# Presentation: 867405

## FluMistTMInfluenza Virus Vaccine Live, Intranasalfor Use in Healthy Children and Healthy Adults 5 – 64 Years of Age

- Sponsor
-  MedImmune Vaccines, Inc.
*(Formerly Aviron)*

## Overview, product description and indication

- Sponsor Presentation

*James Young, PhD*
*President, R&D*

## Influenza Vaccine

- 20M-50M annual influenza infections in the US
- Most common cause of medically attended respiratory illness
- 70M lost work days, 38M missed school days
- 20,000-50,000 deaths
- Limitations of current US vaccine program
- 150 million healthy people currently not vaccinated
- <10% of healthy children and < 30% of healthy adults
- Annual *injection* required
- FluMist meets a major public health need for prevention of influenza in healthy children and healthy adults
- Ease/acceptance of administration

## FluMistTM

- Intranasal live, cold-adapted, temperature-sensitive, attenuated influenza virus vaccine
- Annual vaccine strains derived from type A and type B Master Donor Viruses
- Vaccine strains express contemporary hemagglutinin and neuraminidase
- Clinical trials performed with 14 vaccine strains
- 4 A/H1N1, 5 A/H3N2, 5 Type B
- Multiple mutations in multiple genes
- At least four mutations in each MDV each confer attenuation in ferrets
- At least 7 mutations in MDV-A and 8 in MDV-B
- Phenotypically stable, reversion expected at frequency of _<_ 10-20

## Influenza Virus Genomic Structure

**PB1**

**PB2**

**PA**

**HA**

**NP**

**NA**

**M1/M2**

**NS1/NEP**

**Hemagglutinin**

**Neuraminidase**

## Derivation of New Master Virus Strain

***New Wild Type Strain***

***Master Donor Virus***

**Co-infect Cells**

## FluMistTM

- Manufactured in specific pathogen-free eggs
- Comprehensive testing of chickens and vaccine
- Safety testing of new vaccine strains in adults
- Trivalent (A/H1N1, A/H3N2, B)
- 107 TCID50 of each strain / 0.5ml dose
- Unit dose, stored frozen, no thimerosal
- Administered by nasal sprayer
- Large droplets (60μm average diameter; 98% >10 μm)
- Dose = 0.5ml (0.25ml / nostril)
- Single annual dose for _>_ 9 years; two doses < 9 years

## VRBPAC July 2001: Efficacy

| Vote  | Yes | No |
| --- | --- | --- |
| Children 1 – 17 years |   8 | 7 |
| Adults 18 – 64 | 13 | 2 |
| Discussion (Chairman’s Review) |  |  |
| Children 2 – 17 years | 13 | 2 |

- Question #1 Was efficacy established?

- Data adequate to establish efficacy in healthy individuals
- Sample size at the lower end of the proposed age spectrum less robust (12-24 months)

## VRBPAC July 2001: Safety

|  | Yes | No |
| --- | --- | --- |
| Adults and children 1 – 64 years |   4 | 10 |
| Six of the 10 No votes were qualified as “provisional” until analysis complete |  |  |

- Question #2 Was safety established?

- The final safety data had not been submitted and thus CBER review was ongoing
- Analysis needed to be completed to resolve open questions particularly those related to pneumonia and asthma
- Concurrent immunization data needed for children < 24 mos

## Progress Since July 2001 VRBPAC Meeting

- Responded to two Complete Response Letters
- Established 20 studies as final dataset in BLA
- 14 placebo-controlled, 6 open-label
- Representing ~20,000 subjects receiving ~28,000 doses of FluMist
- Submitted final study reports for AV019, AV012, and Finnish Daycare Study
- Final analyses
- No signal for pneumonia
- Possible signal in children < 60 months of age for medically attended asthma/wheezing
- Concurrent immunization study ongoing

## Revised Indication

- “FluMist is indicated for active immunization for the prevention of disease caused by influenza A and B viruses in healthy individuals ages 5 years(60 months) through 64 years of age”

## Not Proposing FluMist Use In: 

- Individuals with history of underlying conditions which predispose them to poor outcomes when infected with wild type infuenza virus such as:
- Asthma or recurrent medically attended wheezing
- Immunodeficiencies or chronic immunosuppression
- Other chronic cardiac or pulmonary disorders
- Chronic metabolic diseases (including diabetes), renal dysfunction, and hemoglobinopathies
- Concurrent use with other vaccines

## Clinical Presentation

## Overview of Clinical Presentation

- Review efficacy/effectiveness and safety of FluMist in children and adults
- Provide final data for specific open safety questions, including
- Asthma and wheezing
- Pneumonia
- Provide data on vaccine virus shedding and transmission

## Children 
AV006 pivotal field trial demonstrating efficacy for H3N2 and Type B
AV011 challenge trial with H1N1 vaccine demonstrated efficacy of 83% (95%CI: 60, 95)
Adults
AV003 wild type challenge trial demonstrating efficacy of 85% (95% CI: 28, 100) 
AV009 pivotal field trial demonstrating effectiveness 

- AV006 pivotal field trial demonstrating efficacy for H3N2 and Type B
- AV011 challenge trial with H1N1 vaccine demonstrated efficacy of 83% (95%CI: 60, 95)
- Adults
- AV003 wild type challenge trial demonstrating efficacy of 85% (95% CI: 28, 100)
- AV009 pivotal field trial demonstrating effectiveness

- Principal Studies Supporting Efficacy/Effectiveness of FluMist

## Efficacy Trial Healthy Children Study AV006

- Randomized (2:1), double-blind, placebo-controlled two year field trial
- 1,602 healthy children age 15-71 months at entry
- One or two doses in Yr 1 and revaccination dose in Yr 2
- Active surveillance with illness cultures
- Primary endpoint: culture-confirmed influenza
- Circulating strains
- A/Wuhan/359/95 (H3N2) and B/Beijing/184/93-like in Year 1
- A/Sydney/05/97 (H3N2), a mismatched strain circulated in Year 2

## Efficacy of FluMist in Healthy Children in Study AV006 (N=1,602)

- * Principal circulating strain A/Sydney/05/97 (H3N2) mismatched from vaccine strain

- FluMist efficacy 93% against culture-confirmed influenza
- Comparable efficacy on annual revaccination

| Endpoint | Year One |
| --- | --- |
|  | % Efficacy (95% CI) |
| Culture-confirmed influenza  | 92.6 (87.3, 95.7) |
|     Associated febrile illness | 95.0 (90.0, 97.5) |
|     Associated otitis media | 97.5 (85.5, 99.6) |
|     Associated lower respiratory illness | 83.4 (-15.4, 97.6) |

| Year Two* |
| --- |
| % Efficacy (95% CI) |
| 87.1 (77.7, 92.6) |
| 89.3 (80.4, 94.2) |
| 94.3 (78.1, 98.5) |
| 100.0 (77.0, 100.0) |

## Efficacy of FluMist in Healthy Children by Age in Study AV006

- * Principal circulating strain A/Sydney/05/97 (H3N2) mismatched from vaccine strain

| Age  | Year One | Year Two* |
| --- | --- | --- |
|  | % Efficacy (95% CI) | % Efficacy (95% CI) |
| 	     < 24 months | 84.7 (57.5, 94.6) |  |
| 	24 – 35 months | 96.2 (85.8, 99.0) | 84.4 (35.2, 96.3) |
| 	36 – 47 months | 87.0 (66.8, 94.9) | 84.5 (56.8, 94.5) |
| 	48 – 59 months | 100 (89.9, 100) | 92.2 (69.0, 98.0) |
| 	      60 months | 90.6 (70.3, 97.1) | 86.9 (70.8, 94.1) |
| 	60 – 71 months | 90.6 (70.3, 97.1) | 86.2 (61.3, 95.1) |
|   72 – 83 months |  | 87.5 (58.9, 96.2) |

- FluMist highly effective in all age groups
- Similar efficacy in children 60-83 months of age

## Effectiveness in AdultsStudy AV009

- Randomized 2:1, double-blind, placebo-controlled
- 4,561 healthy working adults 18 – 64 years of age
- Single dose
- Primary endpoint: incidence of “any febrile illness”
- Secondary
- Associated absenteeism and medically attended illness
- Number and days of illness
- Other illness definitions
- Febrile URI, Severe febrile illness (pre-specified)
- CDC-Influenza-like illness (ILI), DOD-ILI (post-hoc)
- Circulating strain, A/Sydney/05/97 (H3N2), mismatched

## Illness Definitions Study AV009

**URI**
**	****runny nose**
**	****sore throat cough**
**Systemic**
**	****fever**
**	****chills**
** ****	****headache muscle aches**
**	****tired/weak**

## Effectiveness of FluMist in Healthy Adults in Study AV009

**0**

**20**

**40**

**60**

**80**

**100**

**Any Febrile**

**Illness**

**Severe**

**Febrile**

**Illness**

**Febrile URI**

**CDC-ILI**

**DOD-ILI**

- % Reduction

- 

- 

- 

- 

- No significant reduction of “Any Febrile Illness”
- Effective in more influenza-specific syndromes

## Percent Reduction in Healthy Adults in AV009 

- 

**Any Febrile**

**Illness**

**Severe**

**Febrile**

**Illness**

**Febrile URI**

**CDC-ILI**

**DOD-ILI**

- % Reduction

**0**

**20**

**40**

**60**

**80**

**100**

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

## Percent Reduction Healthy Adults in AV009 

- Percent Reduction Healthy Adults in AV009

- All Adults   N = 4567

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

## Effectiveness Against Febrile URI in Adults by Age Group

**50-64**

**All**

**18-49**

**50-64**

**All**

**18-49**

**50-64**

**All**

**18-49**

**50-64**

**All**

**18-49**

**50-64**

**All**

**18-49**

- Confidence intervals overlap
- Evidence does not suggest a difference between 50-64 year olds and the randomized population

**Occurrence**

**Days Of**
**Illness**

**Days Of**
**Lost Work**

**Healthcare Provider Visits**

**Antibiotic Use**

## Efficacy/Effectiveness of FluMistConclusions

- FluMist was demonstrated to be highly effective in prevention of influenza in healthy children and adults
- Efficacy/effectiveness observed across age subgroups
- Efficacy in children _>_ 60 months of age was similar to the group as a whole and to younger children in AV006
- Effectiveness in 50-64 year olds was similar to the randomized population in AV009
- Field efficacy was established for H3N2 and B strains
- H1N1 did not circulate during the study periods
- Challenge studies in children (vaccine strain) and adults (wild-type strain) with H1N1 support activity
- Previous field studies with CAIV demonstrated H1N1 efficacy
- Comparable efficacy after annual revaccination

## Population studied:
~16,000 healthy children, ~3,000 revaccinated
~ 4,000 healthy adults 
General safety measures:
SAEs and mortality
Reactogenicity
Medically attended events 
Specific issues:
Asthma/wheezing
Pneumonia
Conjunctivitis
CNS

- ~16,000 healthy children, ~3,000 revaccinated
- ~ 4,000 healthy adults
- General safety measures:
- SAEs and mortality
- Reactogenicity
- Medically attended events
- Specific issues:
- Asthma/wheezing
- Pneumonia
- Conjunctivitis
- CNS

- Summary of Data Supporting FluMist Safety

## SAEs and Mortality  

- SAEs and Mortality

- Two unrelated deaths (drowning and tumor)
- SAE rate was low and similar in FluMist and placebo
- None were related to vaccine

**0**

**1**

**2**

**3**

**4**

**5**

**1-4 Years**

**5-17 Years**

**1-17 Years**

**1-17 Years**

**FluMist**

**Placebo**

*Placebo-Controlled*

*Open Label*

*Placebo-Controlled*

*Open Label*

**0%**

- Percentage

- SAEs in Children

- SAEs in Adults

## Solicited AEs within 10 Days after Dose One In Placebo-Controlled Studies of Healthy Children 12-71 Mos

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- 70

- 80

- 90

- 100

- Cough

- Runny
- Nose/Nasal Congestion

- SoreThroat

- Irritability

- Headache

- Chills

- Vomiting

- MuscleAches

- DecreasedActivity

- Temp>100F

- Temp>102F

- Temp>104F

- CDC-ILI

**Events**

**Percentage**

- *

- *

- *

- Reactogenicity in Children

- Small but statistically significant increase in mild URI symptoms after Dose One
- CDC-ILI similar between groups
- Absolute rates lower and no significant increases after Dose Two

** ******** ****12.1%**

**  ******** ****2.2%**

**  ******** ****4.6 %**

- FluMist  N = 1517

- Placebo N = 659

**0%**

- Temp >101
- 7.4% vs 6.2%

## Solicited AEs within 7 Days after Vaccination in Placebo-Controlled Studies for Healthy Adults 18-64 Yrs

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- 70

- 80

- 90

- 100

- Cough

- Runny
- Nose

- Sore
- Throat

- Headache

- Chills

- Muscle
- Aches

- Tired/
- Weak

- Temp
- >100F

- Temp
- >102F

- CDC-ILI

**Events**

**Percentage**

- FluMist  N = 2960

- Placebo N= 1478

- *

- *

- *

- *

- *

- Reactogenicity in Adults

- Mild URI symptoms increased following FluMist
- Fever and CDC-ILI similar in the FluMist and placebo groups

** ******** **2.8%

** ******** **16.8%

** ******** **9.3%

** ******** **2.0%

** ******** **3.9%

**0%**

## Medication Use within 10 Days After Dose One in Healthy Children in Placebo-Controlled Studies

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- 70

- 80

- 90

- 100

- FluMist   N = 1704

- Placebo  N = 754

- Antipyretics/Analgesics

- Antibiotics, oral

- Antihistamines/Antitussives/Decongestants

- Beta AgonistsGlucocorticoids(nasal/oral)

**Percentage**

- *

- Medication Use in Children

- Small increase in antipyretic/analgesic use only after Dose One
- No other medication use was significantly increased after either dose

** ******** **5.3%

## Adults with Medication Use within 7 Days in Placebo-Controlled Trials

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

- FluMist

- Placebo

**Percentage**

- Medication Use in Adults

- FluMist was not associated with increase in medication use in adults

## Reactogenicity within 10 Days after Dose One For Children by Age

**Percentage**

- Rates similar or lower for children _>_ 60 vs < 60 months
- None was significantly different from placebo for _>_ 60 mo olds

- 0

- 20

- 40

- 60

- 80

- 100

- 0

- 20

- 40

- 60

- 80

- 100

- FluMist N=231

- Placebo N=101

- Children 12-59 months

**Events**

- Cough

- Runny
- Nose/
- NasalCongestion

- SoreThroat

- Headache

- Chills

- Vomiting

- MuscleAches

- DecreasedActivity

- Temp>100F

- Temp>102F

- Temp>104F

- Irritability

- Children 60-71 months

- *

- *

- *

- FluMist N=1286

- Placebo N=558

## Reactogenicity Events Within 7 Daysin Healthy Adults by Age in AV009

- Cough

- Runny Nose

- SoreThroat

- Headache

- Chills

- MuscleAches

- Tired/Weak

- Temp>100F

- Temp>102F

- CDC-ILI

**Events**

**Percentage**

- Adults 50-64 Years

- Adults 18-49 Years

- Event rates were similar or lower in those 50 – 64 years of age, compared to younger adults

- *

- *

- *

- *

- *

- *

- *

- *

## Reactogenicity of Annual Revaccination in AV006

- Solicited AEs within 10 days in Healthy Children 1-8 Years of Age (n=642) Receiving at Least One Dose of FluMist in Three Consecutive Years

- Reactogenicity event rates were lower on annual revaccination
- The reactogenicity profile was similar during the second and third annual dosing

## Reactogenicity Summary

- FluMist associated with mild URI symptoms in children and adults
- No significant increase in acute influenza-like illness and no significant difference between the groups for fever >101oF following FluMist administration
- Reactogenicity rates lower following annual revaccination

## Medically Attended Eventsin Children and AdolescentsStudy AV019 (Kaiser)

- Randomized 2:1, double-blind, placebo-controlled
- Safety of FluMist in 9,689 children
- Two doses 1-8 yrs of age, One dose 9-17 yrs of age
- Outcomes ascertained from diagnosis in HMO database
- Medically attended events (MAEs) and SAEs within 42 days
- >1,500 comparisons made using setting, dose, age group and diagnosis without statistical adjustment
- Emergency Department (ED), Clinic, Hospital, and Combined settings
- Dose One, Dose Two, and combined doses
- 1-17 years, 1-8 years, 9-17 years, 18-35 months, 12-17 months

## Study AV019 Four Pre-specified Grouped Diagnoses*

- * All settings combined, 1-17 year olds, combined doses

## Study AV019 Individual MAEs 

- 14 MAEs were significantly increased and 21 decreased in FluMist recipients
- Rate significantly increased in FluMist group and a cause-and-effect relationship could not be excluded for:
- URI
- Musculoskeletal pain
- Asthma

## MAE Rates and Risk within 42 Days Study AV019

| Age | Setting | Dose | Rate Per 1000 Person-MonthsFluMist / Placebo | Binomial Relative Risk (90% CI) |
| --- | --- | --- | --- | --- |
| Upper Respiratory Tract Infection |  |  |  |  |
| 1 – 17 yrs | ED | One |            1.35 / 0 | NE (2.14, NE) |
| 1 – 8 yrs | ED | One |            2.05 / 0 |  NE (1.70, NE) |
| 18 – 35 mos | Combined | Combined |           88.9 / 68.6 | 1.30 (1.01, 1.67) |
| Musculoskeletal Pain |  |  |  |  |
| 18 – 35 mos | Clinic | Combined |           4.07 / 0 | NE (1.30, NE) |
| 18 – 35 mos | Clinic | One |            8.2 / 0  | NE (1.30, NE) |

- NE = Not estimable

- Increase in MAEs of URI and musculoskeletal pain is consistent with observations from reactogenicity data in other trials

**URI **
**5 - 17 Years**
**(Combined)**
**25.4 vs 29.9**

- Combined Setting = ED, clinic, hospital

## Study AV019MAE Rates and Risk within 42 Days

| Age | Setting | Dose | Rate Per 1000 Person-MonthsFluMist / Placebo | Binomial Relative Risk (90% CI) |
| --- | --- | --- | --- | --- |
| Asthma |  |  |  |  |
| 18 – 35 mos | Clinic | Combined |          8.72 / 2.29 | 3.81 (1.20, 16.82) |
| 18 – 35 mos | Clinic | One |        10.54 / 0  | NE (1.95, NE) |
| 18 – 35 mos | Combined | Combined |         9.30 / 2.29  | 4.06 (1.29, 17.86) |
| 18 – 35 mos | Combined | One |         11.7 / 0  | NE (1.95, NE) |

- NE = Not estimable

- Possible signal observed for asthma in 18-35 month olds

- Combined Setting = ED, clinic, hospital

## Database searched and medical records reviewed
Assess use of terms to describe asthma and wheezing events 
Assess the circumstances of the medically attended event
Identify history of asthma and wheezing in participants
Additional analyses using: 
“Asthma” or “Asthma + Wheezing” outcomes
Cumulative 6 month age groups
Dose One, Dose Two
History positive and history negative

- Assess use of terms to describe asthma and wheezing events
- Assess the circumstances of the medically attended event
- Identify history of asthma and wheezing in participants
- Additional analyses using:
- “Asthma” or “Asthma + Wheezing” outcomes
- Cumulative 6 month age groups
- Dose One, Dose Two
- History positive and history negative

- Asthma and WheezingStudy AV019

## Asthma and WheezingCumulative Age Analysis AV019

| Age (mos) | Children | Dose | Outcome* (Visits) | Number of Participants |  | Rates per 1000 Person-Months FluMist/Placebo | Relative Risk(90% CI) |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  |  |  |  | FluMist n/N | Placebon/N |  |  |
| 12–59 | All | One | Asthma | 14/2032 | 2/1025 | 5.92 / 1.68 | 3.53(1.10, 15.66) |
| 12 – 59 | All | One | Asthma +Wheezing | 25/2032 | 8/1025 | 10.58/6.72 | 1.58(0.82, 3.20) |

- Asthma and WheezingCumulative Age Analysis AV019

- Only one cumulative age analysis from AV019 significant
- RR using combined terms is lower and not significant
- If signal real, the absolute increase in FluMist group in 12-59 months is 0.4 –0.5%

- * Asthma term is asthma/RAD and wheezing term is Wheezing/SOB in HMO database

## Asthma and WheezingCumulative Age Analysis AV019

- Signal not found in children _>_ 60 months
- Relative Risk all <1 and lower bound of 90% CI < 1

| Age (mos) | Children | Dose | Outcome* (Visits) | Number of Participants |  | Rates per 1000 Person-Months FluMist/Placebo | Relative Risk(90% CI) |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  |  |  |  | FluMist n/N | Placebon/N |  |  |
| 60–107 | All | One | Asthma | 9/1759 | 6/869 | 4.40/5.91 | 0.74(0.31, 1.86) |
| 60–107 | All | One | Asthma + Wheezing | 12/1759 | 10/869 | 5.87/9.87 | 0.60(0.29, 1.23) |
| 60 – 215 | All | One | Asthma | 22/4463 | 15/2216 | 3.75/5.14 | 0.73
(0.42, 1.28) |
| 60 – 215 | All | One | Asthma + Wheezing | 28/4463 | 22/2216 | 4.78/7.54 | 0.63 
(0.40, 1.02) |

- * Asthma term is asthma/RAD and wheezing term is Wheezing/SOB in HMO database

## Asthma and Wheezing Cumulative Age Analysis in AV019

| Age (months) | Dose | Outcome* (Visits) | Number of Participants |  | Relative Risk(90% CI) |  Rate**
 |
| --- | --- | --- | --- | --- | --- | --- |
|  |  |  | FluMist n/N (Rate) | Placebon/N (Rate) |  |  |
| HISTORY POSITIVE |  |  |  |  |  |  |
| 12 – 59 | One | Asthma | 9/557 (13.83) | 2/290 (6.02) | 2.30 (0.67, 10.61) | 7.81 |
| 12 – 59 | One | Asthma +Wheezing | 13/557 (19.98) | 4/290 (12.04) | 1.66 (0.66, 4.67) | 7.94 |
| HISTORY NEGATIVE |  |  |  |  |  |  |
| 12 – 59 | One | Asthma | 5/1475 (2.92) | 0/735 (0) | NE (0.86, NE) | 2.92 |
| 12 – 59 | One | Asthma +Wheezing | 12/1475 (7.01) | 4/735 (4.66) | 1.51 (0.59, 4.27) | 2.35 |

- Asthma and Wheezing Cumulative Age Analysis in AV019

- Asthma term is asthma/RAD and wheezing term is Wheezing/SOB in HMO database
- ** Rate per 1,000 person-months

- No significant difference between the groups by history
- Absolute and  rate higher for history positive children

## In AV006 no significant increase in risk for  asthma or wheezing in cumulative age analysis 
In AV012 the event rate was not inconsistent with rates in AV019 in younger children
No placebo group thus interpretation of comparison between the pre and post vaccination periods is complicated

- In AV012 the event rate was not inconsistent with rates in AV019 in younger children
- No placebo group thus interpretation of comparison between the pre and post vaccination periods is complicated

- Asthma and Wheezing Data from Other Large Safety Studies

## Two children hospitalized for asthma/wheezing
FluMist (AV006) – for 1 day 8 days after dose in Year 2
Placebo (AV002) – 2x for 1 day (4, 33 days post-dosing)
Both had a history of asthma
No hospitalizations in AV019 for asthma
Events were outpatient/ED visits and most were associated with medical treatment

- FluMist (AV006) – for 1 day 8 days after dose in Year 2
- Placebo (AV002) – 2x for 1 day (4, 33 days post-dosing)
- Both had a history of asthma
- No hospitalizations in AV019 for asthma
- Events were outpatient/ED visits and most were associated with medical treatment

- Asthma and Wheezing Severity

## Summary of Asthma/Wheezing

- Among all analyses of large placebo-controlled trials in children, a statistical difference was only observed in AV019
- Children 12 - 59 mos, RR 3.53 (1.10, 15.66) for “Asthma”
- Rate is higher for history positive children
- No signal in those  60 months of age

## Other Open Issues

- Conjunctivitis
- Pneumonia
- CNS events
- Concurrent immunization

## Analysis of Conjunctivitis in AV019 within 14 Days of Dose 1

| 12 – 59 months | 12/2033 | 2/1025 | 11.98/3.96 | 3.03 (0.92, 13.59) |
| --- | --- | --- | --- | --- |
| 60 mos – 17 yrs | 16/4463 | 5/2216 | 7.27/4.58 | 1.59 (0.70, 3.96) |

- Temporal association with vaccination within 14 days
- Mild and self-limited; 0.1% increase in the FluMist group in _>_ 60 months

| Age | FluMistn/N | Placebon/N | Rate per 1000 Person-monthsFluMist/Placebo | Relative Risk(90% CI) |
| --- | --- | --- | --- | --- |
| 12 - 18 months | 1/200 | 2/115 | 10.15/35.29 | 0.29 (0.02, 2.47) |
| 19 - 24 months | 3/242 | 0/119 | 25.15/0 | NE (0.43, NE) |
| 25 - 48 months | 7/1072 | 0/560 | 13.25/0 | NE (1.34, NE) |
| 49 - 71 months | 3/957 | 0/457 | 6.36/0 | NE (0.41, NE) |
| 6 - 8 years | 4/1321 | 2/643 | 6.14/6.31 | 0.97 (0.23, 5.12) |

## Pneumonia in Pivotal Trials 

| Group | FluMist |  | Placebo |  |
| --- | --- | --- | --- | --- |
|  | n/N | Rate per 1,000 person months | n/N | Rate per 1,000 person months |
| All Pivotal | 47/15618 | 2.38 | 25/7752 | 2.56 |
|     Children  | 46/12577 | 2.74 | 25/6232 | 3.00 |
|     Adults | 1/3041 | 0.35 | 0/1520 | 0.0 |

- FluMist was not associated with an increased risk of pneumonia

- Pneumonia events in pivotal trials – 28/42 day observation period

## CNS Events

- Across all studies no cases of:
- Encephalitis
- Acute idiopathic polyneuritis (Guillain-Barré)
- Reye syndrome
- Other rare disorders associated with influenza
- Other CNS events occurred at a low rate
- No significant difference in CNS events in AV019 within 42 days of vaccination
- Events were seizures/epilepsy
- 0.1% FluMist and 0.1% placebo

## Concurrent Immunization

- Excluded from proposed label
- Trial ongoing of MMRII® and VARIVAX®
- Fully enrolled (N=1,251)
- Trials planned and in discussion with CBER for other childhood vaccines

## Characterization of Shed Vaccine Virus and Vaccine Virus Transmission

## Shedding and Infectivity of CAIV

- Following challenge, % shedding, mean peak titer and mean duration of shedding are higher in young children than adults
- HID50 lower in young children compared to adults

| Population | % Shedding | Mean Peak Titer 
(Log 10 TCID50/mL) | Mean Duration
(days) |
| --- | --- | --- | --- |
| Children | 67 - 91 | 2.1 – 3.4 | 4.5 – 9.0 |
| Adults | 14 - 60 | 0.7 – 1.8 | 0.6 – 1.9 |

**Virus Shedding**

| Population | HID50 (Log10 TCID50) |
| --- | --- |
| Children | 2.5 – 4.6 |
| Adults | 4.9 – 6.4 |

**Virus Infectivity**

## Finnish Daycare Trial

- Randomized (1:1), double-blind, placebo-controlled
- 197 children age 8 months - 36 months
- 98 FluMist
- 99 placebo (93 in playgroups with vaccinees)
- 51 playgroups in two cities in Finland
- 45 had both vaccine and placebo children
- All but 2 were in separate buildings with little chance of co-mingling of participants and staff among playgroups
- Average of 4.1 study children per playgroup
- Children attended daycare _>_ 3 days/week and _>_ 4 hours/day
- Each placebo child exposed to an average of 1.9 vaccinees

## Finnish Daycare Trial

- One of the largest and most comprehensive vaccine virus transmission studies
- Nasal cultures on the first two days after dosing and at least 3x/week for 3 weeks
- Over 2,000 cultures: ~10/child
- Extensive genotyping and phenotyping of isolates
- Designed to maximize the chance of vaccine virus transmission
- Statistical methodology
- Estimation of probability of transmission using Reed-Frost model which takes into account the number of vaccine and placebo interactions

## Finnish Daycare Trial Results

- 80% of vaccine recipients shed vaccine virus
- 32% H1N1, 12% H3N2, 74% Type B
- Mean days shedding = 7.6
- One placebo child shed Type B vaccine virus at day 15 visit only

## Finnish Daycare Trial Results

- Wild type A/H3N2 circulating in community
- Six additional placebo children shed Type A influenza virus
- Two shed wild type A strains
- Four shed type A virus that could not be re-isolated and thus could not be confirmed as wild-type or vaccine virus

## Placebo Participants Shedding Unidentified Influenza A Virus

- #4 (Not Possible)
- Shed two days before vaccine introduced into playgroup

- #2 (Unlikely Case)
- Shed on two occasions. The first was before any vaccination occurred in the playgroup; the second was one day after the vaccination in the playgroup
- #3 (Unlikely Case)
- Shed on one occasion. No other participant within the playgroup shed A virus, one shed B five days earlier

- #1 (Possible Case)
- Shed on one day in a playgroup where one vaccinee shed vaccine virus seven and nine days earlier

## Estimated Transmission Probability With Non-Confirmed Cases Included

|  | Probability of Transmission (p)* | Upper Bound95% CI |
| --- | --- | --- |
| Confirmed case | 0.0058 | 0.0170 |
| Confirmed +  1 possible case | 0.0117 | 0.0276 |
| Confirmed +  1 possible + 2 unlikely cases | 0.0236 | 0.0459 |

*** ** Reed-Frost Model of transmission

## Characteristics of Shed and Transmitted Viruses

- Shed Viruses
*ts* and *ca* phenotype confirmed in all isolates tested (N = 124)
- Complete sequencing of 55 shed isolates (last isolate available)
- No reversions of Master Donor Virus attenuating mutations
- As expected, minor number of mutations observed
- Viruses containing mutations observed in more than one isolate retained* att* phenotype in ferrets
- Transmitted Virus
- Retained the 6:2 genotype
- Identical genetic sequence to virus shed by vaccine recipient in same playgroup
- Retained the *ca*, *ts*, and *att *phenotype
- Not associated with increased reactogenicity
- Not observed in other placebo members of the playgroup

## Finnish Daycare StudySummary

- In the day care setting the probability of transmission was estimated to be 0.0058 – 0.0236.
- No phenotypic or genotypic reversion observed in shed or transmitted viruses

## Overall Conclusions

- Efficacy of FluMist demonstrated in preventing culture confirmed influenza in children
- Efficacy consistent across age subgroups studied
- Efficacy in children _>_ 60 months was similar to the group as a whole
- Effectiveness of FluMist demonstrated in adults
- Effectiveness consistent across age subgroups
- No evidence 50 – 64 year olds differed from population as a whole
- Efficacy comparable on annual revaccination

## Overall Conclusions

- FluMist is safe in healthy children _>_ 60 months through17 yrs and healthy adults 18 yrs through 64 yrs of age
- Increase in mild, self-limited URI symptoms
- No increase in fever > 101oF or CDC-ILI following administration
- In adults safety profile consistent across age subgroups, including 50-64 year olds
- Additional information needed to assess risk/benefit in children < 60 months of age
- Safety profile similar and event rates lower on annual revaccination
- Risk of vaccine virus transmission is low
- Transmission probability of 0.006 - 0.024 in daycare
- Rates in older children and adults will be lower
- Genetic and phenotypic reversion not observed

## Proposed Indication

- “FluMist is indicated for active immunization for the prevention of disease caused by influenza A and B viruses in healthy individuals ages 5 years (60 months) through 64 years of age”