Antibody responses against the vaccine antigens Ov-103 and Ov-RAL-2 are associated with protective immunity to Onchocerca volvulus infection in both mice and humans

Author summary Onchocerca volvulus is the causative agent of river blindness that infects approximately 17 million people, mostly in Africa. The current strategy for elimination of O. volvulus focuses on controlling transmission through ivermectin-based mass drug administration programs. Due to potential ivermectin resistance, the lack of macrofilaricidal activity by ivermectin, and the prolonged time (>20 years) needed for successful interruption of transmission in endemic areas, additional tools are critically needed including a vaccine against onchocerciasis. Ov-103 and Ov-RAL-2 are presently the most promising vaccine candidates for a prophylactic vaccine. The mechanism of protective immunity induced in mice by the alum-adjuvanted Ov-103 or Ov-RAL-2 vaccines appear to be multifactorial with essential roles for antibodies, chemokines and the specific effector cells they recruit. In this study, we show for the first time that, anti-Ov-103 and anti-Ov-RAL-2 antibodies, chemokines and innate cells also appear to be associated with protective immunity against O. volvulus infection in humans, similar to the vaccine studies observed in the O. volvulus mouse model. Background The current strategy for the elimination of onchocerciasis is based on annual or bi-annual mass drug administration with ivermectin. However, due to several limiting factors there is a growing concern that elimination of onchocerciasis cannot be achieved solely through the current strategy. Additional tools are critically needed including a prophylactic vaccine. Presently Ov-103 and Ov-RAL-2 are the most promising vaccine candidates against an Onchocerca volvulus infection. Methodology/Principal findings Protection induced by immunization of mice with the alum-adjuvanted Ov-103 or Ov-RAL-2 vaccines appeared to be antibody dependent since AID(-/-) mice that could not mount antigen-specific IgG antibody responses were not protected from an Onchocerca volvulus challenge. To determine a possible association between antigen-specific antibody responses and anti-larvae protective immunity in humans, we analyzed the presence of anti-Ov-103 and anti-Ov-RAL-2 cytophilic antibody responses (IgG1 and IgG3) in individuals classified as putatively immune, and in infected individuals who developed concomitant immunity with age. It was determined that 86% of putatively immune individuals and 95% individuals with concomitant immunity had elevated IgG1 and IgG3 responses to Ov-103 and Ov-RAL-2. Based on the elevated chemokine levels associated with protection in the Ov-103 or Ov-RAL-2 immunized mice, the profile of these chemokines was also analyzed in putatively immune and infected individuals; both groups contained significantly higher levels of KC, IP-10, MCP-1 and MIP-1 beta in comparison to normal human sera. Moreover, human monospecific anti-Ov-103 antibodies but not anti-Ov-RAL-2 significantly inhibited the molting of third-stage larvae (L3) in vitro by 46% in the presence of naive human neutrophils, while both anti-Ov-103 and anti-Ov-RAL-2 antibodies significantly inhibited the molting by 70-80% when cultured in the presence of naive human monocytes. Interestingly, inhibition of molting by Ov-103 antibodies and monocytes was only in part dependent on contact with the cells, while inhibition of molting with Ov-RAL-2 antibodies was completely dependent on contact with the monocytes. In comparison, significant levels of parasite killing in Ov-103 and Ov-RAL-2 vaccinated mice only occurred when cells enter the parasite microenvironment. Taken together, antibodies to Ov-103 and Ov-RAL-2 and cells are required for protection in mice as well as for the development of immunity in humans.