Abstract
BackgroundAscariasis remains the most common helminth infection in humans. As an alternative or complementary approach to global deworming, a pan-anthelminthic vaccine is under development targeting Ascaris, hookworm, and Trichuris infections. As16 and As14 have previously been described as two genetically related proteins from Ascaris suum that induced protective immunity in mice when formulated with cholera toxin B subunit (CTB) as an adjuvant, but the exact protective mechanism was not well understood.Methodology/Principal findingsAs16 and As14 were highly expressed as soluble recombinant proteins (rAs16 and rAs14) in Pichia pastoris. The yeast-expressed rAs16 was highly recognized by immune sera from mice infected with A. suum eggs and elicited 99.6% protection against A. suum re-infection. Mice immunized with rAs16 formulated with ISA720 displayed significant larva reduction (36.7%) and stunted larval development against A. suum eggs challenge. The protective immunity was associated with a predominant Th2-type response characterized by high titers of serological IgG1 (IgG1/IgG2a > 2000) and high levels of IL-4 and IL-5 produced by restimulated splenocytes. A similar level of protection was observed in mice immunized with rAs16 formulated with alum (Alhydrogel), known to induce mainly a Th2-type immune response, whereas mice immunized with rAs16 formulated with MPLA or AddaVax, both known to induce a Th1-type biased response, were not significantly protected against A. suum infection. The rAs14 protein was not recognized by A. suum infected mouse sera and mice immunized with rAs14 formulated with ISA720 did not show significant protection against challenge infection, possibly due to the protein’s inaccessibility to the host immune system or a Th1-type response was induced which would counter a protective Th2-type response.Conclusions/SignificanceYeast-expressed rAs16 formulated with ISA720 or alum induced significant protection in mice against A. suum egg challenge that associates with a Th2-skewed immune response, suggesting that rAS16 could be a feasible vaccine candidate against ascariasis.
Highlights
Ascaris lumbricoides, Trichuris trichiura and the hookworm Necator americanus are the three major soil-transmitted helminths (STH) that infect more than one billion poor people in the world and are the leading neglected tropical diseases (NTDs) in terms of disability-adjusted life years (DALYs) [1]
A similar level of protection was observed in mice immunized with rAs16 formulated with alum (Alhydrogel), known to induce mainly a Th2-type immune response, whereas mice immunized with rAs16 formulated with MPLA or AddaVax, both known to induce a Th1-type biased response, were not significantly protected against A. suum infection
Mice immunized with rAs16 formulated with ISA720 adjuvant produced significant larva reduction (36.7%) and stunted larval development against A. suum egg challenge
Summary
Trichuris trichiura and the hookworm Necator americanus are the three major soil-transmitted helminths (STH) that infect more than one billion poor people in the world and are the leading neglected tropical diseases (NTDs) in terms of disability-adjusted life years (DALYs) [1]. The development of a multivalent pan-anthelminthic vaccine targeting all three major STH infections would be a desirable biotechnology to prevent parasite reinfection and advance efforts for the control and elimination of these diseases [11].To advance such a strategy, two major N. americanus hookworm vaccine antigens are undergoing clinical vaccine tests, but there is a need to simultaneously develop A. lumbricoides and T. trichiura candidate antigens as suitable vaccines to be integrated within the human hookworm vaccine development program [12]. As16 and As14 have previously been described as two genetically related proteins from Ascaris suum that induced protective immunity in mice when formulated with cholera toxin B subunit (CTB) as an adjuvant, but the exact protective mechanism was not well understood.
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