Abstract
Approximately 0.4 billion individuals worldwide are infected with hookworm. An effective vaccine is needed to not only improve the health of those affected and at high risk, but also to improve economic growth in disease-endemic areas. An ideal anti-hookworm therapeutic strategy for mass administration is a stable and orally administered vaccine. Oral vaccines are advantageous as they negate the need for trained medical staff for administration and do not require strict sterility conditions. Vaccination, therefore, can be carried out at a significantly reduced cost. One of the most promising current antigenic targets for hookworm vaccine development is the aspartic protease digestive enzyme (APR-1). Antibody-mediated neutralization of APR-1 deprives the worm of nourishment, leading to reduced worm burdens in vaccinated hosts. Previously, we demonstrated that, when incorporated into vaccine delivery systems, the APR-1-derived p3 epitope (TSLIAGPKAQVEAIQKYIGAEL) was able to greatly reduce worm burdens (≥90%) in BALB/c mice; however, multiple, large doses of the vaccine were required. Here, we investigated a variety of p3-antigen conjugates to optimize antigen delivery and establish immune response/protective efficacy relationships. We synthesized, purified, and characterized four p3 peptide-based vaccine candidates with: (a) lipidic (lipid core peptide (LCP)); (b) classical polymeric (polymethylacrylate (PMA)); and (c) novel polymeric (polyleucine in a branched or linear arrangement, BL10 or LL10, respectively) groups as self-adjuvanting moieties. BL10 and LL10 induced the highest serum anti-p3 and anti-APR-1 IgG titers. Upon challenge with rodent hookworms, the highest significant reduction in worm burden was observed in mice immunized with LL10. APR-1-specific serum IgG titers correlated with worm burden reduction. Thus, we provide the first vaccine-triggered immune response-protection relationship for hookworm infection.
Highlights
IntroductionHookworms are hematophagous parasites that infect half a billion individuals globally [1,2]
The presence of larger aggregates resulted in high polydispersity index (PDI) values for LCP (0.86 ± 0.1), BL10 (0.79 ± 0.2), and LL10 (0.36 ± 0.1)
We determined that APR-1-specific serum IgG is a significant immune correlate of protection against hookworm infection in vivo, in the absence of significant titers of mucosal/fecal APR-1-specific IgA/IgG
Summary
Hookworms are hematophagous parasites that infect half a billion individuals globally [1,2]. Hookworm infection is one of the most widespread but neglected tropical diseases. Its effects cause substantial economic losses to developing countries, in particular [3,4,5]. Despite the high efficacy of anthelmintic drugs, hookworms are developing resistance [6] and they do not prevent reinfection which is common in epidemic areas [7]. An effective anthelmintic vaccine is urgently needed
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