Adjuvanted Schistosoma mansoni-Cathepsin B With Sulfated Lactosyl Archaeol Archaeosomes or AddaVax™ Provides Protection in a Pre-Clinical Schistosomiasis Model

Abstract

Schistosomiasis threatens 800 million people worldwide. Chronic pathology manifests as hepatosplenomegaly, and intestinal schistosomiasis caused by Schistosoma mansoni can lead to liver fibrosis, cirrhosis, and blood in the stool. To assist the only FDA-approved drug, praziquantel, in parasite elimination, the development of a vaccine would be of high value. S. mansoni Cathepsin B (SmCB) is a well-documented vaccine target for intestinal schistosomiasis. Herein, we test the increased efficacy and immunogenicity of SmCB when combined with sulfated lactosyl archaeol (SLA) archaeosomes or AddaVax™ (a squalene based oil-in-water emulsion). Both vaccine formulations resulted in robust humoral and cell mediated immune responses. Impressively, both formulations were able to reduce parasite burden greater than 40% (WHO standard), with AddaVax™ reaching 86.8%. Additionally, SmCB with both adjuvants were able to reduce granuloma size and the amount of larval parasite hatched from feces, which would reduce transmission. Our data support SmCB as a target for S. mansoni vaccination; especially when used in an adjuvanted formulation.

The Synergistic Effects of Sulfated Lactosyl Archaeol Archaeosomes When Combined with Different Adjuvants in a Murine Model

“…We have previously demonstrated that SLA archaeosomes are capable of enhancing both humoral and cell-mediated immune activity when used as an adjuvant with multiple antigens: OVA, HBsAg [15], hepatitis C virus E1/E2 envelope protein [17], H1N1 influenza hemagglutinin protein (18), melanoma cancer [19] and Schistosoma mansoni Cathepsin B [16]. Furthermore, using OVA or HBsAg as antigens, we also demonstrated that SLA archaeosomes induce equivalent or superior antigen-specific immune responses to those obtained with many other adjuvants, including TLR3/4/9 agonists, oil-in-water and water-in-oil emulsions and aluminum hydroxide [15].…”

“…Anti-OVA IgG titers were >2-fold higher in animals receiving formulations adjuvanted with SLA + Poly(I:C) as compared to formulations containing SLA or Poly(I:C) alone (Figure 2; p < 0.01). Geomean titers (GMT; lower-upper 95% confidence intervals (CI)) with OVA/SLA + Poly(I:C) were 69,687 (52,036-93,325) vs. 27,148 (16,233) and 22,400 (13,580-36,948) with SLA and Poly(I:C)-adjuvanted formulations, respectively. Less pronounced increases in anti-OVA IgG titers were also seen in animals immunized with SLA + CpG or SLA + Pam 3 CSK 4 adjuvanted formulations as compared to the single adjuvant formulations, but they did not reach a level of statistical significance when compared to SLA alone.…”

“…Fo munization of mice on days 0 and 21 with OVA alone or OVA formulated w chaeosomes, other adjuvants (Poly(I:C), R848, CpG, MPLA, QS-21 and Pam3C in combination with other adjuvants, antigen-specific IgG responses were ass serum of the immunized mice (day 28, 7 days post-2nd dose). Anti-OVA IgG >2-fold higher in animals receiving formulations adjuvanted with SLA + Poly( pared to formulations containing SLA or Poly(I:C) alone (Figure 2; p < 0.01 titers (GMT; lower-upper 95% confidence intervals (CI)) with OVA/SLA + Po 69,687 (52,036-93,325) vs. 27,148 (16,233) and 22,400 (13,580-36,948) w Poly(I:C)-adjuvanted formulations, respectively. Less pronounced increases IgG titers were also seen in animals immunized with SLA + CpG or SLA + Pa juvanted formulations as compared to the single adjuvant formulations, but reach a level of statistical significance when compared to SLA alone.…”

“…Archaeosome-based formulations were able to protect immunized mice from multiple pathogens including Listeria monocytogenes , Trypanosoma cruzi and Mycobacterium tuberculosis , as well as to protect against solid and metastatic tumors in murine models [ 11 , 12 , 13 , 14 ]. More recently, we showed that a simplified archaeosome formulation composed of sulfated lactosyl archaeal (SLA) glycolipid can stimulate strong humoral and cell-mediated immune responses to multiple antigens in mice, including those targeting various infectious pathogens (influenza virus, Hepatitis B virus, Hepatitis C virus and Schistomiasis mansoni ) [ 15 , 16 , 17 , 18 ] or tumor types (breast cancer and melanoma) [ 19 , 20 ]. While originally used as delivery vehicles for encapsulated antigen, a simplified SLA formulation where antigens were simply admixed with pre-formed empty SLA vesicles was shown to generate equivalent or superior humoral and cell-mediated immune responses to conventional antigen-entrapped archaeosome formulations [ 21 ].…”

A comprehensive and critical overview of schistosomiasis vaccine candidates

“…SmCB formulated with Montanide ISA 720 VG induced significant protection with elevation of both Th1 and Th2 cytokine immune responses (Ricciardi et al 2015 , 2016 ). A two-dose, starting with oral gavage of attenuated Salmonella enterica Typhimurium strain (YS1646) bearing the nirB_SspH1_CB plasmid followed by intramuscular recombinant enzyme (rCB), or immunization with rCB combined with sulfated lactosyl archaeol archaeosomes or addavax™ was able to reduce both worm and tissue egg burdens by 80–90%, which is the best result recorded among S. mansoni vaccine candidates in murine model (Hassan et al 2019 ; Perera et al 2020 ).…”