Abstract
BackgroundThe 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 findingsProtection 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-1β 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 naïve 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.Conclusions/SignificanceAlum-adjuvanted Ov-103 and Ov-RAL-2 vaccines have the potential of reducing infection and thus morbidity associated with onchocerciasis in humans. The development of cytophilic antibodies, that function in antibody-dependent cellular cytotoxicity, is essential for a successful prophylactic vaccine against this infection.
Highlights
Onchocerca volvulus, a filarial nematode, is the etiologic agent of river blindness that infects approximately 17 million people in Africa with more than 10 million people living with skin disease and 1 million with visual impairment [1]
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
Summary
Onchocerca volvulus, a filarial nematode, is the etiologic agent of river blindness that infects approximately 17 million people in Africa with more than 10 million people living with skin disease and 1 million with visual impairment [1]. Role of antigen-specific antibodies in protective immunity against O. volvulus need for lengthy (>20 years) annual drug administration, the inability to implement largescale treatment programs in areas that are co-endemic for loiasis, it remains unlikely that onchocerciasis can be eliminated entirely through MDA with only ivermectin [2]. This realization has stimulated the search for companion intervention tools, including vaccines, to support the efforts to eliminate onchocerciasis [3,4,5]. Ov-103 and Ov-RAL-2 are the most promising vaccine candidates against an Onchocerca volvulus infection
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