Safety and Immunogenicity of the Placental Malaria Vaccine Candidate PAMVAC Variously Adjuvanted
Condition: Malaria, Antepartum
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): PAMVAC; Alhydrogel; GLA-SE; GLA-LSQ; Placebo
Intervention type(s): Biological; Biological; Biological; Biological; Other
Intervention MeSH terms: Aluminum Hydroxide
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention