Safety and immunogenicity of ETVAX®, an oral inactivated vaccine against enterotoxigenic Escherichia coli diarrhoea: a double-blinded, randomized, placebo-controlled trial amongst Finnish travellers to Benin, West Africa.

BACKGROUND: No licensed human vaccines are available against enterotoxigenic Escherichia coli (ETEC), a major diarrhoeal pathogen affecting children in low- and middle-income countries and foreign travellers alike. ETVAX®, a multivalent oral whole-cell vaccine containing four inactivated ETEC strains and the heat-labile enterotoxin B subunit (LTB), has proved promising in Phase 1 and Phase 1/ 2 studies. METHODS: We conducted a Phase 2b double-blinded, randomized, placebo-controlled trial amongst Finnish travellers to Benin, West Africa. This report presents study design and safety and immunogenicity data. Volunteers aged 18-65 years were randomized 1:1 to receive ETVAX® or placebo. They visited Benin for 12 days, provided stool and blood samples and completed adverse event (AE) forms. IgA and IgG antibodies to LTB and O78 lipopolysaccharide (LPS) were measured by electrochemiluminescence. RESULTS: The AEs did not differ significantly between vaccine (n = 374) and placebo (n = 375) recipients. Of the solicited AEs, loose stools/diarrhoea (26.7/25.9%) and stomach ache (23.0/20.0%) were reported most commonly. Of all possibly/probably vaccine-related AEs, the most frequent were gastrointestinal symptoms (54.0/48.8%) and nervous system disorders (20.3/25.1%). Serious AEs were recorded for 4.3/5.6%, all unlikely to be vaccine related. Amongst the ETVAX® recipients, LTB-specific IgA antibodies increased 22-fold. For the 370/372 vaccine/placebo recipients, the frequency of ≥2-fold increases against LTB was 81/2.4%, and against O78 LPS 69/2.7%. The majority of ETVAX® recipients (93%) responded to either LTB or O78. CONCLUSIONS: This Phase 2b trial is the largest on ETVAX® undertaken amongst travellers to date. ETVAX® showed an excellent safety profile and proved strongly immunogenic, which encourages the further development of this vaccine.

Invasive pneumococcal disease in patients with haematological malignancies before routine use of conjugate vaccines in Finland.

The baseline national invasive pneumococcal disease (IPD) incidence rate, serotype distribution and serotype coverage of pneumococcal vaccines were evaluated in patients with Hodgkin's and non-Hodgkin's lymphomas, myeloma and leukaemia within 1 year after haematological diagnosis during 1995-2002, before introduction of pneumococcal conjugate vaccines. Pneumococcal serotype distribution among these patients was different from serotypes causing IPD in the general population. The serotype coverages of PCV13 and PPSV23 were 57% and 64%, respectively, lower than in the general population. This reflects a higher predisposition to IPD in vaccinated patients with haematological malignancies and possibly less benefit of herd immunity gained with the wide use of pneumococcal conjugate vaccines in the general population. This data will be useful as a baseline for determining the future role of adult PCV vaccination in these patient groups.

Economic impact of 13-valent pneumococcal conjugate vaccine in Finnish adults ≥50 years with underlying chronic medical conditions.

RATIONALE, AIMS AND OBJECTIVES: Invasive pneumococcal diseases (IPD) are associated with substantial burden in adults (≥50 years). Moreover, adults with vascular, metabolic or respiratory diseases have been shown to have a 3-6 times higher risk of IPD when compared with their healthy controls. These persons at higher risk are likely to benefit most from pneumococcal vaccinations. The 13-valent pneumococcal conjugate vaccine (PCV13) was recently introduced to prevent the 13 most prevalent serotypes causing invasive pneumococcal disease in adults. The objective of this study was to estimate the expected 5-year economic impact of targeted PCV13 vaccination compared with no vaccination in Finnish adults (≥50 years) at moderate or high risk for IPD. METHODS: A budget impact model was developed to predict the impact of PCV13 vaccination in terms of the costs and IPD events avoided for years 2012-2016. RESULTS: Approximately 35% of the 2.2 million Finns over 50 years of age can be considered to be at moderate or high risk for IPD because of underlying chronic medical conditions. Vaccination of these people with PCV13 could provide an estimated net budget savings of about €218 million compared with the current no-vaccination situation over the next 5 years. Among the risk groups considered, the largest absolute net savings (€66.2 million) could be expected to be obtained by vaccinating people with heart disease, due to its high prevalence in the target population. CONCLUSION: In Finland, the immunization with PCV13 vaccine, of adults (≥50 years) at moderate and high risk of IPD, is estimated to lead to substantial cost savings in the 5 years after vaccination.

Pneumococcal polysaccharide vaccination for adults: new perspectives for Europe.

Vaccination is the only public-health measure likely to reduce the burden of pneumococcal diseases. In 2010, a group of European experts reviewed evidence on the burden of pneumococcal disease and the immunogenicity, clinical effectiveness and cost-effectiveness of vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23). They also considered issues affecting the future use of PPV23 and pneumococcal conjugate vaccines in the elderly and adults at high risk of pneumococcal disease. PPV23 covers 80-90% of the serotypes responsible for invasive pneumococcal disease in Europe. Primary vaccination and revaccination with PPV23 are well tolerated, induce robust, long-lasting immune responses in elderly adults and are cost effective. Ensuring protection against pneumococcal disease requires monitoring of the changing epidemiology of pneumococcal serotypes causing invasive pneumococcal disease and improving vaccine coverage. In the future, it will be critically important for pneumococcal vaccination recommendations for elderly adults to be based on comparative evaluations of PPV23 and newer pneumococcal conjugate vaccines with regard to their long-term immunogenicity, clinical effectiveness and cost-effectiveness.

Epidemic sindbis virus infection in Finland: a population-based case-control study of risk factors.

BACKGROUND: Sindbis virus (SINV) is an arthropod-borne alphavirus that causes rash and arthritis. In Finland, epidemics occur cyclically, but factors associated with clinical SINV infection are largely unknown. We conducted a population-based case-control study during the epidemic year 2002. METHODS: SINV cases were serologically confirmed and reported to the National Infectious Disease Registry. Five control subjects, matched for age, sex, and residence, were selected from the National Population Information System. Data were collected using a self-administered mail survey. Conditional logistic regression models were used to identify independent risk factors; missing data were addressed using Bayesian full-likelihood modeling. RESULTS: A total of 337 case patients (58% female; age range, 1-94 y) and 934 control subjects were enrolled. Reported exposure to mosquito bites (matched odds ratio [mOR], 16.7; 95% confidence interval [CI], 9.1-33.4) and spending time in woods or marshland (mOR, 1.8; 95% CI, 1.3-2.5) were independently associated with SINV infection in the multivariable model. The population-attributable risk for mosquito bites was 87.2%. There were dose-response relations for increased number of insect bites (mOR, 23.8-72.5) and increased time spent in woods or marshland (mOR, 1.3-2.2). CONCLUSIONS: Educating the public in endemic areas to avoid mosquito exposure and use protective measures remain important prevention measures for SINV infection.

Risk of invasive pneumococcal infections among working age adults with asthma.

BACKGROUND: Information about the risk of invasive pneumococcal infection (IPI) among adults with asthma is limited and inconsistent. To evaluate this association, a population-based case-control study was conducted. METHODS: Cases of IPI (Streptococcus pneumoniae isolated from blood or cerebrospinal fluid) were identified through national, population-based laboratory surveillance during 1995-2002. To maximise exclusion of chronic obstructive pulmonary disease, the analysis was limited to patients aged 18-49 years and 10 selected age-, sex- and health district-matched controls for each case from the Population Information System. Information on underlying medical conditions was obtained through linking surveillance data to other national health registries. Asthma requiring > or =1 hospitalisation in the past 12 months was defined as high risk asthma (HRA); low risk asthma (LRA) was defined as entitlement to prescription drug benefits and no hospitalisation for asthma in the past 12 months. RESULTS: 1282 patients with IPI and 12 785 control subjects were identified. Overall, 7.1% of cases and 2.5% of controls had asthma (6.0% and 2.4% had LRA whereas 1.1% and 0.1% had HRA, respectively. After adjustment for other independent risk factors in a conditional logistic regression model, IPI was associated with both LRA (matched OR (mOR) 2.8; 95% CI 2.1 to 3.6) and HRA (mOR, 12.3; 95% CI 5.4 to 28.0). The adjusted population-attributable risk was 0.039 (95% CI 0.023 to 0.055) for LRA and 0.01 (95% CI 0.0035 to 0.017) for HRA. CONCLUSIONS: Working age adults with asthma are at increased risk of IPI. In this population, approximately 5% of disease burden could be attributed to asthma. These findings support adding medicated asthma in adults to the list of indications for pneumococcal vaccination.

Trends and geographical variation in invasive pneumococcal infections in Finland.

We evaluated regional variation and trends in invasive pneumococcal infections (IPI) in Finland by using data from national, population-based laboratory surveillance and number of blood and cerebrospinal fluid (CSF) cultures performed by all microbiology laboratories during 1995-2002. The overall annualized IPI incidence was 10.6/100,000 (range by region, 7.9 15.1): 9.9 for bacteraemias (range 7.3-14.2) and 0.6 for meningitis (range 0.4-1.1). The rate in children aged <5 y was 23.5/100,000. Regional pneumococcal bacteraemia rates were correlated with blood culture sampling rates (p =0.015), but meningitis rates did not correlate with CSF culture rates. During 1995-2002, the overall annual IPI rate increased by 35.1%, from 8.2 to 11.5/100,000 (p<0.001). The annual blood culturing rate increased by 29.6% (p=0.015 for the correlation with IPI rate). Temporal increase and higher regional IPI rates were significantly associated with higher blood culturing rates. Pneumococcal serotypes included in the 7- and 10-valent conjugate vaccines caused 69.8% and 85.2% of IPIs among children aged <5 y and 49.5% and 59.3% in adults, respectively. The true incidence of pneumococcal bacteraemia in Finland may be higher than previously estimated. Introduction of universal childhood pneumococcal conjugate immunization would provide substantial health benefits to Finnish children and adults.

Invasive pneumococcal infections among persons with and without underlying medical conditions: implications for prevention strategies.

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for persons aged < 65 years with chronic medical conditions. We evaluated the risk and mortality from invasive pneumococcal disease (IPD) among persons with and without the underlying medical conditions which are considered PPV23 indications. METHODS: Population-based data on all episodes of IPD (positive blood or cerebrospinal fluid culture) reported by Finnish clinical microbiology laboratories during 1995-2002 were linked to data in national health care registries and vital statistics to obtain information on the patient's preceding hospitalisations, co-morbidities, and outcome of illness. RESULTS: Overall, 4357 first episodes of IPD were identified in all age groups (average annual incidence, 10.6/100,000). Patients aged 18-49 and 50-64 years accounted for 1282 (29%) and 934 (21%) of IPD cases, of which 372 (29%) and 427 (46%) had a current PPV23 indication, respectively. Overall, 536 (12%) IPD patients died within one month of first positive culture. Persons aged 18-64 years accounted for 254 (47%) of all deaths (case-fatality proportion, 12%). Of those who died 117 (46%) did not have a vaccine indication. In a survival model, patients with alcohol-related diseases, non-haematological malignancies, and those aged 50-64 years were most likely to die. CONCLUSION: In the general population of non-elderly adults, almost two-thirds of IPD and half of fatal cases occurred in persons without a recognised PPV23 indication. Policymakers should consider additional prevention strategies such as lowering the age of universal PPV23 vaccination and introducing routine childhood pneumococcal conjugate immunisation which could provide substantial health benefits to this population through indirect vaccine effects.

Defining the population-based burden of nosocomial pneumococcal bacteremia.

BACKGROUND: The characteristics, risk factors, and outcome of patients with nosocomial pneumococcal bacteremia (NPB) have not been described in large, population-based studies. METHODS: All episodes of invasive pneumococcal infections reported by Finnish clinical microbiology laboratories (positive blood or cerebrospinal fluid culture) from January 1, 1995, through December 31, 2002, were linked to data in national health care registries and vital statistics to obtain information on the patient's preceding hospitalizations, comorbidities, and outcome of illness. Pneumococcal bacteremia was defined as nosocomial if the first positive blood culture was obtained more than 2 days after hospital admission, or if the patient had been hospitalized for more than 2 days within 7 days of the first positive blood culture. RESULTS: Information on hospital admission was available for 4217 of 4357 persons (96.8%) with invasive pneumococcal infections. We identified 387 NPBs (9.7%) among 3973 pneumococcal bacteremias. Patients with NPB were older (median age, 67 years vs 52 years; P < .001) and were more likely to have at least 1 high-risk condition (other than age > or = 65 years), for which 23-valent pneumococcal polysaccharide vaccine is recommended (59.2% vs 34.6%; P < .001), compared with patients who had community-associated pneumococcal bacteremias. The case fatality proportion at 28 days was higher in patients with NPB than in those with community-associated pneumococcal bacteremias (23.8% vs 10.8%; P < .001). Pneumococcal serotypes included in 23-valent polysaccharide vaccine and 7-valent conjugate vaccine caused 71.5% and 46.1% of NPBs, respectively. CONCLUSIONS: A substantial proportion of pneumococcal bacteremias are health care associated. The high prevalence of conditions for which pneumococcal polysaccharide vaccine is recommended provides opportunities for strengthening prevention efforts in these patients at high risk of illness and death.

Mediastinitis after more than 10,000 cardiac surgical procedures.

BACKGROUND: Poststernotomy mediastinitis as a complication is rare but disastrous. We assessed incidence, predisposing factors for, and outcome from, mediastinitis after cardiac surgery. METHODS: We studied 10,713 consecutive patients who underwent open-heart surgery from 1990 to 1999 in a tertiary care university hospital using data prospectively recorded in the hospital discharge register, operating room log, and the hospital's cardiothoracic surgery unit register. Those cases with possible mediastinitis were identified from the hospital infection register and discharge register. Patients' charts were reviewed and cases of mediastinitis confirmed based on criteria of the Centers for Disease Control and Prevention. RESULTS: The overall rate of mediastinitis was 1.1% (120 cases), and higher in coronary artery bypass surgery than in valvular surgery (1.2 vs 0.8%). No trend in incidence was detectable, although surgical patients became progressively older (mean age, 59 to 65 years, p < 0.01), and the proportion of women (from 25% to 31%; p < 0.01) and of patients with American Society of Anesthesiologists score over 3 (from 10% to 81%, p < 0.01) both increased. The rate of mediastinitis was almost twice as high in men (1.2% vs 0.7%, p < 0.01). In three body mass index (BMI) categories (<25, 25 to 30, and >30 kg/m2), rates of mediastinitis were 0.5%, 1.0%, and 1.8%. In multivariate analysis adjusted for age, sex, year, operation type, and perfusion time, the only predictor for mediastinitis was BMI. CONCLUSIONS: Mediastinitis is not diminishing. Larger populations at risk, for example proportions of overweight patients, reinforce the importance of surveillance and pose a challenge in focusing preventive measures.

Reactive arthritis following an outbreak of Campylobacter jejuni infection.

OBJECTIVE: To study the occurrence and the clinical picture of musculoskeletal (MSK) complications including reactive arthritis (ReA) following an outbreak of Campylobacter jejuni. METHODS: An outbreak of C. jejuni infection occurred in 2000 in Asikkala, Finland, during which 350 exposed subjects contacted the Municipal Health Centre (MHC). All primary care physicians in the MHC were advised to refer patients with acute MSK complications to the Rheumatism Foundation Hospital (RFH) for a specialist clinical examination, which was performed