To determine protective immunity against a heterologous P. falciparum sporozoites re-challenge after previous CPS immunization and challenge.
ID
Source
Brief title
Condition
- Protozoal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Objective: To determine protective immunity against a heterologous P.
falciparum sporozoites re-challenge after previous CPS immunization and
challenge.
Secondary outcome
Secondary endpoints:
• Parasitemia and kinetics of parasitemia as measured by PCR
• Frequency of signs or symptoms in study groups
• Immune responses between study groups
Background summary
Malaria is one of the major infectious diseases in the world with a tremendous
impact on quality of life, significantly contributing to the ongoing poverty in
endemic countries. It causes approximately 655.000 deaths per year, the
majority of which are children under the age of five. The malaria parasite
enters the human body through the skin, by the bite of an infected mosquito.
Subsequently, it invades the liver, develops and multiplies inside hepatocytes.
After approximately one week, the hepatocytes burst open and parasites are
released in the blood stream, leading to the clinical phase of the disease.
As a unique opportunity to study malaria immunology and efficacy of
immunisation strategies, a protocol has been developed to conduct controlled
human malaria infections (CHMIs). CHMIs are studies consisting of a small group
of malaria-naïve volunteers who are infected through bites of infected (e.g.
Plasmodium. falciparum) laboratory-reared Anopheles mosquitoes. Although
potentially serious or even lethal, P. falciparum malaria can be radically
cured at the earliest stages of blood infection when risks of complications are
virtually absent and symptoms are usually mild.
We have shown previously that healthy human volunteers can be protected from a
P. falciparum challenge by immunization with sporozoites (by mosquito bites)
under chloroquine prophylaxis (CPS immunization). Interestingly, sterile
protection in nearly all human CPS immunized volunteers was achieved by a
relatively low dose, i.e. a total of 45 infectious mosquito bites.
In the ZonMw1 study (NL33904.091.10), we challenged a total of 24 volunteers
after CPS immunization of three groups with 45, 30 or 15 infected
mosquito-bites respectively. Seventeen of 24 these volunteers were fully
protected against a homologous challenge after CPS immunization while 7
volunteers developed parasitaemia with a similar prepatent period as the
control group. The availability of this immunized cohort opens the unique
opportunity to determine protection to a heterologous challenge for both of the
protected and unprotected volunteers as the previous challenge infection might
have served as an immunological boost to the unprotected volunteers.
We therefore aim to investigate through an observational, proof of principle,
study to assess the protection on an individual basis of all previously
immunized and challenged volunteers against a heterologous P. falciparum
NF135.C10 challenge.
Study objective
To determine protective immunity against a heterologous P. falciparum
sporozoites re-challenge after previous CPS immunization and challenge.
Study design
The study is a single centre open label clinical trial. Laboratory personnel
will be blinded, volunteers and the investigators will both not be blinded.
A maximum of 25 volunteers will be divided into two groups as shown in Table 1.
All volunteers will be challenged by the bites of 5 mosquitoes, infected with
the P. falciparum NF135.C10 strain.
Table 1
1. n=20; Immunized subjects ZonMw1
2. n=5; control group
Intervention
All volunteers will be exposed to five P. falciparum NF135.C10 infected
mosquito-bites.
Study burden and risks
Benefits: No benefit can be claimed for any of the volunteers. Even though
previously immunized and challenged volunteers (ZonMw1) might be protected to
P. falciparum in this study, these effects may not apply to field situations.
Therefore, volunteers will be advised to take adequate malaria prophylaxis and
preventative measurements (e.g. bednet, deet etc) when travelling to malaria
endemic areas in the future.
Risks: Risks for volunteers are related to exposure to (early) P. falciparum
malaria infection and side-effects of Malarone® treatment. Volunteers will be
given the results of the screeningstests (HBV, HCV, HIV, pregnancy test and tox
screen).
Burden: Volunteers have to fill in a health questionnaire before screening.
Approximately 10 days before malaria infection (challenge) volunteers will
undergo leukapheresis at Sanquin bloodbank accoding to standard operating
procedures and is located close tot the study centre . By means of a needle in
the forearm PBMCs will be filtered during approximately 30 minutes in order to
study immune responses against malaria. The burden for the volunteer is
minimal, sometimes temporarily tingling sensations can be experienced in lips
or fingers and disappear readily after drinking calcium-containing drinks (e.g.
milk) or taking calcium tablets The challenge infection, in which volunteers
receive mosquito bites, will take place on day 0, and volunteers have to make
visits to the trial centre in the 140 days afterwards, starting on day 5 after
challenge. After challenge there will be a period (35 days) of intense clinical
monitoring with frequent site visits and blood examinations. The first two days
involve once daily visits. The next nine days will involve twice daily visits,
the six days afterwards once a day. After start of Malarone treatment,
volunteers visit the trial centre twice a day. As it is unpredictable if
and/or when subjects will develop a positive thick blood smear after challenge
infection, it is impossible to state the exact number of site visits and blood
examinations. However, the maximum number (in case a subject does not develop a
positive blood smear) of site visits will be 39 (34 blood examinations) with a
maximum amount of collected blood of 500 mL . In addition periodical physical
examinations will be performed and the subject is asked to complete a diary and
measure temperature orally.
Geert Grooteplein 28
6525 GA Nijmegen
NL
Geert Grooteplein 28
6525 GA Nijmegen
NL
Listed location countries
Age
Inclusion criteria
1. Age >= 18 and <= 35 years healthy volunteers (males or females)
2. Good health based on history and clinical examination
3. Negative pregnancy test
4. Use of adequate contraception for females
5. Signing of the informed consent form, thereby demonstrating understanding of the meaning and procedures of the study
6. Agreement to inform the general practitioner and to sign a request to release medical information concerning contra-indications for participation in the study
7. Willingness to undergo a Pf controlled challenge through mosquito bites
8. Agreement to stay in a hotel room close to the trial centre during a part of the study (Day 5 after challenge till treatment is finished)
9. Reachable (24/7) by mobile phone during the whole study period
10. Available to attend all study visits
11. Agreement to refrain from blood donation to Sanquin or for other purposes, during the whole study period
12. Willingness to undergo HIV, hepatitis B and hepatitis C tests
13. Negative urine toxicology screening test at screening visit and the day before challenge
14. Willingness to take a curative regimen of Malarone®
15. Adequate venous access for leukapheresis
Exclusion criteria
1. History of malaria (other than participation in ZonMw1 study) or residence in malaria endemic areas within the past six months
2. Plans to travel to malaria endemic areas during the study period
3. Plans to travel outside of the Netherlands during the challenge period
4. Previous participation in any malaria vaccine study and/or positive serology for Pf (except ZonMw1 volunteers)
5. Symptoms, physical signs and laboratory values suggestive of systemic disorders including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, psychiatric, and other conditions which could interfere with the interpretation of the study results or compromise the health of the volunteers
6. History of diabetes mellitus or cancer (except basal cell carcinoma of the skin)
7. History of arrhythmias or prolonged QT-interval
8. Positive family history in 1st and 2nd degree relatives for cardiac events < 50 years old
9. An estimated, ten year risk of fatal cardiovascular disease of >=5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system
10. Clinically significant abnormalities in electrocardiogram (ECG) at screening
11. Body Mass Index (BMI) below 18 or above 30 kg/m2
12. Any clinically significant deviation from the normal range in biochemistry or hematology blood tests or in urine analysis
13. Positive HIV, HBV or HCV tests
14. Participation in any other clinical study within 30 days prior to the onset of the study
15. Enrollment in any other clinical study during the study period
16. For women: being pregnant or lactating
17. Volunteers unable to give written informed consent
18. Volunteers unable to be closely followed for social, geographic or psychological reasons
19. History of drug or alcohol abuse interfering with normal social function
20. A history of treatment for psychiatric disease
21. A history of convulsions
22. Contra-indications to Malarone®, including hypersensitivity or treatment taken by the volunteer that interferes with Malarone®
23. The use of chronic immunosuppressive drugs, antibiotics, or other immune modifying drugs within three months of study onset (inhaled and topical corticosteroids and oral anti-histaminic are allowed) and during the study period
24. Any confirmed or suspected immunosuppressive or immunodeficient condition, including (functional) asplenia
25. Co-workers or trainees of the departments Infectious Diseases, Medical Microbiology or Parasitology of the Leiden University Medical Centre (LUMC) or Medical Microbiology, Parasitology, Radboud University Nijmegen (RUNMC)
26. A history of sickle cell anaemia, sickle cell trait, thalassaemia (or trait), G6PD deficiency
Design
Recruitment
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 |
|---|---|
| CCMO | NL39414.000.12 |
| Other | volgt |