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Written by Professor Stephen Rogerson and Dr Elizabeth Aitken 

Madang, on the North coast of Papua New Guinea is built around a lagoon, the sometime haunt of crocodiles. It is fringed by coral reefs through which colourful fish swim, and Madang and the villages around it are home to many malaria-carrying mosquitos.

Pregnant women can be severely affected by malaria, because the most common malaria parasite in Papua New Guinea, Plasmodium falciparum, likes to hide out in their placentas, where it causes local infection and inflammation that interferes with the placenta's development. The placenta actually looks like a branching coral. It forms a coral tree of tiny branches, and these lie in a “sea” of the mother’s blood.

When a placenta is infected by malaria, the parasites and the resulting inflammation combine to impact the development of the placental tree and its ability to easily pass critical nutrients from the mother’s blood to the growing baby. This can result in a stunted placental tree, with few, stumpy branches and incomplete roots in the womb.

Babies of women with placental malaria can die in the womb from miscarriages and stillbirths, or they can be born too small or too soon. Their health in childhood and beyond can be adversely affected too. In some cases, the mother herself may suffer from severe malaria and even succumb to the disease.

The effects of placental malaria are triggered when malaria parasites infect red blood cells and produce a protein called VAR2CSA. This protein sticks the infected red cells to a sugar called chondroitin sulphate A (CSA for short) found on the cells lining the placenta. It causes the infected red blood cells to accumulate in the placenta, causing complications for the woman and the child.

VAR2CSA is a large protein, with six “domains” that fold together, forming two grooves which can bind to the CSA sugar.

Although antibodies, produced by B cells, naturally develop following placental malaria and can block placental binding, first and second-time mothers often lack these antibodies. Professor Stephen Rogerson, Dr Liz Aitken and their team at the Doherty Institute are trying to find a new way to stop placental infection. They are looking for lab-made antibodies that could inhibit the binding of VAR2CSA to CSA, potentially by preventing the CSA from binding in the grooves on the protein.

In addition to blocking CSA binding, effective antibodies could serve other functions, such as coating the malaria-infected cells, which would create targets for white blood cells to identify and kill or eat up the malaria-infected cells.

Over the last few years, our research group has developed several methods to test the functions of these antibodies. Our aim is to determine whether these antibodies bind to VAR2CSA on the surface of the malaria-infected cell (where it can do all the mischief!).

More importantly, we want to find whether the antibodies can block the parasites from binding to CSA in the placenta. Equally crucial, we are investigating whether the antibodies can coat the malaria-infected cells with antibodies that immune cells can recognise.

Associate Professor Amy Chung, renowned for her expertise in characterising antibody functions in diseases like HIV, tuberculosis and COVID-19, has brought her expertise to our malaria work. Our collaboration has helped us to develop better methods for measuring antibodies that coat malaria-infected cells and has increased our understanding of the intricate details of these antibodies, such as the receptors they bind to and the effects binding has on the white blood cells.

VAR2CSA proteins vary slightly from person to person and place to place. The goal is to find antibodies that can recognise all variants of the protein to get maximal protection. Data from colleagues in the United States suggest that such antibodies exist. The question is whether we can find them.

The quest to find these antibodies led Dr Aitken to Madang, where she worked with clinicians and scientists from the world-renowned Papua New Guinea Institute of Medical Research. Among the women participating in a trial of new malaria drugs for pregnant women, led by Dr Holger Unger of the Menzies School of Health Research in Darwin, Dr Aitken found some women who had high levels of VAR2CSA antibodies. From these women, she isolated white blood cells, including the key B cells.

Dr Adam Wheatley’s team at the Doherty Institute specialises in isolating B cells that produce specific antibodies. Using a couple of different variants of VAR2CSA, they successfully isolated B cells from pregnant women, which appear to produce antibodies binding to VAR2CSA. Characterisation of these cells is underway, and we should soon have a first batch of antibodies for testing against VAR2CSA. The ultimate goal is to discover antibodies that can block the CSA binding or help the white cells clear malaria.

When we find antibodies that bind to VAR2CSA, Dr Wheatley’s team can help us make more powerful versions of these antibodies, which could become important tools to help put an end to the scourge of placental malaria. There aren’t any crocodiles in the lagoon in Madang anymore. Perhaps, one day, there won’t be placental malaria in the pregnant women of Madang, either.