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Since the introduction of 7-valent pneumococcal conjugate vaccine (PCV7), PCVs with extended coverage have become available, and there is emerging global evidence that these vaccines, in particular PCV13, have further reduced rates of invasive pneumococcal disease compared with PCV7. The present article aims to address emerging topics related to PCV13 use in routine clinical practice; specifically: (1) the potential role of high-valent PCVs in reducing pneumococcal disease burden; (2) the impact of PCVs on nasopharyngeal carriage and how this may contribute to reductions in otitis media and pneumonia, as well as the prevalence of resistant pneumococcal strains; (3) new PCV13 indications and (4) importance of schedule adherence for PCV in the prevention of cases of vaccine serotype-specific invasive pneumococcal disease. The beneficial effects of PCVs in protecting individuals from a wide spectrum of pneumococcal diseases can be increased by improving the vaccine coverage and adhering to the recommended vaccination schedules. There is increasing evidence that PCV13 has reduced much of the post-PCV7 burden of pneumococcal diseases in the pediatric community, including reducing pneumococcal colonization and the incidence of invasive pneumococcal disease and mucosal diseases. This has also led to a reduction in antibiotic-resistant pneumococcal diseases. The role of PCV13 in clinical practice is evolving, with PCV13 now available for children and adolescents between the ages of 6 weeks and 17 years, thus ensuring that children in all age groups can be protected against vaccine-serotype pneumococcal diseases. Continued surveillance is warranted to monitor the impact of PCV13 on disease burden.

Background: In Germany, Haemophilus influenzae type b (Hib), polio and hepatitis B (HBV) vaccines have been combined with diphtheria, tetanus and acellular pertussis vaccines. We examined whether the use of combination vaccines has improved the timing of these vaccinations., Methods: Vaccination information was obtained from representative nationwide telephone interviews about 2701 children born from 1996 through 2003 in Germany. We assessed up-to-date vaccination as the percentage of children vaccinated by 3, 5 and 15 months for the first dose, full primary series and full immunization, respectively. We compared results over periods when different combination vaccines were used. We also compared median age at first dose, full priming and full immunization for children receiving different types of combination vaccines., Results: During the study period, monovalent vaccines were replaced by higher-valent combination vaccines. With the change from mono- to 4-, 5- and 6-valent vaccines, up-to-date vaccination increased for Hib, polio and HBV. Median age at immunization improved by 0.5 month for Hib, 0.4 month for polio and 0.9 month for HBV at the first dose and 2.2 months for Hib, 3.2 months for polio and 1.4 months for HBV at full immunization when comparing hexavalent with monovalent vaccines. Median age for 4-5-valent vaccines was intermediate. The difference between monovalent and 6-valent vaccines remained significant after stratifying/adjusting for the effect of birth cohorts., Conclusion: Combination vaccines are usually advocated for reducing the number of injections. In Germany, however, the use of combination vaccines has also significantly improved timeliness of immunizations.

Toll-like receptor 4 (TLR4) is required for efficient recognition of bacterial infections. We investigated an association between 2 TLR4 mutations (Asp(299)Gly and Thr(399)Ile) and meningococcal disease in 197 patients and 214 healthy controls by allele-specific real time polymerase chain reaction and direct sequencing. Although the allele frequency was not higher in the overall patient population, a significantly higher frequency in the 40 patients younger than 12 months of age (P = 0.007) was observed. We conclude that TLR4 mutations represent a risk factor for meningococcal disease in this age group.

Background: A measles outbreak was recently observed in Coburg, Bavaria, in a population with vaccination rates of 76.5% in 5- to 6-year-old children in the years preceding the outbreak. Only a small proportion of children had received 2 vaccinations against measles. Vaccine effectiveness is estimated in a household contact study and also by a screening method., Methods: A household contact study was conducted in families with at least 1 measles case by standardized computer-assisted telephone interviews to assess secondary attack rate and to estimate vaccine effectiveness. Vaccine effectiveness was also estimated with Farrington's screening method with information from school entry examinations and from questionnaires of confirmed measles cases in the Coburg outbreak., Results: Thirty-eight children were primary cases. Of their contacts, 20 children were included in the study as secondary cases (1 vaccinated), and 23 children were contacts who did not develop measles (12 vaccinated once and 4 vaccinated twice), resulting in a vaccine effectiveness of 90% (95% confidence interval, 35-97%) for one vaccine dose. The proportion of the population vaccinated reached 81.5% during the outbreak and the proportion of the cases vaccinated was 10.9%, resulting in a vaccine effectiveness estimated using the screening method of 97.2% (95% confidence interval, 95.7-98.3%)., Conclusions: With the use of 2 approaches to estimate the effectiveness of measles vaccination, a consistently high vaccine effectiveness of 90% or above was shown during a measles outbreak in Western Europe.

Background: Recently an increase in the number of invasive Haemophilus influenzae type b (Hib) cases was observed in the United Kingdom, which coincided with a temporary change from diphtheria-tetanus toxoids-wild-type pertussis to diphtheria-tetanus toxoids-acellular pertussis (DTaP) Hib vaccines. A study in Germany based on approximately 2 years of follow-up, estimated vaccine effectiveness (VE) of DTaP/Hib and DTaP-inactivated poliovirus/Hib combination vaccines against invasive Hib disease to be high., Objectives: To assess VE of DTaP-containing Hib vaccines against Hib in Germany with the use of extended follow-up of case surveillance and vaccine uptake., Subjects and Methods: Cases with confirmed systemic Hib infections in children born between June 1, 1996 and December 31, 1998 were ascertained by a nationwide active surveillance system from January 1998 through June 2002. A representative subcohort of 667 children born in the same time frame was randomly sampled in a nationwide vaccine coverage survey. VE was determined with a case-cohort approach of Cox regression with time-dependent covariates., Results: Thirty-six cases of Hib disease were reported. Of these, 10 were vaccinated with DTaP-containing Hib vaccines only and 20 were not vaccinated. Of the 10 vaccinated cases, 4 had received an incomplete primary series (1-2 doses), and 6 had received the full primary series (3 doses), 3 of whom also received the booster dose. VE of combination vaccines against invasive Hib infection was 89.6% [95% confidence interval (CI), 67.0-96.7] for an incomplete primary series, 96.7% (95% CI 87.7-99.1) for a full primary series and 98.5% (95% CI 94.5-99.6) for a booster dose (irrespective of priming)., Conclusion: Hib combination vaccines containing acellular pertussis antigens continue to be highly effective in Germany.

Background: In the US a pneumococcal conjugate vaccination program with a 7-valent conjugate vaccine was successfully implemented in 2000. How much invasive pneumococcal disease can potentially be prevented by the 7-valent (or 11-valent) vaccine in Europe?, Methods: Prospective, active surveillance of invasive pneumococcal disease in German children age <16 years was performed between 1997 and 2000. Age- and disease-specific coverage and incidence rates were assessed in children old enough to benefit from complete vaccination to estimate the annual number of cases potentially preventable., Results: A total of 1,743 cases were reported; 667 isolates were serotyped. Coverage of 7-valent (11-valent) conjugate vaccines in children age 6 months and older was age- and diagnosis-dependent, ranging from 10.5% (15.8%) to 78.3% (82.6%) for meningitis and from 13.6% (68.2%) to 75.0% (89.3%) for nonmeningitis invasive pneumococcal disease cases. Of an estimated annual number of 176 children with pneumococcal meningitis age 6 months or older, 112 (122) cases had serotypes included in the 7-valent (11-valent) conjugate vaccine compared with 181 (254) of 324 nonmeningitis invasive pneumococcal disease cases, with 37 of the 73 cases covered by the 11-valent vaccine only in children older than 5 years. Regarding meningitis in this age group the potential benefit was equally poor for both the 7-valent (12 of 37 cases) and the 11-valent vaccine (15 of 37 cases)., Conclusion: Coverage of the 7- and 11-valent conjugate vaccines depends markedly on age and disease. The additional potential benefit of the 11-valent compared with the 7-valent vaccine for pneumococcal meningitis was marginal.

Background: In recent surveillance data there are still many cases of measles and even local epidemics in Germany. We studied whether delayed measles vaccination contributes to this situation., Methods: Vaccine coverage data in children <3 years of age were assessed by a telephone survey. Three data sources for measles surveillance were analyzed: official measles notifications; sentinel data; and official hospital discharge diagnoses., Results: After the time recommended for completion of measles vaccination at Month 15, only 22% of German children had received their first vaccine dose. This percentage increased to 77% at the age of 24 months and to 87% at 36 months of age. According to all three surveillance instruments, the number of measles cases was highest in children age 1 to 4 years with a peak in the second year of life., Conclusions: More than 50% of measles cases in 1-year-old children would be prevented if presently observed vaccine coverage rates in the third year of life could be achieved 12 months earlier. Delayed measles vaccination is responsible for a large number of measles cases still occurring in the German population, where measles has not yet been eliminated. If vaccination were delivered according to the recommended time schedule, the incidence of measles would be considerably reduced.

Background: To compare the antibody concentrations against Bordetella antigens in health care workers in a pediatric hospital with those of two different populations without professional contact with children., Methods: In a pediatric hospital 155 health care workers (135 female, 20 male), 292 male navy recruits after 3 months at sea and 146 regular blood donors (41 female, 105 male) were screened for antibodies of isotypes IgG and IgA to pertussis toxin (PT) and filamentous hemagglutinin (FHA) by enzyme-linked immunosorbent assay., Results: Pediatric health care workers were positive for IgG anti-PT in 88%, for IgA anti-PT in 52%, for IgG anti-FHA in 99% and for IgA anti-FRA in 84%. Relative numbers for blood donors and recruits were 86 and 80% for IgG anti-PT, 56 and 55% for IgA anti-PT, 100 and 98% for IgG anti-FHA and 92 and 82% for IgA anti-FHA, respectively. Reverse cumulative distribution of all antibodies except for IgA anti-FHA showed no differences among the three groups; 2% of pediatric personnel, 3% of blood donors and 3% of navy recruits, respectively, had IgG anti-PT > or = 100 enzyme-linked immunosorbent assay units/ml, indicating a recent contact to Bordetella pertussis., Conclusion: Antibodies to B. pertussis antigens, such as IgG/IgA anti-PT and IgG/IgA anti-FHA, were similarly distributed in all three groups. Our results suggest that exposures leading to measurable immune responses to pertussis antigens in German pediatric health care workers are not significantly more frequent than in other populations without professional contacts with children.

Background: Since 1996 in Germany primary infant immunization against Haemophilus influenzae has been most commonly given in the form of diphtheria-tetanus toxoids-acellular pertussis/H. influenzae type b (DTaP/Hib) or diphtheria-tetanus toxoids-acellular pertussis (-inactivated poliovirus)/H. influenzae type b (DTaP-IPV/Hib) combination vaccines. These combination vaccines elicit lower anti-Hib antibody concentrations than the equivalent Hib conjugate administered as a separate injection, but the clinical relevance of this phenomenon is unknown., Methods and Findings: To assess the impact of DTaP/Hib combination vaccines on the incidence of invasive Hib disease in Germany, two independent surveillance systems, one hospital- and one laboratory-based, were used during 1998 and 1999 for detection of cases. Vaccination histories of all cases detected were obtained by telephone contact with parents or health care providers. During the 2-year study period invasive H. influenzae disease in the <5-year age group continued to fall, with a mean annual incidence of 1.01/100 000 children. National vaccination coverage rates revealed that only 70% of children given DTaP/Hib or DTaP-IPV/Hib received the recommended three doses in their first year of life, but the overall effectiveness of these vaccines was high at 97.5% (95% confidence interval, 96.3 to 98.4) for those who had received at least one dose. In subjects who received the full 3-dose schedule, effectiveness was 98.8% (95% confidence interval, 98.2 to 99.3)., Conclusion: Although it is well-documented that DTaP/Hib vaccines elicit lower anti-Hib titers than separate vaccines, such combinations are effective in reducing the incidence of invasive H. influenzae type b disease.

Objective: To assess the frequency of serologic evidence for an infection with microorganisms other than Bordetella pertussis in children with pertussis-like coughs., Methods: The study was performed within a protective efficacy trial of an acellular pertussis vaccine. Children who coughed for >7 days and had no laboratory evidence of recent infection with B. pertussis were eligible for the present study. Antibodies to Mycoplasma, Chlamydia, respiratory syncytial virus and influenza viruses A and B were measured by complement fixation, and antibodies to adenovirus and parainfluenza viruses 1, 2 and 3 were measured by enzyme-linked immunosorbent assay (ELISA) in acute and convalescent serum samples. Significant titer rises (4-fold titer rise in complement fixation, 100% increase of units in ELISA) and concentrations of antibodies beyond age-specific reference values were regarded as indicative of recent infection. In some children IgM antibodies to Epstein-Barr virus and to cytomegalovirus were also measured by ELISA., Results: A total of 149 of 1179 (12.6%) children had no laboratory evidence of B. pertussis infection. Serologic evidence for other infections were found in 56% (83 of 149). Adenovirus (33), parainfluenza viruses 1, 2 and 3 (18), Mycoplasma pneumoniae (15) and respiratory syncytial virus (14) were most common. Of this group 48% had been vaccinated against pertussis., Conclusion: We present data that a proportion of pertussis-like coughs in children may be caused by adenovirus, parainfluenza viruses, respiratory syncytial virus and Mycoplasma. The differential diagnosis of pertussis-like coughs by laboratory methods should include these infections, especially in vaccinated children.