The History of Anti-Trypanosome Vaccine Development Shows That Highly Immunogenic and Exposed Pathogen-Derived Antigens Are Not Necessarily Good Target Candidates: Enolase and ISG75 as Examples

Abstract

Salivarian trypanosomes comprise a group of extracellular anthroponotic and zoonotic parasites. The only sustainable method for global control of these infection is through vaccination of livestock animals. Despite multiple reports describing promising laboratory results, no single field-applicable solution has been successful so far. Conventionally, vaccine research focusses mostly on exposed immunogenic antigens, or the structural molecular knowledge of surface exposed invariant immunogens. Unfortunately, extracellular parasites (or parasites with extracellular life stages) have devised efficient defense systems against host antibody attacks, so they can deal with the mammalian humoral immune response. In the case of trypanosomes, it appears that these mechanisms have been perfected, leading to vaccine failure in natural hosts. Here, we provide two examples of potential vaccine candidates that, despite being immunogenic and accessible to the immune system, failed to induce a functionally protective memory response. First, trypanosomal enolase was tested as a vaccine candidate, as it was recently characterized as a highly conserved enzyme that is readily recognized during infection by the host antibody response. Secondly, we re-addressed a vaccine approach towards the Invariant Surface Glycoprotein ISG75, and showed that despite being highly immunogenic, trypanosomes can avoid anti-ISG75 mediated parasitemia control.

Cloning and Characterization of Trypanosoma congolense and T. vivax Nucleoside Transporters Reveal the Potential of P1-Type Carriers for the Discovery of Broad-Spectrum Nucleoside-Based Therapeutics against Animal African Trypanosomiasis

“…While these analogs were not as active as the 3′-deoxytubercidin analogs in T. brucei , T. congolense , T. equiperdum and T. evansi, the multispecies activity they have exhibited at ˂ 0.2 µM EC 50 makes them more promising candidates to target both AAT and the non-tsetse transmitted animal trypanosomiases (NTTAT). As the areas of endemicity of veterinary trypanosomes increasingly overlap on the global map [ 5 ], there is an urgent need to develop drugs that are active against all five Trypanosoma species.…”

“…Although the related human disease HAT has been targeted for elimination by the WHO by 2030 [ 2 ], it appears that AAT will continue to be around at least for decades. Despite some promising progress for T. vivax , implementation of a vaccine is at best years away, even for any single Trypanosoma species [ 3 , 4 , 5 ]. Control by chemotherapy is hampered by the paucity of drugs, and the widespread resistance to them [ 6 , 7 ].…”

“…In the last 60 years, only one new veterinary trypanocide has been introduced to the field, melarsomine (Cymelarsan, MelCy), which was developed in the late 1980s [ 14 ]; the other veterinary trypanocides in use are all 60 years old or more [ 15 ]. Therefore, the need for safer and more effective trypanocides cannot be overemphasized, especially considering the slim chances of vaccine development [ 5 ]. Furthermore, different isolates of veterinary trypanosomes have shown great variability in their drug sensitivity profile, which often leads to treatment failure and devastating impact on agricultural and rural economy of developing countries [ 11 , 16 ].…”

The Pathogenesis of African Trypanosomiasis

“…Today, not a single antitrypanosome vaccine has proved successful under field conditions, despite the use of highly immunogenic invariant antigens such as the invariant surface glycoprotein 75 or the recently discovered invariant flagellum antigen from T. vivax (IFX) (144)(145)(146). Hence, even if a successful vaccine candidate were to be discovered for HAT or AT, it should overcome the speed at which the trypanosome manages to ablate functional memory.…”

Low Dose Gamma Irradiation of Trypanosoma evansi Parasites Identifies Molecular Changes That Occur to Repair Radiation Damage and Gene Transcripts That May Be Involved in Establishing Disease in Mice Post-Irradiation

“…Like all other extracellular parasites in the genus, T. evansi primarily evades mammalian host immunity by switching its variable surface glycoprotein (VSG). At the onset of the infection, initial VSG-induced Th1 responses are followed by T cell exhaustion, altered antigen presentation, defective complement activation and eventually the destruction of the bone marrow, marginal zone, and follicular B cell populations, thus eliminating B cell memory and making the host vulnerable to other secondary diseases (9,(18)(19)(20)(21). Vaccinated pigs and water buffalos perform poorly against already vaccinated diseases after acquiring T. evansi infections (9,21).…”