Kari Auranen

Invasiveness of serotypes and clones of Streptococcus pneumoniae among children in Finland

ABSTRACT Streptococcus pneumoniae (the pneumococcus) causes diseases from otitis media to life-threatening invasive infection. The species is extremely antigenically and clonally diverse. We wished to determine odds ratios (ORs) for serotypes and clones of S. pneumoniae that cause invasive disease in Finland. A total of 224 isolates of S. pneumoniae from cases of invasive disease in children <2 years of age in Finland between 1995 and 1999 were serotyped, and sequence types (STs) were determined by multilocus sequence typing. These STs were compared with a previously published carriage data set. STs from invasive disease were significantly less diverse than those from carriage (invasive disease, 0.038 ± 0.01; carriage, 0.019 ± 0.005). The ORs of serotypes 14, 18C, 19A, and 6B were significantly greater than 1, indicating association with invasive disease. The ORs of 6A and 11A were significantly less than 1. The difference between 6A and 6B is significant, which suggests that relatively subtle changes in the capsule may have a dramatic effect upon disease potential. We found that ST 156, the Spain9V-3 clone which mainly expressed serotype 14 in Finland, is strongly associated with invasive disease (OR, 10.1; 95% confidence interval, 1.3 to 79.5). Significant associations with invasive disease were also detected for STs 482, 191, 124, and 138, and associations with carriage were detected for STs 485 and 62. These results demonstrate the invasive phenotype of the serotype 14 variant of the Spain9V-3 clone and differences between members of the same serogroup in invasive disease potential.

Ability of Pneumococcal Serotypes and Clones To Cause Acute Otitis Media: Implications for the Prevention of Otitis Media by Conjugate Vaccines

ABSTRACT The relative abilities of pneumococcal serotypes and strains (clones) to cause acute otitis media (AOM) were investigated by comparing the serotypes and genotypes of pneumococci recovered from cases of AOM (n = 149) in children <2 years of age with those from nasopharyngeal carriage (n = 288) in age-matched controls from the same region. The odds ratio (OR) for association of pooled vaccine serotypes with AOM was found to be slightly elevated over unity, although this was not significantly different from that of pooled nonvaccine or vaccine-related serotypes. Comparing individual serotypes, 19F and 23F had 2- to 2.5-fold higher ORs, although these were not markedly different from the ORs of nonvaccine serotypes. None of the major clones had an OR that was significantly greater than the average, and the differences in ORs among serotypes and clones were much less than those for invasive disease, suggesting little variation in their ability to cause AOM. We conclude that serotype replacement may reduce the long-term efficacy of these vaccines against AOM.

Nasopharyngeal colonization: a target for pneumococcal vaccination

The pneumococcal conjugate vaccine (PCV), licensed in 2000, is highly efficient in preventing serious disease caused by serotypes in the vaccine and also prevents symptomless colonization of the nasopharynx. Prevention of this first step in the infection cycle has important consequences: it reduces chances of spread of the infection and indirectly protects from disease. Through these indirect effects, the protection afforded by the vaccine extends to the whole population, including those not vaccinated (herd immunity). Already now, after 5 years of wide use of PCV for infant immunization in the USA, more cases are prevented through the indirect effects than by vaccine-induced immunity in those vaccinated. The extended protection increases the cost–effectiveness of PCV and should clearly encourage its use in poorly resourced countries. However, the accumulated experience also shows that the herd immunity, due to PCV, is partly offset by replacement of the vaccine serotypes by other, nonvaccine serotypes. Owing to the general reduced virulence of the latter, this has only had a modest effect on disease, but the possibility of more virulent nonvaccine serotypes arising cannot be ignored and should be the focus of continued surveillance.

Pneumococcal carriage in children during their first two years : important role of family exposure

Background. Close family and day-care contacts have been identified as risk factors for pneumococcal (Pnc) carriage. This study addresses the risk of Pnc carriage by infants 2 to 24 months of age in terms of simultaneous carriage of pneumococcus by family members. Methods. Nasopharyngeal swabs were collected from 100 Finnish infants and their family members on 10 scheduled visits (when infant was 2, 3, 4, 5, 6, 9, 12, 15, 18 and 24 months of age). The 7 most common pneumococcal serogroups (4, 6, 9, 14, 18, 19, 23), also represented in the new heptavalent Pnc conjugate vaccine, were analyzed. Marginal logistic regression analyses were performed to assess the relative importance of different predictors for carriage. Results. The carriage of the studied Pnc serogroups increased with age, being highest at the age of 18 months (28%). Among children older than 6 months of age, the strongest predictor of carriage was simultaneous carriage of the same serogroup by another family member (odds ratio, 3.8; 95% confidence interval, 2.1 to 6.9). At the age of 6 months or younger, carriage was rare and was not significantly associated with a family carriage. Conclusions. Young infants (≤6 months old) were largely protected from pneumococcal carriage. After this age family transmission seemed very important despite the small family size. Contrary to some earlier studies communal day care was not associated with an increased risk of Pnc carriage. This could be partly because of the long parental leave in Finland and thus the late age of starting organized day care.

Between-Strain Competition in Acquisition and Clearance of Pneumococcal Carriage—Epidemiologic Evidence From a Longitudinal Study of Day-Care Children

The state of pneumococcal carriage—that is, pneumococcal colonization in the nasopharynx of healthy persons—represents a reservoir for the spread of pneumococci among individuals. In light of the introduction of new pneumococcal conjugate vaccines, further knowledge on the dynamics of pneumococcal carriage is important. Different serotypes (strains) of pneumococcus are known to compete with each other in colonizing human hosts. Understanding the strength and mode of between-serotype competition is important because of its implications for vaccine-induced changes in the ecology of pneumococcal carriage. Competition may work through reduced acquisition of new serotypes, due to concurrent carriage in the individual, or through enhanced clearance of serotypes in carriers who harbor more than 1 serotype simultaneously. The authors employed longitudinal data (1999–2001) on pneumococcal carriage in Danish day-care children to analyze between-serotype competition. The data included observations of carriage in children who had not been vaccinated against pneumococcus, and the level of pneumococcal antibiotic resistance and antibiotic usage in the community was very low. Clearance of any single serotype was not affected by simultaneous carriage of other serotypes. In contrast, acquisition of other serotypes in already-colonized hosts was weak (relative rate of acquisition = 0.09, 95% credible interval: 0.05, 0.15).

Pneumococcal acute otitis media in relation to pneumococcal nasopharyngeal carriage

Background: Acute otitis media (AOM) is closely associated with viral upper respiratory tract infections, but the most common microbial agent found in the middle ear fluid during AOM is Streptococcus pneumoniae (Pnc). Pnc is also a common colonizer of the nasopharynx, and its prevalence is further increased during the viral infection. The aim of this study was to investigate the interplay between viral infection, pneumococcal acquisition and carriage in the development of Pnc AOM. Methods: Pnc carriage was assessed in a longitudinal study of 329 infants at scheduled visits at 3, 6, 9, 12, 15 and 18 months of age (N = 1715). The clinical outcome of the first episode of respiratory infection (“sick visit,” N = 774) in the following 3-month period was recorded. The occurrence and timing of Pnc AOM in relation to serotype specific carriage at the start of the observation period were assessed. Results: The occurrence, timing and duration of symptoms of the sick visits or the frequency of overall AOM were not associated with preceding pneumococcal carriage. Pnc AOM was in each case associated with concurrent carriage and 3.8 times (95% confidence interval, 1.4–10.0) more often with carriage acquired after the start of the observation period than with carriage already present at the scheduled visit. In all, 79% (55 of 70) of Pnc AOM events were caused by a serotype acquired after the start of the period. Conclusion: The majority of Pnc AOM events develop in association with newly acquired carriage of pneumococcus.

Replication in genetic studies of complex traits

Disappointments in replicating initial findings in gene mapping for complex traits are often attributed to small sample sizes and inadequate techniques to determine the threshold value. This is clearly not the whole truth. More fundamental reasons lie in the inherent heterogeneity related to disease, including genetic heterogeneity, differences in allele frequencies, and context‐dependency in genetic architecture. There are also other reasons related to the data collection and analysis. Replication may remain a source of frustration unless more emphasis is put on controlling these sources of heterogeneity between studies.

Transmission of Pneumococcal Carriage in Families: A Latent Markov Process Model for Binary Longitudinal Data

Abstract We present a Bayesian data augmentation model to estimate acquisition and clearance rates of carriage of Streptococcus pneumoniae (Pnc) bacteria. The panel observation data comprise 10 measurements of Pnc carriage (carrier/noncarrier of the bacteria) in all members of 97 families with young children over a period of 2 years. Using natural conditional independence assumptions, a transmission model is constructed for the unobserved dependent binary processes of the augmented data. The model explicitly considers carriage transmission within the family and carriage acquisition from the surrounding community. The joint posterior of the model parameters and the augmented data is explored by Markov chain Monte Carlo sampling. The analysis shows that in young children the rate of acquiring carriage of three common Pnc serotypes increases with age. In children less than 2 years old, the duration of carriage is longer than in older family members. Asymptomatic Pnc carriage is found highly transmittable between members of the same family. In young children, the estimated rate of acquiring carriage from a family member carrying Pnc is more than 20-fold to that from acquiring it from the community.

Longitudinal study on pneumococcal carriage during the first year of life in Bangladesh.

Background: The strong herd immunity effect and the serotype replacement associated with the use of the pneumococcal conjugate vaccine have highlighted the importance of asymptomatic pneumococcal carriage. To describe the development of pneumoccoccal carriage in a developing country setting we carried out a longitudinal pneumococcal carriage study in Bangladesh. Methods: Ninety-nine children, born in Savar, Bangladesh between May 2000 and April 2001, were enrolled in the study with their families. Nasopharyngeal samples were collected at prescheduled 2–4 week intervals from the index children and from their family members. The nasopharyngeal swabs were cultured for pneumococcal growth and pneumococci were identified and serotyped by standard methods. Results: We collected 1459 samples (92% of those planned) from the 99 index children and 2865 samples from other family members. The data showed high point prevalences of pneumococcal carriage among newborns (40–50% from 8 weeks of age on), a rapid pneumococcal acquisition with age (50% of the children had been colonized by pneumococci at least once by the age of 8 weeks) and a wide range of different serogroups/types (SGT). SGT 6 and 19 accounted for 35% of the pneumococci isolated from children <1-year-old, followed by SGT 15, 23, and 10 for a total of 56%. The SGT distribution in children up to 9-year-old was similar to that among the <1 year olds, with SGT 6 and 19 predominating. Older children and adults differed from the younger children by not having clearly predominating SGTs. Conclusions: The features found in our study are typical of pneumococcal carriage in developing countries. We believe that results from longitudinal modeling of carriage based on these extensive data can have wide geographic application.

Long-term persistence of immunity after immunisation with Haemophilus influenzae type b conjugate vaccine.

Although Haemophilus influenzae type b (Hib) conjugate vaccines, after licensure in 1987, are now recommended for world-wide use, the duration of protective immunity afforded by them is not known. We therefore assessed the immunogenity at 9-10 years of age in 37 children who had received the first Hib conjugate, PRP-D, in infancy (the Hib-conjugate group) and were now given a dose of Hib polysaccharide (PS) as a test vaccine. The anti-Hib PS antibodies (Hib-ab) were measured before and after this test vaccination, and the values compared to those in 37 control children who had not previously received any Hib vaccine and in 13 children who had received Hib PS vaccine in infancy (the Hib-PS group). Prior to the test vaccination, the Hib-ab concentrations in the Hib-conjugate group were 3.6-fold higher than in the control group. After the test vaccination, the Hib-conjugate group had higher total Hib-ab concentrations, higher proportion of IgG and higher avidity of Hib-ab than the control or the Hib-PS group, suggesting persisting immunological memory in a Hib-c group. A mathematical model, including memory, predicted accurately the Hib-ab concentrations, which are maintained through anamnestic responses to intervening stimuli (Hib or cross-reacting bacteria).