Back to results

Trial for Malaria Vaccine Candidate, PfPEBS (P. Falciparum Pre-Erythrocytic and Blood Stage) (PEBS-POC1)

Primary Purpose

Malaria

Status

Unknown status

Phase

Phase 1

Locations

Switzerland

Study Type

Interventional

Intervention

Lyophilised PEBS synthetic protein (PfPEBS)

Rehydragel™ HPA

About this trial

This is an interventional prevention trial for Malaria focused on measuring Malaria, Plasmodium falciparum, vaccine, ADCI, sporozoite challenge, pre-erythrocytic, erythrocytic

Eligibility Criteria

18 Years - 44 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Male and female age > 18 and < 45 years
Good general health based on history, physical en laboratory examination
Available for and willingness to undergo a P. falciparum sporozoite infected mosquito challenge following the immunization course
Resident in or near Lausanne for the duration of the study having 24h access to a mobile telephone
Willingness to stay in special accommodation (hotel or equivalent) from day 5 up to one day after parasite positivity , or up to day 15 post EHMI
Agreement to refrain from blood donation during the course of the study and afterwards
Negative pregnancy test and the use of effective contraception during the whole study period if deemed appropriate
Willingness to undergo an HIV test and other serologies
Willingness to allow investigators to notify their general practitioner, if any, of participation in this trial
Willingness to allow investigators to request medical information, relevant for participation in this trial, from their general practitioner, if any
Written informed consent following proper understanding of the meaning and procedures of the Phase I and IIa parts of the trial
Agreement to inform study doctor and to release medical information concerning contra-indications for participation in the study
Willingness to undergo screening for drugs such as amphetamines, opiates and cocaine

Exclusion Criteria:

Any history of malaria
Known exposure to malaria in the previous 6 months, defined as a visit to a malaria endemic region. For practical purposes, all regions for which malaria chemoprophylaxis is advised by travel clinic are considered malaria endemic
Planned to travel to endemic malaria areas during the study period
Prior administration of an investigational malaria vaccine
Administration of a vaccine or gammaglobulin not foreseen by the clinical trial protocol within 30 days prior to the first immunization and up to six months after the last immunization.
Participation in any other clinical trial within 90 days prior to the onset of the trial or more than four clinical trials in the past year
The use of chronic medication (defined as more than 14 days), especially immunosuppressive agents or antibiotics during the study period
The use of chronic immunosuppressive drugs or other immune modifying drugs within three months of vaccination (inhaled and topical corticosteroids are allowed)
Positive serological tests for P. falciparum (PEBS) ELISA and/or a positive P. falciparum whole parasite ELISA
Known hypersensitivity to vaccine components
History of severe reactions or allergy to mosquito bites
Contra indications to Malarone® including treatment taken by the volunteers that interfere with Malarone® (e.g. concurrent use of medicines that prolong QT interval)
History of allergic disease to or reactions likely to be exacerbated by any component of the vaccine
Any confirmed or suspected immunosuppressive or immunodeficiency condition, including asplenia.
History of diabetes mellitus or cancer (except basal cell carcinoma of the skin)
History of >2 hospitalisations for invasive bacterial infections
Symptoms, physical signs and laboratory values suggestive of systemic disorders, including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, psychiatric and other conditions, which could interfere with the interpretation of the study results or compromise the health of the volunteers
An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system.
History of arrhythmia or prolonged QT interval or other cardiac disease
Positive history for cardiac disease in the 1st and 2nd degree relative < 50 years old
Clinically significant abnormalities in electrocardiogram (ECG) at screening
Body Mass Index < 18 kg/m2 or > 32 kg/m2
Blood pressure > 150/90 in two measurements
Seropositive for HIV, HBV or HCV
Any clinically significant deviation from the normal range in biochemistry or haematology blood tests or in urine analysis.
Volunteers unable to be closely followed for social, geographic or psychological reasons
Previous history of drug or addiction to alcohol abuse interfering with normal social function during a period of one year prior to enrolment in the study
Having not reached 10 correct responses to the knowledge questionnaire

Sites / Locations

Centre Hospitalier Universitaire Vaudois (CHUV)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

PEBS Low dose

PEBS High dose

Control

Arm Description

Outcomes

Primary Outcome Measures

Adverse events following vaccination

The safety and reactogenicity of the vaccine will be assessed by comparing the proportion and severity of expected and unexpected adverse events as well as serious adverse events (SAE) between groups.

Change from baseline of antibodies active in the ADCI assay

The vaccine antigen should induce adequate antibodies that are active in the ADCI assay, which measures parasite killing of erythrocytic stages of the malaria parasite by antibodies in Monocyte-dependant manner and is hypothesized to be able to provide protection against clinical malaria disease.

Parasitemia following mosquito challenge

Subjects will be monitored for emergence of malaria parasites in the blood, using the gold standard of thick film slide microscopy, and rapid diagnostic testing, RT-PCR and LAMP. Treatment will be initiated as soon as subjects are parasitemic, defined as >1 parasites per 400 fields in a thick blood film, OR a positive RDT OR two positive RT-PCR OR one positive result with RT-PCR AND one positive result with LAMP OR two positive results with two different methods.

Secondary Outcome Measures

Antibodies against synthetic PEBS

This will be measured by ELISA

Antibodies against parasite antigen

This will be measured by the following methods: whole parasite extract, ELISA, Western Blot, IFAT

PEBS Interferon-Gamma

This will be measured by ELISPOT

Full Information

NCT ID

NCT01605786

First Posted

May 18, 2012

Last Updated

May 22, 2012

Sponsor

Vac4All

Collaborators

Centre Hospitalier Universitaire Vaudois, Radboud University Medical Center, European Commission

1. Study Identification

Unique Protocol Identification Number

NCT01605786

Brief Title

Trial for Malaria Vaccine Candidate, PfPEBS (P. Falciparum Pre-Erythrocytic and Blood Stage)

Acronym

PEBS-POC1

Official Title

Phase I and IIa Trial for Assessment of Safety, Immunogenicity (Phase Ia) and Efficacy (Phase IIa) Against Sporozoite Challenge of P. Falciparum Pre-Erythrocytic and Blood Stage (PfPEBS-LSP) Malaria Vaccine Candidate

Study Type

Interventional

2. Study Status

Record Verification Date

May 2012

Overall Recruitment Status

Unknown status

Study Start Date

May 2012 (undefined)

Primary Completion Date

May 2013 (Anticipated)

Study Completion Date

August 2013 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Vac4All

Collaborators

Centre Hospitalier Universitaire Vaudois, Radboud University Medical Center, European Commission

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study intends to test the hypothesis that the malaria antigen PfPEBS, manufactured as a synthetic protein and adjuvanted with aluminium hydroxide will be well-tolerated and immunogenic (Phase 1), functionally active against the erythrocytic stages (Phase 1) and efficacious (Phase 2) against the pre-erythrocytic stages in protecting against an artificial malaria challenge using Pf sporozoites in a healthy adult population.

Detailed Description

The study will enroll 36 healthy adult subjects (18-45 years) and randomize them in a double-blind manner into 3 arms of 12 subjects each; 2 of the arms will receive either 5μg or 30μg, both adjuvanted with aluminium hydroxide, given as a 2-dose schedule with a 28 day interval. The third arm of 12 subjects will act as controls, and they will receive aluminium hydroxide only injections. If the safety and immunogenicity results permit, the subjects will be challenged with live mosquito challenge delivering P falciparum sporozoites to assess pre-erythrocytic vaccine efficacy. The PfPEBS molecule has been found to have in vivo and in vitro functional activity against the two stages that are clinically significant for malaria namely the pre-erythrocytic stages (sporozoite and liver stages) and the erythrocytic stages. The formulation is a simple combination of a synthetic protein of 131 amino acids adjuvanted with aluminum hydroxide, the adjuvant with the widest safety records. The combined Phase 1/2a study is designed in order to achieve 3 co-primary objectives Phase 1: To demonstrate safety and tolerability Phase 1: To measure the activity against the asexual blood stage of the parasite which is only indirectly estimated by the functional activity of elicited antibodies in ADCI under in-vitro conditions Phase 2: To demonstrate efficacy against liver stages by measuring the proportion of subject that are protected following a live sporozoite challenge. The mechanisms of defenses differ for "liver stages" and "erythrocytic stages". Defenses against "liver stages" are strongly related to the secretion of interferon γ by CD4+Th1 cells, whereas for blood stages the defences depend on antibodies. Preliminary studies have demonstrated that low antigen doses such as 5 or 2μg produce strong CD4+Th1- interferon γ secreting cells with low antibody titers, whereas higher antigen doses such as 30 or 50μg induce lower CD4 Th1 cell response and markedly higher antibody responses. Therefore the choice of the two dose ranges for the Pf-PEBS clinical trial protocol is aimed at testing the two main efficacy objectives, one against "liver stages" with a low dose, the other against "the blood stages" with the higher dose. The Sponsor for the two Phases is Vac4all. The funder for the Phase Ia is the EMVDA programme of the European Commission. The funder for the Phase IIa is Vac4all

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malaria

Keywords

Malaria, Plasmodium falciparum, vaccine, ADCI, sporozoite challenge, pre-erythrocytic, erythrocytic

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

PEBS Low dose

Arm Type

Experimental

Arm Title

PEBS High dose

Arm Type

Experimental

Arm Title

Control

Arm Type

Active Comparator

Intervention Type

Biological

Intervention Name(s)

Lyophilised PEBS synthetic protein (PfPEBS)

Intervention Description

PfPEBS, is a synthetic polypeptide corresponding to amino acids 3112 to 3244 (131 aa) from the Pf 11.1 antigen in 3D7 parasite sequence. It is presented as lyophilised product in multi-dose vials (containing 105 μg for 3 doses of 30 μg ), looking like amorphous white powder. The vaccine is produced by SYNPROSIS in France. The 5μg dose vaccine will be formulated extemporaneously in aluminium hydroxide adjuvant and given as a 2-dose schedule with a 28 day interval.

Intervention Type

Biological

Intervention Name(s)

Lyophilised PEBS synthetic protein (PfPEBS)

Intervention Description

PfPEBS-LSP, is a synthetic polypeptide corresponding to amino acids 3112 to 3244 (131aa) from the Pf 11.1 antigen in 3D7 parasite sequence. It is presented as lyophilised product in multi-dose vials (containing 105 μg for 3 doses of 30 μg ), looking like amorphous white powder. The vaccine is produced by SYNPROSIS in France. The 30 μg dose vaccine will be formulated extemporaneously in aluminium hydroxide adjuvant and given as a 2-dose schedule with a 28 day interval.

Intervention Type

Other

Intervention Name(s)

Rehydragel™ HPA

Intervention Description

Aluminium hydroxide adjuvant is being used as the adjuvant for the vaccine and will be used as the comparator in the control group. Vac4all is using Rehydragel™ (Manufacturer Reheis Inc.) which is a highly active protein adsorbent specially compounded for use as a fluid adjuvant. It has low oxide content and is carefully controlled for Al2O3 content and protein binding capacity. It has a lower viscosity than competing adjuvants, which makes it easier to process and handle. Subjects in the control group will be administered a 0.5 ml injection in a 2-dose schedule at 28 days interval. Each injection will contain approximately 600 µg of Al(OH)3 per injected dose corresponding to 200 µg equivalent of Al3+, similar to the amount being administered in the vaccine group.

Primary Outcome Measure Information:

Title

Adverse events following vaccination

Description

Time Frame

Up to one year following first vaccination

Title

Change from baseline of antibodies active in the ADCI assay

Description

Time Frame

Within one year following first vaccination

Title

Parasitemia following mosquito challenge

Description

Time Frame

From Day 4 up to Day 21 post challenge

Secondary Outcome Measure Information:

Title

Antibodies against synthetic PEBS

Description

This will be measured by ELISA

Time Frame

Within one year following first vaccination

Title

Antibodies against parasite antigen

Description

This will be measured by the following methods: whole parasite extract, ELISA, Western Blot, IFAT

Time Frame

Within one year following first vaccination

Title

PEBS Interferon-Gamma

Description

This will be measured by ELISPOT

Time Frame

Within one year following first vaccination

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

44 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male and female age > 18 and < 45 years Good general health based on history, physical en laboratory examination Available for and willingness to undergo a P. falciparum sporozoite infected mosquito challenge following the immunization course Resident in or near Lausanne for the duration of the study having 24h access to a mobile telephone Willingness to stay in special accommodation (hotel or equivalent) from day 5 up to one day after parasite positivity , or up to day 15 post EHMI Agreement to refrain from blood donation during the course of the study and afterwards Negative pregnancy test and the use of effective contraception during the whole study period if deemed appropriate Willingness to undergo an HIV test and other serologies Willingness to allow investigators to notify their general practitioner, if any, of participation in this trial Willingness to allow investigators to request medical information, relevant for participation in this trial, from their general practitioner, if any Written informed consent following proper understanding of the meaning and procedures of the Phase I and IIa parts of the trial Agreement to inform study doctor and to release medical information concerning contra-indications for participation in the study Willingness to undergo screening for drugs such as amphetamines, opiates and cocaine Exclusion Criteria: Any history of malaria Known exposure to malaria in the previous 6 months, defined as a visit to a malaria endemic region. For practical purposes, all regions for which malaria chemoprophylaxis is advised by travel clinic are considered malaria endemic Planned to travel to endemic malaria areas during the study period Prior administration of an investigational malaria vaccine Administration of a vaccine or gammaglobulin not foreseen by the clinical trial protocol within 30 days prior to the first immunization and up to six months after the last immunization. Participation in any other clinical trial within 90 days prior to the onset of the trial or more than four clinical trials in the past year The use of chronic medication (defined as more than 14 days), especially immunosuppressive agents or antibiotics during the study period The use of chronic immunosuppressive drugs or other immune modifying drugs within three months of vaccination (inhaled and topical corticosteroids are allowed) Positive serological tests for P. falciparum (PEBS) ELISA and/or a positive P. falciparum whole parasite ELISA Known hypersensitivity to vaccine components History of severe reactions or allergy to mosquito bites Contra indications to Malarone® including treatment taken by the volunteers that interfere with Malarone® (e.g. concurrent use of medicines that prolong QT interval) History of allergic disease to or reactions likely to be exacerbated by any component of the vaccine Any confirmed or suspected immunosuppressive or immunodeficiency condition, including asplenia. History of diabetes mellitus or cancer (except basal cell carcinoma of the skin) History of >2 hospitalisations for invasive bacterial infections Symptoms, physical signs and laboratory values suggestive of systemic disorders, including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, psychiatric and other conditions, which could interfere with the interpretation of the study results or compromise the health of the volunteers An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system. History of arrhythmia or prolonged QT interval or other cardiac disease Positive history for cardiac disease in the 1st and 2nd degree relative < 50 years old Clinically significant abnormalities in electrocardiogram (ECG) at screening Body Mass Index < 18 kg/m2 or > 32 kg/m2 Blood pressure > 150/90 in two measurements Seropositive for HIV, HBV or HCV Any clinically significant deviation from the normal range in biochemistry or haematology blood tests or in urine analysis. Volunteers unable to be closely followed for social, geographic or psychological reasons Previous history of drug or addiction to alcohol abuse interfering with normal social function during a period of one year prior to enrolment in the study Having not reached 10 correct responses to the knowledge questionnaire

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Pierre Druilhe, MD

Phone

+33142733541

druilhe@vac4all.org

First Name & Middle Initial & Last Name or Official Title & Degree

Blaise Genton, MD

Phone

+41 21 556 58 68

Blaise.Genton@chuv.ch

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pierre L Druilhe, MD

Organizational Affiliation

Vac4All

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Francois Spertini, MD

Organizational Affiliation

Centre Hospitalier Universitaire Vaudois (CHUV)

Official's Role

Principal Investigator

Facility Information:

Facility Name

Centre Hospitalier Universitaire Vaudois (CHUV)

City

Lausanne

State/Province

Vaud

ZIP/Postal Code

1011

Country

Switzerland

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Blaise Genton, MD

First Name & Middle Initial & Last Name & Degree

Reza Chakour, MD

First Name & Middle Initial & Last Name & Degree

Voumard Rachel, MD

First Name & Middle Initial & Last Name & Degree

Valerie D'Acremont, MD

First Name & Middle Initial & Last Name & Degree

Regine Audran, Phd

First Name & Middle Initial & Last Name & Degree

Robert Sauerwein, MD

First Name & Middle Initial & Last Name & Degree

Ing GJ van Gemert, Phd

12. IPD Sharing Statement

Learn more about this trial

Trial for Malaria Vaccine Candidate, PfPEBS (P. Falciparum Pre-Erythrocytic and Blood Stage)

We'll reach out to this number within 24 hrs