Safety and Protective Efficacy of Pb(PfCS@UIS4)

NCT03138096 | Completed Phase 1 Results DMC

• 1 other identifier: PbVac
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 2

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).

Conditions

Malaria,Falciparum; Plasmodium Falciparum; Plasmodium Berghei; Controlled Human Malaria Infection (CHMI)

Outcome Measures

Primary Outcomes (3)

• Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety]

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

  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).

• Presence of Breakthrough Parasitemia Following Exposure to Pb(PfCS@UIS4)-Infected Mosquito Bites

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

  Groups 1-3: from (first) exposure until 28 days thereafter.

• Time to Parasitemia After CHMI [Efficacy]

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

  Groups 3&4: from day of CHMI until 28 days thereafter

Secondary Outcomes (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)

Other Outcomes (2)

• 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)

• 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)

Study Arms (5)

Group 1 - five Pb(PfCS@UIS4)-infected mosquitoes

EXPERIMENTAL

(Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes

Biological: Pb(PfCS@UIS4)-infected mosquitoes

Group 2 - 25 Pb(PfCS@UIS4)-infected mosquito bites

EXPERIMENTAL

(group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites

Biological: Pb(PfCS@UIS4)-infected mosquitoes

Group 3 - 75 Pb(PfCS@UIS4)-infected mosquito bites

EXPERIMENTAL

(group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites

Biological: Pb(PfCS@UIS4)-infected mosquitoes; Other: Challenge infection P. falciparum

Group 4 - Infectivity control group of Phase 1

OTHER

Infectivity control group of Phase 1

Other: Challenge infection P. falciparum

Group 5 - Infectivity control group of Phase 2

OTHER

Infectivity control group of Phase 2

Other: Challenge infection P. falciparum

Interventions

Pb(PfCS@UIS4)-infected mosquitoes BIOLOGICAL

Pb(PfCS@UIS4)-infected mosquitoes

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

Challenge infection P. falciparum OTHER

Challenge infection with bites of five infected Pf mosquitoes

Group 3 - 75 Pb(PfCS@UIS4)-infected mosquito bites; Group 4 - Infectivity control group of Phase 1; Group 5 - Infectivity control group of Phase 2

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject is aged ≥ 18 and ≤ 35 years and in good health.
• 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.
• Subject is willing to complete an informed consent questionnaire and is able to answer all questions correctly.
• 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.
• 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.
• 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.
• 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).
• For female subjects: subject agrees to use continuous adequate contraception\*\* and not to breastfeed for the duration of study.
• Subject agrees to refrain from intensive physical exercise (disproportionate to the subject's usual daily activity or exercise routine) during the malaria challenge period.
• Subject agrees to avoid additional triggers that may cause elevations in liver enzymes including alcohol from baseline up to 1 week post treatment.
• Subject has signed written informed consent to participate in the trial.

You may not qualify if:

• A potential subject who meets any of the following criteria will be excluded from participation in this study:
• 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.
• 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.
• A medical history of functional asplenia, sickle cell trait/disease, thalassaemia trait/disease or G6PD-deficiency.
• History of epilepsy in the period of five years prior to study onset, even if no longer on medication.
• 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, ii) 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.
• 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).
• History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years.
• Any history of treatment for severe psychiatric disease by a psychiatrist in the past year.
• 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).
• Any history of malaria, positive serology for P. falciparum, or previous participation in any malaria (vaccine) study.
• 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.
• 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.
• Participation in any other clinical study in the 30 days prior to the start of the study or during the study period.
• 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.

Sponsors & Collaborators

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

Study Sites (2)

Radboud university medical center

Nijmegen, Gelderland, 6525 GA, Netherlands

Location

Havenziekenhuis

Rotterdam, Netherlands

Location

Related Publications (1)

• Reuling IJ, Mendes AM, de Jong GM, Fabra-Garcia A, Nunes-Cabaco H, van Gemert GJ, Graumans W, Coffeng LE, de Vlas SJ, Yang ASP, Lee C, Wu Y, Birkett AJ, Ockenhouse CF, Koelewijn R, van Hellemond JJ, van Genderen PJJ, Sauerwein RW, Prudencio M. An open-label phase 1/2a trial of a genetically modified rodent malaria parasite for immunization against Plasmodium falciparum malaria. Sci Transl Med. 2020 May 20;12(544):eaay2578. doi: 10.1126/scitranslmed.aay2578.

  PMID: 32434846 RESULT

MeSH Terms

Conditions

Malaria, Falciparum

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Results Point of Contact

• Title: Dr. M.B.B. McCall
• Organization: Radboud University Medical Center

Matthew.McCall@radboudumc.nl

+31642166480

Study Officials

• Robert Sauerwein, MD PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 19, 2017
• First Posted: May 3, 2017
• Study Start: May 29, 2017
• Primary Completion: March 28, 2018
• Study Completion: October 3, 2018
• Last Updated: March 4, 2022
• Results First Posted: December 15, 2021

Record last verified: 2017-03

Data Sharing

• IPD Sharing: Will share

Locations

NL (2)