A systematic review of the efficacy of prophylactic control measures for naturally-occurring canine leishmaniosis, part I: Vaccinations

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A systematic review of the efficacy of prophylactic control measures for naturally-occurring canine leishmaniosis, part I: Vaccinations a ˜ C.E. Wylie a,∗ , M. Carbonell-Antonanzas , E. Aiassa b , S. Dhollander b , c d F.J. Zagmutt , D.C. Brodbelt , L. Solano-Gallego a a Universitat Autònoma de Barcelona, Departament de Medicina i Cirurgia Animal, Campus Bellaterra, Edifici V, Cerdanyola del Vallès, Barcelona, Spain b European Food Safety Authority, Via Carlo Magno 1/A, IT-43126 Parma, Italy c Epi␹ Analytics, 1643 Spruce Street, Boulder, CO 80302, USA d Veterinary Epidemiology, Economics and Public Health Group, Department of Production and Population Health, Royal Veterinary College, North Mymms, Hatfield, Hertfordshire, UK

a r t i c l e

i n f o

Article history: Received 11 December 2013 Received in revised form 12 May 2014 Accepted 24 June 2014 Keywords: Leishmania infantum Leishmaniosis Vaccination Canine Systematic review

a b s t r a c t Canine leishmaniosis (CanL) is an important zoonotic disease; however, the efficacy of available vaccines for the prevention of naturally-occurring Leishmania infantum (L. infantum) infection in dogs remains unclear. The objective of this review was to determine the efficacy of currently available vaccines to prevent naturally-occurring L. infantum infection in dogs. Four bibliographic databases (CAB Direct 2011, Web of Science 2011, U.S. National Library of Medicine 2011 and Literatura Latino Americana e do Caribe em Ciências da Saúde) were searched along with eight sets of conference proceedings and the International Veterinary Information Service (IVIS) database, from 1980 to November 2012. Randomised controlled trials (RCTs), non-randomised clinical trials (NRCTs), cohort studies and case–control studies that investigated vaccine efficacy for natural L. infantum infection in dogs were eligible for inclusion. Two review authors independently assessed each study against the inclusion criteria, independently extracted relevant data from all included studies and assessed the risk of methodological shortcomings in each individual study. The odds ratio (OR) and absolute risk reduction (ARR) for dichotomous outcomes and mean difference for continuous outcomes were calculated. Meta-analysis was not performed due to heterogeneity of the studies identified. The search was conducted for all mitigations for CanL and yielded the title and abstract of 937 articles, from which 84 articles were screened based on full text. Twelve studies on vaccinations (five RCTs, seven NRCTs) were identified. Ten studies were at a high risk of methodological shortcomings, whilst two were at an unclear risk. The use of 200 ␮g ALM protein, Leishmune® , CaniLeish® , LiESAp with MDP, and ALM with BCG tended to significantly reduce the proportion of dogs infected with L. infantum based on either parasitological or serological evidence. The use of lyophilized protein vaccine significantly increased the proportion of dogs infected with L. infantum based on either parasitological or serological evidence.

∗ Corresponding author. Current address: Rossdales Equine Hospital, Cotton End Road, Exning, Newmarket, Suffolk, UK. Tel.: +44 01638 577 754; fax: +44 01638 577 989 E-mail address: [email protected] (C.E. Wylie). http://dx.doi.org/10.1016/j.prevetmed.2014.06.015 0167-5877/© 2014 Elsevier B.V. All rights reserved.

Please cite this article in press as: Wylie, C.E., et al., A systematic review of the efficacy of prophylactic control measures for naturally-occurring canine leishmaniosis, part I: Vaccinations. PREVET (2014), http://dx.doi.org/10.1016/j.prevetmed.2014.06.015

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There is peer-reviewed evidence that control measures are effective in preventing CanL with the results suggesting that between 6 and 54% of infections could be prevented with vaccination. However, this evidence is based on a small number of RCTs, all of which are either at high or unclear risk of methodological shortcomings. Well-designed, adequately powered and properly reported randomised clinical trials are needed to clearly establish efficacy of vaccines as CanL control measures. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Canine leishmaniosis (CanL) is a major zoonosis which can potentially cause severe fatal disease in humans and dogs and is transmitted by sandflies. Infections caused by different Leishmania species are present in a variety of regions with different climate conditions throughout the world. Based on its clinical manifestations, Leishmania infection in humans has been divided into cutaneous, mucocutaneous and visceral forms (Desjeux, 2004). Zoonotic leishmaniosis is found in the Mediterranean basin, Asia and South America, with the domestic dog the main reservoir host of Leishmania infantum (L. infantum) infection (Baneth et al., 2008). All cases of canine leishmaniosis in Europe are caused by L. infantum, where no other Leishmania species have been diagnosed (Baneth et al., 2008). L. infantum has previously been called Leishmania chagasi, however the two must be regarded as synonymous (Mauricio et al., 1999; Dantas-Torres, 2006), with by the law of priority the name L. infantum being considered the valid name (Dantas-Torres, 2006). Millions of dogs are infected in South America, with high infection rates in some areas of Brazil and Venezuela (Feliciangeli et al., 2005; Werneck et al., 2007). Seroprevalence studies from Italy, Spain, France and Portugal report that 2.5 million dogs in these countries are infected (Moreno and Alvar, 2002). The seroprevalence in dogs in the Mediterranean basin ranges from 5% to 30% depending on regions (Solano-Gallego et al., 2009). Surveys employing other detection methods to calculate the prevalence of Leishmania infection by amplification of Leishmania DNA from different tissues (Berrahal et al., 1996; Solano-Gallego et al., 2001; Leontides et al., 2002) or by detection of specific anti-Leishmania cellular immunity (Cabral et al., 1998; Cardoso et al., 1998; Solano-Gallego et al., 2000) have revealed even higher infection rates, approaching 60% in some foci. Most dogs in these areas appear to have a chronic infection that may last all their lives (Oliva et al., 2006). A low proportion of dogs develop disease and the majority of dogs harbour the pathogen and are resistant to the development of clinical disease, maintaining a subclinical infection (Baneth et al., 2008; Solano-Gallego et al., 2009) A broad range of clinical manifestations and immune responses have been described for CanL. Canine L. infantum infection can manifest as a chronic subclinical infection, self-limiting disease, or non-self limiting illness (Baneth et al., 2008; Solano-Gallego et al., 2009). In addition, several degrees of disease severity are found in dogs, ranging from mild to severe fatal with different clinical outcomes, prognosis and treatment options. The two extremes of this clinical spectrum are characterized by: (1) “Resistant” dogs

with a protective CD4+ T-cell-mediated immune response featuring production of Th1 cytokines such as interferon-␥, IL-2 and TNF-␣, which induce anti-Leishmania activity by apoptosis of parasites in macrophages via nitric oxide (NO) metabolism (Holzmuller et al., 2006) and, thus capable of controlling infection, and (2) sick dogs which are characterized by a marked humoral immune response, reduced cell mediated immunity with a mixed Th1 and Th2 cytokine pattern and high parasite burden, which is detrimental to the animal (Baneth et al., 2008). As mentioned above, CanL has a wide spectrum of clinical manifestations, classically displaying a chronic disease course with periods of remission after treatment followed by relapse (Solano-Gallego et al., 2009). Clinical signs commonly include skin lesions such as non-pruritic exfoliative dermatitis with or without alopecia, ulcerative, papular or nodular dermatitis. Other clinical signs include generalized lymphadenomegaly, loss of body weight, lethargy and ocular lesions. Affected dogs also display a range of clinicopathological findings (Baneth et al., 2008; Paradies et al., 2010; Solano-Gallego et al., 2011). The diagnosis of CanL is challenging as there are no gold standard tests (SolanoGallego et al., 2009). Real-time polymerase chain reactivity (PCR) is considered to be the most sensitive molecular technique (Maia et al., 2009), with seropositivity in 88–100% of dogs with clinical signs and/or clinicopathological abnormalities consistent with CanL (Solano-Gallego et al., 2009). The prognosis depends on the severity of illness and therefore, clinical staging is essential (Solano-Gallego et al., 2009). The prognosis for treated dogs with mild to moderate disease is reported to be good to excellent, although many dogs remain subclinically infected (Solano-Gallego et al., 2009; Roura et al., 2012). Many Leishmania antigens have been identified as potential vaccine candidates, however, very few have been tested in field trials and only three second-generation canine vaccines have been registered (Palatnik-de-Sousa, 2012). The Fucose mannose ligand (FML)-saponin vaccine (Leishmune® ) was licensed in Brazil in 2003, where a second vaccine, Leish-Tec® , a recombinant A2-gene (A2)antigen of Leishmania amastigotes adjuvanted by saponin, has also been licensed since 2008. In early 2011, CaniLeish® , a formulation related to culture supernatant of L. infantum promastigotes (LiESAp), composed of 54-kDa excreted protein of L. infantum with muramyl dipeptide (MDP) was the first vaccine for CanL licensed for use in Europe. Vaccination is designed to induce a strong protective cellular immune response against the specific antigens of L. infantum, with an effective immune response mounted approximately 4 weeks after the final vaccination (Palatnik-de-Sousa, 2012).

Please cite this article in press as: Wylie, C.E., et al., A systematic review of the efficacy of prophylactic control measures for naturally-occurring canine leishmaniosis, part I: Vaccinations. PREVET (2014), http://dx.doi.org/10.1016/j.prevetmed.2014.06.015

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Two previously published systematic reviews either focused on control measures in Latin America (Romero and Boelaert, 2010) or only included vector control measures such as insecticides/repellents (Noli and Auxilia, 2005). This review, focusing on vaccination efficacy studies, is part of a larger review looking at a range of prophylactic measures for prevention of naturally-occurring L. infantum infections in dogs. The latter are presented in Wylie et al. (2014). The objective of this review was to determine whether currently available vaccines are efficacious at preventing natural L. infantum infection in dogs. This paper is presented considering the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Moher et al., 2009).

2. Materials 2.1. Review question, definitions and protocol All methods were defined a priori in a protocol, which is available from the corresponding author on request. While a meta-analysis was pre-planned, the data collected precluded this from being applied, other than that there were no other deviations from the pre-specified protocol. The primary outcome, for which conclusions about the effects of the interventions under review would largely be based, was the proportion of dogs infected with L. infantum based on either parasite detection or serology methods; including culture, cytology or PCR detection and direct agglutination test (DAT), enzyme-linked immunosorbent assay (ELISA) or immunofluorescence assay (IFA) as described in the original study. A limited number of additional secondary outcomes the review intended to address were also considered as listed below:

1. Proportion of dogs infected with L. infantum: based on parasite detection methods including culture, cytology or PCR detection as described in the original study. 2. Proportion of dogs infected with L. infantum: based only on PCR detection as described in the original study. 3. Quantitative PCR: measured as the mean value depending on the calculation performed by the original study. 4. Proportion of dogs infected with L. infantum: based on serological detection methods including DAT, ELISA or IFA as described in the original study. 5. Quantitative serology: measured as the geometric mean of the titres (DAT or IFA) or the arithmetic mean of the optical density/absorbance in nm (ELISA). 6. Proportion of dogs infected with L. infantum: based on any cellular immunity tests including Delayed Type Hypersensitivity (DTH) reactions or Lymphocyte Proliferation Tests as described in the original study. 7. Size of the DTH reaction: measured as the diameter of skin induration as described in the original study. 8. Proportion of dogs that died and were infected with L. infantum: case definition as described in the original study.

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9. Proportion of clinically ill dogs infected with L. infantum: case definition as described in the original study. 10. Adverse events related to the intervention. 2.2. Search strategy CAB Direct 2011, Web of Science 2011 (WOS), U.S. National Library of Medicine 2011 (MEDLINE) and Literatura Latino Americana e do Caribe em Ciências da Saúde (LILACS) were searched for all mitigation strategies for CanL including vaccination and other prophylactic measures. The following search strategy in CAB Direct was used: abstract:(dog OR dogs OR canis OR canid OR canids OR canidae OR canine) OR title:(dog OR dogs OR canis OR canid OR canids OR canidae OR canine) OR subject:(dog OR canidae) AND title:(Leishmania OR leishmaniosis OR leishmaniasis) OR ab:(Leishmania OR leishmaniosis OR leishmaniasis) OR subject:(Leishmania OR leishmaniosis) AND title:(control OR preventive OR preventative OR prophylactic OR prophylaxis OR prevention OR insecticide OR insecticides OR vaccine OR vaccines OR vaccination OR spot-on OR spot-ons OR collar OR collars OR immune stimulant OR immune stimulants) OR ab:(control OR preventive OR preventative OR prophylactic OR prophylaxis OR prevention OR insecticide OR insecticides OR vaccine OR vaccines OR vaccination OR spot-on OR spot-ons OR collar OR collars OR immune stimulant OR immune stimulants) OR subject:(insecticides OR “insect repellents” OR vaccination)

Similar search strategies were constructed for WOS, MEDLINE and LILACS. Dates were restricted from 1980 to November 2012, and only publications in English, Italian, Portuguese, French or Spanish were included. Eight sets of conference proceedings (1st–4th World Leishmaniasis Congress [WorldLeish], 1st and 2nd International Canine Leishmaniasis Forum, 1st and 2nd Italian Companion Animal Veterinary Association International Congress of Canine Leishmaniasis) and the International Veterinary Information Service (IVIS) database were also checked. Review of the IVIS database was estimated to provide coverage of nearly all international conferences but may have omitted smaller regional proceedings. The reference lists of studies and review articles were checked. Study authors were not contacted for additional information. No further grey literature was searched due to the limited time and resources available for the current review. 2.3. Study inclusion criteria and relevance screening Randomised controlled trials (RCTs), non-randomised clinical trials (NRCTs), cohort studies and case-control studies that investigated prophylactic control measures for naturally-occurring L. infantum infection on parasite load, humoral (serology) or cellular immunity, infectivity, death, clinical disease and/or adverse effects in dogs were eligible for inclusion. Studies that included dogs susceptible to naturallyoccurring L. infantum infection but non-infected at the start of the study were eligible for inclusion. Serology must have been undertaken as a minimum technique to establish noninfection. Any vaccinations used for the prevention of L. infantum infection were eligible, including experimental data, if they were compared to placebo or control intervention.

Please cite this article in press as: Wylie, C.E., et al., A systematic review of the efficacy of prophylactic control measures for naturally-occurring canine leishmaniosis, part I: Vaccinations. PREVET (2014), http://dx.doi.org/10.1016/j.prevetmed.2014.06.015

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Two reviewers (C.E.W. and M.C.-A.) independently assessed each reference identified by the search to check its eligibility against the selection criteria defined a priori. There was good agreement between the review authors following discussion and it was therefore not necessary to consult a third review author to obtain consensus. Those references which appeared to meet the inclusion criteria were retrieved in full and further assessed independently by the same two reviewers. At this stage a third reviewer (L.S.-G.) was consulted to resolve difference of opinion on whether two studies should be included. 2.4. Methodological assessment and data extraction Data extraction was carried out by two reviewers (C.E.W. and M.C.-A.) independently using pre-specified forms (available from the author on request) modified for each study design, regarding study characteristics, population characteristics, pre-trial diagnostics, intervention/comparator, outcomes and interim results with DistillerSR (DistillerSR, Evidence Partners, Ottawa, Canada). No attempts were made to contact the study authors if data were incomplete. Data from studies published in duplicate were included only once. Where studies were available in full paper and abstract form, the full paper version was chosen. All discrepancies were resolved by discussion. Two reviewers (C.E.W. and M.C.-A.) independently assessed the methodological quality of the eligible studies. All discrepancies were resolved by discussion. Assessment was based on the guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins and Green, 2008) and included the following domains: assessment of the methods of randomisation and allocation concealment, level of blinding, presence of incomplete data, selective reporting, study duration (12 months or greater to allow investigation of a complete transmission season and for the potential subsequent development of infection), acknowledgement of financial support and other sources of methodological shortcomings. This was the only assessment tool used as only RCT and NRCT study designs were identified (available from the author on request). Each study was classified as high, unclear or low methodological quality such that if one domain was not met the trial was considered a high risk of methodological shortcomings, and if one domain was unclear the trial was considered to have an unclear risk of methodological shortcomings. 2.5. Data analysis and summary measures For categorical outcome measures the odds ratio (OR) using Haldane’s continuity correction, absolute risk reduction (ARR) and their corresponding 95% confidence interval (95% CI) using an asymptotic normal approximation were calculated for each measure (Agresti, 2007). The baseline for all ORs was the outcome measure in the controls, i.e. OR > 1 signified that the intervention had a lesser protective effect than the control, with the exception of the cellular immunity tests for which immunity was protective. For continuous data the mean difference and the standard error (SE) were calculated for both groups. Study authors

were not contacted to obtain missing data due to time constraints. Pooling of the results using meta-analysis was prespecified in a pre-review protocol if the included studies were considered to be sufficiently comparable. It was prespecified that results from RCT and NRCT studies would not be pooled, and that meta-analysis would not be undertaken on studies considered to have a high risk of methodological shortcomings. Potential sources of clinical heterogeneity were considered to be dog characteristics, intervention characteristics, diagnostic methods of infection prior to, and after to the intervention. Sensitivity analysis was planned to compare only the diagnoses prior to intervention made on the basis of serology, only studies of suitable duration (at least one year of follow-up to allow for examination of the transmission season) and those considered to have a low risk of methodological shortcomings. 3. Results 3.1. Study selection and characteristics The search resulted in 937 publications for all mitigation strategies including vaccination, topically applied insecticide treatments and prophylactic medications. After assessing for relevance of titles and abstracts, 84 potentially relevant studies were retrieved in full text. Twenty-three studies were included and 61 were excluded (Fig. 1), of which 12 studies on vaccination are summarised in this paper. The remaining eleven papers contained information on topically applied insecticides and prophylactic medications and are summarised in Wylie et al. (2014). Sixty-one studies were excluded for the following reasons: • Six studies were not primary research studies • 17 studies were part of another study written up in full elsewhere • One study did not include a domestic dog species • One study did not assess leishmaniosis • Two studies did not assess L. infantum infection • Four studies were not on naturally occurring disease • 14 studies were neither RCTs, NRCTs, or observational analytic epidemiologic studies • Five studies did not include a definitive diagnosis as defined in the methods above • Six studies did not contain information on preventive control interventions • Six studies did not provide results regarding the efficacy of the interventions to provide data for the outcomes of this review Five of the identified studies were RCTs and seven were NRCTs. No observational case-control or cohort studies were identified. Each of the included studies was published in English. Baseline characteristics of the enrolled dogs were reported to some extent for each of the studies. Clear presentation of statistical comparison of intervention groups with respect to signalment and baseline disease characteristics pre-treatment were rarely reported. Pooling

Please cite this article in press as: Wylie, C.E., et al., A systematic review of the efficacy of prophylactic control measures for naturally-occurring canine leishmaniosis, part I: Vaccinations. PREVET (2014), http://dx.doi.org/10.1016/j.prevetmed.2014.06.015

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Fig. 1. Flow chart illustrating the results of the selection process of the studies modified from Moher et al. (2009).

of outcome data from multiple studies investigating similar treatment interventions was not possible owing to the large differences in study designs and reported outcome measures. A number of different vaccines were evaluated. Selected characteristics from different vaccines studies are listed in Table 1. Three NRCTs in Brazil examined Leishmune® vaccine; Study H was a 12 month evaluation of the PCR status of pet dogs in comparison to untreated controls. Study B was a 24 month study evaluating clinical illness in an uncharacterized population of dogs in comparison to controls treated with sterile saline. Study K was a 12 month comparison to BCG in adult pet dogs examined by PCR, cytology and ELISA serology. Study F(a) and F(b) examined multi-subunit recombinant Leishmania polyprotein (MML) and monophosphoryl lipid A stable emulsion (MPL) vaccine using two different adjuvants, monophosphoryl lipid A-stable oil-in-water emulsion (MPL-SE) and Adjuprime respectively. Each of the other studies examined unique

vaccine types as described: Study C was a 24-month NRCT of fucose mannose ligand (FML) vaccine. Study J examined an autoclaved Leishmania major (ALM) vaccine through a 16-month RCT. Study L was a NRCT of CaniLeish® . Study G was a 24-month RCT of LiESAp and MDP vaccine. Study I(a) and (b) examined autoclaved L. infantum (ALi) and Bacille Calmette-Guéri (BCG) vaccine and ALM and BCG respectively through a 12 month RCT. Study A was a 41-month long NRCT of FML and Quillaja saponaria Molina saponin (QuilA). Study D examined lyophilized protein through a 24-month long RCT. Finally, Study E was an 18-month RCT of Leishvacin. 3.1.1. Primary outcome Eleven studies reported data on the proportion of dogs infected with L. infantum based on serology or parasite detection; with two studies reporting data on two interventions (Table 2). There was a statistically significant protective effect in six of the studies (OR range 0.02–0.35,

Please cite this article in press as: Wylie, C.E., et al., A systematic review of the efficacy of prophylactic control measures for naturally-occurring canine leishmaniosis, part I: Vaccinations. PREVET (2014), http://dx.doi.org/10.1016/j.prevetmed.2014.06.015

Type

Age

Gender

Housing

Breed

Intervention

Dose of treatment

Diagnostic method

Diagnostic method

Study A

BorjaCabrera et al. (2002)

Brazil

Pets only

Missing

Missing

Missing

Missing

FML with QuilA

Missing

Serology and PE

Study B

BorjaCabrera et al. (2008) da Silva et al. (2000)

Brazil

Missing

Missing

Missing

Missing

Missing

Leishmune®

Missing

Serology and PE

Serology, PE, parasite detection and cellular immunity PE only

Brazil

Pets only

≥4 months old

Mixed

97.5% mongrels

FML

Serology, PE, parasite detection and cellular immunity

France

Pets only

≥8 months

Missing

Missing

Lyophilized protein

1.5 mg lyophilized FML antigen reconstituted in 1 ml NaCl 0.9% sterile saline solution Missing

Serology and PE

Dunan et al. (1989) Genaro et al. (1996)

Not specified, however ‘domestic dogs’ so probably a combination of homes and outdoors Missing

Serology and PE

Brazil

Missing

>6 months

Missing

Missing

Missing

Leishvacin

Serology, PE and parasite detection Serology, PE and parasite detection

Study F(a)

Gradoni et al. (2005)

Italy

Experimental dogs

Missing

Mixed

Kennels

Beagle

MML with MPL

Study F(b)

Gradoni et al. (2005)

Italy

Experimental dogs

Missing

Mixed

Kennels

Beagle

MML with Adjuprime

45 g/dose MML plus 1 mg/dose Adjuprime

Serology only

Study G

Lemesre et al. (2007)

France

Hunting dogs, some guard dogs, dogs from breeding facilities

Adults and puppies <6 months

Mixed

Outdoors

Missing

LiESAp with MDP

Missing

Serology, PE and parasite detection

Study C

Study D

Study E

First dose 600 ␮g protein and 500 ␮g BCG, 2nd/3rd/annual doses 600 ␮g protein and 100 ␮g BCG 45 g/dose MML plus 50 g/dose MPL-SE

Serology only

Serology only

Serology, laboratory testing, parasite detection and cellular immunity Serology, laboratory testing, parasite detection and cellular immunity Serology, PE and parasite detection

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Please cite this article in press as: Wylie, C.E., et al., A systematic review of the efficacy of prophylactic control measures for naturally-occurring canine leishmaniosis, part I: Vaccinations. PREVET (2014), http://dx.doi.org/10.1016/j.prevetmed.2014.06.015

Table 1 The signalment characteristics for studies on vaccination.

Country

Type

Age

Gender

Housing

Breed

Intervention

Dose of treatment

Diagnostic method

Diagnostic method

Study H

Lima et al. (2010)

Brazil

Pets only

Missing

Mixed

Missing

Leishmune®

Missing

Serology, PE and parasite detection

Parasite detection only

Study I(a)

Mohebali et al. (1999)

Iran

Pets only

Missing

Missing

Missing

ALi with BCG

1 mg ALi protein and 400 ␮g BCG, autoclaved 1 mg protein promastigotes of L. infantum

Serology only

Serology only

Study I(b)

Mohebali et al. (1999)

Iran

Pets only

Missing

Missing

Missing

ALM with BCG

1 mg ALM protein and 400 ␮g BCG, promastigotes of L. major

Serology only

Serology only

Study J

Mohebali et al. (2004)

Iran

Pets only

>3 months

Mixed

Missing

ALM

200 ␮g protein

Serology, PE and Leishmanin Skin Test in 18% of dogs

Serology and PE

Study K

Nogueira et al. (2005)

Brazil

Pets only

Adult

Missing

Missing

Leishmune®

Missing

Serology and PE

Serology, PE and parasite detection

Study L

Oliva et al. (2012)

Italy and Spain

Missing

Missing

Missing

Not specified, however ‘owned’ so probably combination of homes and outdoors Not specified, however ‘domestic dogs’ so probably combination of homes and outdoors Not specified, however ‘domestic dogs’ so probably combination of homes and outdoors Not specified, however ‘owned’ so probably combination of homes and outdoors Not specified, however owned dogs, ‘co-habitated in the same residence’ Kennels

Missing

CaniLeish®

Missing

Missing

Serology, PE, laboratory testing and parasite detection

(a) PE = physical examination; (b) FML = fucose mannose ligand; (c) QuilA = Quillaja saponaria Molina saponin; (d) NaCl = sodium chloride; (e) MML = multi-subunit recombinant Leishmania polyprotein; (f) MPL = monophosphoryl lipid A stable emulsion; (g) BCG = Bacille Calmette-Guéri; (h) LiESAp = culture supernatant of Leishmania infantum promastigotes; (i) ALi = Autoclaved Leishmania infantum; (j) ALM = Autoclaved Leishmania major.

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Study

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Please cite this article in press as: Wylie, C.E., et al., A systematic review of the efficacy of prophylactic control measures for naturally-occurring canine leishmaniosis, part I: Vaccinations. PREVET (2014), http://dx.doi.org/10.1016/j.prevetmed.2014.06.015

Table 1 (Continued)

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Table 2 Measures of effect for the proportion of dogs infected with L. infantum based on serology or parasite detection for vaccinations. Study

Intervention Number of positive Leishmania findings

FML with QuilA (Study A) FML (Study C) Lyophilized protein (Study D) Leishvacin (Study E) MML with MPL (Study Fa) MML with Adjuprime (Study Fb) LiESAp with MDP (Study G) Leishmune® (Study H) ALi with BCG (Study Ia) ALM with BCG (Study Ib) ALM (Study J) Leishmune® (Study K) CaniLeish® (Study L)

Control Number of negative Leishmania findings

Number of positive Leishmania findings

Measures of effect Number of negative Leishmania findings

Odds ratio and 95% CI

Absolute risk reduction and 95% CI

−0.001 (−0.09, −0.09)

44

0

41

0

58

0

40

19

31

138

11

157

3.21 (1.55, 6.62)

−0.12 (−0.19, −0.05)

5

546

4

582

1.33 (0.36, 4.99)

−0.002 (−0.02, 0.01)

13

2

14

0

0.19 (0.01, 4.24)

0.13 (−0.06, 0.29)

10

0

14

0

0.72 (0.01, 39.52)

0.01 (−0.21, 0.29)

1

164

12

163

0.08 (0.01, 0.64)

0.06 (0.02, 0.11)

0

20

9

11

0.03 (0.002, 0.56)

0.43 (0.18, 0.63)

7

15

4

3

0.35 (0.06, 2.00)

0.25 (−0.13, 0.57)

7

16

37

30

0.35 (0.13, 0.97)

0.25 (0.01, 0.43)

6

156

17

124

0.28 (0.11, 0.73)

0.08 (0.02, 0.15)

0

18

17

13

0.02 (0.001, 0.38)

0.54 (0.29, 0.70)

5

36

13

28

0.30 (0.10, 0.94)

0.20 (0.02, 0.36)

ARR range 0.06–0.54), based on DAT serology for ALM vaccine (Study J), ELISA serology for ALM with BCG vaccine (Study I(b)), a case definition of ‘active infection, defined as no clinicopathological signs, positive bone marrow or lymph node PCR and culture’ for CaniLeish® (Study L), combined culture and bone marrow PCR for LiESAp with MDP vaccine (Study G), evidence of parasite DNA for Leishmune® (Study H) and lymph node PCR results for Leishmune® (Study K). There was a statistically significant non-protective effect for Study D on lyophilized protein based on a case definition of ‘a positive antibody test plus parasitological confirmation, or two or more sequential IFA tests showing a rise in antibody titres’. For Study C, there was a 100% positive reaction observed for the intervention group by FML ELISA. The remaining five studies did not detect statistically significant differences between interventions based on ELISA serology for ALi with BCG vaccine (Study I(a)), Leishvacin based on IFAT and ELISA serology (Study E), both studies on MML with MPL/Adjuprime which defined infection as sub-patent, asymptomatic and symptomatic based on bone marrow PCR and/or IFAT serology (Studies F(a) and F(b)), and for Study A reporting a 100% positive reaction in the intervention group based on FML ELISA. Study K found the largest significant ARR (for every 100 dogs given Leishmune® , 54 cases of infection with L. infantum based on serology or parasite detection would be averted), followed by Study H (ARR 0.43) for ALM with BCG vaccine, and Study L (ARR 0.20) for CaniLeish® vaccination.

1.07 (0.02, 55.28) 56.33 (3.31, 959.92)

−0.32 (−0.45, −0.2)

Both Studies G and K reported an ARR of 0.06 and 0.08 due to vaccination with LiESAp with MDP and ALM vaccine respectively. Study D found 12 more cases per 100 dogs would occur in the intervention group in dogs given lyophilized protein compared to the control solution, while Study C found 32 more cases per 100 dogs would occur in the intervention group given FML vaccine. 3.1.2. Secondary outcomes Seven studies reported data on the proportion of dogs infected with L. infantum based on parasite detection; with one study reporting data on two interventions. Data were replicated from the primary outcome for three of the studies as described above (Studies F(a) and F(b) and H), with new data available from five studies. There was a statistically significant protective effect for vaccination for the proportion of dogs infected with L. infantum based on parasite detection only, for two of the studies (OR range 0.05–0.37, ARR range 0.23–0.24), based on bone marrow and/or lymph node PCR for CaniLeish® (Study L) and immunohistochemistry for Leishmune® (Nogueira et al., 2005). There was a statistically significant non-protective effect for one study on lyophilized protein (Study D). The results of the PCR for FML vaccine conducted on oligosymptomatic dogs (Study C) and for the LiESAp and MDP vaccine (Study G) were non-significant. Six studies reported data on the proportion of dogs infected with L. infantum based on PCR detection; with one study reporting data on two interventions. Data were replicated from the primary outcome for three of the studies

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(Studies F(a) and F(b) and H), and from the overall parasite detection result for two studies (Studies C and G). New data were available from two studies. A statistically significant protective effect for vaccination for the proportion of dogs infected with L. infantum based on PCR detection only was identified for combined bone marrow and lymph node PCR for CaniLeish® (Study L) and combined blood and lymph node PCR for Leishmune® (Study K). No studies measured quantitative PCR. Nine studies reported data on the proportion of dogs infected with L. infantum based on serological detection; with two studies reporting data on two interventions. Data were replicated from the primary outcome for five of the studies. It was possible to generate OR for each of the six new results, and ARR for five (due to equal proportions of positive and negative findings in both the intervention and comparator groups in one study). There were two statistically significant results, Study J found a statistically significant protective effect for vaccination for the proportion of dogs infected with L. infantum based on serological detection only using ELISA for ALM vaccine, while Study D found a non-protective effect for lyophilized protein based on IFAT serology. Study K reported new data on the FML ELISA results, while the other non-significant results were from IFAT testing for MML with MPL and Adjuprime vaccines (Studies F(a) and F(b) respectively), and for LiESAp with MDP (Study G). Three studies reported data on quantitative serology. Two studies had a higher reading in the intervention group where the mean serological difference and SE of optical density (OD) were 0.636 ± 0.22 (Study C) and 0.380 ± 0.13 (Study A). One study had a higher reading in the control group where the mean serological difference and SE were 0.394 ± 0.14 (Study G). Two studies reported data on the proportion of dogs infected with L. infantum based on cellular immunity tests. There was a statistically significant protective effect for vaccination for the proportion of dogs infected with L. infantum based on cellular immunity tests for both FML (Study C) and FML with QuilA (Study A). Two studies reported data on the size of the Delayed Type Hypersensitivity reaction. Both studies had a higher reading in the intervention group where the mean difference and SE of diameter of induration in cm was 4.118 ± 1.46 (Study C) and 8.750 ± 3.09 (Study A) respectively. Four studies reported data on the proportion of dogs that died and were infected with L. infantum; with one study reporting data on two interventions. There were statistically significant protective effects for vaccination for the proportion of dogs dying infected with L. infantum, for Leishmune® (Study B) and FML with QuilA (Study A). The ORs ranged from 0.01 to 0.10 and the ARR ranged from 0.17 to 0.27. The results for FML (Study C), MML with MPL (Study F(a)) and MML with Adjuprime (Study F(b)) were not statistically significant. Six studies reported data on the proportion of clinically ill dogs infected with L. infantum; with one study reporting data on two interventions. There was a statistically significant protective effect for vaccination for the proportion of clinically ill dogs infected with L. infantum for FML with

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QuilA (Study A) and for Leishmune® (Study K). There was no statistically significant difference for the remaining five studies. Four studies reported data on adverse effects. Studies F(a) and F(b) reported no adverse side effects; Study J reported that local reactions occurred, including ulcers in 64.51% of dogs, and papules in 4.0% of dogs, while Study D reported signs of anorexia, non-lethal generalized anaphylactic reaction and hypersomnia.

3.2. Methodological assessment None of the studies was considered to be at an overall low risk of methodological shortcomings. Studies E and J were considered to be at an unclear risk. In general, studies had a high risk of methodological shortcomings for the generation of the randomisation sequence, allocation concealment and other potential sources of methodological shortcomings. Of the 12 included studies, only Studies D and E adequately reported the method used to generate the allocation sequence. The remainder of the studies stated they performed randomisation but did not specify the methodology used, undertook NRCTs and did not randomize subjects, or failed to mention randomization in their report. None of the RCT studies adequately reported allocation concealment or were NRCT designs. Six studies reported adequate blinding (Studies A, D, E, F, G and J). One study did not report sufficient information for judgement (Study L), while the others did not undertake adequate blinding. Studies G, I and K reported if there were any subjects lost to follow-up. Studies A, B and F failed to report complete outcome data, and the other studies did not provide sufficient information to assess this. No studies were judged to be free from methodological shortcomings for selective reporting. Study D was judged to be at a high risk of methodological shortcomings as it stated it would carry out DTH skin reaction tests but did not report results of this testing. Eleven studies were considered to be of adequate study duration (12 months or greater), while Study K evaluated outcomes at 11 months post-intervention, and was therefore considered inadequate. Seven studies clearly reported financial support. Studies B, F and K reported commercial financial support but it was judged unclear whether this had affected the results, while Studies I and L failed to report financial support. Study D was considered free from other potential methodological shortcomings. Five studies failed to provide sufficient information to judge this (Studies E, F, H, J and K), while the remainder were considered to have other shortcomings. Study C had a lack of baseline data on dog characteristics and the vaccine product and the repeated leishmanin doses were likely to have interfered with the serological response. Study L did not explain the term ‘naive dogs’, and it was unclear whether there was baseline imbalance between the two locations used to recruit animals. Study B recruited 600 healthy dogs from

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towns where canine visceral leishmaniosis was endemic and reported previous negative results in Leishmania serology by IFA. For ethical reasons, veterinarians were not able to keep an untreated and exposed control dog population. For comparison, 588 asymptomatic FML-seronegative dogs from another endemic area were included as the exposed untreated group. Study G included healthy seronegative dogs in the study, even though 13 were PCR positive at bone marrow examination. Study I had very small numbers in control group one (only seven dogs), and the results reported in the text and tables were inconsistent. Study A non-randomly allocated an equivalent number of control and vaccinated dogs in the prevalent and non-prevalent quarters of their study location, as they argued that the probability of obtaining balanced groups through randomization of a necessarily small number of communities was unlikely to be high. 4. Discussion The primary outcome was the proportion of dogs infected with L. infantum based on either serology or parasite detection. Six studies had a significant protective effect for this outcome; two studies on Leishmune® (Studies H and K), 200 ␮g ALM protein (Study J), CaniLeish® (Study L), LiESAp with MDP (Study G) and ALM with BCG (Study I(b)). Two studies had significant non-protective effects for this outcome, one on FML (Study C) and one using lyophilized protein (Study D). Studies A and C reported data on the FML ELISA results for the FML and FML-QuilA vaccines respectively, resulting in a 100% positive reaction observed for the intervention group. It is interesting to note an apparent lack of evidence of efficacy for the Brazilian commercial licensed Leish-Tec® vaccine, a recombinant A2-antigen of Leishmania amastigotes adjuvanted by saponin vaccine. Evidence concerning all vaccines reviewed was poor due to the risk of methodological shortcomings in existing studies. An a priori sample size was not calculated for most studies and the lack of statistical power limits the adequate evaluation of efficacy of control measures for CanL. While the study protocol allowed for the inclusion of case-control and cohort study designs, none were identified in the final screening. The inclusion of NRCTs as well as RCTs will have affected the overall risk of methodological shortcomings, as the scoring system was heavily biased towards goldstandard RCTs, which provide the best level of evidence. Odds ratios in NRCTs may be biased as the treatments were not allocated at random; however it is considered unlikely that the qualitative assessment of the study findings will be affected (Davies et al., 1998). Several aspects of the review process may have led to inherent bias in the selection and assessment of the reviewed studies. Significant variability in the diagnostic processes between studies may have led to heterogeneity of the clinical status within the enrolled population, potentially influencing the response of dogs to the interventions. The range of study publication dates may have influenced the reliability of the diagnosis, as advancement of serological and parasitological methods of diagnoses have advanced since the earliest publication. Various

signalments of dog were represented in the studies, which reported baseline characteristics and these differences may have been potential sources of variability in the treatment responses. Serological assessment of vaccine efficacy may have affected the results of this study. Some of the available vaccines (such as FML) elicit a humoral response that, with available current methods, cannot be differentiated between active infection and vaccination, whereas other vaccines (such as LiESAp) do not. Due to recently published evidence regarding newly available interventions, such as the first licensed European vaccine (CaniLeish® ), the current review included published abstracts and fullpapers. It was difficult to assess the risk of methodological shortcomings using the limited data provided in abstracts. More robust review of interventions that are to date only published in abstract form will hopefully be available in the near future. It was not possible to request further information from publication authors, which may have improved the assessment of each of the criteria. Furthermore, trial protocols were not sought to aid the assessment of selective reporting, and studies were only included if they could be readily translated into languages spoken by members of the group. This could be considered for future reviews. Substantial within-study variations in baseline characteristics of the dogs involved, such as age, breed and gender, were observed. Furthermore, large differences were also observed between study designs (e.g. occurring with different incidences in different regions) and several potential methodological shortcomings were identified. Therefore, pooling of the estimates using meta-analysis was not pursued. Two previous systematic reviews regarding CanL have been published (Noli and Auxilia, 2005; Romero and Boelaert, 2010). Noli and Auxilia (2005) aimed to identify evidence of efficacy of interventions to treat or prevent CanL. They identified three field trials investigating the preventive effect of repellent collars or spot-ons (Maroli et al., 2001; Gavgani et al., 2002; Giffoni et al., 2002). Romero and Boelaert (2010) undertook a review of the effectiveness of novel visceral leishmaniasis control tools and strategies in Latin America. They identified 14 trials, of which only two were identified in this review (da Silva et al., 2000; Giffoni et al., 2002), as they considered culling an acceptable control measure, evaluated the effect of repellent interventions on sand fly populations and human incidence as outcome measures, which the present review did not. Romero and Boelaert (2010) did not undertake risk of methodological shortcomings assessment or meta-analysis. The present review offers a Cochrane standard risk of methodological shortcomings assessment and a more recent search.

5. Conclusion There are studies to support the use of vaccination to prevent L. infantum infection, in particular vaccination with 200 ␮g ALM protein, Leishmune® , CaniLeish® , LiESAp with MDP, and ALM with BCG. However, the methodological shortcomings with the publications on these interventions needs to be considered.

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Declaration The authors Sofie Dhollander and Elisa Aiassa are employed with the European Food Safety Authority (EFSA). The present article is published under the sole responsibility of the authors and may not be considered as an EFSA scientific output. To know about the views or scientific outputs of EFSA, please consult its website under http://www.efsa.europa.eu. Conflicts of interest The authors declare they have no conflicts of interest. Acknowledgements This study was financed by EFSA (CFT/EFSA/AHAW/ 2012/02). The authors are grateful to Dr. Gioia Capelli, Prof. Maria Grazia Pennisi, Prof. Gaetano Oliva, Prof. Gad Baneth, Prof. Ozbel, Prof. Domenico Otranto and Dr. Filipe Dantas-Torres for providing references used in this study. The authors would like to thank Mrs Madeleine Mattin, Dr. Solenne Costard and Dr. Luis Espejo for their helpful feedback throughout the project. Dr. Laia Solano-Gallego held a Ramón y Cajal senior researcher contract awarded by the Spanish Ministerio de Economia y Competitividad and the European Social Fund. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. prevetmed.2014.06.015. References Agresti, A. (Ed.), 2007. An Introduction to Categorical Data Analysis. John Wiley & Sons Inc., United States of America. Baneth, G., Koutinas, A.F., Solano-Gallego, L., Bourdeau, P., Ferrer, L., 2008. Canine leishmaniosis – new concepts and insights on an expanding zoonosis: part one. Trends Parasitol. 24, 324–330. Berrahal, F., Mary, C., Roze, M., Berenger, A., Escoffier, K., Lamouroux, D., Dunan, S., 1996. Canine leishmaniasis: identification of asymptomatic carriers by polymerase chain reaction and immunoblotting. Am. J. Trop. Med. Hyg. 55, 273–277. Borja-Cabrera, G.P., Pontes, N.N.C., Silva, V.O.d., Souza, E.P.d., Santos, W.R., Gomes, E.M., Luz, K.G., Palatnik, M., Sousa, C.B.P.d., 2002. Long lasting protection against canine kala-azar using the FML-QuilA saponin vaccine in an endemic area of Brazil (São Gonc¸alo do Amarante, RN). Vaccine 20, 3277–3284. Borja-Cabrera, G.P., Santos, F.N., Bauer, F.S., Parra, L.E., Menz, I., Morgado, A.A., Soares, I.S., Batista, L.M.M., Palatnik-de-Sousa, C.B., 2008. Immunogenicity assay of the Leishmune® vaccine against canine visceral leishmaniasis in Brazil. Vaccine 26, 4991–4997. Cabral, M., O’Grady, J.E., Gomes, S., Sousa, J.C., Thompson, H., Alexander, J., 1998. The immunology of canine leishmaniosis: strong evidence for a developing disease spectrum from asymptomatic dogs. Vet. Parasitol. 76, 173–180. Cardoso, L., Neto, F., Sousa, J.C., Rodrigues, M., Cabral, M., 1998. Use of a leishmanin skin test in the detection of canine Leishmania-specific cellular immunity. Vet. Parasitol. 79, 213–220. da Silva, V.O., Borja-Cabrera, G.P., Correia Pontes, N.N., de Souza, E.P., Luz, K.G., Palatnik, M., Palatnik de Sousa, C.B., 2000. A phase III trial of efficacy of the FML-vaccine against canine kala-azar in an endemic area of Brazil (Sao Goncalo do Amaranto, RN). Vaccine 19, 1082–1092. Dantas-Torres, F., 2006. Leishmania infantum versus Leishmania chagasi: do not forget the law of priority. Mem. Inst. Oswaldo Cruz 101, 117–118, discussion 118.

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