Immune responses of B. malayi thioredoxin (TRX) and venom allergen homologue (VAH) chimeric multiple antigen for lymphatic filariasis

Abstract

Although multiple vaccine strategy for lymphatic filariasis has provided tremendous hope, the choice of antigens used in combination has determined its success in the previous studies. Multiple antigens comprising key vaccine candidates from different life cycle stages would provide a promising strategy if the antigenic combination is chosen by careful screening. In order to analyze one such combination, we have used a chimeric construct carrying the well studied B. malayi antigens thioredoxin (BmTRX) and venom allergen homologue (BmVAH) as a fusion protein (TV) and evaluated its immune responses in mice model. The efficacy of fusion protein vaccine was explored in comparison with the single antigen vaccines and their cocktail. In mice, TV induced significantly high antibody titer of 1,28,000 compared to cocktail vaccine TRX+VAH (50,000) and single antigen vaccine TRX (16,000) or VAH (50,000). Furthermore, TV elicited higher level of cellular proliferative response together with elevated levels of IFN-γ, IL-4 and IL-5 indicating a Th1/Th2 balanced response. The isotype antibody profile showed significantly high level of IgG1 and IgG2b confirming the balanced response elicited by TV. Immunization with TV antigen induced high levels of both humoral and cellular immune responses compared to either cocktail or antigen given alone. The result suggests that TV is highly immunogenic in mice and hence the combination needs to be evaluated for its prophylactic potential.

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

“…Given its critical role for survival of the parasite in the host, TPX-2 is a potential target for vaccine development. Our group and others ( 24 , 27 , 28 , 40 – 42 ) have previously reported the vaccine potential of TPX. Studies showed that r Bm TRX could confer 62% protection against B. malayi challenge in Mastomys model ( 43 ) and 43–69.5% protection in mouse and jird models ( 27 , 28 ).…”

“…Thioredoxin peroxidase (TPX-2) is a highly immunogenic protein within the total secretome of B. malayi ( 37 – 39 ). 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 ).…”

“…Analysis of the type of immune responses generated following TPX-2 immunization suggested that predominantly an IFN-γ-mediated response is generated in the mouse model ( 24 , 27 , 28 , 40 – 42 ). Our previous studies using the trivalent formulation (r Bm HAT plus alum) in rhesus macaque showed that a Th2 biased response was predominant with a weak IFN-γ response, which we believed was the reason for poor vaccine-induced protection in macaques ( 34 ).…”

“…Out of the several candidate vaccine antigens reported to date, we selected three best candidate antigens; heat shock protein 12.6 (HSP-12.6) ( 22 ), abundant larval transcript-2 (ALT-2) ( 21 ), and tetraspanin large extracellular loop (TSPLEL) ( 23 ) that repeatedly showed maximum protection in rodent models in our laboratory and other. Two of the selected antigens were then combined with a bivalent vaccine antigen and tested the vaccine potential in rodent models ( 24 – 28 ). Subsequently, we combined three of the antigens with a trivalent fusion protein vaccine and tested in rodents ( 29 – 33 ) and in non-human primates ( 34 ).…”

Prospects of developing a prophylactic vaccine against human lymphatic filariasis – evaluation of protection in non-human primates

“…Our laboratory and others have identified and characterized several potential candidate vaccine antigens of LF and evaluated their vaccine potential in rodent models (Denham, 1980; Dissanayake et al, 1995; Gregory et al, 1997; Anand et al, 2008, 2011; Gnanasekar et al, 2008; Vedi et al, 2008; Veerapathran et al, 2009; Kalyanasundaram and Balumuri, 2011; Babayan et al, 2012; Dakshinamoorthy et al, 2012; Anugraha et al, 2013; Dakshinamoorthy et al, 2013a; Gomase et al, 2013; Arumugam et al, 2014; Gupta et al, 2016). Among the various antigens that we characterized, four antigens, abundant larval transcript-2 (ALT-2) (Anand et al, 2008; Kalyanasundaram and Balumuri, 2011; Madhumathi et al, 2017), heat shock protein (HSP) 12.6 (Dakshinamoorthy et al, 2012), thioredoxin peroxidase-2 (TPX-2) (Anand et al, 2008; Anugraha et al, 2013) and tetraspanin large extracellular loop (TSP-LEL) (Gnanasekar et al, 2008; Dakshinamoorthy et al, 2013a) gave excellent protection in rodent models. Subsequently, we showed that combining three of these antigens as a multivalent fusion protein, rBmHAT (recombinant B. malayi HSP12.6, ALT-2 and TSP-LEL) gave close to sterile immunity in mouse and jird models (Dakshinamoorthy and Kalyanasundaram, 2013; Dakshinamoorthy et al, 2013a).…”