Priming of immunological memory by pneumococcal conjugate vaccine in children unresponsive to 23-valent polysaccharide pneumococcal vaccine

Pneumococcal polysaccharide vaccine (PPV) is of limited immunogenicity in infants and immunocompromised patients. Our prospective randomized controlled trial investigated whether priming with pneumococcal conjugate vaccine (PCV) induced specific immunological memory in previously nonresponders to PPV. Of a total of 33 children (2 to 18 years) with polysaccharide-specific immunodeficiency (PSI), group A (n = 16) received two doses of 7-valent PCV in a 4- to 6-week interval, and a booster dose of 23-valent PPV after one year. Group B (n = 17) received two doses of PPV in a 1-year interval exclusively. Specific antibody concentrations for serotypes 4, 5, 6B, 9V, 14, 18C, 19F, and 23F were determined (enzyme-linked immunosorbent assay) before and at 7 and 28 days after administration of the PPV booster and compared to an opsonophagocytosis assay. Of group A, 64 to 100% had antibody concentrations of > or = 1 microg/ml on day 28 after the booster versus 25 to 94% of group B. Group A had significantly higher antibody concentrations for all PCV-containing serotypes already on day 7, indicating early memory response. Antibody concentrations were in accordance with functional opsonic activity, although opsonic titers varied among individuals. Pneumococcal vaccination was well tolerated. The incidence of airway infections was reduced after priming with PCV (10/year for group A versus 15/year for group B). Following a PPV booster, even patients primarily not responding to PPV showed a rapid and more pronounced memory response after priming with PCV.     

Serum Opsonic Activity in Infants with Sickle-Cell Disease Immunized with Pneumococcal Polysaccharide Protein Conjugate Vaccine

Pneumococcal infections are an important cause of morbidity and mortality in children with sickle-cell disease (SCD). Pneumococcal conjugate vaccines (PCVs) are immunogenic in healthy infants <2 years of age but have not been evaluated in young children with SCD. Infants with SCD were immunized with a 7-valent PCV (Wyeth-Lederle Vaccines & Pediatrics) at 2, 4, and 6 months of age. A booster dose of 23-valent pneumococcal polysaccharide vaccine (PPV; Pnu-Immune) was administered at 24 months of age. Antipneumococcal type 6B and 14 serum opsonic activity was measured to assess the biologic function of the antibody. Following the administration of three doses of PCV, opsonic activity against serotype 6B increased from 4.8% at 2 months to 33.5% at 7 months, with a subsequent decline to 8.1% at 12 months and 7.5% at 24 months and with an increase to 30.7% at 25 months after administration of a booster dose of PPV. Similar trends were seen with serotype 14 (opsonic activities were 9.4% at 2 months, 24.9% at 7 months, 16.5% at 12 months, and 12.6% at 24 months, and the opsonic activity was 27.3% 1 month after the administration of PPV). Serum opsonic activity correlated with antibody levels for both serotypes. PCV induces serum opsonic activity in infants with SCD. Antipneumococcal serum opsonic activity correlates with antibody levels.     

Serum opsonic activity in infants with sickle-cell disease immunized with pneumococcal polysaccharide protein conjugate vaccine. The Pneumococcal Conjugate Vaccine Study Group

Pneumococcal infections are an important cause of morbidity and mortality in children with sickle-cell disease (SCD). Pneumococcal conjugate vaccines (PCVs) are immunogenic in healthy infants <2 years of age but have not been evaluated in young children with SCD. Infants with SCD were immunized with a 7-valent PCV (Wyeth-Lederle Vaccines & Pediatrics) at 2, 4, and 6 months of age. A booster dose of 23-valent pneumococcal polysaccharide vaccine (PPV; Pnu-Immune) was administered at 24 months of age. Antipneumococcal type 6B and 14 serum opsonic activity was measured to assess the biologic function of the antibody. Following the administration of three doses of PCV, opsonic activity against serotype 6B increased from 4. 8% at 2 months to 33.5% at 7 months, with a subsequent decline to 8.1% at 12 months and 7.5% at 24 months and with an increase to 30.7% at 25 months after administration of a booster dose of PPV. Similar trends were seen with serotype 14 (opsonic activities were 9.4% at 2 months, 24.9% at 7 months, 16.5% at 12 months, and 12.6% at 24 months, and the opsonic activity was 27.3% 1 month after the administration of PPV). Serum opsonic activity correlated with antibody levels for both serotypes. PCV induces serum opsonic activity in infants with SCD. Antipneumococcal serum opsonic activity correlates with antibody levels.     

Impact of IgM Antibodies on Cross-Protection against Pneumococcal Serogroups 6 and 19 after Immunization with 7-Valent Pneumococcal Conjugate Vaccine in Children

Although it is well known that pneumococcal conjugate vaccines provide cross-protection against some vaccine-related serotypes, these mechanisms are still unclear. This study was performed to investigate the role of cross-protective IgM antibodies against vaccine-related serotypes 6A, 6C, and 19A induced in children aged 12-23 months after immunization with 7-valent pneumococcal conjugate vaccine (PCV7). We obtained serum samples from 18 Korean children aged 12-23 months after a PCV7 booster immunization. The serum IgG and IgM concentrations of serotypes 6B and 19F were measured by enzyme-linked immunosorbent assay (ELISA) in serum. The opsonic indices (OIs) against vaccine serotypes 6B and 19F and vaccine-related serotypes 6A, 6C, and 19A were determined by an opsonophagocytic killing assay (OPA) in IgM-depleted and control serum. Both IgG and IgM antibodies in ELISA and opsonic indices in OPA against serotypes 6B and 19F were demonstrated in the immune serum. IgM depletion decreased the OIs against vaccine serotypes 6B (geometric means of OIs (GMIs) of 3,009 vs. 1,396, 38% reduction) and 19F (1,117 vs. 750, 36% reduction). In addition, IgM depletion markedly decreased the OIs against vaccine-related serotypes 6A (GMIs of 961 vs. 329, 70% reduction), 6C (432 vs. 185, 72% reduction), and 19A (301 vs. 166, 58% reduction). The booster immunization PCV7 induced protective antibodies in the form of both IgG and IgM isotypes. IgM antibodies contributed to eliciting cross-protection against vaccine-related serotypes as well as against vaccine serotypes.     

Serum IgM Antibodies Contribute to High Levels of Opsonophagocytic Activities in Toddlers Immunized with a Single Dose of the 9-Valent Pneumococcal Conjugate Vaccine

In immunogenicity trials of pneumococcal conjugate vaccines (PCVs), only IgG antibody concentrations to pneumococcal capsular polysaccharides (PPSs) are usually determined, along with the opsonophagocytic activity (OPA) of antipneumococcal antibodies. We aimed to determine the role of both IgG and IgM in OPA in toddlers receiving one dose of 9-valent PCV (PCV9). The IgG and IgM antibody concentrations to PPSs of serotypes 6A, 9V, 14, 19F, and 23F were measured by enzyme immunoassay in sera from toddlers (ages 18 to 35 months) 1 month after a single PCV9 dose. The OPA for the same serotypes was measured by multiplexed opsonophagocytosis assay (MOPA). Further, IgG and IgM concentrations and MOPA were measured to PPS of serotypes 6A, 14, and 19F in sera collected 12 months after vaccination. The detected MOPA titers were high in comparison to the IgG concentrations 1 month after immunization. The IgM concentrations were higher than IgG concentrations for serotypes 6A and 14 (P < 0.001) and as high as IgG for serotypes 9V, 19F, and 23F. Correlation of the IgM antibody concentrations with MOPA (r = 0.35 to 0.65) was stronger compared to that of the IgG antibodies (r = 0.07 to 0.41). The depletion of IgG antibodies in three sets of pooled sera only slightly decreased the OPA activity against serotype 14. At 12 months after immunization, 50 to 100% of serum samples still showed detectable MOPA activity against serotypes 6A, 14, and 19F. Our results suggest that IgM contributes to OPA 1 month after a single PCV9 vaccination in toddlers and that functionally active IgM and IgG antibodies persist for at least a year.     

Responses to a Conjugate Pneumococcal Vaccine in Preterm Infants Immunized at 2, 3, and 4 Months of Age

Preterm infants are at an increased risk of invasive pneumococcal disease infection and, additionally, have a diminished response to Haemophilus influenzae type b (Hib) conjugate vaccines. There are little data examining the response of preterm infants to a seven-valent pneumococcal conjugate vaccine (PCV7). We examined the responses of preterm infants immunized at 2, 3, and 4 months of age to PCV7. A total of 133 preterm and 54 term infants were immunized with PCV7 and the Neisseria meningitidis group C (MCC), diphtheria, tetanus, pertussis, polio, and Hib vaccines. Pneumococcal serotype-specific IgG was measured by enzyme-linked immunosorbent assay (ELISA) pre- and postimmunization and at 12 months or following a booster of PCV7. Term and preterm responses were compared using linear and logistic regression analyses. Term infants had higher preimmunization geometric mean concentrations (GMCs) for all serotypes. Preterm infants had lower postimmunization GMCs for serotype 23F. Gestational age affected postimmunization GMCs for serotypes 4, 6B, and 23F. Preterm infants were as likely to have levels of ≥0.35 μg/ml as term infants for all serotypes except 23F. The proportions of infants with titers of ≥0.35 μg/ml for all 7 serotypes were comparable between groups. A total of 28 of 29 term infants who received a booster had levels of ≥0.35 μg/ml for all serotypes. One infant had undetectable levels for serotype 6B. Of the 32 preterm infants boosted, 9 had levels of <0.35 μg/ml for 1 serotype, and 1 had levels of <0.35 μg/ml for 2 serotypes. In nonboosted infants, GMCs for all serotypes except 6B had fallen by 12 months of age. These results support the need for a booster dose in the second year of life.The primary immunization schedule of the United Kingdom (UK) is continually evolving. While a vaccine may be demonstrated to be immunogenic in one population when administered according to one schedule, apparently, minor changes to that schedule can have an adverse effect on vaccine response. Preterm infants are at an increased risk of many of the infections we immunize against, for example, pertussis (9). Almost half the children who develop pertussis are under 4 months of age (9). Preterm infants are currently recommended to be vaccinated at the same chronological age as term infants rather than at the same age postconception.The UK primary immunization schedule in place between September 2004 and September 2006 consisted of a combined vaccine against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (diphtheria-tetanus-acellular pertussis [DTaP]/inactivated polio vaccine [IPV]/Haemophilus influenzae type b [Hib]) (Pediacel; Aventis Pasteur MSD) and a conjugate vaccine against Neisseria meningitidis group C (MCC) given at 2, 3, and 4 months of age, with no booster in the second year of life (5). In 2002, the chief medical officer advised that children under 2 years of age at risk of invasive pneumococcal disease (IPD) should receive three doses of the seven-valent pneumococcal conjugate vaccine (PCV7; pneumococcal capsular polysaccharide conjugated to the carrier protein CRM₁₉₇), with their primary immunizations followed by a booster in the second year of life (4). Infants were considered to be at increased risk of IPD if they had a chronic respiratory, cardiac, renal, or liver disease or an immunodeficiency. Many preterm infants are included in these categories.A postal questionnaire survey of 73 UK neonatal intensive care units highlighted the fact that many preterm infants who are at an increased risk of IPD were not being adequately immunized because of the lack of evidence that these infants are protected by the conjugate pneumococcal vaccine (11). This survey indicated that many infants who were immunized were not receiving the recommended booster dose in the second year of life. In the UK immunization schedule at this time, none of the other vaccines in the primary schedule were boosted.The immunogenicity of PCV7 when administered to preterm infants according to the then-current UK immunization schedule was examined and compared to the response of a cohort of term infants that was previously described. As many preterm infants were not routinely receiving their 12 -month booster, we also measured antibody levels at 12 months of age.     

Concentration and High Avidity of Pneumococcal Antibodies Persist at Least 4 Years after Immunization with Pneumococcal Conjugate Vaccine in Infancy

To provide more extensive evidence of long-term effects of vaccination on immunity against Streptococcus pneumoniae, a follow-up study of the Finnish Otitis Media (FinOM) Vaccine Trial was conducted. One of the objectives was to assess the persistence and avidity of pneumococcal antibodies 4 years after pneumococcal vaccination given in infancy. Children with complete follow-up in the FinOM trial up to 24 months of age were invited to a single visit in their fifth year of life. A blood sample was taken from all children for determination of anticapsular antibody concentrations to vaccine serotypes and avidity of antibodies to three serotypes. Children had been vaccinated at 2, 4, 6, and 12 months of age with 7-valent pneumococcal capsular polysaccharide, CRM197 conjugate vaccine (PCV7), or a control vaccine. Serum IgG antibody concentrations to vaccine serotypes remained significantly higher in children who had received PCV7 than in control children for 4 years after the fourth PCV7 dose. Concentrations of antibodies to frequently carried serotypes (6B and 19F) declined less than those of antibodies to a rarely carried serotype (4), suggesting that natural boosting contributed to antibody persistence. Furthermore, antibody avidity was significantly higher in PCV7 than control vaccine recipients. Four doses of PCV7 given in infancy elicit long-lasting antibody responses with high avidity. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00378417","term_id":"NCT00378417"}}NCT00378417.)     

Effect of previous vaccination with pneumococcal conjugate vaccine on pneumococcal polysaccharide vaccine antibody responses

During the past 10 years, pneumococcal conjugate vaccine (PCV) has become part of the standard childhood vaccination programme. This may impact upon the diagnosis of polysaccharide antibody deficiency by measurement of anti‐polysaccharide immunoglobulin (Ig)G after immunization with unconjugated pneumococcal polysaccharide vaccine (PPV). Indeed, contrary to PPV, PCV induces a T‐dependent, more pronounced memory response. The antibody response to PPV was studied retrospectively in patients referred for suspected humoral immunodeficiency. The study population was divided into four subgroups based on age (2–5 years versus ≥ 10 years) and time tested (1998–2005 versus 2010–12). Only 2–5‐year‐old children tested in 2010–12 had been vaccinated with PCV prior to PPV. The PCV primed group showed higher antibody responses for PCV–PPV shared serotypes 4 and 18C than the unprimed groups. To a lesser extent, this was also found for non‐PCV serotype 9N, but not for non‐PCV serotypes 19A and 8. Furthermore, PCV‐priming elicited a higher IgG2 response. In conclusion, previous PCV vaccination affects antibody response to PPV for shared serotypes, but can also influence antibody response to some non‐PCV serotypes (9N). With increasing number of serotypes included in PCV, the diagnostic assessment for polysaccharide antibody deficiency requires careful selection of serotypes that are not influenced by prior PCV (e.g. serotype 8). Further research is needed to identify more serotypes that are not influenced.     

Immune response to the 7-valent pneumococcal conjugate vaccine in 30 asplenic children

The aim of the study was to determine the concentration of pneumococcal antibodies after a dose of 7-valent pneumococcal conjugate vaccine (PCV7) in 30 asplenic children between 4 months and 19 years of age. Fifteen children had received pneumococcal polysaccharide vaccine (PPV) approximately 5 years prior to vaccination with PCV7. The antibody concentrations against serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F were measured by ELISA before and after the PCV7 vaccination. Before vaccination with PCV7, the antibody concentrations were similar in children who had or had not received PPV previously. A dose of PCV7 stimulated a good immune response in asplenic patients. Prior immunization with PPV did not affect the antibody concentration after the vaccination with PCV7. In conclusion, asplenic children vaccinated with PPV may need revaccination with PPV earlier than the recommended 3–5 years after the first dose. PCV7 induces a satisfactory immune response in asplenic patients and should be considered as an alternative vaccine in that patient group.     

Antibody Response to a Seven-Valent Pneumococcal Conjugated Vaccine in Patients with Ataxia-Telangiectasia

Immunodeficiency is a characteristic feature of ataxia-telangiectasia (A-T). Humoral immunodeficiency generally consists of hypogammaglobulinemia and impaired antibody response to bacterial and viral antigens. We previously observed defective antibody response to 23-valent pneumococcal polysaccharide vaccine (PPV) in 96% of 29 patients with A-T. In this study, we investigated the antibody response to a seven-valent pneumococcal conjugate vaccine, PCV7, in 14 patients with A-T. IgG antibody levels to four pneumococcal serotypes, 6B, 14, 19F, 23F, which were included in PCV7, were measured by ELISA in pre- and postimmunization serum samples. Antibody titers against each individual Streptococcus pneumoniae serotype was considered to be positive when serotype specific pneumococcal antibody titer was higher than 10% (>10 U/mL) of the reference plasma pool level. However, when the fold increase (FI) in postimmunization antibody titer was less than two, the subject was determined to be unresponsive to the given serotype. The values were compared with the results obtained in age- and ethnic-matched children after one dose of PPV. Only two patients produced antibodies to one serotype each; one to serotype 19 with a fold increase of <2, and the other to serotype 23F with a fold increase of 5.7 based on the above criteria, although the differences between pre- and postvaccine antibody titers for serotypes 14, 19, and 23 appeared to be statistically significant. In conclusion, A-T patients failed to respond to one dose of PCV7 vaccine. Two or more doses of conjugated vaccine may be required to recruit the help of T lymphocytes in A-T patients.     

Pneumococcal conjugate vaccine followed by pneumococcal polysaccharide vaccine; immunogenicity in patients with ataxia-telangiectasia

The immunodeficiency in Ataxia-telangiectasia (A-T) is characterised by low T and B cell counts, low levels of IgE, IgA and/or IgG2, and especially low levels of pneumococcal antibodies. The 23-valent pneumococcal polysaccharide vaccine (PPV23) has previously been shown not to be effective in A-T, but these patients are capable of making protective antibodies to other vaccines such as diphtheria and tetanus toxin, promising effect of the seven-valent pneumococcal conjugated vaccine (PCV7). Nine A-T patients and 25 age and sex matched controls were vaccinated with both PCV7 and PPV23, and three A-T patients were vaccinated with PCV7 only. In the A-T patients, no significant increase in pneumococcal antibody levels were observed after the single PCV7, while the subsequent PPV23 vaccination resulted in a significant increase in antibody levels to the PPV23 mix, as well as to serotype 4, 14, 19F and to the geometric mean of serotype 4, 6B, 14, 18C, 19F, 23F which increased from median 0.2 (range 0.1-0.5) microg/mL to 0.6 (0.2-1.5) microg/mL (P= 0.014). Compared to the patients' baseline levels, the vaccinations induced a 1.5- to 7-fold increase in antibodies to the six different serotypes tested. The increases in pneumococcal antibody titres were lower than those observed in the controls (9- to 34-fold increase). The results are valuable in planning the care of A-T patients, using PCV7 to trigger and PPV23 to booster the immune response and possibly prevent severe pneumococcal disease.     

Specificity of the Antibody Response to the Pneumococcal Polysaccharide and Conjugate Vaccines in Human Immunodeficiency Virus-Infected Adults

Nonspecific antibodies, which are thought to be nonprotective, have been shown to contribute a substantial proportion of the measured concentration in the standardized immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) for pneumococcal polysaccharide capsular antibodies. The presence of such antibodies in human immunodeficiency virus (HIV)-infected persons has not been evaluated. The amount of nonspecific antibodies is proportional to the reduction in IgG antibody concentration that occurs with serum absorption with the heterologous polysaccharide 22F. We measured the amount of nonspecific antibodies before and after vaccination with the pneumococcal conjugate vaccine (PCV; n = 33) or the pneumococcal polysaccharide vaccine (PPV; n = 34) in HIV-infected adults with CD4 counts of ≥200 cells/mm³. Blood was drawn before and 2 months after vaccination. For prevaccination sera, we found a substantial amount of nonspecific antibodies for serotypes 4, 6B, 9V, and 23F (23 to 47% of measured IgG concentration), but not for serotype 14. There tended to be proportionately less nonspecific antibodies in postvaccine sera than prevaccine sera for PCV, but not for PPV. Subjects with a low HIV viral load (≤400 copies/ml) had proportionately more nonspecific antibodies than those with higher viral load before and after both vaccines. After 22F absorption, the geometric mean concentrations of antibodies were significantly higher post-PCV than post-PPV for the high viral load group for all five serotypes, but for no serotypes in the low viral load group. These findings confirm that absorption with a heterologous pneumococcal polysaccharide (e.g., 22F) is necessary to remove nonspecific antibodies in a standardized IgG ELISA for pneumococcal capsular antibodies in HIV-infected adults.     

Serotype-specific immune unresponsiveness to pneumococcal conjugate vaccine following invasive pneumococcal disease

Following the introduction of the pneumococcal 7-valent conjugate vaccine (PCV7) into the routine infant immunization schedule in England, Wales, and Northern Ireland, pneumococcal serotype-specific immunoglobulin G (IgG) antibody testing was offered as a clinical service to all children within the program with invasive pneumococcal disease (IPD) to confirm an adequate antibody response to PCV7. As of March 2008, serum samples taken within 14 to 90 days of vaccination had been submitted from 107 children who had received one or more doses in the second year of life. Sera were assayed by a multiplexed microsphere assay incorporating both cell wall polysaccharide and serotype 22F adsorption. A protective serotype-specific antibody level was defined as a concentration of ≥0.35 μg/ml. Eight children failed to develop a response to their infecting serotype (6B [n = 4], 18C [n = 2], 4 [n = 1], and 14 [n = 1]), despite receiving at least three doses of PCV7 in the second year of life or two doses in the second and two or three in the first year of life. A further two children were nonresponsive to a serotype (6B) different than that causing disease. None of the 10 children had a clinical risk factor for IPD. Two had marginally low levels of total serum IgG but mounted adequate responses to the other six PCV serotypes. This serotype-specific unresponsiveness may reflect immune paralysis due to large pneumococcal polysaccharide antigen loads and/or a potential genetic basis for nonresponse to individual pneumococcal serotypes.     

Assessment of Antibody Response Elicited by a 7-valent Pneumococcal Conjugate Vaccine in Pediatric Human Immunodeficiency Virus Infection

We investigated antibody responses against pneumococci of serotypes 6B, 14, and 23F in 56 children and adolescents with perinatal human immunodeficiency virus (HIV) infection who were vaccinated with 7-valent pneumococcal conjugate vaccine. Overall immune responses differed greatly between serotypes. Correlation coefficients between immunoglobulin G (IgG) measured by enzyme-linked immunosorbent assay (ELISA) and functional antibodies measured by a flow cytometry opsonophagocytosis assay (OPA) varied with serotype and time points studied. After 3 months of administering a second PCV7 dose we got the highest correlation (with significant r values of 0.754, 0.414, and 0.593 for serotypes 6B, 14, and 23F, respectively) but no significant increase in IgG concentration and OPA titers compared to the first dose. We defined a responder to a serotype included in the vaccine with two criteria: frequency of at least twofold OPA and ELISA increases for each serotype and frequency of conversion from negative to positive OPA levels. Responders varied from 43.9% to 46.3%, 28.5% to 50.0%, and 38.0% to 50.0% for serotypes 6B, 14, and 23F, respectively, depending on the response criterion. The present research highlights the importance of demonstrating vaccine immunogenicity with suitable immunological endpoints in immunocompromised patients and also the need to define how much antibody is required for protection from different serotypes, since immunogenicity differed significantly between serotypes.     

Post Hoc Analysis of a Randomized Double-Blind Trial of the Correlation of Functional and Binding Antibody Responses Elicited by 13-Valent and 7-Valent Pneumococcal Conjugate Vaccines and Association with Nasopharyngeal Colonization

In a randomized double-blind trial in healthy Israeli infants in Israel who received the 13-valent or 7-valent pneumococcal conjugate vaccine (PCV13 or PCV7, respectively) at 2, 4, 6, and 12 months, PCV13 significantly reduced nasopharyngeal (NP) colonization of serotypes 1, 6A, 7F, 19A, cross-reacting 6C, and the common PCV7 serotype 19F, from ages 7 to 24 months. No differences were observed between the vaccine groups for serotype 3 or for the remaining common PCV7 serotypes. For serotype 5, too few events were observed to draw an inference. Generally consistent with these findings, PCV13 elicited significantly higher enzyme-linked immunosorbent assay (ELISA) IgG-binding antibody responses than did PCV7 for the additional PCV13 serotypes 1, 3, 5, 6A, 7F, 19A, and for the common serotype 19F, with similar or lower responses for the remaining common serotypes. To further assess immunogenicity and colonization, we conducted a post hoc analysis of PCV13 functional antibody responses measured by opsonophagocytic activity (OPA) assays in a randomly selected subset of subjects. The pattern of functional antibody OPA responses elicited by PCV13 relative to PCV7 was similar to that of the ELISA anticapsular IgG-binding antibody responses described above. In addition, the OPA responses generally correlated positively with IgG responses for all 13 serotypes among the PCV13 recipients and for all 7 common serotypes and the additional serotype 6A but not for 19A or the other serotypes unique to PCV13 among the PCV7 recipients. This post hoc analysis supports an association between serum OPA functional and IgG-binding antibody levels, allowing for a transfer of inferred associations between IgG responses and NP colonization to OPA responses.     

Older adults have a low capacity to opsonize pneumococci due to low IgM antibody response to pneumococcal vaccinations

Since the 23-valent pneumococcal polysaccharide vaccine (PPV23) is less effective for older adults than for young adults, it is important to investigate the immunologic basis for the reduced efficacy of PPV23 among older adults. We determined the effectiveness of PPV23 among young (n = 55) and older (n = 44) adults by measuring the serum IgG, IgM, and IgA concentrations and opsonic capacities against serotypes 14, 18C, and 23F. While young and older adults showed no difference in levels of IgG antibodies against pneumococcal polysaccharide (PPS), older adults had lower IgA and IgM antibody levels than young adults for all three serotypes. In both age groups, anti-PPS IgA or IgM antibody levels were much lower than anti-PPS IgG antibody levels. Young adults showed higher opsonic capacities than older adults for serotypes 14 and 23F. In order to determine the effects of anti-PPS IgA or IgM antibodies on the functional difference between young and older adults, anti-PPS IgA or IgM antibodies were removed from immune sera by affinity chromatography. The difference in opsonic capacity between young and older adults disappeared for serotypes 14 and 23F (but not for serotype 18C) when IgM antibody was removed. However, there was no significant difference between the two age groups when IgA antibody was removed. In conclusion, even though anti-PPS IgG antibody levels are high compared with anti-PPS IgM antibody levels, the low levels of anti-PPS IgM antibody alone can explain the functional difference observed between young and older adults immunized with PPV23 with regard to some pneumococcal serotypes.     

Randomized Controlled Study of the Safety and Immunogenicity of Pneumococcal Vaccine Formulations Containing PhtD and Detoxified Pneumolysin with Alum or Adjuvant System AS02V in Elderly Adults

Six vaccine formulations containing AS02_V or alum (aluminum phosphate [AlPO₄]) adjuvant with pneumococcal proteins, pneumococcal histidine triad D (PhtD), and/or detoxified pneumolysin (dPly), either as a polysaccharide carrier in an 8-valent pneumococcal conjugate vaccine (8PCV) or as free (unconjugated) proteins, were evaluated in adults -65 to 85 years of age. In this phase I observer-blind study, 167 healthy subjects were randomized to receive two doses (days 0 and 60) of 10 or 30 μg PhtD-dPly plus AS02_V or alum, 8PCV plus AS02_V or alum, or one dose (day 0) of 23-valent polysaccharide pneumococcal vaccine (23PPV) as a control (placebo on day 60). The safety, reactogenicity, and antibody-specific responses to these vaccines were evaluated. No vaccine-related serious adverse events were reported. The incidences of solicited local and specific general (fatigue and myalgia) symptoms tended to be higher in the AS02_V groups than in other groups. Anti-PhtD and anti-Ply antibody responses were observed in all groups except the control group. One month post-dose 2, the anti-PhtD and anti-Ply antibody geometric mean concentrations tended to be higher with AS02_V than with alum, higher with a dose of 30 μg than with 10 μg for PhtD-dPly and higher with 30-μg PhtD-dPly formulations than with conjugated PhtD and dPly (8PCV) formulations. Functional antibody responses, measured by an opsonophagocytic activity assay, tended to be higher with 8PCV than with 23PPV. In conclusion, vaccine formulations containing free or conjugated PhtD and dPly had acceptable reactogenicity and safety profiles in elderly adults. Immune responses were enhanced with an AS02_V-adjuvanted formulation containing free 30-μg PhtD-dPly compared to those with alum adjuvant and conjugated proteins. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00756067","term_id":"NCT00756067"}}NCT00756067.)     

The epidemiology of invasive Streptococcus pneumoniae infections in onco-haematology and haematopoietic stem cell transplant patients in France. Are the serotypes covered by the available anti-pneumococcal vaccines?

The pneumococcal antigens contained in the polysaccharide (PPV23) and conjugate (7-valent, PCV7; 13-valent, PCV13) vaccines have been chosen since they represent the serotypes that more frequently cause invasive pneumococcal disease. Whether these vaccines cover the serotypes most frequently isolated in haematology patients is unclear. The serotype distribution among Streptococcus pneumoniae in 25 consecutive pneumococcal infections that occurred over the last 3 years in two French haematology departments was investigated. The pneumococcal vaccines PCV7, PCV13 and PPV23 were found to cover 76, 84 and 92%, respectively, of the serotypes found.     

Pneumococcal serotypes causing pneumonia with pleural effusion in pediatric patients

To determine the prevalence of serotypes of Streptococcus pneumoniae responsible for pneumonia with pleural effusion, we determined the capsular polysaccharide (PS) type directly on 49 pleural fluid specimens collected from pediatric patients during 2007 to 2009 with laboratory-confirmed pneumococcal pneumonia by using monoclonal antibodies and a multiplex, bead array immunoassay. Because the fluids had to be heated to remove nonspecific reactivity before being tested in the immunoassay and type 19A PS is heat labile, the pleural fluid samples were also tested for serotype 19A capsule gene locus by PCR. Use of the multiplex immunoassay combined with type-specific 19A PCR allowed for serotype determination on 40 of 49 pleural fluids. Pneumococcal pneumonia with pleural effusion was associated with a limited number of serotypes, with types 1, 3, 7F/A, and 19A accounting for 75% of the typeable cases. The concentration of capsular PS in the pleural fluids was often greater than 1 μg/ml and sufficient to inhibit the opsonic capacity of sera from individuals who had received the 23-valent pneumococcal PS vaccine. Based on the serotypes observed before and after introduction of the 7-valent pneumococcal conjugate vaccine, the recently licensed 13-valent pneumococcal conjugate vaccine may reduce the incidence of pneumonia with pleural effusions.