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A randomized controlled trial to investigate safety and variability of egg excretion after repeated controlled human hookworm infection.
J Infect Dis. 2020 Jul 10 [Online ahead of print]JI

Abstract

BACKGROUND

Controlled human hookworm infections could significantly contribute to the development of a hookworm vaccine. However, current models are hampered by low and unstable egg output, reducing generalizability and increasing sample sizes. This study aims to investigate the safety, tolerability and egg output of repeated exposure to hookworm larvae.

METHODS

Twenty-four healthy volunteers were randomized double blind to one, two or three doses of 50 Necatoramericanus L3 larvae at 2-week intervals. Volunteers were monitored weekly and were treated with albendazole at week 20.

RESULTS

There was no association between larval dose and number or severity of adverse events. Geomean egg loads stabilized at 697, 1668 and 1914 eggs per gram feces for the 1x50L3, 2x50L3 and 3x50L3 group respectively. Bayesian statistical modelling showed that egg count variability relative to the mean was reduced with a second infectious dose, however the third dose did not increase egg load or decrease variability. We therefore suggest 2x50L3 as an improved challenge dose. Model-based simulations indicates increased frequency of stool sampling optimizes power of hypothetical vaccine trials.

DISCUSSION

Repeated infection with hookworm larvae increased egg counts to levels comparable to the field and reduced relative variability in egg output without aggravating adverse events.

Authors+Show Affiliations

Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.Clinical Microbiology Laboratory, Leiden University Medical Center, Leiden, The Netherlands.Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands. Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32645714

Citation

Hoogerwerf, Marie-Astrid, et al. "A Randomized Controlled Trial to Investigate Safety and Variability of Egg Excretion After Repeated Controlled Human Hookworm Infection." The Journal of Infectious Diseases, 2020.
Hoogerwerf MA, Koopman JPR, Janse JJ, et al. A randomized controlled trial to investigate safety and variability of egg excretion after repeated controlled human hookworm infection. J Infect Dis. 2020.
Hoogerwerf, M. A., Koopman, J. P. R., Janse, J. J., Langenberg, M. C. C., van Schuijlenburg, R., Kruize, Y. C. M., Brienen, E. A. T., Manurung, M. D., Verbeek-Menken, P., van der Beek, M. T., Westra, I. M., Meij, P., Visser, L. G., van Lieshout, L., de Vlas, S. J., Yazdanbakhsh, M., Coffeng, L. E., & Roestenberg, M. (2020). A randomized controlled trial to investigate safety and variability of egg excretion after repeated controlled human hookworm infection. The Journal of Infectious Diseases. https://doi.org/10.1093/infdis/jiaa414
Hoogerwerf MA, et al. A Randomized Controlled Trial to Investigate Safety and Variability of Egg Excretion After Repeated Controlled Human Hookworm Infection. J Infect Dis. 2020 Jul 10; PubMed PMID: 32645714.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A randomized controlled trial to investigate safety and variability of egg excretion after repeated controlled human hookworm infection. AU - Hoogerwerf,Marie-Astrid, AU - Koopman,Jan Pieter R, AU - Janse,Jacqueline J, AU - Langenberg,Marijke C C, AU - van Schuijlenburg,Roos, AU - Kruize,Yvonne C M, AU - Brienen,Eric A T, AU - Manurung,Mikhael D, AU - Verbeek-Menken,Petra, AU - van der Beek,Martha T, AU - Westra,Inge M, AU - Meij,Pauline, AU - Visser,Leo G, AU - van Lieshout,Lisette, AU - de Vlas,Sake J, AU - Yazdanbakhsh,Maria, AU - Coffeng,Luc E, AU - Roestenberg,Meta, Y1 - 2020/07/10/ PY - 2020/05/02/received PY - 2020/7/10/entrez PY - 2020/7/10/pubmed PY - 2020/7/10/medline KW - Bayesian statistics KW - controlled human infection KW - hookworm KW - vaccine development JF - The Journal of infectious diseases JO - J. Infect. Dis. N2 - BACKGROUND: Controlled human hookworm infections could significantly contribute to the development of a hookworm vaccine. However, current models are hampered by low and unstable egg output, reducing generalizability and increasing sample sizes. This study aims to investigate the safety, tolerability and egg output of repeated exposure to hookworm larvae. METHODS: Twenty-four healthy volunteers were randomized double blind to one, two or three doses of 50 Necatoramericanus L3 larvae at 2-week intervals. Volunteers were monitored weekly and were treated with albendazole at week 20. RESULTS: There was no association between larval dose and number or severity of adverse events. Geomean egg loads stabilized at 697, 1668 and 1914 eggs per gram feces for the 1x50L3, 2x50L3 and 3x50L3 group respectively. Bayesian statistical modelling showed that egg count variability relative to the mean was reduced with a second infectious dose, however the third dose did not increase egg load or decrease variability. We therefore suggest 2x50L3 as an improved challenge dose. Model-based simulations indicates increased frequency of stool sampling optimizes power of hypothetical vaccine trials. DISCUSSION: Repeated infection with hookworm larvae increased egg counts to levels comparable to the field and reduced relative variability in egg output without aggravating adverse events. SN - 1537-6613 UR - https://www.unboundmedicine.com/medline/citation/32645714/A_randomized_controlled_trial_to_investigate_safety_and_variability_of_egg_excretion_after_repeated_controlled_human_hookworm_infection L2 - https://academic.oup.com/jid/article-lookup/doi/10.1093/infdis/jiaa414 DB - PRIME DP - Unbound Medicine ER -
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