Sequential Optimization of Dose and Schedule of PfSPZ Vaccine

Sanaria

Status and phase: Completed; Phase 1

Conditions: Malaria

Treatments: Other: Normal saline; Biological: PfSPZ Challenge (7G8); Biological: PfSPZ Challenge (NF54); Biological: PfSPZ Vaccine

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02704533

2015-005123-11 (EudraCT Number)

MAVACHE

Details and patient eligibility

About

MAVACHE is a sequential dose and schedule optimization trial of intravenous immunization with PfSPZ Vaccine in 18 to 54 malaria-naïve, healthy adult volunteers receiving 9x10^5, 1.35x10^6, or 2.7x10^6 PfSPZ per dose and a total dose between 2.7x10^6 and 8.1x10^6 PfSPZ followed by CHMI with 3,200 fully infectious PfSPZ (PfSPZ Challenge).

PfSPZ Challenge (7G8) to assess vaccine efficacy, safety, tolerability and infectivity of ascending PfSPZ doses will be assessed in healthy, malaria-naïve volunteers.

Full description

The study is to take place at Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen Germany.

The study has two phases: 1) dose optimization, and 2) regimen verification. In the first phase groups A, B1, B2, C1, C2 and C3 will be vaccinated sequentially in a pre-specified order, followed by homologous CHMI with 3,200 PfSPZ Challenge (NF54) three weeks after last vaccine injection.

Dose optimization phase A: 9x10^5 PfSPZ on Days 0, 7 and 28 (n = 6) B1: 1.35x10^6 PfSPZ on Days 0 and 7 (n = 6) B2: 1.35x10^6 PfSPZ on Days 0, 7, and 28 (n = 6) C1: 2.7x10^6 PfSPZ on Day 0 (n = 6) C2: 2.7x10^6 PfSPZ on Day 0 and 7 (n = 6) C3: 2.7x10^6 PfSPZ on Days 0, 7 and 28 (n = 6)

In parallel to CHMI with PfSPZ Challenge (NF54) during the optimization phase, a total of nine volunteers will receive either 800, 1,600 or 3,200 PfSPZ Challenge (7G8) (PfSPZ Challenge (7G8) dose finding) to assess safety, tolerability and infectivity of PfSPZ Challenge (7G8) in malaria-naïve healthy adult volunteers.

PfSPZ Challenge (7G8) dose finding/infection D1: 800 PfSPZ (n = 3) D2: 1,600 PfSPZ (n = 3) D3: 3,200 PfSPZ (n = 3)

Subsequently, the shortest efficacious regimen (V1) and a three-dose regimen (Day 0, 7 and 28) of the highest safe dose (V2) will be selected and verified against placebo (normal saline (NS)). Groups V1 and V2 will be vaccinated at approximately the same time and undergo repeat CHMI three and eight weeks after the last immunization. Volunteers will either receive PfSPZ Vaccine or NS as placebo. Allocation will be random and double blind. Repeat CHMI will be done with PfSPZ Challenge (NF54) and PfSPZ Challenge (7G8), given in a randomized sequence. All immunizations are given by direct venous inoculation (DVI).

Regimen verification phase V1: Shortest efficacious regimen (n = 12) against placebo (n = 6) V2: Maximum regimen (n = 12) against placebo (n = 6) P1: Placebo for V1 group (n=6) P2 Placebo for V2 group (n=6)

Enrollment: 45 patients

Sex: All

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Healthy adults aged 18 to 45 years
• Able and willing (in the Investigator's opinion) to comply with all study requirements
• Willing to allow the investigators to discuss the volunteer's medical history with their general practitioner ('Hausarzt' in German) if required
• Residence in Tübingen or surroundings for the period of the trial
• Women only: Must agree to practice continuous effective contraception for the duration of the study (a method which results in a failure rate less than 1% per year)
• Agreement to refrain from blood donation during the course of the study and after the end of their involvement in the study according to the local and national blood banking eligibility criteria (currently there is a four year restriction in Germany)
• Written informed consent to receive PfSPZ products:
• Optimization phase: PfSPZ Vaccine for immunization and PfSPZ Challenge (NF54) for CHMI
• PfSPZ Challenge (7G8) dose finding: PfSPZ Challenge (7G8) for CHMI
• Verification phase: PfSPZ Vaccine for immunization, PfSPZ Challenge (NF54) and PfSPZ Challenge (7G8) for CHMI
• Reachable (24/7) by mobile phone during the immunization and CHMI period
• Willingness to take a curative antimalarial regimen following CHMI
• Agreement to stay overnight for observation during the period of intensive follow-up post-challenge if required
• Answer all questions on the informed consent quiz correctly
• A body mass index <35

Exclusion criteria

• History of P. falciparum malaria
• Planned travel to malaria endemic areas before end of CHMI (28 days after CHMI)
• Use of systemic antibiotics with known antimalarial activity within 30 days of study enrollment (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones, or azithromycin)
• Receipt of an investigational product in the 30 days preceding enrollment, or planned receipt during the study period
• Prior receipt of a malaria vaccine
• Immunization with more than three other vaccines within the past four weeks
• HIV infection
• Any confirmed or suspected immunosuppressive or immunodeficient state, asplenia, recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed)
• Use of immunoglobulins or blood products within 3 months prior to enrolment
• Known or suspected hemolytic disease or presence of hemoglobinopathies
• Pregnancy, lactation or intention to become pregnant during the study
• Contraindications to the use of the following antimalarial medications: atovaquoneproguanil, artemether-lumefantrine or mefloquine
• History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ)
• History of serious psychiatric condition that may affect participation in the study (including but not restricted to organic, including symptomatic, mental disorders [ICD-10 code: F00-F09], schizophrenia, schizotypal and delusional disorders [F20-F29], mood (affective) disorders [F30-F39], mental retardation [F70-F79], Disorders of psychological development [F80-F89] or any other psychiatric condition that required hospitalization or psychiatric treatment over an extended period).
• Any other serious chronic illness requiring hospital specialist supervision
• Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 60 g (men) or 40 g (women) per day or a carbohydrate deficient transferrin (CDT) level ≥2.5%
• Suspected or known injecting drug abuse in the 5 years preceding enrollment
• Positive for hepatitis B surface antigen (HBs-antigen)
• Seropositive for hepatitis C virus (antibodies to HCV)
• Falling in moderate risk or higher categories for fatal or non-fatal cardiovascular event within 5 years (>10%) determined by non-invasive criteria for cardiac risk
• Abnormal electrocardiogram on screening: pathologic Q wave and significant ST-T wave changes, left ventricular hypertrophy, clinically significant arrhythmias, left bundle branch block, secondary or tertiary A-V heart block
• A QT/QTcB interval >450 ms
• Volunteers unable to be closely followed for social, geographic or psychological reasons
• Any clinically significant abnormal finding on biochemistry or hematology blood tests, urine analysis or clinical examination
• History of seizure (except isolated and uncomplicated febrile convulsion at childhood)
• Any other significant disease, disorder or finding which, in the opinion of the investigator, may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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45 participants in 13 patient groups, including a placebo group

Optimization Phase - Group A

Experimental group

Description:

n=6; three times 9x10\^5 PfSPZ Vaccine on Days 0, 7 and 28 by DVI. Group A will undergo homologous CHMI with 3,200 PfSPZ Challenge (NF54), 3 weeks after the last dose of vaccine. If \>75% efficacious, the treatment will be simplified to two times 1.35x10\^6 PfSPZ Vaccine on Days 0 and 7 (Group B1). If \<75% efficacious, the treatment will be increased to three times 1.35x10\^6 PfSPZ Vaccine on Days 0, 7 and 28 (Group B2)

Treatment:

Biological: PfSPZ Challenge (NF54)

Biological: PfSPZ Vaccine

Optimization Phase - Group B1

Experimental group

Description:

n=6; two times 1.35x10\^6 PfSPZ Vaccine on Days 0 and 7 by DVI. Group B1 will undergo homologous CHMI with 3,200 PfSPZ Challenge (NF54), 3 weeks after the last dose of vaccine. If \>75% efficacious, the treatment will be simplified to one injection 2.7x10\^6 PfSPZ Vaccine (Group C1). If \<75% efficacious, the treatment will be increased to two times 2.7x10\^6 PfSPZ Vaccine on Days 0 and 7 (Group C2).

Treatment:

Biological: PfSPZ Challenge (NF54)

Biological: PfSPZ Vaccine

Optimization Phase - Group B2

Experimental group

Description:

n=6; three times 1.35x10\^6 PfSPZ Vaccine on Days 0, 7 and 28 by DVI. Group B2 will undergo homologous CHMI with 3,200 PfSPZ Challenge (NF54), 3 weeks after the last dose of vaccine. If \>75% efficacious, the treatment will be simplified to two times 2.7x10\^6 PfSPZ Vaccine on Days 0 and 7 (Group C2). If \<75% efficacious, the treatment will be increased to three times 2.7x10\^6 PfSPZ Vaccine on Days 0, 7 and 28 (Group C3).

Treatment:

Biological: PfSPZ Challenge (NF54)

Biological: PfSPZ Vaccine

Optimization Phase - Group C1

Experimental group

Description:

n=6; one time 2.7x10\^6 PfSPZ Vaccine by DVI. Group C1 will undergo homologous CHMI with 3,200 PfSPZ Challenge (NF54), 3 weeks after vaccination. If Group C1 gets vaccinated, study will proceed to verification phase after completion.

Treatment:

Biological: PfSPZ Challenge (NF54)

Biological: PfSPZ Vaccine

Optimization Phase - Group C2

Experimental group

Description:

n=6; two times 2.7x10\^6 PfSPZ Vaccine by DVI. Group C2 will undergo homologous CHMI with 3,200 PfSPZ Challenge (NF54), 3 weeks after vaccination. If Group C2 gets vaccinated, study will proceed to verification phase after completion.

Treatment:

Biological: PfSPZ Challenge (NF54)

Biological: PfSPZ Vaccine

Optimization Phase - Group C3

Experimental group

Description:

n=6; three times 2.7x10\^6 PfSPZ Vaccine by DVI. Group C3 will undergo homologous CHMI with 3,200 PfSPZ Challenge (NF54), 3 weeks after vaccination. In case C3 shows \<75% efficacy, verification phase will not be done.

Treatment:

Biological: PfSPZ Challenge (NF54)

Biological: PfSPZ Vaccine

PfSPZ Challenge (7G8) dose finding - Group D1

Experimental group

Description:

n=3, one dose of 800 PfSPZ Challenge (7G8) by DVI. This is a dose finding study to assess safety, tolerability and infectivity of PfSPZ Challenge (7G8) administered DVI. CHMI with PfSPZ Challenge (7G8) will be done approximately at the same time as homologous CHMI to assess efficacy of immunization with PfSPZ Vaccine in the dose optimization phase. All volunteers receiving CHMI will be monitored by thick blood smear microscopy and qPCR until Day 28 or antimalarial treatment.

Treatment:

Biological: PfSPZ Challenge (7G8)

PfSPZ Challenge (7G8) dose finding - Group D2

Experimental group

Description:

n=3, one dose of 1,600 PfSPZ Challenge (7G8) by DVI. This is a dose finding study to assess safety, tolerability and infectivity of PfSPZ Challenge (7G8) administered DVI. CHMI with PfSPZ Challenge (7G8) will be done approximately at the same time as homologous CHMI to assess efficacy of immunization with PfSPZ Vaccine in the dose optimization phase. All volunteers receiving CHMI will be monitored by thick blood smear microscopy and qPCR until Day 28 or antimalarial treatment.

Treatment:

Biological: PfSPZ Challenge (7G8)

PfSPZ Challenge (7G8) dose finding - Group D3

Experimental group

Description:

n=3, one dose of 3,200 PfSPZ Challenge (7G8) by DVI. This is a dose finding study to assess safety, tolerability and infectivity of PfSPZ Challenge (7G8) administered DVI. CHMI with PfSPZ Challenge (7G8) will be done approximately at the same time as homologous CHMI to assess efficacy of immunization with PfSPZ Vaccine in the dose optimization phase. All volunteers receiving CHMI will be monitored by thick blood smear microscopy and qPCR until Day 28 or antimalarial treatment.

Treatment:

Biological: PfSPZ Challenge (7G8)

Verification Phase - Group V1

Experimental group

Description:

n=12; optimal regimen from phase 1 - shortest, well tolerated safe schedule that provides \>75% protection (5/6) against homologous CHMI (V1). Optimal \& maximum regimens will be compared in this phase. The maximum regimen is a 3-dose regimen (Day 0, 7, 28) with highest well-tolerated PfSPZ Vaccine dose/injection (V2). Efficacy will be determined by repeat CHMI 3 and 8 weeks after last immunization. Inoculation of 2 CHMIs will be done about 35 days (5 weeks) apart. CHMI with PfSPZ Challenge (NF54) and CHMI with PfSPZ Challenge (7G8) will be administered in one of 2 sequences (NF54-7G8 or 7G8-NF54). Allocation to the 2 sequences will be double blind, random, at a 1:1 ratio and nested within the intervention groups (V1 and V2 PfSPZ Vaccine and placebo (P1 and P2)). CHMI will be done at a dose of 3,200 PfSPZ unless the dose escalation study of PfSPZ Challenge (7G8) indicates that a different dose would be preferable for 7G8.

Treatment:

Biological: PfSPZ Challenge (NF54)

Biological: PfSPZ Vaccine

Biological: PfSPZ Challenge (7G8)

Verification Phase - Group V2

Experimental group

Description:

n=12; maximum regimen from the phase 1 - 3-dose regimen (Day 0, 7 and 28) with highest well-tolerated PfSPZ Vaccine dose per injection (V2). Optimal \& maximum regimens will be compared in this phase. The optimal regimen (shortest, well tolerated and safe schedule) that provides \>75% protection (5/6) against homologous CHMI (V1). In case that shortest efficacious regimen during phase 1 is C3, 12 volunteers will be vaccinated and 6 volunteers will receive NS during this phase. In this case optimal regimen equals maximum regimen (3 x 2.7x10\^6 PfSPZ). Group V2/P2 will not be immunized. Efficacy will be determined by repeat CHMI 3 and 8 weeks after last immunization. Inoculation of 2 CHMIs will be done about 35 days (5 weeks) apart. CHMI with PfSPZ Challenge (NF54) and CHMI with PfSPZ Challenge (7G8) will be administered as described in Group V1.

Treatment:

Biological: PfSPZ Challenge (NF54)

Biological: PfSPZ Vaccine

Biological: PfSPZ Challenge (7G8)

Verification Phase - Group P1

Placebo Comparator group

Description:

n=6; normal saline as placebo. This group will follow the regimen selected for Group V1. Efficacy of the vaccination regimen will be determined by CHMI which will be done by repeat CHMI three and eight weeks after the last immunization. Inoculation of the two CHMIs will be done approximately 35 days (5 weeks) apart. CHMI with PfSPZ Challenge (NF54) and CHMI with PfSPZ Challenge (7G8) will be administered as described in Group V1.

Treatment:

Biological: PfSPZ Challenge (NF54)

Other: Normal saline

Biological: PfSPZ Challenge (7G8)

Verification Phase - Group P2

Placebo Comparator group

Description:

n=6; NS as placebo. This group will follow the regimen selected for Group V2. In case that shortest efficacious regimen during phase 1 is C3, 12 volunteers will be vaccinated and 6 volunteers will receive NS during this phase. In this case optimal regimen equals maximum regimen (3 x 2.7x10\^6 PfSPZ). Group V2/P2 will not be immunized. Efficacy will be determined by repeat CHMI 3 and 8 weeks after the last immunization. Inoculation of the 2 CHMIs will be done about 35 days (5 weeks) apart. CHMI with PfSPZ Challenge (NF54) and CHMI with PfSPZ Challenge (7G8) will be administered as described in Group V1.

Treatment:

Biological: PfSPZ Challenge (NF54)

Other: Normal saline

Biological: PfSPZ Challenge (7G8)