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

Abstract

Lymphatic filariasis (LF) is a tropical parasitic infection of human transmitted by mosquitoes. Chronic infection results in severe physical disability in the infected patients. Although several potential vaccine antigens were identified by several groups, there are no licensed prophylactic vaccine to date against this infection in the human. Previous attempts from our laboratory to develop a trivalent prophylactic vaccine against LF showed that >90% protection could be achieved in rodent models. However, this trivalent vaccine gave only 35% protection in non-human primates. The major focus of this study was to develop a tetravalent prophylactic vaccine (rBmHAXT) and test the vaccine potential in a mouse model. We evaluated three different adjuvant formulations; alum, glucopyranosyl lipid adjuvant in stable emulsion (GLA/SE) alum (AL019), and mannosylated chitosan (MCA) to determine the optimum adjuvant formulation for rBmHAXT. Results presented in this study show that rBmHAXT + AL019 gave the highest rate of protection (>88%) against challenge infection, compared to rBmHAXT + AL007 (79%), rBmHAXT + MCA (79%) and controls. Analysis of the immune correlates of protection showed that all three adjuvants elicited high titer of antigen-specific IgG1, IgG2a, and IgG2b antibodies. High number of IFN-γ-producing antigen-specific memory cells were generated in the vaccinated animals irrespective of the adjuvants used. Similarly, spleen cells from rBmHAXT-vaccinated animals secreted IL-4, IL-10, and IFN-γ in response to rBmHAXT suggesting the generation of a balanced Th1/Th2 response. There was also an increase in IL-17-secreting cells in rBmHAXT-vaccinated animals. These findings thus suggest that rBmHAXT + AL019 is a better prophylactic formulation for LF.

Promising Technologies in the Field of Helminth Vaccines

“…A significant protection of 88.05% was obtained compared to 79.47% and 78.67% given when rBm-HAXT was adjuvanted with conventional alum and mannosylated chitosan (MCA) respectively. All vaccines tested increased the percentage of central memory T cells (T CM ) in the spleen, with an increased expression of IFNγ specifically in those cells from the GLA-SE vaccine arm ( 110 ). When this vaccine was tested in a non-human primate (NHP) model, despite adding another boosting immunization, vaccine efficacy dropped drastically to 57.14% protection ( 111 ).…”

Highlighting the Relevance of CD8+ T Cells in Filarial Infections

“…The efficacy of these potential vaccine candidates in different animal models ranges from 45% to 94% ( 83 ). The vaccine formulations usually include filarial antigens such as heat shock protein 12.6 ( 86 – 88 ), abundant larval transcript-2 ( 86 , 88 , 89 , 91 ), tetraspanin large extracellular loop ( 86 – 88 ), vespid allergen homologue ( 89 , 91 ), thioredoxin peroxide ( 86 ), calponin ( 92 ), disorganized muscle protein-1 ( 93 ), and trehalose-6-phosphate phosphatase ( 35 ). In addition to these antigens, adjuvants are added to formulations to improve the vaccine-induced responses.…”

“…In addition to these antigens, adjuvants are added to formulations to improve the vaccine-induced responses. The most used adjuvants for antifilaria immunization formulations are alum, tuftsin and TLR agonists ( 86 , 94 – 97 ).…”

Advances in Vaccine Development for Human Lymphatic Filariasis

“…Therefore, targeting a single critical antigen will not have the desired effect, since the LF parasites are notorious for using redundant mechanisms to escape host insults. Subsequent approaches to combine potential vaccine antigens as cocktail vaccines [24,30,51], chimeric antigen [60], multisubunit and multi epitope vaccines [31,32,35,60,62] or multivalent vaccines [37,38,46,61], gave excellent results when tested in experimental rodent models. Thus, vaccine development against LF started focusing more on combining one or more antigens and testing their vaccine potential in experimental animals.…”