PCV13 Group Research Articles

Antibody Responses to Routine Pediatric Vaccines Administered With 13-valent Pneumococcal Conjugate Vaccine

A 13-valent pneumococcal conjugate vaccine (PCV13) has been licensed in >100 countries to broaden coverage against pneumococcal disease. We assessed whether PCV13 interferes with immune responses to concomitantly administered routine pediatric vaccines. Healthy US infants were randomly assigned in 2 studies to receive PCV13 or 7-valent PCV (PCV7) at age 2, 4 and 6 months concomitantly with diphtheria, tetanus, acellular pertussis, inactivated polio virus, hepatitis B and Haemophilus influenzae type b, and at age 12-15 months with measles, mumps, rubella, varicella and hepatitus A. Antibodies to pertussis antigens, diphtheria, tetanus toxoid, poliovirus types 1-3, Haemophilus influenzae type b polyribosylribitol phosphate capsular polysaccharide and polyribosylribitol phosphate capsular polysaccharide were measured 1 month after the infant series; measles, mumps, rubella, varicella and polyribosylribitol phosphate capsular polysaccharide were determined 1 month after the toddler dose. Both the percentages of responders (subjects reaching a prespecified antibody concentration) and immunoglobulin G antibody geometric mean concentrations/titers were calculated for each concomitant vaccine antigen. Not all assays were performed on all subjects. Data were available from 153 to 239 infants and 163-230 toddlers in the PCV13 group and 173-240 infants and 167-214 toddlers in the PCV7 group. One month after both infant series and the toddler dose, noninferiority criteria were met for all antigens with respect to percentage of responders in both PCV7 and PCV13 groups. Immunoglobulin G antibody geometric mean concentration/titer ratios (PCV13/PCV7) were 0.91-1.33 and 0.83-1.03 at 1 month after the infant series and toddler dose, respectively, and met predetermined noninferiority criteria. Immune responses to routine pediatric vaccines concomitantly administered with PCV13 were noninferior to responses achieved when administered with PCV7.

Immunogenicity and Safety of 13-Valent Pneumococcal Conjugate Vaccine Given to Korean Children Receiving Routine Pediatric Vaccines

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. 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. 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. PCV13 is safe and immunogenic in Korean children. PCV13 should provide broader protection than PCV7.

Safety and Immunogenicity of Neonatal Pneumococcal Conjugate Vaccination in Papua New Guinean Children: A Randomised Controlled Trial

BackgroundApproximately 826,000 children, mostly young infants, die annually from invasive pneumococcal disease. A 6-10-14-week schedule of pneumococcal conjugate vaccine (PCV) is efficacious but neonatal PCV may provide earlier protection and better coverage. We conducted an open randomized controlled trial in Papua New Guinea to compare safety, immunogenicity and priming for memory of 7-valent PCV (PCV7) given in a 0-1-2-month (neonatal) schedule with that of the routine 1-2-3-month (infant) schedule.MethodsWe randomized 318 infants at birth to receive PCV7 in the neonatal or infant schedule or no PCV7. All infants received 23-valent pneumococcal polysaccharide vaccine (PPV) at age 9 months. Serotype-specific serum IgG for PCV7 (VT) serotypes and non-VT serotypes 2, 5 and 7F were measured at birth and 2, 3, 4, 9, 10 and 18 months of age. Primary outcomes were geometric mean concentrations (GMCs) and proportions with concentration ≥0.35 µg/ml of VT serotype-specific pneumococcal IgG at age 2 months and one month post-PPV.ResultsWe enrolled 101, 105 and 106 infants, respectively, into neonatal, infant and control groups. Despite high background levels of maternally derived antibody, both PCV7 groups had higher GMCs than controls at age 2 months for serotypes 4 (p<0.001) and 9V (p<0.05) and at age 3 months for all VTs except 6B. GMCs for serotypes 4, 9V, 18C and 19F were significantly higher (p<0.001) at age 2 months in the neonatal (one month post-dose2 PCV7) than in the infant group (one month post-dose1 PCV7). PPV induced significantly higher VT antibody responses in PCV7-primed than unprimed infants, with neonatal and infant groups equivalent. High VT and non-VT antibody concentrations generally persisted to age 18 months.ConclusionsPCV7 is well-tolerated and immunogenic in PNG neonates and young infants and induces immunologic memory to PPV booster at age 9 months with antibody levels maintained to age 18 months.Trial RegistrationClinicalTrials.gov NCT00219401NCT00219401

A phase 3, randomized, double-blind trial comparing the safety and immunogenicity of the 7-valent and 13-valent pneumococcal conjugate vaccines, given with routine pediatric vaccinations, in healthy infants in Brazil

BackgroundThe inclusion of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs in many countries has significantly decreased the incidence of disease caused by Streptococcus pneumoniae. However, a substantial portion of disease remained and, in some areas, there has been an increase in disease produced by serotypes not included in PCV7. A 13-valent pneumococcal conjugate vaccine (PCV13) was studied in healthy Brazilian infants in a phase 3, double-blind, randomized study. MethodsInfants were randomized to receive either PCV7 or PCV13 at 2, 4, 6, (doses 1–3), and 12 (toddler dose) months of age, along with routine pediatric vaccinations (diphtheria, tetanus, whole-cell pertussis, and Haemophilus influenzae type b vaccine). Pneumococcal anticapsular polysaccharide-binding immunoglobulin G (IgG) responses and antibody responses to pertussis antigens were measured 1 month after both dose 3 of the infant series and the toddler dose. Safety and tolerability were also assessed. ResultsThe proportion of subjects achieving a serotype-specific IgG concentration ≥0.35μg/mL measured 1 month after the infant series was comparable in the PCV13 (≥94.2%) and PCV7 (≥93.0%) groups for the 7 serotypes common to both vaccines. The percentage of responders for the 6 additional serotypes ranged from 87.1 to 100% for PCV13. The percentage of responders varied across the pertussis antigens studied, but was not different in PCV13 and PCV7 recipients. Overall, the safety profile of PCV13 was comparable with that of PCV7. ConclusionsPCV13 was comparable to PCV7 in safety and tolerability, elicited comparable immune responses to the common serotypes, and did not interfere with immune responses to concomitantly administered whole-cell pertussis vaccine. The robust immunogenicity exhibited by PCV13 for the additional serotypes suggests that it could provide significant protection against these serotypes.

Randomized, Controlled Trial of a 13-Valent Pneumococcal Conjugate Vaccine Administered Concomitantly with an Influenza Vaccine in Healthy Adults

A randomized, double-blind, phase 3 trial evaluated the immunogenicity, safety, and tolerability of a 13-valent pneumococcal conjugate vaccine (PCV13) coadministered with trivalent inactivated influenza vaccine (TIV) in pneumococcal vaccine-naive adults. Participants ages 50 to 59 years (n = 1,116) received TIV with PCV13 (group 1) or placebo (group 2) (1:1 randomization); 1 month later, group 1 received placebo and group 2 received PCV13. A hemagglutination inhibition (HAI) assay for TIV and a standardized enzyme-linked immunosorbent assay for pneumococcal serotype-specific immunoglobulin G (IgG) were performed and opsonophagocytic activity (OPA) titers (assessed post hoc) were measured at baseline and 1 and 2 months postvaccination. The rises in HAI assay geometric mean titer (GMT) and percentage of participants in groups 1 and 2 with ≥ 4-fold increases in HAI responses (A/H1N1, 84.0% and 81.2%, respectively; A/H3N2, 71.1% and 69.5%, respectively; and B, 60.6% and 60.3%, respectively) were similar. In group 1, all serotypes met the predefined IgG geometric mean concentration (GMC) ratio noninferiority criterion relative to group 2, but GMCs were lower in group 1 than group 2. When comparing group 1 with group 2, 5 serotypes did not meet the OPA GMT ratio noninferiority criterion, and OPA GMTs were significantly lower for 10 serotypes. PCV13 injection site reactions were similar and mostly mild in both groups. Systemic events were more frequent in group 1 (86.2%) than group 2 (76.7%; P < 0.001); no vaccine-related serious adverse events occurred. Coadministration of PCV13 and TIV was well tolerated but associated with lower PCV13 antibody responses and is of unknown clinical significance. Given the positive immunologic attributes of PCV13, concomitant administration with TIV should be dictated by clinical circumstances.

Safety and Immunogenicity of a 13-valent Pneumococcal Conjugate Vaccine in Healthy Infants and Toddlers Given With Routine Pediatric Vaccinations in Canada

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. 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. 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 μg/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 μg/mL, except for serotype 3 (85%). Safety and tolerability did not differ between groups with respect to local or systemic side effects. 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 MMRV and PCV-7 Administered Concomitantly in Healthy Children

We assessed the immunogenicity and safety of a combination measles, mump, rubella, and varicella vaccine (MMRV) (ProQuad [Merck & Co, Inc, West Point, PA]) administered to healthy children concomitantly with a pneumococcal 7-valent conjugate vaccine (PCV-7) (Prevnar [Pfizer, Philadelphia, PA]). Healthy 12- to 15-month-old children who lacked vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster but had written documentation of receipt of a 3-dose primary series of PCV-7 were randomly assigned in a 2:1:1 ratio to receive either the MMRV and PCV-7 (group 1), PCV-7 followed 6 weeks later by MMRV (group 2), or MMRV followed 6 weeks later by PCV-7 (group 3). The primary safety analysis was 56 days (28 days after each visit). Immunogenicity was evaluated 6 weeks after each vaccination. A total of 1027 children were enrolled (group 1: 510; group 2: 258; group 3: 259). For all 3 groups, the antibody response rate was ≥96.8% for measles, mumps, and rubella, ≥88.0% for varicella-zoster virus, and ≥98.3% for all of the 7 Streptococcus pneumoniae serotypes. The immune responses to all antigens present in MMRV and PCV-7 were similar whether administered concomitantly or sequentially. The incidence of local and systemic adverse experiences (AEs) was comparable between group 1 and groups 2 and 3 combined. No vaccine-related serious AEs were reported. Concomitant administration of the MMRV and PCV-7 is highly immunogenic and generally well tolerated. Similar immune responses between the groups support concomitant administration of the MMRV and PCV-7 to healthy children 12 to 15 months of age.

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 ≥5 EU/mL in both groups. These results support the concomitant administration of PCV13 and Infanrix hexa/Infanrix-IPV + Hib as part of routine immunization schedules.

Randomised, controlled trial of concomitant pneumococcal and meningococcal conjugate vaccines

A randomised, open-label study compared the immunogenicity and safety of 7-valent pneumococcal conjugate vaccine (PCV7) and meningococcal C conjugate vaccine (MnCC vaccine) administered concomitantly and individually. Infants received PCV7 + MnCC vaccine ( n = 265), PCV7 alone ( n = 268) or MnCC vaccine alone ( n = 178). PCV7 was administered at 2, 3½, 6 and 12 months, and MnCC vaccine at 2, 6 and 12 months. For the 7 pneumococcal serotypes tested (4, 6B, 9V, 14, 18C, 19F and 23F), proportions of subjects with pneumococcal serotype-specific immunoglobulin G (IgG) antibody concentrations ≥0.35 μg/mL post-infant series were non-inferior for the PCV7 + MnCC vaccine (91.5–99.6%) and PCV7 (89.0–99.6%) groups. Proportions of subjects achieving serogroup C meningococcal serum bactericidal assay titres ≥1:8 post-infant series were non-inferior for the PCV7 + MnCC vaccine (99.6%) and MnCC vaccine groups (98.8%). Pneumococcal IgG antibody levels were similar in the PCV7 + MnCC vaccine and PCV7 groups at each time point. Post-infant and post-toddler meningococcus C serum bactericidal assay titres and IgG levels were similar in the PCV7 + MnCC vaccine and MnCC groups, although pre-toddler, the levels were lower in the PCV7 + MnCC vaccine group than the MnCC vaccine group. Immune response rates to diphtheria antigen approached 100% for all vaccine groups. Local reactions were mostly similar among the treatment groups. The MnCC vaccine group had lower rates of some systemic events than the PCV7 + MnCC vaccine group. Immune responses to PCV7 + MnCC vaccine were non-inferior compared with those seen with each vaccine administered alone.

Safety and Immunogenicity of a 13-Valent Pneumococcal Conjugate Vaccine

Invasive pneumococcal disease rates have declined since immunization with 7-valent pneumococcal conjugate vaccine (PCV7) (Prevenar/Prevnar [Wyeth Pharmaceuticals, Philadelphia, PA]) became routine. Certain nonvaccine Streptococcus pneumoniae serotypes (1, 3, 5, 6A, 7F, and 19A) still cause significant morbidity and mortality. The safety and immunogenicity of PCV7 were compared with those of 13-valent PCV (PCV13), which contains saccharides from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F conjugated to CRM(197). Infants were randomly assigned to receive PCV13 or PCV7 at ages 2, 4, and 6 months with other vaccines. Post-third-dose antibodies to each pneumococcal polysaccharide were measured by immunoglobulin G enzyme-linked immunosorbent assay. Antibacterial functional antibodies were measured by opsonophagocytic assay (OPA). Subjects received PCV13 (n = 122) or PCV7 (n = 127). All PCV13 serotypes were immunogenic, with 88% to 98% of infants achieving antibody concentrations of > or =0.35 microg/mL to shared PCV7 serotypes. For the 6 additional serotypes, 97% to 100% of PCV13-vaccinated infants achieved antibody concentrations of > or =0.35 microg/mL. Geometric mean antibody concentration for PCV13 recipients ranged from 1.32 microg/mL (serotype 23F) to 4.26 microg/mL (serotype 14). The ratio of OPA geometric mean titers for the 7 shared serotypes (PCV13:PCV7) ranged from 0.6 to 1.4, suggesting no clinically meaningful differences. For PCV13-only serotypes, OPA geometric mean titers were significantly higher in the PCV13 group than in the PCV7 group. Local reactions and systemic events were similar between groups. PCV13 was well tolerated and immunogenic, with most infants developing antipolysaccharide antibody concentrations of > or =0.35 microg/mL, as well as OPA responses, to each of the 13 serotypes.

Safety and Immunogenicity of a 13-Valent Pneumococcal Conjugate Vaccine Compared to Those of a 7-Valent Pneumococcal Conjugate Vaccine Given as a Three-Dose Series with Routine Vaccines in Healthy Infants and Toddlers

A 13-valent pneumococcal conjugate vaccine (PCV13) has been developed to improve protection against pneumococcal disease beyond that possible with the licensed 7-valent vaccine (PCV7). This study compared the safety and immunogenicity of PCV13 with those of PCV7 when given as part of the pediatric vaccination schedule recommended in Italy. A total of 606 subjects were randomly assigned to receive either PCV13 or PCV7 at 3, 5, and 11 months of age; all subjects concomitantly received diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type B (DTaP-HBV-IPV/Hib) vaccine. Vaccine reactions were monitored. Antibody responses to DTaP-HBV-IPV/Hib antigens, serotype-specific anticapsular polysaccharide IgG responses, and antipneumococcal opsonophagocytic assay (OPA) activity were measured 1 month after the two-dose primary series and 1 month after the toddler dose. Overall, the safety profile of PCV13 was similar to that of PCV7. The response to DTaP-HBV-IPV/Hib antigens was substantially the same with both PCV13 and PCV7. PCV13 elicited antipneumococcal capsular IgG antibodies to all 13 vaccine serotypes, with notable increases in concentrations seen after the toddler dose. Despite a lower immunogenicity for serotypes 6B and 23F after the primary series of PCV13, responses to the seven common serotypes were comparable between the PCV13 and PCV7 groups when measured after the toddler dose. PCV13 also elicited substantial levels of OPA activity against all 13 serotypes following both the infant series and the toddler dose. In conclusion, PCV13 appeared comparable to PCV7 in safety profile and immunogenicity for common serotypes, demonstrated functional OPA responses for all 13 serotypes, and did not interfere with immune responses to concomitantly administered DTaP-HBV-IPV/Hib vaccine.

Safety and immunogenicity of the 23-valent pneumococcal polysaccharide vaccine at 12 months of age, following one, two, or three doses of the 7-valent pneumococcal conjugate vaccine in infancy

Fijian infants aged 6 weeks were stratified by ethnicity and randomized to receive 0, 1, 2, or 3 PCV-7 doses with or without the 23-valent pneumococcal polysaccharide vaccine (PPV-23) at 12 months. Strong booster effects for all 7 PCV-7 serotypes were elicited, and for 4/7 serotypes these responses were highest in the single PCV-7 group. There were fourfold rises in GMC for all non-PCV-7 serotypes. By 17 months the PPV-23 group still had significantly higher GMC (each p<0.001) for all serotypes. The PPV-23 was well tolerated and induced excellent responses for all serotypes which were greatest in the single PCV-7 group.

Safety and immunogenicity of sequential pneumococcal immunization in preschool asthmatics

ObjectiveRespiratory infections are major triggers of exacerbations in preschool asthma. Many countries’ guidelines recommend immunization against pneumococci for patients suffering from chronic airway disease. Beyond infancy, however, data on the immunogenicity and safety are scarce. Also, the interval between priming and booster is a matter of debate. Patients and MethodsSeventy preschool asthmatics (2–5-year-old; mild to moderate asthma) underwent sequential immunization: one dose of seven-valent pneumococcal conjugate vaccine (PCV-7) followed by a single dose of 23-valent pneumococcal polysaccharide vaccine (PPV-23). We randomly assigned half of the vaccinees to receive PPV-23 eight weeks after PCV-7 (group A), and the rest to a 10-month interval (group B). Pneumococcal antibody concentrations to serotype 4, 5, 6B, 7, 9V, 14, 18c, 19F and 23F were determined initially, after two and 12 months after PCV-7. Local and systemic reactions to each vaccine were recorded. ResultsInitially, depending on the serotype, up to 79.4% (group A) or 80.4% (group B) individuals did not reach the protective antibody threshold of 0.35μg/ml. Sequential pneumococcal immunization was immunogenic in preschool asthmatics, inducing protection in the majority of our children. Subjects boostered after eight weeks had significantly lower antibody levels than those boostered after 10 months. Local and systemic adverse events were mild in character and self-limiting. ConclusionsAlthough both sequential pneumococcal vaccine regimens were safe and immunogenic among preschool asthmatics, immunogenicity was higher when the booster was given after 10 months.

Superior Immune Response to Protein-Conjugate versus Free Pneumococcal Polysaccharide Vaccine in Chronic Obstructive Pulmonary Disease

Debate exists about the immunogenicity and protective efficacy of antibodies produced by the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in chronic obstructive pulmonary disease (COPD). The 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) induces a more robust immune response than PPSV23 in healthy elderly adults. We hypothesized that serotype-specific IgG antibody concentration and functional antibody activity would be superior after PCV7 vaccination compared with PPSV23 in moderate to severe COPD. We also posited that older age and prior PPSV23 vaccination would be associated with reduced vaccine responsiveness. One hundred twenty patients with COPD were randomized to PPSV23 (63 subjects) or PCV7 (57 subjects). IgG concentrations were determined by ELISA; functional antibody activity was assayed with a standardized opsonophagocytosis assay and reported as an opsonization killing index (OPK). Increases in serotype-specific IgG and OPK at 1 month post vaccination were compared within and between vaccine groups. Both vaccines were well tolerated. Within each study group, postvaccination IgG and OPK were higher than baseline (P < 0.01) for all serotypes. Adjusted for baseline levels, postvaccination IgG was higher in the PCV7 group than the PPSV23 group for all seven serotypes, reaching statistical significance for five (P < 0.05). PCV7 resulted in a higher OPK for six of seven serotypes (statistically greater for four) compared with PPSV23. In multivariate analyses, younger age, vaccine naivety, and receipt of PCV7 were associated with increased OPK responses. PCV7 induces a superior immune response at 1 month post vaccination compared with PPSV23 in COPD. Older age and prior PPSV23 reduce vaccine responsiveness. Clinical trial registered with www.clinicaltrials.gov (NCT00457977).

Pneumococcus and influenza: always more to learn

In this issue of The Journal, two studies from the Netherlands, where policies for pneumococcal and influenza vaccines are narrowly focused, remind us that we still can learn more about natural history, impact, and prevention of disease due to influenza and pneumococci—and how their stories are entwined. It is current policy in the Unites States that all children 2 months through 59 months of age should receive pneumococcal conjugate vaccine (PCV7), and policy is being advanced that all children 6 months through 18 years of age should receive influenza vaccine annually. The policies rest on prevention of substantial morbidity due to pneumococcal and influenzal disease in the age groups targeted, as well as compelling information that children are important sources of these infections for the community. The study by Jansen et al is noteworthy in at least 3 ways: 1) It is a double blind, placebo-controlled trial in which children were randomized into one of three study groups to receive either PCV7 + trivalent inactivated influenza vaccine (TIV), TIV + placebo, or hepatitis B vaccine + placebo; 2) The study was performed in pre-school aged children (enrolled at 18 to 72 months of age); and 3) The majority of children were followed over two influenza seasons, with the primary endpoint of febrile acute respiratory tract illnesses (RTIs). With all caveats of a selected population, incomplete follow-up and investigation of illness episodes, and absence of a PCV7 plus placebo group, results support effects of influenza vaccinations (even during seasons of mismatched vaccine and circulating strains) and probable additional effects of PCV7 for the primary outcome (although the authors do not conclude this about RTIs and conclude the opposite for a secondary outcome—acute otitis media). The article deserves careful reading and adds substantially to the evidence base for vaccination of pre-school aged children. The study by Labout et al on nasopharyngeal colonization with Streptococcus pneumoniae is prospective, longitudinal, serotype-specific, and population-based. Also, it was performed just prior to introduction of the PCV7 program. The investigators found that nasopharyngeal colonization with PCV7 serotypes (those serotypes also most likely to lead to disease) increased through infancy (speculated to result from decreasing maternal antibody with age) and was associated with number of siblings and attendance at out-of-home daycare (speculated to represent exposure opportunities).

Safety and effectiveness against respiratory tract infections for pneumococcal conjugate vaccine co-administered with routine vaccine combinations

Streptococcus pneumoniae is a major cause of bacterial pneumonia and other respiratory tract infections (RTI) in children. The heptavalent conjugated pneumococcal vaccine (PCV7) is offering a promising strategy against pneumococcal disease in children younger than 2 years. In this prospective epidemiological study in Germany, children between 2 and 6 months of age received in a 3:1 ratio a routine childhood vaccine combination with or without PCV7 according to a four-dose schedule. Five thousand nine hundred and eighty-four children were evaluable 1 year after the booster dose. Due to German guidelines children with underlying medical conditions were preferentially included into the PCV7 group and hence 66% of the children in the PCV7 group had at least one medical risk factor and 40% were preterm born compared to 18% and 6% in the control group. Overall PCV7 reduced respiratory tract infections by 10.5% (95% CI: 2.9–17.3%) and clinically diagnosed pneumonia by 6.3% (95% CI: −15.9 to 23.7%) in this unbalanced situation. In a propensity score matched pair analysis controlling for risk factors, effectiveness of PCV7 against pneumonia was 24.8% (95% CI: 0.9–43.1%). In children with at least one medical risk factor vaccine effectiveness against pneumonia was 38.4% (95% CI: 10.7–55.9%) compared to 10.9% (95% CI: −20.2 to 33.9%) without a risk factor. In preterm and term born children, PCV7 was well tolerated when simultaneously administered with widely used hexavalent routine vaccine combinations. The results demonstrate that PCV7 is safe and effective against RTI in preterm children and in children with comorbidities stressing the benefit of pneumococcal conjugate vaccine in these children at high risk for pneumococcal disease.

Randomised revaccination with pneumococcal polysaccharide or conjugate vaccine in asplenic children previously vaccinated with polysaccharide vaccine

Asplenic children are at high risk of invasive pneumococcal infection. In this group, the American Academy of Pediatrics recommends a single revaccination with the 23-valent polysaccharide vaccine (PSV23) 3-5 years after a previous PSV23 dose. Despite potential advantages, there are few data available regarding the safety and immunogenicity of the heptavalent pneumococcal conjugate vaccine (PCV7) in this population. The aim of the study was to prospectively determine and to compare, in asplenic children, the vaccine specific antibody titres against the seven serotypes included in the PCV7 after administration of one dose of PCV7 or of PSV23, 3 years or more after an initial vaccination with PSV23. In this randomised, single-centre study, antibody titres were monitored at baseline, at 1 and 6 months after revaccination in 21 children with anatomic or functional asplenia. Response was considered as positive when there was a four-fold increase in antibody titres from baseline. The most frequently reported adverse events were local reactions in 7/11 of PCV7 subjects and in 5/8 of PSV23 subjects, and general reactions (loss of appetite, sleepiness) in 5/11 of PCV7 subjects and in 1/8 of PSV23 subjects; without any serious adverse events. One child in the PCV7 group had increased temperature (38.4 degrees C). At least half of the PCV7 children responded to four or five serotypes, while more than half of the PSV23 subjects responded to less than 3 serotypes (p=0.285). After 1 month, the immune response for serotype 23F was significantly greater after PCV7 vaccination than after PSV23 vaccination (p=0.036). PCV7 revaccination is safe and immunogenic in asplenic children previously vaccinated with PSV23, and could provide appropriate booster response in this high-risk population. The clinical repercussion on invasive pneumococcal diseases remains to be demonstrated.

Impact on respiratory tract infections of heptavalent pneumococcal conjugate vaccine administered at 3, 5 and 11 months of age

BackgroundMedical and public health importance of pneumococcal infections justifies the implementation of measures capable of reducing their incidence and severity, and explains why the recently marketed heptavalent pneumococcal conjugate vaccine (PCV-7) has been widely studied by pediatricians. This study was designed to evaluate the impact of PCV-7 administered at 3, 5 and 11 months of age on respiratory tract infections in very young children.MethodsA total of 1,571 healthy infants (910 males) aged 75–105 days (median 82 days) were enrolled in this prospective cohort trial to receive a hexavalent vaccine (DTaP/IPV/HBV/Hib) and PCV-7 (n = 819) or the hexavalent vaccine alone (n = 752) at 3, 5 and 11 months of age. Morbidity was recorded for the 24 months following the second dose by monthly telephone interviews conducted by investigators blinded to the study treatment assignment using standardised questionnaires. During these interviews, the caregivers and the children's pediatricians were questioned about illnesses and the use of antibiotics since the previous telephone call. All of the data were analysed using SAS Windows v.12.ResultsAmong the 1,555 subjects (98.9%) who completed the study, analysis of the data by the periods of follow-up demonstrated that radiologically confirmed community-acquired pneumonia (CAP) was significantly less frequent in the PCV-7 group during the follow-up as a whole and during the last period of follow-up. Moreover, there were statistically significant between-group differences in the incidence of acute otitis media (AOM) in each half-year period of follow-up except the first, with significantly lower number of episodes in children receiving PCV-7 than in controls. Furthermore, the antibiotic prescription data showed that the probability of receiving an antibiotic course was significantly lower in the PCV-7 group than in the control group.ConclusionOur findings show the effectiveness of the simplified PCV-7 schedule (three doses administered at 3, 5 and 11–12 months of age) in the prevention of CAP and AOM, diseases in which Streptococcus pneumoniae plays a major etiological role. A further benefit is that the use of PCV-7 reduces the number of antibiotic prescriptions. All of these advantages may also be important from an economic point of view.

Immunogenicity and Safety of Measles-Mumps-Rubella, Varicella and Haemophilus influenzae Type b Vaccines Administered Concurrently With a Fourth Dose of Heptavalent Pneumococcal Conjugate Vaccine Compared With the Vaccines Administered Without Heptavalent Pneumococcal Conjugate Vaccine

Prevnar [heptavalent pneumococcal conjugate vaccine (PCV7)] is licensed in the United States for routine administration in infants and may be coadministered with other infant vaccines. Safety and immunogenicity data on the coadministration of the fourth dose of PCV7 with measles-mumps-rubella (MMR), varicella and Haemophilus influenzae type b (Hib) vaccines are limited. Children 12-15 months of age received either MMR with PCV7 (group 1) or MMR without PCV7 (group 2). All subjects received Hib and varicella vaccines. Group 2 received PCV7 6-9 weeks after MMR vaccination. Sera for analysis of all non-PCV7 antibodies were collected just before administration of MMR vaccine and 6 weeks later. Optimal antigen responses were assessed with the use of predetermined antibody titers. The primary end point was >90% response rate (all antigens). Noninferiority was defined as <10% difference between groups. Local and systemic reactions and postvaccination adverse events were monitored and compared between groups. A total of 694 subjects (347 per group) were enrolled. After immunization with MMR plus PCV7 concurrently, or MMR followed 6 weeks later by PCV7, the percentages of subjects seroconverting were significantly greater than 90% for all antigens. The difference between the 2 groups was significantly less than 10%. The immune response to MMR, Hib and varicella vaccines, when administered concurrently with a 4th (booster) dose of PCV7, was noninferior to that of these vaccines when given without PCV7. These results support concomitant administration of PCV7 with MMR, varicella and Hib as part of the recommended immunization schedule for children 12-15 months of age.

Immunogenicity, reactogenicity and safety of a 7-valent pneumococcal conjugate vaccine (PCV7) concurrently administered with a DTPa-HBV-IPV/Hib combination vaccine in healthy infants

Background To evaluate immunogenicity, reactogenicity, and safety of a hexavalent combination vaccine diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus- Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) when coadministered with a 7-valent pneumococcal conjugate vaccine (PCV7). Methods Infants received either a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus- H. influenzae type b vaccine concomitantly with PCV7 or DTPa-HBV-IPV/Hib alone infants were vaccinated at 2, 3 and 4 months (primary immunization) and 12–15 months of age (booster dose). Local and systemic reactions and adverse events were monitored following each dose and compared between groups. Blood was obtained prior to dose 1, one month after dose 3, immediately prior to and 1 month following the booster dose to measure antibody responses to each of the antigens. Results Two hundred and fifty-three subjects (PCV7, 127; Control, 126) were enrolled. Antibody responses were compared in 226 subjects for the primary immunization and 212 for the booster dose (per-protocol (PP) population). Although there were some differences in geometric mean concentrations (GMCs) to the DTPa-HBV-IPV/Hib antigens after the primary series, GMCs for all antigens after the booster dose were similar in both groups, except for diphtheria which was significantly higher in the PCV7 group (PCV7, 7.41 IU/mL; Control, 5.78 IU/mL). Reactogenicity and safety data were compared in 252 infants receiving primary immunization and 235 children receiving the booster dose. Site reactions were similar in both groups. Fever ≥38.0 °C following each vaccination was reported more frequently in the PCV7 group (28.3–50.0%) than in the Control group (15.6–33.6%) whereas fever >39.0 °C occurred only in a few cases and to the same extent in both groups (PCV7, 0.8–2.7%; Control, 1.6–4.1%). Only one reported serious adverse event was characterized as being related to the study vaccines: control subject was hospitalized with a fever. Conclusion DTPa-HBV-IPV/Hib and PCV7 were highly immunogenic, well-tolerated and safe when coadministered at 2, 3 and 4 months of age with a booster dose at 12–15 months of age. These results support the coadministration of PVC7 with DTPa-HBV-IPV/Hib as part of the routine immunization schedule for infants and children.