Immunological responses to pneumococcal vaccine in frail older people
Introduction
The average life expectancy of individuals in developed countries is steadily increasing and this trend is expected to continue increasing with continuing improvements in health care, nutrition and disease prevention. Presently, approximately 13% of the Australian population is aged 65 years and over, projected to increase to over one-quarter by 2051 [1]. Globally, the proportion of the population over 65 years is estimated to reach 21% by 2050 [1]. This shift in population age structure will require an increasing focus on health problems experienced disproportionately by older adults, including certain infectious diseases. Among the most important of these is pneumonia and invasive disease resulting from Streptococcus pneumoniae infection. In developed countries, the annual incidence of invasive pneumococcal disease (IPD) has been estimated at greater than 50 per 100,000 for adults aged 65 years and older [2], [3], who represent a high-risk group, with high morbidity and case mortality which may exceed 50% [4].
Ageing has been associated with a wide range of defects in both innate and adaptive immune system including diminished clonal expansions of B- and T-cells that limit immunological repertoire and are associated with diminished specific antibody responses [5]. Although the decreased capacity of the elderly immune system to respond to new pathogens is likely to reduce the efficacy of most or all vaccines in this population, the evidence for protection of older persons by pneumococcal vaccines is conflicting. Three recent studies illustrate this. One study in a large retrospective cohort study of adults >65 confirmed the efficacy of 23vPPV in preventing bacteremia, but no effect on inpatient or outpatient pneumonia [6]. In contrast, two cohort studies, retrospective and prospective, found decreased rates pneumonia, whether or not associated with bacteremia [7], attributable to 23vPPVvaccination [8]. Because young children do not respond effectively to pneumococcal polysaccharide antigens [9], a 7-valent polysaccharide-protein conjugate vaccine (PCV7) has been recommended for children under 2 years of age [10], [11] that, unlike 23vPPV, induces T-cells to stimulate B-cell development into antibody-producing or memory cells [4]. Because PCV7 prevents pneumonia in young children [11], there is interest in ascertaining whether PCV7 might offer an advantage over 23vPPV in adults. In one study of elderly people who had been previously vaccinated with 23vPPV, a booster dose of PCV7 appeared to be better than a booster does of 23vPPV [12]. Further, the conjugate vaccine has been shown to be effective against invasive disease in children [13] but more clinical research is needed for primary vaccine immunogenicity of conjugate vaccines in adults [14].
Chronological age may not be the best measure of overall vulnerability to disease in the elderly. Though there is considerable disagreement on operational definitions [15], [16], [17], [18], the concept of frailty has evolved to signify “a multidimensional syndrome of loss of reserves (energy, physical ability, cognition, health) that gives rise to vulnerability” [19]. Used in this way, frailty has been shown in various conceptualizations to correlate with a wide range of morbid conditions, including psychiatric illness, obesity and cataract as well as all-cause hospitalization, disability and mortality [20], [21], [22], [23]. The deficit-based Frailty Index (FI) developed by Rockwood et al. has gained support as a measurement tool, and has been validated in various contexts [24]. The essence of this approach is that frailty can be defined as an accumulation of age-related adverse changes, or deficits, in a range of functional systems [25].
We hypothesised that age may not be the only predictor of decline of immune function, but that frailty may also provide such a measure. We evaluated this in the specific context of response to pneumococcal vaccines.
Section snippets
Aim
To evaluate the immunogenicity of the PCV7 versus 23-valent polysaccharide vaccine (23vPPV) and compare the immune response to four serotypes (4, 6B, 18C and 19F), with respect to age or frailty in an elderly population of previously unvaccinated hospitalized patients.
Methods
We conducted a randomized, controlled clinical trial (RCT) specifically targeting frail older people aged ≥60 years who received follow-up care in the Geriatric, cardiology, rheumatology and orthopaedic Departments of a large 800-bed tertiary referral hospital in Sydney, Australia. The hospital is located in the west of Sydney, serves as a tertiary referral base for the western metropolitan area and also acts as the district hospital for the immediately surrounding community. The population
Measurement of pneumococcal antibodies
The prevalence of antibody to PPS were studied using ELISA designed according to the consensus protocol [29], [30] with minor modifications. Serotypes 4, 6B, 18C and 19F were tested as they are in both vaccines (PCV7 and 23PPV).
All serum samples (both pre and post vaccination) were pre-absorbed with purified pneumococcal cell wall polysaccharide (C-PS) (Serum Statens Institute) and a capsular preparation from 22F [29], [30] and antibody concentrations were determined for each sample using three
Interpretation of antibody response
Currently there are no guidelines for the interpretation of the results generated with the serotype-specific assay. No international standard is available; hence antibody responses have been reported in a variety of ways (antibody fold increase, antibody concentration (geometric mean concentration GMC), threshold antibody level or antibody function). These differences have added to the complexity of comparing and interpreting studies [32]. A threshold value (0.35 μg/ml) has been derived from
Analyses
Differences in log-transformed concentrations of capsule specific IgG antibodies between pre and post vaccination sera of both groups were calculated. The differences between groups in IgG increases and fold increases were determined by two-tailed Fisher exact and Pearson Chi-squared tests. The p-values were two-tailed and the level of significance was set at p ≤ 0.05. We used of the Statistical Software SPSS V15 (SPSS, Inc. Chicago, IL). The immunogenicity data for 23PPV and PCV7 are summarized
Results
We recruited 241 patients admitted to the hospital between 16 May 2005 and 20 February 2006 to a pneumococcal vaccine trial [34]. Of whom 119 received 23PPV and 122 PCV7. Patient characteristics were evenly distributed between the arms as shown in (Table 1), except the proportion scoring poorly on MiniMental state. The Frailty Index (FI) results (Table 1) showed that all subjects achieved at least one item, with a wide spread of scores from 1 to 24.
The total pre and post vaccination IgG
Discussion
Pneumococcal disease presents a serious risk of morbidity and mortality in the elderly due to the declining immune response with increasing age [35], [36]. This limits the efficacy of vaccines. Reports of the diminished vaccine efficacy in the elderly may reflect either poor functionality of vaccine induced anti-PPS specific antibodies (or inconsistent antibody measurements). Subsequently, there are doubts amongst physicians about the efficacy of pneumococcal vaccine in the elderly [37], [38].
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