Clinical effectiveness of seven-valent pneumococcal conjugate vaccine (Prevenar) against invasive pneumococcal diseases: prospects for children in France]

A seven-valent pneumococcal polysaccharide-CRM197 carrier protein conjugate vaccine (PNC7V; Prevenar, Wyeth, Paris) targets the serotypes (belonging to serogroups 14, 6, 19, 18, 23, 9, and 4) most often responsible for invasive pneumococcal disease (IPD) among children. A randomized, controlled, double-masked study among 37,868 children in northern California (Northern California Kaiser Permanente, USA) provided a per protocol vaccine efficacy value of 97.7% against invasive pediatric IPD due to the vaccine serotypes. The PNC7V vaccine was registered by the European Agency for the Evaluation of Medicinal Products (EMEA) in October 2000; a favorable "Community Marketing Decision" under the Centralized Procedure was granted in February 2001. PNC7V was recommended for most infants by the Conseil Supérieur d'Hygiène Publique de France in March 2002, on the advice of the Comité Technique des Vaccinations, as S. pneumoniae in children less than 2 years of age is the primary cause of bacterial meningitis and of mortality associated with community-acquired bacterial infections. The theoretical coverage of the vaccine towards pneumococcal invasive disease in France is about 80%, which represents one of the best serotype coverage estimates in Europe, and vaccines serotypes account for 90% of penicillin-nonsusceptible strains. Distinctive characteristics in France in terms of epidemiology, life style, and therapeutic attitudes justify a precise follow up of the consequences of the vaccination on a national level during the coming years. Hence, surveillance programs have been established: (i) to ascertain the future impact of large-scale PNC7V vaccination on invasive pneumococcal disease incidence, (ii) to follow the evolution of carriage and ecology of the pneumococcus, and (iii) to establish an active "vaccinovigilance".     

The pneumococcal conjugate vaccine

Streptococcus pneumoniae is the most frequent cause of otitis media, sinusitis, and pneumonia in children. It is also one of the most common causes of invasive bacterial infections in children including bacteremia and meningitis. One of the current issues regarding S. pneumoniae is the emergence of pneumococcal strains resistant to penicillin and other antibiotics. Children less than two years of age suffer an increased incidence of invasive pneumococcal disease but fail to respond to the 23-valent polysaccharide vaccine because of the immaturity of the T-cell independent immune function. Covalently conjugating the polysaccharide antigen to a carrier protein improves the immune response by permitting the host to utilize a T-cell dependent immune response that is adequately mature in children less than two years of age. Immunogenicity studies of the currently licensed heptavalent conjugated polysaccharide vaccine, (Prevnar, marketed by Wyeth Lederle Vaccines) demonstrated that infants vaccinated with three doses 2 months apart at 2, 4, and 6 months of age successfully developed antibodies to all 7 serotypes; booster doses at 12-15 months demonstrated an amnestic response for each serotype. Immunogenicity studies have similarly demonstrated successful responses in children with sickle cell disease and human immunodeficiency virus infection. An efficacy trial involving nearly 38,000 subjects demonstrated the vaccine's effectiveness in healthy children against invasive pneumococcal disease as well as against pneumonia and otitis media. Currently the US Advisory Committee on Immunization Practices (ACIP) recommends that all infants and children under 24 months of age receive the vaccine. The ACIP recommends that infants receive the vaccine routinely at 2, 4 and 6 months with a fourth dose at 12 to 15 months of age. Infants may receive the first dose as early as 6 weeks of age. The vaccine is also indicated for children 24 to 59 months of age who are at high risk for pneumococcal infection. Adverse events include local reactions in the first two days following vaccination such as approximately 10% reporting erythema, 10% induration, and 20% tenderness. Fever of 38 degrees C or higher occurred in 15% to 25% of children in the first two days following vaccination. Follow-up studies should address important questions regarding the use of pneumococcal conjugate vaccine and other age groups.     

Safety and efficacy of the seven-valent pneumococcal conjugate vaccine: evidence from Northern California

Pneumococcal disease remains a significant cause of morbidity among young children. A large-scale efficacy trial in the Northern California Kaiser Permanente system (the KP trial) demonstrated that a seven-valent conjugate vaccine (PCV) is safe and immunogenic in young children and effective in preventing both invasive pneumococcal disease caused by vaccine serotypes (97.4% efficacy) and episodes of otitis media (7.0% efficacy). Since the publication of the results of the KP trial in 2000, we have performed an additional analysis on the safety, immunogenicity, and efficacy of the vaccine in low birth weight (LBW) and preterm (PT) infants, and have examined the efficacy of the vaccine during 1 year of wide-scale post-licensure use. The vaccine was at least as immunogenic in LBW and PT infants as in normal-weight, full-term infants and was 100% effective, although the LBW and PT infants had higher rates of adverse events such as redness and swelling. LBW and PT infants receiving pneumococcal vaccine also had higher rates of adverse events, such as hives, than those receiving control meningococcal vaccine, but these reactions were not severe. When the PCV was used in the general population, the efficacy remained high and there was no corresponding increase in disease caused by nonvaccine serotypes. There was also evidence that vaccine administration led to herd immunity. Febrile illness was the only adverse event seen more frequently after vaccine administration than during a control period. CONCLUSION: the seven-valent conjugate vaccine is safe and effective for use in the general population.     

Effect of the pneumococcal conjugate vaccine on pneumococcal carriage in Turkish children

Background: The aim of our study was to evaluate the effect of the seven‐valent pneumococcal conjugate vaccine which has recently been included in the national immunization schedule on the nasopharyngeal carriage of Streptococcus pneumoniae in a group of healthy Turkish children. This is the first study determining the efficacy of this vaccine in Turkey. Methods: One hundred and thirty‐eight children who had completed their pneumococcal vaccination series and 109 unvaccinated control subjects aged 12–59 months were included in the study between October 2007 and April 2008. A single nasopharyngeal swab sample was obtained from each subject. Results: S. pneumoniae was isolated in 32 (12.9%) of 247 subjects. No significant differences were detected in pneumococcal carriage rate between the vaccinees and controls (10.1% vs 16.5%). Prevalence of vaccine type (VT) carriage was statistically lower in the vaccinated group than the controls while non‐vaccine type carriage (NVT) was similar. Most frequently isolated vaccine serotype was 23F in the vaccinated group and 19F in the non‐vaccinated group. Of the isolated S. pneumoniae, 13.3% were penicillin susceptible and 86.7% were non‐susceptible. Vaccinees and controls did not differ statistically with respect to carriage rate of penicillin‐resistant S. pneumoniae. All the pneumococcal isolates were susceptible to ceftriaxone, vancomycin, rifampicin and quinolones. Conclusion: Seven‐valent conjugate vaccine induces long‐term protection against carriage of VT S. pneumoniae in Turkish children. The ability of the conjugate vaccine to reduce transmission of antibiotic resistant S. pneumoniae may be possible if its introduction is coupled with a reduction in inappropriate use of antibiotics.     

Effect of the seven-valent conjugate pneumococcal vaccine on carriage and drug resistance of Streptococcus pneumoniae in healthy children attending day-care centers in Lisbon

AIMS: Prospective study to evaluate the impact of the 7-valent pneumococcal conjugate vaccine (Prevenar) on the nasopharyngeal (NP) carriage of drug-resistant Streptococcus pneumoniae (DRPn), by healthy children attending day-care centers (ages 6 months-6 years). METHODS: Vaccinees (238 children) who received vaccine and controls (457 children) were followed for carriage of total S. pneumoniae and DRPn and for the serotypes and genetic backgrounds of DRPn during 6 consecutive sampling periods between May 2001 and February 2003. RESULTS: We detected no significant differences between vaccinees and the control group in the total carriage rate of Pn (average, 68%) or in the frequency of carriage of DRPn (average, 38%), including the frequency of penicillin-nonsusceptible strains (average, 24%). In contrast, there was a decline in the carriage of DRPn with vaccine serotypes which was compensated by the appearance and gradual increase in the frequency of DRPn expressing unusual serotypes (6A, 10A, 15A and 15C, 19A, 23A, 33F) which were not present in the vaccine as well as an increase in nontypable strains. The majority of the DRPn with unusual serotypes showed different pulsed field gel electrophoresis patterns indicating replacement of the original resistant flora by other clonal types of drug-resistant bacteria. Antibiotic consumption and the frequency of respiratory tract infections were similar among the vaccinees and controls. CONCLUSIONS: Pneumococcal vaccination did not change the frequency of carriage of drug-resistant strains being the initially dominant vaccine serotypes replaced by others expressing nonvaccine serotypes. Reduction in the carriage of DRPn may require a combination of the conjugate vaccine and a decrease in antibiotic pressure.     

Management of febrile children in the conjugate pneumococcal vaccine era

The objective of this study was to evaluate physician attitudes toward the management of young febrile children since the introduction of the conjugate heptavalent pneumococcal vaccine (PCV 7). Seven thousand five hundred pediatricians and 7,500 emergency department (ED) physicians were surveyed with regard to their management of a febrile 7-month-old child and 20-month-old child without an apparent fever focus. Specifically, physicians were asked how they would manage a febrile child who had and who had not been vaccinated with PCV 7. When evaluating a febrile 7-month-old child, pediatricians would order 5% fewer complete blood cell (CBC) counts and 6% fewer blood cultures (p<0.0001) if a child was vaccinated. ED physicians would order 13% fewer CBC's and 15% fewer blood cultures (p<0.0001). ED physicians and pediatricians ordered fewer chest radiographs, an 8% and 3% decrease, respectively (p<0.0001). For the PCV 7 immunized 20-month-old child, pediatricians ordered 6% fewer CBC counts and 8% fewer blood cultures (p<0.0001). ED physicians would perform 12% fewer CBC counts and cultures (p<0.0001). Four percent fewer pediatricians and 10% fewer ED physicians would order chest radiographs (p<0.0001). When treating the vaccinated 7-month-old child, pediatricians would use 11% less ceftriaxone and ED physicians 20% less (p<0.0001). Twelve percent fewer pediatricians and 19% fewer ED physicians would administer ceftriaxone (p<0.0001) for the 20-month-old vaccinated child. Our survey suggests that pediatricians and ED physicians would order fewer CBC counts and blood cultures and administer less empiric ceftriaxone if a child was vaccinated with PCV 7.     

Increase in invasive pneumococcal disease in children associated with shortage of heptavalent pneumococcal conjugate vaccine

The authors investigated the impact of heptavalent pneumococcal conjugate vaccine (PCV7) shortage on the rate of invasive pneumococcal disease (IPD). Vaccination status and number of doses delivered was determined. Regression analysis using an exponential decay model was used to predict the expected rate of IPD in the shortage period if IPD continued to decline at the same rate as in the availability period. The rate of IPD decreased from 15.5 to 6.5 with vaccine availability (P < .00001) and increased to 7.2 with shortage (P = .69). Based on the model, IPD rate would have been 3.6 if the decrease continued at the same rate when there was no shortage; this was statistically significant (95% prediction interval, 2.7-4.1). The rate of IPD correlated directly with the number of PCV7 doses delivered, r = -.98. Continuous availability of the PCV7 would have resulted in a statistically significant lower IPD rate compared to the measured IPD rate in the vaccine shortage period.     

Invasive pneumococcal disease in children with sickle cell disease in the pneumococcal conjugate vaccine era

Invasive pneumococcal disease (IPD) in children with sickle cell disease (SCD) can be devastating. We sought to assess the impact of IPD in children with SCD since licensure of the pneumococcal conjugate vaccines (PCVs). We found 11 cases of IPD giving an incidence of 417 per 100,000 person‐years, much higher than that reported in children without SCD. Although all isolates were sensitive to penicillin, 89% of isolates were nonvaccine serotypes. Further study is needed to characterize the incidence of and risk factors for the development of IPD in SCD in the PCV era to help drive better prevention strategies.     

Underlying conditions in children with invasive pneumococcal disease in the conjugate vaccine era

We analyzed characteristics of invasive pneumococcal disease cases occurring in Massachusetts after the introduction and use of conjugate vaccine by underlying risk. Among 578 cases with sufficient information, 16% had high-risk or presumed high-risk conditions (HR/PHR), 3% had asthma, and 80% had no known risk (NKR). The most common HR/PHR conditions were disorders associated with immunosuppression. HR/PHR cases tended to be older and were more likely to be hospitalized than were children with NKR. Children with asthma presented with pneumonia more often than children with NKR.