Glycoconjugate-Based Vaccines for Chagas Disease
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. About 6–8 million people are estimated to be infected worldwide. It is a blood borne pathogen and transmitted to humans by the insect vector (kissing bug), blood transfusion, organ transplant, contaminated foods and juices, and by congenital contagion. The chemotherapy is partially effective in chronic phase of the disease, and the drugs cause several side effects. There is no vaccine to prevent or treat Chagas disease. The great majority of experimental vaccines have employed whole parasite extracts, purified or recombinant proteins, synthetic peptides, or DNA; however, most of them provide only partial protection. The goal of this project is to evaluate the effect of an αGal-based neoglycoprotein (NGP) vaccine against ChD in the α1,3-galactosyltransferase-knockout (α1,3-GalT-KO) mice. In our first study, mice were vaccinated with NGP Galα(1,3)Galβ(1,4)GlcNAcα-BSA (3 atom spacer, Dextra) and T. cruzi -challenged three consecutive times. This study showed that parasitemia is lower after a second and third challenge; however, they were not protected after immunosuppression. In our second study, NGP Galα(1,3)Galβ(1,4)GlcNAcβ-BSA (KM24b) was combined with LMPLA. This study showed that vaccination with KM24b alone gave much lower survival rate as compared to the previous study using Galα(1,3)Galβ(1,4)GlcNAcβ-BSA. The differences between the two NGPs are: (a) the anomeric configuration of the reducing-end GlcNAc residue (α vs. β), (b) and length of the spacer (3-atom linker in the Galα(1,3)Galβ(1,4)GlcNAcβ-BSA vs. 13-atom linker in the KM24b). In our third study, mice were vaccinated with αGal-containing NGPs with linkers with distinct length (3-atom vs. 14-atom-linker) and different carrier proteins (BSA or HSA). This study showed that carrier protein and the linker length are crucial parameters to be considered in the design of NGPs to be tested as experimental vaccines for ChD. In our fourth study, the commercial NGP Galα(1,3)Galβ(1,4)GlcNAc-NH-HSA (3 atom-linker) was combined with LMPLA. This study showed that vaccination with NGP Galα(1,3)Galβ(1,4)GlcNAc-NH-HSA (3 atom-linker) alone gave higher survival rate (100%) and higher protection than vaccination with NGP Galα(1,3)Galβ(1,4)GlcNAc-NH-HSA (3 atom-linker) combined with LMPLA. In conclusion, the use of LMPLA improved the efficacy of KM24b as preventive experimental vaccine against T. cruzi challenge; however, did not improve the efficacy of NGP Galα(1,3)Galβ(1,4)GlcNAc-NH-HSA (3 atom-linker).
Zepeda, Brenda Guadalupe, "Glycoconjugate-Based Vaccines for Chagas Disease" (2018). ETD Collection for University of Texas, El Paso. AAI10823142.