Primary Objectives: - To determine the protective efficacy of repeated exposure to male Schistosoma mansoni (Sm) cercariae in healthy Schistosome-naïve volunteers based on CAA levels.- To determine the safety and tolerability of repeated exposure to…
ID
Source
Brief title
Condition
- Helminthic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- The protective efficacy of repeated exposure to male Sm cercariae measured by
the difference in frequency of serum CAA positivity (>=1.0 pg/mL) between the
reinfection group and the infection control group at any timepoint after the
final infection at week 18;
- Frequency and severity of adverse events after (repeated) human Sm infection
with male cercariae
Secondary outcome
Exploratory endpoints:
- Comparison of time to positive serum and urine CAA test between the
reinfection and infection control groups after the final infection at week 18;
- Comparison of peak serum CAA concentration between the reinfection and
infection control group after the final infection at week 18;
- Comparison of eosinophil counts between the reinfection and infection control
groups after challenge after the final infection at week 18;
- Comparison of (glycan) antibody responses directed against Sm antigens
between the reinfection and infection control participants as well as between
protected and non-protected participants after the final infection at week 18
using protein and glycan arrays;
- Comparison of cellular responses directed against Sm antigens between the
reinfection and infection control participants as well as between protected and
non-protected participants after the final infection at week 18 using flow
cytometry;
- The pooled attack rate after initial exposure to 20 male cercariae, i.e.
proportion CAA positivity between week 0-8 for the reinfection participants and
between week 18-26 for infection control participants.
Background summary
Schistosomiasis is a parasitic disease of global importance that affects around
140 million people mainly living in (sub)tropical regions. The development of a
vaccine against schistosomiasis has been hampered by limited research funding
as well as knowledge gaps relating to how (natural) immunity against
schistosomiasis develops. Epidemiological data suggests that natural immunity
develops in an age- and IgE-dependent manner. Moreover, animal experiments in
mice and non-human primates provide the strongest evidence that development of
protective immunity is feasible: in animals immunised with radiation attenuated
(RA) cercariae worm burden reduction up to 80% were observed. Protection was
associated with upregulated Th1 polarized CD4+ cells and increased IgG, but not
IgE antibodies. At the LUMC, we recently developed a controlled human
Schistosoma mansoni infection (CoHSI) model using single-sex cercariae that do
not produce eggs and therefore prevents egg-associated morbidity in study
participants. Infection with 20 male cercariae was safe and well-tolerated. The
immune responses following infection showed a predominant Th1 skewing coupled
with increases of worm-specific IgG and IgG1, but not IgE. The use of this
model is not only limited to testing of vaccine candidates, but can also
provide a unique opportunity to investigate immune responses after repeated
exposure to cercariae and to establish whether this leads to protective
immunity in humans. Based on the comparable immune responses after CoHSI in
humans and RA immunisation in mice and non-human primates, we hypothesize that
repeated exposure to male cercariae results in protection to reinfection. As
such, correlates of protection may also be identified that improve our
understanding of immunity, as well as also lead to the discovery of new vaccine
targets.
Study objective
Primary Objectives:
- To determine the protective efficacy of repeated exposure to male Schistosoma
mansoni (Sm) cercariae in healthy Schistosome-naïve volunteers based on CAA
levels.
- To determine the safety and tolerability of repeated exposure to male Sm
cercariae;
Exploratory Objectives:
- To investigate the kinetics of circulating anodic antigen (CAA) after
repeated exposure to male Sm cercariae;
- To explore potential differences in immunological responses and CAA kinetics
between single-exposure vs. repeated-exposure to male Sm cercariae;
- To investigate immunological markers associated with protection against
Schistosoma mansoni infection.
Study design
Double-blind, placebo-controlled randomised trial.
Intervention
24 volunteers will be randomised in a 1:1 ratio to the intervention group and
the control group. The intervention group (i.e. reinfection group) will be
exposed three times to 20 male Sm cercariae (weeks 0,9, 18) whereas the control
group (i.e. infection control group) will only be exposed once (week 18). This
group will receive a mock infection with water on weeks 0 and 9. Participants
in the intervention group will be treated with praziquantel at weeks 8,17, and
30 to cure infection, while the control group will receive placebo treatment at
weeks 8 and 17, followed by praziquantel treatment at week 30.
Study burden and risks
Volunteers will visit the trial centre for screening, then at one day prior to
infection, at the day of infection and every other week until the next
infection. On the weeks in between, follow up visits will be conducted per
email/phone. After the final infection (from week 20 onwards), participants
will visit the study centre weekly up until week 30. After week 30, follow-ups
will take place every two weeks until week 38, with in-between phone visits at
weeks 31 and 33. Final visit will be performed at week 54. In total there are
27 regular visits, 3 infection days, and 11 phone visits. At all follow up
visits, adverse events will be recorded, volunteers will undergo a blood draw
by venepuncture and will provide a urine sample. At some visits, nasosorption
samples are collected. They will keep a diary to record adverse events for 38
weeks. Volunteers will be dermally exposed to male cercariae once or three
times, depending on the randomisation group. They may experience adverse
events, such as cercarial dermatitis or symptoms related to acute
schistosomiasis syndrome with fatigue, malaise, and fever. It is unclear
whether repeated infections lead to increased risk of developing symptoms of
acute schistosomiasis or whether this risk decreases with increasing number of
infections. Data from endemic settings suggest the latter, since symptoms of
acute schistosomiasis are not frequently reported. At weeks 8, 17 and 30, those
in the reinfection group will be treated with praziquantel to cure the
Schistosoma infection. Participants in the infection control group are treated
with praziquantel at week 30. Praziquantel is known to potentially give
fatigue, gastrointestinal side effects, and dizziness. There is no benefit to
participation in the trial.
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
1. Subject is aged >= 18 and <= 45 years and in good health.
2. Subject has adequate understanding of the procedures of the study and agrees
to abide strictly thereby.
3. Subject is able to communicate well with the investigator, is available to
attend all study visits.
4. Subject will remain within Europe (excluding Corsica) during the study
period.
5. Subject agrees to refrain from blood and plasma donation to Sanquin or for
other purposes throughout the study period.
6. For female subjects: subject agrees to use adequate contraception and not to
breastfeed for the duration of study.
7. Subject has signed informed consent.
Exclusion criteria
1. Any history, or evidence at screening, of clinically significant symptoms,
physical signs or abnormal laboratory values suggestive of systemic conditions,
such as cardiovascular, pulmonary, renal, hepatic, neurological,
dermatological, endocrine, malignant, haematological, infectious,
immune-deficient, (severe) psychiatric and other disorders, which could
compromise the health of the volunteer during the study or interfere with the
interpretation of the study results. These include, but are not limited to, any
of the following:
- body weight <50 kg or Body Mass Index (BMI) <18.0 or >35.0 kg/m2 at
screening;
- positive HIV, HBV or HCV screening tests;
- the use of immune modifying drugs within three months prior to study onset
(inhaled and topical corticosteroids and oral anti-histamines exempted) or
expected use of such during the study period;
- history of malignancy of any organ system (other than localized basal cell
carcinoma of the skin), treated or untreated, within the past 5 years;
- any history of treatment for severe psychiatric disease by a psychiatrist in
the past year;
- history of drug or alcohol abuse interfering with normal social function in
the period of one year prior to study onset.
2. The chronic use of any drug known to interact with praziquantel, artesunate
or lumefantrine metabolism (e.g. phenytoïn, carbamazepine, phenobarbital,
primidon, dexamethason, rifampicine, cimetidine, flecaïnide, metoprolol,
imipramine, amitriptyline, clomipramine, class IA and III anti-arrythmics,
antipsychotics, antidepressants, macrolides, fluorchinolones, imidazole- and
triazole antimycotics, antihistamines). Because lumefantrine may cause
extension of QT-time, chronic use of drugs with effect on QT interval will
result in exclusion from study participation.
3. For female subjects: positive urine pregnancy test at screening.
4. Any history of schistosomiasis or treatment for schistosomiasis.
5. Positive serology for schistosomiasis or elevated serum CAA at screening.
6. Known hypersensitivity to or contra-indications (including co-medication)
for use of praziquantel, artesunate or lumefantrine.
7. Being an employee or student of the department of Parasitology or Infectious
diseases of the LUMC.
Design
Recruitment
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| CCMO | NL77749.058.21 |
| Other | volgt |