New Insights Into the Kinetics and Variability of Egg Excretion in Controlled Human Hookworm Infections

Hoogerwerf, Marie-Astrid; Coffeng, Luc E.; Brienen, Eric A. T.; Janse, Jacqueline J.; Langenberg, Marijke C. C.; Kruize, Yvonne C. M.; Gootjes, Chelsea; Manurung, Mikhael D.; Dekker, Mark J.; Becker, Luke; Erkens, Marianne A A; Beek, Martha T. van der; Ganesh, Munisha S.; Feijt, C.; Winkel, B.; Westra, Inge M.; Meij, Pauline; Loukas, Alex; Visser, Leo G.; Vlas, Sake J. de; Yazdanbakhsh, Maria; Lieshout, Lisette van; Roestenberg, Meta

doi:10.1093/infdis/jiz218

Cited by 14 publications

(15 citation statements)

References 13 publications

(18 reference statements)

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“…Culture of larvae and procedure of infection was performed according to a previously described method. 40 In short, infective L3 larvae were cultured from feces from a chronic donor, were suspended in water and applied on upper arms and calves using gauzes. Volunteers were followed for twenty weeks after first exposure, after which treatment with albendazole was given to eradicate the infection.…”

Section: Methodsmentioning

confidence: 99%

Dynamics of the bacterial gut microbiota during controlled human infection with Necator americanus larvae

et al. 2020

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Hookworms are soil-transmitted helminths that use immune-evasive strategies to persist in the human duodenum where they are responsible for anemia and protein loss. Given their location and immune regulatory effects, hookworms likely impact the bacterial microbiota. However, microbiota studies struggle to deconvolute the effect of hookworms from confounders such as coinfections and malnutrition. We thus used an experimental human hookworm infection model to explore temporal changes in the gut microbiota before and during hookworm infection. Volunteers were dermally exposed to cumulative dosages of 50, 100 or 150 L3 Necator americanus larvae. Fecal samples were collected for microbiota profiling through 16S rRNA gene amplicon sequencing at weeks zero, four, eight, fourteen and twenty. During the acute infection phase (trial week zero to eight) no changes in bacterial diversity were detected. During the established infection phase (trial week eight to twenty), bacterial richness (Chao1, p = .0174) increased significantly over all volunteers. No relation was found between larval dosage and diversity, stability or relative abundance of individual bacterial taxa. GI symptoms were associated with an unstable microbiota during the first eight weeks and rapid recovery at week twenty. Barnesiella, amongst other taxa, was more abundant in volunteers with more GI symptoms throughout the study. In conclusion, this study showed that clinical GI symptoms following N. americanus infection are associated with temporary microbiota instability and relative abundance of specific bacterial taxa. These results suggest a possible role of hookworm-induced enteritis on microbiota stability.

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Section: Methodsmentioning

confidence: 99%

Dynamics of the bacterial gut microbiota during controlled human infection with Necator americanus larvae

et al. 2020

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“…Culture methods, postculture larval processing and storage, and estimation of viability have been sparsely described in detail. Larvae are produced by mixing hookworm eggs with charcoal or vermiculite, using various modifications of the Harada–Mori method [ 51 – 53 , 83 ]. Although some authors have reported pretreatment of faeces with antifungal and antibacterial agents prior to culture [ 50 – 52 ], the role of antimicrobials at this stage has not been established.…”

Section: Resultsmentioning

confidence: 99%

“…Variability in the age of hookworm larvae used in recent human studies may account for the discordant results demonstrated in recent controlled trials in hookworm-naive participants. Hoogerwerf and colleagues demonstrated 100% patency and robust faecal egg counts (>500 epg) after inoculation with 50 L3 used within 10 days of production [ 48 , 51 ], whereas Diemert and colleagues reported patent infection in only 40% and 90% of participants who received 25 and 50 larvae, respectively, and with modest faecal egg output at 16 to 166 epg. These larvae had been imported to Washington, DC from the UK, and, although the authors stated that larvae batches were 80% motile at the time of use, the age of the larvae was not stated.…”

Section: Larval Infectivity and Viabilitymentioning

confidence: 99%

Experimental human hookworm infection: a narrative historical review

et al. 2021

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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.

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“…Motile larvae are dispensed onto gauzes and applied on the skin of the upper arms and legs of the volunteers. Twenty seven Dutch volunteers have been successfully infected using the model [ 20 , 27 ]. No major safety concerns were identified, infection was reasonably well-tolerated by all participants.…”

Section: Discussionmentioning

confidence: 99%

“…Hoogerwerf and colleagues at the Leiden University Medical Centre (LUMC) have continued with the development of a controlled human infection model for N. americanus (CHHI) to improve it. The infection model was refined in Dutch volunteers [ 20 ], reaching stable egg counts that were comparable to what is seen in low-endemic regions. However, these Dutch volunteers originate from a non-endemic region and have never been exposed to hookworm.…”

Section: Introductionmentioning

confidence: 99%

Establishing a controlled hookworm human infection (CHHI) model for Africa: A report from the stakeholders meeting held in Lambaréné, Gabon, November 10–11, 2019

et al. 2021

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Background Hookworm is a major contributor to worldwide disease burden with over 230 million people infected. It has been identified as one of the Neglected Tropical Diseases that can be controlled and even eliminated through mass drug administration and other effective interventions. Mathematical models have shown that hookworm can only be eliminated via a vaccine. Controlled Hookworm Human Infection (CHHI) models can facilitate rapid development of vaccines and drugs. Methods As a first step towards the establishment of CHHI in Africa, we held a stakeholders meeting in Lamberene, Gabon from 10 to 11 November 2019. Results Discussions revolved around the roles of the different regulatory institutions concerned; the need to strengthen existing regulatory capacity and the role of legislation; creating Gabon-specific ethical guidelines to govern Controlled Human Infection (CHI) studies; development of a study protocol; consideration of cultural and social peculiarities; the need for regular joint review meetings between interested parties throughout the process of protocol implementation; and participant compensation. Moreover, operational considerations concerning the introduction of CHHI in Gabon include the use of the local strain of hookworm for the challenge infections, capacity building for the local production of challenge material, and the establishment of adequate quality assurance procedures. Conclusion The workshop addressed several of the anticipated hurdles to the successful implementation of CHHI in Gabon. It is our aim that this report will stimulate interest in the implementation of this model in the sub-Saharan African setting.

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New Insights Into the Kinetics and Variability of Egg Excretion in Controlled Human Hookworm Infections

Cited by 14 publications

References 13 publications

Dynamics of the bacterial gut microbiota during controlled human infection with Necator americanus larvae

Dynamics of the bacterial gut microbiota during controlled human infection with Necator americanus larvae

Experimental human hookworm infection: a narrative historical review

Establishing a controlled hookworm human infection (CHHI) model for Africa: A report from the stakeholders meeting held in Lambaréné, Gabon, November 10–11, 2019

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