Lotta Siira

Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial

BACKGROUND The Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was designed to assess the effectiveness of a pneumococcal vaccine containing ten serotype-specific polysaccharides conjugated to Haemophilus influenzae protein D, tetanus toxoid, and diphtheria toxoid as the carrier proteins (PHiD-CV10) against invasive pneumococcal disease. METHODS In this cluster-randomised, double-blind trial, children aged younger than 19 months received PHiD-CV10 in 52 clusters or hepatitis vaccines as control in 26 clusters. Infants aged younger than 7 months at the first vaccination received either a 3+1 or a 2+1 vaccination schedule, children aged 7-11 months received a 2+1 schedule, and those 12-18 months of age received a two-dose schedule. The primary and secondary objectives were to assess vaccine effectiveness against culture-confirmed invasive pneumococcal disease due to any of the ten vaccine serotypes for the 3+1 and 2+1 schedules, respectively, in children who received at least one PHiD-CV10 dose before 7 months of age. Masked follow-up of pneumococcal disease lasted from the first vaccination (from February, 2009, to October, 2010) to January 31, 2012. Invasive disease data were retrieved from data accumulated in the national infectious diseases register. This trial and the nested acute otitis media trial are registered with ClinicalTrials.gov, numbers NCT00861380 and NCT00839254, respectively. FINDINGS 47,369 children were enrolled from February, 2009, to October, 2010. 30,528 participants were assessed for the primary objective. 13 culture-confirmed vaccine-type cases of invasive pneumococcal disease were detected: none in the PHiD-CV10 3+1 group, one in the PHiD-CV10 2+1 group, and 12 in the control groups. The estimates for vaccine effectiveness were 100% (95% CI 83-100) for PHiD-CV10 3+1 and 92% (58-100) for PHiD-CV10 2+1 groups. Two cases of any culture-confirmed invasive disease irrespective of serotype were detected in combined PHiD-CV10 infant cohorts compared with 14 in the corresponding control cohorts (vaccine effectiveness 93%, 75-99). In catch-up cohorts, seven cases of invasive disease were reported, all in the control group: two cases in the children enrolled at 7-11 months of age; and five cases in children enrolled at 12-18 months of age (vaccine effectiveness 100%, 79-100). Non-fatal serious adverse events suspected to be vaccine-related were reported via routine post-immunisation safety surveillance in 18 children. INTERPRETATION This nationwide trial showed high PHiD-CV10 effectiveness against invasive pneumococcal disease when given in different schedules. For the first time, effectiveness of a 2+1 schedule in infants was confirmed in a clinical trial. FUNDING GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare, Finland.

Temporal Trends of Antimicrobial Resistance and Clonality of Invasive Streptococcus pneumoniae Isolates in Finland, 2002 to 2006

ABSTRACT The antimicrobial resistance of Streptococcus pneumoniae, or pneumococcus, is a growing global problem. In our study, 3,571 invasive pneumococcal isolates, recovered from blood and cerebrospinal fluid samples from patients in Finland between the years 2002 and 2006, showed an increase in erythromycin nonsusceptibility from 16% to 28% (P < 0.0001) over the 5-year study period, as well as a doubling of penicillin nonsusceptibility from 8% to 16% (P < 0.0001). Erythromycin nonsusceptibility increased especially in isolates derived from 0- to 2-year-old children and was 46% for this age group in 2006. Although multiresistance, defined as nonsusceptibility to penicillin, erythromycin, and tetracycline, was fairly rare (5.1% in 2006), 38% of the erythromycin-nonsusceptible isolates were also penicillin nonsusceptible, while 74% of the penicillin-nonsusceptible isolates were nonsusceptible to erythromycin. In contrast to the situation in continental Europe, but mirroring that in North America, the most frequent macrolide resistance determinant carried by 56% of the tested macrolide-resistant pneumococci was the mef gene. Serotypes 14, 9V, 19A, 6B, and 19F were most frequently nonsusceptible to erythromycin or penicillin. The penicillin-resistant invasive isolates (n = 88) were genotyped by multilocus sequence typing, which revealed the presence of 25 sequence types, 9 of which were novel. The majority of the isolates were related to one of several globally disseminated penicillin- or multiresistant clones, most importantly the rlrA adhesion pilus carrying clones Spain9V ST156 and Taiwan19F ST236. The penicillin-resistant pneumococcal population in Finland is therefore a combination of internationally recognized genotypes as well as novel ones.

A report of Streptococcus pneumoniae serotype 6D in Europe

Serotype 6D of Streptococcus pneumoniae has been reported in Asia and the Fijian islands among nasopharyngeal carriage isolates. We now report a 6D isolate from a Finnish adult with invasive pneumococcal disease. Interestingly, the Finnish isolate and Asian isolate capsule gene loci are almost identical.

Clonality behind the increase of multidrug-resistance among non-invasive pneumococci in Southern Finland

Multidrug-resistance among Streptococcus pneumoniae isolates, especially of serotype 19A, has increased in several countries recently. Even before the introduction of the pneumococcal conjugate vaccine into the Finnish National Vaccination Programme, the proportion of multidrug-resistant (MDR) pneumococci had doubled from 2007 to 2008, when it reached 3.6% in Southern Finland. Our aim was to look for a possible association between antimicrobial susceptibility and clonality among the MDR isolates. Twelve non-invasive isolates non-susceptible to penicillin, erythromycin, clindamycin, trimethoprim/sulfamethoxazole, and doxycycline from 2008 were available for serotyping, genotyping by multilocus sequence typing (MLST), and detection of genes encoding macrolide resistance and adherence-promoting pili. Two isolates were also resistant to ceftriaxone. Five serotypes, 19F, 19A, 6B, 23F, and 14, and six genotypes from three genetic lineages were found, among which CC320 was the largest. All isolates in this study carried the erm(B) macrolide resistance gene, and the CC320 isolates additionally carried the mef(A/E) macrolide resistance gene. Eleven isolates carried pilus islet 1, while the CC320 isolates also carried the pilus islet 2 genes. The findings emphasize the importance of the careful monitoring of antimicrobial susceptibility and serotype distribution among pneumococci, especially now that antimicrobials and pneumococcal vaccines are in widespread use.

Long-term impact of 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease among children in Finland

BACKGROUND The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Programme (NVP) in September 2010. The impact of PCV10 vaccination against invasive pneumococcal disease (IPD) in vaccine-eligible children has been high. We evaluated the long-term impact of PCV10 vaccination against IPD in vaccine-eligible and older, unvaccinated children six years after PCV10 introduction with a special focus on cross-protection against PCV10-related serotypes (serotypes in the same serogroups as the PCV10 types). METHODS We used data on IPD from the national, population-based surveillance. A target cohort of vaccine-eligible children (born June 2010 or later) was followed from 3 months of age until the end of 2016. For the indirect effect, another cohort of older PCV10-ineligible children was followed from 2012 through 2016. IPD rates were compared with those of season- and age-matched reference cohorts before NVP introduction. RESULTS Among vaccine-eligible children, the incidence of all IPD decreased by 79% (95% CI 74-83%). There was a statistically significant reduction in the incidence of 6A IPD, but for 19A, the reduction was non-significant and the incidence of 19A increased towards the end of the study period in the older vaccine-eligible children. The increase in non-PCV10 related serotypes was non-significant. In the unvaccinated older children, the incidence of all IPD decreased by 33% (95% CI 8-52%) compared to the reference cohort, and there was no impact on serotype 6A or 19A IPD. CONCLUSION Overall, the impact of PCV10 vaccination on IPD was high in vaccine-eligible children, with a major reduction in vaccine-type disease, and without notable replacement by other serotype groups. Our data suggest that PCV10 results in long-lasting direct cross-protection against 6A IPD. For 19A, no net reduction was observed six years after NVP introduction in the vaccine-eligible cohort. The indirect impact on IPD in unvaccinated children sustained.

Antimicrobial resistance in relation to sero- and genotypes among invasive Streptococcus pneumoniae in Finland, 2007-2011.

AIM We studied the serotypes and antimicrobial resistance of the invasive Streptococcus pneumoniae that had been isolated in Finland during 5 years. The 10-valent vaccine was introduced into the National Vaccination Programme in September 2010. METHODS We examined the antimicrobial resistance and serotype distribution of the invasive pneumococci (n=4,194) that had been isolated in Finland during 2007-2011. The penicillin-resistant (PEN R) (≥4 mg/L) isolates (n=12) were genotyped by MLST. RESULTS Serotype 14 was consistently the most prominent serotype, covering 18.0-20.1% of all the isolates. The proportion of serotypes 3, 19A, and 22F increased significantly, while that of 6B and the PCV10 vaccine serotypes combined decreased. PEN nonsusceptibility (≥0.12 mg/L) increased, ranging from 14.4% to 23.2% by year, and was the highest (28.5%) among the 0-2 year olds. The PEN and/or erythromycin (ERY) nonsusceptibility of several vaccine serotypes (4, 6B, 14, and 19F) increased significantly over the study period. The ERY nonsusceptibility was 26.6%. There was limited diversity among the PEN R isolates; all were a part of serotype 19F, 19A, or 14, and two globally disseminated genetic lineages carrying one or both pilus-encoding islets. CONCLUSIONS High and/or increasing nonsusceptibility rates underline the importance of monitoring the serotype distribution and antimicrobial susceptibility of pneumococci, especially after large-scale vaccination.Aim: We studied the serotypes and antimicrobial resistance of the invasive Streptococcus pneumoniae that had been isolated in Finland during 5 years. The 10-valent vaccine was introduced into the National Vaccination Programme in September 2010. Methods: We examined the antimicrobial resistance and serotype distribution of the invasive pneumococci (n=4,194) that had been isolated in Finland during 2007–2011. The penicillin-resistant (PEN R) (≥4 mg/L) isolates (n=12) were genotyped by MLST. Results: Serotype 14 was consistently the most prominent serotype, covering 18.0–20.1% of all the isolates. The proportion of serotypes 3, 19A, and 22F increased significantly, while that of 6B and the PCV10 vaccine serotypes combined decreased. PEN nonsusceptibility (≥0.12 mg/L) increased, ranging from 14.4% to 23.2% by year, and was the highest (28.5%) among the 0–2 year olds. The PEN and/or erythromycin (ERY) nonsusceptibility of several vaccine serotypes (4, 6B, 14, and 19F) increased significantly over the study pe...

Pneumococcemia in children – a retrospective study before universal pneumococcal vaccinations

To evaluate the incidence and characteristics of blood culture‐positive occult pneumococcemia compared with blood culture‐positive pneumococcal pneumonia in children.

From Quellung to multiplex PCR in pneumococcal serotyping — and back when needed

ABSTRACT All currently available vaccines against Streptococcus pneumoniae are based on selections of the over 90 different serotypes, which underlines the importance of serotyping for surveillance and vaccine efficacy monitoring. In this study, we modified and validated a PCR-based scheme for deducing the serotypes of the invasive pneumococci isolated in Finland. For validation, 170 isolates were serotyped using the new protocol with six sequential multiplex PCRs for the deduction of serotypes, supplemented with Quellung testing when needed. The results were compared with those obtained by traditional serotyping methods. We found that 98.8% (168/170) of the isolates were correctly serotyped by the new protocol. Subsequently, the scheme was taken into regular use for serotyping the invasive pneumococci isolated in Finland for serotype-specific surveillance purposes and has been applied in the serotyping of more than 1,500 invasive isolates so far. The sequential multiplex PCRs (mPCRs) have given a result for over 99% of the isolates and allowed us to both handle samples in bulk and noticeably reduce the cost of reagents. While serotyping primarily by PCR is precise and effective, Quellung testing remains the most reliable way to discover possible discrepancies between the DNA deduced and the phenotypic serotype of an isolate. Since implementing the protocol for regular use, two serotype 19F PCR-positive isolates were found to be serotype 19A by the Quellung reaction. While a rare occurrence, this is an important observation, which prompted a revision of our serotyping protocol to prevent possible underreporting of serotype 19A, a potential replacement serotype following large-scale vaccination.All currently available vaccines against Streptococcus pneumoniae are based on selections of the over 90 different serotypes, which underlines the importance of serotyping for surveillance and vaccine efficacy monitoring. In this study, we modified and validated a PCR based scheme for deducing the serotypes of the invasive pneumococci isolated in Finland. For validation, 170 isolates were serotyped using the new protocol with six sequential multiplex PCRs for the deduction of serotypes supplemented with Quellung when needed. The results were compared with those obtained by traditional serotyping methods. We found that 98.8 % (168/170) of the isolates were correctly serotyped by the new protocol. Subsequently, the scheme was taken into regular use for serotyping the invasive pneumococci isolated in Finland for serotype-specific surveillance purposes and has been applied in the serotyping of more than 1,500 invasive isolates so far. The sequential mPCRs have given a result for over 99 % of the isolates and allowed us to both handle samples in bulk and noticeably reduce the cost of reagents. While serotyping primarily by PCR is precise and effective, Quellung remains the most reliable way to discover possible discrepancies between the DNA deduced and the phenotypic serotype of an isolate. Since implementing the protocol for regular use, two serotype 19F PCR positive isolates were found to be serotype 19A by Quellung. While a rare occurrence, this is an important observation, which prompted a revision of our serotyping protocol to prevent possible underreporting of serotype 19A, a potential replacement serotype following large-scale vaccination.

External Quality Assurance for Laboratory Identification and Capsular Typing of Streptococcus pneumoniae

An external quality assessment (EQA) scheme for pneumococcal serotype identification has been performed over a period of 11 years, by a network of European pneumococcal reference laboratories. We report the results from the EQA, and present an assessment of the acceptability and utility of the EQA scheme. Reports from 22 EQA panels distributed in 2005–2016 were analysed. Each EQA panel consisted of seven isolates. A questionnaire including seven questions related to the acceptability and utility of the EQA scheme was distributed to all participating laboratories. Altogether, 154 pneumococcal isolates were tested. Of the 92 serologically distinct serotypes currently defined, 49 serotypes were included in the rounds. Discrepant results were observed in eight EQA rounds, involving 11 isolates (7.1%, 95% CI: 4% to 12%). All participating laboratories reported that the EQA scheme was useful for quality assurance purposes. Our results show that comparable serotyping data can be obtained in different laboratories. The EQA participation helps to keep the typing procedures at a high standard and provides data for accreditation purposes. The EQA is helpful when new technologies are introduced, and reveal limitations of both genotypic and phenotypic methods. Continuation of the presented EQA scheme is planned.

Antimicrobial Resistance in Relation to Sero- and Genotypes Among Invasive Streptococcus pneumoniae in Finland, 2007-2011

AIM We studied the serotypes and antimicrobial resistance of the invasive Streptococcus pneumoniae that had been isolated in Finland during 5 years. The 10-valent vaccine was introduced into the National Vaccination Programme in September 2010. METHODS We examined the antimicrobial resistance and serotype distribution of the invasive pneumococci (n=4,194) that had been isolated in Finland during 2007-2011. The penicillin-resistant (PEN R) (≥4 mg/L) isolates (n=12) were genotyped by MLST. RESULTS Serotype 14 was consistently the most prominent serotype, covering 18.0-20.1% of all the isolates. The proportion of serotypes 3, 19A, and 22F increased significantly, while that of 6B and the PCV10 vaccine serotypes combined decreased. PEN nonsusceptibility (≥0.12 mg/L) increased, ranging from 14.4% to 23.2% by year, and was the highest (28.5%) among the 0-2 year olds. The PEN and/or erythromycin (ERY) nonsusceptibility of several vaccine serotypes (4, 6B, 14, and 19F) increased significantly over the study period. The ERY nonsusceptibility was 26.6%. There was limited diversity among the PEN R isolates; all were a part of serotype 19F, 19A, or 14, and two globally disseminated genetic lineages carrying one or both pilus-encoding islets. CONCLUSIONS High and/or increasing nonsusceptibility rates underline the importance of monitoring the serotype distribution and antimicrobial susceptibility of pneumococci, especially after large-scale vaccination.Aim: We studied the serotypes and antimicrobial resistance of the invasive Streptococcus pneumoniae that had been isolated in Finland during 5 years. The 10-valent vaccine was introduced into the National Vaccination Programme in September 2010. Methods: We examined the antimicrobial resistance and serotype distribution of the invasive pneumococci (n=4,194) that had been isolated in Finland during 2007–2011. The penicillin-resistant (PEN R) (≥4 mg/L) isolates (n=12) were genotyped by MLST. Results: Serotype 14 was consistently the most prominent serotype, covering 18.0–20.1% of all the isolates. The proportion of serotypes 3, 19A, and 22F increased significantly, while that of 6B and the PCV10 vaccine serotypes combined decreased. PEN nonsusceptibility (≥0.12 mg/L) increased, ranging from 14.4% to 23.2% by year, and was the highest (28.5%) among the 0–2 year olds. The PEN and/or erythromycin (ERY) nonsusceptibility of several vaccine serotypes (4, 6B, 14, and 19F) increased significantly over the study pe...