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Numerous source attribution studies for foodborne pathogens based on epidemiological and microbiological methods are available. These studies provide empirical data for modelling frameworks that synthetize the quantitative evidence at our disposal and reduce reliance on expert elicitations. Here, we develop a statistical model within a Bayesian estimation framework to integrate attribution estimates from expert elicitations with estimates from microbial subtyping and case-control studies for sporadic infections with four major bacterial zoonotic pathogens in the Netherlands (Campylobacter, Salmonella, Shiga toxin-producing E. coli [STEC] O157 and Listeria). For each pathogen, we pooled the published fractions of human cases attributable to each animal reservoir from the microbial subtyping studies, accounting for the uncertainty arising from the different typing methods, attribution models, and year(s) of data collection. We then combined the population attributable fractions (PAFs) from the case-control studies according to five transmission pathways (domestic food, environment, direct animal contact, human-human transmission and travel) and 11 groups within the foodborne pathway (beef/lamb, pork, poultry meat, eggs, dairy, fish/shellfish, fruit/vegetables, beverages, grains, composite foods and food handlers/vermin). The attribution estimates were biologically plausible, allowing the human cases to be attributed in several ways according to reservoirs, transmission pathways and food groups. All pathogens were predominantly foodborne, with Campylobacter being mostly attributable to the chicken reservoir, Salmonella to pigs (albeit closely followed by layers), and Listeria and STEC O157 to cattle. Food-wise, the attributions reflected those at the reservoir level in terms of ranking. We provided a modelling solution to reach consensus attribution estimates reflecting the empirical evidence in the literature that is particularly useful for policy-making and is extensible to other pathogens and domains., (© 2022 The Authors. Zoonoses and Public Health published by Wiley-VCH GmbH.)

This study investigated the dynamics of SARS-CoV-2 infection and diagnostics in 242 household members of different ages and with different symptom severity after SARS-CoV-2 exposure early in the pandemic (March-April 2020). Households with a SARS-CoV-2 confirmed positive case and at least one child in the Netherlands were followed for 6 weeks. Naso (NP)- and oropharyngeal (OP) swabs, oral fluid and feces specimens were analyzed for SARS-CoV-2 RNA and serum for SARS-CoV-2-specific antibodies. The dynamics of the presence of viral RNA and the serological response was modeled to determine the sampling time-frame and sample type with the highest sensitivity to confirm or reject a SARS-CoV-2 diagnosis. In children higher viral loads compared to adults were detected at symptom onset. Early in infection, higher viral loads were detected in NP and OP specimens, while RNA in especially feces were longer detectable. SARS-CoV-2-specific antibodies have 90% probability of detection from 7 days (total Ig) and 18 days (IgG) since symptom onset. For highest probability of detection in SARS-CoV-2 diagnostics early in infection, RT-PCR on NP and OP specimens are more sensitive than on oral fluid and feces. For SARS-CoV-2 diagnostics late after infection, RT-PCR on feces specimens and serology are more valuable., (© 2022. The Author(s).)

Booster vaccinations for pertussis are advised in many countries during childhood or adulthood. In a phase IV longitudinal interventional study, we assessed long-term immunity following an extra pertussis booster vaccination in children and adults. Children (9 years of age) were primed in infancy with either the Dutch whole cell pertussis (wP) vaccine ( n = 49) or acellular pertussis (aP) vaccines ( n = 59), and all children received a preschool aP booster. Adults (25-29 years, n = 86) were wP-primed in infancy and did not receive a preschool booster. All were followed-up for approximately 6 years. After the additional booster, antibody responses to pertussis were more heterogeneous but generally higher in adults compared with children, and additional modelling showed that antibody concentrations remained higher for at least a decade. Serologic parameters indicative of recent pertussis infection were more often found in aP-primed children (12%) compared with wP-primed individuals (2%) ( p = 0.052). This suggests that the aP booster vaccination in aP-primed children offers less long-term protection against pertussis infection and consequently against transmission. Together, these data show that aP priming in combination with aP boosting may not be sufficient to prevent circulation and transmission, while wP-primed adults may benefit from enhanced long-lasting immunity.

Real-time reverse transcription-polymerase chain reaction (RT-PCR) on upper respiratory tract (URT) samples is the primary method to diagnose SARS-CoV-2 infections and guide public health measures, with a supportive role for serology. We reinforce previous findings on limited sensitivity of PCR testing, and solidify this fact by statistically utilizing a firm basis of multiple tests per individual. We integrate stratifications with respect to several patient characteristics such as severity of disease and time since onset of symptoms. Bayesian statistical modelling was used to retrospectively determine the sensitivity of RT-PCR using SARS-CoV-2 serology in 644 COVID-19-suspected patients with varying degrees of disease severity and duration. The sensitivity of RT-PCR ranged between 80% - 95%; increasing with disease severity, it decreased rapidly over time in mild COVID-19 cases. Negative URT RT-PCR results should be interpreted in the context of clinical characteristics, especially with regard to containment of viral transmission based on 'test, trace and isolate'. Keywords: SARS-CoV-2, RT-PCR, serology, sensitivity, public health., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Soil has been identified as an important source of exposure to a variety of chemical and biological contaminants. Toxoplasma gondii is one of those potential biological contaminants associated with serious health effects in pregnant women and immunocompromised patients. Gardening or consumption of homegrown vegetables may present an important route of T. gondii infection via accidental ingestion of soil. In the Netherlands, there is quantitative information on the risk of T. gondii infection via meat products, but not on the risk of infection through soil. The objective of this study was to develop a quantitative microbial risk assessment (QMRA) model for estimating the risk associated with T. gondii exposure via accidental soil ingestion in the Netherlands. In order to obtain the needed information, a magnetic capture method for detection of T. gondii oocysts in soil samples was developed, and T. gondii DNA was detected using qPCR targeting the 529 bp repeat element. The method was shown to provide 95% probability of detection (95% CI: 88-100%) when at least 34 oocysts are present in 25 g of soil. T. gondii DNA was detected in 5 of 148 soil samples with interpretable results (3%, 95% CI: 1.5-7.7%). Results for 18 samples were not interpretable due to PCR inhibition. The estimated amount of oocysts presented in qPCR positive samples was quantified by a linear model, and the amount varied from 8 to 478 in 25 g of soil. The estimated incidence rate of T. gondii infection from the QMRA model via soil varied from 0.3 to 1.8 per 1000 individuals per day. Several data gaps (e.g., soil contamination/ingestion and oocysts viability) have been identified in this study, the structure of the model can be applied to obtain more accurate estimates of the risk of T. gondii infection via soil when data become available., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Neisseria meningitidis is often asymptomatically carried in the nasopharynx but may cause invasive meningococcal disease, leading to morbidity and mortality. Meningococcal conjugate vaccinations induce functional protective antibodies against capsular antigens, but seroprotection wanes over time. We measured functional antibody titers five years after administration of a single dose of the meningococcal ACWY-polysaccharide-specific tetanus toxoid-conjugated (MenACWY-TT) vaccine in adolescents and middle-aged adults in the Netherlands, using the serum bactericidal antibody with baby rabbit complement (rSBA) assay. Protection was defined as rSBA titer ≥8. The meningococcal ACWY-specific serum IgG concentrations were measured with a multiplex immunoassay. Duration of protection was estimated by a bi-exponential decay model. Sufficient protection for MenC, MenW, and MenY was achieved in 94-96% of the adolescents five years postvaccination, but, in middle-aged adults, only in 32% for MenC, 65% for MenW and 71% for MenY. Median duration of protection for MenCWY was 4, 14, and 21 years, respectively, in middle-aged adults, while, in adolescents, it was 32, 98, and 33 years. Our findings suggest that adolescents, primed in early childhood with MenC conjugate vaccination, remain sufficiently protected after a single dose of MenACWY-TT vaccine. Middle-aged adults without priming vaccination show fast waning of antibodies, particularly MenC, for which protection is lost after four years.

The protozoan parasite Toxoplasma gondii can infect all warm-blooded animals and it causes the disease toxoplasmosis. Meat containing viable T. gondii tissue cysts is considered one of the main sources of human infection. The relative importance of the different types of meat depends, not only on the prevalence of T. gondii infection in the different livestock species, but also on consumed volumes and preparation habits. To take these factors into account and to estimate the relative contribution of different meat products to human infection, a quantitative risk assessment model for meat-borne T. gondii infection was previously developed. However, at the time, the effect of salting on parasite viability was estimated based on a single experiment. In recent years, data using salting methods that are more in line with processing of meat products have come available. Literature data on the effect of salting on T. gondii viability were collected and used to fit a predictive model. In addition to the new salting model, a lower concentration of bradyzoites in cattle, more specific heating profiles, and more recent consumption data were implemented in the QMRA model for meat-borne T. gondii infection in the Netherlands. Results show that beef remains the most important source, as it contributed 84% of the total number of predicted infections in the Dutch population, followed by pork (12%), mutton (3.7%), lamb (0.2%) pork/beef mixed products (0.1%), and veal (0.01%). The predicted number of T. gondii infections is reasonably in line with epidemiological data. At the product level, filet americain (a raw beef spread) alone contributed 80% of the total predicted infections in the base model, but scenario analyses demonstrate that its contribution is highly dependent on the salting parameters. A clear identification of the most risky meat products is important, as interventions focussing on these products could have a great impact on reducing T. gondii disease burden in the Netherlands. For that reason, it is important that the effects of salting and other processing methods are evaluated in line with industrial processing and incorporated in quantitative risk assessment models for meat-borne toxoplasmosis., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Intro: Toxoplasmosis has high disease burden in the Netherlands and in the rest of Europe. It can be acquired directly by ingestion of Toxoplasma gondii (T. gondii) oocysts shed by infected cats, or indirectly via consumption of undercooked meat from infected livestock. Cat vaccination has been proposed for reducing oocyst-acquired human infections but it remains unclear whether such an intervention can be effective. In this study we quantified the effects of using cat vaccination on reducing oocyst-originated T. gondii human infections., Method: By using a disease dynamics compartmental model for T. gondii infections in cats and mice we studied the effects of a hypothetical cat vaccine on the presence of T. gondii oocysts in the environment. A fitted dose response model was used to assess the effect of oocyst reduction on the expected human infections., Results: For rats, mice and pigs, and possibly intermediate hosts in general, ingestion of one oocyst provides 30%-60% probability of T. gondii infection. Assuming a favourable ideal scenario where vaccination completely prevents oocyst shedding and predation rate is of one mouse per week per cat, eight cats can be left susceptible in order to achieve elimination and stop oocyst-originated transmission, independent of the total cat population. Considering populations of 1000, 100, 50 and 20 cats, cat vaccination coverage of 94%, 68%, 54% and 35%, respectively, would reduce expected oocyst-originated human cases by 50%., Conclusion: For attaining elimination of oocyst-originated human infections, only few cats may remain unvaccinated, regardless of the cat-population size, and only a few more cats may remain unvaccinated for reducing infections substantially. Such vaccination coverages can in practice be achieved only when small cat-populations are considered, but in larger cat-populations the large efficacy and vaccination coverage needed are unfeasible., (Copyright © 2019. Published by Elsevier B.V.)

BackgroundTimely notification of infectious diseases is essential for effective disease control and needs regular evaluation.AimOur objective was to evaluate the effects that statutory adjustments in the Netherlands in 2008 and raising awareness during outbreaks had on notification timeliness.MethodsIn a retrospective analyses of routine surveillance data obtained between July 2003 and November 2017, delays between disease onset and laboratory confirmation (disease identification delay), between laboratory confirmation and notification to Municipal Health Services (notification delay) and between notification and reporting to the National Institute for Public Health and the Environment (reporting delay) were analysed for 28 notifiable diseases. Delays before (period 1) and after the law change (periods 2 and 3) were compared with legal timeframes. We studied the effect of outbreak awareness in 10 outbreaks and the effect of specific guidance messages on disease identification delay for two diseases.ResultsWe included 144,066 notifications. Average notification delay decreased from 1.4 to 0.4 days across the three periods (six diseases; p < 0.05), reporting delay decreased mainly in period 2 (from 0.5 to 0.1 days, six diseases; p < 0.05). In 2016-2017, legal timeframes were met overall. Awareness resulted in decreased disease identification delay for three diseases: measles and rubella (outbreaks) and psittacosis (specific guidance messages).ConclusionsLegal adjustments decreased notification and reporting delays, increased awareness reduced identification delays. As disease identification delay dominates the notification chain, insight in patient, doctor and laboratory delay is necessary to further improve timeliness and monitor the impact of control measures during outbreaks.

In the Netherlands, toxoplasmosis ranks second in disease burden among foodborne pathogens with an estimated health loss of 1,900 Disability Adjusted Life Years and a cost-of-illness estimated at €45 million annually. Therefore, effective and preferably cost-effective preventive interventions are warranted. Freezing meat intended for raw or undercooked consumption and improving biosecurity in pig farms are promising interventions to prevent Toxoplasma gondii infections in humans. Putting these interventions into practice would expectedly reduce the number of infections; however, the net benefits for society are unknown. Stakeholders bearing the costs for these interventions will not necessary coincide with the ones having the benefits. We performed a Social Cost-Benefit Analysis to evaluate the net value of two potential interventions for the Dutch society. We assessed the costs and benefits of the two interventions and compared them with the current practice of education, especially during pregnancy. A 'minimum scenario' and a 'maximum scenario' was assumed, using input parameters with least benefits to society and input parameters with most benefits to society, respectively. For both interventions, we performed different scenario analyses. The freezing meat intervention was far more effective than the biosecurity intervention. Despite high freezing costs, freezing two meat products: steak tartare and mutton leg yielded net social benefits in both the minimum and maximum scenario, ranging from €10.6 million to €31 million for steak tartare and €0.6 million to €1.5 million for mutton leg. The biosecurity intervention would result in net costs in all scenarios ranging from €1 million to €2.5 million, due to high intervention costs and limited benefits. From a public health perspective (i.e. reducing the burden of toxoplasmosis) and the societal perspective (i.e. a net benefit for the Dutch society) freezing steak tartare and leg of mutton is to be considered., Competing Interests: The authors have declared that no competing interests exist.

Data from a set of different studies on the infectivity and pathogenicity of Campylobacter jejuni were analyzed with a multilevel model, allowing for effects of host species (nonhuman primates and humans) and different strains of the pathogen. All challenge studies involved high doses of the pathogen, resulting in all exposed subjects to become infected. In only one study a dose response effect (increasing trend with dose) for infection was observed. High susceptibility to infection with C. jejuni was found in a joint analysis of outbreaks and challenge studies. For that reason four outbreaks, associated with raw milk consumption, were also included in the present study. The high doses used for inoculation did not cause all infected subjects to develop acute enteric symptoms. The observed outcomes are consistent with a dose response effect for acute symptoms among infected subjects: a conditional illness dose response relation. Nonhuman primates and human volunteers did not appear to have different susceptibilities for developing enteric symptoms, but exposure in outbreaks (raw milk) did lead to a higher probability of symptomatic campylobacteriosis., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Correlates of protection (CoPs) against the highly contagious respiratory disease whooping cough, caused by Bordetella pertussis, remain elusive. Characterizing the antibody response to this pathogen is essential towards identifying potential CoPs. Here, we evaluate levels, avidity and functionality of B. pertussis-specific-antibodies from paired plasma samples derived from symptomatic and recovered pertussis patients, as well as controls. Natural infection is expected to induce protective immunity. IgG levels and avidity to nine B. pertussis antigens were determined using a novel multiplex panel. Furthermore, opsonophagocytosis of a B. pertussis clinical isolate by neutrophils was measured. Findings indicate that following infection, B. pertussis-specific antibody levels of (ex-) pertussis patients waned, while the avidity of antibodies directed against the majority of studied antigens increased. Opsonophagocytosis indices decreased upon recovery, but remained higher than controls. Random forest analysis of all the data revealed that 28% of the opsonophagocytosis index variances could be explained by filamentous hemagglutinin- followed by pertussis toxin-specific antibodies. We propose to further explore which other B. pertussis-specific antibodies can better predict opsonophagocytosis. Moreover, other B. pertussis-specific antibody functions as well as the possible integration of these functions in combination with other immune cell properties should be evaluated towards the identification of CoPs against pertussis.

Capturing the complexity and waning patterns of co-occurring immunoglobulin (Ig) responses after clinical B. pertussis infection may help understand how the human host gradually loses protection against whooping cough. We applied bi-exponential modelling to characterise and compare B. pertussis specific serological dynamics in a comprehensive database of IgG, IgG subclass and IgA responses to Ptx, FHA, Prn, Fim2/3 and OMV antigens of (ex-) symptomatic pertussis cases across all age groups. The decay model revealed that antigen type and age group were major factors determining differences in levels and kinetics of Ig (sub) classes. IgG-Ptx waned fastest in all age groups, while IgA to Ptx, FHA, Prn and Fim2/3 decreased fast in the younger but remained high in older (ex-) cases, indicating an age-effect. While IgG1 was the main IgG subclass in response to most antigens, IgG2 and IgG3 dominated the anti-OMV response. Moreover, vaccination history plays an important role in post-infection Ig responses, demonstrated by low responsiveness to Fim2/3 in unvaccinated elderly and by elevated IgG4 responses to multiple antigens only in children primed with acellular pertussis vaccine (aP). This work highlights the complexity of the immune response to this re-emerging pathogen and factors determining its Ig quantity and quality.

Bordetella pertussis circulates even in highly vaccinated countries affecting all age groups. Insight into the scale of concealed reinfections is important as they may contribute to transmission. We therefore investigated whether current single-point serodiagnostic methods are suitable to estimate the prevalence of pertussis reinfection. Two methods based on IgG-Ptx plasma levels alone were used to evaluate the proportion of renewed seroconversions in the past year in a cohort of retrospective pertussis cases ≥ 24 months after a proven earlier symptomatic infection. A Dutch population database was used as a baseline. Applying a classical 62.5 IU/ml IgG-Ptx cut-off, we calculated a seroprevalence of 15% in retrospective cases, higher than the 10% observed in the population baseline. However, this method could not discriminate between renewed seroconversion and waning of previously infection-enhanced IgG-Ptx levels. Two-component cluster analysis of the IgG-Ptx datasets of both pertussis cases and the general population revealed a continuum of intermediate IgG-Ptx levels, preventing the establishment of a positive population and the comparison of prevalence by this alternative method. Next, we investigated the complementary serodiagnostic value of IgA-Ptx levels. When modelling datasets including both convalescent and retrospective cases we obtained new cut-offs for both IgG-Ptx and IgA-Ptx that were optimized to evaluate renewed seroconversions in the ex-cases target population. Combining these cut-offs two-dimensionally, we calculated 8.0% reinfections in retrospective cases, being below the baseline seroprevalence. Our study for the first time revealed the shortcomings of using only IgG-Ptx data in conventional serodiagnostic methods to determine pertussis reinfections. Improved results can be obtained with two-dimensional serodiagnostic profiling. The proportion of reinfections thus established suggests a relatively increased period of protection to renewed infection after clinical pertussis.

The extent to which reporting delays should be reduced to gain substantial improvement in outbreak control is unclear. We developed a model to quantitatively assess reporting timeliness. Using reporting speed data for 6 infectious diseases in the notification system in the Netherlands, we calculated the proportion of infections produced by index and secondary cases until the index case is reported. We assumed interventions that immediately stop transmission. Reporting delays render useful only those interventions that stop transmission from index and secondary cases. We found that current reporting delays are adequate for hepatitis A and B control. However, reporting delays should be reduced by a few days to improve measles and mumps control, by at least 10 days to improve shigellosis control, and by at least 5 weeks to substantially improve pertussis control. Our method provides quantitative insight into the required reporting delay reductions needed to achieve outbreak control and other transmission prevention goals.

Which case-based intervention measures should be applied during an epidemic outbreak depends on how timely they can be applied and how effective they are. During the course of each individual's infection, the earlier control measures are applied on him/her the more effectively further disease spread can be prevented. However, quick implementation can lead to loss of efficacy or coverage, e.g., when individuals are targeted based on rapid but poorly sensitive diagnostic tests in place of slower but accurate PCR tests. To analyse this trade off between speed and coverage we used stochastic models considering how the individual reproduction density is modified by interventions. We took as example the case-based intervention strategy employed in the Netherlands during the beginning of the H1N1 pandemic. Suspected cases were isolated and samples were collected for PCR diagnosis. In case of positive diagnosis, antiviral drugs were provided to contacts as post-exposure prophylaxis. At the time there were also rapid influenza diagnostic tests (RIDTs) available which provided results within an hour after sample collection compared to a median of 2.7 days for PCR tests, but they were less sensitive. We studied how interventions based on RIDTs with various sensitivities affect the outbreak size and how these compare to PCR diagnosis based interventions. Using an intervention based on a bedside RIDT with 60% detection ratio or a laboratory RIDT with 70% detection ratio is as effective as the most effective PCR-diagnosis based intervention. Relative performances of interventions are not dependent on the basic reproduction number R0 but only on distributions of individual reproduction density and of delay periods. The individual reproduction density combines R0 and infection time distribution, both crucial in determining the impact of case-based interventions during epidemic outbreaks., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Despite high vaccination coverage in most European countries, large community outbreaks of measles do occur, normally clustered around schools and resulting from suboptimal vaccination coverage. To determine whether or when it is worth implementing outbreak-response vaccination campaigns in schools, we used stochastic outbreak models to reproduce a public school outbreak in Germany, where no vaccination campaign was implemented. We assumed 2 scenarios covering the baseline vaccination ratio range (91.3%-94.3%) estimated for that school and computed outbreaks assuming various vaccination delays. In one scenario, reacting (i.e., implementing outbreak-response vaccination campaigns) within 12-24 days avoided large outbreaks and reacting within 50 days reduced outbreak size. In the other scenario, reacting within 6-14 days avoided large outbreaks and reacting within 40 days reduced the outbreak size. These are realistic time frames for implementing school outbreak response vaccination campaigns. High baseline vaccination ratios extended the time needed for effective response.