1 h5n1 pediatric experience. 2 pediatric h5n1 vaccine trials a randomized, double-blinded, placebo-...

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H5N1 Pediatric Experience

H5N1 Pediatric Experience

Richard L. Gorman, MDAssociate Director for Clinical Research, Division of Microbiology and Infectious

DiseasesNIAID, NIH, DHHS

19 Feb 2009

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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)

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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

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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

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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

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04-077 Data Set

• Gender– 54% boys 46% girls

• Race– 89% Caucasian

• Age– Median 6 years

• 2-5 years: 61• 6-9 years: 52

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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

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04-077 Safety

• Overall, 141 AEs– 61 % mild (# = 86)

– 12 deemed related

– 37% moderate ( # = 52)– 2 deemed related

– 2% severe ( # = 3)– All unrelated

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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)

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

Event 45 µg (n=102)

Placebo (n=23)

Decreased Activity 22 (7) 8 (4)

Body Aches (asked 6-9 yo only, n=47, 12)

8 (6) 0

Injection Site Pain 40 (10) 17 (0)

Decreased Limb Mobility 7 (3) 0

Redness 16 (4) 13 (9)

Swelling 7 (1) 13 (0)

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

Event 45 µg (n=95)

Placebo (n=22)

Decreased Activity 17 (3) 14 (5)

Body Aches (asked 6-9 yo only, n=43, 11)

5 (0) 0

Injection Site Pain 41 (6) 14 (0)

Decreased Limb Mobility 10 (4) 0

Redness 17 (2) 23 (0)

Swelling 8 (1) 14 (0)

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

Event 45 µg (n=58)

Placebo (n=0)

Decreased Activity 10 (3) N/A

Body Aches (asked 6-9 yo only, n=30)

3 (3) N/A

Injection Site Pain 33 (5) N/A

Decreased Limb Mobility 7 (0) N/A

Redness 17 (3) N/A

Swelling 11 (2) N/A

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Reactogenicity Post Vaccination 1

04-077 45 mcg

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04-077 45 mcg

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04-077 45 mcg

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04-077 Peds – 45 mcg 04-063 Adults – 45 mcg

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04-077 MN Results

4-fold Increase MN

0 0 006

53

70

0 2

66

76

05

10152025303540455055606570758085

Before Dose 1 After Dose 1 After Dose 2 After Dose 3

Visit

Per

cen

t R

esp

on

se

Placebo Age 2-5 y Age 6-9 y

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04-077 HAI Results

4-fold Increase HI

0 0 006

35

53

07

41

64

05

1015202530354045505560657075

Before Dose 1 After Dose 1 After Dose 2 After Dose 3

Visit

Per

cen

t R

esp

on

se

Placebo Age 2-5 y Age 6-9 y

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HI - 4-Fold RisesPost vaccination titer >=1:40

Fold rise is relative to baseline titer, prior to vac #1

Time point04-077 Peds45 mcg

04-063 Adults45 mcg

04-076 Elderly45 mcg

Post vac #1 7% 21% 7%

Post vac #2 38% 33% 23%

Post vac #3 58% 38% 17%

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HI - 4-Fold Rises Post vaccination titer >=1:40

Fold rise is relative to baseline titer, prior to vac #1

Time point04-077 Peds45 mcg

04-063 Adults90 mcg

04-076 Elderly90 mcg

Post vac #1 7% 23% 25%

Post vac #2 38% 42% 38%

Post vac #3 58% 55% 40%

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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

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DMID 04-077 Reactogenicity Grading Scale

Local Reactions

Grade 1 Grade 2 Grade 3 Grade 4

ErythemaSwellingRash @ inj. site

1-20 mm 21-50 mm >50 mm but less than entire arm

Entire upper arm

Grade 1 Grade 2 Grade 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

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DMID 04-077 Reactogenicity Grading Scale

Systemic Reactions

Grade 1 Grade 2 Grade 3

Fever ≥100F-101F ≥37.8C-38.3C

>101F-103F >38.3C-39.4C

>103F >39.4C

Body Aches 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, 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

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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.

07FSL011, ROTAVIRUS

Study Group

Days Postlast Vac.

ReasonReported as an SAE

Severity Relationship to vaccine

Outcome Duration MedDRA® SOC/ PT

45 mcg 13 Hospitalization/ Prolonged Hospitalization

Severe Not Associated Resolved without sequelae

8 days Infections and infestations / Gastroenteritis rotavirus

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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 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.

07FSL011, ROTAVIRUS

Study Group

Days Postlast Vac.







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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 Postlast Vac.







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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 Postlast Vac.







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DMID 04-077 Serious Adverse Events07FSL024, RAT BITE FEVER

Study Group

Days Postlast Vac.






6 days Infections 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 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.

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DMID 04-077 Serious Adverse Events07FSL024, RAT BITE FEVER

Study Group

Days Postlast Vac.






6 days Infections 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.

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Effect of Licensed Flu Vaccine on HI Responses

***Post vaccination titer >=1:40 *Wilcoxon rank test **Fisher’s exact test

Protocol 04-077 Received Prior Flu

Vac

Did Not Receive Prior

Flu Vac

P value

N (45 mcg group only)

46 46

Post Dose 2 GMT

9.6 30.3 0.0005*

Post Dose 2 GM Fold Rise

1.9 6.1 0.0005*

Post Dose 2 % w/ 4-Fold Rise***

23.9% 52.2% 0.0095**

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1 h5n1 pediatric experience. 2 pediatric h5n1 vaccine trials a randomized, double-blinded, placebo-...

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