The efficacy of the conventional bacille Calmette-Guérin (BCG) vaccine is often questioned because of conflicting trial results [1]. In this context, a new BCG vaccine developed by Grode et al. [2] has been seen as a favourable development in tuberculosis (TB) control [3]. BCG vaccine development is a challenge for many reasons, not least of which is the complex immunology of mycobacterial infections. The pathogenesis of TB, and prevention of TB by BCG, is predominantly a function of cell-mediated immunity. Mycobacterium tuberculosis (MTB) and BCG are phagocytosed, but remain viable for some time within the phagosome. There, BCG antigens must be presented to major histocompatibility complex (MHC) class II molecules to activate CD4+ cells, and to MHC class I molecules to activate CD8+ cells [3]. However, both MTB and BCG fail to activate CD8+ cells sufficiently. The relative failure of activation of CD8+ cells is thought to be related to the enzyme urease, which keeps the intracellular pH high and thus inhibits presentation of antigens to T cells which would otherwise activate the CD8+ response. Grode et al. [2] have engineered a BCG strain which overcomes this problem and allows release of antigen into the cell and thereby stimulates a CD8+ cell response in addition to the CD4 response seen with conventional BCG. They did this first by engineering a strain of BCG which secretes listeriolysin (Hly), an enzyme from Listeria monocytogenes which perforates cell membranes.

In randomized trials, the treatment assignment mechanism is independent of the outcome of interest and other covariates thought to be relevant in determining this outcome. It also allows, on average, for a balanced distribution of these covariates in the vaccine and placebo groups. Randomization, however, does not guarantee that the estimated effect is an unbiased estimate of the biological effect of interest. We show how exposure to infection can be a confounder even in randomized vaccine field trials. Based on a simple model of the biological efficacy of interest, we extend the arguments on comparability and collapsibility to examine the limits of randomization to control for unmeasured covariates. Estimates from randomized, placebo-controlled Phase III vaccine field trials that differ in baseline transmission are not comparable unless explicit control for baseline transmission is taken into account.

Epidemics of visceral leishmaniasis (VL) in major Brazilian cities are new phenomena since 1980. As determinants of transmission in urban settings probably operate at different geographic scales, and information is not available for each scale, a multilevel approach was used to examine the effect of canine infection and environmental and socio-economic factors on the spatial variability of incidence rates of VL in the city of Teresina. Details on an outbreak of greater than 1200 cases of VL in Teresina during 1993–1996 were available at two hierarchical levels: census tracts (socio-economic characteristics, incidence rates of human VL) and districts, which encompass census tracts (prevalence of canine infection). Remotely sensed data obtained by satellite generated environmental information at both levels. Data from census tracts and districts were analysed simultaneously by multilevel modelling. Poor socio-economic conditions and increased vegetation were associated with a high incidence of human VL. Increasing prevalence of canine infection also predicted a high incidence of human VL, as did high prevalence of canine infection before and during the epidemic. Poor socio-economic conditions had an amplifying effect on the association between canine infection and the incidence of human VL. Focusing interventions on areas with characteristics identified by multilevel analysis could be a cost-effective strategy for controlling VL. Because risk factors for infectious diseases operate simultaneously at several levels and ecological data usually are available at different geographical scales, multilevel modelling is a valuable tool for epidemiological investigation of disease transmission.

Interactions between pathogens and hosts at the population level should be considered when studying the effectiveness of control measures for infectious diseases. The advantage of doing transmission experiments compared to field studies is that they offer a controlled environment in which the effect of a single factor can be investigated, while variation due to other factors is minimized. This paper gives an overview of the biological and mathematical aspects, bottlenecks and solutions of developing and executing transmission experiments with animals. Different methods of analysis and different experimental designs are discussed. Final size methods are often used for analysing transmission data, but have never been published in a refereed journal; therefore, they will be described in detail in this paper. We hope that this information is helpful for scientists who are considering performing transmission experiments.

Although Finland has not experienced a classical swine fever (CSF) epidemic since 1917, the concern about early detection is relevant. The time until detection of CSF on a pig-breeding farm was predicted by simulation, and earlier detection of CSF-infected farms was assessed. Eight to 12 weeks will pass before CSF is detected on a Finnish pig-breeding farm, which resembles detection of the index farm for actual CSF epidemics in Europe. Although notification of suspected CSF on the infected farm accelerates detection the most, interventions aimed at promoting investigations of the general health problem noticed on the farm, or a more comprehensive testing of samples currently arriving from pig farms to the investigating laboratory could shorten detection time by 3 weeks. Results are applicable for further simulation of an event of a CSF epidemic in Finland, and for studying contingency options to promote more rapid detection of infectious diseases of swine not found at present in the country.

The purpose of this study was to describe patterns of seroconversion to bovine leukaemia virus and to estimate the main parameters needed for future model building. A longitudinal study was carried out between February 1999 and November 2001 in seven commercial dairy farms in Argentina using 1535 lactating cows. Time-interval parameters were analysed using a parametric survival model with shared frailty, time until infection was analysed using a Bayesian interval-censoring survival model and the infection transmission parameter (β) was estimated by a generalized linear model. The reproduction ratio (R0) was calculated. In total, 1000 cows tested positive and 494 tested negative. The predicted median age at infection was 4·6 years for seroconverted cows. For infected herds, the proportion of positive calves was as high as for infected cows and showed a large proportion of infected breeding heifers. Peaks in the overall average incidence per season-year were observed during autumn and spring. Results reveal that the period around parturition is a high-risk period. Moreover, heavily infected herds seem to have an increased proportion of young stock infected. The overall β was estimated as 2·9/year (95% CI 1·9–3·7) and combined with a relatively long infectious period it resulted in a high reproductive ratio (R0=8·9). Therefore, a high effectiveness of control measures needs to be achieved to eradicate the disease.

The purpose of this study was to evaluate Salmonella ELISA tests and a culture technique to determine Salmonella status using samples collected from commercial herds. Faecal samples from 15 finisher pigs on each of 40 swine farms were cultured for Salmonella. Sera from the same 600 pigs were analysed for the presence of antibodies to Salmonella by means of two different ELISA kits Salmotype (Salmotype® Labordiagnostik, Leipzig, Germany) and IDEXX (Herdchek* Salmonella; IDEXX Laboratories, Schiphol-Rijk, Noord-Holland, The Netherlands). The Salmotype ELISA test demonstrated a moderate ability to differentiate culture-positive pigs from culture-negative pigs while IDEXX was relatively poor in classifying those pigs correctly (The area under the curves were 0·79 and 0·65 for Salmotype and IDEXX respectively). The maximum value of sensitivity plus specificity was gained at the cut-off optical density (OD) [ges ]25% for Salmotype (sensitivity 0·65, specificity 0·84) and at the OD [ges ]9% for IDEXX (sensitivity 0·59, specificity 0·69). The maximum herd sensitivity and herd specificity was 0·64 (95% CI 0·49–0·79) and 0·72 (95% CI 0·59–0·86) for the Salmotype test and 0·73 (95% CI 0·59–0·87) and 0·62 (95% CI 0·47–0·77) for the IDEXX. Culture and the ELISA tests showed fair agreement at the herd level (κ=0·3, P<0·05). Likewise there was significant disagreement between the two ELISA tests at the pig level, but very good agreement between the two ELISA tests (κ=0·8, P<0·0001) at the herd level. The coating antigens in Salmotype and IDEXX represent only 48% of the antigens of Salmonella isolated in our study and need to be revised based upon the Salmonella serovar distribution in Ontario.

Three conventional regression models were compared using the time-series data of the occurrence of haemorrhagic fever with renal syndrome (HFRS) and several key climatic and occupational variables collected in low-lying land, Anhui Province, China. Model I was a linear time series with normally distributed residuals; model II was a generalized linear model with Poisson-distributed residuals and a log link; and model III was a generalized additive model with the same distributional features as model II. Model I was fitted using least squares whereas models II and III were fitted using maximum likelihood. The results show that the correlations between the HFRS incidence and the independent variables measured (i.e. difference in water level, autumn crop production and density of Apodemus agrarius) ranged from −0·40 to 0·89. The HFRS incidence was positively associated with density of A. agrarius and crop production, but was inversely associated with difference in water level. The residual analyses and the examination of the accuracy of the models indicate that model III may be the most suitable in the assessment of the relationship between the incidence of HFRS and the independent variables.

Pneumonia and influenza represent a significant public health burden in Canada and abroad. Knowledge of how this burden varies geographically provides clues to understanding the determinants of these illnesses, and insight into the effective management of health-care resources. We conducted a retrospective, population-based, ecological-level study to assess age- and gender-specific spatial patterns of pneumonia and influenza hospitalizations in the province of Ontario, Canada from 1992 to 2001. Results revealed marked variability in hospitalization rates by age, as well as clear and statistically significant patterns of high rates in northern rural counties and low rates in southern urban counties. A moderate yet significant level of positive spatial autocorrelation (Moran's I=0·21, P<0·05) was found in the global data, with significant, age-specific clusters of high values or ‘hot spots’ identified in several northern counties. Findings illustrate the need for geographically focused prevention strategies, and resource and service allocation policies informed by regional and population-specific demands.

There is little UK data on hospital admission rates for childhood pneumonia, lobar pneumonia, severity or risk factors. From 13 hospitals serving the catchment population, demographic and clinical details were prospectively collected between 2001 and 2002 for children aged 0–15 years, seen by a paediatrician with community-acquired pneumonia (CAP) and consistent chest X-ray changes. From 750 children assessed in hospital, incidence of CAP was 14·4 (95% CI 13·4–15·4)/10000 children per year and 33·8 (95% CI 31·1–36·7) for <5-year-olds; with an incidence for admission to hospital of 12·2 (95% CI 11·3–13·2) and 28·7 (95% CI 26·2–31·4) respectively. Where ascertainment was confirmed, incidence of CAP assessed in hospital was 16·1 (95% CI 14·9–17·3) and 41·0 (95% CI 37·7–44·5) in the 0–4 years age group, whilst incidence for hospital admission was 13·5 (95% CI 12·4–14·6) and 32 (95% CI 29·1–35·1) respectively. In the <5 years age group incidence of lobar pneumonia was 5·6 (95% CI 4·5–6·8)/10000 per year and severe disease 19·4 (95% CI 17·4–21·7)/10000 per year. Risk of severe CAP was significantly increased for those aged <5 years (OR 1·50, 95% CI 1·07–2·11) and with prematurity, OR 4·02 (95% CI 1·16–13·85). It also varied significantly by county of residence. This is a unique insight into the burden of hospital assessments and admissions caused by childhood pneumonia in the United Kingdom and will help inform future preventative strategies.

Molecular methods for the detection and typing of hepatitis A virus (HAV) strains in sewage were applied to determine its distribution in Cairo and Barcelona. The study revealed the occurrence of different patterns of hepatitis A endemicity in each city. The circulating strains characterized, whether in Cairo or Barcelona, were genotype IB. The effects of a child vaccination programme and the increase in the immigrant population on the overall hepatitis A occurrence in Barcelona were evaluated. While vaccination contributed to a significant decrease in the number of clinical cases, the huge recent immigration flow has probably been responsible for the re-emergence of the disease in the last year of study, in the form of small outbreaks among the non-vaccinated population.

A high prevalence of hepatitis C (HCV) virus infection of up to 80% has been reported for injecting drug users (IDUs) in prison communities. However, there are only very limited data available on the prevalence and course of HCV in young offenders. We performed a study on hepatitis C markers in the largest German Young Offenders' Institution (YOI), a prison for men (aged 16–24 years). In 2002, all 1176 incoming offenders were asked to participate in the study of whom >95% agreed. Ninety-seven inmates (8·6%) tested positive for anti-HCV or HCV RNA, 79% of whom were viraemic. None of the patients had evidence of cirrhosis at presentation. Interestingly, six individuals (6%) tested positive for HCV RNA in the absence of anti-HCV antibodies, four of whom cleared HCV spontaneously during follow-up without either clinical signs of acute hepatitis or developing HCV antibodies. Hepatitis C markers were significantly more prevalent among immigrants from the former Soviet Union (NIS) than among German inmates (31% vs. 6% respectively, P<0·0001). HIV co-infection was found in five individuals, all of whom were German. In contrast, hepatitis B surface antigen (HBsAg) was detected in five NIS immigrants, one Lebanese and one German inmate. HCV genotypes 2 and 3 were more prevalent in immigrants than in German inmates, while biochemical parameters did not differ significantly between the two groups. In conclusion, the prevalence of hepatitis C was relatively low among inmates of German YOIs although there were significant differences in relation to the country of birth. Our data highlight the need for educational programmes for young offenders in order to prevent the further spread of HCV.

We propose an analytical and conceptual framework for a systematic and comprehensive assessment of disease seasonality to detect changes and to quantify and compare temporal patterns. To demonstrate the proposed technique, we examined seasonal patterns of six enterically transmitted reportable diseases (EDs) in Massachusetts collected over a 10-year period (1992–2001). We quantified the timing and intensity of seasonal peaks of ED incidence and examined the synchronization in timing of these peaks with respect to ambient temperature. All EDs, except hepatitis A, exhibited well-defined seasonal patterns which clustered into two groups. The peak in daily incidence of Campylobacter and Salmonella closely followed the peak in ambient temperature with the lag of 2–14 days. Cryptosporidium, Shigella, and Giardia exhibited significant delays relative to the peak in temperature (~40 days, P<0·02). The proposed approach provides a detailed quantification of seasonality that enabled us to detect significant differences in the seasonal peaks of enteric infections which would have been lost in an analysis using monthly or weekly cumulative information. This highly relevant to disease surveillance approach can be used to generate and test hypotheses related to disease seasonality and potential routes of transmission with respect to environmental factors.

From 1996 to 2003, four 12-month population-based surveys were performed in FoodNet sites to determine the burden of diarrhoeal disease in the population. Acute diarrhoeal illness (ADI) was defined as [ges ]3 loose stools in 24 hours with impairment of daily activities or duration of diarrhoea >1 day. A total of 52840 interviews were completed. The overall weighted prevalence of ADI in the previous month was 5·1% (95% CI±0·3%), corresponding to 0·6 episodes of ADI per person per year. The average monthly prevalence of ADI was similar in each of the four survey cycles (range 4·5–5·2%). Rates of ADI were highest in those age <5 years. Of those with ADI, 33·8% (95% CI±2·7%) reported vomiting, 19·5% (95% CI±2·1%) visited a medical provider, and 7·8% (95% CI±1·4%) took antibiotics. Rates of ADI were remarkably consistent over time, and demonstrate the substantial burden placed on the health-care system.

In August–September 2004, a cryptosporidiosis outbreak affected >250 persons who visited a California waterpark. Employees and patrons of the waterpark were affected, and three employees and 16 patrons admitted to going into recreational water while ill with diarrhoea. The median illness onset date for waterpark employees was 8 days earlier than that for patrons. A case-control study determined that getting water in one's mouth on the waterpark's waterslides was associated with illness (adjusted odds ratio 7·4, 95% confidence interval 1·7–32·2). Laboratory studies identified Cryptosporidium oocysts in sand and backwash from the waterslides' filter, and environmental investigations uncovered inadequate water-quality record keeping and a design flaw in one of the filtration systems. Occurring more than a decade after the first reported outbreaks of cryptosporidiosis in swimming pools, this outbreak demonstrates that messages about healthy swimming practices have not been adopted by pool operators and the public.

A family outbreak of Escherichia coli O157 infection was microbiologically associated with consumption of dry-fermented salami made with pork meat only and produced in a local plant. E. coli O157 strains isolated from a wife and husband, both hospitalized with bloody diarrhoea, and from the salami carried vt1, vt2 and eae genes and shared the same PFGE pattern. The food vehicle implicated in this outbreak is unusual because of both the animal species from which it originates and the fermentation and drying steps of the manufacturing process. This could be the first report of an outbreak associated with a product containing pork meat only. Even though sources of contamination other than pork meat could not be excluded, pork products should not be neglected in E. coli O157 outbreak investigations.

Meningococci are regarded as being unlikely to survive outside of their human host although this has possibly been more assumed than demonstrated. Seven strains of meningococci were tested for their ability to survive on glass or plastic while retaining expression of their capsule and important outer membrane proteins. A known number of colony-forming units of each strain were dried onto glass and onto plastic and tested for viability over time. Survival on glass was significantly better than on plastic (P<0·0001). Isolates of the New Zealand epidemic strain, B:4:P1.7-2,4 survived better on glass than all other strains tested. Recovered isolates still expressed their capsules and outer membrane proteins. These findings raise the question of whether meningococci can be transferred from person to person via fomites contaminated with oropharyngeal secretions containing meningococci.

During a group A streptococcus (GAS) outbreak 21 abattoir workers developed skin infections. The unusual outbreak strain (emm 108.1) was cultured from five workers and four persons in the community with links to the abattoir. The attack rate was 26% in the lamb line. Communal nailbrushes were neither routinely disinfected nor changed, and had high bacterial counts. A cohort study found a higher risk from working in the gutting area and getting cuts on hands more than weekly. Despite high bacterial counts daily nailbrush use had a lower risk, as did always wearing disposable gloves. Working in the gutting area (OR 11·44) and nailbrush use at least once a day (OR 0·04) were significant in the multivariate model. Transmission of infection is likely to have occurred on carcasses. GAS infection among abattoir workers was once common. Simple hygiene measures, such as nailbrush use, may reduce the impact of future outbreaks.

With reports of hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) continuing to increase and therapeutic options decrease, infection control methods are of increasing importance. Here we investigate the relationship between surveillance and infection control. Surveillance plays two roles with respect to control: it allows detection of infected/colonized individuals necessary for their removal from the general population, and it allows quantification of control success. We develop a stochastic model of MRSA transmission dynamics exploring the effects of two screening strategies in an epidemic setting: random and on admission. We consider both hospital and community populations and include control and surveillance in a single framework. Random screening was more efficient at hospital surveillance and allowed nosocomial control, which also prevented epidemic behaviour in the community. Therefore, random screening was the more effective control strategy for both the hospital and community populations in this setting. Surveillance strategies have significant impact on both ascertainment of infection prevalence and its control.

The prevalence of metallo-β-lactamase (MBL) production among Pseudomonas aeruginosa nosocomial isolates from a Brazilian teaching hospital was determined. A total of 512 P. aeruginosa isolates were recovered from 245 patients during a 10-month period. Ninety-four (38·4%, 95% CI 32·2–44·8%) isolates were MBL producers. Most resistance to β-lactams was mediated by MBL. Forty-one (16·7%) were resistant to all drugs except polymyxin B and 33 (80·5%) of these were MBL producers. Clonal dissemination, documented by DNA macrorestriction, played a major role for the spread of MBL isolates. The blaSPM-1 gene was demonstrated by PCR in 14 randomly selected MBL isolates. The extremely high prevalence of MBL production found challenges the choice of therapeutics for P. aeruginosa, and measures to control horizontal dissemination of MBL producers are urgently required.