M A Hoogerwerf4; J P Koopman2; 3; J J Janse2; 3; E A Brienen2; 3; M C Langenberg4; Y Kruize2; 3; L E Coffeng1; S J de Vlas1; L G Visser4; L van Lieshout4; M Yazdanbakhsh4; M Roestenberg4;
1 Erasmus MC University Medical Center Rotterdam, Netherlands; 2 Leiden University Medical Center, Netherlands; 3 Leiden University Medical Center, UK; 4 Leiden University Medical Centre, Netherlands
DiscussionIntroduction: Hookworm control programs are proving to be very challenging due to re-infection and insufficient coverage of mass drug administration. A vaccine would be needed to reach the ultimate goal of elimination. However, field testing of potential vaccine candidates needs large sample sizes, is a lengthy process and costly. Experimental infection of humans with hookworm, can provide a more controlled setting for preliminary testing of vaccine efficacy and down-selection of the most promising candidates, thereby cutting time and costs. Current controlled human hookworm infection studies only result in low egg counts and as such do not reflect the natural infection setting. This trial aims to investigate the effect of repeated exposure on median egg count and egg excretion variability in order to develop a suitable model for future vaccine testing. Methods: Twenty-four healthy, male and female volunteers were randomized in a double blind fashion to receive either one, two or three doses of 50 L3 Necator americanus larvae at 2-week intervals divided over four infection sites. Volunteers visited the trial center weekly for twenty weeks after which they were treated with albendazole to clear the infection. Adverse events were collected at each visit, eosinophil counts were measured weekly and faecal samples were collected for Kato-Katz slides from week 6 onwards. Results: Three volunteers received early treatment because of severe abdominal adverse events after the infection. One withdrew informed consent after the first visit for reasons unrelated to the study. Skin adverse events were mild. We found no relation between infectious dose and adverse events, although a trend towards a longer duration of adverse events was seen in the highest dose group which received 150 L3. All volunteers showed patent infection by Kato-Katz 6-9 weeks after first exposure to larvae. At 12 to 16 weeks after first exposure, egg counts reached a plateau phase. Median egg count for the group exposed to 50 L3 for this plateau was significantly lower (480 epg) than the median count for the 100 L3 and 150 L3 group (both 1200 epg). Variability in egg excretion was highest in the 50 L3 group and lowest in the 150 L3 group. Conclusions: Repeated infection reduces the variability in egg excretion without producing a corresponding increase in adverse events. We conclude that doses of 100 or 150 L3 larvae are well tolerated and result in mild-to-moderate level infections according to WHO criteria, thus reflecting egg excretion levels as observed in endemic regions. These improvements in the controlled human hookworm model can accelerate the development of hookworm vaccines.