1. Influenza Vaccine Effectiveness National Immunization Conference Dallas, TX April 2, Anthony Fiore, MD, MPH CAPT, USPHS Influenza Division, CDC

2. Overview Cursory review of influenza epidemiology and vaccinology
Key elements of vaccine effectiveness (VE) studies
Recent VE studies and controversies
Looking ahead and summary

3. Influenza
Highly transmissible respiratory illness caused by influenza viruses
Currently circulating strains
Influenza A (H1N1)
Influenza A (H3N2)
Influenza B (two lineages, Victoria and Yamagata)
Yearly winter epidemics in temperate climates (seasonal influenza)
Illness cannot be distinguished from other acute respiratory illnesses (“influenza-like illness”) without laboratory testing
Antigenic drift – point mutations and recombinations
Diminished immunity among previously infected or immunized persons to “drifted” strains
Requires updating trivalent vaccine yearly to match predicted strains that will be circulating
Sporadic, unpredictable pandemics

4. Composition of Vaccines against Seasonal Influenza
Three strains selected to make a trivalent vaccine based on global viral surveillance and availability of suitable vaccine candidate
1 representative of each influenza A subtype
Influenza A(H1N1)
Influenza A(H3N2)
1 of the two predominant influenza B lineages
Selection decision precedes typical peak influenza season by months
Northern Hemisphere strains selected in February
Southern hemisphere strains selected in September
“New vaccine” (one or more new strains) nearly every season
Three strains are selected to make a trivalent vaccine against seasonal influenza. Strains selected are based on global viral surveillance. The selection decision precedes typical peak influenza season by months. Northern Hemisphere strains are selected in February for the upcoming influenza season, and Southern hemisphere strains are selected in September. The result is that there is usually at least one new strain in each vaccine each season.

5. Determinants of Immune Response to Influenza Vaccines
Age and immune competence
Elderly, infants and chronically ill generally lower antibody response
Immunosenescence – deterioration in overall immune capacity with older age especially beyond 75 years
Prior exposure to virus strains similar to those in vaccine (infection or vaccination)
Virus – strains vary as to how robust immune responses will be
How effective vaccination is going to be in preventing influenza is often predicted by using the antibody response to vaccination as an indicator. For example, the very young and the elderly generally have lower antibody responses. Persons with previous exposure to virus strains similar to those in the vaccine (either because of previous infection or previous vaccination) will usually have a better antibody response.
The immune competence of the person being vaccinated will affect response.
A larger amount of antigen in the vaccine can produce a better response, although a point of diminishing returns is often reached as antigen amounts are increased.
Finally, the type of vaccine affects the immune response. Live attenuated vaccines might provide a better immune response, but this response is more difficult to measure because it requires measuring types of immune responses beyond those that can be measured using serologic samples. Whole virus inactivated vaccines can be more immunogenic, but are also more likely to cause adverse reactions to the vaccine.

6. Measuring Seasonal Influenza Vaccine Effectiveness: What to look for in VE studies
Virus and illness variables
Antigenic match (circulating viruses vs. vaccine)
Intensity of season
Types of viruses circulating (virulence:H3N2 > B > H1N1)
Multiple vs. single season
Study design
Outcomes measured
Influenza-like illness (ILI)
Laboratory-confirmed influenza
Modeling studies of Influenza-related hospitalizations and deaths based medical databases and viral surveillance
Randomized controlled trial (placebo-controlled ideal) vs. observational study
Setting and participants
Age and risk group
Controls
Clearly effectiveness, by any measure, varies according to the age group, influenza risk group, and the degree that the vaccine strains match the circulating strains.
One of the challenges of determining the effectiveness of seasonal influenza vaccination is how to choose an outcome to measure effectiveness. The variety of different outcomes used in the influenza literature to assess effectiveness has made comparison across studies and time very difficult. Some outcomes often used to assess effectiveness is quite non-specific, such as influenza-like illness or ILI, which is usually defined as acute onset of fever and either cough or sore throat. This syndrome can be caused by a variety of respiratory pathogens or even non-infectious etiologies. However, influenza vaccine is only going to prevent ILI caused by influenza virus. Therefore effectiveness estimates that use ILI as an outcome typically find the vaccine to have a relatively low effectiveness in preventing ILI. Effectiveness of influenza vaccine in preventing laboratory-confirmed influenza is typically much higher, but requires more expensive and carefully designed studies. Effectiveness estimates using severe outcomes such as hospitalization or death are usually done retrospectively, and typically require modeling techniques. These studies can substantially overestimate the effectiveness of vaccination in preventing these outcomes if generally healthier persons tend to be preferentially vaccinated.

7. Vaccine match issues: Example of influenza B virus lineages
Two influenza B lineages have co-circulated over the past 10 years
Yamagata-like
Victoria-like
Protection after vaccination with one lineage against other lineage is limited
Co-circulation of both lineages over the past several years means some degree of mismatch between B virus represented in vaccine and circulating strains

8. Influenza B by lineage and season, United States, 1998-2008
Virologic surveillance data
Season %B
% B not represented in vaccine
'98-99
23% 0%
'99-00 1%
'00-01
46%
'01-02
13%
77%
'02-03
43%
'03-04
93%
'04-05
25%
26%
'05-06
19%
78%
'06-07
21%
24%
'07-08
29%
98%

9. Estimated mortality by influenza virus type/subtype, : Impact of variability in circulating strains
Season A(H1N1) A(H3N2) B
, ,235
, ,
,465 12,067 ,
, ,473
, , ,639
, ,803 ,
, ,076
Thompson WW, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179-86

10. Influenza Strains by type/subtype over time, USA, 2007-08
1000
H1N1 B
H3N2
800
600
400
200 40 42 44 46 48 50 52 02 04 06 08 10 12 14 16 18 20
Oct
Nov
Dec
Jan
Feb
Mar
Apr
2007
2008

11. Virus Type/Subtype by Region 2007-08
%A/H1
%A/H3 %B

12. Ideal influenza VE studies: Take virus and season variability into consideration
Multiple seasons
Multiple sites
Good virus surveillance
Typing/subtyping
Antigenic characterization
Reality: Ideal rarely achieved, but important to keep principles in mind when thinking about generalizibility of any single study

13. Measuring Seasonal Influenza Vaccine Effectiveness: What to look for in VE studies
Virus and illness variables
Antigenic match (circulating viruses vs. vaccine)
Intensity of season
Types of viruses circulating (virulence:H3N2 > B > H1N1)
Multiple vs. single season
Study design
Outcomes measured
Influenza-like illness (ILI)
Laboratory-confirmed influenza
Modeling studies of Influenza-related hospitalizations and deaths based medical databases and viral surveillance
Randomized controlled trial (placebo-controlled ideal) vs. observational study
Setting and participants
Age and risk group
Controls
Clearly effectiveness, by any measure, varies according to the age group, influenza risk group, and the degree that the vaccine strains match the circulating strains.
One of the challenges of determining the effectiveness of seasonal influenza vaccination is how to choose an outcome to measure effectiveness. The variety of different outcomes used in the influenza literature to assess effectiveness has made comparison across studies and time very difficult. Some outcomes often used to assess effectiveness is quite non-specific, such as influenza-like illness or ILI, which is usually defined as acute onset of fever and either cough or sore throat. This syndrome can be caused by a variety of respiratory pathogens or even non-infectious etiologies. However, influenza vaccine is only going to prevent ILI caused by influenza virus. Therefore effectiveness estimates that use ILI as an outcome typically find the vaccine to have a relatively low effectiveness in preventing ILI. Effectiveness of influenza vaccine in preventing laboratory-confirmed influenza is typically much higher, but requires more expensive and carefully designed studies. Effectiveness estimates using severe outcomes such as hospitalization or death are usually done retrospectively, and typically require modeling techniques. These studies can substantially overestimate the effectiveness of vaccination in preventing these outcomes if generally healthier persons tend to be preferentially vaccinated.

14. Selection of Influenza Vaccine Effectiveness Outcomes
Outcomes based on symptoms or syndrome without laboratory confirmation
Less specific outcome than laboratory confirmed
Lowers vaccine effectiveness estimate
Affected by level co-circulating respiratory pathogens, i.e. what proportion of influenza-like illness cases are actually influenza?
Examples of outcomes:
Influenza-like illness (e.g. fever + [cough or sore throat])
Influenza-related hospitalization or death based on ICD-9 codes and virus surveillance

15. Effect Of Co-circulation Of Non-influenza Pathogens/Outcome Specificity On VE Estimate
Assuming 100 vaccinated and 100 unvaccinated in each set (A and B):
VE against influenza infection (red) = 75% for both sets A and B,
VE against all respiratory illness (yellow+ red) = 30% in set A and 15% in set B.

16. Influenza-Associated Hospitalizations By Age Group, 1979-2001
Data for this slide comes from Dr. Bill Thompson at CDC and illustrate the substantial number of influenza-related hospitalizations each year. The highest rates occur among persons aged 65 years and older followed by children <5 years of age and then adults years. Among young children, risk of severe outcomes drops steeply after age 1, and the risk is reduced 5 to tenfold by age 5
0-4 Yrs
5-49 Yrs
50-64 Yrs
>65 Yrs
Thompson, et al. JAMA 2004.
Hospitalizations modeled using viral surveillance and
National Hospital Discharge Survey data

17. Selection of Influenza Vaccine Effectiveness Outcomes
Outcomes based on symptoms or syndrome without laboratory confirmation
Less specific outcome than laboratory confirmed
Lowers vaccine effectiveness estimate
Affected by level co-circulating respiratory pathogens, i.e. what proportion of influenza-like illness cases are actually influenza?
Examples of outcomes:
Influenza-like illness (e.g. fever + [cough or sore throat])
Influenza-related hospitalization or death based on ICD-9 codes
Laboratory confirmed influenza
Most specific because ILI can caused by many pathogens
Potential pitfall: Bias in who may be chosen for testing

18. Issues in Vaccine Effectiveness among Older Persons

19. Controlling for differences between vaccinees and unvaccinated persons
Major issue with observational VE studies among elderly that use medical diagnostic databases
“Confounding by indication”
Greater representation in vaccinated group of persons with chronic medical conditions
“Healthy vaccinee effect”
Greater representation in vaccinated group of persons who might less likely to have outcome studied
“Frailty bias”
Greater representation in unvaccinated group of persons with diminished functionality for activities of daily living who are more likely to die or be hospitalized during the observation period
Analysis methods to control for confounding
Statistical control using stratified or multivariable model analyses
Subclassifying or matching patients on propensity to seek care
Frailty bias is difficult to control for when using medical databases
Suggested reading: Nichol N Engl J Med 2007; Simonsen Lancet Infectious Diseases 2007

20. Recent re-analysis of only published randomized, controlled trial of influenza vaccine in persons 60 years and older*
*Thijs et al. Mortality benefits of influenza vaccination in elderly people (letter). Lancet 2008.
Reanalysis of Govaert et al. JAMA 1994 (Note: 27% of participants with chronic illness).

21. ACIP’s Influenza Working Group Statement
Supports prospective, population-based studies with laboratory-confirmed endpoints to monitor influenza vaccine effectiveness
Encourages efforts to increase vaccine immunogenicity in frail elderly population
Plans to review studies of new adjuvanted vaccines, novel delivery methods and alternative doses and schedules
*Slide presented by K Neuzil, Chair, ACIP Influenza Vaccine Working Group
ACIP meeting, October 23, 2008

22. Vaccine Effectiveness Studies among Younger Persons

23. Randomized placebo-controlled trials among young adults: Efficacy of TIV against lab-confirmed* influenza, MI
Season
Placebo (%+)
TIV (%+)
VE (95%CI)
7.8
1.9
75% (42-90)
1.8
1.5
16% (10 to -171)
10.8
3.4
68% (46 to 81)
*Culture and/or PCR
1Ohmit et al. N Engl J Med 2006
2Ohmit et al. Clin Infect Dis 2008
3Ohmit et al. IDSA: Seasonal and pandemic influenza Available at:

24. Interim Within-Season Estimate of VE: Marshfield, Wisconsin, 2007-08 Influenza Season
Objective: Estimate VE for preventing medically attended acute respiratory illness (MAARI) which is lab-confirmed as influenza
Patients living in a 14 postal-code area surrounding the Marshfield Clinic eligible for the study
Enrolled subjects:
Cases: MAARI with influenza infection diagnosed by RT-PCR
Controls: MAARI negative by RT-PCR

25. Interim Within-Season Estimate of VE: Marshfield, Wisconsin, 2007-08 Influenza Season: Conclusions
Suboptimal match (based on antigenic characterization) between 2 of 3 vaccine strains and viruses isolated from study participants
Patient group /influenza type
VE (95% CI)
All enrollees
44% (11 to 65)
ACIP recommended
34% (-34 to 67)
Health 5-49 year olds
54% (12 to 76)
Influenza A, all enrollees
58% (28-76)
Influenza B, all enrollees
-35% (-172 to 33)
MMWR 2008;57:393-8

26. Effectiveness of Maternal Influenza Immunization in Mothers and Infants*
Study participants and design
Bangladesh,
Randomized controlled trial
340 pregnant women received either influenza vaccine or pneumococcal polysaccharide vaccine (control) during 3rd trimester
Follow-up through pregnancy and first 6 months after birth
Outcomes
Febrile respiratory illness among infants
Lab-confirmed influenza among infants
Febrile respiratory illness among mothers
The next 3 slides summarizes results form a study conducted in Bangladesh in , with the results published last month in the New England Journal of Medicine.
* K Zaman et al. N Engl J Med 2008

27. Cumulative Cases of Lab-Confirmed Influenza among Infants, by Receipt of Influenza vaccine, Zaman et al, Bangladesh,
We don’t know how generalizable these results are for the United States, and additional studies need to be done to better understand the benefits of influenza vaccination for the infants born to vaccinated women. But these are powerful results, and should be of interest to clinicians who provide care for pregnant women.

28. Summary of common VE study methodologies
Randomized controlled studies
Gold standard for controlling for confounding
Might not be possible in many age/risk groups already recommended for routine vaccination
Persons who volunteer for RCT are not normal
Observational studies – administrative databases
Might better capture a representative population
Confounding issues unresolved, particularly for studies among the elderly
Observational studies – using test negative controls with acute respiratory illness
Not certain that test negative controls are representative of source populations

29. CDC Plans for Vaccine Assessments
4 U.S. sites funded for 3 years to determine VE for lab-confirmed medically attended outcomes
Include all groups recommended for vaccination
Controls: Persons with acute respiratory illness who are influenza test-negative
Powered to assess VE for hospitalization
Potential for within-season VE estimates
Emerging Infections Program study of VE against hospitalization with lab-confirmed influenza
Controls – persons who were not hospitalized, matched on age and county
Two international sites (locations in Senegal and India) funded to measure VE and indirect effects

30. Issues on the Near Horizon
Replication of intriguing findings
Intradermal vaccination
VE among infants born to women vaccinated while pregnant
Better methods to reduce confounding in observational studies among elderly?
Ongoing discussions among persons on both sides of debate

31. Issues on the Near Horizon
More effective vaccines?
Large RCTs of adjuvanted vs. standard vaccine in elderly are in progress
FDA and manufacturers discussing a quadrivalent (2 A and 2 B strains) vaccine for United States
Better ability to predict circulating strains?
Increased, more representative virus surveillance globally
Molecular epidemiology and geographic spread of drifted strains coming into focus
Better understanding of critical antigenic properties