A novel hookworm vaccine candidate identified through immunomic profiling of human protective immunity

Hookworms infect nearly half a billion people, causing approximately 2.1 million disability-adjusted life-years lost. While anthelmintic drugs are available, they do not prevent reinfection. A vaccine could provide long-term immunity, but none currently exists. We recently demonstrated that human subjects could be safely vaccinated with irradiated hookworm larvae, eliciting humoral and cellular immune responses that induce partial protection against challenge infection with non-irradiated parasites. Using immunomic approaches, we identified IgG targets in vaccinated individuals by screening a proteome microarray containing recombinant proteins sourced from the secretome of Necator americanus. We characterized the most immunoreactive N. americanus proteins and identified their orthologs in the rodent hookworm Nippostrongylus brasiliensis. These N. brasiliensis proteins were expressed recombinantly and tested for efficacy in a mouse challenge model. Our lead vaccine candidate NBR17057 - a homolog of Na_11335 provided robust protection against infection, evidenced by >90% reductions in intestinal worm burden and fecal egg counts, and elevated antigen-specific IgG levels. Vaccination also stimulated IgA⁺ B-cells, IgG1⁺/IgA⁺ plasma cells, and IgG1⁺/IgA⁺ germinal centre B-cells in inguinal lymph nodes, indicating gut immunity. Additionally, high levels of IgG1⁺/IgA⁺ B-cells, germinal centre B-cells, and plasma cells in the spleen suggest protection against systemic larval migration. The presence of IgG1⁺/IgA⁺ memory B-cells in both the lymph nodes and spleen indicates potential long-term immunity against reinfection. Our findings suggest that a N. brasiliensis L3 larval-stage protein NBR17057 and its homolog in N. americanus Na_11335 could serve as a promising subunit vaccine candidate targeting the infective larval stage of human hookworms.