PbVac: Safety and Protective Efficacy of Pb(PfCS@UIS4)

• Sponsor: Radboud University Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT03138096
• Collaborator: Havenziekenhuis (Other), Erasmus Medical Center (Other), The PATH Malaria Vaccine Initiative (MVI) (Other)
• Enrollment: 24
• Locations: 2
• Arms: 5
• Actual Duration (Months): 16.2
• Patients Per Site: 12
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

In the underlying study, a genetically modified P. berghei parasite is used. P. berghei is one of the four Plasmodium species that causes malaria in rodents. The hypothesis is that immunization of humans with P. berghei will induce a cross-species immune response without the risk of a breakthrough infection. To further increase the potential for protective efficacy, the P. falciparum circumsporozoite (CS)- protein gene has been integrated in the P. berghei parasite, generating a genetically modified P. berghei parasite, abbreviated as Pb(PfCS@UIS4).

Condition or Disease	Intervention/Treatment	Phase
Malaria,Falciparum; Plasmodium Falciparum; Plasmodium Berghei; Controlled Human Malaria Infection (CHMI)	Biological: Pb(PfCS@UIS4)-infected mosquitoes; Other: Challenge infection P. falciparum	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Safety and Protective Efficacy of Genetically Modified Plasmodium Berghei (Pb(PfCS@UIS4)) Malaria Parasites in Healthy Volunteers
• Actual Study Start Date: May 29, 2017
• Actual Primary Completion Date: Mar 28, 2018
• Actual Study Completion Date: Oct 3, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 - five Pb(PfCS@UIS4)-infected mosquitoes (Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes	Biological: Pb(PfCS@UIS4)-infected mosquitoes; Pb(PfCS@UIS4)-infected mosquitoes
Experimental: Group 2 - 25 Pb(PfCS@UIS4)-infected mosquito bites (group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites	Biological: Pb(PfCS@UIS4)-infected mosquitoes; Pb(PfCS@UIS4)-infected mosquitoes
Experimental: Group 3 - 75 Pb(PfCS@UIS4)-infected mosquito bites (group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites	Biological: Pb(PfCS@UIS4)-infected mosquitoes; Pb(PfCS@UIS4)-infected mosquitoes; Other: Challenge infection P. falciparum; Challenge infection with bites of five infected Pf mosquitoes
Other: Group 4 - Infectivity control group of Phase 1 Infectivity control group of Phase 1	Other: Challenge infection P. falciparum; Challenge infection with bites of five infected Pf mosquitoes
Other: Group 5 - Infectivity control group of Phase 2 Infectivity control group of Phase 2	Other: Challenge infection P. falciparum; Challenge infection with bites of five infected Pf mosquitoes

Outcome Measures

Primary Outcome Measures

1. Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety] [Groups 1&2: from exposure to Pb(PfCS@UIS4)-infected mosquitoes until 28 days thereafter. Group 3: from first exposure until 21 days after fourth/final exposure (=until day immediately prior to CHMI, i.e. approximately 15 weeks after first exposure).]

   Frequency and magnitude of adverse events in study groups following one or more exposures to Pb(PfCS@UIS4)-infected mosquitoes.

2. Presence of Breakthrough Parasitemia Following Exposure to Pb(PfCS@UIS4)-Infected Mosquito Bites [Groups 1-3: from (first) exposure until 28 days thereafter.]

   Presence of breakthrough parasitemia following (first) exposure to Pb(PfCS@UIS4)-infected mosquito bites, as determined by thick blood smear microscopy

3. Time to Parasitemia After CHMI [Efficacy] [Groups 3&4: from day of CHMI until 28 days thereafter]

   Time to parasitemia after CHMI with the wild-type NF54 P. falciparum strain, as detected by qPCR [Efficacy]

Secondary Outcome Measures

1. Immunogenicity of Pb(PfCS@UIS4) as Assessed by ELISA [Group 3: from baseline until day prior to CHMI (approximately 15 weeks after first Pb(PfCS@UIS4) immunization)]

   Immunogenicity of repeated Pb(PfCS@UIS4) immunization as assessed by fold change in anti-P. falciparum IgG from baseline to post-immunization (day prior to CHMI), as measured by ELISA.

Other Outcome Measures

1. Cellular Immune Responses After Exposure to Pb(PfCS@UIS4) [Exploratory Endpoint] [Group 3: from baseline until day prior to CHMI (approximately 15 weeks after first Pb(PfCS@UIS4) immunization)]

   Cellular immune responses after repeated exposure to Pb(PfCS@UIS4), as determined by increase in %-age IFNg+ lymphocytes following in vitro stimulation of PBMCs with WT P. falciparum sporozoites measured by flow cytometry at baseline and following immunization (day prior to CHMI)

2. Humoral Immune Responses After Exposure to Pb(PfCS@UIS4) [Exploratory Endpoint] [Group 3: from baseline until day prior to CHMI (approximately 15 weeks after first Pb(PfCS@UIS4) immunization)]

   Humoral immune responses after repeated exposure to Pb(PfCS@UIS4) as determined by increase in %-age inhibition of WT P. falciparum sporozoite invasion in HC-04 cells by purified plasma IgG collected at baseline and following immunization (day prior to CHMI).

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 is able and willing (in the investigator's opinion) to comply with all study requirements.

3. Subject is willing to complete an informed consent questionnaire and is able to answer all questions correctly.

4. Subject is able to communicate well with the investigator and is available to attend all study visits, lives in Rotterdam or in proximity to the trial centre (can be on site within 1 hour) or is willing to stay in a hotel close to the trial centre during part of the study (phase 1: from day of immunization to day 12 post-immunization; phase 2: from day of immunization to day 8 post-immunization.

5. The subject will remain within the Netherlands from day -1 until day +28 after immunization during phase 1; from day -1 until day 12 after each immunization during phase 2, and during the challenge period, will not travel to a malaria-endemic area during the study period, and is reachable (24/7) by mobile telephone throughout the entire study period.

6. Subject agrees to their general practitioner being informed and contacted about their participation in the study and agrees to sign a form to request the release by their General Practitioner (GP), and medical specialist when necessary, to the investigator(s), of any relevant medical information concerning possible contra-indications for participation in the study.

7. 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 (3 years minimum, depending on serology).

8. For female subjects: subject agrees to use continuous adequate contraception** and not to breastfeed for the duration of study.

9. Subject agrees to refrain from intensive physical exercise (disproportionate to the subject's usual daily activity or exercise routine) during the malaria challenge period.

10. Subject agrees to avoid additional triggers that may cause elevations in liver enzymes including alcohol from baseline up to 1 week post treatment.

11. Subject has signed written informed consent to participate in the trial.

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

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), active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) 1.6. Chronic use of i) immunosuppressive drugs,

1. antibiotics, 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. Any recent or current systemic therapy with an antibiotic or drug with potential anti-malarial activity (chloroquine, atovaquone-proguanil, arthemether-lumefantrine, sulfadoxine-pyrimethamine, doxycycline, tetracycline, piperaquine, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, erythromycin, hydroxychloroquine, etc.) (allowable timeframe for use at the Investigator's discretion).

1.8. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years.

1.9. Any history of treatment for severe psychiatric disease by a psychiatrist in the past year.

1.10. 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 at inclusion, or positive urine toxicology test for cannabis at inclusion.

1. For female subjects: positive urine pregnancy test at screening and/or at the baseline visits, including baseline of immunizations (I-1) and or baseline before CHMI (C-1).

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 sulfadoxine-pyrimethamine, piperaquine, chloroquine, Malarone®, artemether-lumefantrine, primaquine 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 8 weeks 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 and Infectious Diseases of the Erasmus MC or Radboudumc, or the department of Internal Medicine of the Radboudumc or Havenziekenhuis.

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 center	Nijmegen	Gelderland	Netherlands	6525 GA
2	Havenziekenhuis	Rotterdam		Netherlands

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Robert Sauerwein, MD PhD, Radboud University Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 28, 2017

More Information

Publications

None provided.

• Responsible Party: Radboud University Medical Center
• ClinicalTrials.gov Identifier: NCT03138096
• Other Study ID Numbers: PbVac
• First Posted: May 3, 2017
• Last Update Posted: Mar 4, 2022
• Last Verified: Mar 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Malaria; Malaria, Falciparum

Study Results

Participant Flow

Arm/Group Title	Group 1 - Five Pb(PfCS@UIS4)-Infected Mosquitoes	Group 2 - 25 Pb(PfCS@UIS4)-Infected Mosquito Bites	Group 3 -25 Pb(PfCS@UIS4)-Infected Mosquito Bites	Group 4 - Infectivity Control Group (Phase 1)	Group 5 - Infectivity Control Group (Phase 2)
Arm/Group Description	(Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	(group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	(group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Infectivity control group (Phase 1) Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Infectivity control group of Phase 2 Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Period Title: Overall Study
STARTED	3	3	12	6	0
COMPLETED	3	3	12	6	0
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Group 1	Group 2	Group 3	Group 4	Group 5	Total
Arm/Group Description	(Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	(group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	(group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Total of all reporting groups
Overall Participants	3	3	12	6	0	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 NaN
Between 18 and 65 years	3 100%	3 100%	12 100%	6 100%	24 Infinity
>=65 years	0 0%	0 0%	0 0%	0 0%	0 NaN
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	21.1	26.1	21.5	22.5	22.5
Sex: Female, Male (Count of Participants)
Female	3 100%	1 33.3%	7 58.3%	4 66.7%	15 Infinity
Male	0 0%	2 66.7%	5 41.7%	2 33.3%	9 Infinity
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Netherlands	3 100%	3 100%	12 100%	6 100%	24 Infinity

Outcome Measures

1. Primary Outcome

Title	Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety]
Description	Frequency and magnitude of adverse events in study groups following one or more exposures to Pb(PfCS@UIS4)-infected mosquitoes.
Time Frame	Groups 1&2: from exposure to Pb(PfCS@UIS4)-infected mosquitoes until 28 days thereafter. Group 3: from first exposure until 21 days after fourth/final exposure (=until day immediately prior to CHMI, i.e. approximately 15 weeks after first exposure).

Outcome Measure Data

Analysis Population Description

Groups 1-3, immunization phase only (groups 1&2 underwent only a single immunization; group 3 underwent 4 sequential immunizations). Note: group 4 did NOT undergo immunization. AEs following CHMI with WT-infected mosquitoes (i.e. in group 3&4) were not a protocol-defined endpoint and are NOT included here. Group 5 was not enrolled, as protective efficacy in group 3 following first CHMI was insufficient (per protocol) to warrant a second CHMI and hence a second infectivity control group.

Arm/Group Title	Group 1	Group 2	Group 3	Group 4
Arm/Group Description	(Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	(group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	(group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Measure Participants	3	3	12	0
Immunization 1: Numbers of local adverse events (grade 1/2)	0	3	10
Immunization 2: Numbers of local adverse events (grade 1/2)	9
Immunization 3: Numbers of local adverse events (grade 1/2)	12
Immunization 4: Numbers of local adverse events (grade 1/2)	11
Immunization 1: Numbers of systemic adverse events (grade 1/2)	7	5	9
Immunization 2: Numbers of systemic adverse events (grade 1/2)	2
Immunization 3: Numbers of systemic adverse events (grade 1/2)	4
Immunization 4: Numbers of systemic adverse events (grade 1/2)	4

2. Primary Outcome

Title	Presence of Breakthrough Parasitemia Following Exposure to Pb(PfCS@UIS4)-Infected Mosquito Bites
Description	Presence of breakthrough parasitemia following (first) exposure to Pb(PfCS@UIS4)-infected mosquito bites, as determined by thick blood smear microscopy
Time Frame	Groups 1-3: from (first) exposure until 28 days thereafter.

Outcome Measure Data

Analysis Population Description

Groups 1-3 only. Note: For group 3, only immunisation (exposure) #1 is included here, as immunisations #2-4 fell in phase 2 of the trial, during which this outcome was no longer classified as an endpoint. Group 4 was not exposed to Pb(PfCS@UIS4)-infected mosquitoes (only to CHMI with WT-infected mosquitoes) and group 5 was not enrolled, as protective efficacy in group 3 following first CHMI was insufficient (per protocol) to warrant a second CHMI and hence a second infectivity control group.

Arm/Group Title	Group 1 -Five Pb(PfCS@UIS4)-Infected Mosquitoes	Group 2 - 25 Pb(PfCS@UIS4)-Infected Mosquito Bites	Group 3 - 75 Pb(PfCS@UIS4)-Infected Mosquito Bites	Group 4 - Infectivity Control Group
Arm/Group Description	(Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	(group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	(group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes No exposure to Pb(PfCS@UIS4)
Measure Participants	3	3	12	0
Count of Participants [Participants]	0 0%	0 0%	0 0%

3. Primary Outcome

Title	Time to Parasitemia After CHMI [Efficacy]
Description	Time to parasitemia after CHMI with the wild-type NF54 P. falciparum strain, as detected by qPCR [Efficacy]
Time Frame	Groups 3&4: from day of CHMI until 28 days thereafter

Outcome Measure Data

Analysis Population Description

Groups 3&4 only. Note: Groups 1 & 2 did not undergo CHMI and group 5 was not enrolled, as protective efficacy in group 3 following first CHMI was insufficient (per protocol) to warrant a second CHMI and hence a second infectivity control group

Arm/Group Title	Group 1 -Five Pb(PfCS@UIS4)-Infected Mosquitoes	Group 2 - 25 Pb(PfCS@UIS4)-Infected Mosquito Bites	Group 3 - 75 Pb(PfCS@UIS4)-Infected Mosquito Bites	Group 4 - Infectivity Control Group
Arm/Group Description	(Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Not exposed to P. falciparum	(group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Not exposed to P. falciparum	(group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Measure Participants	0	0	12	6
Mean (Full Range) [days to P. falciparum parasitemia]	9.9	7.7

4. Secondary Outcome

Title	Immunogenicity of Pb(PfCS@UIS4) as Assessed by ELISA
Description	Immunogenicity of repeated Pb(PfCS@UIS4) immunization as assessed by fold change in anti-P. falciparum IgG from baseline to post-immunization (day prior to CHMI), as measured by ELISA.
Time Frame	Group 3: from baseline until day prior to CHMI (approximately 15 weeks after first Pb(PfCS@UIS4) immunization)

Outcome Measure Data

Analysis Population Description

Group 3 only. Note: no analysis of humoral immune responses was performed for Groups 1 & 2 (single immunization only) or group 4 (no immunization); group 5 was not enrolled.

Arm/Group Title	Group 1	Group 2	Group 3	Group 4
Arm/Group Description	(Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes No humoral responses measured	(group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes No humoral responses measured	(group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes No humoral responses measured
Measure Participants	0	0	12	0
Mean (Standard Deviation) [Fold increase in anti-P. falciparum IgG]	3.5 (0.3)

5. Other Pre-specified Outcome

Title	Cellular Immune Responses After Exposure to Pb(PfCS@UIS4) [Exploratory Endpoint]
Description	Cellular immune responses after repeated exposure to Pb(PfCS@UIS4), as determined by increase in %-age IFNg+ lymphocytes following in vitro stimulation of PBMCs with WT P. falciparum sporozoites measured by flow cytometry at baseline and following immunization (day prior to CHMI)
Time Frame	Group 3: from baseline until day prior to CHMI (approximately 15 weeks after first Pb(PfCS@UIS4) immunization)

Outcome Measure Data

Analysis Population Description

Group 3 only. Note: no analysis of cellular immune responses was performed for Groups 1 & 2 (single immunization only) or group 4 (no immunizsation); group 5 was not enrolled.

Arm/Group Title	Group 1 - Five Pb(PfCS@UIS4)-Infected Mosquitoes	Group 2 - 25 Pb(PfCS@UIS4)-Infected Mosquito Bites	Group 3 - 75 Pb(PfCS@UIS4)-Infected Mosquito Bites	Group 4 - Infectivity Control Group
Arm/Group Description	(Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	(group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	(group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Measure Participants	0	0	12	0
Mean (Standard Deviation) [change in %-age IFNg+ lymphocytes]	0.510 (1.102)

6. Other Pre-specified Outcome

Title	Humoral Immune Responses After Exposure to Pb(PfCS@UIS4) [Exploratory Endpoint]
Description	Humoral immune responses after repeated exposure to Pb(PfCS@UIS4) as determined by increase in %-age inhibition of WT P. falciparum sporozoite invasion in HC-04 cells by purified plasma IgG collected at baseline and following immunization (day prior to CHMI).
Time Frame	Group 3: from baseline until day prior to CHMI (approximately 15 weeks after first Pb(PfCS@UIS4) immunization)

Outcome Measure Data

Analysis Population Description

Group 3 only. Note: no analysis of humoral immune responses was performed for Groups 1 & 2 (single immunizsation only) or group 4 (no immunization); group 5 was not enrolled.

Arm/Group Title	Group 1 - Five Pb(PfCS@UIS4)-Infected Mosquitoes	Group 2 - 25 Pb(PfCS@UIS4)-Infected Mosquito Bites	Group 3 - 75 Pb(PfCS@UIS4)-Infected Mosquito Bites	Group 4 - Infectivity Control Group
Arm/Group Description	(Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes No humoral responses measured	(group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes No humoral responses measured	(group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Measure Participants	0	0	12	0
Mean (Standard Deviation) [% change in inhibition of spz invasion]	48.8 (17.5)

Adverse Events

Time Frame	79 days
Adverse Event Reporting Description	Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
Arm/Group Title	Group 1		Group 2		Group 3		Group 4
Arm/Group Description	(Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes		(group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes		(group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes		Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
All Cause Mortality
	Group 1		Group 2		Group 3		Group 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/12 (0%)		0/6 (0%)
Serious Adverse Events
	Group 1		Group 2		Group 3		Group 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/12 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Group 1		Group 2		Group 3		Group 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		11/12 (91.7%)		6/6 (100%)
Blood and lymphatic system disorders
Hematoma / Pain after venapuncture	0/3 (0%)		1/3 (33.3%)		0/12 (0%)		1/6 (16.7%)
General disorders
Headache	2/3 (66.7%)		2/3 (66.7%)		7/12 (58.3%)		6/6 (100%)
Abdominal pain	1/3 (33.3%)		0/3 (0%)		1/12 (8.3%)		0/6 (0%)
Nausea	2/3 (66.7%)		0/3 (0%)		6/12 (50%)		4/6 (66.7%)
Diarrhoea	1/3 (33.3%)		1/3 (33.3%)		1/12 (8.3%)		0/6 (0%)
Stomach pain	0/3 (0%)		1/3 (33.3%)		1/12 (8.3%)		0/6 (0%)
Malaise	0/3 (0%)		0/3 (0%)		4/12 (33.3%)		2/6 (33.3%)
Fatigue	0/3 (0%)		1/3 (33.3%)		4/12 (33.3%)		0/6 (0%)
Angio-oedema	0/3 (0%)		0/3 (0%)		1/12 (8.3%)		0/6 (0%)
Dizziness	1/3 (33.3%)		0/3 (0%)		0/12 (0%)		0/6 (0%)
Night sweating	0/3 (0%)		0/3 (0%)		1/12 (8.3%)		0/6 (0%)
Chills	0/3 (0%)		0/3 (0%)		1/12 (8.3%)		0/6 (0%)
Myalgia	0/3 (0%)		0/3 (0%)		1/12 (8.3%)		1/6 (16.7%)
Skin and subcutaneous tissue disorders
Pruritis	0/3 (0%)		3/3 (100%)		10/12 (83.3%)		1/6 (16.7%)
Edema arms	0/3 (0%)		0/3 (0%)		1/12 (8.3%)		0/6 (0%)
Painful skin arms	0/3 (0%)		0/3 (0%)		1/12 (8.3%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

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.