Monitoring the Effectiveness of

Pandemic Influenza Vaccines

VRBPAC, February 27, 2007

David K. Shay, MD, MPHEpidemiology and Prevention

Branch, Influenza Division (proposed)

Centers for Disease Control & Prevention

Pandemic Vaccines: Background

• Limited immunogenicity and safety data will be available prior to distribution of a pandemic vaccine

• Safety monitoring will be essential• Post-licensure safety studies can

begin with pre-pandemic use of each product, and continue throughout the vaccine program

• If desired, post-licensure immunogenicity data could be collected in the pre-pandemic setting

Pandemic Vaccines: Background

• Data concerning clinical effectiveness of pandemic vaccines will be essential– Immunogenicity and protection from

illness imperfectly correlated– Different populations may receive

vaccine in pre- and post-licensure situations

– Vaccine match, need to change strain

• But obviously must await onset of the pandemic and illness in populations eligible for vaccination

Pandemic Vaccine Effectiveness

• Effectiveness: protection against influenza illness when vaccine is administered in an immunization program

• Effectiveness may vary by age, medical history, and immunocompetence of patient

• Effectiveness may vary with outcomes– Lower for non-specific illnesses that can be

caused by pathogens other than the pandemic virus

– May vary by severity: illness, hospitalization, need for mechanical ventilation, death

• Need to assess effectiveness after 1 and 2 doses of vaccine

CDC’s Existing Influenza VE Projects: Base for Pandemic VE

Assessments• Two projects build on existing

surveillance systems for influenza– Emerging Infections Program (EIP)– New Vaccine Surveillance Network

(NVSN)

• Project with Marshfield Clinic was funded to provide rapid, within season estimates of VE against a laboratory-confirmed outcome

• All use laboratory-confirmed influenza outcomes

Population-Based Influenza Surveillance

• EIP – 12 sites– Children <18 yrs

hospitalized with laboratory-confirmed influenza infection

– Adult surveillance began January 2006

• NVSN – 3 sites– Children <5 yrs with

inpatient or outpatient laboratory-confirmed influenza infection

– Outpatient surveillance in 6-12 yrs started this season

Emerging Infections Program Studies

Study Design Case-control

Seasons 2005-06, 2006-07

Setting Hospitals in 6 (2005-06) and 9 (2006-07) states

Age 6-23 mo (2005-06), 6-59 mo (2006-07)

Cases Children hospitalized with laboratory-confirmed influenza. Tests ordered by clinicians.

Controls Age- and zip-code matched children not hospitalized with influenza

Vaccination data Health care providers and parent report

Source of other data Medical chart review, parent interview

Other data Age, gender, race, insurance status, high-risk conditions, socioeconomic status

NVSN Studies Study Design Case-control

Seasons 2003-04, 2004-05, 2005-06, 2006-07

Setting Hospitals, emergency departments, and outpatient clinics in 3 counties (TN, NY, OH)

Age 6-59 months

Cases Children brought to medical attention with fever or ARI who test positive for influenza by culture or RT-PCR

Controls Children with fever or ARI who test negative for influenza by culture and  RT-PCR

Vaccination data Obtained from health care providers

Source of other data Medical chart review, parent interview

Other data Age, gender, race, insurance status, high-risk conditions, socioeconomic status, and other risk factors

Marshfield Clinic Studies Study Design Cohort and case-control

Seasons 2004-05, 2005-06, 2006-07

Setting Clinic population in north-central WI

Age All ACIP-recommended groups

Cases Patients seeking care for acute respiratory illness who are influenza positive by culture or RT-PCR

Cohort/Controls Cohort of adults and children for whom ACIP recommended annual influenza vaccination

Age-matched persons without ARI symptoms in same healthcare system; test-negative ARI

Vaccination data Obtained from regional electronic vaccine registry and patient report

Source of other data Electronic medical record and interview

Other data Age, gender, race, high-risk conditions, use of health care

Underlying Rationale for Pandemic Vaccine

Prioritization• Everyone will be susceptible• US-based production capacity is not

currently sufficient to provide vaccine rapidly for the entire population

• Earliest doses of vaccine can be projected as becoming available at ~20 weeks after isolation and characterization of the pandemic virus

ACIP/NVAC Priority Groups • Joint work of the two HHS committees• Process included consideration of

– Estimates of vaccine supply and effectiveness

– Effects of pandemic by age and risk group– Potential effects on critical infrastructure

and health care

• Recommendations included in the 2005 HHS pandemic plan – As guidance for State/local planning – To promote further discussion

Top 2 ACIP/NVAC Priority Groups

1.A. Vaccine and antiviral manufacturers and others essential to manufacturing and critical support (~40,000) Medical workers and public health workers who are involved in direct patient contact, other support services essential for direct patient care, and vaccinators (8-9 million)

1.B. Persons > 65 years with 1 or more influenza high-risk conditions, not including essential hypertension (approximately 18.2 million) Persons 6 months to 64 years with 2 or more influenza high-risk conditions, not including essential hypertension (approximately 6.9 million) Persons 6 months or older with history of hospitalization for pneumonia or influenza or other influenza high-risk condition in the past year (740,000)

Interagency Pandemic Vaccine Prioritization Working Group

• Participants from multiple federal agencies

• Consideration of ACIP/NVAC recommendations

• Consideration of National Infrastructure Advisory Council recommendations on critical infrastructure

• Public engagement meetings and stakeholder meeting

Summary of 2 Public Engagement and Stakeholder

Meetings• At each of the 3 meetings, the most

highly rated goals were the same– Maintaining critical societal functions– Protecting those who would help others

during a pandemic– Protecting children as “our future”

• Most other goals were considered moderately important– Including protecting those most likely to

get sick or die during a pandemic– Ratings and rank order varied between

meetings

Pandemic Vaccine Prioritization Interagency WG:

Next Steps• Draft prioritization guidance

developed• Public & stakeholder meetings• Written comments• ACIP updated by Ben Schwartz, NVPO • The working group also will consider

– Pre-pandemic vaccine prioritization– Modifying guidance at the time of a

pandemic

• Final guidance expected by May

Monitoring Pandemic Vaccine Effectiveness: 1

• Lab-confirmed outcomes will be studied– Hospitalizations captured in several systems

• Additional more severe outcomes (e.g, all-cause mortality) may also be studied

• Observational studies must collect data on possible confounding factors

– Selection bias likely, but cannot assume direction

– Need to link existing individual health data to vaccination and outcome data

Monitoring Pandemic Vaccine Effectiveness: 2

• Plans will evolve as vaccine priorities develop– Existing systems cover children well– Community-based studies may not be

efficient if initial vaccine is prioritized to a few critical infrastructure sectors

• Vaccine distribution and tracking methods – State, regional registries may be used to

identify vaccinated individuals– Need to link pandemic vaccine receipt

back to medical and demographic data

Monitoring Pandemic Vaccine Effectiveness: 3

• CDC will expand existing systems– Assess effectiveness among adults in

EIP system– Rapid assessment methods in other

sites

• Potential for new systems– Consider using sentinel provider system

and point-of-care tests being developed • CDC will work with governmental

and other partners to meet needs for effectiveness data

Acknowledgments

• Emerging Infections Program sites– CA– CO– CT– GA– OR– TN

• Marshfield Clinic Research Foundation

• New Vaccine Surveillance Network sites– Children’s

Hospital Medical Center Cincinnati

– University of Rochester

– Vanderbilt University

• Ben Schwartz• Joe Bresee• Tony Fiore• Nancy Cox

Basis for ACIP/NVAC Prioritization

• Primary goal to mitigate adverse health outcomes

• Pandemic severity assumptions– 20-30% attack rate; up to 1% case fatality rate

• Certain benefit of vaccinating high-risk versus unclear benefit of vaccinating critical infrastructure– Estimate of 10-15% absenteeism due to illness or

caring for ill family members at pandemic peak– Much greater mortality risk among vulnerable

persons than general population

ACIP/NVAC Priority Groups Personnel Cumulative Element and Tier (1,000’s) total (1,000’s)

1A. Health care involved in direct patient 9,000 9,000contact + essential support

Vaccine and antiviral drug manufacturing 40 9,040personnel

1B. Highest risk group 25,840 34,880

1C. Household contacts of children <6 mo, severely 10,700 45,580immune compromised, and pregnant women

1D. Key government leaders +critical public 151 45,731health pandemic responders

2. Rest of high risk 59,100 104,831Most CI and other PH emergency responders 8,500 113,331

3. Other key government health decision 500 113,831makers + mortuary services

4. Healthy 2-64 years not in other groups 179,260 293,091

Rationale for Reconsideration of Pandemic Vaccine

Prioritization• Public engagement meetings

– Preserving essential services ranked as top goal

• Evolving planning assumptions

– More severe pandemic

• Evolving pandemic response strategies

– Community mitigation guidance

• Additional analysis of critical infrastructures

EIP Surveillance AreasCalifornia: Kaiser Northern California members in 3 county San Francisco Bay area, and non-Kaiser children aged <2 years

Colorado: 5 county Denver area

Connecticut: 1 county New Haven area

Georgia: 8 county Atlanta area

Maryland: 5 county Baltimore area and Baltimore City

Minnesota: 7 county Minneapolis area

New Mexico: 1 county in Albuquerque area and 3 county Las Cruces area

New York: 8 county Albany area and 7 county Rochester area

Oregon: 3 county Portland area

Tennessee: 8 county Nashville area

Total: 4.7 million children aged <18, or ~7% of US population

NVSV Surveillance Areas

Children aged <5 years in these communities:

Monroe County, New York: 43,720

Davidson County, Tennessee: 56,466

Hamilton County, Ohio: 44,002

Total 144,188

Marshfield Clinic Population• The influenza study cohort was drawn from the Marshfield

Epidemiologic Study Area (MESA), a dynamic, population-based cohort of approximately 54,000 residents living in 14 zip-codes surrounding Marshfield, Wisconsin

• Nearly all MESA residents receive all inpatient and outpatient care from Marshfield Clinic facilities, which use an electronic medical record that captures 90% of outpatient visits, 99% of deaths, and 95% of hospital discharges for the population

• The 2004-05 study cohort included 11,565 people, including 1,881 (16%) with a clinical encounter for acute respiratory illness based on diagnosis codes in the electronic medical record during the 12-week study period

• The 2005-06 study cohort included 18,542 residents