Prior to immunization, the group of elderly subjects had appreciable levels of PPS-specific IgG for all 23 vaccine PPSs, with the GMC in serum for serotypes ranging from 1.5 to 8.1 μg/ml (Table ). Prevaccination GMC in serum for this group of elderly adults did not correlate with the prevalence of the respective serotypes isolated from adults in Minnesota from 1995 to 1998 (17
= 0.96). Although the highest mean levels of prevaccination PPS-specific IgG were found for the most common isolate, type 14, some of the lowest mean baseline antibody levels were detected for other prevalent serotypes (4, 3, 22F, and 8).
TABLE 1 Prevaccination antibody levels for capsular PPSs in elderlysubjects
Comparison of each elderly subject's baseline antibody levels for the 23 vaccine PPSs by cluster analysis revealed a high correlation between the concentrations within individuals of PPS-specific IgG for 20 of the 23 serotypes (Fig. ). In contrast, prevaccination antibody levels for PPSs 14, 3, and 33F correlated distinctly more poorly with those for other vaccine PPSs. In addition, there was no correlation in prevaccination antibody levels between these three distinct PPSs.
FIG. 1 Correlation matrix of prevaccination antibody levels for 23 vaccine PPSs in the elderly. Baseline antibody levels of elderly subjects were compared by using the Pearson correlation for each pair of vaccine serotypes. Correlation coefficients for each (more ...)
Despite the prevalence of baseline antibody for vaccine PPSs, appreciable proportions of the elderly group had serum antibody levels for particular PPSs of less than 1 μg/ml, a level of serotype specific antibody reported to correlate with significant opsonophagocytic activity (34
). Over 25% of the elderly subjects had low baseline antibody levels for serotypes 22F, 8, and 33F, and over 15% of the study group had low antibody levels for serotypes 4, 12F, 17F, and 2.
As a group, elderly subjects showed a statistically significant rise (P < 0.001) in GMC in serum of PPS-specific IgG to all vaccine serotypes after immunization (Table ). GMC in serum of specific antibody increased after vaccination by greater than 1 μg/ml for all serotypes except type 3 (Table ). Of note, immune responses after vaccination correlated inversely (P = 0.009) with the prevalence of the respective serotype as an invasive strain among adults in Minnesota. Increases in PPS-specific IgG determined as either change in GMC or as fold rise were generally smaller for more prevalent serotypes and greater for less prevalent types (Table ). In addition, the immunogenicity of the 23 vaccine PPSs measured as an absolute change in GMC of specific antibody correlated (P = 0.04) with baseline antibody levels (Fig. ). Serotypes for which these elderly subjects had the lowest baseline antibody levels generally elicited less increases in antibody after vaccination, and those for which they had higher baseline antibody levels generally produced greater increases. Absolute changes in specific antibody GMC after vaccination also were significantly correlated with immunogenicity as determined by fold rise in specific antibody concentrations for all serotypes (P < 0.001), even though this latter calculation was influenced by baseline antibody concentrations. In this elderly group, geometric mean fold rises in specific antibody after vaccination were greater than twofold for all serotypes except type 3. Thus, by these criteria, 21 of the 23 vaccine polysaccharides (excluding types 3 and 4) appeared to be highly immunogenic in this group of elderly subjects.
TABLE 2 Change in capsular polysaccharide-specific antibody after pneumococcal vaccination ofelderly
FIG. 2 Antibody responses of elderly adults to 23 vaccine polysaccharides. GMC of polysaccharide-specific IgG were determined for elderly adults prior to pneumococcal vaccination (black bars) and after vaccination (total bar height). Serotypes are arranged in (more ...)
However, when individual rather than group immune responses were assessed, the 23-valent vaccine did not appear to be uniformly immunogenic in these elderly subjects. Vaccination produced a twofold rise in specific antibody in less than 50% of the elderly subjects to common serotypes 4, 1, and 3, as well as to the less common serotype 11A. Furthermore, even the most immunogenic serotypes, 2, 15B, and 33F, produced twofold rises in specific antibody in only 72 to 78% of subjects (Table ). When classified by the number of vaccine serotypes for which they mounted a twofold rise in specific antibody, only 2 of 53 elderly subjects responded to all 23 vaccine serotypes (Fig. ). The median number of serotypes to which they responded was 14, with 25% of elderly subjects responding to fewer than 8 of the 23 PPSs. Eleven elderly subjects (20%) had twofold increases in specific antibody after vaccination for only 5 or fewer of the 23 vaccine PPSs and, by these conservative criteria, were designated low responders. Four of these low responders did not have twofold increases in specific antibody for any PPS, and two low responders showed a twofold rise for only a single vaccine PPS. None of these low responders had twofold increases after vaccination in specific antibody for serotypes 14, 4, 23F, 22F, 6B, 19A, 12F, 9V, 9N, and 20, which include the most common invasive pneumococcal infection-causing serotypes in North America (4
). Thus, one out of five ambulatory elderly adults showed consistently impaired antibody responses to the majority of vaccine serotypes.
FIG. 3 Cumulative immune responses of elderly adults to 23 vaccine polysaccharides after vaccination. Bars indicate the cumulative percent of elderly subjects showing at least a twofold increase in polysaccharide-specific IgG to the indicated number of serotypes. (more ...)
To determine whether their antibody responses to a few selected PPSs could distinguish low responders from other elderly adults with adequate responses to the pneumococcal vaccine, we first grouped the fold rises in specific IgG for the 23 vaccine PPSs among the elderly subjects by using cluster analysis. In these elderly subjects, immune responses to vaccine PPSs were highly correlated within groups of serotypes: group 1, serotypes 1, 19A, and 19F; group 2, serotypes 12F, 17F, 5, 7F, 8, 9N, 9V, 2, 20, 15B, and 33F; group 3, serotypes 18C and 4; and group 4, serotypes 22F, 23F, 14, 6B, 11A, and 3. Within these groups, a twofold increase in antibody levels for a single PPS, serotype 9N, could most efficiently discriminate the low responders from the adequate responders among these elderly adults. All of the elderly low responders were included among the 15 elderly subjects with less than a twofold response to serotype 9N. Furthermore, a twofold response to serotype 9N clearly delineated elderly adults with twofold responses to 12 or fewer of the 23 vaccine PPSs from those with twofold responses to more than 12 of the 23 vaccine PPSs.
Although having a marker PPS for discriminating low from adequate responses to pneumococcal immunization is of great utility in research studies, these measurements require that the measurement of changes in specific IgG in sera be obtained before and after vaccination. However, in clinical application, patients do not routinely have serum drawn prior to pneumococcal immunization. Thus, we investigated whether the absolute levels of specific IgG for any group of vaccine PPSs or for the whole 23-valent pneumococcal vaccine measured in sera collected after vaccination could similarly distinguish low from adequate vaccine responders among elderly adults. Measurement of postvaccination antibody levels for the whole 23-valent vaccine appeared to be a useful estimate of overall antibody responses to the 23 vaccine PPSs, because for each subject antibody levels for the whole vaccine correlated significantly with the sum of the antibody levels for the 23 individual PPSs (Fig. ). However, because of the variability between elderly subjects in levels of postvaccination PPS-specific IgG, no group of marker PPSs could be identified, nor were the results obtained by using the whole pneumococcal vaccine itself as the capture antigen predictive. Thus, although changes in antibody levels for serotype 9N appeared to be useful in research studies of pneumococcal vaccine immunogenicity in elderly adults, measurement of postimmunization antibody levels for a small group of PPSs or the total pneumococcal vaccine cannot be used clinically to distinguish low from more robust vaccine responders among the elderly.
FIG. 4 Correlation of postvaccination antibody levels for whole pneumococcal vaccine and sum of antibody levels for 23 vaccine polysaccharides. For each elderly subject, the sums of postvaccination antibody levels for the 23 vaccine polysaccharides were calculated (more ...)