How to train your myeloid cells: a way forward for helminth vaccines?

Abstract

Soil-transmitted helminths affect approximately 1.5 billion people worldwide. However, as no vaccine is currently available for humans, the current strategy for elimination as a public health problem relies on preventive chemotherapy. Despite more than 20 years of intense research effort, the development of human helminth vaccines (HHVs) has not yet come to fruition. Current vaccine development focuses on peptide antigens that trigger strong humoral immunity, with the goal of generating neutralizing antibodies against key parasite molecules. Notably, this approach aims to reduce the pathology of infection, not worm burden, with only partial protection observed in laboratory models. In addition to the typical translational hurdles that vaccines struggle to overcome, HHVs face several challenges (1): helminth infections have been associated with poor vaccine responses in endemic countries, probably due to the strong immunomodulation caused by these parasites, and (2) the target population displays pre-existing type 2 immune responses to helminth products, increasing the likelihood of adverse events such as allergy or anaphylaxis. We argue that such traditional vaccines are unlikely to be successful on their own and that, based on laboratory models, mucosal and cellular-based vaccines could be a way to move forward in the fight against helminth infection. Here, we review the evidence for the role of innate immune cells, specifically the myeloid compartment, in controlling helminth infections. We explore how the parasite may reprogram myeloid cells to avoid killing, notably using excretory/secretory (ES) proteins and extracellular vesicles (EVs). Finally, learning from the field of tuberculosis, we will discuss how anti-helminth innate memory could be harnessed in a mucosal-trained immunity-based vaccine.

The helminth‐derived peptide, FhHDM‐1, reverses the trained phenotype of NOD bone‐marrow‐derived macrophages and regulates proinflammatory responses

“…Accordingly, helminths have evolved mechanisms to regulate the host's protective innate proinflammatory response such that their presence is tolerated and the tissue damage they cause is repaired. Millennia of endemic exposure to these tolerated infections with parasitic worms has imprinted a regulatory influence on the human immune response, which controls the development of trained inflammatory responses, to prevent immune-mediated disease and to facilitate the homeostatic resolution of infection-fighting inflammation, after pathogen clearance [8,9]. Thus, exploiting these regulatory mecha-nisms employed by helminths offers a new approach for the treatment of immunemediated diseases, such as T1D.…”