The TOVA Partnership has identified three candidate vaccine antigens that have proven to be efficacious in three different filarial animal model systems and in five independent laboratories (Table 3).
Our goal is production and testing of a river blindness vaccine through Phase I trials by 2025.
The vaccine candidates
Parasite antigens were identified as possible vaccine candidates by their ability to stimulate immune responses that killed the various lifecycle stages of the parasites in model systems (https://www.ncbi.nlm.nih.gov/pubmed/28958602).
The life cycle of O volvulus cannot be maintained in the laboratory, although infective L3 larvae recovered from blackflies can survive a short time confined in sub-cutaneous chambers in mice.
To asses killing of adult worms and microfilariae, two models were used: (1), Brugia malayi in gerbils (Meriones unguiculatus) and (2) Litomosoides sigmodontis in mice. B malayi causes lymphatic filariasis or elephantiasis in humans and is found in India, Indonesia, Malaysia and Thailand. L sigmodontis is a natural parasite of cotton rats (Sigmodon spp.) but can undergo complete cyclical development in laboratory mice and hence is a valuable model for detailed investigation of mechanisms of immunity against filariae.
Table 3 summarises results of immunisation experiments performed with the selected vaccine candidates. All three are expressed on the surface of the parasites at all developmental stages, where they provide a target for direct attack by the immune system. This is well demonstrated by the in vitro killing of L3 larvae by antibody and neutrophils.
One of the antigens (CPI-2M) is derived from an immuno-modulator secreted by the parasite to help it avoid potential lethal effects of acquired immune responses of infected individuals. Vaccination with this antigen generates antibodies capable of neutralising the suppressive action of the native molecule and thereby facilitating expression of responses directed against all parasite antigens.
Children: the neglected hosts
Children below 5 years are excluded from ivermectin treatment and this leaves a significant proportion of the population exposed to infection. For example, in Cameroon , 16% of the population are under 5 years (United Nations, http://esa.un.org/unpd/wpp/index.htm). Similar age profiles are found throughout filarial endemic regions of Africa and in populations that are expected to double over the next 25 years (https://www.populationpyramid.net/sub-saharan-africa/2050.htm). Pre-school children comprise a large reservoir of microfilariae that can contribute to transmission.
For the individual, the consequences of not receiving treatment would be the prospect of developing progressive filarial disease and more general long-term health problems as well as associated socio-economic disadvantage. Vaccination would protect the individual and make a major contribution to public health.
It is envisaged that the onchocerciasis vaccine will be used initially to protect vulnerable children (<5 years of age) living in loiasis co-endemic areas. The vaccine will reduce adult worm burden and fecundity with consequential reduction in pathology associated with microfilariae (Figures 7 & 8). In addition, a vaccine will find use in ongoing ivermectin MDA programmes and contribute to reduction in transmission rates; and, will protect areas where local elimination may have been achieved.