Multivalent fusion protein vaccine for lymphatic filariasis

Abstract

Lymphatic filariasis affects approximately 3% of the whole world population. Mass drug administration is currently the major control strategy to eradicate this infection from endemic regions by year 2020. Combination drug treatments are highly efficient in controlling the infection. However, there are no effective vaccines available for human or animal lymphatic filariasis despite the identification of several subunit vaccines. Lymphatic filariasis parasites are multicellular organisms and potentially use multiple mechanisms to survive in the host. Therefore, there is a need to combine two or more vaccine candidate antigens to achieve the desired effect. In this study we combined three well characterized vaccine antigens of Brugia malayi, heat shock protein12.6 (HSP12.6), abundant larval transcript-2 (ALT-2) and tetraspanin large extra cellular loop (TSP-LEL) as a multivalent fusion vaccine. Putative immune individuals carry circulating antibodies against all three antigens. Depletion of these antigen specific antibodies from the sera samples removed the ability of the sera to participate in the killing of B. malayi L3 in an antibody dependent cellular cytotoxicity (ADCC) mechanism. Vaccination trials in mice with a bivalent [HSP12.6+ALT-2 (HA), HSP12.6+TSP-LEL (HT) or TSP-LEL+ALT-2 (TA)] or trivalent [HSP12.6+ALT-2+TSP-LEL (HAT)] vaccines using DNA, protein or heterologous prime boost regimen showed that trivalent HAT vaccine either as protein alone or as heterologous prime boost vaccine could confer significant protection (95%) against B. malayi L3 challenge. Immune correlates of protection suggest a Th1/Th2 bias. These finding suggests that the trivalent HAT fusion protein is a promising prophylactic vaccine against lymphatic filariasis infection in human.

Improving the efficacy of a prophylactic vaccine formulation against lymphatic filariasis

“…There is a need for a more sustained approach such as a prophylactic vaccination to stop transmission and eliminate LF from the endemic areas (Dakshinamoorthy et al 2013c; Jambulingam et al 2016; Harris et al 2017). Our laboratory and others have identified several potential vaccine antigens that are shown to confer significant protection against challenge infections in experimental animals (Samykutty et al 2010; Dakshinamoorthy et al 2013b, Dakshinamoorthy et al 2013c; Arumugam et al 2014). One of our recent trials in non-human primates using a trivalent fusion protein vaccine (r Bm HAT) showed that approximately 40% protection could be achieved in vaccinated animals against a challenge infection (Dakshinamoorthy et al 2012).…”

Effect of muramyl dipeptide and alum adjuvants on immunization with Filarial multi antigen peptide vaccine in mice model

“…Strategies to identify candidate vaccine antigens against brugian or bancroftian fi lariasis include screening expression libraries with immune sera (Freedman et al, 1989), differential screening of abundantly expressed mRNAs (Gregory et al, 2000) or by the Expressed Sequence Tag (EST) approach (Blaxter et al, 1999). These strategies have facilitated the identifi cation of several potential vaccine candidates offering varying degrees of protection against fi larial infection in animal models (Thirugnanam et al, 2007;Anand et al, 2008;Vanam et al, 2009;Dakshinamoorthy et al, 2013). Antioxidant enzymes thioredoxin (TRX), thioredoxin peroxidase (TPX), glutathione-S-transferase (GST), superoxide dismutase (SOD) and glutathione peroxidase (GPX), most of which are present in all stages of the parasite and have been involved to protect the parasites from the host are reported as promising vaccine candidates (Maizels et al, 2001;Veerapathran et al, 2009;Madhumathi et al, 2010).…”

Immunization with Wuchereria bancrofti Glutathione-S-transferase Elicits a Mixed Th1/Th2 Type of Protective Immune Response Against Filarial Infection in Mastomys

“…Therefore, development of vaccines as a preventive tool to control the infection is important. Earlier studies have reported the utilization of recombinant proteins as vaccine candidates for the lymphatic filariasis [5][6][7][8][9].…”