ExpreS2ion Biotech announces the second successful evaluation of safety by the independent safety monitoring board for the phase Ia clinical trial of the placental malaria vaccine candidate, PAMVAC. Due to the trial’s staggered approach, the second evaluation allows initiation of the phase Ib clinical trial to be conducted in Benin, Africa. The clinical trial is funded by the EU under the FP7 program and coordinated by associate professor Morten A Nielsen at University of Copenhagen in collaboration with University of Tübingen, Université d’Abomey-Calavi, European Vaccine Initiative, Institut de Recherche pour le Développement, and ExpreS2ion Biotech.
Women, who have acquired immunity against malaria during childhood, nevertheless become susceptible to malaria again during their first pregnancies. Parasites accumulate in the placenta, where a combination of altered blood flow and expression of chondroitin sulphate A (CSA) provides a new niche for parasites to sequester. Malaria in pregnant women thus constitutes a major health problem in areas south of the Sahara, manifesting as severe disease, anemia in the mother, impaired fetal development, low birth weight or spontaneous abortion. Placental malaria has been estimated by the WHO to be responsible for 20,000 maternal and 200,000 infant deaths annually. Fortunately, women acquire immunity against placental malaria, and in malaria endemic areas the average birth weight is significantly higher among second- and third- compared to first-born babies. This relatively fast development of protection has raised the hope that a vaccine for placental malaria can be developed.
Worldwide collaborations on the vaccine
In 2003 Professor Ali Salanti and others at University of Copenhagen discovered the antigen VAR2CSA, which enable parasite accumulation in the placenta. Since then collaborations with many groups around the world, especially Professor Philippe Deloron at Institut de Recherche pour le Développement, France, has enabled the preclinical development of the vaccine. The European Vaccine Initiative has been instrumental in the mobilization of funds and in the clinical development of the vaccine, where its fast-track strategy is implemented allowing a more efficient development of the vaccine candidate. The phase Ia clinical trial is led by Professor Benjamin Mordmüller (University of Tübingen) and the phase Ib trial is led by Dr. Saadou Issifou (Institut de Recherche Clinique du Bénin). Preparations for a Phase II clinical trial are led by Professor Achille Massougbodji (Université d’Abomey-Calavi), Dr Jean-Philippe Chippaux (Institut de Recherche pour le Developement) and Dr Adrian JF Luty (Institut de Recherche pour le Développement).
ExpreS2ion Biotech contributed to the collaboration through supply of protein antigen variants for selection of the best candidate, as well as developing the production cell line and manufacturing process. Copenhagen University obtained a license to the ExpreS2 system for the production of the PAMVAC vaccine antigen.
The clinical trial
To induce high concentrations of specific IgGs, subjects will receive escalating doses of PAMVAC vaccine antigen adjuvanted with Alhydrogel, GLA-emulsion or GLA-liposome. Three injections with the same dosage and adjuvant will be done, each 28 days apart (Day 0, 28 and 56). Dosage escalation will be staggered to ensure safety during the trial. Control subjects will receive physiological saline instead of the vaccine. The clinical trial is a phase I, 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-emulsion or GLA-liposome will be done in healthy, malaria-naïve adults in Germany (phase 1a). 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-emulsion (phase Ib). In Benin, one group will receive a placebo control (physiological saline). Allocation to placebo, PAMVAC+Alhydrogel or PAMVAC+GLA-emulsion, will be randomized. Each dose-escalation is conditional on a positive safety assessment by an independent safety monitoring board (ISMB) 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 four weeks stagger between the first immunizations in phase Ia and phase Ib.
The PAMCPH project supporting the cGMP manufacture of the vaccine was funded by the German Federal Ministry of Education and Research (BMBF) through Kreditanstalt für Wiederaufbau (KfW) and European Vaccine Initiative, the PlacMalVac (University of Copenhagen, Denmark) project supporting the cGMP manufacture, clinical trial and preparation for phase II was funded by the European Union Seventh Framework Programme, FP7-HEALTH-2012-INNOVATION under grant agreement n° 304815 (http://ec.europa.eu/research/fp7/index_en.cfm?pg=health), the preclinical development of the vaccine was supported by Danish Advanced Technology Foundation under grant number 005-2011-1 (http://innovationsfonden.dk/en).
CEO Steen Klysner comments
“This is a very exciting project and we now look forward to the outcome of the trial. I also note that this further validates the regulatory acceptance of the ExpreS2 platform under GMP for clinical use”