This article is the first to report pneumococcal vaccine responses in people with COPD using measures of functional antibody activity and the latest generation ELISA. We have demonstrated that patients with COPD are able to mount immune responses comparable to those previously reported in healthy elderly patients (14
). We showed that PCV7, when given at twice the dose recommended for children, induces a superior immune response to PPSV23 in COPD. We also showed that both older age and prior PPSV23 vaccination impair PCV7 responsiveness.
Our ELISA results demonstrate that PCV7 (1.0 ml) induces a superior response to PPSV23 in patients with COPD. Although both the PCV7 and PPSV23 groups showed statistically significant increases in postimmunization antibody concentrations, PCV7 vaccination resulted in superior responses for all seven of the tested serotypes (statistically superior for all but serotype 14 and 19F) and more frequently resulted in a twofold increase in antibody titer, a traditional marker of adequate vaccine response (17
). Similar results were reported by Jackson and colleagues who found higher postvaccination antibody levels in previously vaccinated healthy patients older than 70 years of age using the 1.0-ml PCV7 dose and by de Roux and coworkers who demonstrated the same results using the traditional pediatric dose (0.5 ml) in a vaccine-naive elderly population (14
). Taken together, these studies suggest that although protein-conjugate vaccines may induce superior immune responses to the free polysaccharide vaccine, the optimal dose is uncertain and higher doses may be needed in those previously vaccinated with PPSV23.
In our study, both PPSV23 and PCV7 elicited increases in OPK, although this was superior after PCV7 for all serotypes except 19F and reached statistical significance for serotype 4, 9V, 18C, and 23F. These results are comparable to those observed by Jackson and colleagues in healthy elderly patients (15
). Only one prior study has examined OPK in people with COPD after PPSV23 with only a single serotype tested and demonstrating a nonsignificant increase from baseline (18
). Our OPK results suggest that patients with COPD can mount functional antibody responses to both PPSV23 and PCV7, although the conjugate vaccine is likely to offer greater protection against pneumococcal disease.
We also examined the impact of older age and prior vaccination with PPSV23 on the response to vaccination and found that both were associated with reduced OPK responses in multivariate modeling. It has been repeatedly shown that elderly adults develop antibodies with reduced function and our data suggest that this is not eliminated by the administration of a protein-conjugate vaccine (11
). Immune hyporesponsiveness after polysaccharide vaccination has been observed with various vaccines, including meningococcal serogroup C vaccine (20
) and in recent comparative trials of sequential vaccination with PPSV23 and PCV7 (14
). In one of these studies, subjects who received PPSV23 followed by PCV7 1 year later had threefold lower ELISA and OPK than those who received PCV7/PCV7 or PCV7/PPSV23 vaccination regimens (14
). In our study, although all subjects who had been previously vaccinated had received PPSV more than 5 years before enrollment, immunologic hyporesponsiveness was still apparent. Taken together these data suggest that PPSV23 vaccination is associated with a reduction in the availability of memory B cells to respond to subsequent vaccinations, whereas PCV7 may prime the immune system for such reimmunization. Results of the multivariate analysis for IgG response were similar to that for OPK in that PCV7 and younger age were also associated with an increased frequency of twofold increases in serotype-specific IgG. Vaccine naivety was not a significant predictor of response in this model suggesting that prior PPSV23 may reduce postvaccination antibody activity to a greater extent than antibody concentration. Importantly, we also demonstrated that PCV7 was comparably or more immunogenic than PPSV23 regardless of prior vaccination status.
Both PCV7 and PPSV23 were well tolerated and associated with few local or systemic side effects. Although increased reactogenicity has been associated with repeated dosing of polysaccharide vaccines (22
), we observed no increase in adverse events in those who had been previously vaccinated compared with those who had not. This may be due to the requirement that prior vaccinations were received more than 5 years before enrollment.
We believe there are several strengths to this study. Prior studies have examined the immunogenicity of PPSV23 in patients with COPD by ELISA, but older methodology did not detect specific immunological responses and measured nonspecific, nonfunctional antibodies to the pneumococcal capsule and cell wall polysaccharide, which overestimated antibody levels (11
). Prior studies of PPSV immunogenicity in COPD are also limited by the use of ELISA antibody levels as the only surrogate for immunity. The standard ELISA cannot differentiate between functional and nonfunctional antibodies, and measures of antibody-mediated killing, such as opsonophagocytosis, are superior surrogates of protection against pneumonia and bacteremia (19
It should be noted that there are limitations to the PCV7 vaccine. First, although the greater immunogenicity of PCV7 may provide improved protection against invasive pneumococcal disease and pneumonia, it is not clear that the vaccine will prevent acute exacerbations of COPD. Prior studies have shown that patients with COPD are frequently colonized with S pneumoniae
and that this colonization is a predictor of subsequent exacerbation, but higher levels of anti-pneumococcal IgG and OPK have not been associated with bacterial clearance (25
). It is possible that protein-conjugate vaccines may elicit greater IgA antibody responses as compared with polysaccharide vaccines and this may augment the mucosal immune response and better protect against both colonization and exacerbation (26
). Second, the serotypes contained within PCV7 account for only about one-third of pneumococcal isolates recovered from patients with COPD suffering an acute exacerbation (27
). If the vaccine were to offer protection against cross-reactive serotypes (such as 23A/B and 9L/N) then this could be extended to about two-thirds of exacerbation-associated isolates but this would still be inferior to PPSV23, which theoretically protects against 90% of serotypes. In addition, we did not demonstrate a clearly superior immune response after PCV7 vaccination for serotype 14 and in fact, as in most studies, we demonstrated an inferior response to serotype 19F after PCV7 vaccination as compared with PPSV23 (14
). This is of particular concern as these antibodies do not appear to cross-protect against serotype 19A, which is frequently antibiotic resistant and has become a more common cause of invasive disease since the introduction of routine PCV7 vaccination among children (28
). A 13-valent pneumococcal conjugate vaccine (PCV13) is in development that will extend the coverage against COPD-associated pneumococcal serotypes to more than 80% and also contains serotype 19A but the phenomenon of replacement disease may ultimately limit the protection offered by any serotype-specific vaccine (29
There are also limitations to our study. Although the use of a twofold increase in IgG antibody titer has been used previously as a measure of vaccine response (17
), it is not clear how this threshold or the 10-fold increase in OPK, which was selected on the basis of the distribution of the data, correlate with clinically relevant outcomes. It should also be noted that in many cases PPSV23 does elicit immune responses that meet these thresholds and yet appears to have limited efficacy against pneumococcal pneumonia and acute exacerbations in patients with COPD. As a result, it cannot be inferred that the more frequent achievement of serologic responses after PCV7 would definitively translate into improved clinical outcomes. In addition, we excluded subjects with comorbid illnesses known to impair vaccine responses, such as diabetes and alcoholic cirrhosis. As these conditions are very common, it is likely that the immune responses we observed would not be replicated fully in clinical practice. Our study was designed to examine the independent effect of the presence of COPD on pneumococcal vaccine responses as this has not been adequately examined previously.
In conclusion, we show that PCV7 induces a superior immune response to PPSV23 in COPD at 1 month post vaccination, and that both vaccines elicit responses comparable to those previously observed in healthy elderly patients. Despite controversy about the clinical efficacy of PPSV23 in preventing pneumonia (11
), these findings suggest that patients with COPD respond adequately to the vaccine and support its use to prevent episodes of invasive disease in this population. We have also confirmed that prior PPSV23 vaccination and older age are associated with relative immune hyporesponsiveness. Additional studies are needed to confirm the superior immunogenicity of PCV13 in COPD, to determine the relative duration of the immune response after PPSV23 and conjugate vaccination, and to identify the immunologic correlates of protection against both invasive and noninvasive pneumococcal disease. In addition, we believe our data provide the rationale for further study of the clinical efficacy of protein-conjugate pneumococcal vaccines in the high-risk COPD population.