Epidemiology of Pathogens Listed as Potential Bioterrorism Agents, the Netherlands, 2009‒2019.

We provide incidences (cases/10 million persons) in the Netherlands during 2009-2019 for pathogens listed as potential bioterrorism agents. We included pathogens from the highest categories of the European Medicines Agency or the US Centers for Disease Control and Prevention. Notifiable diseases and recently published data were used to calculate the average annual incidence. Coxiella burnetii had the highest incidence because of a Q fever epidemic during 2007-2010. Incidence then decreased to 10.8 cases/. Pathogens with an incidence >1 were Brucella spp. (2.5 cases), Francisella tularensis (1.3 cases), and Burkholderia pseudomallei (1.1 cases). Pathogens with an incidence <1 were hemorrhagic fever viruses (0.3 cases), Clostridium botulinum (0.2 cases), and Bacillus anthracis (0.1 cases). Variola major and Yersinia pestis were absent. The generally low incidences make it unlikely that ill-meaning persons can isolate these pathogens from natural sources in the Netherlands. However, the pathogens are stored in laboratories, underscoring the need for biosecurity measures.

Mpox outbreak in the Netherlands, 2022: public health response, characteristics of the first 1,000 cases and protection of the first-generation smallpox vaccine.

In early May 2022, a global outbreak of mpox started among persons without travel history to regions known to be enzootic for monkeypox virus (MPXV). On 8 August 2022, the Netherlands reported its 1,000th mpox case, representing a cumulative incidence of 55 per million population, one of the highest cumulative incidences worldwide. We describe characteristics of the first 1,000 mpox cases in the Netherlands, reported between 20 May and 8 August 2022, within the context of the public health response. These cases were predominantly men who have sex with men aged 31-45 years. The vast majority of infections were acquired through sexual contact with casual partners in private or recreational settings including LGBTQIA+ venues in the Netherlands. This indicates that, although some larger upsurges occurred from point-source and/or travel-related events, the outbreak was mainly characterised by sustained transmission within the Netherlands. In addition, we estimated the protective effect of first-generation smallpox vaccine against moderate/severe mpox and found a vaccine effectiveness of 58% (95% CI: 17-78%), suggesting moderate protection against moderate/severe mpox symptoms on top of any possible protection by this vaccine against MPXV infection and disease. Communication with and supporting the at-risk population in following mitigation measures remains essential.

Performance of Zika Assays in the Context of Toxoplasma gondii, Parvovirus B19, Rubella Virus, and Cytomegalovirus (TORCH) Diagnostic Assays.

Infections during pregnancy that may cause congenital abnormalities have been recognized for decades, but their diagnosis is challenging. This was again illustrated with the emergence of Zika virus (ZIKV), highlighting the inherent difficulties in estimating the extent of pre- and postnatal ZIKV complications because of the difficulties in establishing definitive diagnoses. We reviewed the epidemiology, infection kinetics, and diagnostic methods used for Toxoplasma gondii, parvovirus B19, rubella virus, and cytomegalovirus (TORCH) infections and compared the results with current knowledge of ZIKV diagnostic assays to provide a basis for the inclusion of ZIKV in the TORCH complex evaluations. Similarities between TORCH pathogens and ZIKV support inclusion of ZIKV as an emerging TORCH infection. Our review evaluates the diagnostic performance of various TORCH diagnostic assays for maternal screening, fetal screening, and neonatal screening. We show that the sensitivity, specificity, and positive and negative predictive value of TORCH complex pathogens are widely variable, stressing the importance of confirmatory testing and the need for novel techniques for earlier and accurate diagnosis of maternal and congenital infections. In this context it is also important to acknowledge different needs and access to care for different geographic and resource settings.

Case of seasonal reassortant A(H1N2) influenza virus infection, the Netherlands, March 2018.

A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general practitioner participating in the routine sentinel surveillance of ILI in the Netherlands. The patient recovered fully. Further epidemiological and virological investigation did not reveal additional cases.

Annual incidence rate of schizophrenia and schizophrenia spectrum disorders in a longitudinal population-based cohort study.

BACKGROUND: Longitudinal incidence studies of schizophrenia spectrum disorders (SSD) performed in mental health service organizations are prone to confounding factors not found in research performed in the general population. OBJECTIVES: To estimate the incidence rates (IRs) over a 10-year period of SSD (broadly defined) and schizophrenia (narrowly defined) in the general population and to analyze associated risk factors. METHODS: A cohort study (1996-2006) in a large general practitioners research database was conducted with longitudinal medical records of 350,524 patients throughout the Netherlands. Cases of SSD were identified and classified by systematic review of medical records. Age- and gender-specific IRs were calculated per calendar year, date of birth, degree of urbanicity and deprivation. RESULTS: Overall IR of SSD in this population was 22/100,000 person years (PY) (95% CI 19-24). IR of schizophrenia was 12/100,000 PY (95% CI 10-14). Period prevalence was 3.5 per 1,000 PY. IRs were higher in men compared to women, had a peak at age 15-25 years, decreasing rapidly after 25 years by 40% per 10 years. IRs of SSD were significantly higher in urban areas, irrespective of deprivation. No association was found between IRs of SSD and living in deprived areas or month of birth. There was no significant time trend of the IR during the period under study. CONCLUSIONS: IRs of SSD are higher in urban areas, independent of social deprivation. Age- and gender-specific differences in IR were found. The magnitude of these differences was larger in narrowly defined schizophrenia than in SSD.

Assessment of hybrid population immunity to SARS-CoV-2 following breakthrough infections of distinct SARS-CoV-2 variants by the detection of antibodies to nucleoprotein.

Immunity induced by vaccination and infection, referred to as hybrid immunity, provides better protection against SARS-CoV-2 infections compared to immunity induced by vaccinations alone. To assess the development of hybrid immunity we investigated the induction of Nucleoprotein-specific antibodies in PCR-confirmed infections by Delta or Omicron in vaccinated individuals (n = 520). Eighty-two percent of the participants with a breakthrough infection reached N-seropositivity. N-seropositivity was accompanied by Spike S1 antibody boosting, and independent of vaccination status or virus variant. Following the infection relatively more antibodies to the infecting virus variant were detected. In conclusion, these data show that hybrid immunity through breakthrough infections is hallmarked by Nucleoprotein antibodies and broadening of the Spike antibody repertoire. Exposure to future SARS-CoV-2 variants may therefore continue to maintain and broaden vaccine-induced population immunity.

Oral fluid: Non-invasive alternative for parvovirus B19 diagnosis?

BACKGROUND: Infections with parvovirus B19 (B19V) have been associated with a wide range of disease manifestations of which erythema infectiosum (fifth disease) in children is most common. Clinical signs following infection of children with B19V can be similar to measles and rubella. Laboratory detection of B19V infections is based on detection of B19V-specific IgM antibodies by enzyme immunoassay (IgM-EIA) and/or B19V DNA by quantitative PCR (qPCR) on blood samples. The need for invasive sampling can be a barrier for public health diagnostics. OBJECTIVES: To evaluate the use of a dual target B19V-qPCR directed against the NS1 and VP2 of B19V on oral fluid samples as a non-invasive alternative for laboratory diagnosis of B19V infections in children below 12 years of age with exanthema. STUDY DESIGN: Oral fluid and serum samples were collected from 116 children with exanthema. All serum samples were tested by IgM-EIA/IgG-EIA, while all oral fluid and 56 serum samples were tested by B19V-qPCR. RESULTS: B19V-specific IgM antibodies were detected in 25 of 116 children in the study. B19V DNA was detected in oral fluid in 17 of the 25 children who were IgM positive, as well as two children who were IgM-equivocal or negative. The child with the equivocal IgM had a high quantity of B19V DNA in oral fluid (7 log IU/ml), compatible with an acute B19V infection. The IgM-negative child was IgG-positive and 4 log IU/ml B19V DNA was detected in the oral fluid sample, suggesting an acute infection and a falsely negative IgM. Sample size calculations indicated that oral fluid samples for qPCR should be collected from 2 to 3 children during outbreaks of exanthema to achieve similar sensitivity as IgM-EIA for one child (≥0.9) to confirm or exclude B19V. CONCLUSIONS: Results indicate that oral fluid samples are a suitable public health alternative for detection of B19V infections, potentially lowering the barriers for sampling.

Annual influenza vaccination in community-dwelling elderly individuals and the risk of lower respiratory tract infections or pneumonia.

BACKGROUND: Influenza vaccination has been associated with a reduction in the number of hospitalizations for respiratory conditions in elderly persons over the period from 1996 to 2002. Little is known, however, about the effect of influenza vaccination on the whole range of severity of respiratory tract infections. METHODS: We investigated the effect of annual influenza vaccination on the occurrence of lower respiratory tract infections (LRTIs) in community-dwelling elderly individuals. From 1996 to 2002, we performed a population-based cohort study, using the computerized Integrated Primary Care Information database in the Netherlands, of community-dwelling subjects who were 65 years or older on January 1 of the year of study entry. For each year, the individual cumulative exposure to influenza vaccination since study entry was computed. We compared the risk of LRTI after a first vaccination or revaccination with the risk for no vaccination using a time-varying multivariate Cox proportional hazard model, adjusted for age, sex, smoking, and underlying disease. RESULTS: In the study population of 26 071 subjects, 3412 developed LRTIs during follow-up. During the influenza epidemic periods, a first vaccination did not reduce risk for LRTI. In the total population, the hazard ratio following a first vaccination was 0.86 (95% confidence interval [CI], 0.71 to 1.05); in the population without or with comorbidity, these ratios were 0.90 (95% CI, 0.56 to 1.45) and 0.83 (95% CI, 0.66 to 1.04), respectively. During epidemic periods, revaccination reduced risk of LRTI by 33% (95% CI, 8% to 52%) in individuals without comorbidity. In individuals with comorbidity, the risk reduction of 5% was nonsignificant (95% CI, -10% to 18%). CONCLUSION: In this study, annual influenza revaccination was associated with a reduction in LRTI in community-dwelling elderly individuals.

A review of the changes to the licensing of influenza vaccines in Europe.

In 2014, the European Committee for Medicinal Products for Human Use (CHMP) published a draft regulatory guideline for the evaluation of influenza vaccines. Following a public consultation round, the final guidance will be published in the near future. Here, we highlight the main changes in the clinical section in this guideline and discuss the background to these changes and whether the new consolidated guidance document can be expected to achieve a better understanding of the performance of seasonal, zoonotic and pandemic influenza vaccines during the regulatory licensing process. The new influenza guideline reflects a changed approach to the regulatory assessment of influenza vaccines, resulting in the abolition of serological criteria, known as the CHMP criteria, which have been the mainstay for evaluating the influenza vaccine immunogenicity for several decades. The new guideline adopts a more diversified approach to the measurement and reporting of the immune response to influenza vaccines and sets a requirement to conduct clinical outcome trials in young children. Importantly, more emphasis is placed on the post-licensure monitoring of the benefit risk of influenza vaccines, including a request for continuous monitoring of efficacy and enhanced safety surveillance. Despite the improvements these new requirements will expectedly bring to the regulatory assessment of influenza vaccines, major challenges remain which cannot be overcome by new guidance alone. Ongoing initiatives in which academia, manufacturers, public health institutes and regulators work together to address these challenges are central to the development of robust tools to evaluate and monitor performance of influenza vaccines in the future.

Influenza vaccination in community-dwelling elderly: impact on mortality and influenza-associated morbidity.

BACKGROUND: Influenza-related morbidity and mortality have been extensively studied with hospital and reimbursement data. However, little is known about the effectiveness of the annual vaccination programs in generally healthy community-dwelling elderly. The objective of our study was to investigate the effectiveness of influenza vaccination in community-dwelling elderly during the 1996 to 1997 influenza epidemic. METHODS: We performed a population-based cohort study using the computerized Integrated Primary Care Information database in the Netherlands. Subjects who were 65 years and older in 1996 with a permanent status in a practice in the source population were considered eligible for study participation. Two cohorts were defined on the basis of vaccination status. We estimated and compared all-cause mortality, pneumonia, and clinical influenza infection rates between the cohorts. RESULTS: Influenza vaccination was associated with a significant reduction of morbidity and mortality in vaccinated elderly (relative risk [RR], 0.72; 95% confidence interval [CI], 0.60-0.87). Influenza infections decreased significantly in the vaccinated population (RR, 0.48; 95% CI, 0.26-0.91). Mortality was reduced significantly in elderly with comorbidity (RR, 0.67; 95% CI, 0.48-0.94). The risk reduction for pneumonia was nonsignificant (RR, 0.77; 95% CI, 0.55-1.07) but was temporally related to the peak influenza activity. CONCLUSIONS: In this study, influenza vaccination was associated with decreased mortality and influenza infections in community-dwelling elderly. Our results indicate that, in a season of mild influenza activity and good antigenic match between vaccine strains and circulating strains, influenza vaccination reduced mortality in the vaccinated population. Our data support an annual vaccination strategy for all community-dwelling elderly.

Effectiveness of MF59™ adjuvanted influenza A(H1N1)pdm09 vaccine in risk groups in the Netherlands.

BACKGROUND: The aim of the present study was to estimate the effectiveness of the MF59™-adjuvanted influenza A(H1N1)pdm09 vaccine against medically attended influenza-like illness and RT-PCR confirmed influenza in the at-risk population and persons over 60 in the Netherlands. METHODS: We conducted a retrospective cohort study in a Dutch based GP medical record database between 30 November 2009 and 1 March 2010 to estimate the vaccine effectiveness against influenza-like illness. Within the cohort we nested a test negative case-control study to estimate the effectiveness against laboratory confirmed influenza. RESULTS: The crude effectiveness in preventing diagnosed or possible influenza-like illness was 17.3% (95%CI: -8.5%-36.9%). Of the measured covariates, age, the severity of disease and health seeking behaviour through devised proxies confounded the association between vaccination and influenza-like illness. The adjusted vaccine effectiveness was 20.8% (95%CI: -5.4%, 40.5%) and varied significantly by age, being highest in adults up to 50 years (59%, 95%CI: 23%, 78%), and non-detectable in adults over 50 years. The number of cases in the nested case control study was too limited to validly estimate the VE against confirmed influenza. CONCLUSIONS: With our study we demonstrated that the approach of combining a cohort study in a primary health care database with field sampling is a feasible and useful option to monitor VE of influenza vaccines in the future.

Characteristics of orphan drug applications that fail to achieve marketing approval in the USA.

The US Orphan Drug Act has fostered the development of drugs for patients with rare diseases by granting 'orphan designations', although several orphan drugs for which a marketing application has been submitted to the FDA have failed to obtain approval. This study identified the clinical trial design, the level of experience of the sponsor and the level of interaction with the FDA to be associated with non-approval. Sponsors, therefore, should engage in dialogue with the FDA and thoughtfully design pivotal clinical trials in accordance with FDA guidance documents.