Didrik F. Vestrheim

Effectiveness of a 2+1 dose schedule pneumococcal conjugate vaccination programme on invasive pneumococcal disease among children in Norway

The 7-valent pneumococcal conjugate vaccine (PCV-7) was licensed in Norway in 2001. In July 2006, PCV-7 was introduced in the Norwegian Childhood Vaccination Programme in a 2+1 dose schedule, with immunizations administered at 3, 5 and 12 months of age. PCV-7 was offered through the vaccination programme to all children born from January 2006, i.e. a catch-up for children aged 3-6 months. Prior to 2006 the use of PCV-7 was negligible. The effectiveness of the PCV-7 vaccination programme was assessed using data on invasive pneumococcal disease (IPD) incidence obtained from the Norwegian Surveillance System for Communicable Diseases, serotype distribution from the National Reference Laboratory for Pneumococci, and vaccine coverage and vaccination status from the Norwegian National Vaccination Register. Vaccine coverage quickly reached high levels; 95% of children >3 months born from January 2006 had received at least one immunization with PCV-7. The incidence rate of IPD among children <2 years rapidly declined; the rate of vaccine serotype IPD in this age group fell from an average of 47.1 cases/100,000 population in the 2 years prior to PCV-7 introduction to 13.7 cases/100,000 population in 2007. The incidence rate of nonvaccine serotype IPD remained stable. The vaccine programme effectiveness was estimated to be 74% (95% CI 57-85%). No vaccine failure was seen after complete primary immunization with two vaccine doses. Our findings indicate that PCV-7 provides highly effective protection against vaccine serotype IPD when administered in a 2+1 dose schedule.

Prompt effect of replacing the 7-valent pneumococcal conjugate vaccine with the 13-valent vaccine on the epidemiology of invasive pneumococcal disease in Norway.

The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the childhood immunisation programme in Norway in 2006 substantially decreased the incidence of vaccine-type (VT) invasive pneumococcal disease (IPD) in all age groups. Additionally, a slight increase in the non-vaccine (NVT) serotype IPD incidence (serotype replacement) was observed. After replacing PCV7 with PCV13 in 2011, a further decrease in IPD incidence is expected. However, the protection by the six additional serotypes opens new nasopharyngeal niches for colonisation, which favours conditions for serotype replacement. Close monitoring of IPD therefore remains important in order to quickly detect changes. In this observational retrospective population-based cohort study we used data notified nationally between 1 January 2004 and 31 December 2012 to determine the VT- and NVT-IPD incidences. The diversity in serotype distribution per year was analysed using the Simpsons index of diversity. Immunisation history of young children was obtained from the Norwegian Vaccination Registry to determine vaccine failure. The incidence of VT-IPD decreased in the targeted (<5 years) and non-targeted (≥5) age groups since PCV7 introduction and further decreased after the replacement with PCV13. Only two cases of vaccine failure were identified. This indicates very high effectiveness of the 2+1 schedules with PCV7 or PCV13 and suggests that non-vaccinated individuals profit through indirect protection. The decrease in incidence of PCV7-IPD in non-targeted age groups became larger in later years, indicating a lag phase for the indirect effects, and suggests that the indirect protection of PCV13 will increase in coming years. The incidence of some NVT, specifically serotypes 23B and 15A, increased after PCV13 introduction. This coincided with an increased Simpsons index of diversity in the targeted age group. As this suggests that serotype replacement is again occurring, continues monitoring of IPD is important so that adaptations to vaccine recommendations can be promptly issued.

Impact of a Pneumococcal Conjugate Vaccination Program on Carriage among Children in Norway

ABSTRACT In July 2006, the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in Norway with a reduced (2 doses + 1 boost) dose schedule. Post-PCV7 shifts in pneumococcal reservoirs were assessed by two point prevalence studies of nasopharyngeal colonization among children in day care centers, before (2006) and after (2008) widespread use of PCV7. Nasopharyngeal swabs were obtained from 1,213 children, 611 in 2006 and 602 in 2008. A total of 1,102 pneumococcal isolates were recovered. Serotyping, multilocus sequence typing, and antimicrobial drug susceptibility testing were performed on all isolates. Although carriage of PCV7 serotypes decreased among both vaccinated and unvaccinated children, the overall prevalence of pneumococcal carriage remained high (80.4%) after vaccine introduction. The pneumococcal populations were diverse, and in the shift toward non-PCV7 serotypes, expansion of a limited number of established clonal complexes was observed. While non-antimicrobial-susceptible clones persisted among PCV7 serotypes, antimicrobial resistance did not increase among non-PCV7 serotypes. Direct and indirect protection of PCV7 against nasopharyngeal colonization was inferred from an overall decrease in carriage of PCV7 serotypes. No preference was found for nonsusceptible clones among the replacing non-PCV7 serotypes.

Indirect effect of conjugate pneumococcal vaccination in a 2+1 dose schedule.

In 2006, the heptavalent pneumococcal conjugate vaccine (PCV7) was introduced in the Norwegian Childhood Vaccination Programme in a 2+1 dose schedule; immunisations are administered at 3, 5 and 12 months. Changes in invasive pneumococcal disease in all ages from the baseline years 2004-2005 to 2008 were assessed, focusing on the indirect effect in the unvaccinated population. Following the introduction of PCV7, incidence rates of IPD caused by vaccine serotypes declined across all age groups, the decline being statistically significant for the age groups <5 years, 5-19 years, 40-64 years and > or = 65 years. In the unvaccinated population aged > or = 5 years the incidence rate of IPD caused by PCV7 serotypes declined by 48% from 12.34 cases/100,000 population to 6.44 cases/100,000 population, accounting for 74% of prevented cases of IPD in 2008. Among the adults aged > or = 65 years the incidence rate of IPD caused by serotypes not included in PCV7 increased. No vaccine failure was identified, indicating a very high effectiveness of the 2+1 dose schedule vaccination programme.

Phenotypic and Genotypic Characterization of Streptococcus pneumoniae Strains Colonizing Children Attending Day-Care Centers in Norway

ABSTRACT A cross-sectional study of nasopharyngeal colonization with Streptococcus pneumoniae was performed among 573 children attending 29 day-care centers (DCCs) in Norway prior to the start of mass vaccination with the heptavalent pneumococcal conjugate vaccine (PCV-7). A sensitive sampling method was employed, including transport in an enrichment broth and serotyping of pneumococci directly from the broth, in addition to traditional single-colony isolation from blood agar plates. The prevalence of carriage was high, peaking at 88.7% in 2-year-olds. More than one serotype was isolated from 12.7% of the carriers. Of 509 isolates obtained, 227 (44.6%) belonged to the PCV-7 serotypes. Penicillin nonsusceptibility was rare (1.8% of the isolates). Nonsusceptibility to erythromycin (5.9%), clindamycin (2.0%), and tetracycline (5.5%) was associated with PCV-7 serotypes (P < 0.001). Multilocus sequence typing was performed on the whole strain collection, revealing 102 sequence types (STs), of which 31 (30.4%) were novel. Eleven isolates (2.2%) belonged to the England14-9 clone, and 19 isolates (3.7%) belonged to, or were single-locus variants of, the Portugal19F-21 clone. The pneumococcal populations within the DCCs were composed of a majority of isolates with STs shared between the DCCs and a minority of isolates with STs unique for each DCC. The highest numbers of different STs, including novel STs, were found within the most frequent serotypes. Our study indicates that carriage of S. pneumoniae is highly prevalent among children in Norwegian DCCs, with a genetically diverse pneumococcal population consisting of unique microepidemic DCC populations.

Decline in Early Childhood Respiratory Tract Infections in the Norwegian Mother and Child Cohort Study after Introduction of Pneumococcal Conjugate Vaccination

Background: The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the Norwegian Childhood Immunization Program in 2006. A substantial effectiveness of PCV7 immunization against invasive pneumococcal disease has been demonstrated, whereas evidence of its impact on respiratory tract infections are less consistent. Methods: This study included children participating in the Norwegian Mother and Child Cohort Study, which recruited pregnant women between 1999 and 2008. Maternal report of acute otitis media (AOM), lower respiratory tract infections (LRTIs) and asthma in the child was compared by PCV7 immunization status, as obtained from the Norwegian Immunization Registry. Generalized linear models with the log-link function were used to report adjusted relative risks (RRs) and 95% confidence intervals (CIs). Results: For children who had received 3 or more PCV7 immunizations by 12 months of age, the adjusted RRs of AOM and LRTIs between 12 and 18 months were 0.86 (95% CI: 0.81, 0.91) and 0.78 (95% CI: 0.70, 0.87) respectively, when compared with nonimmunized children. A reduced risk of AOM, RR 0.92 (95% CI: 0.90, 0.94), and LRTIs, RR 0.75 (95% CI: 0.71, 0.80), between 18 and 36 months of age was also identified among children who had received 3 or more immunizations by 18 months of age. No association was seen between PCV7 immunization and asthma at 36 months of age. Conclusion: Reduced incidences of AOM and LRTIs before 36 months of age were observed among children immunized with PCV7 through the childhood immunization program.

Decreased Carriage and Genetic Shifts in the Streptococcus pneumoniae Population After Changing the Seven-valent to the Thirteen-valent Pneumococcal Vaccine in Norway.

Background: Shifts in the pneumococcal population colonizing healthy children are expected after switching from a 7-valent pneumococcal conjugate vaccine (PCV7) to a 13-valent (PCV13) in the childhood immunization program. We assessed effects of the switch by comparing pneumococcal carriage and serotype and genetic diversity of pneumococci carried by children in the PCV13-era with those carried in the prevaccination-era and PCV7-era. Methods: Nasopharyngeal swabs were obtained in autumn 2013 from children attending day-care centers (874 swabs, 583 isolates). Serotyping, multilocus sequence typing and antimicrobial susceptibility testing were performed on all isolates. Results were compared with samples from 2006 (610 swabs, 538 isolates) and 2008 (600 swabs, 562 isolates). Results: The carriage prevalence in 2013 was 62 of 100 children (95% confidence intervals: 58–66), a significant decrease from 2006 and 2008. PCV13 serotypes accounted for 7% of isolates in 2013. Non-PCV13 prevalence increased from 2006 to 2008 [prevalence ratio: 1.73 (1.40–2.15)] but remained stable in 2013 [0.99 (0.88–1.12)]. Still, non-PCV13 serotypes 21, 23B, 23A and 22F had increased. In 2013, the serotype and genetic diversity had decreased slightly, and distinct serotype and genetic profiles clustered more within day-care centers compared with the earlier samples. Serotype switch was uncommon. Overall, antimicrobial resistance was limited. Conclusions: Carriage of PCV13 serotypes has decreased without a coinciding increase in non-PCV13 serotypes. The serotype and genetic shifts among non-PCV13 serotypes suggest that a new equilibrium has not yet been reached. As the few non-PCV13 serotypes that increased have generally a lower invasive capacity than vaccine serotypes, direct and indirect protection of PCV13 on invasive pneumococcal disease can be expected to continue.

Postvaccination Increase in Serotype 19A Pneumococcal Disease in Norway Is Driven by Expansion of Penicillin-Susceptible Strains of the ST199 Complex

ABSTRACT Serotype replacement in invasive pneumococcal disease has been observed after widespread use of the 7-valent pneumococcal conjugate vaccine (PCV7). Replacement is dominated by penicillin-nonsusceptible serotype 19A in several countries. Antibiotic selection pressure has been proposed to interact with immunization, leading to rapid replacement. In Norway, where prescription of antibiotics is limited, post-PCV7 replacement by serotype 19A is dominated by penicillin-susceptible clones. Hence, serotype 19A replacement occurs, although it is not driven by antibiotic selection pressure.

Effect of high-valency pneumococcal conjugate vaccines on invasive pneumococcal disease in children in SpIDnet countries: an observational multicentre study

BACKGROUND The Streptococcus pneumoniae Invasive Disease network (SpIDnet) actively monitors populations in nine sites in seven European countries for invasive pneumococcal disease. Five sites use 13-valent pneumococcal conjugate vaccine (PCV13) alone and four use the ten-valent PCV (PCV10) and PCV13. Vaccination uptake is greater than 90% in six sites and 67-78% in three sites. We measured the effects of introducing high-valency PCVs on the incidence of invasive pneumococcal disease in children younger than 5 years. METHODS We compared the incidence of invasive pneumococcal disease in each of the 4 years after the introduction of PCV13 alone or PCV10 and PCV13 with the average incidence during the preceding period of heptavalent PCV (PCV7) use, overall and by serotype category. We calculated incidence rate ratios (IRRs) and 95% CIs for each year and pooled the values for all sites in a random effects meta-analysis. FINDINGS 4 years after the introduction of PCV13 alone or PCV10 and PCV13, the pooled IRR was 0·53 (95% CI 0·43-0·65) for invasive pneumococcal disease in children younger than 5 years caused by any serotype, 0·16 (0·07-0·40) for disease caused by PCV7 serotypes, 0·17 (0·07-0·42) for disease caused by 1, 5, and 7F serotypes, and 0·41 (0·25-0·69) for that caused by 3, 6A and 19A serotypes. We saw a similar pattern when we restricted the analysis to sites where only PCV13 was used. The pooled IRR for invasive pneumococcal disease caused by non-PCV13 serotypes was 1·62 (1·09-2·42). INTERPRETATION The incidence of invasive pneumococcal disease caused by all serotypes decreased due to a decline in the incidence of vaccine serotypes. By contrast, that of invasive pneumococcal disease caused by non-PCV13 serotypes increased, which suggests serotype replacement. Long-term surveillance will be crucial to monitor the further effects of PCV10 and PCV13 vaccination programmes in young children. FUNDING European Centre for Disease Prevention and Control, Czech National Institute of Public Health, French National Agency for Public Health, Irish Health Services Executive, Norwegian Institute of Public Health, Public Health Agency of Catalonia, Public Health Department of Community of Madrid, Navarra Hospital Complex, Public Health Institute of Navarra, CIBER Epidemiology and Public Health, Institute of Health Carlos III, Public Health Agency of Sweden, and NHS Scotland.

Pherotypes of pneumococcal strains co-existing in healthy children

Genetic diversity in the species Streptococcus pneumoniae is mainly driven by horizontal gene transfer. S. pneumoniae is naturally competent for transformation. Competence is induced by a pheromone termed competence stimulating peptide (CSP) by a quorum-sensing mechanism. Two CSP pherotypes predominate amongst clinical isolates of S. pneumoniae, CSP-1 and CSP-2, with ability to trigger competence in bacteria of the homologue pherotype. Opposing theories on the effect of pherotypes on speciation have been proposed, either as a barrier for intra-pherotype gene transfer, or as a mechanism for fratricide resulting in lysis of non-competent bacterial cells. The aim of the present study was to determine pherotype distribution in strains of S. pneumococci isolated from the nasopharynges of healthy children. We sequenced the locus encoding CSP, comC, in sets of strains obtained from children colonised by multiple pneumococcal strains simultaneously. The impact of pherotype on co-colonisation was determined by comparing the observed distribution of pherotypes in co-colonising strains with the estimated pair-wise probability based on the overall pherotype distribution in the sample set. Five distinct comC alleles were identified, encoding CSP belonging to the two dominating pherotypes, CSP-1 (62.7%) and CSP-2 (37.3%). The observed distribution of pherotypes in sets of co-colonising pneumococcal strains did not differ from the probability estimate. Thus, co-colonisation of S. pneumoniae in healthy children is not restricted by pherotype.