Experimental human hookworm infection: a narrative historical review

Abstract

In 1896, a serendipitous laboratory accident led to the understanding that hookworms propagate infection by penetrating skin, a theory that was then confirmed with the first experimental human infection, reported in 1901. Experimental human infections undertaken in the 20th century enabled understanding of the natural history of infection and the immune response. More recently, experimental hookworm infection has been performed to investigate the immunomodulatory potential of hookworm infection and for the evaluation of hookworm vaccines and chemotherapeutic interventions. Experimental human hookworm infection has been proven to be safe, with no deaths observed in over 500 participants (although early reports predate systematic adverse event reporting) and no serious adverse events described in over 200 participants enrolled in contemporary clinical trials. While experimental human hookworm infection holds significant promise, as both a challenge model for testing anti-hookworm therapies and for treating various diseases of modernity, there are many challenges that present. These challenges include preparation and storage of larvae, which has not significantly changed since Harada and Mori first described their coproculture method in 1955. In vitro methods of hookworm larval culture, storage, and the development of meaningful potency or release assays are required. Surrogate markers of intestinal infection intensity are required because faecal egg counts or hookworm faecal DNA intensity lack the fidelity required for exploration of hookworm infection as a vaccine/drug testing platform or as a regulated therapy.

Not All Worms Were Created Equal

“…The life cycle, tissue tropism, migratory path and pathogenic sequelae differ widely between helminths, and even between closely related species. For example, the human hookworm Necator americanus , the species typically used in human infection studies is very poorly infectious when applied orally (0.8%) as was the case in this report ( 4 ), compared to the closely related human hookworm Ancylostoma duodenale (50% infective via oral route) ( 3 ). Secondly, although Loeffler’s syndrome is a well described complication of Ascaris infection, it should not be confused with the distinct respiratory features associated with hookworm infection.…”

“…Recent reviews of studies with one of the most widely used helminths, the anthropophilic hookworm, Necator americanus , have shown this helminth to be safe and well tolerated in hundreds of individuals by numerous research groups across Australia, the US and Europe ( 1 – 3 ). In BMC Pulmonary Medicine ( 4 ), Zeynalyan and colleagues report rapidly progressive respiratory failure in a patient with significant comorbidities, including systemic sclerosis, interstitial lung disease and pulmonary hypertension after self-administration of N. americanus larvae that were purchased over the internet.…”

“…N. americanus therapy has been, and continues to be methodically and rigorously tested in clinical environments where the source of the infective inocula is meticulously monitored and validated ( 1 , 3 , 10 ). Purchasing helminths on the internet and administering them without careful clinical oversight should be discouraged.…”

Tissue-specific immunity in helminth infections

“…Emphysema-like pathology and activated macrophages were observed long term in mice infected with N. brasiliensis 120 , suggesting long term effect of hookworm infection in the lung environment. However, lung emphysema, hemorrhage and pulmonary pathology have been associated with high dose of infective larvae transiting the lung, and not observed with lower dose of parasite 121 , possibly lung pathology observed in some infected human reflect high burden of larvae transiting the lungs.…”

“…Even more challenging is the study of local tissue specific immune responses in parasitized humans. Human hookworm studies have been performed in the past, as well as clinical trials for the treatment of inflammatory disorders 190 . Studies in individuals infected with N. americanus showed a transient increase of Th2 cytokines in whole blood cultures, while low levels of T H 1 cytokines or IL-10 were detected 191 .…”