PlacID

Modelling Placental Infection and Disease

Background

Placental malaria is a neglected form of the Plasmodium falciparum malaria that affects pregnant women and leads to a significant risk for both the mother and the foetus.  During the malaria blood-stage infection P. falciparum parasite infects the red blood cells which bind to chondroitin sulphate A (CSA) in the intervillous spaces of the placenta, preventing the efficient transmission of nutrients to the foetus and increasing the risk of spontaneous abortion.  Only women who have previously suffered from placental malaria develop substantial levels of protective antibodies that prevent the adhesion of red blood cells to placental CSA.  The level of the antibody titres increases with the number of subsequent pregnancies.  

There are no licensed vaccines for placental malaria and current strategies to prevent the disease rely on vector eradication (e.g. using chemically-treated bed nets, indoor residual spraying) combined with the intermittent administration of antimalarial drugs.  Such approaches are becoming less effective due to the emergence of pesticide-resistant mosquito populations and drug-resistant strains of the parasite.  Several vaccine candidates against placental malaria are currently under development worldwide.  Two of them based on the Plasmodium falciparum protein VAR2CSA are part of the European Vaccine Initiative’s portfolio.  The two projects PRIMALVAC and PAMCPH/PlacMalVac aim at the development of a VAR2CSA based vaccine that could be administered to nulligravid women (before first pregnancy) thus inducing a state of protective immunity that is comparable to multigravid women and efficiently prevents subsequent episodes of placental malaria.

In order to efficiently evaluate the newly designed vaccine candidates before testing them in clinical trials there is a need for development of reliable preclinical models.  The lack of such models in the past has significantly delayed the development of placental malaria vaccines. 

The Laboratory of Malaria Immunology and Vaccinology (LMIV), U.S. National Institute of Allergy and Infectious Diseases (NIAID) has established a nonhuman primate model of placental malaria that for the first time reproduces all the features of P. falciparum malaria in pregnant women.  The members of the genus Aotus constitute one of the few species that are affected by Plasmodium falciparum, making them suitable for non-human primate experimental models in malaria research.  Importantly, the animals in this model develop broadly neutralising antibodies over successive episodes of placental malaria, as do women, suggesting that this may be an appropriate model for preclinical qualification and down selection of vaccine candidates. 

Stained placenta with P. falciparum infected erythrocytes; source: Muehlenbachs, Fried, and Duffy, LMIV, NIAID, NIH

Stained placenta with P. falciparum infected erythrocytes; source: Muehlenbachs, Fried, and Duffy, LMIV, NIAID, NIH

Objectives

The overall objective of PlacID is to validate the non-human primate animal model developed at NIAID-LMIV for the evaluation of the placental malaria vaccine candidates and to assess it as a platform for testing placental malaria vaccine candidates prior to human testing.

The specific objectives of PlacID are:

  • To confirm that passive transfer of purified immune IgG from multigravid African women will confer protection to pregnant Aotus monkeys when they are exposed to placental infection with P. falciparum. 
  • To conduct a vaccination study that assesses the leading placental malaria vaccine candidates, including the two candidates from the EVI portfolio, as well as appropriate controls. 

Major Milestones:

M1: Passive transfer studies in preclinical model performed; Report on protection by passive therapy with human immune IgG

M2: Vaccination studies in preclinical model performed; Report on safety, immunogenicity, and preclinical efficacy of leading placental malaria vaccines product candidates

Publications

Malar J (2016) 15:476 DOI 10.1186/s12936-016-1527-8