Diseases

Q-Fever

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Control Tools

  • Diagnostics availability

  • Commercial diagnostic kits available worldwide

    Ready-to-use PCR kits are commercially available and can detect C. burnetii DNA in several samples. Only for veterinarian usage licensed.

    Ready-to-use ELISA kits are commercially available for ruminants to detect antibodies.

    List of commercially available diagnostics is available here (Diagnostics for Animals).

    GAPS:

    • Rapid field tests are missing for the detection of C. burnetii..
    • Phase differentiating ELISAs are not commercially available. CMI are not commercially available.
    • The value of CMI test is not clear.
    • Lack of commercially available monoclonal antibodies for IFT and IF staining.
    • Lack of standardized sera and materials.

  • Commercial diagnostic kits available in Europe

    Yes, see Section “Commercial diagnostic kits available worldwide”.

  • Diagnostic kits validated by International, European or National Standards

    No.

  • Diagnostic method(s) described by International, European or National standards

    Methods are described in the OIE Manual of Diagnostic Tests and Vaccines for Terrestrial animals (http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.01.16_Q_FEVER.pdf ) and include;-

    1.Identification of the agent

    Isolation of the agent (Embryonated chicken eggs, Cell culture, Laboratory animals, axenic media). BSL3 laboratories are required for this to fulfil safety regulations.StainingSpecific detection methods: specific immunodetection (capture enzyme linked immunosorbent assay [ELISA], immunohistochemistry), in-situ hybridisation, or DNA amplification. Polymerase chain reaction (PCR) methods have been used successfully to detect C. burnetii DNA in cell cultures and biological samples. The real-time PCR provides an additional means of detection and quantificationGenotyping methods: MLVA (multi-locus variable number of tandem repeats analysis) and multispacer sequence typing (MST) are two PCR-based typing methods, that permit the typing of C. burnetii without the need for isolation of the organism. Research continues on the development of new tools, such as single nucleotide polymorphism (SNP), and the comparison of their discriminatory capabilities and informative value. WGS is more and more available

    2. Serological tests

    Enzyme-linked immunosorbent assayIndirect immunofluorescence testComplement fixation test

    GAPS:

    • No commercial kit of the isolation and identification of C. burnetii.

    • Harmonization of Genotyping methods is lacking (especially MLVA)

    • WGS methods on clinical material.

  • Commercial potential for diagnostic kits in Europe

    Variable with potential markets in those countries with high levels of infection. The initiative to develop new diagnostic kits will depend on awareness and the possible introduction of control measures as occurred in the Netherlands.

    GAP: Point-of-Care-Antigen-Test.

  • DIVA tests required and/or available

    Not available but could be required if extensive vaccination campaigns are introduced.As C. burnetii is ubiquitous present in the environment and can survive for long periods the bacterium is hard to eradicate.

    GAPS:

    • DIVA vaccines are not available.
    • DIVA tests are not available

  • Opportunities for new developments

    - Point-of-Care-Antigen-Test (Vet-material, Laboratory testing)- Identification of phase specific molecules for standardized antigens- MLVA genotyping is used in the investigations of the major outbreak in the Netherlands. Efforts to produce a standardised scheme for MLVA (based on common decisions for allele calling and marker panels to be used) are in progress. Identification of the agent using genotyping methods is useful to molecular epidemiology studies, understanding the transmission routes, distance and speed of spread (between source and humans, within and between herds).- Development of a gold standard serological test with a high sensitivity and avoiding discordant results.

    GAPS:

    • DIVA vaccines and diagnostic tests

    • Rapid field test.

    • CMI test.

    • Rapid viability test.

    • MLVA standardization.

    • Rapid genotyping tests.

  • Vaccines availability

  • Commercial vaccines availability (globally)

    Several vaccines have been developed against animal Q fever but only phase I vaccine has revealed to be protective against C. burnetii infection. The drawback of the present phase I inactivated whole cell vaccine on the market are the side effects and the laborious production including safety regulations. It appears to be difficult to increase production upon increasing demands. The vaccine is not a DIVA vaccine.Phase I vaccines are cross protective.

    GAP: Safe and easy to produce phase I DIVA vaccine.

  • Commercial vaccines authorised in Europe

    A phase I inactivated whole cell vaccine is licensed in Europe. See Section “Commercial vaccines availability (globally)”.

  • Marker vaccines available worldwide

    No.

    GAP: No DIVA system exists.

  • Marker vaccines authorised in Europe

    No.

  • Effectiveness of vaccines / Main shortcomings of current vaccines

    Several inactivated vaccines against Q fever have been developed. Phase I vaccine was effective and prevented both abortion and stillbirth and reduced the shedding of C. burnetii in the milk and vaginal mucus in experimentally challenged goats. In natural conditions, the vaccination of highly shedding goats herds had reduced the bacterial quantities shed, especially by the primiparous animals when vaccinated several months after birth. In cattle herds, which were less infected, it reduced 5 times the risk of infection (and thus of shedding) for susceptible animal vaccinated when not pregnant. Repeated annual vaccination is recommended in heavily infected areas, particularly of young animals.Depending on the epidemiological risks, repeated annual vaccination in non or low infected herds/flocks should be sufficiently preventive against incidence of the infection (see also 9.8 and 16.9).Side effects of repeated vaccination in goats are reported eg: drop in milk production. In cattle has been reported the occurrence of severe swelling at the site of vaccination in animals showing preexisting cell mediated immunity. DIVA vaccines are not available. Sub-unit vaccines are not available. The efficacy of the vaccine in already infected animals is unclear so is the optimal time of vaccination.

    GAPS:

    • Duration of immunity.
    • Target population.
    • Identification of susceptible animals.
    • Limited information on the impact of animal vaccination on human infections (The Netherlands is the first country where disease kinetics are followed after vaccination campaign).
    • No DIVA system available.
    • Limited information about the recommended duration of vaccination programmes

  • Commercial potential for vaccines in Europe

    Commercial potential exists where disease is a problem and where there is a spill over into the human population. This was particularly the case in the Netherlands where infection in goats poses a severe problem and risk for human Q fever. The development of combined vaccines with major abortive agent, such as Chlamydia (in goat and sheep) could be advantageous. The present phase I inactivated whole cell vaccine is difficult to produce.

    GAP: Safe and easy to produce protective DIVA vaccine.

  • Regulatory and/or policy challenges to approval

    Use of genetically modified vaccines might be problematic in some countries.

  • Commercial feasibility (e.g manufacturing)

    Feasible to manufacture in P3/BSL3 facilities.

  • Opportunity for barrier protection

    Possible to use on farms to prevent entry or spread and as a precautionary measure if Q fever is a problem in a region.

  • Opportunity for new developments

    Efforts have been underway to develop a safer to produce, less expensive, more effective new-generation (subunit) vaccine. Also development of combined vaccines in order to reduce the cost for the farmer and modern sub-unit vaccines.For human usage too.Marked vaccine for DIVA testingThere are several reports claiming newly discovered immunoreactive antigens, apart from LPS, of C. burnetii capable for contributing in the development of a subunit vaccine against the infection.

    GAP : DIVA system does not exist

  • Pharmaceutical availability

  • Current therapy (curative and preventive)

    For animals, antibiotic therapy should not be used: antibiotic will not eliminate the C. burnetii in the trophoblasts of pregnant animals. In cattle with reproductive failure due to C. burnetii antibiotic treatment might be effective.In humans the recommended regimen for acute Q fever is doxycycline for 14 days. Standard therapy for chronic Q fever is a combination of doxycycline with hydroxychloroquine for at least 18 months, but cardiovascular surgery is often required.

  • Commercial potential for pharmaceuticals in Europe

    Limited potential.

  • Regulatory and/or policy challenges to approval

    No specific issue.

  • Commercial feasibility (e.g manufacturing)

    Anti-Coxiella compounds may become commercially interesting in the future.

  • Opportunities for new developments

    Development of anti-Coxiella compounds.Screening/study of Coxiella transcriptome/metabolome.Better understanding of the immunopathogenesis of C. burnetii (experiments on laboratory animals and the ruminant species, host/pathogen factors involved based on genomic and proteomic analyses).Identifying proteins important in the pathogenesis of the bacterium could provide hints for the discovery of potential pharmaceutical targets.

  • New developments for diagnostic tests

  • Requirements for diagnostics development

    See Section “Diagnostics availability- opportunities for new developments”.

    Collection of samples and strains with appropriate information for development and validation (see Chapter 1.1.4. of the OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals, 2008).Ring trial study for harmonization (technique, sampling, interpretation thresholds) between laboratoriesStandardized antigens for Phase I and II.The existing sero-diagnostic tools are primarily based on humoral immunity.Implementation of tests able to classify the strain virulence. Standardization of protocols to certify the free-status.

    GAPS:

    • Rapid field test.

    • Viability.

    • DIVA vaccines and tests

    • Diagnostic kits capable of distinguishing the strain virulence.

  • Time to develop new or improved diagnostics

    In general the development of tests is much faster and less expensive than vaccine development. Time and cost depend on the nature of the test and time will elapse between development, validation and entry onto the market.

  • Cost of developing new or improved diagnostics and their validation

    Developing new tests is time consuming and labour intensive which adds to the costs. Costs cannot be specified as they will depend on the tests, basic researches required and the associated equipment and reagents.

  • Research requirements for new or improved diagnostics

    Establishment of a whole genome sequencing network/database for comparative genomics and proteomicsStudy of the host-pathogen interaction to identify metabolic pathwaysMorphological, transcriptomic and proteomic characterization of the sporogenesis and germination of C. burnetii to identify either biomarkers for development of a simple viability test or anti-C. burnetii solutions.- Genomic plasticity studies and assessment of epidemiological markers is required, new markers should be researched in view of molecular epidemiology- Characterization of strains for use as serological antigens for improved serological tests, especially the sensitivity by using a pool of strains as an antigen- Characterization of IgM response and bacteremia in experimentally and naturally infected ruminants- Better knowledge on the spore-like forms (updating its resistance properties), on the environmental sources (updating its duration of survival) and acquisition of environmental sampling methodologiesProtein biomarkers in Q fever patients’ or animal’s serum capable of diagnosis and able to predict the course of infection.

  • Technology to determine virus freedom in animals

    Freedom from Q fever could only be certified by the development of tests which can confirm absence of infection with C. burnetii and a better knowledge of the C. burnetii infection and shedding dynamics in various species and epidemiological circumstances.

    Modalities of sampling and analysis have to be defined for assessment of the intra-herd shedding prevalence and absence. Furthermore, methodologies for assessment of the environmental contamination have to be improved and validated.

    GAP : No protocols available to certify the free-status.

  • New developments for vaccines

  • Requirements for vaccines development / main characteristics for improved vaccines

    Sub-unit vaccines that are safe and easy to produce.

    GAPS: DIVA vaccines, sub unit vaccines without side effects and prolonged immunity

  • Time to develop new or improved vaccines

    A period of 5-10 years for the development, clinical trials and licensing is realistic.

  • Cost of developing new or improved vaccines and their validation

    Very expensive but there could be a market for new vaccines which prevent infection and shedding of the organism if accompanied with a DIVA system.

    GAP: Impact of regulations on incidence of use.

  • Research requirements for new or improved vaccines

    1. Characterization of acquired immunity to C. burnetii infection which will provide a fundamental understanding of the development of protective immunity against Q fever.2. Development of recombinant vaccines against this pathogen offers promise in the pursuit of a new Q fever vaccine.3. Development of combination-vaccines with other components to C.burnetii.4. Develop DIVA vaccines.

    GAP: Probably not protein-like protective antigens: difficulty in subunit antigen production.

  • New developments for pharmaceuticals

  • Requirements for pharmaceuticals development

    Potential of anti-Coxiella substances needs to be researched and evaluatedWhole genome sequencing platform/databaseSee also Section “Research requirements for new or improved diagnostics”.See also Section “Pharmaceutical availability - Opportunities for new developments”

  • Time to develop new or improved pharmaceuticals

    Five to ten years is realistic.

  • Cost of developing new or improved pharmaceuticals and their validation

    Expensive.

  • Research requirements for new or improved pharmaceuticals

    Establishment of a whole genome sequencing network/database for comparative genomics and proteomicsStudy of the host-pathogen interaction to identify metabolic pathwaysMorphological, transcriptomic and proteomic characterization of the sporogenesis and germination of C. burnetii to identify either biomarkers for development of a simple viability test or anti-C. burnetii solutions.

    Development of anti-Coxiella compounds.Screening/study of Coxiella transcriptome/metabolome.Better understanding of the immunopathogenesis of C. burnetii (experiments on laboratory animals and the ruminant species, host/pathogen factors involved based on genomic and proteomic analyses).Identifying proteins important in the pathogenesis of the bacterium could provide hints for the discovery of potential pharmaceutical targets.

Disease details

  • Description and characteristics

  • Pathogen

    Q fever is caused by the organism Coxiella burnetii which is a small pleomorphic gram-negative obligate intracellular coccobacillus. Sequencing of the first complete genome of C. burnetii has been achieved in 2003. This confirmed previous findings on 16S rRNA sequence analysis and has enabled C. burnetii to be placed in the Coxiellaceae family in the order Legionellales of the gamma subdivision of Proteobacteria.

    According to ultrastructural studies, two distinct morphological forms have been described: the Large Cell Variant (LCV), which is the metabolically and replicatively active intracellular form, while the Small Cell Variant (SCV) is a Spore Like Particle (SLP) that can survive outside cells and even after being excreted by the infected host and exposed to environmental conditions (see 1.3). The LCV and the SCV are structurally Gram negative (outer membrane, lipopolysaccharide on the surface). The forms represent different stages of a model of developmental cycle of C. burnetii. During the intracellular life cycle, the bacterium transforms from SCV to the LCV form upon maturation of the phagosome. After an replication period within the mature phagosome with the phagolysosomal characteristics, LCV differentiate again into the SCV forms, that are regarded to perpetuate infection after being released by cell disruption. However, SCV of C. burnetii (even at low numbers) can be found during all stages of the intracellular life cycle of the bacterium.

    Different genotyping schemes are available and different genotypes of C. burnetii are identified. Genotyping facilitates strain identification as well as epidemiological investigations and source identification.

    GAPS:

    • Knowledge about antimicrobial susceptibility.

    • Knowledge about the SCV to LCV and vice versa transformation which can be used to develop tools for treatment and control.

  • Variability of the disease

    The lipopolysaccharide is of particular biological, medical and immunological significance. C. burnetii occurs as two antigenic forms: Phase I (or wild-type variant), isolated from infected animals or humans is highly virulent. Phase II (laboratory-derived variant) which is obtained following propagation on cell culture or embryonated hen eggs is nearly avirulent or highly reduced in virulence. Whilst the two phases are morphologically identical, some of their biochemical characteristics, including their lipopolysaccharide (LPS) composition, differ. The Phase II is a truncated LPS of Phase I that leave exposed the surface proteins. The LPS Phase variation is normally reversible but can also be accompanied by a permanent chromosomal deletion that makes cell reversion from Phase II to Phase I impossible. In human medicine, the reference method for the serodiagnosis of Q fever is based on different serological profiles during the two forms of the infection: during acute Q fever, IgG and IgM antibodies are elevated against Phase II, whereas, during chronic Q fever, high levels of IgG and IgM antibodies to Phase I equal or higher than to Phase II of the bacteria are observed (see 8.2. and 15.1).

    Recently, the hypothesis that C. burnetii isolates are at different stages of pathoadaptation has been formulated after the sequencing of complete genomes of three C. burnetii strains and comparison with the Nine Mile reference strain. Moreover, while isolates contain novel genes, they also harbour disparate collections of virulence-associated pseudogenes that likely contribute to pathogenicity and different phenotypes. Epidemiological links between genotypes of isolates and host species, spatial and temporal or virulence variability are under investigation.

    GAPS:

    • Not all virulence factors are known. The genomic and biochemical bases of virulence of strains and species specificity are not identified. Host and vector specificity of strain need to be characterized.

    • The antigenic structure of the phases is unknown too as well as relationship between strains (or host) and clinical outcome, shedding and serological pattern

    • Plasticity of the genomes and relationship between phenotypes/genotypes and virulence are not fully understood. Comparing strains of different source of isolation and possibly pathogenicity (e.g.Q212 vs Nine Mile) at the level of protein expression emphasizing on the proteins that contribute to the pathogenesis of each strain may provide insight to the variability of the disease. The putative impact of variation in strains regarding Se/Sp of diagnostic test in unknown.

    • The value of differentiating PhI and PhII antibodies in animals for determining disease status is unknown.

  • Stability of the agent/pathogen in the environment

    Outside the host, C. burnetii persists as a small, dense, long lasting spore-like form (SCV) which is able to resist heat, osmotic shock, drying, high pressure, oxidation, ultraviolet light and many common disinfectants. This dormant (no multiplication) and infectious form of C. burnetii contaminate dust and can be spread by wind for long distances. These features enable the bacteria to survive for variable periods in the environment and be a source of infection (see 3.1) and are therefore a main concern in the field of the disinfection means (see 9., 13.). The description of these resistance properties of C. burnetii has been mostly reported in old studies.. Recently viability PCRs are described that can differentiate between viable and not viable C. burnetii which can be of help in survival studies.

    GAPS:

    • It is not exactly know how long C. burnetii can survive in the environment and how the different factors influence survival. Sensitive methods to detect C. burnetii in environmental samples in which concentrations are low, are lacking especially allowing the distinction between viable and not viable bacteria although the recently published viability PCRs will facilitate this evaluation.
    • Resistance to different disinfectants should be evaluated, especially with regard to C. viability post-disinfection.
    • Survival in manure and slurry should be evaluated and methods to decrease the contamination assessed. This will facilitate manure management.

  • Species involved

  • Animal infected/carrier/disease

    The infection has been found in various wild and domestic animals and birds and in some arthropods, such as ticks. The species most commonly infected are cattle, sheep and goats. Infection has been noted in a wide variety of other animals, including other species of livestock and in dogs and cats.

    The infection has been found also in migratory and resident birds, wild ruminants, lagomorphs, foxes and rodents and marine mammels.

    GAPS :

    • Lack of systematic research in other species, Role of pets is not well known. The role of wild life cycle in the transmission and maintenance of C. burnetii needs to be further elucidated Information of host specificity and cross infection, including cross protection of strains is not well known.
    • Potential misdiagnosis with Coxiella-like organisms could be considered, so the range of infected animals (including ticks) could change.
    • The role of other mammals as potential reservoirs should be clarified (see Section “Reservoir”)

  • Human infected/disease

    A worldwide zoonosis in humans. Most infections remain asymptomatic about 2-5% of the infected patients. A great variation of clinical presentation is reported, including self-limited and usually uncomplicated disease, commonly characterized by influenza-like illness, mild pneumonia or hepatitis, to persistent disease, sometimes with poor prognosis. The latter may develop in about 2-5% of the infected patient, and natural or induced immunosuppression, valvulopaty, vascular and osteoarticular conditions are regarded as risk factors.

  • Vector cyclical/non-cyclical

    Some arthropod ectoparasites, such as ticks, play a role as a vector especially in the sylvatic cycle of C. burnetii . The bacterial carriage by ticks seems very variable and the risk of transmission can be associated to bites (mainly in animals) as well to aerosols contaminated by their excrements. C. burnetii is capable of multiplying in the gut cells of ticks and large numbers of the bacterium can be shed in tick faeces contaminating hides and wool which may be a source of infection for people and animals either by direct contact or after faeces have dried and been inhaled as airborne dust particles.

    GAPS:

    • Role of ticks (in interaction with wildlife)Ticks –host interaction could affect the presence of the disease at ecological level in the environment
    • Possible misdiagnosis between C. burnetii and Coxiella-like organisms. Reassessment of the real role of ticks should be considered

  • Reservoir (animal, environment)

    Sheep, and goats are the primary reservoirs of C. burnetii infection in humans outbreaks A herd of a certain size seems necessary to sustain infection in an animal population.There is consensus among public health and veterinary professionals that most of the human Q fever outbreaks are linked to small ruminants, abortion waves on large farms representing the major risk.The exact role of cattle in the epidemiology of human Q fever is not clear. Human outbreaks associated with cattle are scarce in Europe and North America (in cattle probably more individual case and not outbreak).. In these regions a specific genotype of C. burnetii is present in cattle that is scarcely found in infected humans. In Australia, however, Q fever is mainly associated with cattle and especially with cattle slaughterhouses.Possibly, the role of cattle could be overwhelmed, due to the different ways of shedding, or maybe to different Coxiella strains. Small ruminants are often linked to human outbreaks involving many people, while cattle seems to be more linked to single/chronic human cases, easily misdiagnosed. C. burnetii in cows is frequently shed in milk also for long time and that raises the issue of possible zoonotic role in human consumption, especially regarding raw milk and dairy products derived from contaminated raw milk. Actually, the link between raw milk consumption and illness in humans is still controversial.Infection has been noted in a wide variety of other animals, including other species in the vicinity of livestock (dogs of herds, rodents, migratory birds, …), which could play a role as secondary reservoirs.Other animal species have also been implicated in C. burnetii outbreaks in humans. Familial clusters of Q fever were associated to parturient dogs and cats in New Scotia, and few more affecting small-animal professionals or pet exposed individuals in other areas of the world. The epidemiological investigation of a number of other small outbreaks has also suggested the contact with wild species as the likely source of infection, as in Australia (kangaroos), Twain (deer) and Provence (pigeons). In any case, the recent outbreak in French Guiana was the first to relate on a molecular level the variant involved in human cases and its circulation in three-toed sloths.

    GAPS:

    • Role of cattle in the epidemiology of human Q fever.

    • Studies on human cases associated with cattle should be further investigated by means of molecular epidemiology.

    • The role of non-ruminant species like dogs and cats in the epidemiology of human Q fever.Studies on milk as source of infection for humans should be implemented.

    • No knowledge about the intra- and interspecies dynamics

    • The role of ticks and wild life in general as a reservoir in the transmission to humans and maintenance of C. burnetii still remains a gap in our knowledge. The role of other wild and domestic species (dog, cat, rodents, birds) as reservoir has not been clarified.

  • Description of infection & disease in natural hosts

  • Transmissibility

    Very few organisms may be required to cause infection in experimental model (i.e. intraperitoneally on mice, directly on cultural cells) . More recent studies have shown that high numbers of C. burnetii must be present in an aerosols ambient (inhalation route) in order to lead to pathological lesions, otherwise only a seroconversion is observed. This is probably depending on the infection route (ingestion) and dose (ingestion). Large numbers of organisms are excreted in the placenta, foetal fluids, aborted foetus, milk and urine. Both symptomatic and asymptomatic animals may shed organisms. The infection is often latent; the bacteria may be persistently shed into the environment, especially at the time of giving birth. Highest numbers of C. burnetii are found within diseased herds, where relevant proportions of animals excreted high quantities.

    While an epizootic event constitutes the initial moment for transmission, the risk of transmission can last for a long time depending on the bacterial environmental persistency.

    Dogs may be infected by consumption of placentas or milk from infected ruminants, and by the aerosol route. Wild rats may represent a reservoir of C. burnetii from which domestic animals, especially cats, which are natural predators of these animals, may become contaminated/infected.

    The possibility of non-conventional means of transmission through transfer of biological materials (semen, cells-therapy)

    GAPS:

    • Does vertical transmission occur?Very important information for the control of the disease.

    • The oral route of infection by ingestion of milk or cheese is considered unlikely, but further studies are needed.

  • Pathogenic life cycle stages

    Not applicable.

  • Signs/Morbidity

    Infection in non-pregnant animals is usually asymptomatic. In pregnant animals infection may cause abortion and early birth depending on the pregnancy stage at the time of infection, due to placentitis (inflammation of the placenta). Abortion generally occurring in late pregnancy, stillbirths and delivery of weak offspring in cattle, sheep and goats.

    Placental retention, metritits and mastitis were recorded in cattle., but the link between these clinical signs and C. burnetii infection is still controversial. Generally, an epizootic emerges within a weakly- or non- infected herd. In weak offspring due to Q fever nonspecific symptoms can occur such as pneumonia.

    Sheep generally show only one abortion episode if any, whereas goats can show repeated abortions; in cattle abortion are less frequent, other clinical manifestation (infertility, metritis) are difficult to assess.

    GAPS:

    • Lack of experimental data on Q fever in cattle.

    • Is mastitis a symptom of C. burnetii infection?

  • Incubation period

    The incubation period is variable; maybe between one to eight weeks, depending on the gestation stage.

    GAPS: incubation period unknown.

  • Mortality

    Low except the mortality of foetus at the time of abortions in late pregnancy. In some cases C. burnetii can cause abortion of almost all reproductive goats in a herd

    GAPS: Die weakly born new-borns due to C. burnetii or to other causes.

  • Shedding kinetic patterns

    C. burnetii infection persists for several years, and is probably lifelong. Sheep, goats and cows are mainly asymptomatic carriers, but can shed considerable numbers of organisms at parturition, especially during a large Q fever abortion outbreak, and intermittently in various secretions and excreta. Concomitant shedding into the milk, the faeces and the vaginal mucus may be rare. The vaginal shedding at the day of parturition may be the most frequent and contain the highest numbers of bacteria. Although C. burnetii is found in lower numbers in the milk, and the vaginal mucus of infected dairy animals, this type of shedding may persist for several months increasing the risk for bacterial transmission. Shedding kinetic patterns of C. burnetii in wild animals (e.g. foxes, moufflons-wild goats, hares) and migratory birds may contribute to the transmission of the bacterium.

    Shedding patterns (routes and duration) may be different for cattle, goats and sheep.

    Vaginal shedding seems generally limited to 7-10 day after delivery or abortion in all species; milk shedding may last for two years or more in cattle, for many months in goats, for a little time in sheep. On the other hand, sheep may shed Cb mainly through faeces in comparison to goats and cattle.

    GAPS:

    Insufficient information on shedding kinetics in goat, sheep and cattle are available, especially in absence of clinical signs or delay of the abortion. There is no exact knowledge about “shedding” dynamics in pets. There is no adequate information on shedding kinetic patterns concerning wild animals and migratory birds. Shedding of C. burnetii in faeces is controversial

  • Mechanism of pathogenicity

    The principal lesion is a necrotizing placentitis with large numbers of organisms in trophoblasts. Lesions in aborted foetuses are rare (10%) and most consisting of inflammation in liver, lung and kidney.

    GAPS: In chronically infected ruminants, it is not clearly understood how and where C. burnetii persists in the non-pregnant period and which mechanism initiated the bacteria multiplication in the placenta.

  • Zoonotic potential

  • Reported incidence in humans

    Traditionally considered as an occupational disease although most cases are from community outbreaks. In Australia, besides its occupational nature for abattoir workers, higher incidence in rural areas.

  • Risk of occurence in humans, populations at risk, specific risk factors

    Transmission to humans mainly occurs through the inhalation of contaminated aerosols. These originate from infected dust contaminated by dried placental material, birth fluids, and excreta of infected animals or exposure to amniotic fluid or placenta. Possibly, a natural immunisation occurs for rural population. By far the most important risk factor for acute Q fever is living in the vicinity of infected farms or close contact with infected animals. Indeed, most Q fever outbreaks occurred in semi-urban areas, sickening people who live close to farms, but are not working on farms. There is no consensus about the possible role of manure in the transmission of C. burnetii. Manure based on animal faeces is used as a bio-fertilizer in many countries.

    Climatic factors (wind, temperature, humidity) should also be considered as specific risk factors. The role of consumption of raw milk or dairy products remains controversial.Immunological status of the person should be taken into account among the risks (gap). Risk group is veterinarians.

    GAPS:

    • The risk of infection/disease via milk and raw milk products need to be better defined
    • Evaluation of the transmission role of pets is important.
    • The transmission risk of manure has to be evaluated

  • Symptoms described in humans

    Clinical symptoms are seen in less than half of all people infected with C. burnetii. Infection is often self-limiting but some patients may develop a flu-like illness with pneumonia and/or hepatitis occurring in 30 to 50 %. Most patients will recover within several weeks and without treatment. Mortality from acute Q fever in humans is around 1%. A chronic severe debilitating disease can occur in a small percentage (1-5%) of cases in particular in those with pre-existing heart valve or vascular problems or who are immune-compromised. A post Q fever syndrome of chronic fatigue is also recorded. Infection in pregnant women may cause abortion or premature birth, but recent publications did not confirm this. The clinical presentation of Q fever is aspecific, so that diagnosis can only be made by laboratory tests. It is likely that factors such as the inoculum size, affect the expression of C. burnetii infection. Gender and age also affect the expression of C. burnetii infection. Moreover, the prevalence of clinical cases in children significantly increases with age and symptomatic Q fever occurs more frequently in people older than 15 years. Whether the clinical outcome of the infection depends on the route of infection is controversial (see gap under Section “Risk of occurrence in humans”).

    GAPS:

    • Factors influencing the clinical manifestations, the severity of the symptoms as well as the final outcome of Q fever (chronic vs acute) still remain a gap in our knowledge.
    • It is not clear if different genotypes of C. burnetii generate different symptoms in humans.

  • Estimated level of under-reporting in humans

    Because the disease is underreported, scientists cannot reliably assess how many cases of Q fever have actually occurred worldwide. The current method for the diagnosis of Q fever in humans is largely based on serology (IFA, ELISA). The early diagnosis, before antibodies appear, is performed by PCR on blood or respiratory material. Acute Q fever is on the EU list of notifiable infectious diseases, but not all countries comply with this. For example in France and Denmark, Q fever is not notifiable.

    GAPS: Lack of microbiological testing in patients presenting with community-acquired pneumonia.

  • Likelihood of spread in humans

    Human to human transmission is rare. Transmission of Q fever to attendants during autopsies or infection from a patient to the hospital staff can occur. Sexual transmission of Q fever has been reported in humans.

    GAPS: The possibility of human to human transmission needs to be investigated (blood and other donations) .

  • Impact on animal welfare and biodiversity

  • Both disease and prevention/control measures related

    Limited impact; measures to limit the disease or outbreaks may impact welfare of individual animals, for example culling. The use of disinfectants may influence the biodiversity.

    GAPS : Influence of the use of chemical products on manure (risk for farmers, animals…).

  • Endangered wild species affected or not (estimation for Europe / worldwide)

    None.

    GAP :Unknown.

  • Slaughter necessity according to EU rules or other regions

    No. Is used as one of the measures to control the large outbreak in the Netherlands.

    GAP: No harmonized action in the EU.

  • Geographical distribution and spread

  • Current occurence/distribution

    First identified in Australia in 1935, Q fever has since then been found throughout the world with the exception of New Zealand.

    GAP : Prevalence is unknown in many areas.

  • Epizootic/endemic- if epidemic frequency of outbreaks

    Endemic in many countries. Numerous outbreaks can occur and spread can be rapid under certain circumstances.

    GAPS :

    • No rapid alert system existing.
    • Lack of interaction between public health veterinary health professionals can hamper the disease control.

  • Seasonality

    Yes due to seasonality of small ruminant kidding. Higher seroprevalence is reported when time spent in stable increases.

  • Speed of spatial spread during an outbreak

    Variable but can be rapid.

    GAP: Need to be investigated in several conditions (ruminant species, density of animals, type of animal husbandry, climate, topography….

  • Transboundary potential of the disease

    Spread by asymptomatic animals. Importance of wind and dryness.Outbreaks have been reported following exposure to infected pigeon faeces. Thus birds could be a risk for transboundary potential of the disease. International travel (cases described in patients recently traveling abroad, particularly Africa).

    GAP: No rules for animal trade, no tests and sampling standardized to assess the free-status.

  • Route of Transmission

  • Usual mode of transmission (introduction, means of spread)

    The organism may be present in reproductive fluids of infected animals, e.g. sheep and goats, at lambing, with infection of other animals and humans occurring through inhalation of aerosols.

    GAP:

    • Within herd dynamics are not clear especially the role of non-pregnant animals. Role of rodents in the between herd transmission. Role of manure in the transmission to humans, relative role of wind/trade/type of production on between herd transmission and transmission to humans.
    • Again transmission through consumption need to be clarified.

  • Occasional mode of transmission

    Q fever can also be spread by ticks which pass the bacteria from an infected to a susceptible animal. Faeces form infected animals contain the bacteria and can contaminate the environment. The bacteria are also shed in the milk of an infected animal. Seroconversion was observed by drinking non pasteurised infected milk.

    GAPS:

    • Role of sexual transmission must be assessed as it was reported

    • The survival of bacteria in raw dairy products should be studied

    • The possible role for transmission of animal feed (hay) or pasture contaminated by infected manure should be investigated.

  • Conditions that favour spread

    Outbreaks typically occur following a birth or abortion where the environment becomes contaminated with birth fluids and placentas.

    Q fever is an emerging infection, . Geographical factors combined to meteorogical factors, such as a prewailing wind and dry weather, seem to have synergic effects.

    Milk shedding is frequent and long lasting in cattle and goats, but its relevance for Q fever spread should be further investigated.

    GAPS:

    • Role of climate conditions (drought, wind).
    • A better understanding of the modalities of transmission, the sources of contagion and the epidemiological emerging factors could give a clue to avoid human infection from animal and environmental sources.

  • Detection and Immune response to infection

  • Mechanism of host response

    Once a domestic ruminant is infected, C burnetii localizes in mammary glands, supramammary lymph nodes, placenta, and uterus, from which it may be shed in subsequent parturitions and lactations.

    GAPS:

    • Can animals become chronically infected?
    • What is the excretion pattern in these animals?
    • Is immunity sterile?
    • What is the role of the cell midi.

  • Immunological basis of diagnosis

    Development Cell mediated immunity seems to be crucial for the elimination of the agent. A synergy with humoral immunity was demonstrated in experimental models. Intradermal testing can be performed. Humoral response against Phase I and Phase II LPS provides information on the Q fever forms in humans (see 1.2.). IgM response can probably give information about recent infection or on the vaccination status of an initially free Q fever animal. In ruminants, IgG1 and IgG2 isotypes could be of interest for discrimination of evolutive infection and convalescent state. Humoral response against Phase I and Phase II LPS has been poorly investigated in animals.

    GAPS:

    • Development of diagnostic tools based on CMI.
    • Development of DIVA ELISA.
    • Development of test indicating the persistency of immunity (to decide if annual booster is needed or not).
    • Interpretation of Humoral response against Phase I and Phase II LPS in animals.
    • Role of Phase I and II antibodies in assessing the disease status.

  • Main means of prevention, detection and control

  • Sanitary measures

    Control of the infection when required, would concentrate on management practices such as separation of animals, and hygiene measures.

    • When considering introducing new animals into a flock or herd enquire if abortion outbreaks has occurred on the source property in the recent past – do not purchase from flocks or herds where abortion outbreaks was known to occur.
    • Isolate infected pregnant animals.
    • Quarantine imported animals.

    GAP: The efficacy of individual measures and the attribution of these measures to the control of the disease are unknown.

  • Mechanical and biological control

    • Dispose of placenta, birth products, foetal membranes and aborted foetuses by burying or burning.
    • Regular cleaning, particularly of areas where animals give birth to reduce the amount of C. burnetii in the environment.
    • Cleaning can be followed by disinfection with 10% bleach.
    • Removal of manure with caution, avoid spread from dust.
    • Calcium Cyanamide 0.6% during one week.
    • Birthing should be done in barns. Animals should be kept inside for two weeks after birth.
    • No flocks/herds near city limits (min. 500 m distance).

    GAP: The efficacy of individual measures and the attribution of these measures to the control of the disease are unknown

  • Diagnostic tools

    Human and vet diagnostic tools are distinct.

    Veterinary diagnosis could be made by direct isolation of the organism from tissues such as placenta, but in practice it is performed by detection of DNA specific for C. burnetii using one of several PCR protocols, or by immunohistochemical staining for the antigens. PCR technique is now recognised as the most sensitive method to detect C. burnetii. Real-time PCR is less time consuming that the conventional reactions and can provide a quantitative result.

    Although a threshold is not officially approved internationally, one should mention that a group of French experts has considered that abortion in ruminants should be considered due to C. burnetii when at least 104 bacteria per gram of placenta or vaginal swab are detected. In tissues or stomach content from aborted fetuses, the same group considered that a positive result by PCR is sufficient to diagnose Q fever as the origin of abortion. For pooled samples the proposed threshold is 103 bacteria per pool. These thresholds are indicative and may be revised especially if new scientific information becomes availableA number of serologic tests can be used.; the most commonly used assays include indirect immunofluorescence, ELISA and complement fixation test. ELISAs are commercially available. The antibody occurrence indicates a past as well recent exposure to C. burnetii. CF is less sensitive compared to ELISA and indirect immunofluorescence.ELISA should be preferable to IFA for practical reason. ELISA requires a single dilution of sera and can be automated. Serology may be more helpful in screening herds than in individual animals.

    Human definitive diagnosis can be achieved by agent isolation from blood or other tissue if reflecting a particular manifestation of the disease (as cardiac valve, aneurism, vascular tissue, bone biopsies, etc). The isolation attempts are however restricted to practical issues (the availability of BSL3 facilities and trained personnel) and time constrains (demanding procedure that usually take more than two weeks to obtain the result). Immunohistochemical staining of tissue sections can be important to prove the presence of proliferating bacteria and their specific location but as for the veterinary field, direct diagnosis usually relay in the detection of C. burnetii DNA by PCR. Real-time PCR targeting multicopy genes are preferred for the increased sensitivity but sequence identity confirmation is still required. Serology can also be most useful if performed in paired samples collected 2-4 weeks apart. IFA is preferable to ELISA as it allows the simultaneous analysis of serial dilutions of both IgG and IgM against C. burnetii phase I and phase II antigens.

    GAPS:

    • No harmonized practice/methods available. Lack of rapid tests.Especially for attributability for abortion (PCR Is not enough)
    • Evaluation of phase I phase II for recent or chronic infection in ruminants is needed.
    • The development of serological tools distinguishing between former infection and new infection would be very helpful as well as distinguishing between infected and vaccinated animals (DIVA).
    • No diagnostic tools are available to detect infection in pregnant animals, so it is not possible to assess the risk of an infected pregnant animal.
    • Understand the pathophysiology to explain the quite systematic seronegative status of heifers.

  • Vaccines

    Animal vaccination has been used in areas where infections are common. Several vaccines are available in European Member States but only inactivated phase I Coxiella vaccines are efficient. Production of these vaccines is done under BSL3 conditions in in vivo systems with stringent safety measures. Complex production system difficult to scale up.

    GAPS:

    • Phase I vaccine: The duration of immunity and the determination of target population for vaccination (susceptible animals) should be identified.
    • Design should include an easier protocol for application in the field for intensive breeding
    • No DIVA vaccine available, no sub unit vaccines available. Duration of immunity, need for annual booster
    • The efficacy of vaccination on already infected animal should be evaluated.

  • Therapeutics

    Prophylactic treatment is generally not recommended to reduce the risk of abortion and the excretion of C. burnetii shed by infected females while increasing the possibility for the development of antibiotic resistant C. burnetii strains. Antibiotic treatment is not effective in abortion control: Experimental studies have shown no effect in reducing abortion nor shedding in small ruminants. In cattle antibiotic treatment may be associated with shedding reduction and improved fertility.

    GAP: New molecules should be investigated that can be useful in the control of on infection.

  • Biosecurity measures effective as a preventive measure

    In the laboratory, strict controls are needed and C. burnetii is to be handled under biosafety level 3 standards. In the farm, precautions should be taken into account during kidding:

    • Protective clothing and mask, especially for manipulation of placenta and aborted foetus
    • Protective transport
    • Disinfectant

  • Border/trade/movement control sufficient for control

    Limited value due to the airborne transmission of Q fever.No standardised protocols are available to determine the free-status.

    GAPS:

    • Sampling and testing procedure to define a flock/herd as Coxiella-free need to be established.
    • Establishment of guideline to test at introduction (relevance, test, interpretation).

  • Prevention tools

    In a C. burnetii-free flock, introduction of new stock should be minimized, or previously vaccinated, and contact with wildlife should be prevented as much as possible. Appropriate tick control should also be practiced. Prevention may be difficult, as the causative agent can also be introduced on fomites (mainly hay, food) or in aerosols over long distances.Birthing in separate barns is an effective preventive measure,Vaccination is the most important preventive tool. A breeding ban will prevent animals to become a risk. During outbreaks, elimination of infected pregnant animals will prevent spreading of C. burnetii. Quarantine of newly introduced animals can prevent the infection spread.

    GAPS: No available tool for the determination of individual status of animal.

  • Surveillance

    The implementation, development and standardization of schemes for the monitoring and reporting of Q fever in animals are crucial for the prevention and control of this zoonosis.Propositions by EFSA have been elaborated to improve the reporting and to provide and establish comparable data on the occurrence of Q fever in the main animal reservoirs, taking into account the characteristics of Q fever, the traits of the bacterium, the situation of Q fever in most Member States, the availability of the suitable diagnostic tools and a financial compromise.A passive surveillance system should be preferable to active surveillance. This scheme is based upon identification of clinically affected herds (i.e. in which a series of abortion has occurred) by using laboratory-based diagnostic of Q fever.To screen large numbers of animals in a herd or flock, the most used method is serology. Serology can be used for screening herds but not to determine a Q fever status in individual animals. Complement fixation tests exhibit poor sensitivity and are not suitable for serological investigation of Q fever dynamics.

    PCR screening of tank/individual milk, vaginal swabs (single or pooled) could also be done. However, PCR testing should be done at different times and with different types of samples in order to do not miss shedding animals. If a single route is targeted, vaginal swab could be sampled within seven days of kidding or abortion.

    Bulk tank milk testing by PCR and antibody ELISA may be the most accurate sample for monitoring C burnetii infection in dairy herds.In the Netherlands, where dairy goats are incriminated in a large human outbreak, it is hoped that a new test, in which a sample of bulk tank milk coming from farms is PCR-tested for traces of the bacteria, will lead to the discovery of the at risk farms.Similarly in the case of investigation of non-dairy herds, the possibility to test pools of individual samples, such as vaginal swabs or/and milk samples, should be considered.

    GAPS:

    • Method harmonization, sensitivity, specificity evaluation are needed.
    • The intra-herd prevalence based on bulk tank milk or pool tests should be estimated. Forthat, better knowledge of shedding patterns is required.
    • Standardization of international control programmes in case of human outbreaks should be considered.

  • Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

    Vaccination with Phase I vaccine has been effective in cattle, goats and sheep and has reduced clinical problems as well as reducing shedding of the organism but is not eradicating the disease/organism. See also Section “Mechanical and biological control”.In Slovakia, the decrease in the occurrence of human and animal Q fever was suggested as the result of the large-scale vaccination of cattle that was carried out there over a 10 year period, together with improved veterinary control of domestic animal transport within the country.In the Netherlands, a large vaccination programmeme in goat and sheep farms has been implemented, the controlled processing of manure and checks on animal transports, but it is not clear yet whether bacterial shedding by animals is prevented or at least reduced by vaccination. Controlling the epidemic is difficult and can be compromised by the prolonged stability of the bacterium in the environment and the possible role of animal species other than small ruminants. Also in Belgium surveillance via bulk tank milk testing is performed and positive farms are vaccinated. In other countries, no large scale vaccinations for C. burnetii have taken place up to date. However in Greece, brucellosis eradication programmemes have been shown helpful for the reduction of C. burnetii infected animals. The complementary to the vaccination measures undertaken for the control/prevention of animal brucellosis such as controlled slaughtering, improved farm hygiene (including the appropriate disposal of placentas after birth), restriction and control of trade and movement of animals obviously helps not only the reduction of brucellosis, but of many more zoonosis one of which is coxiellosis.

    GAPS:

    • What is duration of immunity after vaccination.

    • The efficacy of individual measures and the attribution of these measures to the control of the disease are unknown

  • Costs of above measures

    Cost of sanitary measures, treatment and vaccination, culling of pregnant goats.

    GAPS:

    • Cost of screening and risk assessment.
    • Containment costs.
    • Vaccine costs. Restriction of raw milk selling (which is applied in Belgium in positive farms) need to be evaluated.

  • Disease information from the WOAH

  • Disease notifiable to the WOAH

    Yes.

  • WOAH disease card available

    Key facts available here.

  • WOAH Terrestrial Animal Health Code

    None.

  • WOAH Terrestrial Manual

    Chapter on Q fever available here.

  • Socio-economic impact

  • Zoonosis: impact on affected individuals and/or aggregated DALY figures

    The distribution is worldwide. Q fever has been described in >59 countries and recently in Artic areas (Greenland).

    Outbreaks of Q fever are infrequently reported. In some countries they were never described despite C. burnetii endemic status and the occurrence of sporadic cases of diseases.

    In Germany an outbreak affected 300 people when one sheep gave birth at a livestock market, and in Canada a group of persons was infected while playing cards in a house where a cat gave birth.

    Netherlands has become World's heaviest Q-fever-infected country, with significant public health concern. Consequent to the unusually extensive infection in humans, in 3 provinces, human surveillance and special preventive and control measures in animals have been applied including vaccination and culling of pregnant goats.

    If outbreaks occur they have a limited duration, the Dutch outbreak in an exception in recent years.

    Expressed in DALYs, Q fever ranked 12th of 32 infectious diseases in the Netherlands over the period 2007-2011, using the methodology developed under the Burden of Communicable Diseases in Europe (BCoDE) project.

    Expressed in DALYs, Q fever ranked 12th of 32 infectious diseases in the Netherlands over the period 2007-2011, using the methodology developed under the Burden of Communicable Diseases in Europe (BCoDE) project.

  • Zoonosis: cost of treatment and control of the disease in humans

    The healthcare-associated costs of the Q fever epidemic in the Netherlands was estimated at €18.4-26.5 million and the productivity loss at an additional €1.3-10.3 million.

  • Direct impact (a) on production

    Variable (see Section “Description of infection & disease in natural hosts – Signs”).Direct impact due to abortions. A survey over 8 years (1991 – 1998) of 221 cases of caprine abortion in southern California reported that C. burnetii was the second most commonly diagnosed cause (9%) of reproductive wastage after Chlamydia abortus (14%). Studies with controversial results about effect on fertility exist, but the study design is not very convincing

    GAP: Real economic impact unknown and has to be studied.

  • Direct impact (b) cost of private and public control measures

    Costs of controls and vaccination where applied.

    GAPS: Culling of animals where applied. Cost of containment.

  • Indirect impact

    Limited.

    GAPS:

    • Possible Impact on trade between countries/areas. Depends also on milk industries.
    • Indirect cost of manure management, control of movements.

  • Trade implications

  • Impact on international trade/exports from the EU

    None. No international standards laid down in the OIE Terrestrial Animal Health code 2009.

  • Impact on EU intra-community trade

    None.

  • Impact on national trade

    Limited due to possible restrictions on movements from known infected herds.

  • Main perceived obstacles for effective prevention and control

    • Difficulties in identifying infected herd/flocks due to lack of clinical signs and of simple, sensitive and specific diagnostic tools to identify shedding animals.

    • Lack of awareness (animal and human); for animal, the Q fever diagnosis is not harmonised and variably included in a differential diagnosis of main abortive infectious agents.

    • Cost of effective diagnosis and vaccines

    • Inefficiency of tetracycline treatment against shedding

    • Lack knowledge of the efficacy of disinfectants

    GAPS:

    • Lack of scientifically established control measures and programmeme.

    • Lack of scientifically established preventive measures.

    • No unified EU diagnostic practice.

  • Main perceived facilitators for effective prevention and control

    • Use of improved diagnostic techniques.
    • Use of efficient vaccines.
    • Improve understanding of human outbreaks (genotyping methods, geographical information system, …)
    • Preventive vaccination of veterinarians, exposed workers and risk groups
    • Financial support for farmers.

    GAP: An effective DIVA vaccine without side effects. Effective disinfectants.

  • Links to climate

    Seasonal cycle linked to climate

    Yes importance of wind and dryness.

    GAPS: Influence of dryness, humidity, temperature on pseudo-spore formation and survival of C burnetii needs to be studied.

  • Distribution of disease or vector linked to climate

    Yes dry weather conditions correlate typically with outbreaks.

  • Outbreaks linked to extreme weather

    Yes (see Section “Distribution of diseased linked to climate”), dryness favors the survival of C. burnetiid.

  • Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

    Humidity increases the number of ticks but in infected tick-faeces dry climate favours the persistence of the bacterium.

    GAP : C. burnetii and Coxiella-like in ticks need to be studied.

Risk

  • Q fever is a potential biological warfare agent being very infectious and very durable in the environment as well as capable of windborne spread.Risks are at least linked to the different sources and routes involved for the transmission which are not well known. Assessment of infectious dose in natural conditions needs to be further studied. Some reports suggested that a great quantity of bacteria in the ambient vicinity is required to be infective and induce pathological lesions (see Section “Zoonotic potential - Risk of occurrence in humans, populations at risk, specific risk factors”). Moreover, the distances of windborne spread has to be better defined.

    GAP: No knowledge on “background”-levels of Coxiella in the environment in the different regions/countries.

Main critical gaps

Conclusion

  • The importance of Q fever is very much depending on the number and size of outbreaks and the number of human cases. Outbreaks are normally limited in time. In goat and cattle herds reproductive problems due to Q fever can be severe and can cause economic losses. The risk of Q fever in cattle for public health seems to be limited. Infection dynamics in ruminant herds are not fully understood. Non symptomatic animals are hard to detect with the currently available diagnostic tools. The available phase I inactivated whole cell vaccine is effective in non-infected animals but cause side effects, are difficult to produce and lack the DIVA principle.

Sources of information

  • Expert group composition

    Hendrik-Jan Roest, Wageningen Bioveterinary Research, The Netherlands – [Leader]

    Elodie Rousset, ANSES, France

    Ana dos Santos, National Health Institute Doutor Ricardo Jorge, Portugal

    Marcella Mori, Sciensano, Belgium

    Wim van der Hoek, National Institute for Public health and the Environment (RIVM), The Netherlands

    Raphael Guatteo, ONIRIS & INRA, France

    Alda Natale, IZS delle Venezie, Italy

    Antonio Barberio, IZS delle Venezie, Italy

  • Reviewed by

    Project Management Board.

  • Date of submission by expert group

    10 August 2018