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Safety and Immunogenicity of the Placental Malaria Vaccine Candidate PAMVAC Variously Adjuvanted (PAMVAC)

This study is currently recruiting participants.
Verified October 2016 by University Hospital Tuebingen
Sponsor:
ClinicalTrials.gov Identifier:
NCT02647489
First Posted: January 6, 2016
Last Update Posted: October 26, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
University of Copenhagen
Université d'Abomey-Calavi
European Malaria Vaccine Initiative
Institut de Recherche pour le Developpement
Expres2ion Biotechnologies APS
Information provided by (Responsible Party):
University Hospital Tuebingen
January 4, 2016
January 6, 2016
October 26, 2017
May 2016
December 2017   (Final data collection date for primary outcome measure)
Number and grade of adverse events (Grade 1-3 and serious adverse events) possibly, likely and definitely related to vaccination [ Time Frame: From the first administration of the interventions through study completion, an average of 1 and a half years ]
Same as current
Complete list of historical versions of study NCT02647489 on ClinicalTrials.gov Archive Site
Area under the curve of anti-PAMVAC IgG concentration [ Time Frame: Before first administration, 1, 4, 5, 8, 9, 12, 24 and 36 weeks after first administration ]
Same as current
Not Provided
Not Provided
 
Safety and Immunogenicity of the Placental Malaria Vaccine Candidate PAMVAC Variously Adjuvanted
Safety and Immunogenicity of the Placental Malaria Vaccine Candidate PAMVAC Adjuvanted With Alhydrogel, GLA-SE or GLA-LSQ in Healthy Malaria-Naïve Adults and Healthy, Lifelong Malaria-Exposed, Nulligravid Adult Women

Despite having developed robust acquired immunity against complications of malaria, women can return to a susceptible state during their first pregnancies and contribute significantly to the burden of severe malaria in highly endemic areas. Naturally acquired protection against placental malaria correlates with the presence of high concentration of immunoglobulin G molecules (IgGs) against VAR2CSA, a parasite protein of the var gene family that is essential for the binding of infected erythrocytes to CSA in the placenta.

To induce high concentrations of specific IgGs, subjects will receive escalating doses of PAMVAC vaccine antigen adjuvanted with Alhydrogel, Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE) or Glucopyranosyl Lipid Adjuvant-Liposome-QS-21 Formulation (GLA-LSQ). Three injections with the same dosage and adjuvant will be done, each 28 days apart (Day 0, 28 and 56). Control subjects will receive physiological saline instead of the vaccine and dose escalation will be staggered to ensure safety during the trial.

Phase 1, staggered, two-center, dose-escalation trial. The trial will be conducted in two stages. The first in Germany (first in man and dose escalation) and the second in a malaria-endemic area in the target group (randomized, controlled, dose-finding).

First in man administration and dose escalation from 20 to 50 μg per injection of PAMVAC adjuvanted with Alhydrogel, GLA-SE and GLA-LSQ will be done in healthy, malaria-naïve adults in Germany (Stage 1).

Subsequently, PAMVAC will be administered to healthy, lifelong malaria-exposed nulligravid women in Benin at doses of 50 and 100 μg, adjuvanted with Alhydrogel and GLA-SE (Stage 2).

The PAMVAC vaccine is a VAR2CSA protein-based vaccine, aiming to protect fetus and mother against the adverse effects of placental malaria during pregnancy. As the interaction between the parasite protein VAR2CSA and CSA in the human placenta is a key element in the pathogenesis of placental malaria, a vaccine should elicit the type of immunoglobulins that block the binding of VAR2CSA to CSA. A small sub-unit of the VAR2CSA protein (ID1-ID2a) has been selected as the PAMVAC vaccine antigen. In animal models IgGs induced by immunization with the recombinant PAMVAC antigen are able to inhibit homologous parasite-infected erythrocyte adhesion to CSA in vitro.

The three adjuvants are Alhydrogel, an aluminum hydroxide gel widely used as adjuvant in this trial; GLA-SE and GLA-LSQ, synthetic TLR-4 agonists with a strong immune stimulatory effect formulated either in a stable oil-in-water emulsion (SE) or together with QS-21 (Saponin derived from the Quillaja saponaria tree) as liposome (LSQ).

In Benin, one group will receive a placebo control (physiological saline). Allocation to placebo, PAMVAC+Alhydrogel or PAMVAC+GLA-SE, will be randomized and the trial team as well as the participants will be kept blinded (double-blinded) to their allocation.

All participants (Stage 1+2) will receive three intramuscular injections in four-week intervals.

Each dose-escalation is conditional on a positive safety assessment by an independent Safety Monitoring Board (SMB) and sponsor approval. One individual of each PAMVAC-adjuvant combination will serve as sentinel. The sentinel will be injected one day before the rest of the group.

There will be a minimum of 4 weeks stagger between the first immunization of Groups 1A-3A and Groups 4A-6A.

Group 1A (n = 3) - 20 µg PAMVAC+Alhydrogel Group 2A (n = 3) - 20 µg PAMVAC+GLA-SE Group 3A (n = 3) - 20 µg PAMVAC+GLA-LSQ Group 4A (n = 9) - 50 µg PAMVAC+Alhydrogel Group 5A (n = 9) - 50 µg PAMVAC+GLA-SE Group 6A (n = 9) - 50 µg PAMVAC+GLA-LSQ

Following safety assessment by the SMB after the first dose in Groups 4A-6A and approval by the sponsor, Stage 2 (in Benin) will be initiated. Here, the target population of PAMVAC (healthy nulligravid women in a malaria-endemic area) will be vaccinated. Upon SMB review and approval by the sponsor Groups 1B-2B and half the subjects from the control Group 5B will receive vaccinations. One participant allocated to group 1B, 2B and 5B will receive the first immunization at least one day before the rest of the group.

Group 1B (n=9) - 50 µg PAMVAC+Alhydrogel Group 2B (n=9) - 50 µg PAMVAC+GLA-SE Group 3B (n=3) - 100 µg PAMVAC+Alhydrogel Group 4B (n=3) - 100 µg PAMVAC+GLA-SE Group 5B (n=6) - Placebo (physiological saline solution)

There will be a 4 weeks stagger between Groups 1B-2B and Group 3B-4B and the remaining subjects of the control Group 5B to allow for safety evaluation by the SMB. Here, the same system of sentinel vaccination as for the lower dose will be used; one participant allocated to group 3B, 4B and 5B will receive the first immunization at least one day before the rest of the group.

Interventional
Phase 1
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Malaria, Antepartum
  • Biological: PAMVAC
  • Biological: Alhydrogel
  • Biological: GLA-SE
  • Biological: GLA-LSQ
  • Other: Placebo
  • Experimental: 1A - 20 µg PAMVAC + Alhydrogel
    The study participant will get 20 µg of PAMVAC adjuvanted with Alhydrogel administrated three times with each time 28 days interval (day 0-28-56)
    Interventions:
    • Biological: PAMVAC
    • Biological: Alhydrogel
  • Experimental: 2A - 20 µg PAMVAC + GLA-SE
    The study participant will get 20 µg of PAMVAC adjuvanted with GLA-SE administrated three times with each time 28 days interval (day 0-28-56)
    Interventions:
    • Biological: PAMVAC
    • Biological: GLA-SE
  • Experimental: 3A - 20 µg PAMVAC + GLA-LSQ
    The study participant will get 20 µg of PAMVAC adjuvanted with GLA-LSQ administrated three times with each time 28 days interval (day 0-28-56)
    Interventions:
    • Biological: PAMVAC
    • Biological: GLA-LSQ
  • Experimental: 4A - 50 µg PAMVAC + Alhydrogel
    The study participant will get 50 µg of PAMVAC adjuvanted with Alhydrogel administrated three times with each time 28 days interval (day 0-28-56)
    Interventions:
    • Biological: PAMVAC
    • Biological: Alhydrogel
  • Experimental: 5A - 50 µg PAMVAC + GLA-SE
    The study participant will get 50 µg of PAMVAC adjuvanted with GLA-SE administrated three times with each time 28 days interval (day 0-28-56)
    Interventions:
    • Biological: PAMVAC
    • Biological: GLA-SE
  • Experimental: 6A - 50 µg PAMVAC + GLA-LSQ
    The study participant will get 50 µg of PAMVAC adjuvanted with GLA-LSQ administrated three times with each time 28 days interval (day 0-28-56)
    Interventions:
    • Biological: PAMVAC
    • Biological: GLA-LSQ
  • Experimental: 1B - 50 µg PAMVAC + Alhydrogel
    The study participant will get 50 µg of PAMVAC adjuvanted with Alhydrogel administrated three times with each time 28 days interval (day 0-28-56)
    Interventions:
    • Biological: PAMVAC
    • Biological: Alhydrogel
  • Experimental: 2B - 50 µg PAMVAC + GLA-SE
    The study participant will get 50 µg of PAMVAC adjuvanted with GLA-SE administrated three times with each time 28 days interval (day 0-28-56)
    Interventions:
    • Biological: PAMVAC
    • Biological: GLA-SE
  • Experimental: 3B - 100 µg PAMVAC + Alhydrogel
    The study participant will get 100 µg of PAMVAC adjuvanted with Alhydrogel administrated three times with each time 28 days interval (day 0-28-56)
    Interventions:
    • Biological: PAMVAC
    • Biological: Alhydrogel
  • Experimental: 4B - 100 µg PAMVAC + GLA-SE
    The study participant will get 100 µg of PAMVAC adjuvanted with GLA-SE administrated three times with each time 28 days interval (day 0-28-56)
    Interventions:
    • Biological: PAMVAC
    • Biological: GLA-SE
  • Placebo Comparator: 5B - Placebo
    The study participant will get Placebo (physiological saline solution) administrated three times with each time 28 days interval (day 0-28-56)
    Intervention: Other: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
66
December 2017
December 2017   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Healthy male and female volunteers aged 18-45 years.
  • Able and willing (in the investigator's opinion) to comply with all trial requirements.
  • General good health based on history and clinical examination
  • Written informed consent
  • Women only: Must agree to practice continuous effective contraception for the duration of the trial (a method which results in a low failure rate; i.e. less than 1% per year). Women will be counseled about effective contraception methods and, if required, can be provided with adequate contraceptives by the investigator team.
  • Available to participate in follow up for the duration of trial (36 weeks following first injection)
  • Reachable by phone during the whole trial period

Exclusion Criteria:

  • Pregnancy, lactation or intention to become pregnant during the trial
  • Previous participation in a malaria vaccine trial
  • 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)
  • Presence of autoimmune diseases requiring systemic treatment (e.g. rheumatic diseases)
  • Use of immunoglobulins or blood products within 3 months prior to enrolment
  • Receipt of an investigational product in the 30 days preceding enrolment, or planned receipt during the trial period
  • History of malaria or travel in malaria-endemic areas within the past 6 months
  • Intention to travel to malaria endemic countries during the trial period
  • 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 trial
  • 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 enrolment
  • Positive for hepatitis B surface antigen (HBs-antigen)
  • Seropositive for hepatitis C virus (antibodies to HCV)
  • Volunteers unable to be closely followed for social, geographic or psychological reasons
  • Known hypersensitivity to any of the vaccine components (adjuvant or peptide)
  • Any clinically significant abnormal finding on biochemistry or hematology blood tests, urine analysis or clinical examination
  • History of seizure, except for sporadic febrile convulsions in 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 trial; affect the ability of the volunteer to participate in the trial or impair interpretation of the trial data.
Sexes Eligible for Study: All
18 Years to 45 Years   (Adult)
Yes
Contact: Diane Egger-Adam, Dr. +4970712982191 diane.egger-adam@uni-tuebingen.de
Benin
 
 
NCT02647489
PAMVAC1_15
Yes
Not Provided
Not Provided
University Hospital Tuebingen
University Hospital Tuebingen
  • University of Copenhagen
  • Université d'Abomey-Calavi
  • European Malaria Vaccine Initiative
  • Institut de Recherche pour le Developpement
  • Expres2ion Biotechnologies APS
Principal Investigator: Benjamin G Mordmüller, MD University Hospital Tübingen
Principal Investigator: Saadou Issifou, MD Université d'Abomey-Calavi
University Hospital Tuebingen
October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP