Abstract
Two hookworm vaccine candidates, Na-GST-1 and Na-APR-1, formulated with Glucopyranosyl Lipid A (GLA-AF) adjuvant, have been shown to be safe, well tolerated, and to induce antibody responses in a Phase 1 clinical trial (Clinicaltrials.gov NCT02126462) conducted in Gabon. Here, we characterized T cell responses in 24 Gabonese volunteers randomized to get vaccinated three times with Na-GST-1 and Na-APR-1 at doses of 30μg (n = 8) or 100μg (n = 10) and as control Hepatitis B (n = 6). Blood was collected pre- and post-vaccination on days 0, 28, and 180 as well as 2-weeks after each vaccine dose on days 14, 42, and 194 for PBMCs isolation. PBMCs were stimulated with recombinant Na-GST-1 or Na-APR-1, before (days 0, 28 and 180) and two weeks after (days 14, 42 and 194) each vaccination and used to characterize T cell responses by flow and mass cytometry. A significant increase in Na-GST-1 -specific CD4+ T cells producing IL-2 and TNF, correlated with specific IgG antibody levels, after the third vaccination (day 194) was observed. In contrast, no increase in Na-APR-1 specific T cell responses were induced by the vaccine. Mass cytometry revealed that, Na-GST-1 cytokine producing CD4+ T cells were CD161+ memory cells expressing CTLA-4 and CD40-L. Blocking CTLA-4 enhanced the cytokine response to Na-GST-1. In Gabonese volunteers, hookworm vaccine candidate, Na-GST-1, induces detectable CD4+ T cell responses that correlate with specific antibody levels. As these CD4+ T cells express CTLA-4, and blocking this inhibitory molecules resulted in enhanced cytokine production, the question arises whether this pathway can be targeted to enhance vaccine immunogenicity.
Highlights
Human hookworm infection affects approximately 740 million people worldwide and, 85% of cases are caused by Necator americanus (N. americanus), while the remaining are accounted by Ancylostoma duodenale (A. duodenale) [1, 2]
We found that NaGST-1 induced CD4+ T cell responses (IL-2, tumor necrosis factor (TNF)) among the vaccinated volunteers that received the high vaccine dose (100 ug)
Na-glutathione S-transferase (GST)-1 specific memory T cells were found to express the inhibitory molecule CTLA-4. These responses was not observed in those who received the low dose of the Na-GST-1 vaccine, or those who received NaAPR-1 or hepatitis B vaccine (HBV)
Summary
Human hookworm infection affects approximately 740 million people worldwide and, 85% of cases are caused by Necator americanus (N. americanus), while the remaining are accounted by Ancylostoma duodenale (A. duodenale) [1, 2]. Subsequent approaches targeted hidden proteins, less likely to induce sensitization during natural hookworm infection, such as enzymes involved in the blood-feeding process of adult worms [11, 12]. This led to the selection of the glutathione S-transferase (GST) and the aspartic protease (APR) hemoglobinases [13] as vaccine candidates. The Na-GST-1 vaccine candidate has already been tested in Phase 1 trials in hookworm-naive (in USA) and hookwormexposed (in Brazil) adult volunteers [14] and was found to be safe and immunogenic leading to the induction of antigen-specific IgG antibodies in a dose-dependent manner [14]
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