Christine Juergens

Safety, tolerability, and immunologic noninferiority of a 13-valent pneumococcal conjugate vaccine compared to a 7-valent pneumococcal conjugate vaccine given with routine pediatric vaccinations in Germany

13-valent pneumococcal conjugate vaccine (PCV13) was compared to PCV7 in infants administered 4 doses. For the 7 common serotypes, PCV13- and PCV7-elicited responses showed comparable percent responders achieving 0.35mug/mL IgG threshold (exception 6B, 77.5% versus 87.1%, respectively) and OPA titers of 1:8; IgGs were lower than PCV7 but functional responses were generally comparable. For the 6 additional serotypes, PCV13-elicited IgG and functional OPA responses were notably greater than PCV7. The toddler dose boosted immune responses. Vaccines were comparable with regard to safety. PCV13 should be as effective as PCV7 in preventing pneumococcal disease caused by the common serotypes and may provide protection against the additional serotypes.

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

BACKGROUND The 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. METHODS This 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. RESULTS The 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. CONCLUSIONS PCV13 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. CLINICAL TRIALS REGISTRATION NCT00508742.

A randomized, double-blind trial to evaluate immunogenicity and safety of 13-valent pneumococcal conjugate vaccine given concomitantly with trivalent influenza vaccine in adults aged ≥65 years

This randomized, double-blind study evaluated concomitant administration of 13-valent pneumococcal conjugate vaccine (PCV13) and trivalent inactivated influenza vaccine (TIV) in adults aged ≥65 years who were naïve to 23-valent pneumococcal polysaccharide vaccine. Patients (N=1160) were randomized 1:1 to receive PCV13+TIV followed by placebo, or Placebo+TIV followed by PCV13 at 0 and 1 months, with blood draws at 0, 1, and 2 months. Slightly lower pneumococcal serotype-specific anticapsular polysaccharide immunoglobulin G geometric mean concentrations were observed with PCV13+TIV relative to PCV13. Concomitant PCV13+TIV demonstrates acceptable immunogenicity and safety compared with either agent given alone.

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

BACKGROUND Pediatric 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. METHODS Healthy 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. RESULTS In 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. CONCLUSIONS PCV13 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. CLINICAL TRIALS REGISTRATION NCT00508742.

Immunogenicity, Safety, and Tolerability of 13-Valent Pneumococcal Conjugate Vaccine Followed by 23-Valent Pneumococcal Polysaccharide Vaccine in Recipients of Allogeneic Hematopoietic Stem Cell Transplant Aged ≥2 Years: An Open-Label Study

Severe Streptococcus pneumoniae infections are frequent complications after hematopoietic stem cell transplant (HSCT). A 3-dose regimen of 13-valent pneumococcal conjugate vaccine, starting 3–6 months after HSCT and followed by a booster dose, may be required for adequate protection.

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

ABSTRACT 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.

Immunogenicity of a combination vaccine containing diphtheria toxoid, tetanus toxoid, three-component acellular pertussis, hepatitis B, inactivated polio virus, and Haemophilus influenzae type b when given concomitantly with 13-valent pneumococcal conjugate vaccine.

Two randomized trials of 13-valent pneumococcal conjugate vaccine (PCV13) relative to PCV7 evaluated the immune responses of coadministered antigens comprising Infanrix(®) hexa/Infanrix(®)-IPV+Hib (diphtheria, tetanus, 3-component acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b). After the 3-dose infant series, immunogenic noninferiority was demonstrated for all concomitantly administered antigens between the PCV13 and PCV7 groups. All antigens elicited good booster responses after the toddler dose except pertussis toxoid; however, 99.6% subjects achieved pertussis toxoid protective antibody level ≥5EU/mL in both groups. These results support the concomitant administration of PCV13 and Infanrix hexa/Infanrix-IPV+Hib as part of routine immunization schedules.

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine given with routine pediatric vaccines in Taiwan.

UNLABELLED Immunogenicity and safety of 13-valent and 7-valent pneumococcal conjugate vaccines (PCV13; PCV7) were compared in Taiwanese children. In this double-blind, multicenter study, healthy children were randomly assigned to receive PCV13 (n=84) or PCV7 (n=84) at 2, 4, 6 and 15 months with routine pediatric vaccines. For the 7 PCV13/PCV7 common serotypes, serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) were high 1 month postinfant series, with ≥95.0% in both groups achieving IgG levels ≥0.35 μg/mL, with a trend to lower IgG GMCs for PCV13 compared with PCV7 (PCV13:PCV7 GMC ratios 0.59-0.91). For the 6 additional serotypes unique to PCV13, GMCs were notably higher after PCV13 than PCV7 (PCV13:PCV7 GMC ratios 1.50-202.58). Immune responses generally increased posttoddler dose. Safety was similar between groups. PCV13 was safe and immunogenic in this Taiwanese population. PCV13 should offer broader protection than PCV7 against pneumococcal disease. CLINICAL TRIALS REGISTRATION NUMBER NCT00688870.

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.

Immunogenicity and safety of the 13-valent pneumococcal conjugate vaccine compared to the 23-valent pneumococcal polysaccharide vaccine in elderly Japanese adults

Streptococcus pneumoniae is a major cause of severe disease worldwide, particularly in the elderly population. Due to increasing life expectancy in Japan and elsewhere, an effective vaccine which offers the possibility of prolonged protection is required. Protein conjugated pneumococcal vaccines, which have the ability to boost immunity (immunologic memory) on natural exposure or revaccination, may meet these requirements. An unconjugated 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been available for decades; however data on protection against pneumonia are inconsistent. For the first time, a randomized, modified double-blind trial comparing the 13-valent pneumococcal conjugate vaccine (PCV13) with PPSV23 was conducted in PPSV23-naive adults ≥65 years of age in Japan. This study showed that statistically significantly greater functional antibody responses as measured by opsonophagocytic assays 1 month after vaccination were elicited in the PCV13 group (n = 366) compared with the PPSV23 group (n = 367) for 9 of the 12 serotypes in common with both vaccines and for serotype 6A, unique to PCV13. Local reactions collected within 14 days of vaccination were more frequent in the PCV13 (57.5%, 211/367) than PPSV23 (44.9%, 166/370) group, although severity was generally mild to moderate; systemic and adverse events were similar across groups. There were no treatment-related serious adverse events. Consistent with global studies comparing PCV13 with PPSV23, PCV13 use in Japanese subjects was safe and well-tolerated and elicited greater functional immune responses than PPSV23 for the majority of PCV13-serotypes. PCV13 has the potential to protect against pneumococcal disease in Japanese elderly adults.