Factors associated with acceleration of clinical development for infectious diseases: a cross-sectional analysis of 10-year EMA registration data.

Background: Clinical trials feature centrally in the development of drugs and vaccines to determine safety and efficacy. Clinical development can be slow and may have a duration of more than ten years. Global public health threats such as Ebola virus disease (EVD) and COVID-19 have demonstrated that it is possible to accelerate clinical trials while maintaining safety and efficacy. We investigated acceleration in clinical trials over the past decade and identified factors associated with acceleration for drugs targeting infectious diseases. Methods: A cross-sectional study was performed of all medicinal compounds targeting infectious diseases that received marketing authorisation by the European Medicines Agency (EMA) between 2012 and 2022. We calculated median clinical development time in years between the first phase 1 trial enrolment date and the authorisation date. Multivariable linear regression analysis was performed to identify factors associated with shorter development times. Findings: Eighty-one trajectories were included. The median clinical development time was 7.3 years (IQR 4.4-12.3). The fastest times belonged to drugs and vaccines targeting COVID-19 (1.3 years, IQR 0.8-1.6), EVD (5.5 years, IQR 5.1-5.8), and Hepatitis A-E (5.5 years, IQR 3.9-8.2). Factors associated with shorter development times were outbreak setting (-5.4 years [95% CI, -8.2 to -2.6]), accelerated assessment status (-4.0 years [95% CI, -7.6 to -0.5]), and drugs with combined compounds (-2.7 years [95% CI, -4.9 to -0.4]). Interpretation: Clinical development time for infectious disease-related drugs and vaccines was relatively short, and outbreak setting and accelerated EMA assessment were associated with shorter development times. Funding: Amsterdam Public Health research institute.

Rabies knowledge gaps and risk behaviour in Dutch travellers: An observational cohort study.

BACKGROUND: Travellers visiting rabies-endemic countries are at risk of rabies infection. Assessing travellers' knowledge and risk perception of rabies and risk behaviour during travel can help identify knowledge gaps and improve pre-travel risk education. METHODS: Cohort study in Dutch adult travellers, using two surveys: one before travel to assess knowledge and perception of rabies, and one after return to identify risk behaviour during travel. RESULTS: The pre-travel and post-travel survey were completed by 301 and 276 participants, respectively. 222 participants had travelled to a high-risk rabies-endemic country. 21.6 % of the participants scored their rabies knowledge as poor. Some participants were unaware cats or bats can transmit rabies (26.6 % and 13.6 %, respectively), or that post-exposure prophylaxis (PEP) is required for certain exposures such as skin abrasions without bleeding or licks on damaged skin (35.5 % and 18.9 %, respectively), while 27.9 % of participants did not know PEP needs to be administered within one day. 115 participants (51.8 %) reported any form of contact with any animal during travel. Two participants reported animal exposure, of which one took adequate PEP measures. Risk factors for animal contact abroad were regularly touching cats or dogs at home or abroad, longer travel duration, having pets during childhood and being an animal lover. CONCLUSIONS: Pre-travel rabies risk education currently does not meet travellers' needs, which is reflected in knowledge gaps and engagement in risk behaviour during travel. During pre-travel health advice, avoiding animal contact abroad should be emphasized, and additional education is required about indications for PEP.

Post-tuberculosis treatment paradoxical reactions.

Paradoxical reactions (PR) to tuberculosis (TB) treatment are common during treatment, but have also been described after treatment. A presentation with recurrent signs or symptoms of TB after cure or completion of prior treatment needs to be differentiated between microbiological relapse and a paradoxical reaction. We searched all published literature on post-treatment PR, and present a synthesis of 30 studies, focusing on the epidemiology, diagnosis and management of this phenomenon. We report an additional case vignette. The majority of studies were of lymph node TB (LN-TB), followed by central nervous system TB (CNS-TB). A total of 112 confirmed and 42 possible post-treatment PR cases were reported. The incidence ranged between 3 and 14% in LN-TB and was more frequent than relapses, and between 0 and 2% in all TB. We found four reports of pulmonary or pleural TB post-treatment PR cases. The incidence did not differ by length of treatment, but was associated with younger age at initial diagnosis, and having had a PR (later) during treatment. Post-treatment PR developed mainly within the first 6 months after the end of TB treatment but has been reported many years later (longest report 10 years). The mainstays of diagnosis and management are negative mycobacterial cultures and anti-inflammatory treatment, respectively. Due to the favourable prognosis in LN-TB recurrent symptoms, a short period of observation is warranted to assess for spontaneous regression. In CNS-TB with recurrent symptoms, immediate investigation and anti-inflammatory treatment with the possibility of TB retreatment should be undertaken.

Drug-induced hepatotoxicity and association with slow acetylation variants NAT2*5 and NAT2*6 in Cameroonian patients with tuberculosis and HIV co-infection.

BACKGROUND: Human immunodeficiency virus (HIV) and tuberculosis (TB) are major contributors to morbidity and mortality in sub-Saharan Africa including Cameroon. Pharmacogenetic variants could serve as predictors of drug-induced hepatotoxicity (DIH), in patients with TB co-infected with HIV. We evaluated the occurrence of DIH and pharmacogenetic variants in Cameroonian patients. METHODS: Treatment-naïve patients with HIV, TB or TB/HIV co-infection were recruited at three hospitals in Cameroon, between September 2018 and November 2019. Appropriate treatment was initiated, and patients followed up for 12 weeks to assess DIH. Pharmacogenetic variants were assessed by allele discrimination TaqMan SNP assays. RESULTS: Of the 141 treatment naïve patients, the overall incidence of DIH was 38% (53/141). The highest incidence of DIH, 52% (32/61), was observed among HIV patients. Of 32 pharmacogenetic variants, the slow acetylation variants NAT2*5 was associated with a decreased risk of DIH (OR: 0.4; 95%CI: 0.17-0.96; p = 0.038), while NAT2*6 was found to be associated with an increased risk of DIH (OR: 4.2; 95%CI: 1.1-15.2; p = 0.017) among patients treated for TB. Up to 15 SNPs differed in ≥ 5% of allele frequencies among African populations, while 25 SNPs differed in ≥ 5% of the allele frequencies among non-African populations, respectively. CONCLUSIONS: DIH is an important clinical problem in African patients with TB and HIV. The NAT2*5 and NAT2*6 variants were found to be associated with DIH in the Cameroonian population. Prior screening for the slow acetylation variants NAT2*5 and NAT2*6 may prevent DIH in TB and HIV-coinfected patients.

Repurposing of anti-malarial drugs for the treatment of tuberculosis: realistic strategy or fanciful dead end?

BACKGROUND: Drug repurposing offers a strategic alternative to the development of novel compounds, leveraging the known safety and pharmacokinetic profiles of medications, such as linezolid and levofloxacin for tuberculosis (TB). Anti-malarial drugs, including quinolones and artemisinins, are already applied to other diseases and infections and could be promising for TB treatment. METHODS: This review included studies on the activity of anti-malarial drugs, specifically quinolones and artemisinins, against Mycobacterium tuberculosis complex (MTC), summarizing results from in vitro, in vivo (animal models) studies, and clinical trials. Studies on drugs not primarily developed for TB (doxycycline, sulfonamides) and any novel developed compounds were excluded. Analysis focused on in vitro activity (minimal inhibitory concentrations), synergistic effects, pre-clinical activity, and clinical trials. RESULTS: Nineteen studies, including one ongoing Phase 1 clinical trial, were analysed: primarily investigating quinolones like mefloquine and chloroquine, and, to a lesser extent, artemisinins. In vitro findings revealed high MIC values for anti-malarials versus standard TB drugs, suggesting a limited activity. Synergistic effects with anti-TB drugs were modest, with some synergy observed in combinations with isoniazid or pyrazinamide. In vivo animal studies showed limited activity of anti-malarials against MTC, except for one study of the combination of chloroquine with isoniazid. CONCLUSIONS: The repurposing of anti-malarials for TB treatment is limited by high MIC values, poor synergy, and minimal in vivo effects. Concerns about potential toxicity at effective dosages and the risk of antimicrobial resistance, especially where TB and malaria overlap, further question their repurposing. These findings suggest that focusing on novel compounds might be both more beneficial and rewarding.

Consensus definitions in imported human schistosomiasis: a GeoSentinel and TropNet Delphi study.

Terminology in schistosomiasis is not harmonised, generating misunderstanding in data interpretation and clinical descriptions. This study aimed to achieve consensus on definitions of clinical aspects of schistosomiasis in migrants and returning travellers. We applied the Delphi method. Experts from institutions affiliated with GeoSentinel and TropNet, identified through clinical and scientific criteria, were invited to participate. Five external reviewers revised and pilot-tested the statements. Statements focusing on the definitions of acute or chronic; possible, probable, or confirmed; active; and complicated schistosomiasis were managed through REDCap and replies managed in a blinded manner. Round 1 mapped the definitions used by experts; subsequent rounds were done to reach consensus, or quantify disagreement, on the proposed statements. Data were analysed with percentages, medians, and IQRs of a 5-point Likert scale. The study was terminated on the basis of consensus or stability-related and time-related criteria. 28 clinicians and scientists met the criteria for experts. 25 (89%) of 28 experts replied to Round 1, 18 (64%) of 28 to Round 2, 19 (68%) of 28 to Round 3, and 21 (75%) of 28 to at least two rounds. High-level consensus (79-100% agreement and IQRs ≤1) was reached for all definitions. Consensus definitions will foster harmonised scientific and clinical communication and support future research and development of management guidelines for schistosomiasis.

Safety and immunogenicity of the co-administered Na-APR-1 and Na-GST-1 hookworm vaccines in school-aged children in Gabon: a randomised, controlled, observer-blind, phase 1, dose-escalation trial.

BACKGROUND: A human hookworm vaccine is being developed to protect children against iron deficiency and anaemia associated with chronic infection with hookworms. Necator americanus aspartic protease-1 (Na-APR-1) and N americanus glutathione S-transferase-1 (Na-GST-1) are components of the blood digestion pathway critical to hookworm survival in the host. Recombinant Na-GST-1 and catalytically inactive Na-APR-1 (Na-APR-1[M74]) adsorbed to Alhydrogel were safe and immunogenic when delivered separately or co-administered to adults in phase 1 trials in non-endemic and endemic areas. We aimed to investigate the safety and immunogenicity of these antigens in healthy children in a hookworm-endemic area. METHODS: This was a randomised, controlled, observer-blind, phase 1, dose-escalation trial, conducted in a clinical research centre, in 60 children aged six to ten years in Lambaréné, a hookworm-endemic region of Gabon. Healthy children (determined by clinical examination and safety laboratory testing) were randomised 4:1 to receive co-administered Na-GST-1 on Alhydrogel plus Na-APR-1(M74) on Alhydrogel and glucopyranosyl lipid A in aqueous formulation (GLA-AF), or co-administered ENGERIX-B hepatitis B vaccine (HBV) and saline placebo, injected into the deltoid of each arm. Allocation to vaccine groups was observer-masked. In each vaccine group, children were randomised 1:1 to receive intramuscular injections into each deltoid on two vaccine schedules, one at months 0, 2, and 4 or at months 0, 2, and 6. 10 µg, 30 µg, and 100 µg of each antigen were administered in the first, second, and third cohorts, respectively. The intention-to-treat population was used for safety analyses; while for immunogenicity analyses, the per-protocol population was used (children who received all scheduled vaccinations). The primary outcome was to evaluate the vaccines' safety and reactogenicity in healthy children aged between six and ten years. The secondary outcome was to measure antigen-specific serum IgG antibody levels at pre-vaccination and post-vaccination timepoints by qualified ELISAs. The trial is registered with ClinicalTrials.gov, NCT02839161, and is completed. FINDINGS: Between Jan 23 and Oct 3, 2017, 137 children were screened, of whom 76 were eligible for this trial. 60 children were recruited, and allocated to either 10 µg of the co-administered antigens (n=8 for each injection schedule), 30 µg (n=8 for each schedule), 100 µg (n=8 for each schedule), or HBV and placebo (n=6 for each schedule) in three sequential cohorts. Co-administration of the vaccines was well tolerated; the most frequent solicited adverse events were mild-to-moderate injection-site pain, observed in up to 12 (75%) of 16 participants per vaccine group, and mild headache (12 [25%] of 48) and fever (11 [23%] of 48). No vaccine-related serious adverse events were observed. Significant anti-Na-APR-1(M74) and anti-Na-GST-1 IgG levels were induced in a dose-dependent manner, with peaks seen 14 days after the third vaccinations, regardless of dose (for Na-APR-1[M74], geometric mean levels [GML]=2295·97 arbitrary units [AU] and 726·89 AU, while for Na-GST-1, GMLs=331·2 AU and 21·4 AU for the month 0, 2, and 6 and month 0, 2, and 4 schedules, respectively). The month 0, 2, and 6 schedule induced significantly higher IgG responses to both antigens (p=0·01 and p=0·04 for Na-APR-1[M74] and Na-GST-1, respectively). INTERPRETATION: Co-administration of recombinant Na-APR-1(M74) and Na-GST-1 to school-aged Gabonese children was well tolerated and induced significant IgG responses. These results justify further evaluation of this antigen combination in proof-of-concept controlled-infection and efficacy studies in hookworm-endemic areas. FUNDING: European Union Seventh Framework Programme.

So, what's best? Accuracy and acceptance of thermometers in triage and inpatients in a low-resource tropical setting - The MaTe study.

Objectives: We searched for the most-suitable thermometry method in the low-resource, tropical setting of Sierra Leone, both in terms of accuracy and also patient and user acceptance. Methods: We conducted a prospective comparative study of different methods of body temperature measurement. Each participant had their temperature taken by four different methods: non-contact infrared temperature (NCIT), axillary, tympanic membrane and rectal measurements. Rectal temperature was considered clinical gold standard. Primary outcome was predicted sensitivity and specificity of thermometry methods in detecting fever (rectal temperature ≥38.0 °C). Questionnaires were used to explore patient and healthcare worker attitudes towards different methods of temperature-taking. Results: 824 rectal body temperature readings were taken from 562 participants. The mean rectal temperature was 37.4 °C (IQR 37 °C to 37.7 °C), with a minimum reading of 35.2 °C and maximum of 41.0 °C. Tympanic membrane thermometry showed the highest sensitivity of fever detection using the Genius3 TM thermometer (sensitivity 70.8 %, 95 % CI 60.2%-79.9 %; specificity 97.2 %, 95 % CI 95.5-98.4 %); and Braun TM (sensitivity 51.5 %, 95 % CI 42.6%-62.0 %; specificity 98.8 %, 95 % CI 97.7-99.5). NCIT thermometry sensitivity was low (36.8 %-41.4 % for the two devices used). Axillary thermometry sensitivity was 40.6 %. Participants ranked NCIT as the most and rectal as the least preferred method. Questionnaires from 32 participating nurses showed agreeability to using NCIT, TM and axillary methods routinely, but less so for rectal thermometry. Conclusions: When combining the accuracy of different thermometry methods in detecting fever with user and patient acceptability, tympanic membrane thermometry appears most suitable but also has limitations.

Long-term immunity following yellow fever vaccination: a systematic review and meta-analysis.

BACKGROUND: Long-term immunity following yellow fever vaccination remains controversial. We aimed to summarise the literature regarding the long-term protection (≥10 years) conveyed by a single dose of yellow fever vaccination. METHODS: In this systematic review and meta-analysis, we searched 11 databases from database inception to Aug 24, 2023. We included cohort and cross-sectional studies reporting immunogenicity outcomes for children or adults who received a single dose of yellow fever vaccination 10 or more years ago. Case series and single case reports were excluded. Participants who received more than one dose of yellow fever vaccination before measurement of the outcome were excluded. Identified records were reviewed by two independent reviewers. The primary outcome of the meta-analysis was the pooled seroprotection rate. Risk of bias was assessed with the Risk Of Bias In Non-randomized Studies of Interventions tool, and the Joanna Briggs Institute tool for analytical cross-sectional studies. Studies of moderate or good quality that reported seroprotection were included for random-effects meta-analysis and stratified by endemicity and specific risk groups. The study was registered with PROSPERO, CRD42023384087. FINDINGS: Of the 7363 articles identified by our search, 39 were eligible for inclusion for systematic review. These studies comprised 2895 individuals vaccinated 10-60 years ago. 20 studies were included in the meta-analysis. Pooled seroprotection rates were 94% (95% CI 86-99) among healthy adults in a non-endemic setting (mostly travellers) and 76% (65-85) in an endemic setting (all Brazilian studies). The pooled seroprotection rate was 47% (35-60) in children (aged 9-23 months at time of vaccination) and 61% (38-82) in people living with HIV. Reported criteria for seroprotection were highly heterogeneous. INTERPRETATION: The gathered evidence suggests that a single dose of yellow fever vaccination provides lifelong protection in travellers. However, in people living with HIV and children (younger than 2 years), booster doses might still be required because lower proportions of vaccinees were seroprotected 10 or more years post-vaccination. Lower observed seroprotection rates among residents of endemic areas were partly explained by the use of a higher cutoff for seroprotection that was applied in Brazil. Studies from sub-Saharan Africa were scarce and of low quality; thus no conclusions could be drawn for this region. FUNDING: None.

Monoclonal antibody applications in travel medicine.

For decades, immunoglobulin preparations have been used to prevent or treat infectious diseases. Since only a few years, monoclonal antibody applications (mAbs) are taking flight and are increasingly dominating this field. In 2014, only two mAbs were registered; end of October 2023, more than ten mAbs are registered or have been granted emergency use authorization, and many more are in (pre)clinical phases. Especially the COVID-19 pandemic has generated this surge in licensed monoclonal antibodies, although multiple phase 1 studies were already underway in 2019 for other infectious diseases such as malaria and yellow fever. Monoclonal antibodies could function as prophylaxis (i.e., for the prevention of malaria), or could be used to treat (tropical) infections (i.e., rabies, dengue fever, yellow fever). This review focuses on the discussion of the prospects of, and obstacles for, using mAbs in the prevention and treatment of (tropical) infectious diseases seen in the returning traveler; and provides an update on the mAbs currently being developed for infectious diseases, which could potentially be of interest for travelers.

Boostability after single-visit pre-exposure prophylaxis with rabies vaccine: a randomised controlled non-inferiority trial.

BACKGROUND: After rabies pre-exposure prophylaxis (PrEP) vaccination, scarcely available rabies immunoglobulins are not required for post-exposure prophylaxis (PEP). However, PrEP is not sufficiently accessible as it is cost-intensive and time-intensive. This study investigates whether rabies PrEP schedules can be shortened to one visit, removing some of these barriers. METHODS: In a block-randomised (2:2:2:1) controlled, multicentre non-inferiority trial, healthy adult travellers (aged 18-50 years and >50 years) were randomly assigned to (A) single-visit intramuscular (1·0 mL); (B) single-visit intradermal (0·2 mL); (C) standard two-visit intramuscular (1·0 mL; day 0 and 7) PrEP; or (D) no rabies vaccination. 6 months later, participants received simulated intramuscular rabies PEP (1·0 mL; day 0 and 3). Rabies virus neutralising antibody (RVNA) concentrations were measured repeatedly. The primary outcome was the fold increase in geometric mean RVNA concentrations between day 0 and 7 after simulated PEP for all participants. The two main comparisons of this primary outcome are between the standard two-visit schedule and the one-visit intramuscular schedule, and between the standard two-visit schedule and the one-visit intradermal schedule. The non-inferiority margin was 0·67. This study is registered with EudraCT, 2017-000089-31. FINDINGS: Between May 16, 2018, and March 26, 2020, 288 healthy adult travellers were randomly assigned and 214 participants were evaluated for the primary outcome. Single-visit intramuscular rabies PrEP induced an anamnestic antibody response non-inferior compared with the two-visit intramuscular schedule; single-visit intradermal PrEP did not. The fold increases in the single-visit intramuscular and the single-visit intradermal schedule were 2·32 (95% CI [1·43-3·77]) and 1·11 (0·66-1·87) times as high as the fold increase in the standard schedule, respectively. No vaccine-related serious adverse events were observed. Adverse events related to vaccination were mostly mild. INTERPRETATION: Single intramuscular rabies vaccination can effectively prime travellers (aged 18-50 years), and potentially other populations, and could replace current standard two-visit rabies vaccination as PrEP. FUNDING: ZonMW. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

Overcoming publication and dissemination bias in infectious diseases clinical trials.

Non-timely reporting, selective reporting, or non-reporting of clinical trial results are prevalent and serious issues. WHO mandates that summary results be available in registries within 12 months of study completion and published in full text within 24 months. However, only a limited number of clinical trials in infectious diseases, including those done during the COVID-19 pandemic, have their results posted on ClinicalTrials.gov. An analysis of 50 trials of eight antiviral drugs tested against COVID-19 with a completion date of at least 2 years ago revealed that only 18% had their results published in the registry, with 40% not publishing any results. Non-timely and non-reporting practices undermine patient participation and are ethically unacceptable. Strategies should include obligatory reporting of summary results within 12 months in clinical trial registries, with progress towards peer-reviewed publication within 24 months indicated. Timely publication of research papers should be encouraged through an automated flagging mechanism in clinical trial registries that draws attention to the status of results reporting, such as a green tick for trials that have reported summary results within 12 months and a red tick in case of failure to do so. We propose the inclusion of mandatory clinical trial reporting standards in the International Conference on Harmonization Good Clinical Practice guidelines, which should prohibit sponsor contract clauses that restrict reporting (referred to as gag clauses) and require timely reporting of results as part of the ethics committees' clearance process for clinical trial protocols.

Infections with long latency in international refugees, immigrants, and migrants seen at GeoSentinel sites, 2016-2018.

BACKGROUND: The continued increase in global migration compels clinicians to be aware of specific health problems faced by refugees, immigrants, and migrants (RIM). This analysis aimed to characterize RIM evaluated at GeoSentinel sites, their migration history, and infectious diseases detected through screening and diagnostic workups. METHODS: A case report form was used to collect data on demographics, migration route, infectious diseases screened, test results, and primary infectious disease diagnosis for RIM patients seen at GeoSentinel sites. Descriptive statistics were performed. RESULTS: Between October 2016 and November 2018, 5,319 RIM patients were evaluated at GeoSentinel sites in 19 countries. Africa was the region of birth for 2,436 patients (46 %), followed by the Americas (1,644, 31 %), and Asia (1,098, 21 %). Tuberculosis (TB) was the most common infection screened and reported as positive (853/2,273, 38 % positive by any method). TB, strongyloidiasis, and hepatitis B surface antigen positivity were observed across all migration administrative categories and regions of birth. Chagas disease was reported only among RIM patients from the Americas (393/394, 100 %) and schistosomiasis predominantly in those from Africa (480/510, 94 %). TB infection (694/5,319, 13 %) and Chagas disease (524/5,319, 10 %) were the leading primary infectious disease diagnoses. CONCLUSIONS: Several infections of long latency (e.g. TB, hepatitis B, and strongyloidiasis) with potential for long-term sequelae were seen among RIM patients across all migration administrative categories and regions of origin. Obtaining detailed epidemiologic information from RIM patients is critical to optimize detection of diseases of individual and public health importance, particularly those with long latency periods.

Expanding the role of village malaria workers in Cambodia: Implementation and evaluation of four health education packages.

BACKGROUND: Early access to correct diagnosis and appropriate treatment is essential for malaria elimination, and in Cambodia this relies on village malaria workers (VMWs). Decreasing malaria transmission leave VMWs with diminished roles. Activities related to the control of other health conditions could keep these community health workers relevant. METHODS: During 2022, 120 VMWs attended training at local health centres on four health education packages: 1. hygiene and sanitation; 2. disease surveillance; 3. management of mild illness; 4. vaccination and antenatal care. All training and evaluation sessions were documented through meeting minutes, and 19 focus group discussions (FGDs) were conducted among VMWs and health centre personnel. Audio-records of FGDs were transcribed and translated in English and underwent thematic analysis. RESULTS: VMWs reported strong interest in the training and welcomed the expansion of their roles thus assuring their continued relevance. VMWs prioritized disease surveillance and management of mild illness among the available training packages because these topics were seen as most relevant. While training was considered comprehensible and important, the low literacy among VMWs was an impediment suggesting training materials need to be delivered visually. Since VMWs have limited resources, incentives could ensure that VMWs are motivated to undertake additional roles and responsibilities. CONCLUSIONS: The transformation of VMWs into community health workers with roles beyond malaria is a promising approach for sustaining health care provision in remote areas. Training needs to consider the low scientific literacy, time constraints and limited resources of VMWs.

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.