Influenza vaccination and mortality: differentiating vaccine effects from bias

Abstract

It is widely believed that influenza (flu) vaccination of the elderly reduces all-cause mortality, yet randomized trials for assessing vaccine effectiveness are not feasible and the observational research has been controversial. Efforts to differentiate vaccine effectiveness from selection bias have been problematic. The authors examined mortality before, during, and after 9 flu seasons in relation to time-varying vaccination status in an elderly California population in which 115,823 deaths occurred from 1996 to 2005, including 20,484 deaths during laboratory-defined flu seasons. Vaccine coverage averaged 63%; excess mortality when the flu virus was circulating averaged 7.8%. In analyses that omitted weeks when flu circulated, the odds ratio measuring the vaccination-mortality association increased monotonically from 0.34 early in November to 0.56 in January, 0.67 in April, and 0.76 in August. This reflects the trajectory of selection effects in the absence of flu. In analyses that included weeks with flu and adjustment for selection effects, flu season multiplied the odds ratio by 0.954. The corresponding vaccine effectiveness estimate was 4.6% (95% confidence interval: 0.7, 8.3). To differentiate vaccine effects from selection bias, the authors used logistic regression with a novel case-centered specification that may be useful in other population-based studies when the exposure-outcome association varies markedly over time.

Figure 1.

Influenza vaccine coverage by age and sex among elderly members of Kaiser Permanente, Northern California, 1996–2005.

Figure 2.

Influenza vaccine coverage in relation to insurance risk score among elderly members of Kaiser Permanente, Northern California, 1996–2005. Intervals on the horizontal axis are spaced unevenly to sharpen the focus on higher-risk patients.

Figure 3.

Influenza vaccine coverage in relation to probability of death among elderly members of Kaiser Permanente, Northern California, 1996–2005. Intervals on the horizontal axis are spaced unevenly to sharpen the focus on higher-risk patients.

Figure 4.

Mortality (deaths per 100 person-years) by week after influenza vaccination among higher-risk vaccinees, lower-risk vaccinees, and all vaccinees (1.9 million flu shots), Kaiser Permanente, Northern California, 1996–2005. The flat reference line shows the average monthly mortality during all unvaccinated time in the study population. COPD, chronic obstructive pulmonary disease.

Figure 5.

Observed and expected proportions of decedents with influenza vaccination and the corresponding bias in vaccine effectiveness (VE), Kaiser Permanente, Northern California, 1996–2005. Deaths occurring during the 9 influenza seasons were omitted, so “VE” reflects bias rather than effectiveness.