Characterization of antibody responses to annual influenza vaccination over four years in a healthy elderly population
Introduction
Influenza is a serious public health problem that disproportionately affects the elderly, as evidenced by increased morbidity and mortality from pneumonia and other pulmonary and cardiac complications [1], [2], [3], [4]. Although annual influenza vaccination is recommended for all individuals 65 years of age or older [3], [4], recent estimates indicate that only about 63% of the elderly in the United States receive influenza immunization in any given year [3], [4]. One reason for this inadequacy in vaccine coverage is that a significant risk of influenza disease exists, even for those elderly who have been vaccinated. Statistics indicate that influenza immunization prevents influenza-related illness in 70–90% of healthy individuals <65 years old when the vaccine and infecting virus are antigenically similar [5], [6], [7] whereas only a 50% reduction is seen after influenza immunization of healthy subjects >60 years old [8]. Protection rates from illness in institutionalized ‘frail’ elderly have been reported as being as low as 30% [9], [10], [11].
Although the exact mechanism involved in reduced vaccine efficacy in the elderly is not known, it is believed that decreased antibody responses play a significant role since reduced mean antibody titers to influenza vaccine in the elderly compared to young subjects have been reported [12], [13], [14], [15]. In addition, while hemagglutination inhibition (HI) antibody titers ≥40 are considered protective [5], [6], [16], [17], several studies have shown that at least 25% of the elderly, including those who are healthy and ambulatory, do not develop HI antibody titers ≥40 in response to vaccination [7], [12], [13], [14], [18], [19], [20]. However, it is still important to recognize that influenza vaccination is a highly effective measure to prevent severe influenza illness, secondary bacterial pneumonias, and death in both healthy and frail elderly.
The value of repeated annual influenza vaccination of both young and elderly has also been questioned. An early study [21] reported that influenza vaccination of English schoolboys afforded protection only in those immunized for the first time, but not in those vaccinated in previous years. However, a more recent study [22] of adults 16 years and older indicated that influenza vaccination was more efficacious in reducing influenza-related mortality when administered over multiple years than after the first administration. Other studies have shown that repeated influenza vaccinations over a ten-year period in young adults with Cystic Fibrosis [23], or over a three-year period in healthy young adults [24], showed no diminution of antibody titers, although higher pre-existing antibody titers to a given strain did limit increases in antibody titers pre- to post-vaccination in the latter study [24]. This is not surprising since high levels of existing circulating antibodies to a specific antigen have been shown repeatedly to inhibit antibody production upon subsequent immunization with the same antigen, presumably by clearing the antigen before a secondary immune response is produced [25].
Despite current CDC recommendations to vaccinate all elderly ≥65 years old [3], [4], there is still considerable debate about whether or not annual influenza vaccination is beneficial for the elderly. Some reports have shown no significant change in vaccine efficacy or in post-vaccination titers between subjects, with or without a history of recent influenza immunization [11], [26], [27], [28], [29], [30], while others have indicated either detrimental effects [31], [32] or significant benefits [33], [34] on the level of antibody production or vaccine efficacy with repeated vaccination. The interpretation of these results is further complicated by the evaluation of: (1) small sample groups; (2) different subjects over multiple study years; (3) different vaccine preparations (e.g. whole or split) across years; and (4) different strains of influenza in repeated years. Thus, the current study was specifically designed to circumvent these problems by: (1) using the same large group of 92 healthy elderly subjects; (2) evaluating antibody responses to the same H1N1 strain, A/Texas, over four contiguous years (1993–1996); and (3) assessing antibody titers to A/Texas collectively at the end of four years, rather than separately after each year. Our data clearly indicate that repeated vaccination with A/Texas over multiple years does not impair antibody responses to influenza vaccination. In addition, we have shown the importance of assaying antibody samples simultaneously if a direct comparison among years is desired.
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Subjects
Healthy elderly subjects living independently in six local continuing care retirement communities (CCRC) were evaluated in this study. Initially, a small cohort of 19 subjects was recruited from the CCRCs in 1992–1993 for a pilot study to determine optimal parameters for assessments of immune function. The mean age of this cohort was 76.1±9.0 (range 65–91); 68% were women. During the next four years (1993–1996), a larger cohort of 92 subjects (71.7% women), with a mean age of 79.1±5.0 (range
Antibody titers to A/Texas after annual immunization with influenza vaccine
The first objective of this study was to determine the effect of annual influenza immunization on both current and subsequent antibody responses to A/Texas over four contiguous years (1993–1996). Initially, antibody responses to A/Texas were evaluated separately at the end of each year of the study, rather than collectively upon completion of the study. As shown in Fig. 1A, antibody responses to A/Texas increased significantly (P≤0.001) from pre- to post-vaccination in all four years of the
Discussion
The present study was undertaken to address the controversy that exists concerning the effect of annual influenza vaccination on the antibody response to influenza, particularly when the same influenza strain is included in multiple years. Interpretation of the inconsistency among previous studies that have addressed this question is complicated by: (1) small sample sizes, which are highly vulnerable to sample bias in studies of immune function in aging individuals; (2) inclusion of different
Acknowledgements
We are indebted to the residents and staff of the participating CCRCs: Rydal Park, Cathedral Village, Medford Leas, Foulkeways at Gwynedd, Pennswood Village and Stapely Hall of Germantown. We thank Caroline Fidew for her database management assistance and Marion Dorfman for excellent technical assistance. This work was supported by the National Institutes of Health Grant NIH AG03934.
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