Malaria,Falciparum, Controlled Human Malaria Infection, Immunization; Infection
Conditions
Keywords
Mosquito bites, Sporozoite, Immunization, Malaria, Falciparum
Brief summary
This is an open label, randomized, controlled clinical trial. The primary aim of this project is to determine the safety and tolerability of NF135.C10 sporozoite immunization under chemoprophylaxis against homologous and heterologous challenge infection.
Detailed description
A total of 49 healthy 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=6). Immunizations in cohort A (n=20) will be performed under mefloquine prophylaxis, spaced 4 weeks apart. In cohort B, volunteers will not take mefloquine prophylaxis, instead all volunteers will be treated presumptively on day 7 after each immunization with a curative regimen of artemether/lumefantrine, regardless of parasitaemia or symptoms. Nineteen weeks after the last immunization, all volunteers plus naïve controls will be challenged either by the bites of 5 NF135.C10 (n=36) or 5 NF54 (n=13) 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 atovaquone/proguanil, either at the time of detection of blood stage parasitemia, or 28 days after challenge infection.
Interventions
BIOLOGICALCPS-immunization
Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.
Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.
Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.
BIOLOGICALCPS-immunization (A/L)
Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes and receive presumptive treatment with artemether/lumefantrine initiated on day 7 after each immunization.
DRUGAtovaquone / Proguanil Oral Tablet [Malarone]
All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection.
Sponsors
The PATH Malaria Vaccine Initiative (MVI)
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
Healthy volunteers
Yes
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 throughout the study period and for a defined period thereafter according to current 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 cardiovascular events (including ischemia and myocarditis) 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 severe psychiatric disease diagnosed by a psychiatrist. 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 outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Adverse Events After NF135.C10 CPS Immunization | Cohort A: Inclusion until 35 days after challenge infection (35 weeks) Cohort B: Inclusion - premature end of study (22 weeks) | The number of adverse events will be recorded by the trial clinicians for all participants. |
| Magnitude of Adverse Events After NF135.C10 CPS Immunization | Cohort A: Inclusion until 35 days after challenge infection (35 weeks) Cohort B: Inclusion - premature end of study (22 weeks) | The severity of adverse events will be recorded (mild/moderate/severe) for each adverse event |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Parasitemia | Day 1 - 28 after malaria challenge infection (28 days) | The effectiveness of CPS-immunization with NF135 sporozoites to protect against malaria challenge infection with homologous N135.C10 or heterologous NF54 sporozoites will be determined by the time to parasitemia in immunized versus non-immunized volunteers after the challenge infection. |
Countries
Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1: NF135 CPS-immunization Challenged by NF135 10 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.
Atovaquone / Proguanil Oral Tablet \[Malarone\]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection. | 10 |
| 2: Low Dose NF135 CPS-immunization Challenged by NF135 10 volunteers will receive three immunizations with 5 NF135.C10 infected Anopheles mosquitoes under mefloquine prophylaxis. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.
CPS-immunization: Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.
Atovaquone / Proguanil Oral Tablet \[Malarone\]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection. | 10 |
| 3: NF135 CPS-immunization (A/L) Challenged by NF135 Cohorst B 20 volunteers will receive three immunizations with 15 NF135.C10 infected Anopheles mosquitoes and are presumptively treated with artemether/lumefantrine starting on day 7 after each immunization. 10 volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes. 10 volunteers will be challenged by the bites of 5 NF54 infected Anopheles mosquitoes.
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.
CPS-immunization (A/L): Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes and receive presumptive treatment with artemether/lumefantrine initiated on day 7 after each immunization.
Atovaquone / Proguanil Oral Tablet \[Malarone\]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection. | 20 |
| 5: Control Group Challenged by NF135.C10 Cohort A Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.
Atovaquone / Proguanil Oral Tablet \[Malarone\]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection. | 3 |
| 6: Control Group Challenged by NF54 Cohort B Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF54 infected Anopheles mosquitoes 19 weeks after the last immunization.
malaria challenge infection, P. falciparum NF54: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.
Atovaquone / Proguanil Oral Tablet \[Malarone\]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection. | 0 |
| 7: Control Group Challenged by NF135 Cohort B Challenge infection control group: 3 volunteers will receive no immunization and will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes 19 weeks after the last immunization.
malaria challenge infection, P. falciparum NF135.C10: Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.
Atovaquone / Proguanil Oral Tablet \[Malarone\]: All participants will be treated with atovaquone/proguanil (1000/400 mg (= 4 tablets) 1×/day during 3 consecutive days) when they develop a malaria infection or on day 28 after malaria challenge infection. | 0 |
| Total | 43 |
Baseline characteristics
| Characteristic | 1: NF135 CPS-immunization Challenged by NF135 | 2: Low Dose NF135 CPS-immunization Challenged by NF135 | 3: NF135 CPS-immunization (A/L) Challenged by NF135 Cohorst B | 5: Control Group Challenged by NF135.C10 Cohort A | 6: Control Group Challenged by NF54 Cohort B | 7: Control Group Challenged by NF135 Cohort B | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 10 Participants | 20 Participants | 3 Participants | 0 Participants | 0 Participants | 43 Participants |
| Age, Continuous | 24 years | 23.5 years | 23.0 years | 21 years | — | — | 23 years |
| Body Mass Index (kg/m^2) | 23.2 kg/m^2 | 23.7 kg/m^2 | 23.4 kg/m^2 | 22 kg/m^2 | — | — | 23.2 kg/m^2 |
| Hemoglobin (mmol/L) | 9.3 mmol/L | 9.0 mmol/L | 9.0 mmol/L | 8.3 mmol/L | — | — | 9.0 mmol/L |
| Race/Ethnicity, Customized Race Asian | 2 Participants | 1 Participants | 0 Participants | 0 Participants | — | — | 3 Participants |
| Race/Ethnicity, Customized Race Caucasian | 7 Participants | 8 Participants | 15 Participants | 3 Participants | — | — | 33 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 1 Participants | 5 Participants | 0 Participants | — | — | 7 Participants |
| Region of Enrollment Netherlands | 10 participants | 10 participants | 20 participants | 3 participants | — | — | 43 participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 10 Participants | 2 Participants | — | — | 23 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 10 Participants | 1 Participants | — | — | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 20 | 0 / 3 |
| other Total, other adverse events | 10 / 10 | 10 / 10 | 20 / 20 | 2 / 3 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 1 / 20 | 0 / 3 |
Outcome results
Primary
Frequency of Adverse Events After NF135.C10 CPS Immunization
The number of adverse events will be recorded by the trial clinicians for all participants.
Time frame: Cohort A: Inclusion until 35 days after challenge infection (35 weeks) Cohort B: Inclusion - premature end of study (22 weeks)
Population: The Control Group Challenged by NF135.C10 Cohort A, was not included in this analysis as it served only as infection control. As subjects in cohort B did not complete their immunizations they were not yet randomized for infection when the trial ended prematurely. Cohort is therefore analyzed as one group that received 1 immunization with 15 NF135.C10 infected mosquitoes under presumptive A/L treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1: NF135 CPS-immunization Challenged by NF135 | Frequency of Adverse Events After NF135.C10 CPS Immunization | 139 Adverse events |
| 2: Low Dose NF135 CPS-immunization Challenged by NF135 | Frequency of Adverse Events After NF135.C10 CPS Immunization | 173 Adverse events |
| 3: NF135 CPS-immunization (A/L) Cohort B | Frequency of Adverse Events After NF135.C10 CPS Immunization | 172 Adverse events |
Primary
Magnitude of Adverse Events After NF135.C10 CPS Immunization
The severity of adverse events will be recorded (mild/moderate/severe) for each adverse event
Time frame: Cohort A: Inclusion until 35 days after challenge infection (35 weeks) Cohort B: Inclusion - premature end of study (22 weeks)
Population: The Control Group Challenged by NF135.C10 Cohort A, was not included in this analysis as it served only as infection control. As subjects in cohort B did not complete their immunizations they were not yet randomized for infection when the trial ended prematurely. Cohort is therefore analyzed as one group that received 1 immunization with 15 NF135.C10 infected mosquitoes under presumptive A/L treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1: NF135 CPS-immunization Challenged by NF135 | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Moderate adverse events (grade 2) | 20 Adverse events |
| 1: NF135 CPS-immunization Challenged by NF135 | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Serious adverse events (grade 4) | 0 Adverse events |
| 1: NF135 CPS-immunization Challenged by NF135 | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Severe adverse events (grade 3) | 11 Adverse events |
| 1: NF135 CPS-immunization Challenged by NF135 | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Mild adverse events (grade 1) | 108 Adverse events |
| 2: Low Dose NF135 CPS-immunization Challenged by NF135 | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Moderate adverse events (grade 2) | 35 Adverse events |
| 2: Low Dose NF135 CPS-immunization Challenged by NF135 | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Mild adverse events (grade 1) | 128 Adverse events |
| 2: Low Dose NF135 CPS-immunization Challenged by NF135 | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Serious adverse events (grade 4) | 0 Adverse events |
| 2: Low Dose NF135 CPS-immunization Challenged by NF135 | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Severe adverse events (grade 3) | 10 Adverse events |
| 3: NF135 CPS-immunization (A/L) Cohort B | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Serious adverse events (grade 4) | 1 Adverse events |
| 3: NF135 CPS-immunization (A/L) Cohort B | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Severe adverse events (grade 3) | 19 Adverse events |
| 3: NF135 CPS-immunization (A/L) Cohort B | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Mild adverse events (grade 1) | 121 Adverse events |
| 3: NF135 CPS-immunization (A/L) Cohort B | Magnitude of Adverse Events After NF135.C10 CPS Immunization | Moderate adverse events (grade 2) | 31 Adverse events |
Secondary
Time to Parasitemia
The effectiveness of CPS-immunization with NF135 sporozoites to protect against malaria challenge infection with homologous N135.C10 or heterologous NF54 sporozoites will be determined by the time to parasitemia in immunized versus non-immunized volunteers after the challenge infection.
Time frame: Day 1 - 28 after malaria challenge infection (28 days)
Population: The trial was prematurely ended before the challenge infection in cohort B. Only arms that received challenge infection are included in this analysis. In arm 1, 2 subjects withdrew from the trial before challenge infection and 3 subjects were sterily protected and not included in the analysis. In arm 2, 1 subject withdrew from the trial before challenge infection and 2 subjects were sterily protected and not included in this analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1: NF135 CPS-immunization Challenged by NF135 | Time to Parasitemia | 9 days to parasitaemia |
| 2: Low Dose NF135 CPS-immunization Challenged by NF135 | Time to Parasitemia | 7 days to parasitaemia |
| 3: NF135 CPS-immunization (A/L) Cohort B | Time to Parasitemia | 7 days to parasitaemia |
Post Hoc
Break Through Infections
Number of subjects that required rescue treatment with atovaquone/proguanil due to a positive thick smear in combination with symptoms following NF135.C10 immunizations despite mefloquine prophylaxis (Cohort A) or presumptive artemether/lumefantrine treatment (Cohort B).
Time frame: From day 0 until 28 days after each immunization (28 days)
Population: Only study groups that received NF135.C10 immunizations were included in this analysis. One subject in group 2: Low dose NF135 CPS-immunization challenged by NF135, withdrew consent after the first immunization, and thus did not receive immunization 2 and 3. The study was prematurely terminated, therefore subjects in group 3: NF135 CPS-immunization (A/L) Cohort B only received immunization 1.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1: NF135 CPS-immunization Challenged by NF135 | Break Through Infections | Break through following immunization 2 | 3 participants |
| 1: NF135 CPS-immunization Challenged by NF135 | Break Through Infections | Break through following immunization 1 | 10 participants |
| 1: NF135 CPS-immunization Challenged by NF135 | Break Through Infections | Break through following immunization 3 | 4 participants |
| 2: Low Dose NF135 CPS-immunization Challenged by NF135 | Break Through Infections | Break through following immunization 3 | 5 participants |
| 2: Low Dose NF135 CPS-immunization Challenged by NF135 | Break Through Infections | Break through following immunization 2 | 3 participants |
| 2: Low Dose NF135 CPS-immunization Challenged by NF135 | Break Through Infections | Break through following immunization 1 | 10 participants |
| 3: NF135 CPS-immunization (A/L) Cohort B | Break Through Infections | Break through following immunization 1 | 2 participants |