 160 CCA 86%; Children SC 400 CCA 86% Brown H, et al, J Infect Dis 1977;136(suppl2):s466-s ml ID equivalent antibody titers to 0.5 ml IM ID Influenza Vaccination by Needle Halperin W, et al, AJPH, 1979;69(12): Bivalent: A/NewJersey/76 + A/Victoria/75 Age: years, 1 dose ( swine flu campaign cancelled) Different antigen quantity: ID and SC Antigen A/New Jersey/8/76 Hsw1Nsw1 A/Victoria/3/ 75 H3N2 Route and dose ID 0.1 ml SC 0.5 ml ID 0.1 ml SC 0.5 ml 4-fold rise nr nr 17/31 (55%)* 11/28 (39%)* page 8 HAI 40 13/64 (20%)* 12/60 (20%)* 18/33 (55%)* 11/33 (33%)* HAI GMT * 25.19* 28.94* 39.12* Local reactions 23/56 (41%)* 13/56 (23%)* ditto ditto * No significant differences between ID and SC nr = not reported Analyses limited to subjects with pre-vaccine titers <10

9 ID Influenza Vaccination by Needle 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 dose ID 0.1 ml 80 CCA n 34 4-fold rise 27 (79%)* HAI (53%) HAI GMT Significant local reactions 7/35 (20%) SC 0.5 ml 400 CCA (89%)* 53 (75%) /80 (19%) IN 0.5 ml 400 CCA (73%)* 13 (39%) /34 (3%) * no significant differences ID Needle Influenza Vaccination Herbert FA, et al, JID, 1979;140(2): Bivalent: A/NewJersey/76 + A/Victoria/75 Age: years, 1 dose Different antigen quantity: ID and SC Antigen A/New Jersey/8/76 Hsw1Nsw1 Route and dose (n=) ID 0.1 ml 40 CCA (70) SC 0.5 ml 200 CCA (70) ID 0.1 ml A/Victoria/3/ 40 CCA (70) 75 H3N2 SC 0.5 ml 200 CCA (70) 4-fold rise 30 (43%) 41 (59%) 30 (43%)* 24 (34%)* HAI (76%) 62 (89%) 58 (83%) 56 (80%) Post HAI GMT -1 (post/pre) 127 (3.26x) 196 (7.00x) 106 (2.86x) 98 (2.72x) Local reactions 26% 12% ditto ditto * No significant differences between ID and SC p< year olds had high pre-titers page 9

10 Intradermal Influenza Vaccination by Needle, 1930s-1970s literature - continued Question: Is ID Influenza Really Dose-sparing vs. SC (i.e., in same dose quantity by different routes)? 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 McCarroll J, et al, N Engl J Med 1958;259: Adults: small doses ID equivalent to small doses SC Stille W, et al, J Clin Lab Med 1959:53: Dose ranging, equal ID vs. SC: small antigen mass - ID > SC large antigen mass - SC > ID Klein M, et al, J Peds 1961;58: m-5y children, same dose ID vs. SC: no difference seroconversion or GMTs See next study ID Influenza Vaccination by Jet Injector Davies JW, et al, Can J Public Health 1969;60: Monovalent: A 2 /Australia/54 (600 CCA/mL) Same antigen quantity compared ID vs. SC Conclusion: intradermal superior to subcutaneous at same dosage Method Jet Injection Needlesyringe Route and dose (n=) ID 0.1 ml 60 CCA (64) SC 0.1 ml 60 CCA (91) SC 0.5 ml 300 CCA (85) SC 0.5 ml 300 CCA (77) HAI titer 4-fold rise 37 (58%) 29 (32%) 50 (59%) 31 (40%) Serologic results shown are for vaccine strain p<0.05 for Jet injection vs. needle-syringe Post HAI GMT -1 (post/pre) (3.3x) 77.6 (2.3x) (4.0x) 75.8 (2.5x) page 10

11 Influenza Vaccination Immune Response by Needle: Minority of Reports: ID Less than SC, or Uncertain Boger W, et al, JAMA 1957;165: Elderly: SC 500 CCA 79% seroconv > ID 50 CCA 36% (ID lower) Saslaw S, et al, Am J Med Sci 1963;245: 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: 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) Influenza Vaccination by Classical Intradermal (ID) Route, Pandemic preparedness research agendas Traditional classical ID delivery methods Future classical ID delivery methods Historical clinical trials s-1970s Recent clinical trials 2000s 22 page 11

12 Recent ID Influenza Vaccination Studies by Needle Kenney RT, et al, New Engl J Med 2004;351: Trivalent Fluvirin (Evans/Chiron), season N=100, age: years, 1 dose ml ID vs. 0.5 ml IM Seroprotection by HAI -1 40, all 3 strains: no difference ID vs. IM A/New Caledonia/20/99 (H1N1) HAI titer, fold increase, s.c. rate: no difference ID vs. IM A/Panama/2007/99 (H3N2) HAI titer, fold increase: ID > IM (p<0.001) B/Shangdong/7/97 (like B/Hong Kong) HAI titer, fold increase: ID > IM (p<0.04) Local reactions: erythema, pruritis, swelling, induration ID > IM (p<0.05) Recent ID Influenza Vaccination Studies Belshe RB, et al, New Engl J Med 2004;351: Trivalent, investigational, GSK AS -adjuvanted 6 μg/strain (60% sparing) 1.5mm, 30-gauge, BD intradermal syringe (not stated in text) Control: IM full-dose trivalent: Fluzone (Aventis), 15 μg/strain N=238, years, 0.1 ml ID vs. 0.5 ml IM Subjects years All strains, HAI GMT, seroprotection rate 40, fold increases no difference ID vs. IM Subjects years Generally decreased GMT, all 3 strains, compared to younger group A/Panama/2007/99 (H3N2) GMT HAI titer, seroconversion rate: ID less than IM (p=0.02) Seroprotection rate: no difference ID vs. IM A/New Caledonia/20/99 (H1N1); B strains (Johannesburg, Victoria) GMT HAI titer, sero-conversion/-protection: no difference ID vs. IM Local reactions Induration, redness, swelling: ID > IM Grade 2-3 pain: IM > ID page 12

13 Recent ID Influenza Vaccination Studies by Needle Chiu SS, et al, Pediatrics 2007;119: Fluarix (GSK), ml ID vs. 0.5 ml IM Children 3-17 years, 1 dose (3 - <9 with prior vaccination) Immunogenicity ID equivalent to IM Reactogenicity Mild induration ID (25%) > IM (5.4%) Mild erythema ID (57%) > IM (3.6%) 25 Recent ID Influenza Vaccination Studies by Needle NIAID-Sponsored phase I trial VTEU at Baylor College of Medicine, S. Patel et al year old healthy adults Intervals: 0, 1, then 8 months Doses 1+2: n=100 Dose 3: n=77 H5N1 recombinant A/Vietnam strain ID: 3 μg or 9 μg in 0.1 ml IM: 15 μg or 45 μg in 0.5 ml Reactogenicity ID > IM, but both routes safe and well tolerated page 13

14 Intradermal H5N1 Study, Baylor U. Immunogenicity Results Reduced-dose ID (3 or 9 μg) as poor as routine dose quantity (15 μg) IM All doses <45 μg not immunogenic, even after 3 rd dose at 8 months Source: Shital M. Patel, et al. IDSA 44 th Annual Meeting, October 2006, Toronto, Canada, abstract LB Intradermal Seasonal INF Study, Thailand Auewarakul, et al., Vaccine 2007;25: N=500 (100 IM, 400 ID) year old healthy adults 1 dose during January-March, 2006 Trivalent, inactivated INF vaccine from Govt. Pharm. Org. Bulk-supplied antigen from Mérieux Biological Products Co., Ltd. 3 μg per strain via ID (0.1 ml); 15 μg per strain via (0.5 ml) control H1N1: A/New Caledonia/20/99-like strain H3N2: A/Wellington/1/2004-like strain B/Shanghai/361/2002-like strain Local reactions: ID>IM, but in all cases mild and transient Erythema: ID 92% IM 2% (p=0.001) Induration: ID 68% IM 4% (p=0.001) Pruritis: ID 49% IM 6% (p=0.001) Systemic reactions: no differences ID vs. IM except: Generalized itchiness: ID 16% IM 5% (p=0.005) Malaise: ID 13% IM 24% (p=0.006) Myalgia: ID 18% IM 30% (p=0.008) page 14

15 2006 Intradermal Seasonal INF Study, Thailand Immunogenicity results at day 28 ID < IM in both naive and non-naive subjects Satisfies CPMP registration requirements Source: Prasert Auewarakul, et al. Vaccine, 2007;25: Comparing Equal Doses by ID and IM Routes Belshe, et al, Vaccine 2007;25:37-38 Adults years of age, 3-year-retrospective naïves Equal doses of Fluzone INF ( ) 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) Immune response: ID >= IM at all doses Local reactions: ID > IM page 15

16 Influenza Vaccination by Classical Intradermal (ID) Route Jet-injected Intradermal Influenza Vaccination Trial, Dom. Rep. trials.gov/ct2/ show/nct Jet-injected Intradermal Influenza Vaccination Trial, Dom. Rep. Subjects: Healthy 6-to-<24 month old children Design: Size: Total N=450 (150 per study arm) Two/thirds blinding Phase 1 n=48 (16 per arm) Phase 2 n=402 (134 per arm) Sized to demonstrate non-inferiority (10% decrement) Unblinded nurses inject doses (avoids double or triple shots each visit) Blinded parents and physician investigators do all assessments page 16

17 Influenza Vaccination by Classical Intradermal (ID) Route Routine photography of injection site on days 2 and 7 Optional photography day 0 if any injury, or day 28 if any visible reaction still present Phase I Results (n=48) from Still-blinded Trial of Intradermal Influenza Vaccination by Jet Injector page 17

18 Phase I Results (n=48) from Still-blinded Trial of Intradermal Influenza Vaccination by Jet Injector, Local Reactions by Interval after Dose WHO International Clinical Trials Registry Platform Search Portal Inflexal V (Berna Biotech/Crucell) Vaxigrip (sanofi pasteur / CDC) INF i unspecified (University Health, Toronto) INF rdna-h5n1plasmid (NIAID, NIH) Vaxigrip (sanofi pasteur) Vaxigrip? (sanofi pasteur MSD) INF ih5n1 (sanofi pasteur / NIAID, NIH) INF i3 (NIAID, NIH) Fluzone (sanofi pasteur / NIAID, NIH) INF ih5n1 (sanofi pasteur / NIAID/NIH) As of 6 April 2008 Fluzone (sanofi pasteur / PATH) (duplicate) page 18

19 Influenza Vaccination by Classical Intradermal (ID) Route, Pandemic preparedness research agendas Traditional classical ID delivery methods Future classical ID delivery methods Historical clinical trials s-1970s Recent clinical trials 2000s 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 Centers for Disease Control and Prevention, have not been formally disseminated by CDC, and should not be construed to represent any agency determination or policy. 37 page 19