Direct, indirect and total effects of 13-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in children in Navarra, Spain, 2001 to 2014: cohort and case-control study.

We estimated the direct, indirect and total effects of the 13-valent pneumococcal conjugate vaccine (PCV13) on invasive pneumococcal disease (IPD) in children. A population-based cohort study followed children aged between 2.5 and 59 months between 2001 and 2014 in Navarra, Spain. IPD incidence was compared by PCV status and period. All cases diagnosed from July 2010 to December 2014 and eight matched controls per case were analysed to estimate the adjusted direct effect of PCV13. A total of 120,980 children were followed and 206 IPD cases were detected. Compared with unvaccinated children in the baseline period (2001-2004), overall IPD incidence in 2011-2014 (76% average PCV coverage) declined equally in vaccinated (total effect: 76%; hazard ratio (HR): 0.24; 95% confidence interval (CI): 0.14-0.40) and unvaccinated children (indirect effect: 78%; HR: 0.22; 95% CI: 0.09-0.55). IPD incidence from non-PCV13 serotypes increased among vaccinated children (HR: 2.84; 95% CI: 1.02-7.88). The direct effect of one or more doses of PCV13 against vaccine serotypes was 95% (odds ratio: 0.05; 95% CI: 0.01-0.55). PCV13 was highly effective in preventing vaccine-serotype IPD. The results suggest substantial and similar population-level vaccine benefits in vaccinated and unvaccinated children through strong total and indirect effects.

[Meningococcal C conjugate vaccine: Impact of a vaccination program and long-term effectiveness in Navarra, Spain, 2000-2014]. / Vacuna conjugada frente al meningococo C: impacto del programa de vacunación y efectividad a largo plazo en Navarra, 2000-2014.

BACKGROUND: Since 2000, when the meningococcal serogroupC conjugate vaccine (MenCC) was introduced in the childhood immunization schedule in Spain, several changes in the schedule and catch-up campaigns have been performed. We aim to estimate the impact and effectiveness of this vaccine in Navarra up to 2014. METHODS: The impact of the vaccination program was analysed by comparing incidence, mortality and lethality rates of disease before (1995-1999) and after (2004-2014) the introduction of the MenCC. Vaccine effectiveness was estimated using the screening method (Farrington) and the indirect cohort method (Broome). Data on cases were obtained from the active surveillance of meningococcal disease. RESULTS: During 1995-1999 the mean annual incidence of meningococcalC disease was 1.32 per 100,000, and 7.18 per 100,000 in children younger than 15years. The fall of meningococcalC disease incidence was significant in cohorts targeted for vaccination from the beginning and progressive in the general population. No cases were reported between 2011 and 2014. The estimated vaccine effectiveness was 96% by the screening method, and 99% by the indirect cohort method. CONCLUSION: The MenCC vaccination program has been successful in decreasing the incidence rate of serogroupC meningococcal disease in Navarra, and schedule changes have maintained high vaccine effectiveness throughout the study period.

Pneumococcal Vaccination and Pneumonia Associated With Pleural Effusion in a Pediatric Population.

OBJECTIVE: The aim was to assess the effect of the nonsystematic pneumococcal conjugate vaccine (PCV) on incidence of pneumonia associated with parapneumonic pleural effusion (PPE) in vaccinated and unvaccinated children. METHODS: Cases were patients <15 years of age who had been diagnosed with pneumonia associated with PPE in a tertiary hospital in Navarra (Spain) between 1995 and 2014. The population <15 years of age and covered by the public health service was used as reference. The vaccination status of the cases and population was obtained from computerized medical records. Logistic regression analyses included vaccination status, age group and time periods: prevaccine (1995-2001) and vaccination with PCV7 (2002-2010) and PCV13 (2011-2014). RESULTS: A total of 321 cases of PPE were included. The risk of PPE increased between the prevaccine and PCV7 period (adjusted odds ratio [OR], 3.34; 95% confidence interval [CI]: 2.37-4.71), while vaccination with PCV7 was found to be an independent risk factor (OR, 1.44; 95% CI: 1.09-1.89) in the same analysis. In the PCV13 period, the risk of PPE returned to the prevaccination incidence level among children vaccinated with PCV13 (OR, 1.07; 95% CI: 0.56-2.04), while unvaccinated children (OR, 1.69; 95% CI: 0.96-2.98) and overall those vaccinated with PCV7 (OR, 3.64; 95% CI: 2.15-6.17) maintained an increased risk of PPE. CONCLUSION: The nonsystematic introduction of PCV7 was followed by an increased incidence of PPE. The subsequent introduction of PCV13 was associated with a return to the incidence level in the prevaccine period, mainly in children vaccinated with PCV13.

[Invasive meningococcal disease in Navarra in the era of a meningococcal C vaccine]. / Enfermedad meningocócica invasiva en Navarra en la era de la vacuna conjugada antimeningocócica C.

INTRODUCTION: Systematic childhood vaccination against meningococcus C has had a considerable impact on meningococcal invasive disease (MID). The aim of this study is to perform an analysis on the epidemiology, the clinical features, and the factors associated with a worse prognosis of MID, in the era of a meningococcal C vaccine. MATERIAL AND METHODS: The study included confirmed cases of MID in children less than 15 years of age in Navarra, Spain, between 2008 and 2014. The risk of death or permanent sequelae was evaluated according to the presence of clinical features and analytical parameters at diagnosis. RESULTS: The average annual incidence was 7.9 cases per 100,000 children, with the highest attack rate in children < 1 year. Of 53 cases analysed, 87% were due to meningococcus B. Fever (100%), rash (91%), and elevation of procalcitonin (94%) were the most frequent findings at diagnosis. Some sign of shock was observed in 70% upon arrival at the hospital. The case-fatality rate was 3.8% and 10 % survived with permanent sequelae. Glasgow coma scale < 15 (odds ratio [OR]= 9.2), seizure (OR=8.3), sepsis without meningitis (OR=9.1), thrombocytopenia (OR=30.5), and disseminated intravascular coagulation (OR= 10.9) showed a greater association with a worse prognosis. CONCLUSION: The MID continues to be a significant cause of morbidity and mortality in children. Therefore, new advances are needed in the prevention, early diagnosis, and detection of the factors associated with poor prognosis.

Evaluation of 13-valent pneumococcal conjugate vaccine and concomitant meningococcal group C conjugate vaccine in healthy infants and toddlers in Spain.

BACKGROUND: Given the concurrent administration of multiple vaccines during routine pediatric immunizations, efforts to elucidate the potential interference of any vaccine on the immune response to the concomitantly administered antigens are fundamental to prelicensure clinical research. METHODS: This phase 3 randomized controlled trial of 13-valent pneumococcal conjugate vaccine (PCV13) versus 7-valent PCV (PCV7) assessed immune responses of concomitantly administered meningococcal group C conjugated to diphtheria toxin cross-reactive material 197 (MnCCV-CRM197) in a 2-dose infant series and 15-month toddler dose. RESULTS: 619 subjects were randomized, 315 to PCV13 and 304 to PCV7. MnCCV-CRM197-induced immune responses were similar between the PCV13 and PCV7 groups, with >97% of the subjects achieving a ≥1:8 meningococcal serum bactericidal assay (SBA) titer after both dose 2 and the toddler dose. Geometric mean titers were lower in the PCV13 group 191.22 (167.72, 218.02) versus 266.19 (234.86, 301.71) following dose 2 and 432.28 (361.22, 517.31) versus 730.84 (642.05, 831.91) following the toddler dose. The geometric mean (GM) meningococcal SBA titer ratios (PCV13/PCV7) were 0.72 after dose 2 and 0.59 after the toddler dose. The criteria for MnCCV-CRM197 non-inferiority for GM titers were satisfied after dose 2. Percent responders was similar up to titers of 1:128. PCV13 elicited substantial antipneumococcal responses against all 13 serotypes, with ≥90% of the subjects achieving an antibody concentration ≥0.35µg/mL after dose 3 in the infant series. Safety and tolerability were similar between the vaccine groups. CONCLUSIONS: Immunogenicity results of MnCCV-CRM197 for PCV13 compared with PCV7 included lower GMTs, but the clinical significance of this is unknown as the proportion of infants achieving protective MenC antibody titers was comparable in the two groups. Percent responders were similar up to titers of 1:128. PCV13 has an acceptable safety profile in infants and toddlers, while providing expanded coverage against pneumococcal disease.

Enfermedad meningocócica invasiva en Navarra en la era de la vacuna conjugada antimeningocócica C / Invasive meningococcal disease in Navarra in the era of a meningococcal C vaccine

INTRODUCCIÓN: La vacunación sistemática infantil frente al meningococo C ha tenido un impacto considerable en la enfermedad meningocócica invasiva (EMI). El objetivo de este estudio es analizar la epidemiología, las manifestaciones clínicas y los factores asociados a un peor pronóstico de la EMI en la era de la vacuna antimeningocócica C. MATERIAL Y MÉTODOS: Se analizaron los casos de EMI confirmados en menores de 15 años diagnosticados en Navarra entre 2008 y 2014, y se evaluó el riesgo de muerte o secuelas permanentes, según la presencia de determinados hallazgos clínicos o analíticos al diagnóstico. RESULTADOS: La incidencia media anual fue 7,9 casos por 100.000 niños, con mayor tasa de ataque en niños < 1 año. De 53 casos analizados, el 87% fueron por meningococo B. Fiebre (100%), exantema (91%) y elevación de la procalcitonina (94%) fueron los hallazgos más frecuentes al diagnóstico. El 70% de los casos presentaba algún signo de shock a su llegada al hospital. La letalidad fue del 3,8% y un 10% sobrevivió con secuelas permanentes. Una puntuación en la escala de coma de Glasgow < 15 (odds ratio [OR] = 9,2), convulsión (OR = 8,3), sepsis sin meningitis (OR = 9,1), trombocitopenia (OR = 30,5) y coagulación intravascular diseminada (OR = 10,9) se asociaron con un peor pronóstico. CONCLUSIÓN: La EMI continúa causando una morbimortalidad importante en la población infantil, por lo que sigue siendo necesario avanzar en su prevención, en su diagnóstico temprano y en reconocer los factores asociados a mal pronóstico

INTRODUCTION: Systematic childhood vaccination against meningococcus C has had a considerable impact on meningococcal invasive disease (MID). The aim of this study is to perform an analysis on the epidemiology, the clinical features, and the factors associated with a worse prognosis of MID, in the era of a meningococcal C vaccine. MATERIAL AND METHODS: The study included confirmed cases of MID in children less than 15 years of age in Navarra, Spain, between 2008 and 2014. The risk of death or permanent sequelae was evaluated according to the presence of clinical features and analytical parameters at diagnosis. RESULTS: The average annual incidence was 7.9 cases per 100,000 children, with the highest attack rate in children < 1 year. Of 53 cases analysed, 87% were due to meningococcus B. Fever (100%), rash (91%), and elevation of procalcitonin (94%) were the most frequent findings at diagnosis. Some sign of shock was observed in 70% upon arrival at the hospital. The casefatality rate was 3.8% and 10 % survived with permanent sequelae. Glasgow coma scale < 15 (odds ratio [OR] = 9.2), seizure (OR = 8.3), sepsis without meningitis (OR = 9.1), thrombocytopenia (OR = 30.5), and disseminated intravascular coagulation (OR = 10.9) showed a greater association with a worse prognosis. CONCLUSION: The MID continues to be a significant cause of morbidity and mortality in children. Therefore, new advances are needed in the prevention, early diagnosis, and detection of the factors associated with poor prognosis

Safety of a 2-dose regimen of a combined measles, mumps, rubella and varicella live vaccine manufactured with recombinant human albumin.

BACKGROUND: ProQuad, a vaccine containing antigens from M-M-RVAXPRO (measles, mumps and rubella vaccine) and VARIVAX (varicella vaccine), is indicated for simultaneous vaccination against measles, mumps, rubella and varicella (MMRV) in individuals from 12 months of age. To eliminate blood-derived products of human origin from the manufacturing process of the MMRV vaccine, recombinant human albumin was selected as a replacement for human serum albumin. METHODS: This open-label, multicenter clinical trial (clinicaltrials.gov identifier NCT00560755) was designed to describe the safety profile of a 2-dose schedule of the MMRV vaccine at a 1-month interval in healthy children aged 12-22 months. RESULTS: In total, 3388 children received at least 1 dose of the MMRV vaccine. Overall, 3376 (99.65%) children were included in the post-dose 1 safety analysis and 3342 (98.64%) in the post-dose 2 safety analysis. After doses 1 and 2, the frequencies of children experiencing solicited injection-site reactions (post-dose 1: erythema 14.31%; swelling 5.57% and pain 10.31%; post-dose 2: erythema 30.46%; swelling 13.23% and pain 11.49%), rashes of interest (post-dose 1: 11.4%; post-dose 2: 2.78%), vaccine-related nonserious systemic adverse events (post-dose 1: 34.86%; post-dose 2: 13.4%) and temperature ≥39.4 °C (post-dose 1: 25.24%; post-dose 2: 12.06%) were consistent with those observed in previous studies of the MMRV vaccine manufactured with human serum albumin. Neither serious allergic-type adverse events nor anaphylactic reactions were reported. CONCLUSION: The results confirm the good safety profiles of MMRV and of measles, mumps and rubella vaccines manufactured with recombinant human albumin.

13-valent pneumococcal conjugate vaccine given with meningococcal C-tetanus toxoid conjugate and other routine pediatric vaccinations: immunogenicity and safety.

BACKGROUND: As multiple vaccines are administered concomitantly during routine pediatric immunizations, it is important to ascertain the potential interference of any new vaccine on the immune response to the concomitantly administered vaccines. Immune responses to meningococcal serogroup C-tetanus toxoid conjugate vaccine (MnCC-TT) and the diphtheria and tetanus antigens in routine pediatric vaccines (diphtheria, tetanus, acellular pertussis-hepatitis B virus-inactivated poliovirus/Haemophilus influenza type b [DTaP-HBV-IPV/Hib] and DTaP-IPV+Hib) when given concomitantly with the 13-valent pneumococcal conjugate vaccine (PCV13) were compared with responses when given with PCV7. In addition, the immunogenicity and safety of PCV13 were assessed. METHODS: Healthy infants were randomized to receive PCV13 or PCV7 (ages 2, 4, 6 and 15 months), concomitant with MnCC-TT (2, 4 and 15 months), DTaP-HBV-IPV/Hib (2, 4 and 6 months), and DTaP-IPV+Hib (15 months). RESULTS: Immune responses to MnCC-TT and to the diphtheria and tetanus antigens administered with PCV13 were noninferior to the responses observed when the vaccines were administered with PCV7; ≥96.6 (postinfant) and ≥99.4% (posttoddler) subjects achieved prespecified immune response levels to each antigen in each group. After the infant series, ≥93.0% of subjects receiving PCV13 achieved pneumococcal anticapsular immunoglobulin G concentrations ≥0.35 µg/mL for all serotypes except serotype 3 (86.2%), increasing to 98.1-100% for most serotypes (serotype 3: 93.6%) after the toddler dose. Local and systemic reactions were similar between groups. CONCLUSIONS: Immune responses to MnCC-TT, and other childhood vaccines (DTaP-HBV-IPV/Hib, DTaP-IPV+Hib) were noninferior when concomitantly administered with PCV13 compared with PCV7. PCV13 does not interfere with MnCC-TT. PCV13 is highly immunogenic with a favorable safety profile.

Vacuna conjugada frente al meningococo C: impacto del programa de vacunación y efectividad a largo plazo en Navarra, 2000-2014 / Meningococcal C conjugate vaccine: Impact of a vaccination program and long-term effectiveness in Navarra, Spain, 2000-2014

INTRODUCCIÓN: Desde la introducción en el calendario de vacunación infantil de la vacuna conjugada frente al meningococo C (Men CC) en el año 2000, se ha modificado la pauta y se han realizado campañas de vacunación en cohortes de nacimiento específicas. El objetivo de este estudio es estimar el impacto y la efectividad de esta vacuna en Navarra hasta 2014. MÉTODOS: El impacto se evaluó comparando incidencia, mortalidad y letalidad de enfermedad por meningococo C en los periodos anterior (1995-1999) y posterior (2001-2014) a la vacunación. La efectividad se estimó mediante el método de cribado (Farrington) y el de cohorte indirecta (Broome). Los casos se recogieron del sistema de vigilancia de la enfermedad meningocócica en Navarra. RESULTADOS: En el periodo 1995-1999 la incidencia media anual de enfermedad por meningococo C era de 1,32 por 100.000 habitantes, y de 7,18 por 100.000 en menores de 15 años. El descenso de la incidencia fue contundente en los grupos de edad diana de la vacuna desde su introducción y ha sido progresivo en la población total. Entre 2011 y 2014 no se registraron casos por meningococo C. La efectividad de la vacuna para prevenir casos por este serogrupo se estimó entre el 96% (método de cribado) y el 99% (método de cohorte indirecta). CONCLUSIÓN: El programa de vacunación con Men CC ha logrado con éxito disminuir la incidencia de la enfermedad por serogrupo C en Navarra, y los ajustes en la pauta vacunal han conseguido mantener una elevada efectividad vacunal en el tiempo

BACKGROUND: Since 2000, when the meningococcal serogroup C conjugate vaccine (Men CC) was introduced in the childhood immunization schedule in Spain, several changes in the schedule and catch-up campaigns have been performed. We aim to estimate the impact and effectiveness of this vaccine in Navarra up to 2014. METHODS: The impact of the vaccination program was analysed by comparing incidence, mortality and lethality rates of disease before (1995-1999) and after (2004-2014) the introduction of the Men CC. Vaccine effectiveness was estimated using the screening method (Farrington) and the indirect cohort method (Broome). Data on cases were obtained from the active surveillance of meningococcal disease. RESULTS: During 1995-1999 the mean annual incidence of meningococcal C disease was 1.32 per 100,000, and 7.18 per 100,000 in children younger than 15 years. The fall of meningococcal C disease incidence was significant in cohorts targeted for vaccination from the beginning and progressive in the general population. No cases were reported between 2011 and 2014. The estimated vaccine effectiveness was 96% by the screening method, and 99% by the indirect cohort method. CONCLUSION: The Men CC vaccination program has been successful in decreasing the incidence rate of serogroup C meningococcal disease in Navarra, and schedule changes have maintained high vaccine effectiveness throughout the study period

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.