Dynamics and Determinants of Pneumococcal Antibodies Specific against 13 Vaccine Serotypes in the Pre-Vaccination Era

Introduction

Introduction of pneumococcal conjugate vaccines (PCVs) for infants decreased overall invasive pneumococcal disease (IPD), while non-vaccine serotype IPD increased. To fully understand this serotype replacement, knowledge about serotype dynamics in the pre-vaccine era is needed. In addition to IPD surveillance and carriage studies, the serotype replacement can be investigated by serosurveillance studies. The current study compared the results of two Dutch serosurveillance studies conducted in 1995–1996 (PIENTER1) and 2006–2007 (PIENTER2).

Methods

Participants in these studies donated a blood sample and completed a questionnaire. Pneumococcal antibodies of serotypes included in PCV13 were measured with a fluorescent-bead based multiplex immunoassay. Geometric mean antibody concentrations (GMCs) and determinants of pneumococcal antibody levels were investigated.

Results

GMCs were higher in PIENTER2 for serotypes 1, 6A, 6B, 9V, 18C, 19F and 23F and lower for 3 and 5. Age, day care attendance, household size, vaccination coverage, and urbanisation rate were associated with pneumococcal antibodies in children. Education level, ethnicity, age, low vaccination coverage sample, urbanisation rate, and asthma/COPD were associated with pneumococcal antibodies in elderly. The determinants significantly associated with pneumococcal IgG were slightly different for the elderly in PIENTER1 compared to the elderly in PIENTER2.

Conclusion

Although most of the serotype antibody levels remained stable, some of the serotype-specific antibody levels varied during the pre-vaccine era, indicating that exposure of certain serotypes changes without interference of PCVs.     

A Genomic Approach to Resolving Relapse versus Reinfection among Four Cases of Buruli Ulcer

Background

Increased availability of Next Generation Sequencing (NGS) techniques allows, for the first time, to distinguish relapses from reinfections in patients with multiple Buruli ulcer (BU) episodes.

Methodology

We compared the number and location of single nucleotide polymorphisms (SNPs) identified by genomic screening between four pairs of Mycobacterium ulcerans isolates collected at the time of first diagnosis and at recurrence, derived from a collection of almost 5000 well characterized clinical samples from one BU treatment center in Benin.

Principal Findings

The findings suggest that after surgical treatment—without antibiotics—the second episodes were due to relapse rather than reinfection. Since specific antibiotics were introduced for the treatment of BU, the one patient with a culture available from both disease episodes had M. ulcerans isolates with a genomic distance of 20 SNPs, suggesting the patient was most likely reinfected rather than having a relapse.

Conclusions

To our knowledge, this study is the first to study recurrences in M. ulcerans using NGS, and to identify exogenous reinfection as causing a recurrence of BU. The occurrence of reinfection highlights the contribution of ongoing exposure to M. ulcerans to disease recurrence, and has implications for vaccine development.     

Impact of Ten-Valent Pneumococcal Conjugate Vaccination on Invasive Pneumococcal Disease in Finnish Children – A Population-Based Study

Background

The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Program (NVP) in September 2010 with a 2+1 schedule (3, 5, 12 months) without catch-up vaccinations. We evaluated the direct and indirect effects of PCV10 on invasive pneumococcal disease (IPD) among children ≤5 years of age during the first three years after NVP introduction.

Methods

We conducted a population-based, observational follow-up study. The cohort of vaccine-eligible children (all children born June 1, 2010 or later) was followed from 3 months of age until the end of 2013. For the indirect effect, another cohort of older children ineligible for PCV10 vaccination was followed from 2011 through 2013. Both cohorts were compared with season- and age-matched reference cohorts before NVP introduction. National, population-based laboratory surveillance data were used to compare culture-confirmed serotype-specific IPD rates in the vaccine target and reference cohorts by using Poisson regression models.

Results

The overall IPD rate among vaccine-eligible children was reduced by 80% (95%CI 72 to 85); the reduction in vaccine-type IPD was 92% (95%CI 86 to 95). However, a non-significant increase in non-vaccine type IPD was observed. During 2012–2013, we also observed a 48% (95%CI 18 to 69) reduction in IPD among unvaccinated children 2 to 5 years of age, which was mostly attributable to the ten vaccine serotypes.

Conclusions

This is the first population-based study investigating the impact of PCV10 introduction without prior PCV7 use. A substantial decrease in IPD rates among vaccine-eligible children was observed. A smaller and temporally delayed reduction among older, unvaccinated children suggests that PCV10 also provides indirect protection against vaccine-type IPD. Changes in serotype distribution warrant continuous monitoring of potential increases in non-vaccine serotypes.     

Invasive Pneumococcal Disease in Healthy Adults: Increase of Empyema Associated with the Clonal-Type Sweden(1)-ST306

Background

Adult invasive pneumococcal disease (IPD) occurs mainly in the elderly and patients with co-morbidities. Little is known about the clinical characteristics, serotypes and genotypes causing IPD in healthy adults.

Methods

We studied 745 culture-proven cases of IPD in adult patients aged 18–64 years (1996–2010). Patients were included in two groups: 1.) adults with co-morbidities, and 2.) healthy adults, who had no prior or coincident diagnosis of a chronic or immunosuppressive underlying disease. Microbiological studies included pneumococcal serotyping and genotyping.

Results

Of 745 IPD episodes, 525 (70%) occurred in patients with co-morbidities and 220 (30%) in healthy adults. The healthy adults with IPD were often smokers (56%) or alcohol abusers (18%). As compared to patients with co-morbidities, the healthy adults had (P<0.05): younger age (43.5+/−13.1 vs. 48.7+/−11.3 years); higher proportions of women (45% vs. 24%), pneumonia with empyema (15% vs. 7%) and infection with non-PCV7 serotypes including serotypes 1 (25% vs. 5%), 7F (13% vs. 4%), and 5 (7% vs. 2%); and lower mortality (5% vs. 20%). Empyema was more frequently caused by serotype 1. No death occurred among 79 patients with serotype 1 IPD. There was an emergence of virulent clonal-types Sweden¹-ST306 and Netherlands^7F-ST191. The vaccine serotype coverage with the PCV13 was higher in healthy adults than in patients with co-morbidities: 82% and 56%, respectively, P<0.001.

Conclusion

In this clinical study, one-third of adults with IPD had no underlying chronic or immunosuppressive diseases (healthy adults). They were often smokers and alcohol abusers, and frequently presents with pneumonia and empyema caused by virulent clones of non-PCV7 serotypes such as the Sweden¹-ST306. Thus, implementing tobacco and alcohol abuse-cessation measures and a proper pneumococcal vaccination, such as PCV13 policy, in active smokers and alcohol abusers may diminish the burden of IPD in adults.     

HIV Infection and the Epidemiology of Invasive Pneumococcal Disease (IPD) in South African Adults and Older Children Prior to the Introduction of a Pneumococcal Conjugate Vaccine (PCV)

Introduction

Streptococcus pneumoniae is the commonest cause of bacteremic pneumonia among HIV-infected persons. As more countries with high HIV prevalence are implementing infant pneumococcal conjugate vaccine (PCV) programs, we aimed to describe the baseline clinical characteristics of adult invasive pneumococcal disease (IPD) in the pre-PCV era in South Africa in order to interpret potential indirect effects following vaccine use.

Methods

National, active, laboratory-based surveillance for IPD was conducted in South Africa from 1 January 2003 through 31 December 2008. At 25 enhanced surveillance (ES) hospital sites, clinical data, including HIV serostatus, were collected from IPD patients ≥ 5 years of age. We compared the clinical characteristics of individuals with IPD in those HIV-infected and -uninfected using multivariable analysis. PCV was introduced into the routine South African Expanded Program on Immunization (EPI) in 2009.

Results

In South Africa, from 2003–2008, 17 604 cases of IPD occurred amongst persons ≥ 5 years of age, with an average incidence of 7 cases per 100 000 person-years. Against a national HIV-prevalence of 18%, 89% (4190/4734) of IPD patients from ES sites were HIV-infected. IPD incidence in HIV-infected individuals is 43 times higher than in HIV-uninfected persons (52 per 100 000 vs. 1.2 per 100 000), with a peak in the HIV-infected elderly population of 237 per 100 000 persons. Most HIV-infected individuals presented with bacteremia (74%, 3 091/4 190). HIV-uninfected individuals were older; and had more chronic conditions (excluding HIV) than HIV-infected persons (39% (210/544) vs. 19% (790/4190), p<0.001). During the pre-PCV immunization era in South Africa, 71% of serotypes amongst HIV-infected persons were covered by PCV13 vs. 73% amongst HIV-uninfected persons, p = 0.4, OR 0.9 (CI 0.7–1.1).

Conclusion

Seventy to eighty-five percent of adult IPD in the pre-PCV era were vaccine serotypes and 93% of cases had recognized risk factors (including HIV-infection) for pneumococcal vaccination. These data describe the epidemiology of IPD amongst HIV-infected and -uninfected adults during the pre-PCV era and provide a robust baseline to calculate the indirect effect of PCV in future studies.     

Emerging,Non-PCV13 Serotypes 11A and 35B of Streptococcus pneumoniae Show High Potential for Biofilm Formation In Vitro

Background

Since the use of pneumococcal conjugate vaccines PCV7 and PCV13 in children became widespread, invasive pneumococcal disease (IPD) has dramatically decreased. Nevertheless, there has been a rise in incidence of Streptococcus pneumoniae non-vaccine serotypes (NVT) colonising the human nasopharynx. Nasopharyngeal colonisation, an essential step in the development of S. pneumoniae-induced IPD, is associated with biofilm formation. Although the capsule is the main pneumococcal virulence factor, the formation of pneumococcal biofilms might, in fact, be limited by the presence of capsular polysaccharide (CPS).

Methodology/Principal Findings

We used clinical isolates of 16 emerging, non-PCV13 serotypes as well as isogenic transformants of the same serotypes. The biofilm formation capacity of isogenic transformants expressing CPSs from NVT was evaluated in vitro to ascertain whether this trait can be used to predict the emergence of NVT. Fourteen out of 16 NVT analysed were not good biofilm formers, presumably because of the presence of CPS. In contrast, serotypes 11A and 35B formed ≥45% of the biofilm produced by the non-encapsulated M11 strain.

Conclusions/Significance

This study suggest that emerging, NVT serotypes 11A and 35B deserve a close surveillance.     

Some Pneumococcal Serotypes Are More Frequently Associated with Relapses of Acute Exacerbations in COPD Patients

Objectives

To analyze the role of the capsular type in pneumococci causing relapse and reinfection episodes of acute exacerbation in COPD patients.

Methods

A total of 79 patients with 116 recurrent episodes of acute exacerbations caused by S. pneumoniae were included into this study (1995–2010). A relapse episode was considered when two consecutive episodes were caused by the same strain (identical serotype and genotype); otherwise it was considered reinfection.Antimicrobial susceptibility testing (microdilution), serotyping (PCR, Quellung) and molecular typing (PFGE/MLST) were performed.

Results

Among 116 recurrent episodes, 81 (69.8%) were reinfections, caused by the acquisition of a new pneumococcus, and 35 (30.2%) were relapses, caused by a pre-existing strain. Four serotypes (9V, 19F, 15A and 11A) caused the majority (60.0%) of relapses. When serotypes causing relapses and reinfection were compared, only two serotypes were associated with relapses: 9V (OR 8.0; 95% CI, 1.34–85.59) and 19F (OR 16.1; 95% CI, 1.84–767.20). Pneumococci isolated from relapses were more resistant to antimicrobials than those isolated from the reinfection episodes: penicillin (74.3% vs. 34.6%, p<0.001), ciprofloxacin (25.7% vs. 9.9%, p<0.027), levofloxacin (22.9% vs. 7.4%, p = 0.029), and co-trimoxazole (54.3% vs. 25.9%, p<0.001).

Conclusions

Although the acquisition of a new S. pneumoniae strain was the most frequent cause of recurrences, a third of the recurrent episodes were caused by a pre-existing strain. These relapse episodes were mainly caused by serotypes 9V and 19F, suggesting an important role for capsular type.     

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

Background

Pneumococcal disease is a leading cause of morbidity and mortality worldwide. The aim of this study was to investigate the association between specific pneumococcal serotypes and mortality from invasive pneumococcal disease (IPD).

Methods and Findings

In a nationwide population-based cohort study of IPD in Denmark during 1977–2007, 30-d mortality associated with pneumococcal serotypes was examined by multivariate logistic regression analysis after controlling for potential confounders. A total of 18,858 IPD patients were included. Overall 30-d mortality was 18%, and 3% in children younger than age 5 y. Age, male sex, meningitis, high comorbidity level, alcoholism, and early decade of diagnosis were significantly associated with mortality. Among individuals aged 5 y and older, serotypes 31, 11A, 35F, 17F, 3, 16F, 19F, 15B, and 10A were associated with highly increased mortality as compared with serotype 1 (all: adjusted odds ratio ≥3, p<0.001). In children younger than 5 y, associations between serotypes and mortality were different than in adults but statistical precision was limited because of low overall childhood-related mortality.

Conclusions

Specific pneumococcal serotypes strongly and independently affect IPD associated mortality.     

Risk Factors for the Failure of Spinal Burst Fractures Treated Conservatively According to the Thoracolumbar Injury Classification and Severity Score (TLICS): A Retrospective Cohort Trial

Background

The management of thoracolumbar (TL) burst fractures is still controversial. The thoracolumbar injury classification and severity score (TLICS) algorithm is now widely used to guide clinical decision making, however, in clinical practice, we come to realize that TLICS also has its limitations for treating patients with total scores less than 4, for which conservative treatment may not be optimal in all cases.

Purpose

The aim of this study is to identify several risk factors for the failure of conservative treatment of TL burst fractures according to TLICS algorithm.

Methods

From June 2008 to December 2013, a cohort of 129 patients with T10-l2 TL burst fractures with a TLISC score ≤3 treated non-operatively were identified and included into this retrospective study. Age, sex, pain intensity, interpedicular distance (IPD), canal compromise, loss of vertebral body height and kyphotic angle (KA) were selected as potential risk factors and compared between the non-operative success group and the non-operative failure group.

Results

One hundred and four patients successfully completed non-operative treatment, the other 25 patients were converted to surgical treatment because of persistent local back pain or progressive neurological deficits during follow-up. Our results showed that age, visual analogue scale (VAS) score and IPD, KA were significantly different between the two groups. Furthermore, regression analysis indicated that VAS score and IPD could be considered as significant predictors for the failure of conservative treatment.

Conclusion

The recommendation of non-operative treatment for TLICS score ≤3 has limitations in some patients, and VAS score and IPD could be considered as risk factors for the failure of conservative treatment. Thus, conservative treatment should be decided with caution in patients with greater VAS scores or IPD. If non-operative management is decided, a close follow-up is necessary.     

Cost-Effectiveness Analysis of Universal Vaccination of Adults Aged 60 Years with 23-Valent Pneumococcal Polysaccharide Vaccine versus Current Practice in Brazil

Objective

To evaluate the cost-effectiveness of introducing universal vaccination of adults aged 60 years with the 23-valent pneumococcal polysaccharide vaccine (PPV23) into the National Immunization Program (NIP) in Brazil.

Methods

Economic evaluation using a Markov model to compare two strategies: (1) universal vaccination of adults aged 60 years with one dose of PPV23 and 2) current practice (vaccination of institutionalized elderly and elderly with underlying diseases). The perspective was from the health system and society. Temporal horizon was 10 years. Discount rate of 5% was applied to costs and benefits. Clinical syndromes of interest were invasive pneumococcal disease (IPD) including meningitis, sepsis and others and pneumonia. Vaccine efficacy against IPD was obtained from a meta-analysis of randomized control trials and randomized studies, whereas vaccine effectiveness against pneumonia was obtained from cohort studies. Resource utilization and costs were obtained from the Brazilian Health Information Systems. The primary outcome was cost per life year saved (LYS). Univariate and multivariate sensitivity analysis were performed.

Results

The universal vaccination strategy avoided 7,810 hospitalizations and 514 deaths, saving 3,787 years of life and costing a total of USD$31,507,012 and USD$44,548,180, respectively, from the health system and societal perspective. The universal immunization would result in ICERs of USD$1,297 per LYS, from the perspective of the health system, and USD$904 per LYS, from the societal perspective.

Conclusion

The results suggest that universal vaccination of adults aged 60 years with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is a very cost-effective intervention for preventing hospitalization and deaths for IPD and pneumonia is this age group in Brazil.     

Ten years of surveillance for invasive Streptococcus pneumoniae during the era of antiretroviral scale-up and cotrimoxazole prophylaxis in Malawi

Objective

To document trends in invasive pneumococcal disease (IPD) in a central hospital in Malawi during the period of national scale-up of antiretroviral therapy (ART) and cotrimoxazole prophylaxis.

Methods

Between 1 January 2000 and 31 December 2009 almost 100,000 blood cultures and 40,000 cerebrospinal fluid (CSF) cultures were obtained from adults and children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi with suspected severe bacterial infection.

Results

4,445 pneumococcal isolates were obtained over the 10 year period. 1,837 were from children: 885 (19.9%) from blood and 952 (21.4%) from CSF. 2,608 were from adults: 1,813 (40.8%) from blood and 795 (17.9%) from CSF. At the start of the surveillance period cotrimoxazole resistance was 73.8% and at the end was 92.6%. Multidrug resistance (MDR) was present in almost one third of isolates and was constant over time. Free ART was introduced in Malawi in 2004. From 2005 onwards there was a decline in invasive pneumococcal infections with a negative correlation between ART scale-up and the decline in IPD (Pearson''s correlation r = −0.91; p<0.001).

Conclusion

During 2004–2009, national ART scale-up in Malawi was associated with a downward trend in IPD at QECH. The introduction of cotrimoxazole prophylaxis in HIV-infected groups has not coincided with a further increase in pneumococcal cotrimoxazole or multidrug resistance. These data highlight the importance of surveillance for high disease burden infections such as IPD in the region, which will be vital for monitoring pneumococcal conjugate vaccine introduction into national immunisation programmes.     

Effect of serotype on focus and mortality of invasive pneumococcal disease: coverage of different vaccines and insight into non-vaccine serotypes

Background

Differences in pathogenicity between pneumococcal serotypes are important when assessing the potential benefit of different valency vaccines. We investigated the effect of serotype on clinical presentation, outcome, and quality of life lost from invasive pneumococcal disease (IPD) in the context of the 7, 10, and 13 valent pneumococcal conjugate vaccines (PCV7, PCV10, PCV13).

Method

Serotyped IPD cases in England were linked to the national dataset of hospital admissions for April 2002 to March 2011. Based on patients’ diagnostic codes and vital status at the end of the admission, disease focus (meningitis, empyema, sepsis, or respiratory disease) and case fatality rates by serotype and age group (5, 5–64, and 65 years and over) were obtained. Using these data the quality adjusted life years (QALY) lost from the IPD remaining when use of PCV7 stopped in 2010 was estimated for the serotypes covered by higher valency vaccines.

Results

The linked dataset contained 23,688 cases with information on diagnosis, mortality, and serotype. There were significant differences between serotypes in the propensity to cause meningitis, death, and QALY loss in each of the investigated age groups. As a result, vaccines’ coverage of disease burden differed by endpoint. For example, in children under 5 years in 2009/10, PCV10 covered 39% of meningitis, 19% of deaths and 28% of the QALY loss of attributable to IPD, whereas the respective percentages for PCV13 were 65%, 67%, and 66%. The highest QALY loss per serotype in this age group was for 6A. Non-PCV serotypes causing the highest QALY loss were 22F and 33F in <5 year olds and 31 in older individuals.

Conclusion

Marked differences exist between serotypes in clinical presentation and outcome, and these should be considered when evaluating the potential impact of higher valency vaccines on overall disease burden and associated QALY loss.     

Evaluation of coseasonality of influenza and invasive pneumococcal disease: results from prospective surveillance

Background

The wintertime co-occurrence of peaks in influenza and invasive pneumococcal disease (IPD) is well documented, but how and whether wintertime peaks caused by these two pathogens are causally related is still uncertain. We aimed to investigate the relationship between influenza infection and IPD in Ontario, Canada, using several complementary methodological tools.

Methods and Findings

We evaluated a total number of 38,501 positive influenza tests in Central Ontario and 6,191 episodes of IPD in the Toronto/Peel area, Ontario, Canada, between 1 January 1995 and 3 October 2009, reported through population-based surveillance. We assessed the relationship between the seasonal wave forms for influenza and IPD using fast Fourier transforms in order to examine the relationship between these two pathogens over yearly timescales. We also used three complementary statistical methods (time-series methods, negative binomial regression, and case-crossover methods) to evaluate the short-term effect of influenza dynamics on pneumococcal risk. Annual periodicity with wintertime peaks could be demonstrated for IPD, whereas periodicity for influenza was less regular. As for long-term effects, phase and amplitude terms of pneumococcal and influenza seasonal sine waves were not correlated and meta-analysis confirmed significant heterogeneity of influenza, but not pneumococcal phase terms. In contrast, influenza was shown to Granger-cause pneumococcal disease. A short-term association between IPD and influenza could be demonstrated for 1-week lags in both case-crossover (odds ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.10 [1.02–1.18]) and negative binomial regression analysis (incidence rate ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.09 [1.05–1.14]).

Conclusions

Our data support the hypothesis that influenza influences bacterial disease incidence by enhancing short-term risk of invasion in colonized individuals. The absence of correlation between seasonal waveforms, on the other hand, suggests that bacterial disease transmission is affected to a lesser extent. Please see later in the article for the Editors'' Summary     

7-Valent Pneumococcal Conjugate Vaccination in England and Wales: Is It Still Beneficial Despite High Levels of Serotype Replacement?

Background

The UK introduced the 7-valent pneumococcal conjugate vaccine (PCV7) into the national vaccination program in September 2006. Previous modelling assumed that the likely impact of PCV7 on invasive pneumococcal disease (IPD) would be similar to the US experience with PCV7. However, recent surveillance data show a more rapid replacement of PCV7 IPD cases by non-PCV7 IPD cases than was seen in the US.

Methods and Findings

A previous model of pneumococcal vaccination was re-parameterised using data on vaccine coverage and IPD from England and Wales between 2006 and 2009. Disease incidence was adjusted for the increasing trend in reported IPD cases prior to vaccination. Using this data we estimated that individuals carrying PCV7 serotypes have much higher protection (96%;95% CI 72%-100%) against acquisition of NVT carriage than the 15% previously estimated from US data, which leads to greater replacement. However, even with this level of replacement, the annual number of IPD cases may be 560 (95% CI, -100 to 1230) lower ten years after vaccine introduction compared to what it may have been without vaccination. A particularly marked fall of 39% in children under 15 years by 2015/6 is predicted.

Conclusion

Our model suggests that PCV7 vaccination could result in a decrease in overall invasive pneumococcal disease, particularly in children, even in an environment of rapid replacement with non-PCV7 serotypes within 5 years of vaccine introduction at high coverage.     

Invasive Pneumococcal Isolates from Danish Infants (0 - 90 Days) during the Years 1943 to 2013

Background

The seven-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the Danish childhood immunization program (at 3, 5 and 12 months of age) in 2007 and was replaced with PCV-13 in 2010 without changes to the schedule. After the introduction of these vaccines the incidence of invasive pneumococcal disease (IPD) due to vaccine types (VTs) declined markedly in children aged 0–2 years; however, cases among infants too young to be protected by vaccination have not been studied in detail. We present data on IPD in infants less than 90 days from 1943 until 2013.

Study design

The study included all infants younger than 90 days born from 1943 through 2013, who had not been PCV vaccinated and from whom a pneumococcus isolate from blood or cerebrospinal fluid had been submitted to the Danish national reference laboratory. All isolates were serotyped using Pneumotest Latex and Quellung reaction.

Results

A total of 216 IPD cases were identified. The age group specific incidence (total number of IPD cases per 100,000 live births) varied from 0 to 16 in the period 1943 to 2007 and from 1.7 to 9.2 in the period 2008 to 2013. IPD cases due to PCV-7 serotypes were not observed later than 2009.

Conclusion

In Danish infants younger than 90 days, IPD due to PCV-7 serotypes has decreased and has not been observed since 2009, but the total incidence of IPD has not changed.     

Effect of Pneumococcal Conjugate Vaccination in Uruguay,a Middle-Income Country

Background

In 2008, a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the routine childhood immunization program in Uruguay, with a 2+1 schedule. In 2010, PCV13 replaced PCV7, and the same 2+1 schedule was used. The effect of these pneumococcal vaccines on the incidence of invasive pneumococcal infections (IPD) and on serotype distribution was analyzed retrospectively, based on passive national laboratory surveillance.

Methods

Data from 1,887 IPD isolates from 5 years before and 5 years after PCV7 introduction (7 before and 3 after PCV13 introduction) was examined to assess the incidence rate per 100,000 age-specific population of all IPD, PCV7-serotypes, and PCV13-serotypes associated IPD among children <2 years and 2 to 4 years old, and patients ≥5 years old. Trends of frequency for each serotype were also analyzed.

Results

Comparison of pre-vaccination (2003–2007) and post-vaccination (2008–2012) periods showed a significant decrease in IPD incidence among children <2 years old (IR 68.7 to IR 29.6, p<0.001) and children 2 to 4 years (p<0.04). IPD caused by serotypes in PCV7 was reduced by 95.6% and IPD caused by 6 serotypes added in PCV13 was reduced by 83.9% in children <5 years old. Indirect effects of both conjugate vaccines were observed among patients ≥5 years old one year after the introduction of each vaccine, in 2010 for PCV7 and in 2012 for PCV13. Nevertheless, for reasons that still need to be explained, perhaps due to ascertainment bias, total IPD in this group increased after 2007. In 2012, the relative frequency of vaccine serotypes among vaccinated and unvaccinated population declined, except for serotype 3. Non vaccine serotypes with increasing frequency were identified, in rank order: 12F, 8, 24F, 22F, 24A, 15C, 9N, 10A and 33.

Conclusion

Consecutive immunization with PCV7 and PCV13 has significantly reduced IPD in children <5 years of age in Uruguay.     

Tuberculosis Recurrence after Completion Treatment in a European City: Reinfection or Relapse?

Background

Tuberculosis (TB) recurrence can be due to reinfection or relapse. The contribution of each to TB incidence and the factors associated with recurrence are not well known. Effectiveness of TB control programs is assessed in part by recurrence rates. The aim of this study was to establish the recurrence rate of TB in Barcelona, the associated risk factors and the role of reinfection.

Methods

A population-based retrospective longitudinal study was performed in Barcelona, Spain. TB patients with positive culture results who completed treatment between Jan 1^st, 2003 and Dec 31^st, 2006 were followed-up until December 31st, 2009 by the TB Control Program. The incidence rate of recurrence was calculated per person-year of follow-up (py). Kaplan-Meier and Cox regression methods were used for the survival analysis by calculating the hazard ratio (HR) with 95% confidence intervals (CI).

Results

Of the 1,823 TB cases identified, 971 fulfilled the inclusion criteria and 13 (1.3%) had recurrent TB. The recurrence rate was 341 cases per 100,000 py, 13 times higher than the TB incidence of the general population. Likelihood of TB recurrence at the 1st, 3rd and 5th year of follow-up was 0.1%, 1.4% and 1.6%, respectively. Factors associated with recurrence were HIV infection (HR: 4.7, CI: 1.4–15.7), living in the inner city district (HR: 3.9, CI: 1.3–11.8) and history of TB treatment (HR: 5.2, CI: 1.7–16.2). Genotyping results of recurrent cases were available for 6 patients (3 reinfections and 3 relapses).

Conclusion

The rate of TB recurrence in Barcelona is low and most episodes occur within the first three years. Patients at higher risk of recurrence are co-infected with HIV, living in neighborhoods with high TB incidence or with a history of TB treatment. When available, genotyping results help determine whether the recurrence is due to reinfection or relapse.     

Propensity Score-Based Approaches to Confounding by Indication in Individual Patient Data Meta-Analysis: Non-Standardized Treatment for Multidrug Resistant Tuberculosis

Background

In the absence of randomized clinical trials, meta-analysis of individual patient data (IPD) from observational studies may provide the most accurate effect estimates for an intervention. However, confounding by indication remains an important concern that can be addressed by incorporating individual patient covariates in different ways. We compared different analytic approaches to account for confounding in IPD from patients treated for multi-drug resistant tuberculosis (MDR-TB).

Methods

Two antibiotic classes were evaluated, fluoroquinolones—considered the cornerstone of effective MDR-TB treatment—and macrolides, which are known to be safe, yet are ineffective in vitro. The primary outcome was treatment success against treatment failure, relapse or death. Effect estimates were obtained using multivariable and propensity-score based approaches.

Results

Fluoroquinolone antibiotics were used in 28 included studies, within which 6,612 patients received a fluoroquinolone and 723 patients did not. Macrolides were used in 15 included studies, within which 459 patients received this class of antibiotics and 3,670 did not. Both standard multivariable regression and propensity score-based methods resulted in similar effect estimates for early and late generation fluoroquinolones, while macrolide antibiotics use was associated with reduced treatment success.

Conclusions

In this individual patient data meta-analysis, standard multivariable and propensity-score based methods of adjusting for individual patient covariates for observational studies yielded produced similar effect estimates. Even when adjustment is made for potential confounding, interpretation of adjusted estimates must still consider the potential for residual bias.     

IgG Responses to Pneumococcal and Haemophilus Influenzae Protein Antigens Are Not Impaired in Children with a History of Recurrent Acute Otitis Media

Background

Vaccines including conserved antigens from Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi) have the potential to reduce the burden of acute otitis media. Little is known about the antibody response to such antigens in young children with recurrent acute otitis media, however, it has been suggested antibody production may be impaired in these children.

Methods

We measured serum IgG levels against 4 pneumococcal (PspA1, PspA 2, CbpA and Ply) and 3 NTHi (P4, P6 and PD) proteins in a cross-sectional study of 172 children under 3 years of age with a history of recurrent acute otitis media (median 7 episodes, requiring ventilation tube insertion) and 63 healthy age-matched controls, using a newly developed multiplex bead assay.

Results

Children with a history of recurrent acute otitis media had significantly higher geometric mean serum IgG levels against NTHi proteins P4, P6 and PD compared with healthy controls, whereas there was no difference in antibody levels against pneumococcal protein antigens. In both children with and without a history of acute otitis media, antibody levels increased with age and were significantly higher in children colonised with S. pneumoniae or NTHi compared with children that were not colonised.

Conclusions

Proteins from S. pneumoniae and NTHi induce serum IgG in children with a history of acute otitis media. The mechanisms in which proteins induce immunity and potential protection requires further investigation but the dogma of impaired antibody responses in children with recurrent acute otitis media should be reconsidered.     

Health Gains and Financial Protection from Pneumococcal Vaccination and Pneumonia Treatment in Ethiopia: Results from an Extended Cost-Effectiveness Analysis

Background

Pneumonia and pneumococcal disease cause a large disease burden in resource-constrained settings. We pursue an extended cost-effectiveness analysis (ECEA) of two fully publicly financed interventions in Ethiopia: pneumococcal vaccination for newborns and pneumonia treatment for under-five children in Ethiopia.

Methods

We apply ECEA methods and estimate the program impact on: (1) government program costs; (2) pneumonia and pneumococcal deaths averted; (3) household expenses related to pneumonia/pneumococcal disease treatment averted; (4) prevention of household medical impoverishment measured by an imputed money-metric value of financial risk protection; and (5) distributional consequences across the wealth strata of the country population. Available epidemiological and cost data from Ethiopia are applied and the two interventions are assessed separately at various incremental coverage levels.

Results

Scaling-up pneumococcal vaccines at around 40% coverage would cost about $11.5 million and avert about 2090 child deaths annually, while a 10% increase of pneumonia treatment to all children under 5 years of age would cost about $13.9 million and avert 2610 deaths annually. Health benefits of the two interventions publicly financed would be concentrated among the bottom income quintile, where 30–40% of all deaths averted would be expected to occur in the poorest quintile. In sum, the two interventions would eliminate a total of $2.4 million of private household expenditures annually, where the richest quintile benefits from around 30% of the total private expenditures averted. The financial risk protection benefits would be largely concentrated among the bottom income quintile. The results are most sensitive to variations in vaccine price, population size, number of deaths due to pneumonia, efficacy of interventions and out-of-pocket copayment share.

Conclusions

Vaccine and treatment interventions for children, as shown with the illustrative examples of pneumococcal vaccine and pneumonia treatment, can bring large health and financial benefits to households in Ethiopia, most particularly among the poorest socio-economic groups.