Leptospira vaccines have long been available for active immunisation of dogs. All the available vaccines contain inactivated antigens representing two serogroups of the bacterium (Icterohaemorrhagiae and Canicola). Some contain one or two additional Leptospira serogroups (Grippotyphosa alone, or plus Australis). This new module updates the information in our article of August 2015, and compares the features of the available vaccines with the aim of reducing confusion and helping prescribers make rational choices. The module also looks into concerns about the safety of the newer vaccines.
By doing this module you will:
- understand the naming system for Leptospira and the relevance to vaccination;
- be aware of the limitations of serological testing in determining the type of infecting Leptospira and the immune status of dogs;
- understand what is known about the types of Leptospira affecting dogs in the UK;
- understand the features of the different vaccines and how they compare;
- be aware of what is known about the safety of the vaccines.
Leptospira infection, a zoonosis, can cause serious and potentially life-threatening disease in many species, including dogs and humans. Leptospira are excreted in the urine of infected animals and can survive for several weeks under the right environmental conditions in contaminated water and moist soil. UV radiation, freezing, desiccation and most disinfectants will inactivate the organism (Levett 2001; Sykes 2011; Schuller 2015). Climate change and flooding may encourage greater survival and spread of the organism.
Infection can occur by direct contact of mucous membranes or broken skin with urine from infected animals or with contaminated soil or surface water. Maintenance (reservoir) hosts (e.g. rodents) can harbour Leptospira in the renal tubules for long periods and shed the organism via urine, generally without showing clinical signs of infection.
- The naming system for Leptospira is complex, but is relevant to understanding the epidemiology, interpretation of laboratory results and the coverage of vaccines.
- The name is made up of the genus followed by the species followed by the serovar (e.g. Leptospira interrogans serovar Icterohaemorrhagiae). See more examples in the table below.
- The current naming system is a phenotypic classification based on the reaction of specific antiserum with antigens on the outer membrane of the organism (to determine serovar). Within the species interrogans alone there are over 200 serovars (Levett 2001). Serovars may be further divided into strains.
- Serovars found to be related antigenically are grouped into serogroups. These have no taxonomic use but are relevant, because vaccines are considered to induce serogroup-specific immunity (Levett 2001; Sonrier 2001; Sykes 2011; Schuller 2015).
- Genotyping of Leptospira has introduced confusion because it does not correlate with the serological classification. Serovars in the same serogroup may belong to different genomic species.
- Serological determination of serovars is still epidemiologically important because different serovars are adapted to specific reservoir hosts (Levett 2001; Sykes 2011; Ellis 2010; Schuller 2015). For example:
- Icterohaemorrhagiae and Copenhageni are associated with rats;
- Pomona and Hardjo with cattle;
- Grippotyphosa with mice and voles;
- Canicola with dogs;
- Bratislava with hedgehogs, horses, pigs and dogs.
- There are geographical differences in the prevalence of the various serovars, across Europe and within countries, reflecting the presence of the appropriate infected intermediate hosts. The serogroups Icterohaemorrhagiae and Canicola are widespread because rats and dogs are ubiquitous.
- The nomenclature of Leptospira also has an historical element. For example, names may reflect clinical signs (as in Icterohaemorrhagiae) or place of discovery (as in Copenhageni or Bratislava).
Leptospira infection can result in a wide range of effects, from subclinical to life-threatening acute disease. Dogs are susceptible to infection with a wide range of serovars (Levett 2001; Schuller 2015), but there is no clear relationship between the infecting serovar and clinical presentation (Sykes 2011; Schuller 2015).
Culture of Leptospira from urine or blood, the definitive evidence of infection, is not practicable for clinical diagnosis because culture takes several months. The standard test for diagnosis and for determination of serovars is the Microscopic Agglutination Test (MAT), which detects anti-leptospiral antibodies in the patient’s serum. The test is difficult and hazardous because it involves reacting serial dilutions of patient sera with a range of antigens on live Leptospira cultures. Diagnosis typically relies on detecting a significant rise in titre in paired samples from acute and convalescent phases. The MAT is difficult to interpret and unreliable for identifying the infecting serogroup or serovar (Miller 2011; Martin 2014; Andre-Fontaine 2013). There are patient-side tests (e.g. Witness Lepto, Snap Lepto Test) that may help confirm a general diagnosis of leptospirosis in the early stages through antibody detection.
Public concern about ‘over-vaccination’ and ‘unnecessary boosters’ has led to the use of serological tests to check for protective antibody levels. However, such tests are not helpful in the context of Leptospira because vaccination induces a relatively short-lived antibody response (Martin 2014). Also, serological testing takes no account of a cell-mediated immune response that may contribute to immunity. Serological testing should therefore not be used to determine an animal’s resistance to Leptospira infection (Day 2015; BSAVA 2016).
Leptospirosis is not notifiable and there is no routine surveillance related to this disease. So there is a lack of clinical, cultural and seroprevalence data relevant to dog populations in the UK.
In 2010, the serovar Icterohaemorrhagiae was reported to be the most common recognised cause of clinical leptospirosis in dogs in the UK and clinical infection due to the serovar Canicola appeared rare, possibly because of vaccination (Ellis 2010). There was also tentative evidence for the presence of the serovar Grippotyphosa and anecdotal evidence of an emergence of the serovar Bratislava (Ellis 2010). Data from the Animal and Plant Health Agency for the years 2013–2015 and the first quarter of 2016 shows that the most common serovar detected by MAT in canine serum submissions was Canicola followed by Icterohaemorrhagiae, Copenhagenii and Bratislava (APHA 2016). Whether these were due to clinical cases or vaccination is not known.
The current World Small Animal Veterinary Association vaccination guidelines define core vaccines as “those which ALL dogs and cats, regardless of circumstances or geographical location, should receive” and non-core vaccines as “those that are required by only those animals whose geographical location, local environment or lifestyle places them at risk of contracting specific infections” (Day et al 2016). In global terms, Leptospira is not considered a ‘core’ vaccine.
In the UK, Leptospira vaccine is regarded as ‘core’ by the British Small Animal Veterinary Association (BSAVA) because dogs are at risk from contact with rodents and potentially contaminated water (BSAVA 2012); the vaccine is widely used in practice (Ball 2014). The new British Standard Institution specification for greyhound kennels states that “all greyhounds shall be vaccinated with the core vaccinations against distemper, parvovirus, adenovirus and the four leptospirosis serovars” (BSI PAS 251 2017).
All Leptospira vaccines authorised in the UK for use in dogs contain killed (inactivated) cultures or purified antigens of Icterohaemorrhagiae and Canicola serogroups or serovars (see the tables).
- Six brands contain these two Leptospira types alone (bivalent or L2 vaccines).
- One brand also contains L. interrogans serogroup and serovar Grippotyphosa (trivalent or L3 vaccine).
- Three brands also contain L. interrogans serogroup Australis plus L. kirschneri serogroup Grippotyphosa (quadrivalent or L4 vaccines).
Two of the bivalent brands (Canigen Lepto 2 and Nobivac Lepto 2) and two of the quadrivalent brands (Canigen L4 and Nobivac L4) are identical (VMD product database; CVMP 2015). Versican Plus L4 contains aluminium hydroxide as an adjuvant (used to increase the immune response to the vaccine). All have been shown to provide immunity for at least 1 year. The summaries of product characteristics (SPCs) for all state that annual boosters are needed. Many of the vaccines are also available in multicomponent products together with viral vaccines.
The additional serogroups were included in the vaccines on the basis of a meeting in September 2012 of an expert panel gathered by the International Society of Companion Animal Infectious Diseases (Schuller 2015). The panel agreed that bivalent vaccines did not sufficiently cross-protect against serovars that are responsible for most infections in dogs in Europe. For example, in north eastern Germany, leptospirosis cases were most commonly associated with Grippotyphosa, Bratislava and Pomona and may be linked to an increase in an urban wild boar population (Kohn 2010). Whether the additional serovars (in the new vaccines) protect more dogs in Europe from leptospirosis than the available bivalent vaccines is not yet known (Schuller 2015).
The indications in the SPCs (data sheets) vary between the different vaccines (see the tables). This is a source of confusion for prescribers. The indications include reduction of infection, clinical signs, urinary tract infection, kidney colonisation, renal lesions, urinary excretion; and prevention of mortality, clinical signs, urinary excretion. They reflect the clinical data presented in support of marketing claims included in the applications for marketing authorisation (CVMP 2003). There is no published evidence on the comparative efficacy of the vaccines. The BSAVA recommends choosing a vaccine with ability to provide protection against clinical disease, renal carriage and urinary shedding (BSAVA 2016).
SPCs for the bivalent vaccines list local adverse reactions (such as swelling). One (Eurican L) lists transient temperature increase and one (Canixin L) lists systemic reactions (transient lethargy reported commonly, and hyperthermia and digestive disorders reported rarely, in clinical trials). All include hypersensitivity as a rare, very rare or occasional effect. Similar adverse effects are listed in the SPCs of the trivalent and quadrivalent vaccines. Additionally, for Nobivac L4 and Canigen L4, the SPC lists very rare reports (i.e. in fewer than 0.01% of animals) of signs of immune-mediated haemolytic anaemia, thrombocytopenia or polyarthritis. Ensuring the vaccine is warmed to room temperature may help prevent a painful local reaction (VMD 2017).
In 2016 there was high-profile coverage in the media of anecdotal reports of serious adverse effects to quadrivalent vaccines (Yorke, Telegraph 2016). The European Medicines Agency reported receiving a “high number” of reports of painful local reactions and systemic reactions associated with quadrivalent vaccines in 2016 and is investigating any possible underlying cause (including a role of the additional antigenic load) (EMA 2017). In March 2017, the Veterinary Medicines Directorate stated that the incidence of reported adverse effects was 0.015% for all L2 vaccine products and 0.069% for all L4 vaccine products combined (VMD 2017). These figures include every suspected adverse event reported, even cases that were considered unclassifiable or were later found to be unrelated to the vaccine. Most were linked to allergic-type reactions.
The figures do not confirm that adverse effects are more likely with the quadrivalent vaccines. This is because there may be confounding factors, such as a greater propensity for people to report adverse effects associated with new products and an influence of media coverage on reporting. Also, pharmacovigilance data are difficult to interpret because other vaccines or treatments may have been given concurrently.
There is no conclusive evidence that Leptospira vaccines cause more adverse effects than other vaccines (Day 2016). A study in the USA of adverse events following vaccination of all types found no increased risk from Leptospira vaccines (Moore 2015), although Leptospira vaccines used in the study have no equivalents in the UK.
Vets should report all suspected adverse events to vaccines, including suspected lack of efficacy, to the marketing company or the VMD. Reporting is essential for helping identify new adverse effects, and for understanding the frequency of known effects and the need for changes in the composition of vaccines.
As with any vaccine, the decision on whether to vaccinate against Leptospira should be based on an assessment of the likely exposure to the organism in the environment or through contact with reservoir hosts (BSAVA 2012; 2016). This will be informed by environmental risks and the lifestyle of the dog.
The Veterinary Medicines Directorate advises giving careful consideration to whether the additional protection provided by vaccines containing four strains of Leptospira is necessary for the individual dog (VMD 2017). To do this, vets will need to use any knowledge about serovars in circulation in their locality (Ball 2014; BSAVA 2016). A vaccine with broader serogroup coverage is a logical choice for dogs travelling to mainland Europe.
Clients should be told the facts about the benefits and the potential harms of the Leptospira vaccine and about the uncertainties. There should be a discussion about the choice of vaccine for the individual dog.
Leptospira vaccine is used widely in the UK. For a long time, the available vaccines contained the two Leptospira serogroups that were found most commonly in the UK (Canicola and Icterohaemorrhagiae). Now, there are four newer vaccine brands that contain one or two additional Leptospira types. The move to include the additional types appears to follow changes in the prevalence of serovars infecting dogs in mainland Europe.
Unfortunately, at present there is sparse information on leptospirosis incidence in the UK and on the prevalence of infecting Leptospira serovars. There is some evidence of a changing pattern but this is not quantifiable and does not help in deciding which vaccines to use in practice. Adverse effects are reported rarely (in 0.01–0.1% of dogs) with all Leptospira vaccines; on current evidence there is no certainty that they are more likely with the tri- or quadrivalent products compared with bivalent products.
The choice of vaccine should take into consideration local knowledge of leptospirosis cases and infecting serovars, and the licensed indications of the vaccines. Dogs travelling to mainland Europe where there is a known risk of infection with Bratislava and Grippotyphosa serogroups should receive a quadrivalent vaccine. There is no clear rationale for specifying the use of a quadrivalent vaccine for racing greyhounds in the UK, as a new published standard recommends.
Annual boosters are required to maintain immunity. Serological testing does not help determine an animal’s immunity to Leptospira and should not be used to make decisions about re-vaccination.
Clients should be told the facts about the benefits and potential harms of the Leptospira vaccine, and about the uncertainties. The choice of vaccine should be discussed. It is important to report suspected adverse effects of all Leptospira vaccines.
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How we produced this module
Our modules start with a detailed outline and electronic literature search. We commission a collaborating author, who is a specialist in the module topic, to write a draft module. The collaborating author on this module was Julian Kupfer. The draft is circulated unsigned to a wide range of commentators, include practising first-opinion vets, other topic specialists, the companies that market any mentioned drugs and other organisations and individuals, as appropriate. They can raise points about the interpretation of evidence, ask questions that are important to clinical practice, and present alternative viewpoints. There is a rigorous editing and checking process and the result is a module that is evidence-based, impartial and relevant to clinical practice. The final module is unsigned because it is the result of collaboration.
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