Canine Leishmania vaccines: Still a long way to go
Introduction
Protozoa of the genus Leishmania are obligatory intracellular parasites of mammalian macrophages. They are transmitted by the bite of phlebotomine sand flies and are the causative agents of a broad spectrum of human diseases ranging from self-healing cutaneous lesions to severe visceral dissemination. Several nosogeographical entities of leishmaniasis are found worldwide, depending on the parasite species and distribution, the phlebotomine vectors involved, the disease forms caused in humans, and the presence of animal reservoir hosts. Among 15 well-recognized Leishmania species affecting humans and with known reservoirs, 13 are zoonotic (Gramiccia and Gradoni, 2005, World Health Organization, 2010). Zoonotic visceral leishmaniasis is the most widespread entity of leishmaniasis caused by a single parasite species, Leishmania infantum, being endemic in the Mediterranean basin, Middle East, Central Asia and Latin America (Alvar et al., 2012). In this range domestic dogs are the main reservoir host; the parasite is efficiently transmitted to other dogs or humans by the bite of sand fly species of the subgenus Phlebotomus (Larroussius) (e.g. Phlebotomus perniciosus, P. ariasi, P. neglectus, P. tobbi, and others) in most of the Old World, whereas members of the Lutzomyia longipalpis complex are the main vectors in Latin America (Quinnell and Courtenay, 2009). Non-vectorial (e.g. transplacental) transmission in naturally infected dogs has been also demonstrated, although rarely (Boggiatto et al., 2011). The global burden of L. infantum infections in domestic dogs is unknown; in southwestern Europe alone, 947 serosurveys involving more than 500,000 dogs have shown a median seroprevalence of 10% (Franco et al., 2011), which means a much higher infection prevalence if sensitive molecular methods were used (Miró et al., 2008). In this subregion, the recent spread of canine leishmaniasis (CanL) foci beyond traditional endemic ranges has also been documented (Maroli et al., 2008, Dereure et al., 2009).
Besides representing a zoonotic risk for human populations in endemic areas, dogs may suffer from a severe disease characterized by the chronic evolution of polymorphic viscerocutaneous signs that manifest only several months after exposure to infection (Foglia Manzillo et al., 2013). In endemic areas, the infection prevalence appears to be considerably higher than that of apparent clinical illness, its magnitude depending on the presence of optimal conditions for transmission (Baneth et al., 2008). Only a susceptible canine fraction – usually less than 40% of infected dogs – tends to progress towards severe clinical disease, whereas a resistant population does not (Alvar et al., 2004). This latter group appears to be controlling the parasite; however this condition may not be stable so that immunosuppression or intercurrent diseases may permit latent infections to become progressive even years after exposure. Both subclinically infected and diseased dogs can be infectious to phlebotomine vectors, but infectiousness is higher in dogs with overt clinical signs (Courtenay et al., 2014).
In recent years, there have been advances in diagnosis, infection/disease staging, treatment, and prevention of CanL (see reviews by Alvar et al., 2004, Maia and Campino, 2008, Miró et al., 2008, Solano-Gallego et al., 2009, Maroli et al., 2010, Paltrinieri et al., 2010). A major advance in prevention includes evidence that the incidence of zoonotic visceral leishmaniasis, both in humans and dogs, can be significantly reduced by the topical treatment of dogs with synthetic pyrethroids, that have a potent anti-feeding (individual protection) and lethal-by-contact activity (mass protection) against sand flies (Maroli et al., 2001, Mazloumi-Gavgani et al., 2002, Otranto et al., 2013). However, available pyrethroid formulations cannot prevent all potentially infectious sand fly bites and, unlike what was observed in controlled studies, in the hands of owners they have been found not sufficiently effective (Cortes et al., 2012). Hence, the development of effective canine Leishmania vaccine is highly desirable in both fields of veterinary medicine and public health as an additional control measure against the disease.
Section snippets
What we expect from a vaccine to be effective against CanL
The determining factor of the outcome of canine Leishmania infections is the ability of the immune system to manage the parasite efficiently. The protective response against Leishmania is cell-mediated immunity: classically, a T helper (Th)1 response correlates with resistance whereas a Th2 response is associated with susceptibility to infection, revealed by increasing parasite burden and a strong but ineffective humoral response. This dichotomous paradigm comes from experimental models of
Promising Leishmania antigens: from rodent models to dogs
Preclinical research in rodent models (mouse and hamster) has evaluated the efficacy of several generations/categories of Leishmania antigens, and have identified those with promising activity of immune protection when delivered as prophylactic vaccines. Exhaustive lists of such antigens are available from recent reviews (Palatnik-de-Sousa, 2008, Duthie et al., 2012, Mutiso et al., 2013) and include killed parasites, cell purified fractions, parasite protein components or subunits, single or
From artificial to natural challenge for testing Leishmania vaccines in dogs
Because of the role of sand fly saliva and gut components in the pathogenesis and immune control of Leishmania infection (Rohousová and Volf, 2006, Andrade et al., 2007, Rogers, 2012), and because a standard method for laboratory challenge by means of colonized infected sand flies is not available yet (Aslan et al., 2011), an increasing number of efficacy trials have privileged the use of a natural challenge model (Phase III) consisting in the long-term exposure of vaccinated dogs to sand fly
A standardized field model for testing Leishmania vaccines in dogs
The regular assessments performed for each dog through a standard set of diagnostic markers for infection and clinical scoring proposed by Gradoni et al. (2005) have resulted in a highly reproducible model for CanL staging confirmed by subsequent studies and found useful for the interpretation of Leishmania vaccine efficacy (Oliva et al., 2006, Foglia Manzillo et al., 2013). Basically, in a context of a cumulative incidence of 80% of Leishmania infection, three conditions were invariably
Conclusions
Despite advances in Leishmania genomics and proteomics (Myler and Fasel, 2008), modern biotechnology for antigen expression, purification and delivery, and the large availability of murine models in the field of experimental immunology, Leishmania vaccinology still suffers from several bottlenecks that limit the progress towards effective and universal vaccines. Among them, the great genetic diversity of parasites, the difficulty of identifying surrogate markers of resistance in naturally
Conflicts of interest statement
The author knows of no financial or personal conflicts of interest with any person or organisation that could inappropriately influence this work. Funders had no role in study design or the collection, analysis and interpretation of data. Mention of proprietary products does not constitute an endorsement or a recommendation by the author for their use.
Acknowledgments
This study was funded by EU grant FP7-261504 EDENext and is catalogued by the EDENext Steering Committee as EDENext284 (http://www.edenext.eu). The contents of this publication are the sole responsibility of the author and do not necessarily reflect the views of the European Commission.
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