Co-Administration of Adjuvanted Recombinant Ov-103 and Ov-RAL-2 Vaccines Confer Protection against Natural Challenge in A Bovine Onchocerca ochengi Infection Model of Human Onchocerciasis

Abstract

Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, is a neglected tropical disease mainly of sub-Saharan Africa. Worldwide, an estimated 20.9 million individuals live with infection and a further 205 million are at risk of disease. Current control methods rely on mass drug administration of ivermectin to kill microfilariae and inhibit female worm fecundity. The identification and development of efficacious vaccines as complementary preventive tools to support ongoing elimination efforts are therefore an important objective of onchocerciasis research. We evaluated the protective effects of co-administering leading O. volvulus-derived recombinant vaccine candidates (Ov-103 and Ov-RAL-2) with subsequent natural exposure to the closely related cattle parasite Onchocerca ochengi. Over a 24-month exposure period, vaccinated calves (n = 11) were shown to acquire infection and microfilaridermia at a significantly lower rate compared to unvaccinated control animals (n = 10). Furthermore, adult female worm burdens were negatively correlated with anti-Ov-103 and Ov-RAL-2 IgG1 and IgG2 responses. Peptide arrays identified several Ov-103 and Ov-RAL-2-specific epitopes homologous to those identified as human B-cell and helper T-cell epitope candidates and by naturally-infected human subjects in previous studies. Overall, this study demonstrates co-administration of Ov-103 and Ov-RAL-2 with Montanide™ ISA 206 VG is highly immunogenic in cattle, conferring partial protection against natural challenge with O. ochengi. The strong, antigen-specific IgG1 and IgG2 responses associated with vaccine-induced protection are highly suggestive of a mixed Th1/Th2 associated antibody responses. Collectively, this evidence suggests vaccine formulations for human onchocerciasis should aim to elicit similarly balanced Th1/Th2 immune responses.

Predictive Immunoinformatics Reveal Promising Safety and Anti-Onchocerciasis Protective Immune Response Profiles to Vaccine Candidates (Ov-RAL-2 and Ov-103) in Anticipation of Phase I Clinical Trials

“…As the global health approach for combating the disease transitions from control to elimination, there has been a consensus on the need for alternative control tools such as prophylactic/therapeutic vaccines. Several preclinical studies have provided consistent evidence of protective immunity against the disease, targeting various candidate antigens, notably Ov -RAL-2 and Ov -103 (35–39). The TOVA Initiative was established in 2015, to advance at least one vaccine candidate through Phase I trials by 2025 (9, 11).…”

“…The TOVA Initiative was established in 2015, to advance at least one vaccine candidate through Phase I trials by 2025 (9,11). Although preclinical studies explored the use of both antigens individually, in combination, or as a fused single protein (Ov-Fus-1), and yielded promising results in mice and cattle (12,(38)(39)(40), the overall success rate of vaccine candidates, similar to drugs, during clinical development remains relatively low. In the vaccine development pipeline, bioinformatics tools continue to play crucial roles, facilitating rational antigen design and predictions of efficacy in clinical trials.…”

Eosinophils in filarial infections: Inducers of protection or pathology?

“…Similarly to the human infection, adult worms reside in subcutaneous nodules, while MF can be found in the skin ( Table 2 ) ( 21 ). It is regularly used to test antifilarial drugs and vaccines ( 22 – 24 , 33 , 34 ). Gerbils and immunodeficient mice also maintain O. ochengi or B. malayi filariae after intraperitoneal implantation, which allows preclinical testing of drug candidates in a small rodent model ( 35 – 37 ).…”

Potential of Nucleic Acid Receptor Ligands to Improve Vaccination Efficacy against the Filarial Nematode Litomosoides sigmodontis

“…For the nematode Onchocerca volvulus , there has been progress using recombinant O. volvulus antigen, i.e., Ov -103 and Ov -RAL-2, which induced protections of up to 64% in combination with alum-based adjuvants in a murine model [ 8 , 9 ]. Further, coadministration of Ov-103 and Ov- RAL-2 in the bovine model utilizing infections with Onchocerca ochengi led to a significant decrease in the rate of infection and development of microfilaridermia in cows that were infected via natural exposure [ 10 ]. Similarly, vaccinations with a fusion protein of the orthologous proteins from Brugia malayi ( Bm- 103 and Bm- RAL-2) coadministered with alum resulted in a significant worm reduction (61%) and reduced the embryogenesis of the remaining worms in a gerbil model [ 11 ].…”