Decreased immune response to pneumococcal conjugate vaccine after 23-valent pneumococcal polysaccharide vaccine in children.

BACKGROUND: Pneumococcal polysaccharide vaccine (PPV) is used in children at high risk of IPD. PPV is generally not considered to induce immunologic memory, whereas pneumococcal conjugate vaccines (PCVs) elicit protective antibody responses in infants and induce immunologic memory. Little is known about the characteristics of immune responses to PCV in children who previously received PCV and PPV in series. OBJECTIVE: To characterize immune responses to 13-valent pneumococcal CRM197 conjugate vaccine (PCV13; serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) in children vaccinated in infancy with 9-valent pneumococcal-meningococcal C-CRM197 conjugate combination vaccine (PCV9-MnCC), followed by a toddler dose of PCV9-MnCC or 23-valent pneumococcal polysaccharide vaccine (PPV23). METHODS: Children (n=89) who received PCV9-MnCC in infancy and PPV23 or PCV9-MnCC at age 12 months in a previous (2002-2003) study were vaccinated at age 7.5 years with PCV13; groups PPV23/PCV13 (n=50) and PCV9/PCV13 (n=39). Immunoglobulin (Ig)G antibodies, avidity, and opsonophagocytic activity (OPA) were measured before and at 1 and 4 weeks postvaccination. RESULTS: One week postvaccination, IgG levels increased significantly for all serotypes in both groups, and >97% of vaccinees achieved IgG ≥0.35µg/ml 4 weeks after PCV13 vaccination. The PCV9/PCV13 group had higher IgG responses compared with the PPV23/PCV13 group. The upper limits of the 95% confidence intervals of the PPV23/PCV13:PCV9/PCV13 IgG geometric mean concentration ratios were <1.0 for serotypes 1, 4, 5, 9V, 18C, and 23F at 1 week. OPA and avidity results supported these findings. CONCLUSIONS: PPV23 vaccination of toddlers may compromise subsequent responses to pneumococcal conjugate vaccines. The clinical relevance of this finding is unclear.

Safety and immunogenicity of CRM197-conjugated pneumococcal-meningococcal C combination vaccine (9vPnC-MnCC) whether given in two or three primary doses.

This randomized trial compares safety and immunogenicity when vaccinating infants with a pneumococcal-meningococcal conjugate vaccine in two doses vs. three doses. Infants (N=223) received 9vPnC-MnCC (CRM197-conjugated pneumococcal serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F and meningococcal C polysaccharides) either at 3 and 5 or 3, 4 and 5 months and a booster with either 9vPnC-MnCC or 23-valent pneumococcal-polysaccharide vaccine (23vPPS) and CRM197-MnCC, at 12 months. Safety was monitored and IgG measured at 3, 6, 12 and 13 months in all subjects and serum bactericidal activity (SBA) in half. The 9vPnC-MnCC vaccine was safe and induced significant IgG to all components. Three doses induced higher antibody GMCs (geometric mean concentrations) at 6 months to seven of nine pneumococcal serotypes. This was most significant for 6B and 23F (p<0.001), that also showed lower rate of responders>0.35 (6B, 23F) and >0.5 microg/mL (6B). Antibody GMCs remained lower following 9vPnC-MnCC booster in subjects primed with two doses although only significant for serotype 18C. Significant memory responses were observed 1 week after the 23vPPS toddler dose. MnCC-IgG GMC was lower after two doses, however with comparable SBA. This study shows that the 9vPnC-MnCC vaccine is safe and induces successful immunological memory, whether given in two or three primary doses.

The role of antimicrobial use in the epidemiology of resistant pneumococci: A 10-year follow up.

The relative effects of risk factors on the prevalence of resistant pneumococcal clones are hard to determine. Our aim was to evaluate the effect of risk factors on the prevalence of resistant pneumococci in Iceland in 2003 and compare these data with results of identical studies performed in 1993 and 1998. A randomized sample of 1,107 children was chosen from all 2,532 children 1 to 6 years old living in four communities. Pneumococci were carried by 64% of the 824 children enrolled and 9.5% were penicillin nonsusceptible (PNSP), as opposed to 8.1% (1998) and 8.5% (1993), and multiresistant strains of serotype 6B were 2.5% compared to 7.5% and 7.7% (p < 0.001). Antimicrobial use had declined in 10 years from 1.5 to 1.0 courses/child per year. The only significant risk factor for carriage of PNSP and erythromycin-resistant pneumococci was antimicrobial consumption. The multiresistant type 6B strains disappeared from the areas with the lowest antimicrobial use but maintained unchanged prevalence in the area with the highest use. The number of erythromycin- resistant, penicillin-susceptible strains of all pneumococci (37/475, 7.8%) increased significantly from the previous studies (7/353, 2.0%, 1998, and 2/390, 0.5%, 1993). This observation is associated with increased use of macrolides, especially azithromycin, in one of the study areas. Spread of novel resistant clones appears to be the main reason for rapid and significant changes in pneumococcal resistance rates. The choice of antimicrobial class appears to influence the selective environment favoring particular resistant clones.

Otitis media, tympanostomy tube placement, and use of antibiotics. Cross-sectional community study repeated after five years.

OBJECTIVE: To investigate potential links between antimicrobial drug use for acute otitis media (AOM) and tympanostomy tube placements, and the relationship between parental views and physician antimicrobial prescribing habits. DESIGN: Cross-sectional community study repeated after five years. SUBJECTS: Representative samples of children aged 1-6 years in four well-defined communities in Iceland, examined in 2003 (n = 889) and 1998 (n = 804). MAIN OUTCOME MEASURES: Prevalence of antimicrobial treatments for AOM, tympanostomy tube placements, and parental expectations of antimicrobial treatment. Results. Tympanostomy tubes had been placed at some time in 34% of children in 2003, as compared with 30% in 1998. A statistically significant association was found between tympanostomy tube placement rate and antimicrobial use for AOM in 2003. In the area where antimicrobial use for AOM was lowest in 1998, drug use had further diminished significantly. At the same time, the prevalence of tympanostomy tube placements had diminished from 26% to 17%. Tube placements had increased significantly, from 35% to 44%, in the area where antimicrobial use for AOM was highest. Parents in the area where antimicrobial consumption was lowest and narrow spectrum antimicrobials were most often used were less likely to be in favour of antimicrobial treatment. CONCLUSIONS: Comparison between communities showed a positive correlation between antimicrobial use for AOM and tympanostomy tube placements. The study supports a restrictive policy in relation to prescriptions of antibiotics for AOM. It also indicates that well-informed parents predict a restrictive prescription policy.

Tympanostomy tube placements, sociodemographic factors and parental expectations for management of acute otitis media in Iceland.

BACKGROUND: Widespread antimicrobial use is a risk factor for development of antimicrobial resistance. Antimicrobial treatment of acute otitis media (AOM) may not always be necessary. Little is known about the influence of parental expectations on physicians' decision-making in relation to treatment of AOM. Evidence is insufficient as to whether tympanostomy tube placement reduces antibiotic consumption. METHODS: We randomly selected 1,030 children 1 to 6 years old living in 4 geographic areas in Iceland to be invited to participate in the study. Information about sociodemographic factors, antimicrobial prescriptions and their indications during the preceding 12 months, tympanostomy tube placements and parental views on antimicrobial use and bacterial resistance were obtained from a questionnaire completed by the parents and medical records. RESULTS: The incidence of AOM episodes resulting in antimicrobial prescription for 804 children recruited into the study was 0.7 (95% confidence interval, 0.6 to 0.8) per child per year, highest among children age 1 year, i.e. 1.8 prescriptions (95% confidence interval, 1.4 to 2.2). The cumulative incidence of tympanostomy tube placements was approximately 30%. Antimicrobial use during the preceding 8 weeks for children with and without tubes did not differ (P = 0.36). Fifteen percent of children with tubes had received antimicrobials during the preceding 8 weeks at last once for AOM compared with 14% of those without tubes (P = 0.97). Parents in the area where antimicrobial consumption was lowest were less likely to accept antimicrobial treatment than parents in the other areas (P = 0.005). Parents of children who had previously received antimicrobials for AOM were more likely to accept antimicrobials (P = 0.04). CONCLUSIONS: Parental expectations to antimicrobial treatment and awareness about resistance development appear to influence treatment strategies for AOM. The high rate of tympanostomy tube placement in preschool children does not result in reduced antimicrobial consumption.

Clonal spread of resistant pneumococci despite diminished antimicrobial use.

The effects of community-wide interventions to reduce resistance rates are poorly understood. This study evaluated the effect of reduced antimicrobial usage on the spread of penicillin-nonsusceptible pneumococci (PNSP) in four communities in Iceland. The study was performed after interventions to reduce antimicrobial usage and compared to an identical study performed 5 years before. A randomized sample of 953 children was chosen from all 2,900 1- to 6-year-old children living in four well-defined communities. The main outcome measures were nasopharyngeal carriage of PNSP and individual and community use of antimicrobials. Pneumococci were carried by 51.7% of the 743 children enrolled, and 8.1% of the pneumococci were PNSP as opposed to 8.5% in the previous study. The antimicrobial use of participants had been reduced from 1.5 to 1.1 courses/year and the overall use among children <7 years old living in the study areas from 13.6 to 11.1 defined daily dosages/1000 children per day. The prevalence of PNSP increased in the two areas furthest away from the capital area despite reduced consumption. The major risk factors for carriage of PNSP remained the same. Interventions can be effective in reducing antimicrobial use. Pandemic multiresistant clones can also spread fast in small communities with low antimicrobial use, where their appearance may be delayed compared to highly populated urban areas. Clonal spread and herd immunity are important factors to be considered in the evaluation of intervention effects.