Malaria, Antepartum Clinical Trial
Official title:
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.
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT01941264 -
Community-based Screening and Treatment of Malaria in Pregnancy: a Cluster-randomized Trial
|
N/A |