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20 009 7/15

Morbidity and Mortality Weekly Report


April 18, 2008 / Vol. 57 / No. 15

nterim Within-Season Estimate of the Effectiveness of Trivalent Inactivated

Influenza Vaccine Marshfield, Wisconsin, 2007–08 Influenza Season During clinical trials, the efficacy of vaccination with These findings demonstrate that, in any season, assessment activated influenza vaccines for the prevention of sero- of the clinical effectiveness of influenza vaccines cannot be zically confirmed influenza infection has been estimated determined solely by laboratory evaluation of the degree of

high as 70%-90% among healthier adults. However, antigenic match between vaccine and circulation strains. e effectiveness of annual influenza vaccination typically Patients living in a 14 postal-code area surrounding Flower during those influenza seasons when a suboptimal Marshfield, Wisconsin, were eligible to participate in this atch between the vaccine strains and circulating influ- study. Nearly all residents in this area receive outpatient za strains is observed. For example, in a 4-year random- and inpatient care from Marshfield Clinic health-care prod study of influenza vaccine among healthy persons aged viders. Study enrollment began on January 21, 2008, based 65 years, the predominant strain was drifted from the on laboratory evidence of influenza circulation from both ccine strain in 2 of the 4 years. Inactivated vaccine effec- Marshfield Clinic laboratories and the Wisconsin State eness (VE) against culture-confirmed influenza ranged Laboratory of Hygiene and continued through March 28, im 71% to 79% when the vaccine and circulating strains 2008. Patients who visited a Marshfield Clinic facility with ere suboptimally matched to 74% to 79% when the medically attended illnesses were screened for study eligiatches were well matched (1). In contrast, a 2-year study bility during outpatient or inpatient visits. Patients who inactivated influenza vaccine among healthy adults aged reported feverishness, chills, or cough were eligible for -64 years found no measurable VE during a year when enrollment. Those who reported symptoms for 8 or more poorly matched strain circulated, but found VE of 86% days were not eligible for enrollment because influenza ainst laboratory-confirmed influenza during the follow- virus shedding decreases with illness duration, making 3 year when the vaccine and circulating strains were well detection of the virus unlikely after 8 days of symptoms. atched (2). Although laboratory data on the antigenic The majority of ill patients not approached during a aracteristics of circulating influenza viruses compared with ccine strains are available during influenza seasons, esti

INSIDE ites of VE usually have not been made until months er the conclusion of the season. This report summarizes

398 Rotavirus Vaccination Coverage and Adherence to the

Advisory Committee on Immunization Practices (ACIP)erim results of a 2008 case-control study to estimate

Recommended Vaccination Schedule – United States, effectiveness of trivalent inactivated influenza vaccine

February 2006-May 2007 prevention of medically attended, laboratory-confirmed 401 Laboratory-Acquired Vaccinia Exposures and Infections luenza during the 2007–08 influenza season, when most

United States, 2005-2007 culating influenza A (H3N2) and B viruses were 404 Update: Influenza Activity – United States, September poptimally matched to the vaccine strains. Despite the

30, 2007-April 5, 2008, and Composition of the 2008-09

Influenza Vaccine soptimal match between two of three vaccine strains and

409 Notices to Readers culating influenza strains, overall VE in the study popu

411 QuickStats ion during January 21-February 8, 2008, was 44%.


The MMWR series of publications is published by the Coordinating
Center for Health Information and Service, Centers for Disease
Control and Prevention (CDC), U.S. Department of Health and
Human Services, Atlanta, GA 30333.
Suggested Citation: Centers for Disease Control and Prevention.
[Article title). MMWR 2008;57:(inclusive page numbers).
Centers for Disease Control and Prevention
Julie L. Gerberding, MD, MPH

Tanja Popovic, MD, PhD

Chief Science Officer
James W. Stephens, PhD
Associate Director for Science

Steven L. Solomon, MD
Director, Coordinating Center for Health Information and Service

Jay M. Bernhardt, PhD, MPH
Director, National Center for Health Marketing

Katherine L. Daniel, PhD
Deputy Director, National Center for Health Marketing
Editorial and Production Staff

Frederic E. Shaw, MD, JD
Editor, MMWR Series

Teresa F. Rutledge
(Acting) Managing Editor, MMWR Series

Douglas W. Weatherwax
Lead Technical Writer-Editor
Donald G. Meadows, MA

Jude C. Rutledge


Peter M. Jenkins
(Acting) Lead Visual Information Specialist

Lynda G. Cupell

Malbea A. LaPete
Visual Information Specialists
Quang M. Doan, MBA

Erica R. Shaver
Information Technology Specialists

clinical encounter were identified the next day by usir electronic diagnosis codes entered by the clinician; then patients were contacted by telephone and enrolled at hor: if they met eligibility criteria. The Marshfield Clinic he search Foundation institutional review board approved tha study.

Nasal or nasopharyngeal swabs were obtained from corsenting patients and were tested for influenza A or B inteition by reverse transcription-polymerase chain reaction (RT-PCR) at the Marshfield Clinic Research Foundatie using CDC-recommended probes and primers. Viral ceture was performed on all samples that were RT-PCR pos: tive to provide virus isolates for antigenic characterizatie Influenza vaccination status was determined through a immunization information system (Regional Early Chii hood Immunization Network*) used by all public and p: vate immunization providers for vaccines administered us adults and children. Previous validations have demonstrac that the system captures 96%-98% of influenza vaccin administered to area residents (Marshfield Clinic Researce Foundation, unpublished data, 2005–2007). Trivale: inactivated influenza vaccine from Sanofi-Pasteu: ([Fluzone®], Swiftwater, Pennsylvania) was the only intiu enza vaccine used by Marshfield Clinic during the 200 08 influenza season.

For this case-control study, a case of medically attenda: influenza was defined as an acute illness in a patient wa feverishness, chills, or cough and documentation of infli enza infection by RT-PCR. Controls were defined 4 patients with the same symptoms who had a negative RI PCR test for influenza. Using persons with actute respica tory symptoms who test negative for influenza as contro is a method that in modeling studies has compared favor ably with cohort studies and traditional case-control designs for the assessment of vaccine effectiveness 13 Patients were categorized as immunized if they had receita influenza vaccine 14 days or more before enrollment; addition, children aged <9 years were categorized : immunized if they had received 2 doses of influenza cine. Twenty-three children were excluded because they ha received only 1 of the 2 recommended doses; this subgroup was too small to permit a separate analysis of VE for part.. immunization.

VE was estimated by using logistic regression to com pare patients with laboratory-confirmed influenza wito patients who tested negative for influenza. The likeliho of receiving influenza vaccination in this population associated with a propensity to seek health care, and use of

Editorial Board William L. Roper, MD, MPH, Chapel Hill, NC, Chairman

Virginia A. Caine, MD, Indianapolis, IN

David W. Fleming, MD, Seattle, WA
William E. Halperin, MD, DrPH, MPH, Newark, NJ
Margaret A. Hamburg, MD, Washington, DC
King K. Holmes, MD, PhD, Seattle, WA
Deborah Holtzman, PhD, Atlanta, GA

John K. Iglehart, Bethesda, MD
Dennis G. Maki, MD, Madison, WI
Sue Mallonee, MPH, Oklahoma City, OK

Stanley A. Plotkin, MD, Doylestown, PA
Patricia Quinlisk, MD, MPH, Des Moines, IA
Patrick L. Remington, MD, MPH, Madison, WI

Barbara K. Rimer, DrPH, Chapel Hill, NC
John V. Rullan, MD, MPH, San Juan, PR

Anne Schuchat, MD, Atlanta, GA
Dixie E. Snider, MD, MPH, Atlanta, GA

John W. Ward, MD, Atlanta, GA

* Available at

*-negative controls helped adjust for this source of bias estimating VE for medically attended influenza illness.

mparisons of this study design to traditional cohort and 2-control methods for assessing VE have been published Cently (3). For this analysis, the enrolled patients were

egorized into two groups: persons for whom influenza cine was recommended by the Advisory Committee on munization Practices (ACIP) for the 2007–08 season ed on age or an existing chronic medical condition that reased their risk for influenza-related complications (i.e., - ACIP recommended group), and healthy children and ults aged 5-49 years (i.e., the healthy group). Logistic regression models were adjusted for age, week of -:ollment, and presence of a chronic medical condition. e last variable was not included in the models restricted healthy patients aged 5–49 years. VE was estimated as _] x [1 – adjusted odds ratio]) and was interpreted as o if the percentage was negative. The first 59 influenza us isolates obtained during the study were submitted to C for detailed antigenic characterization. During January 21-February 8, 2008, a total of 1,779 ients were assessed for study eligibility after a clinical counter for acute respiratory illness or febrile illness. A al of 850 (48%) did not meet eligibility criteria; 773 %) of exclusions resulted from absence of feverishness,

chills, or cough or an illness duration 8 days or longer. Of the 929 eligible patients, 639 (69%) consented to the study and were tested for influenza infection. Final enrollment for this interim analysis was reduced to 616 patients after exclusion of 23 partially immunized children who had received only 1 of 2 recommended vaccine doses.

Influenza was detected by RT-PCR in 191 (31%) enrollees; 75% of influenza infections were type A. Distribution by sex was similar for patients who tested positive and patients who tested negative for influenza (Table 1); however, the median age was higher for patients who tested positive (21 years) than those who tested negative (10 years). Approximately 19% of patients who tested positive and 39% of those who tested negative had been vaccinated against influenza.

The overall interim estimate of VE was 44% (Table 2); the estimate was higher among persons in the healthy group aged 5–49 years (54%). The overall estimate of VE for prevention of medically attended influenza A infections was 58%. No VE was observed for prevention of medically attended influenza B infections.

Subtyping by RT-PCR performed at CDC demonstrated that 40 of 41 influenza A specimens were influenza A (H3N2) viruses; the remaining specimen was an H3N2 and B virus mixture. Preliminary data on antigenic characterizations were available for nine influenza A (H3N2) viruses and 18 of 20 influenza B viruses. Two of nine influenza A (H3N2) viruses were A/Wisconsin/67/2005-like, the H3N2 component of the 2007–08 Northern Hemisphere vaccine; the other seven were A/Brisbane/10/2007like (H3N2) viruses, a strain that is drifted from the

efined as existing if the patient had two or more health-care visits with relevant ternational Classification of Diseases, Ninth Revision, Clinical Modification agnosis codes during 2007. Diagnosis codes were based on ACIP criteria, cluding cardiac, pulmonary, renal, neurological/musculoskeletal, metabolic, rebrovascular, immunosuppressive, circulatory system, and liver disorders; abetes mellitus; and malignancies.

BLE 1. Number and percentage of patients with medically attended acute respiratory illness who were enrolled* in a study and ited for influenza, by selected characteristics — Marshfield, Wisconsin, January 21-February 8, 2008

Patients testing positive Patients testing negative
for influenzat
for influenza

(n = 191)

(n = 425)

(N = 616) aracteristic

No. (%)

No. (%)

No. (%)

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(44) (56)

188 237

282 334

(46) (54)

e group ;-59 mos

1,-49 yrs 1-64 yrs 265 yrs

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23 (12)


171 (28)
139 (73)

219 (52)

358 (58)
24 (13)


63 (10)
5 (3)

19 (4)

24 (4) isting chronic medical conditions

17 (9)

62 (15)

79 (13) atients who reported having feverishness, chills, or cough for <8 days were eligible for enrollment. y reverse transcription-polymerase chain reaction. efined as existing if the patient had two or more health-care visits with relevant International Classification of Diseases, Ninth Revision, Clinical lodification diagnosis codes during 2007. Diagnosis codes were based on Advisory Committee on Immunization Practices (ACIP) criteria, including ardiac, pulmonary, renal, neurological/musculoskeletal, metabolic, cerebrovascular, immunosuppressive, circulatory system, and liver disorders; abetes mellitus; and malignancies.

TABLE 2. Interim vaccine effectiveness (VE) estimates among patients with medically attended acute respiratory illness who were enroller in a study and tested for influenza, by influenza type and selected categories - Marshfield, Wisconsin, January 21-February 8, 2008

Patients testing positive Patients testing negative
for influenzat

for influenza
(n = 191)

(n = 425) Not


Adjusted VE Influenza type/Patient group Vaccinated vaccinated Vaccinated vaccinated

% (95% CIT) All influenza All enrollees



44** (11-65) ACIP recommendedtt



34 (-31-67) Healthy persons aged 5–49 yrs $8



54** (12–76) Influenza A All enrollees



58** (28–76) ACIP recommended



49 (-14-77) Healthy persons aged 5–49 yrs



68** (29–86) Influenza B All enrollees



-35 (-172-33) ACIP recommended



(-287-55) Healthy persons aged 5–49 yrs




(-241-48) Patients who reported having feverishness, chills, or cough for <8 days were eligible for enrollment. By reverse transcription-polymerase chain reaction. § Patients were categorized as vaccinated if they had received influenza vaccine >14 days before enrollment; in addition, children aged <9 years we categorized as vaccinated if they had received 2 doses of influenza vaccine. Twenty-three children were excluded because they had received on:

of the 2 recommended doses. 1 Confidence interval.

Statistically significant. 17 All children aged 6–59 months, all adults aged >50 years, and persons aged 5-49 years with an existing chronic medical condition for whom influera

vaccination is recommended by the Advisory Committee on Immunization Practices (ACIP). $& Persons aged 5-49 years with no chronic medical conditions for which ACIP recommends influenza vaccination.


A/Wisconsin/76/2005 strain. All 18 influenza B viruses
were B/Florida/04/2006-like, belonging to the B/Yamagatal
16/88 lineage of viruses. B/Yamagata-like viruses are anti-
genically distinct from the B/Victoria-like lineage virus that
was included in the 2007–08 influenza vaccine.
Reported by: E Belongia, MD, B Kieke, L Coleman, PhD, J Donahue,
DVM, PhD, S Irving, ) Meece, PhD, M Vandermause, Marshfield Clinic
Research Foundation, Marshfield, Wisconsin. D Shay, MD, P Gargiullo,
PhD, A Balish, A Foust, MA, L Guo, MD, S Lindstrom, PhD, X Xu, MD,
A Klimov, PhD, J Bresee, MD, N Cox, PhD Influenza Div, National
Center for Immunization and Respiratory Disease, CDC.
Editorial Note: Influenza infections result in substantial
morbidity and mortality each year in the United States (4,5).
Because of the sizeable burden of influenza-associated dis-
ease, annual influenza vaccination was recommended by
ACIP for the 2007–08 season for children aged 6-59
months, adults aged 250 years, persons with chronic medi-
cal conditions that place them at high risk for serious
influenza-related complications, and close contacts of these
groups and of children aged <6 months (6).

Viral data reported to World Health Organization (WHO) and National Respiratory and Enteric Virus Surveillance System (NREVSS) laboratories in the United States during the 2007–08 influenza season through April 5, 2008, demonstrated that influenza A and B viruses accounted for 74% and 26%, respectively, of influenza viruses characterized in the United States (7). Of influenza A viruses subtyped,

27% were influenza A (H1N1) viruses, and 73% Wi".
influenza A (H3N2) viruses. Antigenic characterization
a subset of these viruses by CDC indicated that 699,
A (H1N1) viruses were A/Solomon Islands/3/2006-lik
the A (H1N1) vaccine component, but that 710.94
A (H3N2) viruses were A/Brisbane/10/2007-like, a rece
antigenic variant of the A/Wisconsin/67/2005-like vir
the A (H3N2) vaccine component. In addition, 959.
antigenically characterized B viruses belonged to .
B/Yamagata lineage. Viruses in this lineage are antigen
cally distinct from the B/Malaysia/2506/2004-like com
ponent of the 2007-08 vaccine, which is in the B/Victor
lineage. These viral surveillance data suggested that it
effectiveness of the 2007–08 influenza vaccine might b
reduced against circulating influenza A (H3N2) and!
viruses. However, in this analysis, preliminary VE resus
indicated that, despite the antigenic differences betwet
vaccine and circulating H3N2 strains, the effectiveness,
vaccine in preventing medically attended respiratory i!
nesses from influenza A infections was 58%. In contras
no VE could be demonstrated against influenza B.

Multiple previous studies of the effectiveness of influen: vaccines have been reported (i.e., observational studies of the clinical effects of vaccination as opposed to randomized clinical trials) (8). VE varies from influenza season to sea son, based in part on the degree of antigenic march

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ween vaccine and circulating influenza strains. VE pre-usly has been assessed sporadically in different populans and by using different methods. Annual systematic essments of VE using laboratory-confirmed outcomes have not been available within an influenza season. Furtermore, antigenic characterization data rarely have been ilable for influenza viruses isolated from participants of i studies, and not previously from the population for Flom annual vaccination is recommended by ACIP. spite a mismatch between the vaccine influenza A 3N2) strain and seven of nine influenza A (H3N2) , uses isolated from study participants, the data in this jort are consistent with results obtained in seasons with noderate antigenic mismatch between vaccine and circuing strains of H3N2 viruses (1,8). Based on preliminary analyses of A/Brisbane/10/20072 (H3N2) viruses and the 2007–08 vaccine H3N2 strain ng

the method of antigenic mapping (9), an average irfold difference was observed between the homologous er for the vaccine strain and average titers for circulating ains. These differences were measured with hemagglutition inhibition tests by using a panel of reference stinfection ferret antisera. The degree of mismatch tween the A/Wisconsin/67/2005 vaccine strain and 3N2 viruses tested at CDC thus far during the U.S. 07-08 influenza season can be described as moderate in ation to antigenic distances seen over time for H3N2 uses (10). By contrast, all the influenza B viruses isoed in the Marshfield Clinic study this season and antinically characterized thus far belong to the B lineage not ntained in this season's vaccine. Viruses from the Victoria-like lineage and B/Yamagata-like lineage are subntially more antigenically distinct from each other than Wisconsin/67/2005-like and A/Brisbane/10/2007-like 3N2 viruses are from each other. The findings in this report are subject to at least four nitations. First, analyses were conducted while enrollment d laboratory testing were ongoing, and not all RT-PCR sitive samples had yet been confirmed by culture. Thus, e preliminary subtype distribution and antigenic charterization results might not be representative of all tients in the study with influenza. Second, VE was estiited only for prevention of influenza among persons who ught care for acute respiratory illness, comparing patients 10 tested positive for influenza with patients who tested gative. Certain patients who tested negative for influza might actually have had influenza virus infections, hough RT-PCR is the most sensitive diagnostic test availle. In addition, although simulation models have monstrated that VE estimated with test-negative

controls was close to the actual VE when test specificity was high, as is also the case with RT-PCR (3), this method is only beginning to be used in studies. VE was assessed against medically attended influenza and not against more severe outcomes of influenza infection, such as influenza hospitalizations; VE might vary with severity of the outcome studied. Third, if the antigenic characteristics of influenza viruses circulating in other regions of the United States differ substantially from viruses isolated from the Marshfield, Wisconsin, study participants, VE might vary by region. Finally, enrollment of patients continued in this study thorough March 28, and final analyses might differ from these interim assessments of VE.

These preliminary data based on study enrollment during January 21-February 8 suggest several conclusions. First, when assessing VE, laboratory data on antigenic characterization of circulating influenza viruses compared with vaccine strains should be interpreted together with data on the clinical effectiveness of vaccination in preventing laboratory-confirmed influenza illnesses. Although two of three vaccine strains were not optimally matched with circulating viruses this season, an interim VE estimate suggests that vaccination provided substantial protection against medically attended acute respiratory illness in this study population. In addition, intraseason estimates of VE, such as those from this analysis, might be useful to public health authorities and medical practitioners in their communications about the benefits of vaccination, especially late in the influenza season. Such data also might be helpful to practitioners when evaluating the need for antiviral treatment and prophylaxis for their patients. Therefore, creating systems that enable collection and dissemination of timely VE data during an influenza season are a priority for CDC. Finally, health-care providers should be aware of the types and subtypes of influenza circulating in their communities over the course of each influenza season. If influenza B strains predominate during the remainder of this season, providers can anticipate an increased risk for vaccine failures and should consider early use of antiviral medications for treatment and prophylaxis of persons at high risk for complications from influenza infection.

Acknowledgments The findings in this report are based, in part, on contributions from V Allison, J Anderson, E Bergmann, C Beyer, L Bennetti, N Berger, C Becker, A Bernitt, A Brockman, K Buedding, D Cole, A Deedon, J Frahmann, D Gamble, L Gavigan, D Gentz, G Greenwald, N Hartl, J Herr, D Hilgemann, L Ivacic, D Johnson, D Kempf, T KronenwetterKoeppel, D Marx, C Meyer, C Reis, S Reisner, J Salzwedel, S Strey, P Siegler, P Stockwell, L Verhagen, D York, J Zygarlicke, Marshfield Clinic Research Foundation, Marshfield, Wisconsin.

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