Improving the efficacy of a prophylactic vaccine formulation against lymphatic filariasis

Abstract

Mass drug administration (MDA) is the current strategy for interrupting the transmission of lymphatic filariasis (LF) infection and control of the disease in endemic areas. However, subject noncompliance has resulted in the presence of several ‘transmission hotspots’ in the endemic regions threatening the reemergence of LF. This situation is further complicated by the fact that the drugs used in MDA are not effective against adult LF worms, a major concern for the control strategy. Thus, there is clearly a need for an effective and sustainable approach to control LF. Prophylactic vaccine combined with targeted treatment of infected patients and vector control is suggested as a more sustainable strategy to eliminate LF infection from endemic regions. A multivalent vaccine (rBmHAT) developed in our laboratory confered about 90% protection in rodents. However, when we tested the rBmHAT vaccine along with alum in rhesus macaques only about 40% protection was achieved and the immune response obtained was Th2 biased. In an attempt to improve the vaccine, in this study we tested two vaccine antigens (rBmHAT and rBmHAX) along with two adjuvant formulations [alum+GLA (AL019) and mannosylated chitosan (MCA)] in a mouse model. Our results show that rBmHAT is a better vaccine antigen than rBmHAX. Combination of rBmHAT with AL019 or MCA adjuvants gave 94% and 88% protection respectively against challenge infections. Immunized animals developed antigen specific memory T cells that secreted significant levels of IL-4, IFN-γ and IL-17 suggesting the generation of a balanced Th1/Th2 responses following immunization. A major advantage of MCA adjuvant is that the vaccine booster doses can be administered orally. These studies thus showed that rBmHAT is a better vaccine antigen and can be given in combination with AL019 or MCA adjuvant to obtain excellent results.

Evaluating the Vaccine Potential of a Tetravalent Fusion Protein (rBmHAXT) Vaccine Antigen Against Lymphatic Filariasis in a Mouse Model

“…One of our recent studies suggested that including GLA-SE/alum (a synthetic toll-like receptor 4 agonist on alhydrogel, AL019) as an adjuvant along with the trivalent formulation (r Bm HAT) promoted a balanced Th1/Th2 response in the mouse model and gave better protection ( 30 ). GLA-SE is shown to be an excellent adjuvant for several human vaccine formulations ( 62 , 63 ) and other helminth vaccine formulations ( 64 ).…”

“…Several groups including ours have reported the vaccine potential of TPX-2 previously ( 24 , 27 , 28 , 40 – 42 ). In fact, one of our studies showed that a trivalent fusion protein rBm HAX (HSP12.6 + ALT-2 + TPX-2) vaccine conferred 67.5% protection in the mouse model ( 30 ). Immunization with TPX-2 skewed the protective immune response to a Th1 bias ( 30 , 41 , 43 ).…”

“…In fact, one of our studies showed that a trivalent fusion protein rBm HAX (HSP12.6 + ALT-2 + TPX-2) vaccine conferred 67.5% protection in the mouse model ( 30 ). Immunization with TPX-2 skewed the protective immune response to a Th1 bias ( 30 , 41 , 43 ). Therefore, we hypothesized that a tetravalent fusion protein could generate a more balanced Th1/Th2 response and will be more effective as a prophylactic vaccine against LF infection.…”

“…In this study, we also evaluated the potential of three different adjuvant formulations [alum (AL007), glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE)/alum (a synthetic toll-like receptor 4 agonist on alhydrogel, AL019), and mannosylated chitosan (MCA)] for their ability to promote a balanced Th1/Th2 response when given along with the tetravalent r Bm HAXT vaccine. One of our previous studies showed that AL019 and MCA are excellent adjuvants for the trivalent r Bm HAT vaccine antigen and promoted significant vaccine-induced protection in the mouse model ( 30 ).…”

Metazoan Parasite Vaccines: Present Status and Future Prospects

“…Previous pre-clinical immunization studies in mice indicated a reduction in adult parasite and liver egg burdens of 57 and 64%, respectively, following challenge with S. mansoni (Tran et al, 2006 ). A similar tetraspanin loop protein (TSP-LEL) has also been successfully evaluated in mice and non-human primates (~95% and >88% protection, respectively) as a multivalent fusion protein (rBmHAT vaccine) as a treatment against human lymphatic filariasis caused by the nematode Brugia malayi (Dakshinamoorthy et al, 2013 , 2014 ; Chauhan et al, 2017a ). A membrane surface calpain (Sm-p80) involved in parasite membrane renewal, is also showing promise as a lead candidate (Siddiqui et al, 1993 ; Ahmad et al, 2009 ) with proof-of-concept studies completed in animal models (including non-human primates) showing significant cross-species protection against S. haematobium and S. japonicum (Zhang et al, 2001 ; Karmakar et al, 2014a , b ; Molehin et al, 2016 ).…”