H5N1 Pediatric Experience

1. H5N1 Pediatric Experience

2. 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) Pediatric H5N1 Vaccine Trials

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. 04-077 Study Design • Procedures • 2 IM doses of vaccine or placebo • Given 1 month apart • 3rd 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. 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. 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. 04-077 Safety • 2 Serious Adverse Events • Both deemed unrelated • Rotavirus diarrhea • 13 days after second vaccination • Other family members ill • Rat bite fever • 55 days after 2nd vaccination • Due to Julie, newly purchased pet rat • Hospitalized

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

9. 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) 04-077 Reactogenicity

10. 04-077 Reactogenicity - Dose 1% any severity (% moderate/severe)

11. 04-077 Reactogenicity - Dose 2% any severity (% moderate/severe)

12. 04-077 Reactogenicity - Dose 3% any severity (% moderate/severe)

13. Reactogenicity Post Vaccination 1 04-077 45 mcg

14. Reactogenicity Post Vaccination 2 04-077 45 mcg

15. Reactogenicity Post Vaccination 3 04-077 45 mcg

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

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

18. 04-077 MN Results

19. 04-077 HAI Results

20. HI - 4-Fold RisesPost vaccination titer >=1:40Fold rise is relative to baseline titer, prior to vac #1

21. HI - 4-Fold RisesPost vaccination titer >=1:40Fold rise is relative to baseline titer, prior to vac #1

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. DMID 04-077 Reactogenicity Grading Scale

24. DMID 04-077 Reactogenicity Grading Scale

25. DMID 04-077 Serious Adverse Events23 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 notreceiving 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.

26. DMID 04-077 Serious Adverse Events19 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 subject’s bowel sounds were hypoactive and mild epigastric tenderness was noted. Her remaining physical assessment was benign. Maintenance intravenous fluids were started to treat the subject’s dehydration and famotidine was given for epigastric discomfort. On 10 Mar 2006, the subject’s 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.

27. DMID 04-077 Serious Adverse Events02 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.

28. DMID 04-077 Serious Adverse Events23 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.

29. DMID 04-077 Serious Adverse Events 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 subject’s 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. DMID 04-077 Serious Adverse Events 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. Effect of Licensed Flu Vaccine on HI Responses***Post vaccination titer >=1:40*Wilcoxon rank test **Fisher’s exact test

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

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

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

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

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

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

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

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

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

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

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

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