Primary Objective: To determine the safety and tolerability of NF135.C10 sporozoite immunization under chemoprophylaxisSecondary Objectives:• To determine the dose-dependent protective efficacy of NF135.C10 CPS-immunization against homologous…
ID
Source
Brief title
Condition
- Other condition
- Protozoal infectious disorders
Synonym
Health condition
Malaria infectie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Frequency and magnitude of adverse events after NF135.C10 CPS immunization
Secondary outcome
Secondary study endpoints
• Time to blood stage parasitemia detectable by qPCR after malaria challenge
infection
• Sterile protection after controlled human malaria infection
Exploratory study endpoints
• The phenoptype and cytokine profile of P. falciparum specific T cell
responses induced by NF135.C10 CPS immunization
• The antigen specificity of T cell responses induced by NF135.C10 CPS
immunization
• The antigen specificity and/or functionality of P. falciparum specific
antibodies induced by NF135.C10 CPS immunization
• The phenotype and/or function of innate and semi-innate immune responses to
NF135.C10 CPS immunization and/or CHMI, including γδT cells, invariant T cells,
antigen presenting cells, NK cells and granulocytes
• Epigenetic profiles of innate immune cell subsets, with emphasis on both
activation (H3K4me3, H3K4me1, H3K27Ac) and repression (H3K9me3, H3K27me)
markers
• RNA transcriptome profiling through whole mRNA-sequencing, PCR and/or
microarray
Background summary
Malaria, a disease caused by the parasite Plasmodium, is one of the world*s
major infectious diseases. Ultimately, the key to malaria control and hopefully
eradication would be an effective vaccine. Chemo-Prophylaxis and Sporozoite
immunization (CPS) has repeatedly shown to be an extremely efficient regimen
for induction of long lasting sterile homologous protection. However, it
provided only 20% and 10% sterile protection against heterologous NF135.C10 and
NF166.C8 clones, respectively. We propose to make use of the increased liver
infectivity of NF135.C10, to increase the late liver stage load without the
need for increasing the number of sporozoites administered. The presumably
generated higher titers and broader repertoire of specific antibodies can
increase heterologous protection.
Study objective
Primary Objective: To determine the safety and tolerability of NF135.C10
sporozoite immunization under chemoprophylaxis
Secondary Objectives:
• To determine the dose-dependent protective efficacy of NF135.C10
CPS-immunization against homologous controlled human malaria infection
• To determine the protective efficacy of NF135.C10 CPS-immunization against
heterologous NF54 controlled human malaria infection
• To assess the longevity of protective immunity after NF135.C10
CPS-|mmunization against homologous challenge (cohort A).
Exploratory Objectives:
• To analyse P. falciparum specific T cell responses in NF135.C10 CPS-immunized
volunteers
• To delineate the antibody repertoire directed against P. falciparum in
NF135.C10 CPS-immunized volunteers
• To evaluate changes in phenotype and function of innate and semi-innate
immune cells following NF135.C10 immunization
• To explore the (innate) immunology of early malaria infection, with specific
attention to γδ-T cells, monocytes, antigen presenting cells and natural killer
cells
• To analyse changes in epigenetic and transcriptome profiles of (innate)
immune cells after NF135.C10 CPS immunization and/or after malaria infection
Study design
In an open label, randomized, controlled clinical trial a maximum of 52
volunteers will be allocated to receive either three immunizations with 15
NF135.C10 infected Anopheles mosquitoes (n=30), 3 immunizations with 5
NF135.C10 infected mosquitoes (n=10) or no immunizations (n=12). Immunizations
will be perfomed under mefloquine prophylaxis in cohort A. Volunteers of cohort
B will be treated with artemether/lumefantrine on day 7 after each immunisation.
Nineteen weeks after the last immunization, all volunteers will be challenged
either by the bites of 5 NF135.C10 or 5 NF54 infected mosquitoes. After
challenge infection, volunteers will be followed up on an out-patient basis
once daily for qPCR and safety lab measurements from day 6 until day 21 post
challenge. All volunteers will be treated with a curative regimen of Malarone,
either at the time of detection of blood stage parasitemia (for treatment
criteria see paragraph 8.3.3), or 28 days after challenge infection. All
volunteers will be checked for parasites after treatment.
One year after the last immunization, if >50% of immunized volunteers were
protected in cohort A, the protected volunteers will undergo a second
homologous CHMI. During the immunization and challenge phases, blood will also
be drawn for exploratory immunology and parasitology objectives. These samples
will be analyzed by Radboudumc and its collaborators.The total study period
will last a maximum of 14 months.
Three reserve volunteers will be recruited per cohort. If one of the volunteers
is not fit to participate in the study before the first immunization, another
volunteer who passed screening will be included as replacement. To allow for
subjects intolerant of mefloquine to leave the study prior to the first CPS
immunization without impacting the study sample size, three reserve volunteers
for cohort A will also begin mefloquine prophylaxis. If they are not used to
replace a withdrawn volunteer, these reserve volunteers will stop mefloquine
prophylaxis after the third dose.
Intervention
1. CPS immunization
On the first day of the study, all study subjects of cohort A will be seen by
the investigators to initiate mefloquine prophylaxis. All volunteers will
receive 250mg mefloquine once a week according to a standard prophylactic
regime. They will receive four doses prior to the first CPS immunization. 3
weeks after initiation of mefloquine prophylaxis, subjects will receive CPS
immunization with bites from 5 or 15 NF135.C10 P. falciparum infected A.
stephensi mosquitoes, depending on allocation. This procedure will be repeated
three times at four week intervals. Volunteers of cohort A will continue
mefloquine prophylaxis throughout CPS immunization and for four weeks after the
last immunization.
Volunteers of cohort B will receive CPS immunization with bites from 15
NF135.C10 P. falciparum infected A. stephensi mosquitoes. Volunteers will be
treated with artemether/lumefantrine on day 7 after each immunization.
Mosquitoes will be prepared by technicians of the Radboudumc malaria unit and
placed in identical boxes, numbered to correspond with the participant*s study
code. Treatment allocation will not be blinded. The infections will be
performed by placing a box containing mosquitoes on the forearm of the
volunteer. Directly after the feed, the mosquitoes will be dissected by a
technician of the mosquito unit. This will be done to assure that the mosquito
has fed and the presence of sporozoites in the salivary glands of the
mosquitoes. Exposure will be repeated until the exact number of infected
mosquito bites has been reached.
In a previous study, the prophylactic dose of mefloquine was sufficient to
overcome bites of 15 NF54 infected mosquitoes (Bijker, Schats et al. 2014), and
the sensitivity of NF135.C10 to mefloquine is similar to NF54. As long as there
are volunteers present in the mosquito unit, there will be supervision of one
of the clinical investigators. Another clinical investigator will be on call,
in case of emergency. Emergency aid kits will be present and readily available
at any location, whenever there are volunteers present. All volunteers will be
seen by the trial clinicians on days 6 - 10 after each immunization for safety
assessments. In cohort A, on days 7-9 after each immunization blood will be
taken for thick smears. A thick smear will also be performed in any volunteer
with a temperature above 38.0° Celsius after immunization. In cohort B, all
volunteers will start artemether/lumefantrine treatment on day 7 after each
immunization. Blood will be drawn for prospective qPCR on day 6 through 10
after the first immunization. On day 10 after the second and third
immunization, blood will be taken for thick smears.
Throughout the entire trial, blood will be drawn on day 6 through 10 after each
immunization for (retrospective) qPCR in volunteers from cohort A and B.
2. Controlled Human Malaria Infection
Nineteen weeks after the last CPS immunization, all immunized subjects plus
naïve controls will undergo malaria challenge infection. On the challenge day,
all subjects will be exposed to the bites of five NF135.C10 or NF54 strain P.
falciparum infected mosquitoes. Mosquito feeding will be allowed for 10
minutes. Volunteers will receive a local treatment (tripelennamine crème) for
mosquito bites and will be observed for 15 minutes after the feed. Directly
after the feed, the mosquitoes will be dissected by a technician of the
mosquito unit. Exposure will be repeated until five infected mosquitoes have
fed on each volunteer.
After malaria challenge infection subjects will be observed closely according
to an intensive out-patient follow-up schedule including frequent safety
analyses. From the sixth day until the twenty-first day post-CHMI, assessments
of parasite densities using qPCR will be performed once daily. qPCR assessment
of parasite densities will be performed directly in volunteer samples. As soon
as a qPCR is deemed positive for malaria parasites, the technician will inform
the trial clinician. Treatment will be initiated after a single positive qPCR.
If treatment has to be initiated, the trial clinician will contact the
volunteer who will return to the clinic to receive atovaquone/proguanil
treatment. Subjects will also visit the study site for a follow-up visit on day
1, 2 and 3 after treatment (TD+1, 2 & 3). All subjects will be seen for a final
control visit on day 35 after CHMI.
During the entire study period subjects will be instructed to call the trial
physicians at any time if they experience symptoms. The trial physician can
decide to initiate any additional diagnostics (including safety laboratory
evaluations and/or diagnostics for malaria parasites) or treatment at all
times. For unexpected laboratory abnormalities, the laboratory test will be
repeated. If there is any ambiguity regarding the decision to include or
exclude a volunteer, the study physician or the clinical supervisor will
discuss the case with the local safety monitor and make the final decision
after that, if necessary with consultation of a specialist. If volunteers prove
to be eligible, they will be invited to the next visit.
3. Treatment with Malarone.
All volunteers will be treated with Malarone® based on the predetermined
criteria mentioned above. The treatment will consist of the drug Malarone®
(atovaquon/proguanil). Dosing will be as follows: once daily 4 tablets of
250/100mg, during three days according to Dutch SWAB guidelines. This drug has
been chosen because of its fast clinical response and the few side-effects.
Furthermore, it has not been reported to have any cardiac side-effects. During
treatment, complaints of malaria infection will be treated symptomatically. In
addition to specific treatment with Malarone®, symptomatic treatment will be
administered at the discretion of the study physician.
During and one day after Malarone® treatment qPCR is performed directly in
collected blood samples. If qPCR remains positive on day three after Malarone®
treatment (usually the result of parasite debris remaining in the bloodstream)
a thick blood smear will be performed to confirm the absence of intact malaria
parasites.
4. Re-challenge infection
Approximately 10 months after the last CPS immunization of cohort A, if >50% of
immunized volunteers were protected in cohort A, immunized and protected
volunteers will undergo a second challenge infection to assess the duration of
homologous protection.
Study burden and risks
There is no benefit expected for subjects participating in this study. The risk
to subjects after exposure to P. falciparum infected mosquitoes in this trial
will be minimized by adherence to the inclusion/exclusion criteria and close
clinical monitoring, which ensures that subjects with malaria are detected and
treated early.
The risks associated with CPS immunizations are those related to exposure to P.
falciparum infected mosquitoes and those associated with taking mefloquine. In
this part of the trial, the risk of developing clinical malaria is low, as
volunteers in cohort A will be taking standard mefloquine prophylaxis. Any
volunteer with a positive thick smear during the immunization phase will be
treated with treated with Malarone®.
All volunteers in cohort B will be treated with artemether/lumefantrine on day
7 after each immunisation. Mefloquine is a marketed medication registered for
use as a malaria prophylactic agent for Plasmodium strains sensitive to it.
Common side effects include sleeplessness and vivid dreaming (>10%),
psychiatric symptoms such as fear and depression (1-10%), headache (1-10%) and
gastro-intestinal symptoms (1-10%).
The risks of a CHMI for malaria-naïve subjects include the discomfort sustained
by mosquito bites, the discomfort associated with periodic blood draws and the
risk of acquiring clinical P. falciparum malaria.
Mosquito bites are known to cause mild discomfort associated with mosquito
feeding. A small amount of inflammation and pruritus typically accompanies the
bite of the insect. Anaphylaxis to the bite of a mosquito is extremely rare and
has never been reported after CHMI. While significant allergic reactions are
extremely rare, in the event of an allergic reaction, epinephrine,
anti-histamines, on-call physician and resuscitation equipment are available on
site. The Radboudumc, an established site for CHMIs, is fully equipped to
manage anaphylaxis and any other medical emergency.
Frequent blood draws will be necessary to closely monitor the subjects and to
perform qPCR for early detection of P. falciparum parasitemia after challenge
infection. Universal precautions will be maintained for the protection of the
volunteer and the study personnel during venapuncture. Throughout this study,
the amount of blood collected will be maximally 500 mL during the immunization
period and 500 mL during each challenge period. This amount is similar to
widely accepted guidelines used by the Sanquin blood bank.
Intensive follow-up with qPCR performed on samples taken once daily will allow
for detection of parasites at a very early stage. As therapy will be initiated
at this early stage, dangerously high levels or prolonged duration of
parasitemia that would put the subject at undue risk, will not occur. Severe
malaria has never been described in a CHMI. Mild malaria symptoms include
headache, myalgia, fever, chills, sweats, nausea, vomiting, and diarrhoea.
Researchers at the Radboudumc have extensive experience with the care of
clinical malaria.
Although subjects often become symptomatic with mild malaria after CHMI, rapid
diagnosis by qPCR and treatment quickly attenuates the illness so that the
infection does not place the subject at undue risk. Additional information
about the potential risks associated with CHMI and a summary of relevant
reported Serious Adverse Events is given in section 1.5 and section 13 of the
protocol.
Geert Grooteplein Zuid 28
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 28
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
1. Subject is aged >= 18 and <= 35 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 and is available
to attend all study visits.
4. The subject will remain within the Netherlands during the challenge period,
not travel to a malaria-endemic area during the study period, and is reachable
(24/7) by mobile telephone throughout the entire study period.
5. Subject agrees to inform his/her general practitioner about participation in
the study and to sign a request to release by the General Practitioner (GP),
and medical specialist when necessary, any relevant medical information
concerning possible contra-indications for participation in the study.
6. The subject agrees to refrain from blood donation to Sanquin or for other
purposes throughout the study period and for a defined period thereafter
according to current Sanquin guidelines.
7. For female subjects: subject agrees to use adequate contraception and not to
breastfeed for the duration of study. Acceptable forms of contraception
include: established use of oral, injected or implanted hormonal
contraceptives; intrauterine device or intrauterine system; barrier methods
(condoms or diaphragm with additional spermicide); male partner*s sterilisation
(with appropriate post-vasectomy documentation of absence of sperm in the
ejaculate); true abstinence when this is in line with the preferred and usual
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of contraception.
8. Subject agrees to refrain from intensive physical exercise (disproportionate
to the subjects usual daily activity or exercise routine) during the malaria
challenge period.
9. Subject agrees to avoid additional triggers that may cause elevations in
liver enzymes including alcohol from baseline up to 1 week post treatment.
10. 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,
immunodeficient, 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.
1.1 Body weight <50 kg or Body Mass Index (BMI) <18 or >30 kg/m2 at screening.
1.2 A heightened risk of cardiovascular disease, as determined by: an estimated
ten year risk of fatal cardiovascular disease of >=5% at screening, as
determined by the Systematic Coronary Risk Evaluation (SCORE); history, or
evidence at screening, of clinically significant arrhythmia*s, prolonged
QT-interval or other clinically relevant ECG abnormalities; or a positive
family history of cardiac events in 1st or 2nd degree relatives <50 years old.
1.3 A medical history of functional asplenia, sickle cell trait/disease,
thalassaemia trait/disease or G6PD deficiency.
1.4 History of epilepsy in the period of five years prior to study onset, even
if no longer on medication.
1.5 Screening tests positive for Human Immunodeficiency Virus (HIV), or active
Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV).
1.6 Chronic use of i) immunosuppressive drugs, ii) antibiotics or
antimalarials, iii) or other 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.
1.7 History of malignancy of any organ system (other than localized basal cell
carcinoma of the skin), treated or untreated, within the past 5 years.
1.8 Any history of treatment for severe psychiatric disease by a psychiatrist
in the past year.
1.9 History of drug or alcohol abuse interfering with normal social function in
the period of one year prior to study onset, positive urine toxicology test for
cocaine or amphetamines at screening or inclusion, or positive urine toxicology
test for cannabis at inclusion.
2. For female subjects: positive urine pregnancy test at screening or at
inclusion.
3. Any history of malaria, positive serology for P. falciparum, or previous
participation in any malaria (vaccine) study.
4. Known hypersensitivity to or contra-indications (including co-medication)
for use of Mefloquine, Malarone or artemether-lumefantrine, or history of
severe (allergic) reactions to mosquito bites.
5. Receipt of any vaccinations in the 3 months prior to the start of the study
or plans to receive any other vaccinations during the study period or up to 90
days thereafter.
6. Participation in any other clinical study in the 30 days prior to the start
of the study or during the study period.
7. Being an employee or student of the department of Medical Microbiology of
the Radboudumc or the department of Internal Medicine.
8. Any other condition or situation that would, in the opinion of the
investigator, place the subject at an unacceptable risk of injury or render the
subject unable to meet the requirements of the protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | clinicaltrials.gov (NCT03813108) |
| CCMO | NL63594.091.17 |