Abstract
Lymphatic filariasis affects 120 million people worldwide and another 1.2 billion people are at risk of acquiring the infection. Chemotherapy with mass drug administration is substantially reducing the incidence of the infection. Nevertheless, an effective vaccine is needed to prevent the infection and eradicate the disease. Previously we reported that a multivalent fusion protein vaccine (rBmHAT) composed of small heat shock proteins 12.6 (HSP12.6), abundant larval transcript-2 (ALT-2) and large extracellular domain of tetraspanin (TSP LEL) could confer >95% protection against the challenge infection with Brugia malayi infective larvae (L3) in mouse and gerbil models. In this study we evaluated the immunogenicity and efficacy of rBmHAT fusion protein vaccine in a rhesus macaque model. Our results show that rBmHAT is highly immunogenic in rhesus macaques. All the vaccinated monkeys developed significant titers of antigen-specific IgG antibodies against each of the component antigens (16,000 for rBmHSP12.6), (24,000 for rBmALT-2) and (16,000 for rBmTSP-LEL). An in vitro antibody dependent cellular cytotoxicity (ADCC) assay performed using the sera samples from vaccinated monkeys showed that the anti-rBmHAT antibodies are functional with 35% killing of B. malayi L3s. Vaccinated monkeys also had antigen responding cells in the peripheral blood. Vaccine-induced protection was determined after challenging the monkeys with 500 B. malayi L3. Following challenge infection, 3 out of 5 vaccinated macaques failed to develop the infection. These three protected macaques had high titers of IgG1 antibodies and their PBMC secreted significantly high levels of IFN-γ in response to the vaccine antigens. The two vaccinated macaques that picked the infection had slightly low titers of antibodies and their PBMC secreted high levels of IL-10. Based on these findings we conclude that the rBmHAT vaccine is highly immunogenic and safe and can confer significant protection against challenge infections in rhesus macaques.
Highlights
Human lymphatic filariasis caused mainly by Wuchereria bancrofti and Brugia malayi affects 120 million people and elicits a wide spectrum of pathological disorders of the lymphatic system with varied clinical manifestations
L3 transmitted by mosquitoes develop into adult parasites that live in the lymphatic system for several years often more than 30 years evading the host immune system
Current mass drug treatment administration (MDA) strategy uses these drugs to clear the parasite from the circulation to reduce the incidence of the infection and leading the way for elimination of lymphatic filariasis from the endemic regions
Summary
Human lymphatic filariasis caused mainly by Wuchereria bancrofti and Brugia malayi affects 120 million people and elicits a wide spectrum of pathological disorders of the lymphatic system with varied clinical manifestations. Previous studies showed that these serum antibodies are cytotoxic to infective larvae of the parasite (L3), suggesting that these individuals are naturally immune to the infection [3,4]. Using an iterative screening of a phage cDNA expression library of the parasite with the sera from EN subjects, we identified several parasite antigens that were recognized by the antibodies in the sera of EN subjects [5] These antigens were cloned and their vaccine potential was evaluated in a mouse and/or jird models [3,4,6,7,8]. Vaccination trials with a multivalent fusion combination of the three proteins (rBmHAT) showed that approximately 95% protection can be achieved against challenge infections with B. malayi L3 in a mouse and jird model of lymphatic filariasis [9]. Several other vaccines that are currently in use against infectious diseases were developed through studies in NHPs [11,12]
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