Abstract
The development of vaccines for human leishmaniasis is one of the most important approaches for effectively controlling and/or eradicating the several forms of the disease. Based on the knowledge obtained from the practice of leishmanization and its protective immune response, several strategies have been used to develop vaccines against Leishmania species, such as the use of whole killed and attenuated parasites, recombinant proteins, and DNA vaccines. An ideal vaccine should be safe, effective, and immunogenic. Although several candidates have achieved safety and some level of effectiveness, the current challenge in the development of prophylactic vaccines is to achieve long-lasting immune protection by generating a robust and irreversible Th1 adaptive immune response in the host, with rapid recruitment of memory and effectors T cells at key acute points of infection. However, despite all efforts over the years, due to the antigenic diversity of the parasite and the complexity of the host’s immune response, human vaccine trials have been disappointing in mediating long-term immunity against sandfly-delivered infection. Therefore, more investments in this field should be carried out to translate preclinical findings from mice to humans through effective vaccine development strategies.
You have full access to this open access chapter, Download chapter PDF
Similar content being viewed by others
Keywords
1 History of Human Leishmaniasis Vaccines
Leishmaniasis has afflicted mankind from ancient to modern times. Even though Leishmania were only described as a new genus at the beginning of the C20th [1, 2], their presence has been reported in Egyptian mummies dated as early as 2050–1650 BCE [3, 4]. In fact, ancient societies had already observed a key fact from cutaneous leishmaniasis (CL) that healed individuals achieved lifelong protection from new infections [5]. Especially in endemic areas of Asia and Africa, this knowledge would be later applied as the rationale for the first attempt of active immunization against Leishmania parasites [6].
This practice, known as leishmanization, was based on inoculating exudates from active lesions into a hidden part of the body of healthy individuals, which would produce a single self-healing lesion and consequently induce a protective response against future infections [6]. This type of immunization was used in several countries for decades, especially in hyperendemic areas [7,8,9]. Large-scale vaccination trials were conducted in conflict areas during the 1970s and 1980s, including one in which almost two million soldiers and refugees in Iran were immunized with live virulent L. major harvested from culture media [10]. Although leishmanization is considered to this day the most effective control measure against CL, concerns regarding vaccine safety, the lack of standardization, and numerous adverse effects caused it to be discontinued in most countries that still adopted this method [11]. Taking into account these limitations, attention has shifted into new approaches aimed at developing a safe and effective Leishmania vaccine for humans (Table 14.1). This includes a refinement of the leishmanization method, which will be discussed later in this chapter.
First-generation vaccines against leishmaniasis focused on whole killed parasites. This method is very attractive, since they are quite simple to produce at low cost, which is a prerequisite for wide distribution in developing countries [29]. The first trials of a vaccine against leishmaniasis using dead parasites took place in Brazil in the 1940s, using a polyvalent vaccine of 18 strains of Leishmania, and these trials had conflicting results [29,30,31]. These studies were resumed in the 1970s by other Brazilian research groups, through the evaluation of a pentavalent preparation without adjuvant known as Leishvacin® [12,13,14,15]. Other efforts were made worldwide, associating different Leishmania preparations with adjuvants such as BCG and aluminum hydroxide [16,17,18,19,20]. However, despite showing promising results regarding their safety and immunogenicity, overall, these vaccines failed to provide satisfactory levels of protection [32].
Second-generation vaccines then began to exploit purified or recombinant proteins as vaccine antigens. Associated with different adjuvants responsible for optimizing their immunogenicity [33, 34], vaccines using this method have advantages such as purity and ease of large-scale production [35]. Some second-generation vaccines against leishmaniasis that have reached clinical trials include LEISH-F1, LEISH-F2, and LEISH-F3 [36]. LEISH-F1, one of the first second-generation vaccines tested in humans, is made up of the fusion of the TSA, LmSTI1, and LeIF proteins (Table 14.1), associated with the adjuvant MPL-SE. Several phase I trials have demonstrated the vaccine’s immunogenicity and safety, in addition to its therapeutic efficacy in patients with cutaneous and mucocutaneous leishmaniasis [21, 22]. Based on the positive results of phase I, the same group reformulated the vaccine, now called LEISH-F2. This time, the aim was to achieve a protein more like its wild-type version, by excluding the histidine tail present in its recombinant predecessor. After having its safety and immunogenicity evaluated in phase I, the vaccine entered phase II to have its therapeutic effects evaluated on CL patients [23, 24]. LEISH-F3 is composed of NH36 and SMT proteins (Table 14.1) fused in tandem, formulated with the adjuvant GLA-SE. Phase I trials have demonstrated its safety and immunogenicity in a healthy population in the United States and Bangladesh [25, 26].
In order to optimize the specificity of protein-based vaccines, third-generation vaccines began to explore the potential of coding DNA in their composition [37]. The advantages of this type of approach include ease of production and administration, stability, and immunogenic potential [38, 39]. While many Leishmania genes have been evaluated for their vaccine efficacy, only one candidate has reached the clinical trial stage [36]. This vaccine uses the ChAd63 adenovirus as a vector for expression of the KH gene, constituted by the KMP-11 and HASPB antigens of L. donovani (Table 14.1). The results of phase I trials demonstrated the safety and immunogenicity of the vaccine, which is currently being evaluated for its therapeutic effect in patients with post-kala-azar dermal leishmaniasis (PKDL). Preliminary phase II results reported that the vaccine induced a potent cellular immune response and was responsible for the emergence of mild adverse effects [27, 28]. Despite promising results, the level of protection obtained by DNA vaccines is still limited, so more studies should be carried out to increase their effectiveness.
2 Strategies to Vaccine Design: Where Are Good Candidates to Be Found and How Do We Explore Their Potential?
Since the vaccine development field started to focus on immunogenic fractions instead of whole parasites, screening methods to search for these candidates became crucial. Therefore, genome sequencing of Leishmania spp. was a key step to understanding the molecular biology of these organisms [40,41,42,43]. Although different Leishmania species exhibit variable numbers of chromosomes and some species-specific genes, their genomes display a high degree of genetic conservation [44, 45]. This aspect becomes especially attractive when we consider the design of a pan-Leishmania vaccine.
Among other approaches to discover novel vaccine candidates, bioinformatics has been widely explored for its potential to process large amounts of data that are deposited on different databases. This interdisciplinary field combines computational techniques with biological data, supporting a large area of studies [46]. Regarding vaccine design, several tools and algorithms can be applied to predict a number of important antigen features, such as transmembrane domains, subcellular localization, secondary and tertiary structures, HLA recognition, and B- and T-cell epitopes [47,48,49,50,51,52]. Such characteristics not only help to understand the function of these molecules but also contribute to the search for dominant and therefore increasingly promising epitopes, which should be recognized by the human immune system and hopefully can stimulate a protective response. Furthermore, given the processing and analytical capabilities inherent to bioinformatics, this approach substantially reduces the time required for the simultaneous screening of thousands of targets [53]. On the other hand, a major limitation to this method is that the output data quality is highly affected by the accuracy of the annotations and predictions made upon them [54, 55].
A different approach to antigen discovery is based on bacteriophage libraries. In 1985, it was demonstrated that an exogenous gene could be fused to the gene from a capsid protein of the phage M13, resulting in the expression of a hybrid protein on the viral surface [56]. This technique, known as phage display, made it possible to create phage libraries composed of billions of phages capable of expressing different exogenous peptide sequences on their surface. These sequences can then be selected through their affinity for different types of ligands, such as enzymes, antibodies, and cell surface receptors [57]. An important aspect of this technology is the link between genotype and phenotype, since it is possible to find the selected peptide sequence through the nucleotide sequence fused to the viral genome [58].
Libraries constructed by random peptide sequences are the most common type of library used in phage display selection, often helping to identify epitopes [59], many of which have been evaluated as candidates for a Leishmania vaccine in experimental models [60,61,62,63,64,65] (Table 14.2). The application of this method in vaccinology explores both the role of the bacteriophage as an immunogenic carrier of antigens as well as the identification of mimotopes. These are peptides that, despite having a different sequence from that of the native epitope, are able to interact with the paratope in an analogous way, often mimicking conformational epitopes [66, 67]. Besides the ease of large-scale production, relatively low cost, and safety, one of the main advantages of phage display is the possibility of selecting mimotopes, since it is estimated that approximately 90% of B-cell epitopes are discontinuous in nature [35, 68]. Furthermore, the use of phages as antigen carriers is capable of inducing both the cellular and humoral arms of immunity, which is fundamental in orchestrating an effective response against intra- and extracellular pathogens [59, 69].
Although having good candidates is important while developing a promising vaccine, it is only the first step in a very long process. A fundamental aspect for a successful vaccine is, in fact, how these candidates are explored. Despite peptide-based vaccines offer advantages like safety and ease for production, it is well-known that synthetic single peptides are poor immunogens and require some tweaks to be able to elicit a potent and hopefully long-lasting immune response [70]. Among commonly used approaches to overcome this issue and, in the right context, drive a protective immune response is the use of adjuvants, adenovirus vector, or chimeras [71].
Chimera vaccines are composed of multiple epitopes which can be repeated in tandem to enhance the immune response [72]. Several studies have demonstrated the potential of these vaccines against leishmaniasis in a murine model (Table 14.3), including polyproteins composed by conjugated antigens such as KSAC [82] and Q protein [73], T-cell epitopes for a specific protein [72, 74,75,76,77,78,79,80,81], and MHC I- and MHC II-specific epitopes from different proteins [83, 84]. Regardless of the specific target, multicomponent vaccines are especially interesting in the case of complex organisms such as Leishmania spp. that present an extensive antigen repertoire [76]. In addition to optimizing the chances of triggering an immunogenic response by recognizing at least one of its epitopes, vaccines composed of polyproteins demonstrate greater potential for mass application [85], especially when considering the genetic polymorphism of the mammalian immune system and the possible interactions of these antigens with different types of MHC [86]. Furthermore, the high level of conservation among the genomes of Leishmania spp. makes possible the development of a pan-effective vaccine against several species [87]. Despite these advantages, chimeric vaccines still need to be associated with adjuvants that are safe for use in humans and that together can stimulate the robust and long-lasting response associated with protection. This vaccine is yet to be developed.
Although whole parasite vaccines have the advantage of exhibiting the complete repertoire of antigens to the immune system [88], one of the biggest caveats about using attenuated organisms is the risk of reversion to virulence [89]. Particularly, older approaches such as maintaining the parasites in culture for long periods of time and exposure to chemical and physical attenuation did not ensure its safety. Random mutations and the return to a virulent state were often observed [90,91,92]. Fortunately, the use of attenuated strains gained a new momentum thanks to the progress made in genetic manipulation techniques. The discovery of the CRISPR-Cas9 system, for instance, proved to be of great importance for editing the genomes of several organisms, including different Leishmania species [93,94,95]. This system is based on two components: Cas9, an RNA-guided endonuclease, and a guide RNA sequence, which has the function of directing Cas9 to the complementary strand of the target DNA that will be cleaved [96]. Since genetic manipulation before CRISPR-Cas9 was largely based on homologous recombination with the use of antibiotics as selection markers [97,98,99], the development of this technology improved the ability to explore and edit the genome of a number of organisms. In addition to other possibilities, this method allows the precise deletion and insertion of genes in known locations, being able to introduce mutations, selection markers, and protein sequences of interest [94].
Several important genes for the survival of Leishmania spp. have been explored in vaccine development, such as those responsible for the expression of cysteine protease, biopterin transporter, p27, and centrin [100,101,102,103,104,105,106,107,108,109] (Table 14.4). Centrin is a constitutive protein of the eukaryotic cytoskeleton, responsible for the duplication and segregation of the centrosome. Deletion of the centrin encoding gene in L. donovani reduced the growth of the amastigote forms, although it did not interfere with the viability of the promastigotes [107, 110]. While multiplying inside macrophages, mutant amastigotes were unable to properly perform cell division, becoming multinucleated and entering a process of programmed cell death [107]. Immunization with this strain, called LdCEN−/−, was able to provide protection against infection by L. donovani [108, 111, 112], L. infantum [113, 114], L. mexicana [115], and L. braziliensis [116] in mice, hamsters, and dogs. Immunity generated by vaccination was mediated by a CD4+ and CD8+ T-cell response, characterized by potent production of pro-inflammatory cytokines IL-12, IFN-ɣ, and IL-17 and reduction of IL-10 by macrophages [88, 116,117,118].
Despite all benefits, the use of this strain as a human vaccine raises concerns regarding its potential for visceralization, which can be fatal. Furthermore, the method used to obtain the centrin gene knockout required the insertion of an antibiotic resistance marker gene, an inadmissible feature from a human vaccine candidate. In light of these limitations, an attenuated L. major centrin gene deletion mutant (LmCen−/−) was generated using the CRISPR-Cas technique. This technology eliminates the need for resistance markers, which facilitates the approval of this strain as a vaccine by regulatory agencies and makes its evaluation possible in human clinical trials. Another relevant aspect for the safety of this strain is that L. major is a dermotropic species and its infection, unlike L. donovani, remains in the skin and does not cause visceral disease. Evaluation of LmCen−/− in a murine model was able to prevent the appearance of lesions after challenge by L. major, in addition to having reduced the parasite load within internal organs and induced a protective immune response analogous to leishmanization. Moreover, inoculation of LmCen−/− was unable to generate pathology in susceptible and immunodeficient mice, proving the safety of this vaccine [109].
The pursuit for knowledge and the advancement of new technologies have facilitated the search for increasingly promising vaccine candidates against leishmaniasis. The support of bioinformatics and genetic manipulation techniques has allowed the design and evaluation of different types of vaccines, whether composed of parasite fractions or those that exploited genetically modified whole parasites. Even though many candidates have been evaluated in preclinical trials, few had a chance to reach human clinical trials. There is still no vaccine available against human leishmaniasis. However, scientific efforts made in recent decades have brought us closer to achieving a safe, immunogenic, and effective human vaccine.
3 Immunological Insights into Vaccine Development
The host’s immunity during leishmaniasis is complex and varies according to parasite or host species, parasite load and sandfly, or needle challenge. In general, a protective immune response during Leishmania spp. infection involves the cross talk between the innate immune response, including neutrophils, monocytes/macrophages and dendritic cells (DCs), and subsequent activation of a Th1 adaptive immune response. Both CD4+ Th1 and antigen-specific CD8+ T-cell activation result in the production of IFN-γ and TNF-α cytokines that upregulate inducible oxide nitric synthase (iNOS) and reactive oxygen species (ROS) expression by macrophages, important molecules that have been associated with disease control and parasite clearance [119,120,121].
The resolution of a primary Leishmania spp. infection in humans who recover from the cutaneous manifestation, but maintain chronic infection in the skin, leads to long-lasting immunity mediated by CD4+ T cells. Healed patients establish a strong Th1 memory response with low number of parasites due to immune regulation mediated by IL-10, known as concomitant immunity, which confers resistance to a secondary infection, the same protection observed in the practice of leishmanization [122, 123]. Thus, from the knowledge of concomitant immunity comes the idea of developing vaccine-mediated immunity against different forms of leishmaniasis using several approaches, such as the use of attenuated live parasites, whole killed parasites, parasite protein, recombinant vaccines, and DNA vaccines, among others. However, despite all efforts in this field, human vaccine trials have been disappointing in mediating long-term immunity when compared to leishmanization.
Healed humans and mice from experimental models of CL showed that upon antigen presentation, different populations of memory and effector CD4+ T cells are generated. Central memory T (TCM) cells (Ly6C−CD62L+CCR7+Ki-67+) reside in lymph nodes and can survive for life, regardless of persistent antigen presentation. During concomitant immunity, they have the capacity to transition into effector T (TEFF) cells after the period of antigen presentation and activation by DCs. Moreover, they are important for the production of IFN-γ and TNF-α [119, 124]. Effector memory T (TEM) cells (Ly6C−CD62L−CCR7−Ki-67+) can also produce these Th1 cytokines and are longer lived than TEFF cells in the absence of antigen, but shorter lived than TCM cells. They can be found in secondary lymphoid organs, blood, or periphery [119, 125]. Tissue resident memory (TRM) cells (Ly6C−CD62L−CCR7− Ki-67+) are a non-circulatory population of memory T cells found at the distal site to the primary infection that respond quickly upon restimulation, producing IFN-γ and recruiting TEFF cells [125, 126]. Along with TEFF cells, TRM cells are crucial in IFN-γ production at very acute time points of infection.
Regarding TEFF cells, studies in experimental mouse models have demonstrated that the constant presence of the parasite in chronic subclinical infection is the key factor in Th1 concomitant immunity. Therefore, Peters et al. have shown that persistent antigen presentation is crucial for the maintenance of circulating TEFF cells, short-lived CD4+ T cells expressing Ly6C+CD44+CD62L− that are predominantly single producers of IFN-γ. These cells are rapidly recruited and responsible for IFN-γ production almost instantly after secondary challenge by sandfly bite, preventing the formation of a phagosomal pathogen niche and the development of the disease in mice [125, 127].
Several experimental vaccine formulations have been able to generate Leishmania-specific TCM and TEM cells and have successfully protected mice against needle challenge. However, although these memory T cells enhance Th1 response by cytokine production upon re-exposure to parasite antigen weeks to months after vaccination, the same vaccine formulations were ineffective in providing protection against sandfly bite-mediated challenge [127,128,129,130,131]. These observations highlight that the failure of Leishmania vaccines is not due to a lack of generating an appropriate Th1 memory response but due to a lack of generating TEFF and TRM cells, in addition to inflammatory conditions at the sandfly bite site that compromise the effector function of the memory response and should be considered when designing and testing vaccines. The human counterparts of TEFF cells in mice are not characterized yet, and understanding how to best induce generation of TRM and TEFF cells in humans during vaccination against Leishmania infection is one of the major challenges that remains undefined [132].
Immune protection against sandfly bite, rather than just the needle challenge, is the other big issue that needs to be overcome in successful vaccine design. Vector transmission of Leishmania by female sandfly bite delivers into the skin a low number of promastigote parasites and active molecules present in the saliva, inducing a robust local inflammatory response associated with the recruitment of neutrophils and monocytes. This specific inflammatory response in vector transmission has an important impact in the context of vaccination. Studies have shown that neutrophil recruitment is an important factor in impairing IFN-γ production by CD4+ T cells and vaccine efficacy, due to suppression of T-cell activation by macrophages and DCs that are engaged in both antigen presentation and efferocytosis (i.e., clearance of apoptotic cells) of infected neutrophils [119, 132,133,134]. In addition, another important aspect that must be taken into account is the shortage of antigen availability during vector transmission when compared to needle challenge in many experimental models. The low number of parasites delivered by sandfly bite can hamper the development of a protective immune response, including TCM activation in the draining lymph node. Despite the difficulty of maintaining sandfly colonies to reproduce the context of natural infection, efforts to replicate the low dose and inflammatory response conditions of vector transmission is an essential concern and should be used as the “gold standard” of preclinical research to interpret the effectiveness of protective immunity and vaccination [119, 123, 132].
4 Lessons from the COVID Era: What Have We Learned, and How Can We Translate It to Leishmania Vaccines?
Vaccine development is a lengthy process—a decade can easily pass by between the discovering phase and the start of clinical trials. In 2020, the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic shook the entire world, both for the speed with which it infected and killed millions of people and for the agility with which vaccines capable of containing the spread of the virus were developed. Coronaviruses are a group of large enveloped RNA viruses that usually cause mild disease in humans, the main reason why vaccination efforts were nonexistent up until recently [135]. This scenario dramatically shifted after the SARS-CoV and MERS-CoV (Middle Eastern respiratory syndrome coronavirus) outbreaks revealed a highly transmissible and pathogenic profile for these viruses [136].
Studies soon found a promising antigenic candidate for coronaviruses vaccines, a large surface protein responsible for receptor binding and cell invasion mechanisms known as “spike” protein [137]. Thankfully, due to the close relation between these pathogens, the discovery phase during vaccine design for SARS-CoV-2 could be significantly shortened and effective vaccines could be evaluated in clinical trials at an unprecedented speed. A pandemic like the one caused by SARS-CoV-2 justifies all the great scientific efforts and the number of financial investments made all over the world. It is also noteworthy that the success of different strategies explored during vaccine design brought attention not only to their advantages as a SARS-CoV-2 vaccine per se but more importantly to its capacity to be applied to vaccines against all types of etiologies, including leishmaniasis. Adenovirus (Ad) vector-based mRNA vaccines such as the ones developed by Johnson and Johnson and Oxford/AstraZeneca showed large potential as a platform for numerous infectious diseases. Aside from their high transduction efficiency and thermostability, Ad vectors are especially attractive when we consider their ability to induce moderate levels of innate immunity, a key feature needed to activate adaptive immunity that is usually obtained only by the use of adjuvants [138]. This is one of many design approaches used in SARS-CoV-2 vaccines that we can draw experience from and that can be certainly translated to Leishmania vaccines.
A different kind of reflection provoked by the COVID-19 pandemic is what an effective vaccine looks like and what we should expect from it. Sterile immunity is often thought as the main goal for vaccination, despite being rather difficult to achieve. Admittedly, several vaccines including those against influenza, rotavirus, and the ones recently developed for SARS-CoV-2 fall under that category. However, the fact that these vaccines are unable to entirely block the infection does not mean they cannot prevent diseases or even reduce associated burden. We have witnessed first-hand COVID-19 vaccines significantly reducing hospitalization, morbidity, and mortality rates worldwide—while aided by important safety guidelines like social distancing and implementation of face mask obligation. Taking that into account, one can argue if we absolutely need to induce sterile immunity in a Leishmania vaccine, particularly since it is well-known that parasite persistence is required for long-life immunity. Furthermore, no vaccine alone can eradicate a complex multifactorial disease like leishmaniasis. Much like COVID-19, leishmaniasis control needs far more than an effective vaccine; it needs a One Health approach that encompasses vector control, reservoir vigilance, and environmental conservation programs.
5 Conclusions
The main concept of Leishmania long-lasting vaccination is to generate a robust and irreversible CD4+ Th1 memory response and early IFN-γ-producing effector T-cell responsiveness at challenge site, which is crucial in preventing the establishment of a parasite niche, in addition to mediating parasite killing and infection control. Therefore, key points must be considered in vaccine evaluation: (a) cytokine production and cell differentiation by parasite-specific memory T cells (TCM and TEM), (b) persistent antigen presentation to maintain circulating IFN-γ-producing TEFF cells required to mediate an optimal response, (c) induction of TRM populations at the inoculated inflamed skin, and (d) to replicate the low-dose/high-inflammation conditions of experimental sandfly challenge as the “gold standard” of preclinical research. In conclusion, understanding of aspects related to the protective immune response in leishmaniasis has made important advances over the years and is crucial for translating preclinical findings from mice to humans through effective vaccine development strategies. The current prophylactic vaccine approach against all forms of leishmaniasis aims to obtain immune protection through a rapid recruitment of IFN-γ-producing TEFF and TRM cells in key acute times of Leishmania infection. This outcome should be able to occur even after natural sandfly challenge, preventing the development of the disease.
References
Donovan C. On the possibility of the occurrence of trypanosomiasis in India. 1903. Natl Med J India. 1904;7:201–2.
Leishman WB. On the possibility of the occurrence of trypanosomiasis in India. Br Med J. 1903;1:1252–4.
Zink AR, Spigelman M, Schraut B, Greenblatt CL, Nerlich AG, Donoghue HD. Leishmaniasis in ancient Egypt and upper Nubia. Emerg Infect Dis. 2006;12:1616–7.
Frías L, Leles D, Araújo A. Studies on protozoa in ancient remains—a review. Mem Inst Oswaldo Cruz. 2013;108:1–12.
Boelaert M, Sundar S. Leishmaniasis. In: Manson’s tropical infectious diseases. 23rd ed. Philadelphia, PA: Elsevier; 2013. p. 631–51.
Bray RS, Modabber F. The history of leishmaniasis. In: Protozoal diseases; 2000. p. 414–9.
Marzinowsky EI, Schurenkowa A. Oriental sore and immunity against it. Trans R Soc Trop Med Hyg. 1924;18:67. https://doi.org/10.1016/B978-0-12-374279-7.13011-5.
Senekji HA, Beattie CP. Artificial infection and immunization of man with cultures of L. tropica. Trans R Soc Trop Med Hyg. 1941;34:415–9.
Dunning N. Leishmania vaccines: from leishmanization to the era of DNA technology. Biosci Horiz. 2009;2:73–83.
Nadim A, Javadian E, Mohebali M. The experience of leishmanization in the Islamic Republic of Iran. East Mediterr Health J. 1997;3:284–9.
Gillespie PM, Beaumier CM, Strych U, Hayward T, Hotez PJ, Bottazzi ME. Status of vaccine research and development of vaccines for leishmaniasis. Vaccine. 2016;34:2996–3000.
Mayrink W, Magalhaes P, Dias M, da Costa C, Melo M, Lima A. Responses to Montenegro antigen after immunization with killed leishmania promastigotes. Trans R Soc Trop Med Hyg. 1978;72:676.
Mayrink W, Costa CA, Magalhães PA, Melo MN, Dias M, Oliveira Lima A, Michalick MS, Williams P. A field trial of a vaccine against American dermal leishmaniasis. Trans R Soc Trop Med Hyg. 1979;73:385–7.
Mayrink W, Williams P, dA Costa CA, et al. An experimental vaccine against American dermal leishmaniasis: experience in the state of Espirito Santo, Brazil. Ann Trop Med Parasitol. 1985;79:259–69.
Mayrink W, Dos Santos GC, Peixoto De Toledo VDPC, Dabés Guimarães TMP, Lins Machado-Coelho GL, Genaro O, Da Costa CA. Vaccination of C57BL/10 mice against cutaneous leishmaniasis using killed promastigotes of different strains and species of leishmania. Rev Soc Bras Med Trop. 2002;35:125–32.
Bahar K, Dowlati Y, Shidani B, Alimohammadian MH, Khamesipour A, Ehsasi S, Hashemi-Fesharki R, Ale-Agha S, Modabber F. Comparative safety and immunogenicity trial of two killed leishmania major vaccines with or without BCG in human volunteers. Clin Dermatol. 1996;14:489–95.
Vélez ID, Agudelo SP, Arbelaez MP, Gilchrist K, Robledo SM, Puerta JA, Zicker F, Berman J, Modabber F. Safety and immunogenicity of a killed leishmania (L.) amazonensis vaccine against cutaneous leishmaniasis in Colombia: a randomized controlled trial. Trans R Soc Trop Med Hyg. 2000;94:698–703.
Kamil AA, Khalil EAG, Musa AM, et al. Alum-precipitated autoclaved leishmania major plus bacille Calmette-Guérrin, a candidate vaccine for visceral leishmaniasis: safety, skin-delayed type hypersensitivity response and dose finding in healthy volunteers. Trans R Soc Trop Med Hyg. 2003;97:365–8.
Armijos RX, Weigel MM, Calvopina M, Hidalgo A, Cevallos W, Correa J. Safety, immunogenecity, and efficacy of an autoclaved leishmania amazonensis vaccine plus BCG adjuvant against New World cutaneous leishmaniasis. Vaccine. 2004;22:1320–6.
Khalil EAG, Musa AM, Modabber F, El-Hassan AM. Safety and immunogenicity of a candidate vaccine for visceral leishmaniasis (alum-precipitated autoclaved leishmania major + BCG) in children: an extended phase II study. Ann Trop Paediatr. 2006;26:357–61.
Chakravarty J, Kumar S, Trivedi S, et al. A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1 + MPL-SE vaccine for use in the prevention of visceral leishmaniasis. Vaccine. 2011;29:3531–7.
Llanos-Cuentas A, Calderón W, Cruz M, et al. A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1+MPL-SE vaccine when used in combination with sodium stibogluconate for the treatment of mucosal leishmaniasis. Vaccine. 2010;28:7427–35.
NCT01011309. A study of the efficacy and safety of the LEISH-F2 + MPL-SE vaccine for treatment of cutaneous leishmaniasis. In: Clin Bethesda Natl Libr Med; 2013. https://clinicaltrials.gov/ct2/show/NCT01011309.
NCT00982774. Safety and immunogenicity of the LEISH-F2 + MPL-SE vaccine with SSG for patients with PKDL. In: Clin Bethesda Natl Libr Med; 2011. https://clinicaltrials.gov/ct2/show/NCT00982774.
Coler RN, Duthie MS, Hofmeyer KA, et al. From mouse to man: safety, immunogenicity and efficacy of a candidate leishmaniasis vaccine LEISH-F3+GLA-SE. Clin Transl Immunology. 2015;4:e35–13.
NCT01751048. LEISH-F3 + GLA-SE and the LEISH-F3 + MPL-SE vaccine. In: Clin Bethesda Natl Libr Med; 2017. https://clinicaltrials.gov/ct2/show/NCT01751048.
Osman M, Mistry A, Keding A, et al. A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: first-in-human trial of ChAd63-KH. PLoS Negl Trop Dis. 2017;11:1–24.
Younis BM, Osman M, Khalil EAG, et al. Safety and immunogenicity of ChAd63-KH vaccine in post-kala-azar dermal leishmaniasis patients in Sudan. Mol Ther. 2021;29:1–12.
Noazin S, Modabber F, Khamesipour A, et al. First generation leishmaniasis vaccines: a review of field efficacy trials. Vaccine. 2008;26:6759–67.
Pessoa S, Pestana B. Ensaio sobre vacinacao preventiva na leishmaniose tegumentar americana com germenes mortos. Arq Hig Saude Publica. 1941;6:141–7.
Pessoa S. Segunda nota sobre a vacinacao preventiva na leishmaniose tegumentar americana com leptomones mortas. Rev Paul Med. 1941;19:106.
Noazin S, Khamesipour A, Moulton LH, et al. Efficacy of killed whole-parasite vaccines in the prevention of leishmaniasis-a meta-analysis. Vaccine. 2009;27:4747–53.
Duthie MS, Raman VS, Piazza FM, Reed SG. The development and clinical evaluation of second-generation leishmaniasis vaccines. Vaccine. 2012;30:134–41.
Raman VS, Duthie MS, Fox CB, Matlashewski G, Reed SG. Adjuvants for leishmania vaccines: from models to clinical application. Front Immunol. 2012;3:1–15.
Duarte MC, Lage DP, Martins VT, Chávez-Fumagalli MA, Roatt BM, Menezes-Souza D, Goulart LR, Soto M, Tavares CAP, Coelho EAF. Recent updates and perspectives on approaches for the development of vaccines against visceral leishmaniasis. Rev Soc Bras Med Trop. 2016;49:398–407.
Moafi M, Rezvan H, Sherkat R, Taleban R. Leishmania vaccines entered in clinical trials: a review of literature. Int J Prev Med. 2019;10:1–9.
Jain K, Jain NK. Vaccines for visceral leishmaniasis: a review. J Immunol Methods. 2015;422:1–12.
Joshi S, Rawat K, Yadav NK, Kumar V, Siddiqi MI, Dube A. Visceral leishmaniasis: advancements in vaccine development via classical and molecular approaches. Front Immunol. 2014;5:1–18.
Liu MA, Wahren B, Hedestam GBK. DNA vaccines: recent developments and future possibilities. Hum Gene Ther. 2006;17:1051–61.
Ivens AC, Peacock CS, Worthey EA, et al. The genome of the kinetoplastid parasite, leishmania major. Science. 2005;309:436–42.
Peacock CS, Seeger K, Harris D, et al. Comparative genomic analysis of three leishmania species that cause diverse human disease. Nat Genet. 2007;39:839–47.
Rogers MB, Hilley JD, Dickens NJ, et al. Chromosome and gene copy number variation allow major structural change between species and strains of leishmania. Genome Res. 2011;21:2129–42.
Downing T, Imamura H, Decuypere S, et al. Whole genome sequencing of multiple leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance. Genome Res. 2011;21:2143–56.
Wincker P, Ravel C, Blaineau C, Pages M, Jauffret Y, Dedet JP, Bastien P. The leishmania genome comprises 36 chromosomes conserved across widely divergent human pathogenic species. Nucleic Acids Res. 1996;24:1688–94.
Britto C, Ravel C, Bastien P, Blaineau C, Pagès M, Dedet JP, Wincker P. Conserved linkage groups associated with large-scale chromosomal rearrangements between Old World and New World leishmania genomes. Gene. 1998;222:107–17.
Luscombe NM, Greenbaum D, Gerstein M. Review what is bioinformatics? An introduction and overview. Gene Expr. 2001;40:83–100.
Arai M, Mitsuke H, Ikeda M, Xia JX, Kikuchi T, Satake M, Shimizu T. ConPred II: a consensus prediction method for obtaining transmembrane topology models with high reliability. Nucleic Acids Res. 2004;32:390–3.
Saha S, Raghava GPS. BcePred: prediction of continuous B-cell epitopes in antigenic sequences using physico-chemical properties. Lect Notes Comput Sci (including Subser Lect Notes Artif Intell Lect Notes Bioinformatics). 2004;3239:197–204.
Guex N, Peitsch MC, Schwede T. Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: a historical perspective. Electrophoresis. 2009;30:162–73.
Fleri W, Paul S, Dhanda SK, Mahajan S, Xu X, Peters B, Sette A. The immune epitope database and analysis resource in epitope discovery and synthetic vaccine design. Front Immunol. 2017;8:1–16.
Buchan DWA, Jones DT. The PSIPRED protein analysis workbench: 20 years on. Nucleic Acids Res. 2019;47:W402–7.
Dhanda SK, Mahajan S, Paul S, et al. IEDB-AR: immune epitope database—analysis resource in 2019. Nucleic Acids Res. 2019;47:W502–6.
Parvizpour S, Pourseif MM, Razmara J, Rafi MA, Omidi Y. Epitope-based vaccine design: a comprehensive overview of bioinformatics approaches. Drug Discov Today. 2020;25:1034–42.
Yok NG, Rosen GL. Combining gene prediction methods to improve metagenomic gene annotation. BMC Bioinformatics. 2011;12:20. https://doi.org/10.1186/1471-2105-12-20.
Dimonaco NJ, Aubrey W, Kenobi K, Clare A, Creevey CJ. No one tool to rule them all: prokaryotic gene prediction tool annotations are highly dependent on the organism of study. Bioinformatics. 2022;38:1198–207.
Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science. 1985;228:1315–7.
Scott JK, Smith GP. Searching for peptide ligands epitope library with an epitope library. Science. 1990;249:386–90.
Sidhu SS. Phage display in pharmaceutical biotechnology. Curr Opin Biotechnol. 2000;11:610–6.
Aghebati-Maleki L, Bakhshinejad B, Baradaran B, Motallebnezhad M, Aghebati-Maleki A, Nickho H, Yousefi M, Majidi J. Phage display as a promising approach for vaccine development. J Biomed Sci. 2016;23:1–18.
Costa GLR, De Jesus Pereira NC, et al. Mimotope-based vaccines of leishmania infantum antigens and their protective efficacy against visceral leishmaniasis. PLoS One. 2014;9:e110014. https://doi.org/10.1371/journal.pone.0110014.
Costa LE, Chávez-Fumagalli MA, Martins VT, et al. Phage-fused epitopes from leishmania infantum used as immunogenic vaccines confer partial protection against leishmania amazonensis infection. Parasitology. 2015;142:1335–47.
Toledo-Machado CM, Bueno LL, Menezes-Souza D, Machado-De-Avila RA, Nguyen C, Granier C, Bartholomeu DC, Chávez-Olórtegui C, Fujiwara RT. Use of phage display technology in development of canine visceral leishmaniasis vaccine using synthetic peptide trapped in sphingomyelin/cholesterol liposomes. Parasit Vectors. 2015;8:1–8.
Ben RR, Houimel M. Targeting leishmania major parasite with peptides derived from a combinatorial phage display library. Acta Trop. 2016;159:11–9.
Ramos FF, Costa LE, Dias DS, et al. Selection strategy of phage-displayed immunogens based on an in vitro evaluation of the Th1 response of PBMCs and their potential use as a vaccine against leishmania infantum infection. Parasit Vectors. 2017;10:1–14.
Carvalho GB, Costa LE, Lage DP, et al. High-through identification of T cell-specific phage-exposed mimotopes using PBMCs from tegumentary leishmaniasis patients and their use as vaccine candidates against leishmania amazonensis infection. Parasitology. 2018;146:1–11.
Geysen HM, Rodda SJ, Mason TJ. A priori delineation of a peptide which mimics a discontinuous antigenic determinant. Mol Immunol. 1986;23:709–15.
Wang L-F, Yu M. Epitope identification and discovery using phage display libraries: applications in vaccine development and diagnostics. Curr Drug Targets. 2004;5:1–15.
Ferdous S, Kelm S, Baker TS, Shi J, Martin ACR. B-cell epitopes: discontinuity and conformational analysis. Mol Immunol. 2019;114:643–50.
Hess KL, Jewell CM. Phage display as a tool for vaccine and immunotherapy development. Bioeng Transl Med. 2019;5:1–15.
Purcell AW, McCluskey J, Rossjohn J. More than one reason to rethink the use of peptides in vaccine design. Nat Rev Drug Discov. 2007;6:404–14.
De Brito RCF, de Cardoso JMO, Reis LES, Vieira JF, Mathias FAS, Roatt BM, Aguiar-Soares RDDO, Ruiz JC, de Resende DM, Reis AB. Peptide vaccines for leishmaniasis. Front Immunol. 2018;9:1043. https://doi.org/10.3389/fimmu.2018.01043.
De Brito RCF, Ruiz JC, Reis LES, Mathias FAS, Aguiar-Soares RDDO, Roatt BM, Correa-Oliveira R, Resende DDM, Reis AB. Chimeric vaccines designed by immunoinformatics-activated polyfunctional and memory T cells that trigger protection against experimental visceral leishmaniasis. Vaccine. 2020;8:1–20.
Carcelén J, Iniesta V, Fernández-Cotrina J, et al. The chimerical multi-component Q protein from leishmania in the absence of adjuvant protects dogs against an experimental leishmania infantum infection. Vaccine. 2009;27:5964–73.
Martins VT, Duarte MC, Lage DP, Costa LE, Carvalho AMRS, Mendes TAO, Roatt BM, Menezes-Souza D, Soto M, Coelho EAF. A recombinant chimeric protein composed of human and mice-specific CD4 + and CD8 + T-cell epitopes protects against visceral leishmaniasis. Parasite Immunol. 2017;39:1. https://doi.org/10.1111/pim.12359.
Alves-Silva MV, Nico D, Morrot A, Palatnik M, Palatnik-de-Sousa CB. A chimera containing CD4+ and CD8+ T-cell epitopes of the leishmania donovani nucleoside hydrolase (NH36) optimizes cross-protection against leishmania amazonesis infection. Front Immunol. 2017;8:100. https://doi.org/10.3389/fimmu.2017.00100.
Dias DS, Ribeiro PAF, Martins VT, et al. Vaccination with a CD4 + and CD8 + T-cell epitopes-based recombinant chimeric protein derived from leishmania infantum proteins confers protective immunity against visceral leishmaniasis. Transl Res. 2018;200:18–34.
Lage DP, Ribeiro PAF, Dias DS, et al. A candidate vaccine for human visceral leishmaniasis based on a specific T cell epitope-containing chimeric protein protects mice against leishmania infantum infection. NPJ vaccines. 2020;5:75. https://doi.org/10.1038/s41541-020-00224-0.
Lage DP, Ribeiro PAF, Dias DS, et al. Liposomal formulation of ChimeraT, a multiple T-cell epitope-containing recombinant protein, is a candidate vaccine for human visceral leishmaniasis. Vaccine. 2020;8:1–20.
Agallou M, Margaroni M, Kotsakis SD, Karagouni E. A canine-directed chimeric multi-epitope vaccine induced protective immune responses in balb/c mice infected with leishmania infantum. Vaccine. 2020;8:1–35.
Ostolin TLVDP, Gusmão MR, Mathias FAS, de JMO C, Roatt BM, de RDO A-S, Ruiz JC, de Resende DM, de RCF B, Reis AB. A chimeric vaccine combined with adjuvant system induces immunogenicity and protection against visceral leishmaniasis in BALB/c mice. Vaccine. 2021;39:2755–63.
Lage DP, Vale DL, Linhares P, et al. A recombinant chimeric protein-based vaccine containing T-cell epitopes from amastigote proteins and combined with distinct adjuvants, induces immunogenicity and protection against leishmania infantum infection. Vaccine. 2022;10:1146.
Goto Y, Bhatia A, Raman VS, Liang H, Mohamath R, Picone AF, Vidal SEZ, Vedvick TS, Howard RF, Reed SG. KSAC, the first defined polyprotein vaccine candidate for visceral leishmaniasis. Clin Vaccine Immunol. 2011;18:1118–24.
Seyed N, Taheri T, Vauchy C, et al. Immunogenicity evaluation of a rationally designed polytope construct encoding HLA-A&z.ast;0201 restricted epitopes derived from leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine. PLoS One. 2014;9(10):e108848. https://doi.org/10.1371/journal.pone.0108848.
Dikhit MR, Kumar A, Amit A, et al. Mining the proteome of leishmania donovani for the development of novel MHC class I restricted epitope for the control of visceral leishmaniasis. J Cell Biochem. 2018;119:378–91.
Reed SG, Coler RN, Campos-Neto A. Development of a leishmaniasis vaccine: the importance of MPL. Expert Rev Vaccines. 2003;2:239–52.
Stäger S, Rafati S. CD8+ T cells in leishmania infections: friends or foes? Front Immunol. 2012;3:1–8.
Kumar R, Engwerda C. Vaccines to prevent leishmaniasis. Clin Transl Immunology. 2014;3:e13.
Selvapandiyan A, Dey R, Gannavaram S, Lakhal-Naouar I, Duncan R, Salotra P, Nakhasi HL. Immunity to visceral leishmaniasis using genetically defined live-attenuated parasites. J Trop Med. 2012;2012:1. https://doi.org/10.1155/2012/631460.
Saljoughian N, Taheri T, Rafati S. Live vaccination tactics: possible approaches for controlling visceral leishmaniasis. Front Immunol. 2014;5:1–11.
Bhaumik SK, Singh MK, Karmakar S, De T. UDP-gal: N-acetylglucosamine β 1–4 galactosyltransferase expressing live attenuated parasites as vaccine for visceral leishmaniasis. Glycoconj J. 2009;26:663–73.
Daneshvar H, Namazi MJ, Kamiabi H, Burchmore R, Cleaveland S, Phillips S. Gentamicin-attenuated leishmania infantum vaccine : protection of dogs against canine visceral leishmaniosis in endemic area of southeast of Iran. PLoS Negl Trop Dis. 2014;8:2–8.
Datta S, Adak R, Chakraborty P, Kumar A, Bhattacharjee S, Chakraborty A, Roy S, Manna M. Experimental parasitology radio-attenuated leishmanial parasites as immunoprophylactic agent against experimental murine visceral leishmaniasis. Exp Parasitol. 2012;130:39–47.
Sollelis L, Ghorbal M, Macpherson CR, Martins RM, Kuk N, Crobu L, Bastien P, Scherf A, Lopez-Rubio JJ, Sterkers Y. First efficient CRISPR-Cas9-mediated genome editing in leishmania parasites. Cell Microbiol. 2015;17:1405–12.
Zhang W-W, Matlashewski G. CRISPR-Cas9-mediated genome editing in leishmania donovani. MBio. 2015;6:e00861.
Ishemgulova A, Hlaváčová J, Majerová K, Butenko A, Lukeš J, Votýpka J, Volf P, Yurchenko V. CRISPR/Cas9 in leishmania mexicana: a case study of LmxBTN1. PLoS One. 2018;13:1–17.
Doudna JA, Charpentier E. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346(6213):1258096. https://doi.org/10.1126/science.1258096.
Duraisingh MT, Triglia T, Cowman AF. Negative selection of plasmodium falciparum reveals targeted gene deletion by double crossover recombination. Int J Parasitol. 2002;32:81–9.
Cortazar TM, Walker J. Genetic manipulation and the study of the protozoan parasite leishmania. Biomedica. 2004;24:438–55.
Roberts SC, Kline C, Liu W, Ullman B. Generating Knock-in parasites: integration of an ornithine decarboxylase transgene into its chromosomal locus in leishmania donovani. Exp Parasitol. 2011;128:166–9.
Papadopoulou B, Breton M, Ku C, Dumas C, Fillion I, Singh AK, Olivier M, Ouellette M. Reduced infectivity of a leishmania donovani biopterin transporter genetic mutant and its use as an attenuated strain for vaccination. Infect Immun. 2002;70:62–8.
Saravia NG, Escorcia B, Osorio Y, Valderrama L, Brooks D, Arteaga L, Coombs G, Mottram J, Travi BL. Pathogenicity and protective immunogenicity of cysteine proteinase-deficient mutants of leishmania mexicana in non-murine models. Vaccine. 2006;24:4247–59.
Dey R, Dagur PK, Selvapandiyan A, McCoy JP, Salotra P, Duncan R, Nakhasi HL. Live attenuated leishmania donovani p27 gene knockout parasites are nonpathogenic and elicit long-term protective immunity in BALB/c mice. J Immunol. 2013;190:2138–49.
Santi AMM, Lanza JS, Tunes LG, et al. Growth arrested live-attenuated leishmania infantum KHARON1 null mutants display cytokinesis defect and protective immunity in mice. Sci Rep. 2018;8:1–15.
Solana JC, Ramı L, Corvo L, De OCI, Barral-Netto M, Requena JM, Iborra S, Soto M. Vaccination with a leishmania infantum HSP70-II null mutant confers long-term protective immunity against leishmania major infection in two mice models. PLoS Negl Trop Dis. 2017;11:1–26.
Solana JC, Ramírez L, Cook ECL, et al. Subcutaneous immunization of leishmania HSP70-II null mutant line reduces the severity of the experimental visceral leishmaniasis in BALB/c mice. Vaccine. 2020;8:141.
Soto M, Ramírez L, Solana JC, Cook ECL, Hernández-García E, Requena JM, Iborra S. Inoculation of the leishmania infantum HSP70-II null mutant induces long-term protection against L. amazonensis infection in BALB/c mice. Microorganisms. 2021;9:1–14.
Selvapandiyan A, Debrabant A, Duncan R, Muller J, Salotra P, Sreenivas G, Salisbury JL, Nakhasi HL. Centrin gene disruption impairs stage-specific basal body duplication and cell cycle progression in leishmania. J Biol Chem. 2004;279:25703–10.
Ismail N, Kaul A, Bhattacharya P, Gannavaram S, Nakhasi HL. Immunization with live attenuated leishmania donovani centrin−/− parasites is efficacious in asymptomatic infection. Front Immunol. 2017;8:1788. https://doi.org/10.3389/fimmu.2017.01788.
Zhang W-W, Karmakar S, Gannavaram S, et al. A second generation leishmanization vaccine with a markerless attenuated leishmania major strain using CRISPR gene editing. Nat Commun. 2020;11:1–14.
Selvapandiyan A, Duncan R, Debrabant A, Bertholet S, Sreenivas G, Negi NS, Salotra P, Nakhasi HL. Expression of a mutant form of leishmania donovani Centrin reduces the growth of the parasite. J Biol Chem. 2001;276:43253–61.
Bhattacharya P, Dey R, Dagur PK, et al. Live attenuated leishmania donovani Centrin knock out parasites generate non-inferior protective immune response in aged mice against visceral leishmaniasis. PLoS Negl Trop Dis. 2016;10:1–28.
Fiuza JA, Dey R, Davenport D, Abdeladhim M, Meneses C, Oliveira F, Kamhawi S, Valenzuela JG, Gannavaram S, Nakhasi HL. Intradermal immunization of leishmania donovani Centrin knock-out parasites in combination with salivary protein LJM19 from sand Fly vector induces a durable protective immune response in hamsters. PLoS Negl Trop Dis. 2016;10:1–17.
Fiuza JA, Gannavaram S, da Santiago HC, et al. Vaccination using live attenuated leishmania donovani centrin deleted parasites induces protection in dogs against leishmania infantum. Vaccine. 2015;33:280–8.
Fiuza JA, da Santiago HC, Selvapandiyan A, Gannavaram S, Ricci ND, Bueno LL, Bartholomeu DC, Correa-Oliveira R, Nakhasi HL, Fujiwara RT. Induction of immunogenicity by live attenuated leishmania donovani centrin deleted parasites in dogs. Vaccine. 2013;31:1785–92.
Dey R, Natarajan G, Bhattacharya P, et al. Characterization of cross-protection by genetically modified live-attenuated leishmania donovani parasites against leishmania mexicana. J Immunol. 2014;193:3513–27.
Selvapandiyan A, Dey R, Nylen S, Duncan R, Sacks D, Nakhasi HL. Intracellular replication-deficient leishmania donovani induces long lasting protective immunity against visceral leishmaniasis. J Immunol. 2009;183:1813–20.
Banerjee A, Bhattacharya P, Dagur PK, et al. Live Attenuated leishmania donovani Centrin gene–deleted parasites induce IL-23–dependent IL-17–protective immune response against visceral leishmaniasis in a murine model. J Immunol. 2018;200:163–76.
Bhattacharya P, Dey R, Dagur PK, et al. Genetically modified live attenuated leishmania donovani parasites induce innate immunity through classical activation of macrophages that direct the Th1 response in mice. Infect Immun. 2015;83:3800–15.
Hohman LS, Peters NC. CD4 + T cell-mediated immunity against the phagosomal pathogen leishmania : implications for vaccination. Trends Parasitol. 2019;35:423–35.
Rochael NC, Guimarães-Costa AB, Nascimento MTC, Desouza-Vieira TS, Oliveira MP, Garciae Souza LF, Oliveira MF, Saraiva EM. Classical ROS-dependent and early/rapid ROS-independent release of neutrophil extracellular traps triggered by leishmania parasites. Sci Rep. 2015;5:1–11.
Qadoumi M, Becker I, Donhauser N, Röllinghoff M, Bogdan C. Expression of inducible nitric oxide synthase in skin lesions of patients with American cutaneous leishmaniasis. Infect Immun. 2002;70:4638–42.
Belkaid Y, Hoffmann KF, Mendez S, Kamhawi S, Udey MC, Wynn TA, Sacks DL. The role of interleukin (IL)-10 in the persistence of leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J Exp Med. 2001;194:1497–506.
Seyed N, Peters NC, Rafati S. Translating observations from leishmanization into non-living vaccines: the potential of dendritic cell-based vaccination strategies against leishmania. Front Immunol. 2018;9:1–10.
Zaph C, Uzonna J, Beverley SM, Scott P. Central memory T cells mediate long-term immunity to leishmania major in the absence of persistent parasites. Nat Med. 2004;10:1104–10.
Peters NC, Pagán AJ, Lawyer PG, Hand TW, Henrique Roma E, Stamper LW, Romano A, Sacks DL. Chronic parasitic infection maintains high frequencies of short-lived Ly6C+CD4+ effector T cells that are required for protection against re-infection. PLoS Pathog. 2014;10:e1004538. https://doi.org/10.1371/journal.ppat.1004538.
Glennie ND, Yeramilli VA, Beiting DP, Volk SW, Weaver CT, Scott P. Skin-resident memory CD4+ T cells enhance protection against leishmania major infection. J Exp Med. 2015;212:1405–14.
Darrah PA, Patel DT, De Luca PM, et al. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against leishmania major. Nat Med. 2007;13:843–50.
Peters NC, Kimblin N, Secundino N, Kamhawi S, Lawyer P, Sacks DL. Vector transmission of leishmania abrogates vaccine-induced protective immunity. PLoS Pathog. 2009;5:e1000484. https://doi.org/10.1371/journal.ppat.1000484.
Peters NC, Bertholet S, Lawyer PG, Charmoy M, Romano A, Ribeiro-Gomes FL, Stamper LW, Sacks DL. Evaluation of recombinant leishmania polyprotein plus glucopyranosyl lipid a stable emulsion vaccines against sand Fly-transmitted leishmania major in C57BL/6 mice. J Immunol. 2012;189:4832–41.
Mou Z, Li J, Boussoffara T, et al. Identification of broadly conserved cross-species protective leishmania antigen and its responding CD4+ T cells. Sci Transl Med. 2015;7:1–12.
Duthie MS, Van Hoeven N, MacMillen Z, Picone A, Mohamath R, Erasmus J, Hsu FC, Stinchcomb DT, Reed SG. Heterologous immunization with defined RNA and subunit vaccines enhances T cell responses that protect against leishmania donovani. Front Immunol. 2018;9:1–9.
Seyed N, Rafati S. Th1 concomitant immune response mediated by IFN-γ protects against sand fly delivered leishmania infection: implications for vaccine design. Cytokine. 2021;147:155247.
Ribeiro-Gomes FL, Sacks D. The influence of early neutrophil-leishmania interactions on the host immune response to infection. Front Cell Infect Microbiol. 2012;2:59.
Ribeiro-Gomes FL, Romano A, Lee S, Roffê E, Peters NC, Debrabant A, Sacks D. Apoptotic cell clearance of leishmania major-infected neutrophils by dendritic cells inhibits CD8+ T-cell priming in vitro by Mer tyrosine kinase-dependent signaling. Cell Death Dis. 2015;6:1–12.
Krammer F. SARS-CoV-2 vaccines in development. Nature. 2020;586:516–27.
Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019;17:181–92.
Graham RL, Donaldson EF, Baric RS. A decade after SARS: strategies for controlling emerging coronaviruses. Nat Rev Microbiol. 2013;11:836–48.
Sakurai F, Tachibana M, Mizuguchi H. Adenovirus vector-based vaccine for infectious diseases. Drug Metab Pharmacokinet. 2022;42:100432.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.
The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Copyright information
© 2023 The Author(s)
About this chapter
Cite this chapter
de Carvalho Clímaco, M., Kraemer, L., Fujiwara, R.T. (2023). Vaccine Development for Human Leishmaniasis. In: Christodoulides, M. (eds) Vaccines for Neglected Pathogens: Strategies, Achievements and Challenges . Springer, Cham. https://doi.org/10.1007/978-3-031-24355-4_14
Download citation
DOI: https://doi.org/10.1007/978-3-031-24355-4_14
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-24354-7
Online ISBN: 978-3-031-24355-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)