1. Introduction
The principle of antimicrobial vaccines is to increase immunity against a specific infectious agent so when the individual is challenged by that agent the appropriate immune response is mounted rapidly and efficiently. Vaccines for infectious agents have historically developed from whole live or dead microorganisms to more defined native or recombinant pure fractions, following antigen-coding DNA and the latest approaches of antigen-pulsed dendritic cells. Although bacterial and viral infections have a quite long list of effective vaccines, parasitic infections – from worms to protozoa – have been a hard challenge for researchers to be able to develop proper vaccines. Currently, the most advanced anti-parasitic vaccine is the RTS,S/AS01 for malaria with a protection that covers 30-40% [1]. Despite several attempts during seven decades of research with some promising approaches, so far there is no vaccine available for human leishmaniasis and the options available for veterinary use have zone-restricted market authorization, being inaccessible to many endemic countries.
Traditionally, live vaccines incorporate attenuated strains that after entering the host cause a non-pathological short-lived infection, being rapidly controlled by the innate and adaptive immune systems. In few words, the microorganism is taken up and processed by antigen presenting cells (APCs) that efficiently expose the microbial antigens
In this chapter we address some general aspects of the epidemiology of human and canine leishmaniasis to introduce the needs for a vaccine and the desirable immune response to be generated upon vaccination. We present the animal models most commonly used in leishmaniasis vaccine research, the road so far travelled by the scientific community attempting to discover the vaccine for leishmaniasis and its current status. Finally, we show our experimental study in BALB/c mice about the influence of a primary infection of
1.1. Human leishmaniasis
Leishmaniasis is endemic in 98 countries and 3 territories ranging the Mediterranean Basin, the Middle East, the Indian sub-continent, and the tropical regions from America and Africa [4]. The last WHO report on the epidemiology of leishmaniasis estimates that every year 0.7 to 1.2 million new cases of cutaneous leishmaniasis (CL) are mounted and 0.2 to 0.4 million people develop visceral leishmaniasis (VL) which, in turn, is responsible for 20000 to 40000 deaths [4]. Nevertheless, in endemic countries most of the
The relation of leishmaniasis with poverty catalogues it as a neglected tropical disease. In fact, 72 of the endemic countries are developing nations with a burden of 90% of the VL, CL and mucocutaneous leishmaniasis (MCL) [7]. In these regions, the majority of the population lives in rural areas, where higher densities of sand flies are found, and is malnourished, a condition that leads to immunosuppression. In addition, HIV concomitant infection is frequent, contributing to a severe state of immunodeficiency [8]. The close geographical overlap of
The progression of a
Both in mice as in humans, macrophages are classically activated by IFNγ. This leads to the transcription of inducible nitric oxide synthase (iNOS) and phagocyte NADPH oxidase (phox) that produce nitric oxide (NO) and reactive oxygen species, respectively, specimens generally considered indispensable for macrophage-direct killing of
Effector CD4+ and CD8+ T cells that were activated by the recognition of
Memory cells were demonstrated to have great importance in the control of leishmaniasis, with distinct roles described for TCM and TEM cells. Zaph
Nevertheless, concomitant immunity,
1.2. Canine leishmaniasis
Dogs are primary reservoir hosts of zoonotic visceral leishmaniasis (ZVL) caused by
The high prevalence of infected dogs in endemic areas, their common presence in the domestic surroundings where ZVL transmission occurs, and the high infectiousness of both symptomatic and asymptomatic animals makes that
The outcome of
The natural history of canine leishmaniasis mostly depends on the efficacy of the dog´s immune response to
Different attempts have been made to confirm a correlation between the classes and subclasses of immunoglobulins and the type of response against
It is important to remark that the lack of
2. Vaccine research for leishmaniasis
The ideal vaccine for leishmaniasis should be safe, effective, long lasting, transversal to all infective
2.1. Animal models for vaccine research for leishmaniasis
Much of the knowledge generated from leishmaniasis research come from experimental infections in animal models. Differently from human population and natural infections, the most common models of disease employed in leishmaniasis research are based on infection of inbred mice with cloned lines of parasites. These experimental settings reduce the variety of factors that play a role on the disease manifestation, such as host’s genetic background and immune competence, concomitant infections with other microorganisms, autoimmune or inflammatory diseases or drug treatments that may affect the fitness of the immune system, diversity of parasite’s strains and species, site of infection and inoculum dose, infecting sand fly’s species, etc. However, in comparison to the natural transmission and disease, the same limitations are also the major advantages, as in laboratorial settings researchers control all those variables and are able to focus on their specific target to unravel the molecular and immunological mechanisms behind leishmaniasis.
Many models of leishmaniasis have been tested, although none is able to mimic the exact pathology of cutaneous and, principally, visceral human diseases, or to develop the same immune responses. Despite valuable information has come from animal models, careful generalizations must be done when transposing it to the human disease.
The animal species applied on studies of human CL is almost exclusively the mouse (
Considering animal models for VL, golden hamsters (
The use of dogs (
Non-human primates are usually confined to pre-clinical trials in humans. Some models based on artificial inoculation of rhesus macaques (
2.2. Leishmanization
Until date, the only successful, long-lasting strategy for human immunization against leishmaniasis is the leishmanization process. It consists on the inoculation of live virulent parasites in a hidden area of the skin of healthy people with the purpose of development of immunity for protection when the individuals are challenged by a natural infection. Leishmanization showed 100% protection when used as prophylaxis for cutaneous leishmaniasis (CL) throughout the ex-Soviet Union, Asia, and the Middle East [45]. Due to risk of complications in healthy people and difficult standardization of the live
A “natural” form of leishmanization may be the reason why in Sri Lanka so many cases of CL by
2.3. First generation vaccines
First generation vaccines comprise whole killed parasites and live attenuated parasites. They were primarily developed to overcome one of the major concerns related to leishmanization: the risk of disease development in immunocompetent persons and the total improperness for immunosuppressed patients for this same reason.
2.3.1. Killed parasites
With more or less success, some examples of killed vaccines include
2.3.2. Live attenuated parasites
For the live attenuated parasites many are the works reported whether using physical, chemical or genetic manipulation for reducing the virulence of the strains, or even naturally attenuated strains, like the non-pathogenic
2.4. Second generation vaccines
A different approach relies on recombinant proteins, polyproteins, DNA vaccines, liposomal formulations and dendritic cell vaccine delivery systems [45]; these constitute the second generation vaccines.
2.4.1. Purified or recombinant Leishmania antigens and engineered polyproteins
The
Concerning the recombinant polyproteins, rLeish-111f (or LEISH-F1, composed of three molecules fused in tandem: the
Another polyprotein named Protein Q, composed of the fusion of four fragments of the acidic ribosomal protein Lip2a, Lip2b, P0 and histone 2A, has shown 90% protection as measured by parasite clearance in vaccinated dogs using BCG as adjuvant [79]. After testing other adjuvants in mice, 99% protection was achieved against
2.4.2. DNA vaccines
DNA vaccines are able to activate both CD4+ and CD8+ T cells through the engagement of MHC class II and MHC class I, respectively [38]. In addition, co-administration of cytokines and CpG oligonucleotides allows the modulation of the cellular immune response [81]. Besides being relatively easy to prepare and stable, another unique advantage is the appropriate folding of the intracellularly synthetized peptide on its native structure [38].
The first DNA vaccines to be studied were the classical candidates that have been tested as proteins. As single plasmids or in multicomponent DNA vaccines, there are successful examples that have shown to protect from some
2.4.3. Dendritic cell vaccine and liposomal formulations delivery systems
The unique capacity of DCs in amplifying the innate defense mechanisms and providing the link between these and the acquired immune responses makes them ideal candidates for anti-
On another approach, the concept behind the use of liposomes to deliver
2.5. Adjuvants
Adjuvants are synthetic or natural highly immunogenic components that are combined with the specific immunizing antigen with the purpose of efficiently stimulate the immune cells to mount a strong response against that antigen. Adjuvants are usually categorized in two classes. Immunostimulatory or non-particulate adjuvants are agonists of the pathogen-recognition receptors (PRRs) that localize at the surface or inside intracellular vesicles of innate immune cells [93]. These are activated by the binding of the cognate pathogen associated molecular patterns (PAMPs) (or their agonists) and signal a complex cascade of events that triggers the secretion of cytokines, chemokines and type I interferons [98]. The other class comprise the particulate adjuvants which are mineral-, lipid- or polymer-based delivery systems that, along with being transporters of the
In a vaccine for leishmaniasis, it is expected that adjuvants modulate the immune system towards a Th1 response, with high amounts of secreted IL-12 and IFNγ. Indeed, recombinant IL-12 has been successfully tested in animal models as a potent adjuvant. However, stimulation with IL-12 was unable to induce a strong memory response to the immunizing antigen in BALB/c mice [99]. Nevertheless, when administered as IL-12 DNA it induced long-lasting protection against
MPL® is a purified derivative of the monophosphoryl lipid A hydrophobic moiety of
Other TLR agonists are CpG-containing oligonucleotides (CpG ODNs) and imiquimod, which are ligands for the TLR9 and TLR7/8, respectively. CpG ODNs are strong immunostimulators by the upregulation on macrophages and DCs of CD40 and MHC class II costimulatory receptors [104] and the induction of IFNα, IFNβ and IFNγ, IL-12, IL-18 and TNFα secretion by lymphocytes [105]. In the same direction, imiquimod, a synthetic imidazoquinoline, is a Th1 activator. But noteworthy, imiquimod has itself anti-leishmanial activity through the activation of macrophages leading to the secretion of IL-12 and IFNγ [106]. Also, signal transduction directed to NO production was detected on
Bacillus Calmette-Guérin (BCG), besides being the most widely administered vaccine in the world, it is also commonly used as adjuvant in numerous vaccine candidates for infectious diseases. In anti-
Saponins are natural products from the
Particulate adjuvants have many properties that can be designed to bias the immune system in the desirable way which make them very versatile adjuvants. They serve as carriers for antigens and non-particulate adjuvants, targeting both vaccine components to the same APC and controlling their release. They can be used to increase the stability of antigens, like proteins, peptides or oligonucleotides, to improve the solubility of hydrophobic compounds or to bypass gastric degradation [93].
Aluminum salts are common in human and veterinary vaccines, though they are not proper adjuvants
Micelles and emulsions likewise fall in this category of particulate adjuvants as, for example, MPL® and GLA formulated in stable emulsions (MPL-SE and GLA-SE). The oil-in-water emulsion formed with squalene (SE) is itself an adjuvant that has been included in the ongoing clinical trials run by IDRI (see section 2.6.2), though immunization with Leish-110f antigen plus SE led to the development of a Th2 response in BALB/c mice [77].
Finally, thought without great expression in
2.6. Current status of vaccine research
2.6.1. Vaccines for zoonotic visceral leishmaniasis
In canine vaccinology three authorized vaccine options are available.
Leishmune® was the first vaccine licensed for the prevention of ZVL but is authorized only in Brazil. It consists of
Some years later, Leish-Tec® was released, also only in Brazil. The recombinant A2 protein is the antigen that constitutes the vaccine along with saponin adjuvant. Protection was found to be related to high levels of anti-A2 IgG and IgG2, without the presence of IgG1, and high amounts of specific IFNγ with low levels of IL-10 [127]. However, there is no updated information about the efficacy of the vaccine in the field.
Recently, a new vaccine, CaniLeish®, the only authorized in Europe, has entered the market for the prophylaxis of ZVL. The manufacturer claims that vaccinated dogs have a 4-fold reduced risk of developing the disease compared to non-vaccinated animals [128]. The use of
2.6.2. Ongoing clinical trials for a vaccine for VL
On February 2012 the Infectious Disease Research Institute (IDRI) has launched a phase 1 clinical trial for the first vaccine against VL [130]. Thirty six healthy adult American volunteers were recruited to evaluate the safety, tolerability and immunogenicity of the LEISH-F3 recombinant antigen (composed of two fused proteins) with GLA-SE, MPL-SE or SE adjuvants [131]. About one year and a half later, this first clinical trial was completed and the vaccine was shown to be safe and to induce potent immune responses in healthy volunteers [132]. Later, IDRI partnered with the Indian pharmaceutical company Zydus Cadila to develop, register and market the three vaccine candidates to ensure that the possible future vaccine is affordable and accessible by the people that really need it. Also, in July 2013 this partnership has started phase 1 clinical trials in India to evaluate the effectiveness of the vaccine on individuals from endemic regions [132].
3. Experimental data: Highly infective Leishmania infantum strain induces strong central and effector memory CD4+ and CD8+ immunity required for partial protection against re-infection
3.1. Aim of the study
It is well accepted that the broad clinical manifestations described in leishmaniasis are associated with the different cytokine milieu developed in response to the infection, which is highly dependent on the parasite itself. Accordingly, a diversity of immune responses have been described for
Some studies on re-infection have been performed in mice as model for visceral leishmaniasis. Streit
To our knowledge, there is no previous literature about the concomitant immunity developed with live virulent
3.2. Development of protection needs highly infective Leishmania
Many efforts have been made to understand how
To understand the strain-specific immunomodulation mechanisms that lead to protection to re-infection we used two strains of
In our model, mice that were previously imprinted with HL strain and then challenged with the same highly infective strain (Figure 1, Re-inf HL bars) were able to sustain the splenic parasite load and to decrease in about 1 logarithm the number of parasites colonizing the liver and bone marrow. On the contrary, HL re-infection after ST imprinting led to a significant increase of about 1000 times in all the target tissues. Concomitant immunity was more pronounced when the animals were infected with the highly infective HL strain and then challenged with ST due to its lower infectivity (Figure 1, Re-inf ST bars). As such, the infections in the spleen and liver of HL imprinted mice suffered a significant reduction of ~1000-fold in the parasite loads to levels close to the quantification limit, and in the bone marrow parasitic presence was detected but not quantifiable. Accordingly, ST imprinting and consecutive challenge resulted in a ~10-fold increase in the splenic and hepatic parasite burden compared to the primary infection numbers, though no changes were noticed in the parasite load of the bone marrow.
Based on the data exposed above, in terms of parasitological analysis we established that the onset of pathology (set as hepatosplenomegaly (data not shown; see [136]) and high parasite loads) by an infective
3.3. Infectivity may influence downstream adaptive response-triggering events
To understand the immune response behind this protective phenotype, we analyzed the splenic populations and the T cells functionality. We observed that infection with HL produced a significant increase in the total cellularity and major leukocyte populations when compared to naïve animals, which was not noticed when mice were infected with ST strain (Figure 2A-E).
Interestingly, when the animals were subjected to a secondary infection by HL, regardless of the infectivity of the imprinting strain, we detected the same increase in the number of splenocytes, while after challenge with ST there was no change in the cellularity.
Inflammatory macrophages/monocytes and neutrophils, besides its recognition as host cells [137, 138], have been implicated in the remodeling of the spleen during splenomegaly in leishmaniasis [139, 140], as well as in the modulation of the specific CD4+ T cells response in late phases of infection, at least with
As these are the first cells that need to be committed, we determined the number of inflammatory macrophages, DCs and neutrophils by the expression of CCR2 (Figure 2F-H). Infection and challenge with HL led to the significant increase of these inflammatory cells in the spleen. Similarly, infection with ST also significantly increased the inflammatory DCs and neutrophils, but only with a second wave of parasites the CCR2+ macrophages arisen in numbers significantly higher than in uninfected animals. However, this difference in the number of CCR2+ macrophages relates with the total macrophages present in the spleen, as the relative percentages were similar between HL and ST (data not shown). These CCR2+ macrophages exert an important role in the defense against
Thus, monocyte and neutrophil activation showed no major differences between HL and ST strains, similarly to the findings of Meddeb-Garnaoui
3.4. Highly infective L. infantum triggers memory and effector CD4+ and CD8+ T cells
We have studied the generation of CD4+ and CD8+ memory T cells 6 weeks post-infection and upon challenge with the same strain by the surface expression of CD44 and CD62L (Figure 3).
HL infection potentiated the expansion of central memory CD8+ (Figure 3C, TCM bars) and especially CD4+ T cells (Figure 3A, TCM bars) that doubled in percentage compared to uninfected mice. These memory populations are probably an important factor in the control of the parasite load in the spleen, as presented before (Figure 1A), when the animals were subjected to re-infection. Memory cells constitute a source of experienced-antigen cells that are able to rapidly respond to face a similar challenge. While TEM cells display protective effector functions, TCM are thought to replenish the TEM pool [146].
In fact, after challenge with HL, both CD4+ (Figure 3B) and CD8+ (Figure 3D) TCM pools remained high and TEM cells also significantly increased compared to naïve mice. Moreover, taking into account that the total numbers of T lymphocytes in the infected animals were significantly increased in relation to naïve mice (Figure 2B and C), the number of memory (CD44hi) T cells was even more expressive in the spleens of those HL re-infected animals. On the contrary, ST strain showed no potential in clonal expansion of memory populations or at least in their high number maintenance in order to bring advantage upon re-infection. Neither in the imprinting infection nor after challenge could we detect CD4+ or CD8+ central or effector memory T cells in a percentage higher than that of the naïve animals. The decrease in the CD8+ TCM cells 6 weeks after ST infection (Figure 3C) was considered not to have any biological meaning since, when adjusted to total number of cells, both naïve and infected mice have similar amounts of that subpopulation.
From the data exposed, we justified the partial protection that a primary infection with HL
3.5. Double producers CD4+IFNγ+IL-10+ and CD8+IFNγ+TNFα+ T cells arise after re-infection
To appreciate the mechanisms underlying the protection observed after re-infection with a highly infective strain, we analyzed the magnitude of the developed T cell response in infected and re-infected mice with HL strain. After infection, we detected high levels of IFNγ-producing CD4+ and CD8+ T cells (Figures 4A and C, respectively). This finding was suspected after having noticed the massive cellular infiltrate of leukocytes in the spleen (Figure 2) and also the existence of approximately 15 % of effector memory lymphocytes (combined CD4+ and CD8+) that classically secrete this cytokine [147]. Upon re-infection (Figures 4B and D), however, a more interesting panel of effector cells has emerged. Along with the same IFNγ+ cells, detected in both CD4+ and CD8+ lymphocytes, we identified IL-10+ in ~1.5 % and IFNγ+IL-10+ double producers in ~0.75 % of the CD4+ T cells, which represent an increment of ~1.7 and ~3.1, respectively, compared to uninfected animals.
CD4+T-bet+IFNγ+IL-10+ cells were recently described by us and others upon infection of BALB/c mice with
In CD8+ T cells, conversely, cytokine double producing cells were found for IFNγ+TNFα+, in a representation of ~0.86 %, meaning an increase of ~3.4 fold compared to naïve mice. IFNγ and TNFα concomitant production by Th1 and CD8+ T cells has for long proven to be more efficient in the killing of
3.6. Conclusions
Taken together, our results show that HL
Taking the fact that HL is a dermotropic strain that caused CL in a human patient, its tropism is possibly justified by the inflammatory potential of the strain that impedes a silent entry into the host. A protective response may immediately be mounted in the skin, abrogating any chance of the parasite to reach internal organs and visceralize [157]. Concerning the ST strain, an agent of human VL, the initial activation of the innate immune system does not translate into efficient adaptive immunity as no memory cells were detected. With this, a primary infection does not serve as imprinting, since a re-infection with the same strain led to the increase of the parasite load in the spleen and liver.
With this work we contributed to the better understanding of the complex modulation that
4. Final remarks
Leishmaniasis is a tropical neglected disease that urgently needs control measures, as vaccination, since nowadays the global population is at risk. As some vaccines are available for ZVL, the discovery of an effective human vaccine for VL is near. Choosing the right antigen coupled with the appropriate adjuvant for the formulation is crucial to have an effective vaccine, but immunogenicity sometimes countervail safety and complicates the scenario. Effective immunization requires the presentation of the antigen by proper APCs to mount a strong immune response and develop immunological memory, as well as it entails antigen persistence. As described previously, live vaccines produce more robust immune responses than dead parasites or defined protein or peptides but they represent an important health risk, mainly in immunosuppressed people. Furthermore, the immune response developed against live
In this chapter, we have updated the main aspects to consider when a vaccination study against
5. Abbreviations
Acknowledgments
We thank Doctor Maria da Luz Duarte from São Marcos Hospital, Braga, Portugal, for kindly providing us the skin sample infected with HL strain of
This work was funded by FEDER funds through the Operational Competitiveness Programme – COMPETE and by National Funds through FCT – Fundação para a Ciência e a Tecnologia under the projects FCOMP-01-0124-FEDER-019648 (PTDC/BIA-MIC/118644/2010) and FCOMP-01-0124-FEDER-011058 (PTDC/SAU-FCF/101017/2008) as well as the MICINN’s project number PIM2010-ENI00627. The research leading to these results has also received funding from the European Community’s Seventh Framework Programme under grant agreement No.603181 (Project MuLeVaClin).
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