Explore the vast range of titles available.

Background. Life-threatening Streptococcus pneumoniae infections often occur after hematopoietic stem cell transplant (HSCT); vaccination is important for prevention. Methods. In an open-label study, patients (n = 251) 3–6 months after allogeneic HSCT received 3 doses of 13-valent pneumococcal conjugate vaccine (PCV13) at 1-month intervals, a fourth dose 6 months later, and 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) 1 month later. Immunogenicity at prespecified time points and vaccine safety were assessed. Results. In the evaluable immunogenicity population (N = 216; mean age, 37.8 years), geometric mean fold rises (GMFRs) of immunoglobulin G geometric mean concentrations from baseline to postdose 3 showed significant increases in antibody levels across all PCV13 serotypes (GMFR range, 2.99–23.85; 95% confidence interval lower limit, >1); there were significant declines over the next 6 months, significant increases from predose 4 to postdose 4 (GMFR range, 3.00–6.97), and little change after PPSV23 (GMFR range, 0.86–1.12). Local and systemic reactions were more frequent after dose 4. Six patients experienced serious adverse events possibly related to PCV13 (facial diplegia, injection-site erythema and pyrexia, autoimmune hemolytic anemia, and suspected lack of vaccine efficacy after dose 3 leading to pneumococcal infection), PCV13 and PPSV23 (Guillain-Barré syndrome), or PPSV23 (cellulitis). There were 14 deaths, none related to study vaccines. Conclusions. A 3-dose PCV13 regimen followed by a booster dose may be required to protect against pneumococcal disease in HSCT recipients. Dose 4 was associated with increased local and systemic reactions, but the overall safety profile of a 4-dose regimen was considered acceptable. Clinical Trials Registration. NCT00980655.

Background: 2-Phenoxyethanol (2-PE) has been safely included as a preservative and/or stabilizer in more than thirty vaccine formulations at amounts ranging from 0.5 to 5 mg per dose; however, the nonclinical safety data publicly available for intramuscular (IM) or subcutaneous (SC) administration are relatively limited. Here, in addition to the available clinical and nonclinical data for 2-PE, we summarize the nonclinical safety data of experimental 13vPnC (Prev(e)nar 13) formulations with or without 2-PE. Methods: Two repeat-dose toxicity studies in rabbits, one for a 2-PE-free formulation of 13vPnC and the other for an MDV formulation of 13vPnC with 5 mg/dose 2-PE, were conducted as part of an overall nonclinical safety package for vaccine development. The studies were designed and conducted in compliance with the relevant guidelines and regulations. Results: In repeat-dose toxicity studies in rabbits, five IM administrations of a preservative-free 13vPnC single-dose syringe formulation or a 13vPnC multi-dose vial (MDV) formulation containing 5 mg 2-PE/0.5 mL dose were well tolerated with no systemic toxicity. Robust serotype-specific IgG antibody responses to each of the 13 pneumococcal serotypes were also confirmed for both formulations. The observations for the 13vPnC MDV including local inflammatory reaction, increases in fibrinogen, and increased splenic germinal centers were nonadverse, reversible, and consistent with findings previously observed for the IM administration of vaccines, including the 2-PE-free 13vPnC single-dose syringe formulation. Conclusions: Together with the other available nonclinical and clinical data of 2-PE and vaccine formulations containing 2-PE and following the 3Rs principle, our risk-assessment-based recommendation is that no additional nonclinical safety studies are needed when evaluating a 2-PE-containing presentation of a previously well-characterized vaccine product if the amount of 2-PE is ≤10 mg/dose.

Group B streptococcus (GBS) is a major cause of invasive disease in young infants. Infants born to women with sufficient pre-existing anti-GBS capsular IgG antibodies are at reduced risk of GBS disease, making maternal immunisation a potential strategy for prevention. We aimed to assess the safety and immunogenicity of a novel hexavalent (serotypes Ia, Ib, II, III, IV, and V) GBS conjugate vaccine (GBS6). This phase 1/2, placebo-controlled, observer-blinded, dose-escalation trial, was done at four clinical research centres in the USA (Kentucky, Georgia, and two sites in Utah). Healthy, non-pregnant adults aged 18–49 years were randomly assigned using an interactive, web-based response technology system. Within each dose group (low, medium, or high), participants in sentinel cohorts were randomly assigned 2:2:1 and expanded cohort participants were randomly assigned 4:4:1 to receive GBS6 with aluminium phosphate (AlPO4), GBS6 without AlPO4, or placebo (saline control). One 0·5 mL dose of either saline placebo or 5 μg capsular polysaccharide per serotype in the low-dose group, 10 μg capsular polysaccharide per serotype in the medium-dose group, or 20 μg capsular polysaccharide per serotype in the high-dose group was administered by intramuscular injection into the deltoid muscle on day 1. The primary outcome was safety up to 6 months after vaccination, including the proportion of sentinel cohort participants with clinical laboratory abnormalities at 1 week, the proportion of all participants reporting solicited local reactions, systemic events, or use of antipyretic or pain medication within 14 days, adverse events up to 1 month, and medically attended or serious adverse events up to 6 months. The secondary outcome was GBS immunogenicity (serotype-specific IgG geometric mean concentrations at 1 month). This study is registered with ClinicalTrials.gov, NCT03170609. Between June 5, 2017, and June 25, 2018, 365 participants were randomly assigned and 364 (52 in each dose group) were vaccinated and included in the safety analysis. Unsolicited adverse events were reported by 15 (29%) participants in the 5 μg with AlPO4 group, 13 (25%) in the 5 μg without AlPO4 group, 22 (42%) in the 10 μg with AlPO4 group, 12 (23%) in the 10 μg without AlPO4 group, 25 (48%) in the 20 μg with AlPO4 group, 21 (40%) in the 20 μg without AlPO4 group, and 20 (38%) in the placebo group. The most common unsolicited adverse events were in the system organ class of infections and infestations in any dose or formulation of GBS6 (ranging from six [12%] in the 10 μg without AlPO4 group to 15 [29%] in the 20 μg with AlPO4 group and placebo group). Three participants reported at least one serious adverse event during the study, one each in the 5 μg GBS6 with AlPO4 group (diabetic ketoacidosis, two events; resolved), 10 μg GBS6 with AlPO4 group (died by suicide), and 20 μg GBS6 with AlPO4 group (metrorrhagia; resolved). None of these serious adverse events were considered related to the vaccine. 11 of the 365 participants were excluded from the evaluable immunogenicity population, including one participant who did not receive the vaccine, and ten who at 1 month after vaccination were withdrawn for various reasons. GBS serotype-specific IgG geometric mean concentrations increased by 1 week after vaccination for all GBS6 groups, peaked at 2 weeks, stabilised by 1 month, and declined gradually but remained higher than placebo at 6 months. GBS6 was well tolerated in healthy adults and elicited robust immune responses for all dose levels and formulations that persisted 6 months after vaccination. This study supports further evaluation of GBS6 in pregnant women. Pfizer.

The pneumococcal enzyme-linked immunosorbent assay (ELISA) measures IgG antibodies in human serum, and it is an important assay that supports licensure of pneumococcal vaccines. The immune correlate of protection, 0.35 µg/ml of IgG antibodies, was determined by the ELISA method. Pfizer has developed a new Luminex-based assay platform to replace the ELISA. These papers describe the important work of (i) validating the Luminex-based assay and (ii) bridging the immune correlate of protection (0.35 µg/ml IgG) to equivalent values reported by the Luminex platform. This article describes the results of a study designed to bridge the World Health Organization (WHO) pneumococcal enzyme-linked immunosorbent assay (ELISA) platform to the validated Luminex-based 13-plex direct immunoassay (dLIA) platform developed by Pfizer, Inc. Both assay platforms quantify serotype-specific serum IgG antibodies (in micrograms per milliliter) against an international reference standard serum. The primary goal of this study was to determine if the dLIA is a suitable replacement for the ELISA to support clinical vaccine studies that include the evaluation of immune responses to serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. Serum samples were selected from four pivotal 13-valent pneumococcal conjugate vaccine (13vPnC; Prevnar 13) clinical trials on the basis of their serotype-specific IgG concentrations by ELISA. In these studies, subjects were immunized either with 13vPnC or with 7-valent pneumococcal conjugate vaccine (7vPnC; Prevnar). There were 1,528 of 1,574 selected samples with sufficient remaining volume for reanalysis in the dLIA. A comparison of assay results from the dLIA and ELISA platforms showed clear and robust linear quantitative relationships across all 13 serotypes. In addition, lower IgG antibody concentrations in preimmunization samples were measured in the dLIA, thus allowing better differentiation between preimmunization and low-titer postimmunization samples. Overall, the results showed that the established population-level protective threshold IgG concentration, 0.35 µg/ml of serotype-specific serum IgG antibodies, is appropriate for use for data generated using the dLIA platform developed by Pfizer, Inc., for 10 serotypes: serotypes 1, 3, 4, 6A, 7F, 9V, 14, 18C, 19F, and 23F. On the basis of the extensive bridging analyses, however, the use of dLIA cutoff values of 0.23, 0.10, and 0.12 µg/ml is recommended for serotypes 5, 6B, and 19A, respectively. This adjustment will ensure that the consistency of the established population-level protective threshold IgG concentration is maintained when switching from the ELISA to the dLIA platform. The results of this bridging study demonstrate that the 13-plex dLIA platform is a suitable replacement for the WHO reference ELISA platform. IMPORTANCE The pneumococcal enzyme-linked immunosorbent assay (ELISA) measures IgG antibodies in human serum, and it is an important assay that supports licensure of pneumococcal vaccines. The immune correlate of protection, 0.35 µg/ml of IgG antibodies, was determined by the ELISA method. Pfizer has developed a new Luminex-based assay platform to replace the ELISA. These papers describe the important work of (i) validating the Luminex-based assay and (ii) bridging the immune correlate of protection (0.35 µg/ml IgG) to equivalent values reported by the Luminex platform.

This phase 3, randomized, partially double-blind study investigated the safety, tolerability, and immunogenicity of 20-valent pneumococcal conjugate vaccine (PCV20) in healthy toddlers ≥12–<24 months of age who had previously received 2 infant doses of 13-valent PCV (PCV13). Participants were randomized to receive 1 or 2 doses of PCV20 (the second dose was administered 56–70 days after the first dose), or 1 dose of PCV13. The primary pneumococcal immunogenicity endpoint was the percentages of participants with predefined serotype-specific immunoglobulin G (IgG) concentrations (≥0.35 μg/mL) for the 7 additional serotypes 1 month after the last vaccination. Percentages of participants with predefined IgG concentrations for the 13 matched serotypes, IgG geometric mean concentrations, and opsonophagocytic activity (OPA) geometric mean titers were also evaluated for all 20 vaccine serotypes. Safety endpoints included local reactions, systemic events, adverse events, and serious adverse events. Overall, 356 participants were randomized (2-dose PCV20, n = 121; 1-dose PCV20, n = 118; PCV13, n = 117). One month after 1 PCV20 dose, ≥75.9 % of participants had IgG concentrations ≥0.35 μg/mL for all 7 additional serotypes, except serotype 12F (54.6 %). After 2 PCV20 doses, the percentage of participants with IgG concentrations ≥0.35 μg/mL for the 7 additional serotypes was ≥91.2 %. PCV20 elicited IgG and OPA responses for all 20 serotypes including serotype 12F. IgG distributions were well differentiated and substantially higher in PCV20 groups than the PCV13 group for the 7 additional serotypes, and generally similar between all groups for the 13 matched serotypes. In conclusion, a single toddler dose of PCV20 after 2 infant PCV13 doses elicited immune responses expected to help provide protection against the 7 additional serotypes and to provide similar protection against the 13 matched serotypes as PCV13. These data support a transition from PCV13 to PCV20 at the toddler dose. The safety and tolerability profile of PCV20 was similar to PCV13. Trial registration:Clinicaltrials.gov, NCT05408429. •PCV20 safety, tolerability, and immunogenicity in healthy toddlers was investigated.•Participants had previously received 2 infant doses of PCV13.•PCV20 single toddler dose expected to help protect against 7 additional serotypes.•PCV20 expected to provide similar protection as PCV13 against 13 matched serotypes.•The safety/tolerability profile of PCV20 toddler doses was similar to PCV13.

•PCV13 use was studied in Japanese subjects aged 6–64 years at increased risk for pneumococcal disease.•PCV13 was well tolerated with an acceptable safety profile; no serious adverse events occurred.•Robust immune responses were observed 1 month after PCV13 vaccination.•Opsonophagocytic activity and IgG geometric mean fold rises assessed immune responses.•These data support PCV13 use in Japanese subjects aged 6–64 years at increased risk for pneumococcal disease. This open-label, single-arm, phase 3 study evaluated safety and immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13) in pneumococcal vaccine-naive Japanese individuals aged 6–64 years at increased risk of pneumococcal disease (PD). Participants received 1 PCV13 dose. Reactogenicity events were recorded for 7 days (individuals aged 6- to 17-year-old) or 14 days (individuals aged 18 to 64 years old) postvaccination. Adverse events (AEs) were collected for 1 month postvaccination. Opsonophagocytic activity (OPA) and anticapsular immunoglobulin G (IgG) geometric mean concentrations (GMCs) were measured for vaccine serotypes before and 1 month postvaccination. Post hoc analyses compared immunogenicity in participants categorized as at-risk (immunocompetent but having chronic medical conditions associated with increased PD risk) or high-risk (immunocompromised due to diseases/conditions and/or medications). 206 participants aged 6- to 17-year-old (n = 53) and 18 to 64 years old (n = 153) completed the study. Reactogenicity events were generally mild to moderate in severity. AEs were reported in 16% (33/206) of participants; 1.0% (2/206) were severe. Six AEs were vaccine-related; most were associated with local reactions. No serious AEs occurred. Circulating antibody levels for all 13 serotypes increased postvaccination. OPA geometric mean fold rises (GMFRs) from prevaccination to 1 month postvaccination were 5.5–61.7; lower limits of the 2-sided, 95% CI were > 1 for all serotypes. IgG GMFRs were consistent with OPA analyses. In post hoc analyses, 55.8% (115/206) and 44.2% (91/206) of participants were categorized as at risk and at high risk of PD, respectively; OPA GMFRs from prevaccination to 1 month postvaccination were 3.9–635.1, with lower limits of the 2-sided 95% CIs > 1 for all 13 serotypes across these risk groups; IgG GMFRs were consistent with OPA analyses. PCV13 was well tolerated and immunogenic in Japanese individuals aged 6–64 years considered at increased risk of PD. Results were broadly comparable with past PCV13 studies in other Japanese and non-Japanese populations. Registration number: NCT03571607; JapicCTI-184024.

Prophylactic antipyretic use during pediatric vaccination is common. This study assessed whether paracetamol or ibuprofen prophylaxis interfere with immune responses to the 13-valent pneumococcal conjugate vaccine (PCV13) given concomitantly with the combined DTaP/HBV/IPV/Hib vaccine. Subjects received prophylactic paracetamol or ibuprofen at 0, 6–8, and 12–16 h after vaccination, or 6–8 and 12–16 h after vaccination at 2, 3, 4, and 12months of age. At 5 and 13months, immune responses were evaluated versus responses in controls who received no prophylaxis. After the infant series, paracetamol recipients had lower levels of circulating serotype-specific pneumococcal anticapsular immunoglobulin G than controls, reaching significance (P<0.0125) for 5 serotypes (serotypes 3, 4, 5, 6B, and 23F) when paracetamol was started at vaccination. Opsonophagocytic activity assay (OPA) results were similar between groups. Ibuprofen did not affect pneumococcal responses, but significantly (P<0.0125) reduced antibody responses to pertussis filamentous hemagglutinin and tetanus antigens after the infant series when started at vaccination. No differences were observed for any group after the toddler dose. Prophylactic antipyretics affect immune responses to vaccines; these effects vary depending on the vaccine, antipyretic agent, and time of administration. In infants, paracetamol may interfere with immune responses to pneumococcal antigens, and ibuprofen may reduce responses to pertussis and tetanus antigens. The use of antipyretics for fever prophylaxis during infant vaccination merits careful consideration. ClinicalTrials.gov identifier: NCT01392378https://clinicaltrials.gov/ct2/show/NCT01392378?term=NCT01392378&rank=1

The pneumococcal enzyme-linked immunosorbent assay (ELISA) measures IgG antibodies in human serum, and it is an important assay that supports licensure of pneumococcal vaccines. The immune correlate of protection, 0.35 µg/ml of IgG antibodies, was determined by the ELISA method. Pfizer has developed a new Luminex-based assay platform to replace the ELISA. These papers describe the important work of (i) validating the Luminex-based assay and (ii) bridging the immune correlate of protection (0.35 µg/ml IgG) to equivalent values reported by the Luminex platform. A Luminex-based direct immunoassay (dLIA) platform has been developed to replace the standardized pneumococcal enzyme-linked immunosorbent assay platform. The multiplex dLIA simultaneously measures the concentration of serum immunoglobulin G (IgG) antibodies specific for pneumococcal capsular polysaccharide (PnPS) serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. The assay uses poly- l -lysine (PLL)-conjugated PnPS, chemically coupled to spectrally distinct Luminex microspheres. Assay validation experiments were performed using residual human serum samples obtained from 13-valent pneumococcal conjugate vaccine (13vPnC) clinical studies. Assay results are expressed as IgG antibody concentrations in micrograms per milliliter using the international reference serum, 007sp. The lower limit of quantitation (LLOQ) for all serotypes covered in the 13-plex dLIA fell within the range of 0.002 to 0.038 µg/ml serum IgG. The difference between the lower limit and upper limit of the assay range was >500-fold for all serotypes, and assay variability was <20% relative standard deviation (RSD) for all serotypes. IgG antibody measurements were shown to be serotype-specific (some cross-reactivity was observed only between the structurally related serotypes 6A and 6B as well as 19A and 19F), and no interference was observed between the serotypes when the assay was performed in the 13-plex format compared to the singleplex assays. The 13-plex dLIA platform developed by Pfizer Inc. generates up to 143 test results in a single 96-well plate and is a suitable replacement of the enzyme-linked immunosorbent assay (ELISA) platform for evaluating vaccine clinical trials. IMPORTANCE The pneumococcal enzyme-linked immunosorbent assay (ELISA) measures IgG antibodies in human serum, and it is an important assay that supports licensure of pneumococcal vaccines. The immune correlate of protection, 0.35 µg/ml of IgG antibodies, was determined by the ELISA method. Pfizer has developed a new Luminex-based assay platform to replace the ELISA. These papers describe the important work of (i) validating the Luminex-based assay and (ii) bridging the immune correlate of protection (0.35 µg/ml IgG) to equivalent values reported by the Luminex platform.

•Some children may not receive pneumococcal conjugate vaccine (PCV) as infants.•PCV13 was evaluated in pneumococcal vaccine-naïve children aged 7 months to 5 years.•Age-specific “catch-up” vaccination schedules were evaluated.•The proportion of immunological responders ranged from 88% to 100% for all 13 serotypes.•PCV13 was generally well-tolerated; trend for greater tenderness in older subjects. Streptococcus pneumoniae infections are a major cause of morbidity and mortality in children <5 years old worldwide. To increase serotype coverage globally, a 13-valent pneumococcal conjugate vaccine (PCV13) has been developed and approved in many countries worldwide. Assess the safety and immunogenicity of PCV13 in healthy older infants and children naïve to previous pneumococcal vaccination. This was a phase 3, open-label, multicenter study conducted in Polish children (N=354) who were vaccinated according to 3 age-appropriate catch-up schedules: Group 1 (aged 7 to <12 months) received two PCV13 doses with a booster at 12–16 months of age; Group 2 (aged 12 to <24 months) received two vaccine doses only; and Group 3 (aged 24 to <72 months) received a single dose of PCV13. Statistical analyses were descriptive. The proportion of immunological “responders” achieving serotype-specific antipneumococcal polysaccharide concentrations ≥0.35μg/mL, 1-month after the last dose of vaccine, was determined for each vaccine serotype. In addition, antipolysaccharide immunoglobulin (Ig) G geometric mean concentrations (GMCs) were calculated. Safety assessments included systemic and local reactions, and adverse events. The proportion of immunological responders was ≥88% across groups for all serotypes. Antipolysaccharide IgG GMCs were generally similar across groups. Each schedule elicited immune response levels against all 13 serotypes comparable to or greater than levels previously reported in infants after a 3-dose series. The 3 catch-up schedules had similar tolerability and safety profiles; a trend was present towards greater local tenderness with increasing age and subsequent dose administration. Immunological responses and safety results support the use of PCV13 for catch-up schedules in older infants and children naïve to pneumococcal vaccination.

•In a previous study, Chinese infants were vaccinated with PCV7, PCV7+DTaP, or DTaP.•Antibody persistence was assessed at a single time point 3years after last dose.•After 3years, serum IgG had declined but remained higher than before vaccination.•PCV7 serospecific antibodies were generally similar after PCV7 and PCV7+DTaP.•Protective immunity was not influenced by the concomitant administration of DTaP. In a previous study, Chinese infants were vaccinated with 7-valent pneumococcal conjugate vaccine (PCV7) ⩾7days before routine diphtheria, tetanus, and acellular pertussis vaccine (DTaP); PCV7 administered concomitantly with DTaP (PCV7+DTaP); or DTaP alone. This study examined antibody persistence at a single time point 3years after the last vaccination. Children who participated in the prior PCV7 study were eligible to participate. A single blood sample was drawn at enrollment. Immunoglobulin G (IgG) geometric mean concentrations (GMCs) specific to the PCV7 serotypes and percentages of subjects with IgG ⩾0.35μg/mL were compared for subjects receiving PCV7 versus PCV7+DTaP (concomitant) and for PCV7 or PCV7+DTaP (concomitant) versus DTaP alone. IgG concentrations at 3years after the last vaccination were also compared with those after the infant series and toddler dose. Three years after the last vaccination with PCV7 or PCV7+DTaP (concomitant), IgG GMCs for most PCV7 serotypes were lower than after the infant series or toddler dose but remained above prevaccination concentrations. IgG GMC were similar between the PCV7 and PCV7+DTaP (concomitant) groups for 5 out of 7 serotypes but serotypes 4 and 19F were significantly lower in the PCV7+DTaP (concomitant) recipients. Three years after the last vaccination, IgG GMCs were significantly higher for 6 of 7 PCV7 serotypes among those receiving PCV7 or PCV7+DTaP (concomitant) compared with recipients of DTaP alone. Among subjects receiving DTaP alone, serotype-specific antibody concentrations were significantly higher for all serotypes 3years after the last vaccination compared with after the infant series. Three years after PCV7 vaccination, serotype-specific antibodies were lower than after the primary infant series but higher than prevaccination levels and higher among subjects who received PCV7 compared with those who did not. The immune response was comparable in children who received PCV7 with and without concomitant DTaP. Clinical Trial Registration: NCT01298544