Zitta B. Harboe

Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis.

BACKGROUND The 92 capsular serotypes of Streptococcus pneumoniae differ greatly in nasopharyngeal carriage prevalence, invasiveness, and disease incidence. There has been some debate, though, regarding whether serotype independently affects the outcome of invasive pneumococcal disease (IPD). Published studies have shown variable results with regard to case-fatality ratios for specific serotypes and the role of host factors in affecting these relationships. We evaluated whether risk of death due to IPD is a stable serotype-associated property across studies and then compared the pooled effect estimates with epidemiologic and biological correlates. METHODS We performed a systematic review and meta-analysis of serotype-specific disease outcomes for patients with pneumonia and meningitis. Study-specific estimates of risk of death (risk ratio [RR]) were pooled from 9 studies that provided serotype-specific data on pneumonia and meningitis using a random-effects method with serotype 14 as the reference. Pooled RRs were compared with RRs from adults with low comorbidity scores to evaluate potential confounding by host factors. RESULTS Significant differences were found in the RR estimates among serotypes in patients with bacteremic pneumonia. Overall, serotypes 1, 7F, and 8 were associated with decreased RRs, and serotypes 3, 6A, 6B, 9N, and 19F were associated with increased RRs. Outcomes among meningitis patients did not differ significantly among serotypes. Serotypes with increased RRs had a high carriage prevalence, had low invasiveness, and were more heavily encapsulated in vitro. CONCLUSIONS These results suggest that IPD outcome, like other epidemiologic measures, is a stable serotype-associated property.

Pneumococcal Serotypes and Mortality following Invasive Pneumococcal Disease: A Population-Based Cohort Study

Analyzing population-based data collected over 30 years in more than 18,000 patients with invasive pneumococcal infection, Zitta Harboe and colleagues find specific pneumococcal serotypes to be associated with increased mortality.

Impact of 13-Valent Pneumococcal Conjugate Vaccination in Invasive Pneumococcal Disease Incidence and Mortality

BACKGROUND The impact of the 13-valent pneumococcal conjugate vaccine (PCV13) at the population level is unclear. We explored PCV13s effect in reducing invasive pneumococcal disease (IPD)-related morbidity and mortality, and whether serotype-specific changes were attributable to vaccination or expected as a part of natural, cyclical variations. METHODS This was a Danish nationwide population-based cohort study based on the linkage of laboratory surveillance data and the Danish Civil Registration System. Changes in IPD incidence and mortality during baseline (2000-2007), 7-valent pneumococcal conjugate vaccine (PCV7) (2008-2010), and PCV13 (2011-2013) periods were estimated. Predicted incidences of serotypes were estimated controlling for cyclical trends from historical patterns observed during the past 20 years. RESULTS We observed a 21% reduction (95% confidence interval [CI], 17%-25%) in IPD incidence in the total population after PCV13s introduction, and a 71% reduction (95% CI, 62%-79%) in children aged <2 years, considered as the vaccine effectiveness. We estimated a 28% reduction (95% CI, 18%-37%) in IPD-related 30-day mortality, from 3.4 deaths (95% CI, 3.2-3.6) per 100 000 population in the pre-PCV period to 2.4 (95% CI, 2.2-2.7) in the PCV13 period. The decline in mortality was observed across all age groups but was mainly related to mortality reductions in the nonvaccinated population. For serotypes 1 and 3, there were no significant changes in incidence beyond what would be expected from natural cyclical patterns. Serotype 19A significantly increased following PCV7s introduction, but the incidence declined toward baseline in 2012. CONCLUSIONS PCV13 has brought greater benefits than we had expected in our setting. We observed a further decline on IPD incidence shortly after the shift from PCV7 to PCV13 in the national immunization program. This decline was accompanied by a substantial population-level decline in pneumococcal-related mortality of nearly 30% among nonvaccinated persons.

Temporal Trends in Invasive Pneumococcal Disease and Pneumococcal Serotypes over 7 Decades

Background. Pneumococcal infections have historically played a major role in terms of morbidity and mortality. We explored historical trends of invasive pneumococcal disease (IPD) and pneumococcal serotypes in a population exposed to limited antibiotic selective pressure and conjugate pneumococcal vaccination (PCV). Methods. Retrospective cohort study based on nationwide laboratory surveillance data on IPD collected uninterruptedly in Denmark during 1938-2007. Changes in the reported incidence and trends of pneumococcal serotypes were explored using nonlinear regression analysis. Results. There were 25,502 IPD cases included in our study. The median incidence of IPD increased from 2.8 cases per 100,000 population (interquartile range [IQR], 1.5-2.6) during the first 4 decades to 15.7 cases per 100,000 population (IQR, 7-20.4) during the 1980s and 1990s, mainly attributed to an increase in the number of bacteremia cases. The incidence of meningitis remained relatively stable, with a median of 1.3 cases per 100,000 population (IQR, 0.9-1.6). The proportions of serotypes/groups 4 and 9 increased; the proportion of serotype 18C decreased; the proportions of serotypes 6, 7F, 14, and 23F remained stable; and serotype 2 nearly disappeared. Before the 1960s, serotypes 1, 2, 3, and 5 presented peaks every 2-3 years, becoming less frequent during the 1970s with peaks every 7-10 years. Between 20% and 90% of IPD in children <5 years were caused by PCV serotypes during the last 4 decades. Cases of IPD caused by serotype 19A increased before introduction of PCV. Between 1993 and 2007, the level of resistance to macrolides and β-lactams was ≤6%. Conclusions. The epidemiology of IPD and single serotypes has constantly changed over the past 7 decades. PCV serotypes appeared to dominate the pneumococcal population.

Improving the Immunogenicity of Pneumococcal Conjugate Vaccine in HIV-Infected Adults with a Toll-Like Receptor 9 Agonist Adjuvant: A Randomized, Controlled Trial

BACKGROUND Persons infected with human immunodeficiency virus (HIV) are often hyporesponsive to immunization, including pneumococcal vaccines. We hypothesized that adding CPG 7909, a toll-like receptor 9 (TLR9) agonist and vaccine adjuvant, to 7-valent pneumococcal conjugate vaccine (7vPnC) would increase its immunogenicity in HIV-infected adults. METHODS We performed a double-blind, placebo-controlled, phase 1b/2a trial randomizing HIV-positive patients to receive double doses of 7vPnC (Prevnar) at 0 and 3 months and 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPV-23; Pneumo Novum) at 9 months, with experimental patients receiving 1 mg of CPG 7909 added to each of their 3 vaccine doses; control patients had phosphate-buffered saline added instead. Immunogenicity and safety were evaluated for up to 10 months. The primary end point was the proportion of vaccine high responders at 9 months, defined as a 2-fold increase in IgG levels to > or = 1 microg/mL for at least 5 of 7 of the 7vPnC serotypes. RESULTS Ninety-seven participants were included in the study. The proportion of vaccine high responders was higher in the experimental group (n = 48) than among controls (n = 49; 48.8% vs 25.0%; P = .02) at 9 months. Greater proportions of high responders were also observed at 3 (51.1% vs 39.6%; P = .26), 4 (77.3% vs 56.3%; P = .03), and 10 months (87.8% vs 51.1%; P < .001). Mild systemic and injection site reactions to 7vPnC were more common in the experimental group than the control group (100% vs 81.3%; P = .002). CPG 7909 did not increase non-7vPnC IgG levels after PPV-23 immunization. No adverse effects on CD4(+) cell count or organ functions occurred in either group. CONCLUSIONS The addition of a TLR9 agonist to 7vPnC significantly enhanced the proportion of vaccine high responders. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00562939 .

Early effectiveness of heptavalent conjugate pneumococcal vaccination on invasive pneumococcal disease after the introduction in the Danish Childhood Immunization Programme.

We evaluated the effectiveness of the heptavalent pneumococcal conjugate vaccine (PCV7) on invasive pneumococcal disease (IPD) 1 year after PCV7s introduction in the childhood immunization programme through a nationwide cohort study based on laboratory surveillance data. There was a decline in the overall incidence of IPD from 19.4 to 17.1 cases per 100,000 population (incidence rate ratios (IRR) 0.87; 95% confidence interval (CI) [0.81-0.96]), and of meningitis from 1.56 to 1.16 (IRR 0.74; 95% CI [0.57-0.97]) comparing pre-PCV7 (years 2000-2007) and PCV7 (year 2008) periods. In children <2 years, the incidence decreased from 54 to 23 cases per 100,000 (IRR 0.43; 95% CI [0.29-0.62]) and for vaccine-serotypes from 36.7 to 7.7 (IRR 0.20; 95% CI [0.09-0.38]). The incidence of IPD declined approximately 10% (IRR 0.90; 95% CI [0.84-0.97]) in patients aged >or=2 years. The case fatality was 17% in both periods. The administration of PCV7 was followed by a marked decline in the incidence of IPD in both vaccinated and non-vaccinated individuals.

Antibody responses to pertussis toxin display different kinetics after clinical Bordetella pertussis infection than after vaccination with an acellular pertussis vaccine.

The measurement of IgG anti-pertussis toxin (IgG anti-PT) antibodies by ELISA is a frequently used method for studying the antibody responses after pertussis vaccination and after Bordetella pertussis infection. Such responses vary according to the different vaccines used as well as to the immunization and infection history of the participants. In the present study, the decay kinetics of the IgG anti-PT antibody response was determined for 71 Danish children and adults with bacteriologically confirmed B. pertussis infection and for 20 Danish adults booster-vaccinated with an acellular pertussis vaccine. For both groups, biphasic decay was seen, but the individual antibody responses varied greatly. No differences related to age were seen. Within each group, individual decay profiles showed parallel log-linear decay for the late part of the response. Antibody half-life was calculated for the late, slower part of the biphasic response curves for both groups (>5 months after diagnosis for individuals with confirmed infection; >3 months for vaccinated individuals). The median half-life for post-infection antibodies was 221 days [interquartile range (IQR) 159-314 days, 36 individuals], and the median half-life for post-vaccination antibodies was 508 days (IQR 428-616 days, 14 individuals). This difference was statistically significant (P<0.0001). Thus, in this setting, we found that the IgG anti-PT antibody decay after an infection with B. pertussis is more than twice as fast as the decay after booster vaccination with an acellular pertussis vaccine. Such knowledge of the IgG anti-PT decay kinetics is crucial for interpretation of serological data that will be used either for diagnosis or for epidemiological studies and surveillance of B. pertussis infections.

Impact of pneumococcal vaccination in Denmark during the first 3 years after PCV introduction in the childhood immunization programme.

BACKGROUND AND AIMS The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in Denmark in October 2007 in a 2+1 schedule with a catch-up programme for children up to 17 months of age. To assess the impact of PCV we evaluated on the whole population: (1) direct and indirect effects on incidence of invasive pneumococcal disease (IPD), (2) changes in pneumococcal serotype distribution and (3) IPD related mortality. METHODS We compared disease incidence in pre-PCV (years 2000-2007) and PCV periods (years 2008-2010) based on national surveillance data. RESULTS In children aged 0-5 years the overall incidence of IPD decreased from 26.7 to 16.3 cases per 100,000 (IRR 0.58; 95% Confidence Interval (CI) [0.48-0.69]) and case fatality declined from 1.8% (12 deaths) in the eight-year pre-PCV period to 0% (no deaths) in the three-year PCV period. In the whole population the overall incidence of IPD and of IPD caused by vaccine serotypes declined significantly from 19.5 to 17.7 and from 7.7 to 3.8 cases per 100,000 persons comparing the two periods. The incidence of IPD due to non-vaccine serotypes (NVT-IPD) increased significantly from 11.8 to 13.9 cases per 100,000 in the whole population (incidence rate ratio 1.18; 95% CI [1.12-1.24]) with predominance of the serotypes 1.7F and 19A. CONCLUSIONS We report a marked decline in incidence in IPD in both vaccinated and non-vaccinated age groups and a minor but statistically significant increase in incidence of IPD due to NVTs in both vaccinated and non-vaccinated groups with predominance of serotypes covered by higher valence pneumococcal conjugate vaccines.

Robustness of genome-wide scanning using archived dried blood spot samples as a DNA source

BackgroundThe search to identify disease-susceptible genes requires access to biological material from numerous well-characterized subjects. Archived residual dried blood spot (DBS) samples, also known as Guthrie cards, from national newborn screening programs may provide a DNA source for entire populations. Combined with clinical information from medical registries, DBS samples could provide a rich source for productive research. However, the amounts of DNA which can be extracted from these precious samples are minute and may be prohibitive for numerous genotypings. Previously, we demonstrated that DBS DNA can be whole-genome amplified and used for reliable genetic analysis on different platforms, including genome-wide scanning arrays. However, it remains unclear whether this approach is workable on a large sample scale. We examined the robustness of using DBS samples for whole-genome amplification following genome-wide scanning, using arrays from Illumina and Affymetrix.ResultsThis study is based on 4,641 DBS samples from the Danish Newborn Screening Biobank, extracted for three separate genome-wide association studies. The amount of amplified DNA was significantly (P < 0.05) affected by the year of storage and storage conditions. Nine (0.2%) DBS samples failed whole-genome amplification. A total of 4,586 (98.8%) samples met our criterion of success of a genetic call-rate above 97%. The three studies used different arrays, with mean genotyping call-rates of 99.385% (Illumina Infinium Human610-Quad), 99.722% (Illumina Infinium HD HumanOmni1-Quad), and 99.206% (Affymetrix Axiom Genome-Wide CEU). We observed a concordance rate of 99.997% in the 38 methodological replications, and 99.999% in the 27 technical replications. Handling variables such as time of storage, storage conditions and type of filter paper were shown too significantly (P < 0.05) affect the genotype call-rates in some of the arrays, although the effect was minimal.ConclusionOur study indicates that archived DBS samples from the Danish Newborn Screening Biobank represent a reliable resource of DNA for whole-genome amplification and subsequent genome-wide association studies. With call-rates equivalent to high quality DNA samples, our results point to new opportunities for using the neonatal biobanks available worldwide in the hunt for genetic components of disease.

Estimated effect of pneumococcal conjugate vaccination on invasive pneumococcal disease and associated mortality, Denmark 2000–2005

In order to provide an estimation of the direct and indirect benefits of pneumococcal vaccination with three protein-conjugate pneumococcal vaccines (PCV) we described the epidemiology and mortality from invasive pneumococcal disease (IPD) in Denmark between 2000 and 2005. Approximately 1080 cases were registered annually during the period. The overall incidence of IPD increased significantly, from 15.4 cases per 100,000 population in 2000 to 20.7 cases per 100,000 in 2005 (p<0.01), mainly due to an increase in bacteraemia cases. The serotype coverage in children under 5 years varied from 64% to 91% depending on the PCV used. The mean mortality proportion after IPD was 18%, with approximately 190 deaths annually. One to two deaths among children younger than 5 years and approximately 50 deaths related to IPD caused by vaccine serotypes among older age groups could be prevented annually by introducing a PCV. Approximately 70% of all deaths occurred in adults over 65 years, underlining the need for protection against IPD in this age group.