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1.  Effectiveness of Pandemic and Seasonal Influenza Vaccines in Preventing Laboratory-Confirmed Influenza in Adults: A Clinical Cohort Study during Epidemic Seasons 2009–2010 and 2010–2011 in Finland 
PLoS ONE  2014;9(9):e108538.
One dose of pandemic influenza vaccine Pandemrix (GlaxoSmithKline) was offered to the entire population of Finland in 2009–10. We conducted a prospective clinical cohort study to determine the vaccine effectiveness in preventing febrile laboratory-confirmed influenza infection during the influenza season 2009–10 and continued the study in 2010–11.
In total, 3,518 community dwelling adults aged 18–75 years living in Tampere city were enrolled. The participants were not assigned to any vaccination regimen, but they could participate in the study regardless of their vaccination status or intention to be vaccinated with the pandemic or seasonal influenza vaccine. They were asked to report if they received Pandemrix in 2009–10 and/or trivalent influenza vaccine in 2010–11. Vaccinations were verified from medical records. The participants were instructed to report all acute symptoms of respiratory tract infection with fever (at least 38°C) and pneumonias to the study staff. Nasal and oral swabs were obtained within 5–7 days after symptom onset and influenza-specific RNA was identified by reverse transcription polymerase chain reaction.
In 2009–10, the estimated vaccine effectiveness was 81% (95%CI 30–97). However, the vaccine effectiveness could not be estimated reliably, because only persons in prioritized groups were vaccinated before/during the first pandemic wave and many participants were enrolled when they already had the symptoms of A(H1N1)pdm09 influenza infection. In 2010–11, 2,276 participants continued the follow-up. The vaccine effectiveness, adjusted for potential confounding factors was 81% (95%CI 41–96) for Pandemrix only and 88% (95%CI 63–97) for either Pandemrix or trivalent influenza vaccine 2010–11 or both, respectively.
Vaccination with an AS03-adjuvanted pandemic vaccine in 2009–10 was still effective in preventing A(H1N1)pdm09 influenza during the following epidemic season in 2010–11.
Trial Registration NCT01024725. NCT01206114.
PMCID: PMC4180439  PMID: 25265186
2.  No Serological Evidence of Influenza A H1N1pdm09 Virus Infection as a Contributing Factor in Childhood Narcolepsy after Pandemrix Vaccination Campaign in Finland 
PLoS ONE  2013;8(8):e68402.
Narcolepsy cataplexy syndrome, characterised by excessive daytime sleepiness and cataplexy, is strongly associated with a genetic marker, human leukocyte antigen (HLA) DQB1*06:02. A sudden increase in the incidence of childhood narcolepsy was observed after vaccination with AS03-adjuvanted Pandemrix influenza vaccine in Finland at the beginning of 2010. Here, we analysed whether the coinciding influenza A H1N1pdm pandemic contributed, together with the Pandemrix vaccination, to the increased incidence of childhood narcolepsy in 2010. The analysis was based on the presence or absence of antibody response against non-structural protein 1 (NS1) from H1N1pdm09 virus, which was not a component of Pandemrix vaccine.
Non-structural (NS) 1 proteins from recombinant influenza A/Udorn/72 (H3N2) and influenza A/Finland/554/09 (H1N1pdm09) viruses were purified and used in Western blot analysis to determine specific antibody responses in human sera. The sera were obtained from 45 patients who fell ill with narcolepsy after vaccination with AS03-adjuvanted Pandemrix at the end of 2009, and from controls.
Based on quantitative Western blot analysis, only two of the 45 (4.4%) Pandemrix-vaccinated narcoleptic patients showed specific antibody response against the NS1 protein from the H1N1pdm09 virus, indicating past infection with the H1N1pdm09 virus. Instead, paired serum samples from patients, who suffered from a laboratory confirmed H1N1pdm09 infection, showed high levels or diagnostic rises (96%) in H1N1pdm virus NS1-specific antibodies and very high cross-reactivity to H3N2 subtype influenza A virus NS1 protein.
Based on our findings, it is unlikely that H1N1pdm09 virus infection contributed to a sudden increase in the incidence of childhood narcolepsy observed in Finland in 2010 after AS03-adjuvanted Pandemrix vaccination.
PMCID: PMC3738560  PMID: 23950869
3.  Comparative analysis of Streptococcus pneumoniae transmission in Portuguese and Finnish day-care centres 
BMC Infectious Diseases  2013;13:180.
Day-care centre (DCC) attendees play a central role in maintaining the circulation of Streptococcus pneumoniae (pneumococcus) in the population. The prevalence of pneumococcal carriage is highest in DCC attendees but varies across countries and is found to be consistently lower in Finland than in Portugal. We compared key parameters underlying pneumococcal transmission in DCCs to understand which of these contributed to the observed differences in carriage prevalence.
Longitudinal data about serotype-specific carriage in DCC attendees in Portugal (47 children in three rooms; mean age 2 years; range 1–3 years) and Finland (91 children in seven rooms; mean age 4 years; range 1–7 years) were analysed with a continuous-time event history model in a Bayesian framework. The monthly rates of within-room transmission, community acquisition and clearing carriage were estimated.
The posterior mean of within-room transmission rate was 1.05 per month (Portugal) vs. 0.63 per month (Finland). The smaller rate of clearance in Portugal (0.57 vs. 0.73 per month) is in accordance with the children being younger. The overall community rate of acquisition was larger in the Portuguese setting (0.25 vs. 0.11 per month), in agreement with that the groups belonged to a larger DCC. The model adequately predicted the observed levels of carriage prevalence and longitudinal patterns in carriage acquisition and clearance.
The difference in prevalence of carriage (61% in Portuguese vs. 26% among Finnish DCC attendees) was assigned to the longer duration of carriage in younger attendees and a significantly higher rate of within-room transmission and community acquisition in the Portuguese setting.
PMCID: PMC3652738  PMID: 23597389
Streptococcus pneumoniae; Pneumococcus; Day care; Child; Transmission; Carriage; Prevalence; Longitudinal studies; Portugal; Finland; Statistical models; Bayesian inference; Data augmentation
4.  Clustering of serotypes in a longitudinal study of Streptococcus pneumoniae carriage in three day care centres 
Streptococcus pneumoniae (pneumococcus) causes a wide range of clinical manifestations that together constitute a major burden of disease worldwide. The main route of pneumococcal transmission is through asymptomatic colonisation of the nasopharynx. Studies of transmission are currently of general interest because of the impact of the new conjugate-polysaccharide vaccines on nasopharyngeal colonisation (carriage). Here we report the first longitudinal study of pneumococcal carriage that records serotype specific exposure to pneumococci simultaneously within the two most important mixing groups, families and day care facilities.
We followed attendees (N = 59) with their family members (N = 117) and the employees (N = 37) in three Finnish day care centres for 9 months with monthly sampling of nasopharyngeal carriage. Pneumococci were cultured, identified and serotyped by standard methods.
Children in day care constitute a core group of pneumococcal carriage: of the 36 acquisitions of carriage with documented exposure to homologous pneumococci, the attendee had been exposed in her/his day care centre in 35 cases and in the family in 9 cases. Day care children introduce pneumococci to the family: 66% of acquisitions of a new serotype in a family were associated with simultaneous or previous carriage of the same type in the child attending day care. Consequently, pneumococcal transmission was found to take place as micro-epidemics driven by the day care centres. Each of the three day care centres was dominated by a serotype of its own, accounting for 100% of the isolates of that serotype among all samples from the day care attendees.
The transmission of pneumococci is more intense within than across clusters defined by day care facilities. The ensuing micro-epidemic behaviour enhances pneumococcal transmission.
PMCID: PMC2639357  PMID: 19116005
5.  Using Multilocus Sequence Data To Define the Pneumococcus 
Journal of Bacteriology  2005;187(17):6223-6230.
We investigated the genetic relationships between serotypeable pneumococci and nonserotypeable presumptive pneumococci using multilocus sequence typing (MLST) and partial sequencing of the pneumolysin gene (ply). Among 121 nonserotypeable presumptive pneumococci from Finland, we identified isolates of three classes: those with sequence types (STs) identical to those of serotypeable pneumococci, suggesting authentic pneumococci in which capsular expression had been downregulated or lost; isolates that clustered among serotypeable pneumococci on a tree based on the concatenated sequences of the MLST loci but which had STs that differed from those of serotypeable pneumococci in the MLST database; and a more diverse collection of isolates that did not cluster with serotypeable pneumococci. The latter isolates typically had sequences at all seven MLST loci that were 5 to 10% divergent from those of authentic pneumococci and also had distinct and divergent ply alleles. These isolates are proposed to be distinct from pneumococci but cannot be resolved from them by optochin susceptibility, bile solubility, or the presence of the ply gene. Complete resolution of pneumococci from the related but distinct population is problematic, as recombination between them was evident, and a few isolates of each population possessed alleles at one or occasionally more MLST loci from the other population. However, a tree based on the concatenated sequences of the MLST loci in most cases unambiguously distinguished whether a nonserotypeable isolate was or was not a pneumococcus, and the sequence of the ply gene fragment was found to be useful to resolve difficult cases.
PMCID: PMC1196147  PMID: 16109964
6.  Invasiveness of Serotypes and Clones of Streptococcus pneumoniae among Children in Finland  
Infection and Immunity  2005;73(1):431-435.
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.
PMCID: PMC538975  PMID: 15618181
7.  Ability of Pneumococcal Serotypes and Clones To Cause Acute Otitis Media: Implications for the Prevention of Otitis Media by Conjugate Vaccines  
Infection and Immunity  2004;72(1):76-81.
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.
PMCID: PMC343969  PMID: 14688083

Results 1-7 (7)