CPS135: Safety and Efficacy of NF135 CPS Immunization

• Sponsor: Radboud University Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03813108
• Collaborator: The PATH Malaria Vaccine Initiative (MVI) (Other)
• Enrollment: 43
• Location: 1
• Arms: 7
• Actual Duration (Months): 22.1
• Patients Per Site Per Month: 1.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Malaria,Falciparum; Controlled Human Malaria Infection; Immunization; Infection	Biological: CPS-immunization; Biological: malaria challenge infection, P. falciparum NF135.C10; Biological: malaria challenge infection, P. falciparum NF54; Biological: CPS-immunization (A/L); Drug: Atovaquone / Proguanil Oral Tablet [Malarone]	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Safety and Protective Efficacy of Chemoprophylaxis and Sporozoite Immunization With Plasmodium Falciparum NF135 Against Homologous and Heterologous Challenge Infection in Healthy Volunteers in the Netherlands
• Actual Study Start Date: Apr 1, 2019
• Actual Primary Completion Date: Feb 1, 2021
• Actual Study Completion Date: Feb 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Biological: CPS-immunization; Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.; Other Names: Plasmodium falciparum NF135.C10 sporozoites Mefloquine ; Biological: malaria challenge infection, P. falciparum NF135.C10; Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.; Other Names: Plasmodium falciparum NF135.C10 sporozoites ; Drug: 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.
Experimental: 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.	Biological: CPS-immunization; Subjects will be immunized 3 times by exposure to the bites of P. falciparum NF135.C10 infected mosquitoes while taking mefloquine prophylaxis.; Other Names: Plasmodium falciparum NF135.C10 sporozoites Mefloquine ; Biological: malaria challenge infection, P. falciparum NF135.C10; Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.; Other Names: Plasmodium falciparum NF135.C10 sporozoites ; Drug: 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.
Experimental: 3: NF135 CPS-immunization (A/L) challenged by NF135 10 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. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes.	Biological: malaria challenge infection, P. falciparum NF135.C10; Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.; Other Names: Plasmodium falciparum NF135.C10 sporozoites ; Biological: 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.; Other Names: Plasmodium falciparum NF135.C10 sporozoites Artemether/lumefantrine (A/L) ; Drug: 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.
Experimental: 4: NF135 CPS-immunization (A/L) challenged by NF54 10 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. Volunteers will be challenged by the bites of 5 NF54 infected Anopheles mosquitoes 19 weeks after the last immunization.	Biological: malaria challenge infection, P. falciparum NF54; Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.; Other Names: Plasmodium falciparum NF54 sporozoites ; Biological: 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.; Other Names: Plasmodium falciparum NF135.C10 sporozoites Artemether/lumefantrine (A/L) ; Drug: 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.
Other: 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.	Biological: malaria challenge infection, P. falciparum NF135.C10; Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.; Other Names: Plasmodium falciparum NF135.C10 sporozoites ; Drug: 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.
Other: 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.	Biological: malaria challenge infection, P. falciparum NF54; Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 sporozoites.; Other Names: Plasmodium falciparum NF54 sporozoites ; Drug: 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.
Other: 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.	Biological: malaria challenge infection, P. falciparum NF135.C10; Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites.; Other Names: Plasmodium falciparum NF135.C10 sporozoites ; Drug: 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.

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: All
• Accepts 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.

1. For female subjects: positive urine pregnancy test at screening or at inclusion.

2. Any history of malaria, positive serology for P. falciparum, or previous participation in any malaria (vaccine) study.

3. 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.

4. 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.

5. Participation in any other clinical study in the 30 days prior to the start of the study or during the study period.

6. Being an employee or student of the department of Medical Microbiology of the Radboudumc or the department of Internal Medicine.

7. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Radboud university medical centre	Nijmegen	Gelderland	Netherlands	6525 GA

Sponsors and Collaborators

• Radboud University Medical Center
• The PATH Malaria Vaccine Initiative (MVI)

Investigators

• Principal Investigator: Matthew BB McCall, MD PhD DTMH, Radboud University Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 3, 2020

More Information

Publications

None provided.

• Responsible Party: Matthew McCall, dr. MBB McCall, Radboud University Medical Center
• ClinicalTrials.gov Identifier: NCT03813108
• Other Study ID Numbers: CPS135
• First Posted: Jan 23, 2019
• Last Update Posted: May 11, 2022
• Last Verified: Feb 1, 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Matthew McCall, dr. MBB McCall, Radboud University Medical Center: Mosquito bites; Sporozoite; Immunization; Malaria; Falciparum
• Additional relevant MeSH terms: Infections; Communicable Diseases; Malaria; Malaria, Falciparum; Lumefantrine; Artemether; Mefloquine; Atovaquone; Proguanil; Atovaquone, proguanil drug combination; Artemether, Lumefantrine Drug Combination

Study Results

Participant Flow

Arm/Group Title	1: NF135 CPS-immunization Challenged by NF135	2: Low Dose NF135 CPS-immunization Challenged by NF135	3: NF135 CPS-immunization (A/L) Cohort 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
Arm/Group Description	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 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.	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. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes. malaria challenge infection, P. falciparum NF135.C10: 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites. 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 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.	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.	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.	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.
Period Title: Overall Study
STARTED	10	10	20	3	0	0
COMPLETED	8	9	0	3	0	0
NOT COMPLETED	2	1	20	0	0	0

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	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 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.	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	10	10	20	3	0	0	43
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 0%
Between 18 and 65 years	10 100%	10 100%	20 100%	3 100%	0 NaN	0 NaN	43 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	24	23.5	23.0	21	23
Sex: Female, Male (Count of Participants)
Female	7 70%	4 40%	10 50%	2 66.7%	23 Infinity
Male	3 30%	6 60%	10 50%	1 33.3%	20 Infinity
Race/Ethnicity, Customized (Count of Participants)
Caucasian	7 70%	8 80%	15 75%	3 100%	33 Infinity
Asian	2 20%	1 10%	0 0%	0 0%	3 Infinity
Other	1 10%	1 10%	5 25%	0 0%	7 Infinity
Region of Enrollment (participants) [Number]
Netherlands	10 100%	10 100%	20 100%	3 100%	43 Infinity
Body Mass Index (kg/m^2) (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	23.2	23.7	23.4	22	23.2
Hemoglobin (mmol/L) (mmol/L) [Median (Full Range) ]
Median (Full Range) [mmol/L]	9.3	9.0	9.0	8.3	9.0

Outcome Measures

1. Primary Outcome

Title	Frequency of Adverse Events After NF135.C10 CPS Immunization
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	1: NF135 CPS-immunization Challenged by NF135	2: Low Dose NF135 CPS-immunization Challenged by NF135	3: NF135 CPS-immunization (A/L) Cohort B
Arm/Group Description	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 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.	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. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes. malaria challenge infection, P. falciparum NF135.C10: 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites. 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 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.
Measure Participants	10	10	20
Number [Adverse events]	139	173	172

2. Primary Outcome

Title	Magnitude of Adverse Events After NF135.C10 CPS Immunization
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	1: NF135 CPS-immunization Challenged by NF135	2: Low Dose NF135 CPS-immunization Challenged by NF135	3: NF135 CPS-immunization (A/L) Cohort B
Arm/Group Description	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 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.	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. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes. malaria challenge infection, P. falciparum NF135.C10: 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites. 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 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.
Measure Participants	10	10	20
Mild adverse events (grade 1)	108	128	121
Moderate adverse events (grade 2)	20	35	31
Severe adverse events (grade 3)	11	10	19
Serious adverse events (grade 4)	0	0	1

3. Secondary Outcome

Title	Time to Parasitemia
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	1: NF135 CPS-immunization Challenged by NF135	2: Low Dose NF135 CPS-immunization Challenged by NF135	5: Control Group Challenged by NF135.C10 Cohort A
Arm/Group Description	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 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.	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.
Measure Participants	5	7	3
Median (Full Range) [days to parasitaemia]	9	7	7

4. Post-Hoc Outcome

Title	Break Through Infections
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	1: NF135 CPS-immunization Challenged by NF135	2: Low Dose NF135 CPS-immunization Challenged by NF135	3: NF135 CPS-immunization (A/L) Cohort B
Arm/Group Description	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 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.	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. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes. malaria challenge infection, P. falciparum NF135.C10: 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites. 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 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.
Measure Participants	10	10	20
Break through following immunization 1	10 100%	10 100%	2 10%
Break through following immunization 2	3 30%	3 30%
Break through following immunization 3	4 40%	5 50%

Adverse Events

Time Frame	Groups 1 and 2 (Cohort A ): Inclusion until 35 days after challenge infection (35 weeks) Group 3 (Cohort B): Inclusion until premature end of study (22 weeks) Group 5 (Cohort A): Inclusion until 35 days after challenge infection (5 weeks)
Adverse Event Reporting Description	As subjects in cohort B did not complete their immunizations, they were not yet randomized for infection when the trial ended prematurely. Cohort B is therefore analyzed as one group that received 1 immunization with 15 NF135.C10 infected mosquitoes under presumptive A/L treatment.
Arm/Group Title	1: NF135 CPS-immunization Challenged by NF135		2: Low Dose NF135 CPS-immunization Challenged by NF135		3: NF135 CPS-immunization (A/L) Cohort B		5: Control Group Challenged by NF135.C10 Cohort A
Arm/Group Description	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 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.		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. Volunteers will be challenged by the bites of 5 NF135.C10 infected Anopheles mosquitoes. malaria challenge infection, P. falciparum NF135.C10: 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF135.C10 sporozoites. 10 Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum NF54 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.		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.
All Cause Mortality
	1: NF135 CPS-immunization Challenged by NF135		2: Low Dose NF135 CPS-immunization Challenged by NF135		3: NF135 CPS-immunization (A/L) Cohort B		5: Control Group Challenged by NF135.C10 Cohort A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/20 (0%)		0/3 (0%)
Serious Adverse Events
	1: NF135 CPS-immunization Challenged by NF135		2: Low Dose NF135 CPS-immunization Challenged by NF135		3: NF135 CPS-immunization (A/L) Cohort B		5: Control Group Challenged by NF135.C10 Cohort A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		1/20 (5%)		0/3 (0%)
Cardiac disorders
Acute coronary syndrome	0/10 (0%)	0	0/10 (0%)	0	1/20 (5%)	1	0/3 (0%)	0
Other (Not Including Serious) Adverse Events
	1: NF135 CPS-immunization Challenged by NF135		2: Low Dose NF135 CPS-immunization Challenged by NF135		3: NF135 CPS-immunization (A/L) Cohort B		5: Control Group Challenged by NF135.C10 Cohort A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/10 (100%)		10/10 (100%)		20/20 (100%)		2/3 (66.7%)
Gastrointestinal disorders
Pyrosis	0/10 (0%)	0	0/10 (0%)	0	1/20 (5%)	1	0/3 (0%)	0
General disorders
Insomnia	2/10 (20%)	2	4/10 (40%)	7	0/20 (0%)	0	0/3 (0%)	0
Vivid dreams	3/10 (30%)	3	1/10 (10%)	1	0/20 (0%)	0	0/3 (0%)	0
Sadness	1/10 (10%)	1	1/10 (10%)	1	0/20 (0%)	0	0/3 (0%)	0
restlessness	1/10 (10%)	1	0/10 (0%)	0	0/20 (0%)	0	0/3 (0%)	0
Infections and infestations
Fever	8/10 (80%)	19	8/10 (80%)	16	18/20 (90%)	39	0/3 (0%)	0
Chills	1/10 (10%)	1	2/10 (20%)	3	9/20 (45%)	13	0/3 (0%)	0
Sweats	0/10 (0%)	0	0/10 (0%)	0	6/20 (30%)	7	0/3 (0%)	0
Abdominal pain	2/10 (20%)	2	2/10 (20%)	2	3/20 (15%)	4	1/3 (33.3%)	2
Fatigue	6/10 (60%)	8	5/10 (50%)	12	7/20 (35%)	10	1/3 (33.3%)	2
Headache	10/10 (100%)	35	10/10 (100%)	62	18/20 (90%)	37	1/3 (33.3%)	2
Malaise	7/10 (70%)	13	4/10 (40%)	4	12/20 (60%)	16	0/3 (0%)	0
Myalgia	6/10 (60%)	11	6/10 (60%)	20	11/20 (55%)	13	1/3 (33.3%)	1
Nausea	8/10 (80%)	20	8/10 (80%)	17	7/20 (35%)	10	2/3 (66.7%)	3
Decreased appetite	2/10 (20%)	2	1/10 (10%)	1	6/20 (30%)	6	0/3 (0%)	0
Dizziness	1/10 (10%)	1	5/10 (50%)	6	7/20 (35%)	7	0/3 (0%)	0
Diarrhoea	1/10 (10%)	1	2/10 (20%)	2	0/20 (0%)	0	0/3 (0%)	0
Back pain	0/10 (0%)	0	1/10 (10%)	1	2/20 (10%)	4	0/3 (0%)	0
Arthralgia	1/10 (10%)	1	1/10 (10%)	1	1/20 (5%)	1	0/3 (0%)	0
Pruritus	10/10 (100%)	15	7/10 (70%)	10	2/20 (10%)	2	0/3 (0%)	0
Erythema	3/10 (30%)	3	1/10 (10%)	3	0/20 (0%)	0	0/3 (0%)	0
Swelling	0/10 (0%)	0	1/10 (10%)	3	0/20 (0%)	0	0/3 (0%)	0
Canker sores	0/10 (0%)	0	1/10 (10%)	1	0/20 (0%)	0	0/3 (0%)	0
Herpes simplex	0/10 (0%)	0	0/10 (0%)	0	1/20 (5%)	1	0/3 (0%)	0

Limitations/Caveats

- Early termination of cohort B; heterologous protection could not be assessed.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.