# Presentation: 188446

** **
**Influenza Vaccine Recommendations: **
**Past, Present, and Future**
- Anthony Fiore, MD, MPH
- Influenza Division, NCIRD, CDC
- September 13, 2007_ _

**Notes:**
	Good afternoon. Over the next few minutes I am going to discuss some of the many factors that we need to consider 
as we move towards expanding influenza vaccination recommendations

## Burden of influenza

Current recommendations and vaccine coverage

2007-08 recommendation updates

Basis for making changes to recommendations

Expanding recommendations to other age groups – challenges and potential timeline

Update on LAIV (FluMist)

- Current recommendations and vaccine coverage
- 2007-08 recommendation updates
- Basis for making changes to recommendations
- Expanding recommendations to other age groups – challenges and potential timeline
- Update on LAIV (FluMist)

**Presentation Overview**

## Burden of Influenza

- 5-20% of US population infected with influenza virus each year
- Higher infection rates among children
- Large year-to-year and community-to-community variation
- Average of 226,000 hospitalizations annually
- Approximately half among persons 65 years and older
- Rates in children <2 years old are similar to rates in adults 65 years and older
- Large year-to-year variation (55,000  to 431,000 persons annually)
- Average of 34,000 deaths annually
- More than 90% in adults _>_ 65 years
- Large year-to-year variation (8,000 – 72,000)

## Percentage of visits for influenza-like illness (ILI) reported by the Sentinel Provider Surveillance Network, by week – United States, 2004-05, 2005-06, and 2006-07 influenza seasons

**Notes:**
 The next 4 slides show data from several surveillance systems, and together indicate that this past season was fairly similar in intensity to the past 2 seasons. The % of visits to sentinel providers for influenza like illness during this past season is shown in the red line with diamonds. This also suggests peak respiratory virus season was in late February, and was similar to the past 2 seasons which are shown by the other two lines

## EIP Influenza Laboratory-Confirmed Cumulative Hospitalization Rates for Children Aged 0-4 and 5-17 years, 2006-07 

- EIP Influenza Laboratory-Confirmed Cumulative Hospitalization Rates for Children Aged 0-4 and 5-17 years, 2006-07
- and Previous 3 Seasons

**Notes:**
 Cumulative hospitalization rates for lab confirmed influenza in the Emerging infections program, which also collects population based surveillance data, are shown here in the diamond red line for children 4 years of age or younger, and in red dashes for children 5-17.
1.6 per 10,000 for 0-4
.23 per 10,000 for 5-17

## Surveillance for Pediatric Deaths Attributed to Influenza Complications

- CDC received 68 reports of influenza-associated pediatric deaths this influenza season (2006-2007)
- 2005-2006: 45 deaths
- 2004-2005: 46 deaths
- 2003-2004: 153 deaths
- Compared to previous 2 seasons
- Increase in mean age to 7 years (from 4-5 years in 2004-2006)*
- Increase in proportion with invasive MRSA-associated co-infection from <5% to 27%*
- Planning additional investigations and increased surveillance during upcoming season for MRSA-influenza co-infections among children

- *CDC. MMWR, August 10, 2007

**Notes:**
 As of June 22, 2007, CDC has received 68 reports of influenza-associated pediatric deaths this influenza season (2006-2007). BY comparison, there were 45 to 46 deaths in the past 2 seasons, but 153 in the 2003-04 season, when the reporting system began.
Compared to previous 2 seasons
Increase in mean age to 7 years (from 4-5 years in 2004-2006)*
Increase in proportion with invasive MRSA-associated co-infection from <5% to 27%*
CDC and the state health departments are now planning additional investigations and increased surveillance during upcoming season for MRSA-influenza co-infections among children

## Recommendation Changes for Influenza Vaccination: Recent Milestones

**Before 2000: **
**	****	**Persons 65 or older
- 		Persons with chronic medical conditions that make them more 			likely to have complications of influenza
- 		Pregnant women in the second or third trimester
- 		Healthcare workers
**2000**: 	Adults 50 or older
**2004**: 	Children 6 through 23 months old
- 		Contacts of children newborn through 23 months old
- 		Women who will be pregnant during influenza season
**2006**: 	Children 6 through 59 months old and their household contacts and out-		of-home caregivers

***220 million (73% of the population) are currently recommended ***
***for annual influenza vaccination!***

## ACIP Recommendations, 2007

**ACIP Recommendations, 2007**
**Published July 2007**
**http://www.cdc.gov/flu/**

_**Simple Version**_
**Vaccinate persons at higher risk for influenza **
**complications**
**Vaccinate persons who are close contacts of **
**persons at higher risk for influenza complications**
**Vaccinate anyone who wants to be vaccinated**

## Gulf Between Recommendations and Reality

- 220 million persons (73% of the population) should get vaccinated annually
- Fewer than 100 million get vaccinated

## Self-Reported Influenza Vaccination Coverage Levels Among Selected Adult Priority U.S. Populations, 1989-2005, National Health Interview Survey

**Self-Reported Influenza Vaccination Coverage Levels Among Selected Adult Priority U.S. Populations, ****1989-2005, National Health Interview Survey**

**Vaccine shortage: 2004-05 season**

**Notes:**
As we consider ways for decreasing the burden of influenza disease by expanding vaccination recommendations to other age groups, we need to continue to improve vaccination coverage levels among existing target groups by improving public awareness and by improving provider education and practices, including the vaccination of health care workers.

For example, with respect to vaccine naïve children:  Among the 33% of children who received at least one dose of influenza vaccine during the 2004-05 season, 47% needed but did not receive a second dose of vaccine.

## Self-Reported Influenza Vaccination Coverage Levels Among Selected Adult Priority U.S. Populations, 1989-2006*, National Health Interview Survey

**Self-Reported Influenza Vaccination Coverage Levels Among Selected Adult Priority U.S. Populations, ****1989-2006*, National Health Interview Survey**

***2006: preliminary results; no results available for risk groups**

**Notes:**
As we consider ways for decreasing the burden of influenza disease by expanding vaccination recommendations to other age groups, we need to continue to improve vaccination coverage levels among existing target groups by improving public awareness and by improving provider education and practices, including the vaccination of health care workers.

For example, with respect to vaccine naïve children:  Among the 33% of children who received at least one dose of influenza vaccine during the 2004-05 season, 47% needed but did not receive a second dose of vaccine.

## Influenza Vaccination Coverage among Children 6-23 Months of Age, National Immunization Survey, 2002-2005

**First season of “vaccinate all 6-23 month olds” **
**recommendation**

**Note: Preliminary data from 2006 NIS indicates **
**small increase in coverage**

**Notes:**
This bar chart shows vaccination coverage levels among children 6 thru 23 months of age for the 2002-2003 and 2003-2004 seasons when ACIP encouraged vaccination of this age group.  Based upon National Immunization Survey (or NIS) data, we estimate that 17.5% of children 6 thru 23 months of age received one or more doses of influenza vaccine, and 8% were fully vaccinated during the 2003-2004 influenza vaccination season, the second year of the ACIP encouragement.

Although not shown on this slide, there are data available regarding coverage levels during the first year of the full recommendation for vaccinating children 6 thru 23 months (the 2004-2005 season).  February 2005 Behavioral Risk Factor Surveillance System (or BRFSS) data indicated 48.4% coverage with at least 1 dose of influenza vaccine for children aged 6 thru 23 months; this coverage also reflected effective prioritization of vaccine delivery despite an overall vaccine shortage during that influenza season. 

Any comparison between BRFSS and NIS data, must be made with caution – there are differing birth cohorts and vaccination periods being measured.  Furthermore, BRFSS data are based on parental report, whereas NIS relies on provider-reported data. 

## New Annual Recommendations butSame Indications for Vaccination

***Age groups and risk groups for whom ***
***routine vaccination is recommended is ***
***not changed compared to 2006 recommendations***

## What’s New?2007 Recommendations

- Changed vaccine composition (1 strain)
- Change in recommendations for children less than 9 years old who received a single dose during their first (previous) year of vaccination

## Vaccine Strain Recommendations, 2007-2008*

- A/Solomon Islands/3/2006 (H1N1)-like virus (new strain)
- A/Wisconsin/67/2005 (H3N2)-like virus (no change)
- B/Malaysia/2506/2004-like virus (no change)

***Vaccines and Related Biological Products Advisory Committee, FDA, **
**	****February 28, 2007**

**Notes:**
 I wanted to briefly mention the strain selections for the upcoming season. The selections were made about a week after the February ACIP, so this is old news, but in brief only 1 strain changed: the H1N1 strain will be a Solomon Islands like strain. The other 2 strains are unchanged from last season.

## Vaccinating children <9 years old

- Children less than 9 years old should receive 2 doses of either live, attenuated influenza vaccine (LAIV, only for those 5 year old and older) or inactivated influenza vaccine (TIV) with single annual doses in subsequent years
- NEW – IN ADDITION TO ABOVE: Children less than 9 years old who received only 1 dose in their first year of vaccination should receive 2 doses the following year, with single annual doses in subsequent years
- One dose per year in third or later year after first vaccination, regardless of number of doses given in first two years

## What’s Re-emphasized?2007 Recommendations

- Use only neuraminidase inhibitor drugs for prophylaxis or treatment
- Oseltamivir (Tamiflu)
- Zanamivir (Relenza)
- Resistance to these drugs is rare (<0.5% are resistant)
- _Don’t_ use adamantane drugs (amantadine or rimantadine)
- Vaccinate any person who wants to be vaccinated
- Immunization providers should offer influenza vaccine and schedule immunization clinics throughout the influenza season
- Clinics, providers and programs should adopt practices shown to improve vaccine coverage
- Influenza vaccines are safe and effective

## Key Points from the 2007 Influenza Vaccine Recommendations (1)

- All persons, including school-aged children, who want to reduce the risk of becoming ill with influenza or of transmitting influenza to others should be vaccinated.
- For children whose parents want them vaccinated: VFC vaccine can be used for this “indication”.

## Key Points from the 2007 Influenza Vaccine Recommendations (2)

- _Immunization providers should offer influenza vaccine and schedule immunization clinics throughout the influenza season_
- Begin vaccinating soon after vaccine becomes available, because getting vaccinated before transmission starts is always a good idea
- Vaccinate through December and into January, and beyond, because most influenza seasons don’t peak until January or later, and some communities might not see any influenza transmission until after the New Year
- Several waves of influenza illness might be seen in some communities, so vaccinating after community transmission has already started can still provide protection

## Key Points from the 2007 Influenza Vaccine Recommendations (3)

- _Coverage remains lower than hoped for every group_ recommended for vaccination, and renewed efforts to increase coverage are needed.
- _Example_: Increasing coverage among health care personnel (HCP) is  one measure of a patient safety quality program
- Adopt policies to encourage HCP vaccination (e.g., obtaining signed statements from HCP who decline influenza vaccination)
- _Example_: Persons at risk for complications often access healthcare but miss opportunities to be vaccinated
- Use standing orders and reminder recall systems

## Key Points from the 2007 Influenza Vaccine Recommendations (4)

- No scientifically conclusive evidence has demonstrated harm from exposure to thimerosal preservative-containing vaccine
- _Persons recommended to receive TIV may receive any age- and risk factor-appropriate vaccine preparation_, depending on availability

## Expanding recommendations for routine vaccination – who is left?

- Burden of severe illness much lower compared to infants and young children
- ~40% already have an indication: contact with a high risk person
- In some studies, benefits of vaccinating children extend to unvaccinated household members (indirect effects or herd immunity)

***Healthy children from 5 through 18 years old***

## Expanding U.S. recommendations – who is left?

- Burden of severe illness much lower compared to the elderly and those with chronic medical conditions
- ~51% already have an indication: contact with a high risk person

***Healthy adults from 19 through 49 years old***

## Expanding U.S. recommendations – who is left?

- Burden of severe illness is high, but current vaccines unlikely to be licensed in this age group
- Contacts of these children already high priority group recommended for vaccination, including persons soon to be close contacts (pregnant mother)

***Infants less than 6 months old***

## Assessing the Need to Change Recommendations: Critical Factors

- Effectiveness
- Safety
- Feasibility of sustained implementation
- Cost-effectiveness
- Vaccine supply

## Setting the Stage: Changing the ACIP Influenza Vaccination Recommendations

- Improve surveillance
- Safety – yearly and long term
- Effectiveness – yearly and sustained
- Develop implementation strategies
- School-based programs or medical home?
- Communication messages
- Funding
- Evaluate impact
- Need to document to ensure sustainability
- Assess capacity
- Vaccine manufacturing
- Immunization delivery infrastructure
- Cost

## Potential Time-Frame for Modifying Influenza Vaccination Recommendations

**2007-2008**:  Consider expanding recommendations to include all children (6 months-18 years)
**2010-2011**:  Possible expansion of recommendations to include household contacts and caregivers of school-aged children
**2012-2013**:  Possible expansion to universal vaccination (extend recommendations to persons 19-49 years)
- Each time recommendations are changed:
- need to assist manufacturers, immunization programs, and public health communication experts in planning implementation

**Notes:**
Its not going to be easy, and each step should be accompanied by a clear-eyed view of the supporting science and the implementation challenges

## LAIV (FluMist) Licensure History 

**January 2007**: FluMist liquid formulation licensed to replace frozen formulation (first commercial use anticipated during 2007/08 influenza season)
**May 2007: **FDA Vaccine and Related Biologic Products Advisory Committee (VRPBAC) reviewed MedImmune’s application for use of FluMist (liquid) in children aged 12-59 months without a history of wheeze/asthma
**May 2007**: FDA identifies manufacturing issues that result in Warning Letter which result in delay for application decision
- FluMist still expected to be available for 2007-08 season

***FDA website: **_[http://www.fda.gov/foi/warning_letters/s6370c.htm](http://www.fda.gov/foi/warning_letters/s6370c.htm)_
** **_[http://www.fda.gov/cber/faq/medimmuneqa.htm](http://www.fda.gov/cber/faq/medimmuneqa.htm)_

**Notes:**
Shifting topics again, the next few slides, as well as Karen Broder’s upcoming presentation, will focus on the complicated situation with FluMist. Here is the timeline of FLuMist licensure changes. The product was first licensed for use in healthy persons aged 5-49 years. In January 2007, a FluMist liquid formulation was licensed to replace frozen formulation, and the first commercial use anticipated during 2007/08 influenza season. Recently the manufacturer submitted a Biologics License Application supplement for use of FluMist (liquid) in children aged 12-59 months without a history of wheeze/asthma

## Current Status of LAIV (FluMist) Licensure for Young Children

**September 2007**: Resolution of manufacturing issues discussed in May 2007 Warning Letter
- License change for use in young children pending
- FluMist lot release pending, which would make it available for 5-49 year olds, unless license change occurs first
- ACIP discussion and vote on use in children younger than 5 years old will occur

**Notes:**
 FDA was due to make a decision on licensure shortly after that, but this decision is on hold pending resolution of an unrelated topic: manufacturing issues identified during plant inspections and described in a May 24 warning letter. Until these issues are resolved, the BLA supplement decision is on hold. FDA notes that the Warning letter is not expected to significantly affect availability of FluMist for 2007-2008 influenza season” and that MedImmune can continue to manufacture their products while simultaneously making corrective actions. However, this delay means that we can’t vote on the age indication change (and we don’t  yet know what it will be). This vote as well as the VFC vote will therefore be delayed until licensure, which is in turn dependent on resolution for the issues identified in the Warning letter. 

## Changes (and Possible Changes) in Storage and Use of LAIV (FluMist)

- New refrigerator stable formulation
- Shipped and stored at refrigerator temperature
- Smaller spray volume
_*Possible*_ change: Spacing between doses decreased to _4_ or more weeks (same as inactivated vaccine)*
_*Possible*_ change: Use of FluMist in children younger than 5 years old without history of asthma or wheezing*

***Change not reflected in 2007 ACIP Recommendations**
** ****because 2007-08 formulation LAIV not licensed at that time**

## Progress in Influenza Prevention

- Better epidemiologic data
- More timely population-based surveillance data to inform policy
- Vaccine safety and effectiveness demonstrated
- More timely data based on lab-confirmed infections in larger studies
- Critical questions being addressed (e.g., 2 doses for vaccine-naive young children)

## Progress in Influenza Prevention

- Vaccine coverage stable or increasing
- Rebounding among older adults after vaccine shortage season
- Proven strategies to improve vaccination coverage being identified
- Increased manufacturing capacity
- Expanding - ~100 million doses distributed during pasts season
- Increasing availability of preservative-free formulations
- More immunogenic vaccines in pipeline
- Immunization programs increasing flexibility
- Extended vaccination seasons
- Gaining experience with innovative settings (e.g., school-based programs)

## Thank You!

**Thank You!**

## Projected Overall Manufacturing Capacity 

- 2007-2008:
- ~130 million doses might be available for 2007-2008 season
- ~20 million preservative free doses
- Only 1 manufacturer currently licensed to supply preservative-free TIV for children
- LAIV is thimerosal-free
- Next 3-5 years:
- 150-200 million doses possible
- Increased preservative-free capacity expected
- All estimates contingent on growth characteristics of vaccine strains, manufacturing and licensure constraints, and market demand

## Influenza Vaccine Workgroup: Conclusions from FluMist Data Presentations

- Data indicate FluMist efficacy to be non-inferior c/w TIV for children 6 months and older
- Data indicate no safety signal among children 24 months and older without history of wheezing
- Additional information on safety is needed for children 6-23 months old, particularly for children 6-11 months old
- Wheezing outcomes
- All-cause hospitalization rates c/w TIV
- Additional information on safety is needed for children _>_24 months old with history of asthma or wheezing

**Notes:**
 We have had numerous discussion within the Influenza working Group both before and after the VRBPAC meeting and the Warning letter issues. This slide summarizes the conclusions from these discussions. Data indicate FluMist efficacy to be non-inferior c/w TIV for children 6 months and older

Data indicate no safety signal among children 24 months and older without history of wheezing 

Additional information on safety is needed for children 6-23 months old, particularly for children 6-11 months old
Wheezing
Hospitalization rates c/w TIV

Additional information on safety is needed for children >24 months old with history of asthma or wheezing

## FluMist Licensure History 

**June 2003**: FluMist (frozen) licensed for use in healthy persons aged 5-49 years
**January 2007**: FluMist liquid formulation licensed to replace frozen formulation (first commercial use anticipated during 2007/08 influenza season)
**May 2007: **FDA Vaccine and Related Product Biologics Advisory Committee (VRPBAC) reviewed MedImmune’s Biologics License Application supplement for use of FluMist (liquid) in children aged 12-59 months without a history of wheeze/asthma

**Notes:**
Shifting topics again, the next few slides, as well as Karen Broder’s upcoming presentation, will focus on the complicated situation with FluMist. Here is the timeline of FLuMist licensure changes. The product was first licensed for use in healthy persons aged 5-49 years. In January 2007, a FluMist liquid formulation was licensed to replace frozen formulation, and the first commercial use anticipated during 2007/08 influenza season. Recently the manufacturer submitted a Biologics License Application supplement for use of FluMist (liquid) in children aged 12-59 months without a history of wheeze/asthma

## Update on Proposed FluMist Licensure Change

- May 16, 2007: MedImmune and FDA presented analyses to VRBPAC
- BLA supplement requested by MedImmune:
- Children aged 12-59 months w/o history of wheezing and asthma
- Primary data source: Pivotal trial CP111, published as Belshe et al, N Engl J Med, 2007*
- Randomized double blind, active control (TIV) multicenter study
- Pre-specified analyses for 6-23 months olds and 24-59 month olds

***Presented to ACIP in October 2006 and February 2007**

**Notes:**
This application was discussed at the May 16 Vaccines and Related Biological Products Advisory Committee meeting in May. 
The BLA supplement requested by MedImmune was for:
Children aged 12-59 months w/o history of wheezing and asthma
Primary data source: Pivotal trial CP111, published as Belshe et al, N Engl J Med, 2007*
Randomized double blind, active control (TIV) multicenter study
Pre-specified analyses for 6-23 months olds and 24-59 month olds. This data was discussed in detail at each of the last 2 ACIP meetings, and I won’t attempt to give it a thorough review here. Instead I will focus on the FDA actions and analyses, and Karen will discuss the safety issues, and plans for safety monitoring in greater detail in a few minutes.

## Summary Findings from FDA Clinical Reviewer Analyses, CP111*

- FluMist is safe and effective in subjects 24 months of age and older
- Among subjects <24 months of age, participants who received FluMist had:
- Increased hospitalizations
- Increased severity of wheezing
- Increased severity of respiratory events
- History of wheezing was poorly predictive of wheezing post-vaccination among FluMist recipients
- Post hoc analyses conducted among 6-11 month olds should be interpreted with caution

***T Cvetkovich, M Baylor and S Ahnn, VRBPAC presentations, May 16, 2007**
**Available at: ****http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4292S1-0-index.html**

**Notes:**
 The FDA clinical reviewers summarized their findings at the end of each of their presentations, and this slide pulls these summaries together.
 FDA concluded that FluMist is safe and effective in subjects 24 months of age and older
Among subjects <24 months of age, participants who received FluMist had:
Increased hospitalizations
Increased severity of wheezing
Increased severity of respiratory events
History of wheezing was poorly predictive of wheezing post-vaccination among FluMist recipients. All of these adverse evnts were uncommon, and most of these events were among children 6-11 months old. However FDA noted that
Post hoc analyses conducted among 6-11 month olds should be interpreted with caution – recall that the the pre-specified age group analyses was for 6-23 month olds and 24-59 month olds.

## VRBPAC Recommendations, Supplement to FluMist BLA, May 16, 2007

**Question 1: Do the data demonstrate the efficacy of FluMist for prevention of influenza in young children**
**All 15 voting members indicated efficacy demonstrated for children 6 months and older**
**Question 2: Do the data demonstrate that the benefits will exceed the risk of FluMist****®**** for use in**
- The applicant’s proposed population (children 12 to 59 months of age without a history of wheeze/asthma)
- Vote –Yes: 9 and No: 6
- Children in the age strata 6-23 months, regardless of wheezing history?
- Vote –Yes: 3 and No: 12
- Children in the age strata 24-59 months, regardless of wheezing history?
- Vote –Yes: 15 and No: 0

**Notes:**
 After hearing the evidence from the manufacturer and FDA, the committee voted. The voting summary is on this slide. Efficacy that was non-inferior to TIV was considered to have been demonstrated – you will recall form the published study that LAIV had approximately a 45-55% greater relative efficacy compared to TIV and this was a statistically significant difference. For the safety data voting, 
Question 2: Do the data demonstrate that the benefits will exceed the risk of FluMist® for use in
The applicant’s proposed population (children 12 to 59 months of age without a history of wheeze/asthma)
Vote –Yes: 9 and No: 6
Children in the age strata 6-23, regardless of wheezing history?
Vote –Yes: 3 and No: 12
Children in the age strata 24-59 months, regardless of wheezing history?
Vote –Yes: 15 and No: 0

## Current Status of FluMist Licensure for Young Children

- FDA decision likely soon now that there was resolution of manufacturing issues identified during routine inspection and discussed in May 2007 Warning Letter*
- Delay in BLA supplement decision will require ACIP discussion and vote, and VFC vote, after licensure

***FDA website: **_[http://www.fda.gov/foi/warning_letters/s6370c.htm](http://www.fda.gov/foi/warning_letters/s6370c.htm)_
**†****FDA website: **_[http://www.fda.gov/cber/faq/medimmuneqa.htm](http://www.fda.gov/cber/faq/medimmuneqa.htm)_

**Notes:**
 FDA was due to make a decision on licensure shortly after that, but this decision is on hold pending resolution of an unrelated topic: manufacturing issues identified during plant inspections and described in a May 24 warning letter. Until these issues are resolved, the BLA supplement decision is on hold. FDA notes that the Warning letter is not expected to significantly affect availability of FluMist for 2007-2008 influenza season” and that MedImmune can continue to manufacture their products while simultaneously making corrective actions. However, this delay means that we can’t vote on the age indication change (and we don’t  yet know what it will be). This vote as well as the VFC vote will therefore be delayed until licensure, which is in turn dependent on resolution for the issues identified in the Warning letter. 

## Influenza Vaccine Workgroup: Conclusions from FluMist Data Presentations

- Data indicate FluMist efficacy to be non-inferior c/w TIV for children 6 months and older
- Data indicate no safety signal among children 24 months and older without history of wheezing
- Additional information on safety is needed for children 6-23 months old, particularly for children 6-11 months old
- Wheezing outcomes
- All-cause hospitalization rates c/w TIV
- Additional information on safety is needed for children _>_24 months old with history of asthma or wheezing

**Notes:**
 We have had numerous discussion within the Influenza working Group both before and after the VRBPAC meeting and the Warning letter issues. This slide summarizes the conclusions from these discussions. Data indicate FluMist efficacy to be non-inferior c/w TIV for children 6 months and older

Data indicate no safety signal among children 24 months and older without history of wheezing 

Additional information on safety is needed for children 6-23 months old, particularly for children 6-11 months old
Wheezing
Hospitalization rates c/w TIV

Additional information on safety is needed for children >24 months old with history of asthma or wheezing

## Influenza Vaccine Workgroup: Planned Discussions after Licensure Decision

- Review FDA-approved age and medical condition indications
- Develop guidance for screening for a history of asthma or recurrent wheezing
- Continue discussions on advantages and disadvantages of recommending LAIV over TIV for healthy young children
- Assess safety analyses from VAERS, VSD, post-licensure studies

**Notes:**
The discussions will need to continue because the Flumist trial data raises several interesting and potentially tricky questions. 
The first order of business will be to review FDA-approved age and medical condition indications once they are available.
Because of the issues with wheezing, clinicians and immunization programs will need to be able to screen for conditions that are a relative contraindication to LAIV use. For example guidance will need to be developed for screening for a history of asthma or recurrent wheezing. We will need to continue discussions on advantages and disadvantages of recommending LAIV over TIV for healthy young children, based on the interesting but limited data showing the LAIV might have better efficacy among young children. Also, monitoring safety will be critical, and we will need to hear about data from Vaccine Adverse Events Reporting System, the Vaccine Safety Datalink, and other post-licensure safety and efficacy studies. That serves as an introduction for Karen Broder’s talk. Karen is from the Immunization Safety Office and she will discuss a few points about the safety data for LAIV and describe the safety monitoring plans. Dr. Abramson I can take questions now if you prefer, or we can move on to Karen's presentation. Thanks

## Update: Characterization of H3N2 isolates (n=289) from 2006-2007 season

**There are two recent genetic/antigenic groups evolved from  the A/Wisconsin/67/2005 (H3N2) vaccine strain: **
** ****A/Brisbane/9/2006**
** ****A/Nepal/921/2006**
**Variants exhibit reduced titers to ferret antiserum produced against A/Wisconsin/67/2005 in HI tests**
**Some low-reacting isolates are low avid viruses:**
**react poorly with all antisera including antisera made against these low reacting viruses, and may not be true antigenic variants**
**H3N2 vaccine strain selection reconfirmed by VRBPAC (May 16, 2007)**

## Options to Further Reduce the Burden of Influenza

- Improve vaccination of existing target groups
- Improve public awareness
- Improve provider education and practices
- Establish a universal vaccination recommendation
- Work toward universal vaccination recommendation incrementally, beginning with children
- Strengthen adult vaccination efforts, more generally

**Notes:**
Continuing to emphasize vaccination coverage levels among existing target populations remains important. Greater efforts may be needed to increase public awareness about the benefits of vaccination, and to improve provider education and vaccination practices so that they vaccinate more high-risk persons.  However, as noted earlier, the relatively low vaccination coverage levels highlight the limitations of the current risk-based recommendations for vaccination. 

To simplify the vaccination recommendations, there has been increasing support for establishing a universal vaccination recommendation.  This approach would expand vaccination to include an additional 78 million people beyond the existing target populations that already number 218 million.  However, it is unclear to what extent this strategy would result in greater vaccination coverage levels overall, or more importantly, protection of those persons at greatest risk of severe complications from influenza.  The sufficiency of the vaccine supply also remains a concern.

In October 2005, a workshop was held to discuss universal vaccination.  The meeting participants supported the concept of universal vaccination, but felt that the recommendations should be implemented using an incremental approach, beginning with children.  Children were preferred because of their greater risk of illness compared to healthy adults, a sense of a greater feasibility of implementation, and the possibility of indirect benefits resulting in community immunity. 

## Vaccine safety: thimerosal

- “No scientifically conclusive evidence has demonstrated harm from exposure to thimerosal preservative-containing vaccine. Persons recommended to receive TIV may receive any age- and risk factor-appropriate vaccine preparation, depending on availability.”

## Considerations for Expanding Recommendations to Include Routine Vaccination of all School-Age Children

- Many healthy school-age children are already recommended for annual vaccination
- Household contacts of younger children
- Household contacts of children at risk for complications
- Household contacts of older (_>_50 years) adults
- Their parents want them to avoid getting influenza
- Routine influenza vaccination of school-age children
- Would reduce morbidity and mortality among children who are vaccinated
- Might reduce community-wide morbidity and mortality by indirect effects
- Creates expectation of immediate implementation that might not be possible
- Might exacerbate vaccine supply shortages and distribution delays if lead time for planning is insufficient

## Future Challenges as Recommendations Expand

- Implementation of large-scale vaccination programs is difficult
- Require flexibility in scheduling and capacity
-  55 million school-age children each year over ~10 weeks
- Two thirds would require an extra healthcare visit
- Supply delays or shortages
- Unpredictable public demand and sustainability
- Communication messages are challenging
- Vaccine registries need to be ready
- Vaccinating everybody ≠ simpler recommendations
- Varying, changing indications for different vaccines
- Not “one vaccine fits all” - medical and age contraindications
- LAIV might be better at some ages, TIV at other ages
- New vaccines (cell culture-based, adjuvanted) might be targeted to specific ages or groups

***Risk- and age- based recommendations redux!***