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1 H5N1 Pediatric Experience. 2 Pediatric H5N1 Vaccine Trials A Randomized, Double-blinded, Placebo- controlled, Phase I/II, Study of the Safety, Reactogenicity,

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Presentation on theme: "1 H5N1 Pediatric Experience. 2 Pediatric H5N1 Vaccine Trials A Randomized, Double-blinded, Placebo- controlled, Phase I/II, Study of the Safety, Reactogenicity,"— Presentation transcript:

1 1 H5N1 Pediatric Experience

2 2 Pediatric H5N1 Vaccine Trials A Randomized, Double-blinded, Placebo- controlled, Phase I/II, Study of the Safety, Reactogenicity, and Immunogenicity of Intramuscular Inactivated Influenza A/H5N1 Vaccine In Healthy Children Aged 2 Years Through 9 Years (DMID 04-077) Open-Label Study of Intramuscular Inactivated Influenza A/H5N1 Vaccine in Healthy Children Aged 2 Years to 10 Years (DMID 06-0072)

3 3 04-077 Study Design Multi center: 3 Participating Centers Randomized: 5:1 Double-blind Population –Healthy children –2-9 years old (strata: 2-5 yo, 6-9 yo) Vaccine –Inactivated subunit –rg influenza A/Vietnam/1203/04/H5N1 Dose, Volume, Route –45 µg HA in 0.5 mL given IM Manufacturer –Sanofi Pasteur, Swiftwater PA USA

4 4 04-077 Study Design Procedures –2 IM doses of vaccine or placebo –Given 1 month apart –3 rd dose at 6 months vaccine recipients only, optional Reactogenicity –Memory aid –Clinic visits and telephone calls –SAE follow-up for at least 12 months Immunogenicity –Sera for HI and MN Before vaccination 1 month after each dose

5 5 04-077 Data Set 125 children enrolled 23 placebo 102 Vaccine 117 received 2 doses 113 with all sera available 21 placebo 92 vaccine Booster dose at 6 months 58 vaccine recipients boosted 55 with sera at 28 days

6 6 04-077 Data Set Gender –54% boys 46% girls Race –89% Caucasian Age –Median 6 years 2-5 years: 61 6-9 years: 52

7 7 04-077 Safety 2 Serious Adverse Events2 Serious Adverse Events Both deemed unrelated Both deemed unrelated – Rotavirus diarrhea 13 days after second vaccination 13 days after second vaccination Other family members ill Other family members ill – Rat bite fever 55 days after 2nd vaccination 55 days after 2nd vaccination Due to Julie, newly purchased pet rat Due to Julie, newly purchased pet rat Hospitalized Hospitalized

8 8 04-077 Safety 141 AEsOverall, 141 AEs – 61 % mild (# = 86) –12 deemed related – 37% moderate ( # = 52) – 2 deemed related – 2% severe ( # = 3) –All unrelated

9 9 04-077 Reactogenicity Fever – None severe (103 degrees F or greater) – 1 mild and 2 moderate after dose 1 – 2 moderate after dose 2 – 1 moderate after dose 3 Injection site pain – None severe Redness – Most mild (up to 20 mm)

10 10 04-077 Reactogenicity - Dose 1 % any severity (% moderate/severe) Event45 µg (n=102) Placebo (n=23) Decreased Activity22 (7)8 (4) Body Aches (asked 6-9 yo only, n=47, 12) 8 (6)0 Injection Site Pain40 (10)17 (0) Decreased Limb Mobility7 (3)0 Redness16 (4)13 (9) Swelling7 (1)13 (0)

11 11 04-077 Reactogenicity - Dose 2 % any severity (% moderate/severe) Event45 µg (n=95) Placebo (n=22) Decreased Activity17 (3)14 (5) Body Aches (asked 6-9 yo only, n=43, 11) 5 (0)0 Injection Site Pain41 (6)14 (0) Decreased Limb Mobility10 (4)0 Redness17 (2)23 (0) Swelling8 (1)14 (0)

12 12 04-077 Reactogenicity - Dose 3 % any severity (% moderate/severe) Event45 µg (n=58) Placebo (n=0) Decreased Activity10 (3)N/A Body Aches (asked 6-9 yo only, n=30) 3 (3)N/A Injection Site Pain33 (5)N/A Decreased Limb Mobility7 (0)N/A Redness17 (3)N/A Swelling11 (2)N/A

13 13 Reactogenicity Post Vaccination 1 04-077 45 mcg

14 14 Reactogenicity Post Vaccination 2 04-077 45 mcg

15 15 Reactogenicity Post Vaccination 3 04-077 45 mcg

16 16 Reactogenicity Post Vaccination 1 04-077 Peds – 45 mcg04-063 Adults – 45 mcg

17 17 Reactogenicity Post Vaccination 1 04-077 Peds – 45 mcg04-063 Adults – 90 mcg

18 18 04-077 MN Results

19 19 04-077 HAI Results

20 20 HI - 4-Fold Rises Post vaccination titer >=1:40 Fold rise is relative to baseline titer, prior to vac #1 Time point 04-077 Peds 45 mcg 04-063 Adults 45 mcg 04-076 Elderly 45 mcg Post vac #1 7%21%7% Post vac #2 38%33%23% Post vac #3 58%38%17%

21 21 HI - 4-Fold Rises Post vaccination titer >=1:40 Fold rise is relative to baseline titer, prior to vac #1 Time point 04-077 Peds 45 mcg 04-063 Adults 90 mcg 04-076 Elderly 90 mcg Post vac #1 7%23%25% Post vac #2 38%42%38% Post vac #3 58%55%40%

22 22 04-077 Summary 2 IM doses of 45 µg unadjuvanted inactivated H5N1 vaccine in children –Well-tolerated –Led to immune responses comparable to adult responses –Slightly better responses in 6-9 year olds compared to 2-5 year olds

23 23 DMID 04-077 Reactogenicity Grading Scale Local Reactions Grade 1Grade 2Grade 3Grade 4 Erythema Swelling Rash @ inj. site 1-20 mm21-50 mm>50 mm but less than entire arm Entire upper arm Grade 1Grade 2Grade 3 Pain @ Inj. Site Winced when site pressed Complained that arm hurt when moved Cried or screamed when arm moved Mobility of Injection Site Limb (Fxn Score) Limitation of use but uses it without interference with daily activities Limitation of use but uses it with interference with daily activities No use of limb

24 24 DMID 04-077 Reactogenicity Grading Scale Systemic Reactions Grade 1Grade 2Grade 3 Fever 100 F-101 F 37.8 C-38.3 C >101 F-103 F >38.3 C-39.4 C >103 F >39.4 C Body AchesLess Active Than Normal without interference with essential daily tasks (e.g., eating, sleeping) Less Active Than Normal with interference with essential daily tasks (e.g., eating, sleeping) Stayed in bed or on couch General Activity Level Less Active Than Normal without interference with essential daily tasks (e.g., eating, sleeping) Less Active Than Normal with interference with essential daily tasks (e.g., eating and sleeping) Stayed in bed or on couch

25 25 DMID 04-077 Serious Adverse Events 23 Mar 2006: This 6-year-old female subject was enrolled in the study and received blinded study product on 25 Jan 2006 and on 22 Feb 2006. She experienced the SAE of "Rotavirus" on 07 Mar 2006, reported as resolved without sequelae on 14 Mar 2006. The site reported that the subject was not receiving any concomitant medications. On 07 Mar 2006, the subject developed diarrhea which increased in severity. On 09 Mar 2006, the subject was unable to tolerate oral fluids and was admitted to the hospital to receive IV fluids. The mother reported that other members of the family had the same symptoms, although not as severe, and that the diagnosis of rotavirus was made after tests performed at the hospital. This event was considered resolved without sequelae on 14 Mar 2006. 07FSL011, ROTAVIRUS Study Group Days Post last Vac. Reason Reported as an SAE SeverityRelationship to vaccine OutcomeDurationMedDRA® SOC/ PT 45 mcg13Hospitalization/ Prolonged Hospitalization SevereNot AssociatedResolved without sequelae 8 daysInfections and infestations / Gastroenteritis rotavirus

26 26 DMID 04-077 Serious Adverse Events 19 May 2006 :Additional information including a follow-up email from the site and a discharge summary was received and reviewed. On 09 Mar 2006, the subject was admitted to the hospital with vomiting, diarrhea, listlessness, lethargy and dry mucus membranes. Upon physical examination, the subjects bowel sounds were hypoactive and mild epigastric tenderness was noted. Her remaining physical assessment was benign. Maintenance intravenous fluids were started to treat the subjects dehydration and famotidine was given for epigastric discomfort. On 10 Mar 2006, the subjects blood glucose was 79 (reference range and units not provided); she was tolerating oral fluids well and she was discharged to home. Discharge medications included Tylenol, Motrin and Pepcid. 07FSL011, ROTAVIRUS Study Group Days Post last Vac. Reason Reported as an SAE SeverityRelationship to vaccine OutcomeDurationMedDRA® SOC/ PT 45 mcg13Hospitalization/ Prolonged Hospitalization SevereNot AssociatedResolved without sequelae 8 daysInfections and infestations / Gastroenteritis rotavirus

27 27 DMID 04-077 Serious Adverse Events 02 Aug 2006 :Additional information including a follow-up SAE report form was received and reviewed. The event term was amended to Rotaviral Gastroenteritis, as stool culture obtained on 09 March 2006 was subsequently positive for rotavirus. 07FSL011, ROTAVIRUS Study Group Days Post last Vac. Reason Reported as an SAE SeverityRelationship to vaccine OutcomeDurationMedDRA® SOC/ PT 45 mcg13Hospitalization/ Prolonged Hospitalization SevereNot AssociatedResolved without sequelae 8 daysInfections and infestations / Gastroenteritis rotavirus

28 28 DMID 04-077 Serious Adverse Events 23 Mar 2006: This 6-year-old female subject was enrolled in the study and received blinded study product on 25 Jan 2006 and on 22 Feb 2006. She experienced the SAE of "Rotavirus" on 07 Mar 2006, reported as resolved without sequelae on 14 Mar 2006. The site reported that the subject was not receiving any concomitant medications. On 07 Mar 2006, the subject developed diarrhea which increased in severity. On 09 Mar 2006, the subject was unable to tolerate oral fluids and was admitted to the hospital to receive IV fluids. The mother reported that other members of the family had the same symptoms, although not as severe, and that the diagnosis of rotavirus was made after tests performed at the hospital. This event was considered resolved without sequelae on 14 Mar 2006. 07FSL011, ROTAVIRUS Study Group Days Post last Vac. Reason Reported as an SAE SeverityRelationship to vaccine OutcomeDurationMedDRA® SOC/ PT 45 mcg13Hospitalization/ Prolonged Hospitalization SevereNot AssociatedResolved without sequelae 8 daysInfections and infestations / Gastroenteritis rotavirus

29 29 DMID 04-077 Serious Adverse Events 07FSL024, RAT BITE FEVER Study Group Days Post last Vac. Reason Reported as an SAE SeverityRelationship to vaccine OutcomeDurationMedDRA® SOC/ PT 45 mcg55Hospitalization/ Prolonged Hospitalization SevereNot AssociatedResolved without sequelae 6 daysInfections and infestations / Zoonotic bacterial infection 31 Jul 2006: Additional information including a follow-up SAE report form and medical reports was received and reviewed. Medical history includes tube placement for otitis media and low birth weight. On 18 Apr 2006, the subject presented to her primary care physician with vomiting and fever for one day. Upon physical examination, it was noted that her left tympanic membrane was red and bulging. Otitis media and gastroenteritis were diagnosed and Amoxil was prescribed. On 19 Apr 2006, the subject returned for follow-up. She had experienced an intermittent fever for 24 hours that peaked at 103°, vomiting and also complained of painful abdomen and legs. She was noted to have a maculopapular rash with petechiae on the buttocks and extremities including palms and soles. Amoxil had been prescribed at the previous visit for an ear infection, but the subject had not taken it. Upon physical examination, it was noted that the subjects left tympanic membrane was dull and red and her oropharynx area was erythematous. A urinalysis and culture was negative. Laboratory analysis revealed the following abnormal results: sodium 134 mmol/L (reference range 136-145 mmol/L), hemoglobin 13.6 gm/dL (reference range 11.0-13.0 gm/dL), and lymphocytes 10.3% (reference range 40-60%). A blood culture obtained was negative. Medical notes from the follow-up visit later that day indicate that the subject was bitten by a pet rat on her index finger. The father reported that the bite was deep enough to cause bleeding. On 20 Apr 2006, the subject was admitted to the hospital and empirically treated for rat bite fever with intravenous penicillin. Rocky Mountain spotted fever antibody serologies were sent. Her condition improved and on 23 Apr 2006, the subject was discharged from the hospital with instructions to complete a 10-day regimen of amoxicillin and to follow-up with her primary care physician. Medical notes from her follow-up visit on 24 Apr 2006 indicate that the subject was taking amoxicillin as prescribed and improving.

30 30 DMID 04-077 Serious Adverse Events 07FSL024, RAT BITE FEVER Study Group Days Post last Vac. Reason Reported as an SAE SeverityRelationship to vaccine OutcomeDurationMedDRA® SOC/ PT 45 mcg55Hospitalization/ Prolonged Hospitalization SevereNot AssociatedResolved without sequelae 6 daysInfections and infestations / Zoonotic bacterial infection 27 Oct 2006: Additional information including a follow-up SAE report form and hospital reports was received and reviewed. Blood cultures were negative, as well as the Rocky Mountain spotted fever antibody, respiratory syncytial virus direct antigen enzyme immunoassay, respiratory virus antigen and culture, and influenza direct antigen screen. On 07 Jul 2006, the subject was seen for follow- up and had no complaints. On 24 Apr 2006, this event was considered resolved without sequelae.

31 31 Effect of Licensed Flu Vaccine on HI Responses ***Post vaccination titer >=1:40 *Wilcoxon rank test**Fishers exact test Protocol 04-077 Received Prior Flu Vac Did Not Receive Prior Flu Vac P value N (45 mcg group only) 46 Post Dose 2 GMT 9.630.3 0.0005* Post Dose 2 GM Fold Rise 1.96.1 0.0005* Post Dose 2 % w/ 4-Fold Rise*** 23.9%52.2% 0.0095**

32 32 Reactogenicity Post Vaccination 1 04-077 Peds – 45 mcg04-063 Adults – 45 mcg

33 33 Reactogenicity Post Vaccination 2 04-077 Peds – 45 mcg04-063 Adults – 45 mcg

34 34 Reactogenicity Post Vaccination 3 04-077 Peds – 45 mcg04-063 Adults – 45 mcg

35 35 Reactogenicity Post Vaccination 1 04-077 Peds – 45 mcg04-063 Adults – 90 mcg

36 36 Reactogenicity Post Vaccination 2 04-077 Peds – 45 mcg04-063 Adults – 90 mcg

37 37 Reactogenicity Post Vaccination 3 04-077 Peds – 45 mcg04-063 Adults – 90 mcg

38 38 Reactogenicity Post Vaccination 1 04-077 Peds – 45 mcg04-063 Adults – 45 mcg

39 39 Reactogenicity Post Vaccination 2 04-077 Peds – 45 mcg04-063 Adults – 45 mcg

40 40 Reactogenicity Post Vaccination 3 04-077 Peds – 45 mcg04-063 Adults – 45 mcg

41 41 Reactogenicity Post Vaccination 1 04-077 Peds – 45 mcg04-063 Adults – 90 mcg

42 42 Reactogenicity Post Vaccination 2 04-077 Peds – 45 mcg04-063 Adults – 90 mcg

43 43 Reactogenicity Post Vaccination 3 04-077 Peds – 45 mcg04-063 Adults – 90 mcg


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