study authors were solely and independently re- sponsible for the study design, the data analysis, the writing and preparation of all drafts of the manuscript, and the submission of the manuscript. The basic study design and methods have been de- scribed previously.10-13 The institutional research committees of the HMOs approved the project. In- formed consent was not required.

n engl j med 357;14 www.nejm.org october 4, 2007 1373

The new england journal of medicine established in 1812 october 4, 2007 vol. 357 no. 14

Effectiveness of Influenza Vaccine in the Community-Dwelling Elderly

Kristin L. Nichol, M.D., M.P.H., M.B.A., James D. Nordin, M.D., M.P.H., David B. Nelson, Ph.D., John P. Mullooly, Ph.D., and Eelko Hak, Ph.D.

A B S T R A C T

From the Medicine Service and Center for Chronic Disease Outcomes Research, Min- neapolis Veterans Affairs Medical Center and University of Minnesota, Minneapo- lis (K.L.N., D.B.N.); the HealthPartners Research Foundation, Minneapolis (J.D.N.); Kaiser Permanente Northwest, Portland, OR ( J.P.M.); and the Julius Center for Health Services and Primary Care, Univer- sity Medical Center, Utrecht, the Nether- lands (E.H.). Address reprint requests to Dr. Nichol at Medicine Service (111), VA Medical Center, 1 Veterans Dr., Minne- apolis, MN 55417, or at nicho014@umn. edu.

N Engl J Med 2007;357:1373-81. Copyright © 2007 Massachusetts Medical Society.

Background

Reliable estimates of the effectiveness of influenza vaccine among persons 65 years of age and older are important for informed vaccination policies and programs. Short- term studies may provide misleading pictures of long-term benefits, and residual confounding may have biased past results. This study examined the effectiveness of influenza vaccine in seniors over the long term while addressing potential bias and residual confounding in the results.

Methods

Data were pooled from 18 cohorts of community-dwelling elderly members of one U.S. health maintenance organization (HMO) for 1990–1991 through 1999–2000 and of two other HMOs for 1996–1997 through 1999–2000. Logistic regression was used to estimate the effectiveness of the vaccine for the prevention of hospitalization for pneumonia or influenza and death after adjustment for important covariates. Ad- ditional analyses explored for evidence of bias and the potential effect of residual confounding.

Results

There were 713,872 person-seasons of observation. Most high-risk medical conditions that were measured were more prevalent among vaccinated than among unvaccinated persons. Vaccination was associated with a 27% reduction in the risk of hospitaliza- tion for pneumonia or influenza (adjusted odds ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.77) and a 48% reduction in the risk of death (adjusted odds ratio, 0.52; 95% CI, 0.50 to 0.55). Estimates were generally stable across age and risk subgroups. In the sensitivity analyses, we modeled the effect of a hypothetical unmeasured con- founder that would have caused overestimation of vaccine effectiveness in the main analysis; vaccination was still associated with statistically significant — though lower — reductions in the risks of both hospitalization and death.

Conclusions

During 10 seasons, influenza vaccination was associated with significant reductions in the risk of hospitalization for pneumonia or influenza and in the risk of death among community-dwelling elderly persons. Vaccine delivery to this high-priority group should be improved.

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 357;14 www.nejm.org october 4, 20071374

Influenza continues to be a major cause of illness and death, especially among the elderly. Each year, influenza and its com- plications are responsible for about 186,000 ex- cess hospitalizations for respiratory and circula- tory illness1 and 44,000 excess deaths from all causes2 in this high-risk group. Influenza vaccines are safe and effective, and the elderly are included among the high-priority groups targeted for annual vaccination.3

Reliable estimates of the benefits of vaccination are important for establishing informed policies regarding resource allocation for the delivery of immunizations and identifying the need for new vaccines and strategies for the prevention and con- trol of inf luenza in this group.4 However, most studies assessing the effectiveness of inf luenza vaccination in the elderly have included one or only a few influenza seasons.5 Because of the variabil- ity of influenza from season to season, the results of these short-term studies — either favorable or unfavorable — might provide incomplete or mis- leading pictures about the benefits of vaccination over longer periods of time6; furthermore, hetero- geneity between studies may limit the ability to pool results appropriately across studies.7

Because of ethical constraints imposed by rec- ommendations that target the elderly for annual vaccination, most studies of the effectiveness of inf luenza vaccine in elderly persons have been observational studies and not randomized, con- trolled trials. Questions have been raised about the effects of potential bias and residual confounding on past estimates of vaccine effectiveness from these observational studies.8,9

In this study, we analyzed the effectiveness of influenza vaccination among 18 cohorts of com- munity-dwelling elderly members of health main- tenance organizations (HMOs) during 10 seasons. Our purpose was to provide a long-term view of the effectiveness of inf luenza vaccine while ad- dressing potential bias and residual confounding.

M e t h o d s

We pooled subject-level data from 18 cohorts of elderly members of one U.S. HMO for the 1990– 1991 through the 1999–2000 seasons and of two other U.S. HMOs for the 1996–1997 through the 1999–2000 seasons. Each cohort provided data for more than 20,000 person-seasons, for a total of 713,872 person-seasons during 10 seasons. The

study authors were solely and independently re- sponsible for the study design, the data analysis, the writing and preparation of all drafts of the manuscript, and the submission of the manuscript. The basic study design and methods have been de- scribed previously.10-13 The institutional research committees of the HMOs approved the project. In- formed consent was not required.

Study Sites and Participants

The participating HMOs were HealthPartners in Minnesota and Wisconsin (1990–1991 through 1999–2000); Kaiser Permanente Northwest in the Portland, Oregon, and Vancouver, Washington, area (1996–1997 through 1999–2000); and Oxford Health Plans in New York City and surrounding counties (1996–1997 through 1999–2000). All non- institutionalized members of the plans were in- cluded in that season’s cohort if they were 65 years of age or older as of October 1, had been con- tinuously enrolled in the plan for the preceding 12 months, were alive on the first day of the in- fluenza season, and were either continuously en- rolled or died during the outcome period. We se- lected these criteria to ensure adequate baseline and follow-up data and to reduce the potential for survivor bias.

Study Data

Data were extracted retrospectively fr