This study examined possible benefits of PCV, PPV, or sequential administration of these two vaccines in adults whose high risk for pneumococcal pneumonia was documented by their having just recovered from that disease. PCV has been remarkably successful in infants and young children whose immature immune systems do not respond to PPV, eliciting antibody and protecting against invasive pneumococcal disease [11
]. In contrast, PCV in healthy or immune-compromised adults stimulates IgG levels that, 4
weeks post-vaccine, equal or only modestly exceed those following PPV [14
]. We hypothesized that PCV might lead to better antibody responses than PPV, albeit for a limited number of vaccine serotypes, in our high-risk patients. We found that IgG levels and opsonic activity in serum increased after vaccination and, at 4–8 weeks, were similar in recipients of PPV or PCV. Six months after vaccination, however, IgG and OPK levels had returned to baseline in recipients of PPV; in contrast, although levels fell in those vaccinated with PCV, they remained measurably greater than baseline,, as recently reported in healthy elderly adults [17
A further hypothesis of our work was that sequential vaccination with PCV followed by PPV might elicit a priming/boosting response, as had been described in patients with Hodgkin disease [18
] or HIV-infection [19
]. Other studies have failed to demonstrate this effect [15
], perhaps due to vaccine dose, preparation or schedule. Our PCV dose was subsequently shown to be optimal in older adults [17
], and our boosting dose was higher than in some earlier studies. In Group 1 patients, administration of PCV 6 months after PPV caused antibody at 4–8 weeks to increase but not to exceed the original, post-PPV peak. This finding is consistent with Heidelberger’s [26
] meticulous observations on responses to polysaccharide antigens and indicates the lack of participation by long-lived T-helper cells in response to polysaccharide antigens. In contrast, in Group 2 patients who received PCV followed by PPV, IgG and OPK levels rose to greater levels 4–8 weeks after PPV, consistent with a priming/boosting effect suggestive of participation by amplifying B or T cells [28
The major contribution of our study, however, is in the long-term follow-up of our subjects. Six months after the second vaccination, antibody in both groups fell precipitously, returning nearly to original, baseline levels. Previous investigations of a priming/boosting effect [17
] only studied subjects 3
weeks after the boost. Our findings suggest the induction of a long-lasting suppressor effect [28
] rather than a simple waning of the antibody response since, in Group 2 subjects, IgG levels originally rose and then declined rapidly after the second dose of vaccine. We hypothesize that, in elderly subjects, induction of a population of relatively long-lived memory suppressor T regulatory cells is responsible for the observed suppression and may be intrinsic to the immune response to polysaccharide antigens [31
]. This interpretation is supported by our important observation that subjects who had received PPV within a year of enrolling in the study had almost no response to PPV or PCV, whereas IgG levels increased in proportion to time elapsed since, or in the absence of, prior vaccination. Alternatively, repeated administration of antigen may deplete the existing pool of sensitized lymphocytes in a classically described immunologic tolerance [28
], but If this mechanism were responsible, we do not think there should be such a nice initial response 4–8 weeks after the boosting dose.
The results of this study have both clinical and basic implications. First, they raise serious question about the value of administering pneumococcal vaccine routinely to patients who have recovered from pneumococcal pneumonia, a policy that has been elevated to the status of a quality indicator at many medical centers. They also suggest that, in these patients, a priming/boosting strategy with PCV followed by PPV is unlikely to provide protective benefit, at least with the presently available conjugate vaccine. At a more basic level, they support the hypothesis that the magnitude of the antibody response to polysaccharide antigens is determined by the interplay of amplifying and suppressive B or T cells or by a balance between generation and depletion of sensitized B cells [26
]. Except in infants, multiple doses of polysaccharide, whether pure or protein-conjugated, have long been known to exert a suppressive effect [26
]. Infants may respond well to several doses of PCV because of the delayed ontogeny of the regulatory suppressor T cells. Although other mechanisms, such as immunological paralysis or tolerance [33
], or genetically mediated [35
] or acquired [36
] failure [36
] to respond to polysaccharide antigens might be responsible for our observed results, adequate responses at 4–8 weeks oppose these possibilities and favor induction of a suppressor effect. This suppressive effect appears to wane after 5 years; interestingly, in a recent study [37
] showing that previously vaccinated older adults respond well to a repeat dose of PPV, the mean time between the first and second dose was 5.4 years.
There are several limitations of this study. (1) We only studied a single population of adults who are susceptible to pneumococcal infection, namely those who had pneumococcal pneumonia and survived, and only a small proportion of these patients survived to the final analysis. Furthermore, the majority of these patients had previously received pneumococcal vaccine, which could possibly indicate that they constitute a poorly-responding subgroup. A recent study of conjugate followed by polysaccharide pneumococcal vaccine in HIV-infected children 1–2 year follow-up [38
] did not find evidence for suppression; as noted above, this difference could reflect the immaturity of the regulatory T cell population in children. Otherwise healthy adults might respond differently to vaccination. (2) Since no subjects received only PCV, we can not exclude the possibility that we simply detected a waning antibody response when we gave PPV after PCV; this explanation seems unlikely considering how well antibody had persisted for 6 months after PCV alone and how striking the decline was 6 months after the putative boosting dose. (3) We did not include a group that received only two doses of PCV, for example, at 6-month intervals [28
]; such a study is now in progress in our laboratory. Notable strengths of the present study include the availability of an exceptionally accurate vaccine history thanks to reliability of MEDVAMC automated records, measurement both of IgG levels and OPK activity, and the 6-month follow-up after vaccination.
Based solely on our findings, one might still propose a vaccination strategy that relies solely on conjugate vaccine for at-risk adults. There are at least two problems with such an approach: (1) presently known techniques of protein-conjugation limit the number of CPS that can be included in a vaccine; in accord with current vaccine recommendations, PPV might still need to be given to cover a greater range of serotypes [39
]; and (2) the emergence of ‘replacement types’ of S. pneumoniae
] may severely limit the long-term efficacy of conjugate vaccines.
In conclusion, our findings suggest that a vaccination strategy based on repeated doses of pneumococcal polysaccharide, including ‘priming’ with PCV and ‘boosting’ with PPV is not likely to be beneficial in adults who are most at risk, such as those who have recently recovered from pneumococcal pneumonia. Depletion of sensitized B-cells or induction of long-lived T regulator suppressor cells may be responsible, and this phenomenon may be an intrinsic property of the response to polysaccharides in adults These results question the long-term value of administering PPV to persons who have recovered from pneumonia. They further reinforce the need to develop protein vaccines for high-risk adults, for example, those derived from pneumolysin, from surface-exposed pneumococcal surface proteins A or C [43
], or from other proteins newly recognized by microarray analysis [44
] in order to protect our highest risk populations from pneumococcal disease.