Recombinant antigens in vaccine
Parasitic diseases are responsible for some of the most devastating and common diseases of humans and also cause disease in animals that are widely associated with significant economic loss. Therefore, the control strategies such as vaccine development for parasitic diseases is necessary (35). There are various strategies for designing and developing vaccine against parasites. Killed or attenuated pathogens, are first generation vaccines to induce immunity systems against parasites. Advances in immunology, molecular biology, biochemistry, genomics, and proteomics as well as our understanding of antigen presentation, including single proteins or synthetic peptides containing many B- and T-cell epitopes led to creation of next generation of vaccine (second generation). Moreover, novel molecular-based strategies applied for vaccine development such as DNA vaccines such viral vector-based vaccines established vaccine third generation (36) .
Conventional vaccine methods against parasitic infections are relatively unsuccessful in eliminating the pathogen because parasitic infections tend to be chronic in nature. This is the result of several factors including inappropriate and ineffective immune responses in the host, various immune evasion strategies such as antigenic variation, molecular mimicry and complex lifecycles and other biological characteristics (37).
Vaccines based on recombinant proteins have several benefits over traditional vaccines, including safety and production cost. Nevertheless, they generate weakly immunogenic response when given alone due to dilution, degradation and elimination of vaccine by the host. As a result, use of adjuvants is necessary for eliciting a protective and long-lasting immune response (38) and increasing innate immune responses or lengthening their half-life (39). Adjuvants should be selected in accordance with desired immune response for a particular vaccine. Different adjuvant formulations used in providing vaccines can induce very different levels of protective responses (40).
Immunogenic surface antigens, which are expressed in almost every stage of the parasite lifecycle, are the most common antigens used for the construction of protein-based vaccines. Moreover, synthetic peptides are promising candidate vaccines for controlling parasitic diseases because they are highly immunogenic, safer and less inexpensive (41).
World Health Organization (WHO) reported that Leishmaniasis is among the category-1 diseases described as emerging and uncontrolled diseases. Development of potential vaccine candidates is one of the prevention mechanisms (42). The major challenges in the development of vaccine against leishmaniasis are including the antigenic complexity, variability of the species Leishmania, wide range of responses among different hosts, and cost associated with the development (43). There have been many attempts to develop a vaccine but there are still no efficacious vaccines or against leishmaniasis and therefore innovative control methods are required. One way is through using reverse genetic engineering on important enzymes, proteins and macromolecules. For example, Almani et al. showed that by generating a null mutant using remove of two alleles of GlcNAc-PI-de-N-acetylase (GPI12), might produce a mutant leishmania without any damaging to the host (44). One of the major limitations in providing vaccine for leishmaniasis is the requirement of combining two or more antigens to conserve antigenic properties for various Leishmania species as well amastigote and promastigote phases of parasite (45). Recombinant antigens studied to development of vaccines against visceral leishmaniasis include P0 , CPI and CPII , GP63 , FML , GP36 , LiESAp , rLdccys1 , SLA , rLdp45 , rLelF-2, rLdPDI , rA2 , KMP-11 , rLeish-111f, Ldp27, pSP, rSMT , Histone H1 , HSP70 and HSP83 , LBSap , GP63 and HSP70, rLiHyp. The important parameters for designing anti-leishmanial vaccine are identification of suitable antigen, antigen delivery and induction of strong Th1 type immune response. Leishmune'' as a second generation vaccine, has been shown good results for controlling canine visceral leishmaniasis (46)
Toxoplasma gondii, the etiological agent of toxoplasmosis, which has a worldwide distribution, can induce abortion or considerable morbidity of fetuses. However, T. gondii infection in adults is usually asymptomatic or associated with self-limited symptoms (e.g., fever, malaise, lymphadenopathy). Vaccination against toxoplasma should be including of prevention of infection in human or that of clinical disease animals rose for human consumption, thereby preventing transmission also contamination of the environment by oocysts. Therefore, development of an effective vaccine against toxoplasmosis that can be used in animals or humans can be valuable.
The effective recombinant vaccines have been shown that have ability to act against both sexual and asexual stages of the parasite. Using recombinant proteins as vaccine antigens against toxoplasmosis has become popular after 1990s. At the first, SAG1 which is protein presented on the surface of the parasite and GRA1 (a dense granule protein) were evaluated as recombinant proteins in vaccination. The studies on mice vaccination against toxoplasma based on the selection of ideal protective antigens and recently more attention on combined proteins from membrane associated surface antigen, excreted-secreted dense granule proteins, rhoptry proteins and micronemal proteins (47).
GRA7 , ROP2 ,SAG2, SAG3, SRS1 , HSP70, HSP30 (BAG1) , MIC1, MIC2, MIC3, MIC4, MIC6 ,GRA2, GRA4, GRA5, GRA6, AMA1, MAG1 ROP4 MIC8, MIC11, and MIC13, ROP1, ROP5, ROP8, ROP9, ROP 13, ROP16, ROP17, ROP18, and ROP38, RON2, RON4, SAG2CDX, SAG5D, SRS4, and SRS9 from SRS , PLP1 (perforin-like protein 1), IMP1 ,ROM1, CDPK3 , eIF4A ,eIF2'' , CyP , cathepsin B and L like , ACT (Actin, CDPK5 , DPA , RACK-1, GST are the proteins that have been used for developing toxoplasma vaccines. Most of these vaccine antigens were chosen randomly without taking into account of T. gondii's multistage property and consequently did not confer the desired immune responses.
The development of a multivalent vaccine against different life cycle stages of T. gondii could be generally more efficient. T. gondii BAG1 and GRA1 proteins have important roles in parasite's life cycle. It is well known that BAG1 is expressed by the bradyzoite form of the parasite which promotes the differentiation of tachyzoites to bradyzoites and takes role at inducing dendritic cells and activating cellular immune response and GRA1 protein is expressed by tachyzoite, bradyzoite and sporozoite forms which is excreted to parasitophorous vacuole during the invasion of host cell for stability of the parasite through parasitophorous network. Previously, GRA1 and BAG1 genes were used individually as vaccine candidate antigens in DNA vaccination and recombinant protein-based vaccination studies with induction protective immune responses. The selection of appropriate model is a basic principle in protective approach, whereas infection usually occurs via ingestion of cysts and oocyst in animals (48).
Malaria as the most devastating parasitic disease is an infectious disease caused by five species of parasites belonging to the genus Plasmodium. This parasite in the multiple stages of lifecycle displays various antigens at the cell surface that can be used to develop vaccines (49). Recombinant malaria antigens progressed to clinical testing include PfCSP; PfTRAP; PfCelTOS; PfAMA1; PfLSA1; PfLSA3; PfMSP1; PfMSP2; PfMSP3; PfGLURP; PfRESA; Pf27A; Pf11.1; PfEBA175; PfSERA5; Pfs230; Pfs25; PvCSP; Pvs25; [PfRH5; VAR2CSA; Pfs48/45; PvDBP] (50). For example recombinant proteins made from fusion of PfGLURP and PfMSP3 expressed in Lactococcus lactis (a generally recognized as safe or 'GRAS' organism) is a type of antigens served in preventing the disease. This vaccine was targeted for a sexual blood-stage and aimed at reducing the parasite load in order to confer protection against clinical malaria.
According to the multistage life cycle of malaria parasites therefore, multivalent vaccines would be required to provide sufficient protection against plasmodium. One approach is the design of vaccine that incorporates several antigens. Synthetic peptides containing defined B and T-cell epitopes of different antigens expressed in various stages that can effectively target multiple stages of the parasite cycle. For example, Tamborrini et al. have described the immunological characterization of linear and cyclized synthetic peptides comprising amino acids 211-237 of P. falciparum merozoite surface protein (MSP-3) (51).
Trypanosomes are eukaryotic, flagellated hemo-protozoan parasites. Different species of trypanosomes infect a wide host range, including animals and humans. Since eradication of entire parasite reservoir of endemic areas is impassible and trypanotolerance is occurred in many mammals endemic, therefore the ultimate goal in the fight against this disease is to develop an effective vaccine (52).
Tc24 is an excretory/secretory antigen which localizes into the plasma membrane throughout all life stages. Tc24 is produced by T. cruzi which, is a B-cell superantigen. Immune response to a Tc24 recombinant protein was evaluated by Meagan A. et al. In their study, a poly(lactic-co-glycolic acid) nanoparticle delivery system combined with CpG motif-containing oligodeoxynucleotides as an immunomodulatory adjuvant for elicitation cell-mediated immune response in a BALB/c mouse model. Result of this work demonstrated efficacy and immunogenicity of a therapeutic Chagas vaccine using a nanoparticle delivery system (53).
However, so far development of a vaccine against trypanosomiasis do not have significant success because this parasite have potential of antigenic variation and thereby ability to escape the host immune response (54). Accordingly, it is necessary to develop a vaccine based on the other potential target proteins of trypanosome. For example, San-Qiang Li et al. repoted that the recombinant T. evansiactin induces protective immunity against T.equiperdum, T. evansi, and T. brucei infection (55).
...(download the rest of the essay above)