Scott Patterson

Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults.

BACKGROUNDnPneumococcal polysaccharide conjugate vaccines prevent pneumococcal disease in infants, but their efficacy against pneumococcal community-acquired pneumonia in adults 65 years of age or older is unknown.nnnMETHODSnIn a randomized, double-blind, placebo-controlled trial involving 84,496 adults 65 years of age or older, we evaluated the efficacy of 13-valent polysaccharide conjugate vaccine (PCV13) in preventing first episodes of vaccine-type strains of pneumococcal community-acquired pneumonia, nonbacteremic and noninvasive pneumococcal community-acquired pneumonia, and invasive pneumococcal disease. Standard laboratory methods and a serotype-specific urinary antigen detection assay were used to identify community-acquired pneumonia and invasive pneumococcal disease.nnnRESULTSnIn the per-protocol analysis of first episodes of infections due to vaccine-type strains, community-acquired pneumonia occurred in 49 persons in the PCV13 group and 90 persons in the placebo group (vaccine efficacy, 45.6%; 95.2% confidence interval [CI], 21.8 to 62.5), nonbacteremic and noninvasive community-acquired pneumonia occurred in 33 persons in the PCV13 group and 60 persons in the placebo group (vaccine efficacy, 45.0%; 95.2% CI, 14.2 to 65.3), and invasive pneumococcal disease occurred in 7 persons in the PCV13 group and 28 persons in the placebo group (vaccine efficacy, 75.0%; 95% CI, 41.4 to 90.8). Efficacy persisted throughout the trial (mean follow-up, 3.97 years). In the modified intention-to-treat analysis, similar efficacy was observed (vaccine efficacy, 37.7%, 41.1%, and 75.8%, respectively), and community-acquired pneumonia occurred in 747 persons in the PCV13 group and 787 persons in placebo group (vaccine efficacy, 5.1%; 95% CI, -5.1 to 14.2). Numbers of serious adverse events and deaths were similar in the two groups, but there were more local reactions in the PCV13 group.nnnCONCLUSIONSnAmong older adults, PCV13 was effective in preventing vaccine-type pneumococcal, bacteremic, and nonbacteremic community-acquired pneumonia and vaccine-type invasive pneumococcal disease but not in preventing community-acquired pneumonia from any cause. (Funded by Pfizer; CAPITA ClinicalTrials.gov number NCT00744263.).

Immunogenicity and Safety of 13-Valent Pneumococcal Conjugate Vaccine in Infants and Toddlers

BACKGROUND: 7-Valent pneumococcal conjugate vaccine (PCV7 [Prevnar, Wyeth Pharmaceuticals Inc, Philadelphia, PA], serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) is effective in preventing vaccine-serotype pneumococcal disease. 13-Valent pneumococcal conjugate vaccine (PCV13) (PCV7 serotypes plus 1, 3, 5, 6A, 7F, and 19A) was designed to provide broader pneumococcal disease coverage. We evaluated the immunogenicity and safety of PCV13 compared with PCV7. METHODS: Infants received PCV13 or PCV7 at ages 2, 4, 6, and 12 to 15 months with routine pediatric vaccinations. Pneumococcal anticapsular polysaccharide-binding immunoglobulin G responses and functional antipneumococcal opsonophagocytic activity were assessed 1 month after dose 3, before the toddler dose, and 1 month after the toddler dose. Safety and tolerability were also assessed. RESULTS: For the 7 common serotypes, PCV13-elicited immunoglobulin G titers were noninferior to those elicited by PCV7, although PCV13 responses were generally somewhat lower. PCV13 also elicited functional opsonophagocytic activity comparable with that elicited by PCV7. For the 6 additional serotypes in PCV13, PCV13 elicited binding and functional antibody levels notably greater than those in PCV7 recipients. After PCV13 immunization, concordance between antipolysaccharide and opsonophagocytic responses was noted for all 13 serotypes. The PCV13 toddler dose resulted in higher immune responses compared with infant-series doses. Safety and tolerability were comparable; reactogenicity was generally mild. CONCLUSIONS: PCV13 will be as effective as PCV7 in the prevention of pneumococcal disease caused by the 7 common serotypes and could provide expanded protection against the 6 additional serotypes. The PCV13 safety profile was comparable to that of PCV7.

Comparative Immunogenicity and Efficacy of 13-Valent and 7-Valent Pneumococcal Conjugate Vaccines in Reducing Nasopharyngeal Colonization: A Randomized Double-Blind Trial

BACKGROUNDnThe 13-valent pneumococcal conjugate vaccine (PCV13) was licensed to replace the 7-valent pneumococcal conjugate vaccine (PCV7) based on serological noninferiority criteria. To date no randomized PCV13 pediatric trial has included clinical endpoints.nnnMETHODSnThis randomized double-blind trial compared the impact of PCV13 versus PCV7 on nasopharyngeal (NP) colonization and immunogenicity. Healthy infants were randomized (1:1) to receive PCV7 or PCV13 at ages 2, 4, 6, and 12 months; NP swabs were collected at 2, 4, 6, 7, 12, 13, 18, and 24 months, and blood was drawn at 7 and 13 months. Rates of NP acquisition and prevalence, and serotype-specific immunoglobulin G (IgG) concentrations were assessed.nnnRESULTSnThe per protocol analysis population included 881 PCV13 and 873 PCV7 recipients. PCV13 significantly reduced NP acquisition of the additional PCV13 serotypes 1, 6A, 7F, and 19A; the cross-reacting serotype 6C; and the common PCV7 serotype 19F. For serotype 3, and the other PCV7 serotypes, there were no significant differences between the vaccine groups. There were too few serotype 5 events to draw inference. The impact on prevalence at predefined time points was similar to that observed with NP acquisition. PCV13 elicited significantly higher IgG responses for PCV13 additional serotypes and serotype 19F, and similar or lower responses for 6/7 PCV7 serotypes.nnnCONCLUSIONSnPCV13 resulted in lower acquisition and prevalence of NP colonization than PCV7 did for 4 additional PCV13 serotypes, and serotypes 6C and 19F. It was comparable with PCV7 for all other common serotypes. These findings predict vaccine effectiveness through both direct and indirect protection.nnnCLINICAL TRIALS REGISTRATIONnNCT00508742.

Efficacy of 13-Valent Pneumococcal Conjugate Vaccine (PCV13) Versus That of 7-Valent PCV (PCV7) Against Nasopharyngeal Colonization of Antibiotic-Nonsusceptible Streptococcus pneumoniae

BACKGROUNDnPediatric respiratory infections caused by antibiotic-nonsusceptible Streptococcus pneumoniae (ANSP) continue to present an important challenge, even after introduction of 7-valent pneumococcal conjugate vaccine (PCV7). This randomized double-blind trial assessed the potential additional impact of PCV13 over PCV7 on reducing ANSP carriage.nnnMETHODSnHealthy infants were randomly assigned to receive PCV13 (n = 932) or PCV7 (n = 934) at ages 2, 4, 6, or 12 months. Eight nasopharyngeal specimens were collected by swabbing between ages 2 and 24 months. S. pneumoniae isolates were serotyped and tested for antimicrobial susceptibility by the disk-diffusion method and the Etest. Nasopharyngeal acquisition and prevalence of ANSP during ages 7-24 months were compared between the 2 vaccine groups.nnnRESULTSnIn general, new acquisition of pneumococci nonsusceptible to penicillin, erythromycin, clindamycin, penicillin plus erythromycin, and multiple drugs (≥3 antibiotics) was significantly lower in the PCV13 group compared with the PCV7 group; the main serotypes contributing to this significant decrease were serotype 19F, present in PCV13 and PCV7, and serotypes 6A and 19A, present in PCV13 only.nnnCONCLUSIONSnPCV13 has a significant added benefit over PCV7 in reducing carriage of ANSP. Because carriage determines transmission, these results suggest that PCV13 will provide protection against ANSP disease that exceeds protection provided by PCV7.nnnCLINICAL TRIALS REGISTRATIONnNCT00508742.

Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine in healthy infants and toddlers given with routine pediatric vaccinations in Canada.

Background: The global distribution of pneumococcal disease and emergence of nonvaccine pneumococcal serotypes prompted the development of a 13-valent pneumococcal conjugate vaccine (PCV13), with broader coverage than 7-valent PCV (PCV7). This study compared compatibility of PCV13 and PCV7 with concurrently administered diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b vaccine, and meningococcal C conjugate vaccine (menC), and assessed the safety and immunogenicity of PCV13. Methods: In this double-blind, randomized trial, children received PCV7 or PCV13 at 2, 4, 6, and 12 months with routine vaccinations. One month following the infant series and toddler dose, the responses to Hib, pertussis, menC, and specific pneumococcal serotypes were measured. Safety and tolerability were assessed daily for 4 days by parents. Results: Subjects received PCV13 (n = 300) or PCV7 (n = 303); immunogenicity assessment was completed in 265 and 268 subjects, respectively. There were no statistically significant differences between the groups in responses to Hib, pertussis, or menC after primary or booster vaccinations. More than 95% of subjects in the PCV13 group produced >0.35 &mgr;g/mL antibody to each pneumococcal serotype 1 month after the third dose, except with serotypes 23F (90%), 3 (80%), and 5 (87%). After the fourth dose, 98% to 100% of subjects achieved serotype-specific antibody concentrations >0.35 &mgr;g/mL, except for serotype 3 (85%). Safety and tolerability did not differ between groups with respect to local or systemic side effects. Conclusions: Responses to routine childhood vaccines did not differ with PCV7 or PCV13 coadministration. Serotype-specific pneumococcal antibody concentrations were protective. The safety profile of PCV13 was favorable.

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in children previously immunized with 7-valent pneumococcal conjugate vaccine.

Background: The 7-valent pneumococcal conjugate vaccine (PCV7) has proven highly effective in preventing diseases caused by Streptococcus pneumoniae; however, in some regions, serotype coverage is limited. A recently licensed 13-valent PCV (PCV13) was developed to provide additional coverage globally. Children previously vaccinated with PCV7 could benefit from supplemental vaccination with PCV13 to provide protection against the 6 additional serotypes in PCV13. This open-label study evaluated the immunogenicity and safety of administering PCV13 to healthy children previously vaccinated with PCV7. Methods: Children between 15 months and 2 years of age (group 1) received 2 doses of PCV13; children between 2 and 5 years (group 2) received 1 dose. Antibodies (immunoglobulin G) against the polysaccharide antigens in PCV13 were measured before vaccination and 1 month after the final dose. Solicited local and systemic adverse events (AEs) were collected for 7 days postvaccination. Unsolicited and serious AEs were collected throughout. Results: A total of 284 subjects (group 1: n = 109; group 2: n = 175) had blood available for testing. Antipneumococcal immunoglobulin G geometric mean fold rises ranged from 2- to 19-fold for the PCV7 serotypes and from approximately 2- to 124-fold for the 6 additional serotypes. Additionally, postvaccination titers in excess of 0.35 &mgr;g/mL, the serologic correlate of immunity against pneumococcus for children, occurred in ≥98% of subjects in both groups for 12 of the 13 serotypes in PCV13. Slightly lower percentage of subjects, 94.5% and 92% of subjects in group 1 and group 2, respectively, had postvaccine titers for serotype 3 exceeding the serologic correlate of immunity. Reactogenicity was typically mild and self-limited, and unsolicited AEs reported were generally consistent with common childhood illnesses. Conclusion: PCV13 was safe and immunogenic when administered to children who had previously received PCV7, and can be used for supplemental vaccination to provide additional protection against the 6 additional serotypes.

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine (PCV13) when given as a toddler dose to children immunized with PCV7 as infants

13-Valent pneumococcal conjugate vaccine (PCV13) administered as a 4-dose series in infants, and as a toddler dose in infants previously vaccinated with PCV7 elicited comparable vaccine serotypes IgG responses to the seven common serotypes. PCV13 elicited functional responses to the six additional serotypes in both schedules after the toddler dose. The toddler dose boosted immune responses. The two regimens had comparable safety profiles. A toddler dose of PCV13 given in children previously vaccinated with PCV7 should be effective in preventing pneumococcal disease caused by common serotypes, providing protection against the additional serotypes, and supporting the transition from PCV7 to PCV13.

Pneumococcal conjugate vaccine herd effects on non-invasive pneumococcal pneumonia in elderly

BACKGROUNDnHerd protection from infant pneumococcal conjugate vaccination is well established for invasive pneumococcal disease (IPD) but not for non-IPD pneumococcal community-acquired pneumonia (PCAP). We assessed the contribution of vaccine-serotypes in non-IPD PCAP in adults 65 years and older in the period 2008-2013.nnnMETHODSnThis is a post hoc analysis of two prospective studies from the Netherlands. Serotype specific urinary antigen detection and routine microbiological testing were used to categorize episodes as IPD or non-IPD PCAP caused by 7-valent pneumococcal conjugate vaccine (PCV7), PCV10-7 (three additional PCV10 serotypes), PCV13-10 (three additional PCV13 serotypes), and non-PCV13 serotypes. Proportions per vaccine-serotype group were assessed per year from June 1st to May 31st. Time trends were compared to national IPD data.nnnRESULTSnOf 270 non-IPD PCAP episodes with known serotype, PCV7 serotypes decreased from 28% in 2008/2009 to 7% in 2012/2013 (p-value for trend <0.001). No change in PCV10-7 (19% overall) and PCV13-10 (29% overall) serotypes was observed. Non-PCV13 serotypes increased from 30% in 2008/2009 to 37% in 2012/2013 (p-value for trend 0.048). Trends corresponded with national IPD data.nnnCONCLUSIONnPCV7 serotypes declined in non-IPD PCAP among elderly between 2008 and 2013, comparable to IPD data. No reduction in the additional PCV10 serotypes could be demonstrated within the first two years after PCV10 introduction.

Immune response to 13-valent pneumococcal conjugate vaccine with a reduced dosing schedule

BACKGROUNDnThe 7-valent pneumococcal conjugate vaccine (PCV7) has demonstrated effectiveness against pneumococcal illnesses when administered as 3 infant doses plus a toddler dose (3+1 schedule) or as an abbreviated schedule of 2 infant doses plus a toddler dose (2+1 schedule). The 13-valent pneumococcal conjugate vaccine (PCV13) is approved and World Health Organization-prequalified for administration in a 2+1 schedule when used as part of routine immunization programs.nnnOBJECTIVEnTo summarize immunologic responses elicited by PCV13 administered in a 2+1 schedule and following 2 doses in a 3+1 schedule.nnnMETHODSnStudies were double-blind, randomized, active-controlled, multicenter studies except the Mexico study (open-label, single-arm). In 2+1 studies, PCV13 was administered at 2, 4, and 12 (UK) or 3, 5, and 11 (Italy) months. In 3+1 studies (Spain and Mexico), assessment was made postdose 2 of the primary series (2, 4, and 6 months). The primary immunogenicity endpoint was the proportion of participants achieving serotype-specific antipolysaccharide immunoglobulin (Ig)G concentrations ≥ 0.35μg/mL (i.e., responders) 1 month postdose 2. Pneumococcal IgG geometric mean concentrations (GMCs), opsonophagocytic activity (OPA), and concomitant vaccine responses were assessed.nnnRESULTSnPCV13 and PCV7 elicited comparable immune responses for the 7 common serotypes after 2 infant doses. The proportion of PCV13 responders postdose 2 was >85% for most of the 7 common and 6 additional serotypes, except common serotypes 6B (27.9-81.4%) and 23F (55.8-77.5%) and additional serotypes 3 (73.8-96.9%) and 6A (79.2-94.4%). Serotypes 6B and 23F elicited lower IgG GMCs postdose 2 compared with other serotypes; all serotypes demonstrated boosting posttoddler dose. All serotypes demonstrated functional activity; >95% of participants achieved OPA levels ≥ 1:8 postdose 2. Concomitant vaccine responses were similar between PCV13 and PCV7 groups.nnnCONCLUSIONnImmune responses elicited by PCV13 following 2 infant doses support transition from PCV7 to PCV13 in countries using a 2+1 schedule.

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine given to Korean children receiving routine pediatric vaccines

Background: The immunogenicity and safety of 13-valent and 7-valent pneumococcal conjugate vaccines (PCV13 and PCV7) were compared when administered with routine vaccines in Korea. Methods: Healthy infants (n = 180) were randomly assigned (1:1) to receive PCV13 or PCV7 at 2, 4, 6 (infant series) and 12 months (toddler dose). Immune responses 1 month after the infant series and toddler dose were measured by enzyme-linked immunosorbent assay and opsonophagocytic activity (OPA) assay. IgG antibody geometric mean concentrations and OPA functional antibody geometric mean titers were calculated. Safety was assessed. Results: After the infant series, for the 7 common serotypes, proportions of responders with IgG concentrations ≥0.35 µg/mL were comparable (≥97.6%) between groups; IgG geometric mean concentrations and OPA geometric mean titers were generally similar, but tended to be lower in the PCV13 group for some serotypes. For the 6 serotypes unique to PCV13, IgG geometric mean concentrations and OPA geometric mean titers were notably higher in the PCV13 group. Importantly, although PCV7 elicited IgG antibodies to PCV13 serotypes 5 and 19A, OPA responses were minimal, whereas serotype 6A elicited both IgG and OPA responses. These observations are consistent with at least some protection by PCV7 against 6A-mediated invasive pneumococcal disease, but no cross-protection for serotypes 5 and 19A. The toddler dose elicited higher IgG and OPA responses than postinfant series responses for most serotypes; however, for serotypes 3 and 14 only OPA responses were increased posttoddler dose. Vaccine safety profiles were similar. Conclusions: PCV13 is safe and immunogenic in Korean children. PCV13 should provide broader protection than PCV7.