Immunisation with a Multivalent, Subunit Vaccine Reduces Patent Infection in a Natural Bovine Model of Onchocerciasis during Intense Field Exposure

Abstract

Human onchocerciasis, caused by the filarial nematode Onchocerca volvulus, is controlled almost exclusively by the drug ivermectin, which prevents pathology by targeting the microfilariae. However, this reliance on a single control tool has led to interest in vaccination as a potentially complementary strategy. Here, we describe the results of a trial in West Africa to evaluate a multivalent, subunit vaccine for onchocerciasis in the naturally evolved host-parasite relationship of Onchocerca ochengi in cattle. Naïve calves, reared in fly-proof accommodation, were immunised with eight recombinant antigens of O. ochengi, administered separately with either Freund's adjuvant or alum. The selected antigens were orthologues of O. volvulus recombinant proteins that had previously been shown to confer protection against filarial larvae in rodent models and, in some cases, were recognised by serum antibodies from putatively immune humans. The vaccine was highly immunogenic, eliciting a mixed IgG isotype response. Four weeks after the final immunisation, vaccinated and adjuvant-treated control calves were exposed to natural parasite transmission by the blackfly vectors in an area of Cameroon hyperendemic for O. ochengi. After 22 months, all the control animals had patent infections (i.e., microfilaridermia), compared with only 58% of vaccinated cattle (P = 0.015). This study indicates that vaccination to prevent patent infection may be an achievable goal in onchocerciasis, reducing both the pathology and transmissibility of the infection. The cattle model has also demonstrated its utility for preclinical vaccine discovery, although much research will be required to achieve the requisite target product profile of a clinical candidate. River blindness, or onchocerciasis, is caused by a parasitic worm (Onchocerca volvulus) that is transmitted by blood-feeding blackflies, which breed in fast-flowing rivers. More than 37 million people are infected and may experience visual impairment and/or severe dermatitis. Control of onchocerciasis is largely dependent on a single drug, ivermectin. Whilst this is extremely effective at killing the worms' offspring (microfilariae) and preventing symptoms, ivermectin does not eliminate the long-lived adult parasites or always stop transmission. Consequently, treatments must be repeated for many years, and drug resistance may be emerging. Against this background, a vaccine against onchocerciasis would provide an important additional tool to sustain effective control. In this study, we evaluated eight worm antigens as vaccine components in cattle, which are often parasitized by O. ochengi (the closest relative of O. volvulus) in West Africa. Twelve uninfected animals received all eight antigens and were exposed to natural transmission of O. ochengi alongside 13 unvaccinated cattle. After almost two years, 92% of vaccinated animals had acquired adult worms, but only 58% were positive for microfilariae; whereas 100% of unvaccinated animals harboured both parasite stages. This suggests that a vaccine against microfilariae to prevent development of disease in humans may be achievable.