Preventing placental malaria
Understanding why some women are susceptible to placental malaria infections could open the door to new vaccines and treatments to protect pregnant women and their unborn babies.
Research from a team at the Doherty Institute published in eLife has identified six antibody characteristics that help protect women and may help clinicians identify those at risk thanks to a new technique of measuring and analysing antibody responses.
Malaria infections can be devastating for pregnant mothers and their children, particularly during their first pregnancies, and causes approximately 900,000 low birth weight deliveries and an estimated 100,000 infant deaths each year.
If malaria parasites invade the placenta, they can starve babies of nutrition, potentially causing low birth weight, preterm deliveries, stillbirths, and pregnancy loss.
But not all women are susceptible to placental malaria infections.
For years, University of Melbourne Professor Stephen Rogerson’s laboratory at the Doherty Institute have been trying to understand why.
Placental malaria occurs when a protein made by the malaria parasites, called VAR2CSA, enables malaria-infected cells to attach to the placental walls and invade, explains University of Melbourne Dr Elizabeth Aitken a senior researcher in his team and co-first author on the study.
“We had been measuring antibody responses to the parasite, but they didn’t really correlate very well with protection a lot of the time,” says Dr Aitken.
“We knew that many women acquire immunity that can prevent this, and that those who have placental malaria during their first pregnancy are less likely to become infected in subsequent pregnancies, but we didn’t know which antibody was enabling this protection.”
“Traditionally when we are studying antibody immunity, we have been focused on measuring the number of antibodies produced,” explains Professor Rogerson, senior author on the study.
“We wanted to shift away from this approach and find a way to examine the specific function of each antibody to understand what was providing this immunity for some women.”
The team only needed to look a few floors higher to help them get that answer.
“We saw that University of Melbourne Dr Amy Chung, who heads up another laboratory at the Doherty Institute and is a senior author on this study, had been publishing some papers using a technique called ‘systems serology’ which allows you to measure lots of different kinds of antibody responses and identify the ones that are best associated with protection,” explains Professor Rogerson.
“No one had ever taken this systematic approach towards placental malaria, or malaria in general, and so we thought it would be a really good way to really identify exactly what kind of antibody responses are needed to establish protection for the women from placental malaria.”
So that's what they did.
The system that Chung’s Laboratory was using was high-end computing.
“Imagine it like putting all your data into a Powerball machine and allowing it to select different combinations and seeing how that can differentiate those who are protected from those who are susceptible to disease,” says Professor Rogerson.
“The computer does this over and over and eventually, you can rank your antibodies that contribute most to the separation and plot them on a curve.”
Using this technique, they analysed 169 antibody features in 77 pregnant women from Madang, Papua New Guinea.
Of these features, they identified six that were associated with protection from placental malaria at delivery. These fell into two broad groups: those related to preventing the parasites from binding to placental cells, and those that led to the destruction of infected blood cells.
Once they had these features, Dr Saber Dini a data scientist at the Centre for Epidemiology and Biostatistics and co-first author Timon Damelang, a University of Melbourne PhD student in Dr Chung’s lab, used a model that could predict which pregnant woman would develop placental malaria infections with 86 per cent accuracy.
Amaya Ortega-Pajares is another University of Melbourne PhD student who worked on the research and co-first authored the paper, working under the supervision of Professor Rogerson.
“One of the really interesting things that came out of it was that these antibody responses are very heterogeneous, so just because a woman had one kind of antibody response didn't really mean that she had another,” explains Ms Ortega-Pajares.
“This suggests there it is likely there are multiple pathways to protection against placental malaria – whether that be stopping the malaria-infected red blood cells from attaching to the placenta in the first place, or by destroying the infected blood cells,” she says.
The multiple pathways may, in part explain why the team has had so much trouble in the past correlating antibody response with protection.
The team is hopeful that these findings can now be used to develop new therapies to protect pregnant women from malaria and related complications.
“If you were to make a vaccine, you would be able to look for these particular features and identify whether the vaccine is inducing the kind of immunity you want it to,” says Dr Aitken.
Along with looking for new vaccines and treatments – what’s next?
“It will be interesting to learn whether this same combination of features can protect pregnant women from placental malaria infections in other populations,” says Professor Rogerson.
“Right now, we are measuring these features in a cohort of women from Malawi. We also want to know if this approach could be used to prevent severe malaria in children. Can we figure out which features protect them?”
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