1. Monitoring the Effectiveness of Pandemic Influenza Vaccines VRBPAC, February 27, 2007 David K. Shay, MD, MPH Epidemiology and Prevention Branch, Influenza Division (proposed) Centers for Disease Control & Prevention

2. 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

3. 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

4. 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

5. 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

6. 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

7. Emerging Infections Program Studies Study DesignCase-control Seasons2005-06, 2006-07 SettingHospitals in 6 (2005-06) and 9 (2006-07) states Age6-23 mo (2005-06), 6-59 mo (2006-07) CasesChildren hospitalized with laboratory-confirmed influenza. Tests ordered by clinicians. ControlsAge- and zip-code matched children not hospitalized with influenza Vaccination dataHealth care providers and parent report Source of other dataMedical chart review, parent interview Other dataAge, gender, race, insurance status, high-risk conditions, socioeconomic status

8. NVSN Studies Study DesignCase-control Seasons2003-04, 2004-05, 2005-06, 2006-07 SettingHospitals, emergency departments, and outpatient clinics in 3 counties (TN, NY, OH) Age6-59 months CasesChildren brought to medical attention with fever or ARI who test positive for influenza by culture or RT-PCR ControlsChildren with fever or ARI who test negative for influenza by culture and RT-PCR Vaccination dataObtained from health care providers Source of other dataMedical chart review, parent interview Other dataAge, gender, race, insurance status, high-risk conditions, socioeconomic status, and other risk factors

9. Marshfield Clinic Studies Study DesignCohort and case-control Seasons2004-05, 2005-06, 2006-07 SettingClinic population in north-central WI AgeAll ACIP-recommended groups CasesPatients seeking care for acute respiratory illness who are influenza positive by culture or RT-PCR Cohort/ControlsCohort 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 dataObtained from regional electronic vaccine registry and patient report Source of other dataElectronic medical record and interview Other dataAge, gender, race, high-risk conditions, use of health care

10. 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

11. 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

12. 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)

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

21. 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

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

23. 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

24. EIP Surveillance Areas California: 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

25. 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

26. 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