Immune response to pneumococcal conjugate vaccination in asplenic ...

[Human Vaccines 5:2, 85-91; February 2009]; ©2009 Landes Bioscience

Research Paper

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Immune response to pneumococcal conjugate vaccination in asplenic individuals

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Elaine Stanford,1,* Fiona Print,2 Michelle Falconer,3 Kenneth Lamden,2 Samuel Ghebrehewet,3 Nick Phin,3 David Baxter,4 Matthew Helbert,5 Rosemary McCann,6 Nick Andrews,7 Paul Balmer,1 Ray Borrow1 and Edward Kaczmarski1

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1Health Protection Agency North West; Manchester Laboratory; Manchester Medical Microbiology Partnership; 5Department of Immunology; Manchester Royal Infirmary; Manchester, UK; 2Cumbria & Lancashire Health Protection Unit; Central Lancashire Primary Care Trust; Ormskirk, Lancashire UK; 3Cheshire and Merseyside Health Protection Team; Chester Microbiology Laboratory; Chester, UK; 4Infection Control Unit; Regent House; Stockport, UK; 6Greater Manchester Health Protection Unit; Manchester, UK; 7Health Protection Agency; Centre for Infections; London, UK

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to PCV7, though protective levels were demonstrated pre-PCV7 in majority of participants due to prior PPV23. Although immunogenic, there is insufficient evidence here to recommend routine PCV7 immunization over PPV23 immunization in adult asplenic individuals.

Introduction

Due to the impairment of immune responses, asplenic individuals are at increased risk of infection with encapsulated bacteria and risk developing overwhelming post-splenectomy infection (OPSI) which is fatal in approximately 50% of patients.1 To prevent this, the UK Department of Health recommends that all individuals who are asplenic or have dysfunction of the spleen are immunized against Streptococcus pneumoniae, Neisseria meningitidis serogroup C (MenC), Haemophilus influenzae type B (Hib) as well as influenza.2 Long-term or emergency stand-by antibiotic prophylaxis is also recommended because OPSI is a life long risk for asplenic individuals with cases occurring up to 65 years post-splenectomy.3,4 S. pneumoniae is responsible for more than 50% of cases of OPSI.5 Asplenic individuals over five years of age are recommended to receive one dose of a 23-valent pneumococcal polysaccharide vaccine (PPV23) every five years due to the increased rate of decline of antibody levels observed in this patient group.2,6,7 PPV23 is also given to other patient groups at high risk of pneumococcal disease, and one dose is offered routinely to all adults ≥65 years of age in the UK.2 Following the introduction of a 7-valent pneumococcal conjugate vaccine (PCV7) into the UK childhood immunization schedule in September 2006, all children aged between 2 and 12 months receive one dose of PCV7 at 2 and 4 months of age, with a booster at 13 months. However, asplenic children should also receive one dose of PPV23 after their second birthday.2 Children aged from 12 months to five years of age who are asplenic should receive two doses of PCV7, separated by at least two months, and one dose of PPV23 after their second birthday or at least two months after their last dose of PCV7.2 Various studies have provided conflicting evidence on the immune response to pneumococcal polysaccharide antigens in asplenic individuals.8,9 However some limitations of polysaccharide vaccines in individuals with impaired immune response can be overcome by

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Asplenic individuals are at increased risk of infection with Streptococcus pneumoniae. The immune response to pneumococcal conjugate vaccine has not been investigated in this clinical risk group. We investigated immune responses to pneumococcal vaccination in asplenic individuals. Eligible subjects aged ≥4 years received one dose 7-valent pneumococcal conjugate vaccine (PCV7) and, if no prior 23-valent polysaccharide vaccine (PPV23) had been received within previous 5 years, one dose was given 6 months following PCV7. Pre- and post-vaccination blood samples were taken. Pneumococcal serotype-specific IgG levels were determined for 9 serotypes; the 7 in PCV7 plus serotypes1 and by standardized ELISA. One hundred and eleven asplenic individuals were recruited [median age 54.8 years, (18.1–81.8)]. Median age at splenectomy was 29.6 years (3.6–78.3); 108 (97.3%) individuals had previously received PPV23. Compliance with UK recommendations on immunization and prophylaxis in this group was poor, 91 (82%) subjects had received Haemophilus influenzae type b conjugate vaccine and only 68 (62%) had received meningococcal serogroup C conjugate vaccine. In total 61 (55%) subjects were taking antibiotic prophylaxis and 12 subjects had reported previous invasive pneumococcal disease, five episodes of which occurred post-splenectomy. High serotype-specific IgG concentrations were observed pre-PCV7, with significant increases (p < 0.01) in geometric mean concentrations pre- to post-PCV7 for the PCV7 serotypes. Post-PCV7, between 27% (serotype 14) and 69% (serotype 23F) of subjects had a ≥2-fold rise in IgG. Pre-PCV7, the percentage of individuals with levels ≥0.35 μg/mL ranged between 77% (serotype 4) and 97% (serotypes 14, 19F), whilst post-PCV7 this was 90% (serotype 6B) and 99% (serotype 14). No significant increases were observed post-PPV23. Asplenic individuals responded well

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Key words: pneumococcal, asplenic, conjugate vaccine, polysaccharide vaccine, immunization

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*Correspondence to: Elaine Stanford; Health Protection Agency North West, Manchester Laboratory; Manchester Medical Microbiology Partnership; P.O. Box 209; Clinical Sciences Building, Manchester Royal Infirmary; Oxford Road; Manchester, Lancashire M13 9WZ UK; Tel.: +44.16127.66791; Fax: +44.16127.66792; Email: [email protected]

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Submitted: 05/02/08; Revised: 06/26/08; Accepted: 07/07/08 Previously published online as a Human Vaccines E-publication: http://www.landesbioscience.com/journals/vaccines/article/6557

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immunized with PPV23, and 78 (70%) had received a dose within 5 years prior to this study. The median time since the last dose of PPV23 was 3.3 years (range 0.6–11.3 years). A total of 91 (82%) subjects had received a prior dose of HibCV and 68 (62%) had received MCCV. A total of 61 (55.0%) asplenic individuals were taking prescribed antibiotics at the time of the study, and 90 (81.1%) were taking other prescribed medication. A total of 64 (57.7%) individuals had reported ongoing chronic illness requiring treatment. Of the 111 participants, twelve (10.8%) were known to have had at least one previous episode of pneumococcal infection, five episodes occurred post-splenectomy. Pneumococcal serotype-specific IgG concentrations. Geometric mean IgG concentrations before and after immunization with PCV7 and before and after PPV23 are given in Tables 1 and 2. High levels of serotype-specific IgG concentrations were observed pre-PCV7, with significant increases (p < 0.01) in IgG GMC before to after PCV7 vaccination observed for the seven serotypes included within PCV7. No significant changes in IgG concentration were observed for serotypes 1 and 5, which are not included in PCV7. The serotype-specific IgG concentrations in the subset of the study population who required a dose of PPV23 six months following a dose of PCV7, were not significantly higher following PPV23 for all nine serotypes analyzed when compared to the post-PCV7 concentrations (Table 2). Four hypo-responders were referred to an Immunologist as following PCV7, three or more of the PCV7 serotypes were 65 years) compared to younger adults (18–45 years) in response to 1 dose of PPV23.15 Reduction in functional antibody activity in vaccinated elderly individuals has also been shown to highly correlate with decreased IgG antibody avidity.16 Previous pneumococcal serotype-specific immunogenicity studies in the elderly have used >1.00 μg/mL17,18 or ≥1.00 μg/mL as a threshold for analysis.19 In the present study significantly fewer individuals had putatively protective concentrations when ≥1.00 μg/mL was taken as opposed to ≥0.35 μg/mL. Four participants with a poor response to PCV7 were referred for follow-up. Two of these patients had been splenectomized for NHL, while the remaining two patients referred had been splenectomized following trauma and had reported no underlying malignant or haematological disorders. It is possible that further doses of PCV7 may increase antibody levels where primary responses were poor, although repeated doses of PCV7 were not included in the protocol for this study. Studies on re-vaccination with PPV23 have reported a variety of findings, some showing a decline in antibody levels while other studies reported no evidence of hyporesponsiveness or adverse effects.20,21 The current UK recommendation for asplenic individuals is to receive further doses of PPV23 at 5-year intervals.2 There was slight evidence in this study of immune hyporesponsiveness, where antibody concentrations decline with repeated doses of some polysaccharide vaccines, as there was a general trend across the majority of PCV7 serotypes for participants with two previous doses of PPV23 to have lower antibody concentrations than the group with one previous dose, although those with three previous doses had slightly higher responses, and there were no significant postPPV23 increases in IgG concentration for serotypes 1 and 5 in the subset of individuals who required PPV23. The highest fold changes in antibody concentrations before to after PCV7 were seen in the group with no previous doses of PPV23. As this group also had lower baseline levels, this was not unexpected and the serotype-specific IgG GMCs were comparable to recent seroprevalence data in adults,14 although levels for serotypes 9V, 14, 18C and 23F were very high. These results, however, are not considered statisically significant due to the size of the group (n = 3). Analysis of demographic data to assess any effects of additional factors on antibody concentrations revealed few statistically significant factors, which affected only a few serotypes so it is difficult to make any specific recommendations based upon these results. The general, non-significant trend observed here of lower antibody levels in individuals splenectomized due to malignant conditions compared with those splenectomized as a result of trauma supports similar observations in a recent study in which total pneumococcal IgG and IgM responses to PPV23 were higher in trauma patients compared to those with malignant conditions.22 However, in this study, patients splenectomized due to a malignant condition responded to PCV7 as well as the trauma group for serotypes 14, 18C and 19F. The study provided an opportunity to assess compliance with guidelines on the management of asplenic individuals,3 and provide additional vaccinations to update patient care. Although the proportion of participants with at least one previous dose of PPV23 was

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individuals ≥1.00 μg/mL for the serotypes included within PCV7 or serotypes 1 and 5. Factors affecting antibody responses. Few statistically significant conclusions were made as a result of the single and multivariable analyses, although a number of general trends were observed. Significant findings. The number of years since splenectomy had a significant effect on IgG GMCs for serotype 9V, with fold increases of 1.02 (CI 1.01–1.03) per year since splenectomy pre-PCV7, and 1.03 (CI 1.01–1.04) per year since splenectomy post-PCV7. The numbers of years since the last dose of PPV23 had a significant effect on IgG GMCs for serotype 18C, with a fold increase of 1.08 per year since the last PPV23 dose (CI 1.02–1.15, p = 0.007) from pre-to post-PCV7. The number of prior doses of PPV23 was grouped into participants with 1 (baseline), 2, 3 and 0 doses. The lowest antibody concentrations were observed before PCV7 for the group with no prior PPV23. Significantly higher fold changes in antibody concentrations were observed before to after PCV7 for this group (n = 3) for serotypes 9V and 14 (p < 0.001), compared with the 1, 2 and 3-dose groups. General trends observed. Reasons for splenectomy were categorized as trauma (baseline), elective (non-malignant), elective (malignant) and miscellaneous for analysis. The elective (malignant) group had lower antibody concentrations compared with the trauma group before and after PCV7 for all serotypes tested. The elective (non-malignant) group had slightly lower antibody concentrations compared to the trauma group for the majority of serotypes, but responses were higher than the elective (malignant group). However, the before to after PCV7 change for both elective groups was comparable to the trauma group for serotypes 14, 18C and 19F. These observations were not statistically significant. Pneumococcal serotype-specific IgG GMCs by the number of previous doses of PPV23 (Table 6) suggested that antibody concentrations were generally higher among the 3-dose group compared to the one dose group. Antibody concentrations among the 2-dose group were generally lower than the 1 and 3 dose groups.

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Discussion

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Antibody levels before administration of PCV7 exceeded the putative protective level in the majority of participants, perhaps because previous PPV23 had been received by 108 of the 111 participants. The majority of study participants responded well, as significant increases in IgG GMCs for the pneumococcal serotypes in PCV7 were observed 3–6 weeks after vaccination. However, individuals without a functional spleen are particularly susceptible to pneumococcal disease and need protection against the maximum number of serotypes possible. The proportion of individuals with serotype-specific antibody concentrations ≥0.35 μg/mL were high before PCV7 was given, and this proportion remained high following a dose of PPV23 in the subset of participants requiring PPV23. The relevance of a threshold of ≥0.35 μg/mL has been recently questioned in older adults.14 In a recent study, the proportions of older individuals with antibody levels ≥0.35 μg/mL observed was high for all serotypes except 6B, however, the incidence of IPD in these age groups is increased compared to younger adults.14 The main protective mechanism against pneumococci is antibody-mediated opsonophagocytosis and www.landesbioscience.com

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Study population. Splenectomized individuals were recruited from South Cheshire, South Lancashire, Salford and Trafford, after ethical approval was confirmed from local and multicentre research ethics committees. Potential participants were identified through asplenic registers and databases held by local Consultants in Communicable Disease Control and General Practitioner (GP) surgeries. An invitation letter to participate in the study was sent to eligible patients by medical/nursing personnel. Eligible patients included splenectomized patients aged four years and over and able to give written, informed consent or consent from a parent or guardian. Patients with acute febrile illness, previous hypersensitivity reaction to any study vaccine or its excipients, prior vaccination with PCV7, participation in a clinical trial at the time of the study or within the previous six months, steroid use at the time of the study or pregnancy were not considered eligible for the study. Participants completed all study visits at their local GP surgery. All those vaccinated were asked to complete a record form that provided information on age, reason for asplenia, date of splenectomy, dates of previous PPV23, history of pneumococcal disease, current medication including immunoglobulin, cytotoxic drugs, azathiaprine and prophylactic antibiotics, details of any chronic illness and dates of prior meningococcal A & C polysaccharide, MenC conjugate (MCCV) and Hib conjugate (HibCV) vaccines. Vaccines. Splenectomized individuals received one dose of the PCV7 (PrevenarTM, Wyeth Vaccines, Pearl River, NY). If no prior PPV23 (Pneumovax II, Sanofi Pasteur) had been received within the last five years, one dose was given six months following the PCV7. Additionally, participants were given Hib (HiberixTM, GlaxoSmithKline; Act-HibTM Pasteur Merieux MSD) and meningococcal serogroup C (MenjugateTM, Novartis; NeisVac-CTM, Baxter; MeningitecTM, Wyeth) conjugate vaccines if necessary in accordance with the UK immunization policy for asplenic individuals at the time of study commencement (one dose of each). Blood samples were obtained prior to and three to six weeks following PCV7 from all participants and, from participants who were given PPV23

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Materials and Methods

six months later, prior to and three to six weeks following PPV23 immunization. Specimen receipt and storage. Whole clotted blood specimens for all participants were sent to the Vaccine Evaluation Unit (VEU) at the Health Protection Agency North West Laboratory in Manchester. Upon receipt, serum was retrieved by centrifugation at 1,278 g for 10 minutes, aliquoted into plastic vials (Nunc, Denmark) and stored at -70°C to -85°C until analysis. Antibody assays. Pneumococcal serotype-specific IgG levels were determined for nine serotypes (1, 4, 5, 6B, 9V, 14, 18C, 19F and 23F) using the WHO ELISA protocol incorporating adsorption with pneumococcal cell wall polysaccharide and serotype 22F capsular polysaccharide (Wyeth Vaccines).23,24 The pneumococcal serotypespecific capsular polysaccharides used in the preparation of the assay plates and the reference serum, 89-SF, used for generating standard curves and quality control sera were supplied by Wyeth Vaccines. Sera from participants were tested at a starting dilution of 1:50. Raw optical density (OD) data were transferred into assay- and serotypespecific Softmax PROTM templates which automatically check data against pre-determined assay acceptance criteria. Softmax PRO™ templates were used to plot titration curves for the standard reference serum ODs and to calculate serotype-specific pneumococcal IgG in study participants and control sera based upon the assignment of weight-based antibody units in μg/mL to pneumococcal serotypes in 89-SF.25,26 Statistical analysis. Pneumococcal serotype-specific IgG concentrations for each sample were expressed as geometric mean concentrations (GMC) with 95% confidence intervals (CI). The proportion of subjects with serotype-specific IgG concentrations ≥0.35 μg/mL and ≥1.00 μg/mL were calculated with exact 95% CI. Significance of changes in proportions of subjects with serotype-specific IgG concentrations ≥0.35 μg/mL and ≥1.00 μg/mL pre- to post-PCV7 were tested for each serotype using an exact McNemar’s test. Fold changes before and three to six weeks following PCV7, three to six weeks after PCV7 to before PPV23 and before and three to six weeks after PPV23 were calculated with 95% CI. Paired t-tests were also used to compare log-IgG concentrations before and three to six weeks following PCV7 vaccination. Single-variable normal errors regression was used to examine the effects of various factors (age group, gender, reason for removal of the spleen, years since splenectomy, years since last PPV23 and the number of previous PPV23) on pre- and post-PCV7 log-IgG concentrations and the fold change from pre- to post-PCV7 (nine serotypes). Where more than one unrelated variable showed some evidence (p < 0.1) of an association with antibody concentrations for a serotype, multivariable normal errors regression was performed to determine the independent effect of the variables. Statistical analyses were carried out using Microsoft Office Excel 2003 and StataTM 8.2 (StataCorp).

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high at 97%, uptake of other recommended vaccines HibCV (82%) and MCCV (61%), were lower. Disappointingly, only 55% of participants were taking prophylactic antibiotics. Antibiotic prophylaxis is particularly important for asplenic patients due to poor antibody production and a reduced number of phagocytes in this patient group. Only one of the five participants who reported at least one episode of pneumococcal infection post-splenectomy had been taking antibiotics at the time that the study began. In conclusion, PCV7 was found to be immunogenic in the majority of asplenic individuals although most participants had high antibody levels before PCV7 from prior doses of PPV23. Pneumococcal serotype-specific IgG concentrations were typically ≥0.35 μg/mL, but there were notably fewer individuals in this study who could achieve and maintain a level of 1.00 μg/mL. There is insufficient evidence here to recommend routine PCV7 immunization in asplenic individuals aged 18 years and over, however, maintaining the currently recommended vaccination schedule and monitoring individuals at the level of 1.00 μg/mL may be beneficial. We would recommend that higher valency pneumococcal conjugate vaccines should be tested in this group when they become available.

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Acknowledgements

This study was sponsored by Wyeth Vaccines and the authors would like to acknowledge Elizabeth Monk and Ros Hollingsworth (both Wyeth UK) and Keith Friedman (Wyeth US) for support during the study. The authors would also like to acknowledge Liz Sheasby and Helen Campbell from HPA CfI for monitoring the study,

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R.B. has received assistance to attend scientific meetings and has been an occasional member of expert panels for Baxter Bioscience, GSK, Novartis, Sanofi-Pasteur and Wyeth. M.H. has received assistance to attend scientific meetings from Z.L.B., B.P.L., Grifols, Octapharma and has been an expert panel member for G.S.K. P.B. has received assistance to attend scientific meetings from Baxter Bioscience and Wyeth. N.P. has received assistance to attend scientific meetings and has been an occasional member of expert panels for Novartis and SanofiPasteur. E.S. has received assistance to attend a scientific meeting from Wyeth.

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Competing interests disclosure

18. Örtqvist Å, Henckaerts I, Hedlund J, Poolman J. Non-response to specific serotypes likely cause for failure to 23-valent pneumococcal polysaccharide vaccine in the elderly. Vaccine 2007; 25:2445-50. 19. Musher DM, Groover JE, Graviss EA, Baughn RE. The lack of association between aging and postvaccination levels of IgG antibody to capsular polysaccharides of Streptococcus pneumoniae. Clin Infect Dis 1996; 22:165-7. 20. Bernatoniene J, Finn A. Advances in pneumococcal vaccines. Drugs 2005; 65:229-55. 21. O’Brien KL, Hochman M, Goldblatt D. Combined schedules of pneumococcal conjugate and polysaccharide vaccines: is hyporesponsiveness an issue? Lancet Infect Dis 2007; 7:597-606. 22. Eigenberger K, Sillaber C, Greitbauer M, Herkner H, Wolf H, Graninger W, et al. Antibody responses to pneumococcal and hemophilus vaccinations in splenectomized patients with haematological malignancies or trauma. Wien Klin Wochenschr 2007; 119:228-34. 23. Wernette CM, Frasch CE, Madore D, Carlone G, Goldblatt D, Plikaytis B, et al. Enzymelinked immunosorbent assay for quantitation of human antibodies to pneumococcal polysaccharides. Clin Diag Lab Immunol 2003; 10:514-9. 24. Training manual for Enzyme linked immunosorbent assay for the quantitation of Streptococcus pneumoniae serotype specific IgG (Pn PS ELISA). http://www.vaccine.uab.edu/ ELISA%20Protocol.pdf (last accessed 09/10/07). 25. Quataert SA, Kirch CS, Weidl LJ, Phipps DC, Strohmeyer S, Cimino CO, et al. Assignment of weight-based antibody units to a human antipneumococcal standard reference serum, Lot 89-S. Clin Diag Lab Immunol 1995; 2:590-7. 26. Quataert SA, Rittenhouse-Olsen K, Kirch CS, Hu B, Secor S, Strong N, et al. Assignment of weight-based antibody units for 13 serotypes to a human antipneumococcal standard reference serum, Lot 89-S(F). Clin Diag Lab Immunol 2004; 11:1064-9.

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immunization co-ordinators Julie Pieske (Salford PCT) and Lynn Tickle (Trafford PCT) and the study nurses at all participating GP surgeries.

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