Spiraling Towards an Answer

What begins as a tiny bite from a mosquito, driven by its thirst for blood, can transmit an illness that causes nearly half a million deaths every year: malaria. And though $2.7 billion was spent in an effort to control and eliminate the number of cases of malaria worldwide, risk of transmission remains high, with case incidence steadily rising in the Americas, South-East Asia, Western Pacific and African regions (1).

The battle against malaria has been long and arduous for scientists and healthcare professionals on the front line. The sheer structural complexity of Plasmodium falciparum – the parasite responsible for causing the deadliest form of malaria – makes it a particularly difficult disease to treat.

RTS,S  is a malaria vaccine that has demonstrated protective effects in both children and infants – it received a positive opinion from the European regulatory authorities in July and will be rolled out through a pilot introduction in areas of three African countries beginning in 2019. Scientists at the Scripps Research Institute and PATH’s Malaria Vaccine Initiative have been conducting a cryo-electron microscopy (cryo-EM) investigation, as part of an international effort to further improve the vaccine. Specifically, the researchers looked at antibodies isolated from people who received the RTS,S vaccine and revealed, for the first time, how they interact with P. falciparum by locking the circumsporoite protein on the parasite surface into a spiral-like conformation (2). “We were absolutely delighted to see the first images. No-one could have predicted that we would see a structure like this,” says Ian Wilson, Professor at Scripps Research and co-corresponding author of the study.

“We even remade the sample to validate our results,” adds David Oyen, research fellow at Scripps Research and co-first author of the paper.

Capturing how the human immune system interacts with P. falciparum was previously considered intractable; imaging techniques simply weren’t able to resolve the details.

“Since the CSP contains a multitude of low complexity repeats, different antibodies can bind at the same time, resulting in heterogeneity that is nearly impossible to study and made it crucial for cryo-EM to be used,” says Andrew Ward at Scripps Research, and a corresponding author on the paper.

The team now says it will screen a variety of antibodies from different sources to map the structural features and configurational changes that occur when they bind to circumsporozoite proteins – and hope it will reveal new information about how to block the parasite’s lifecycle in humans. Collaboration with other labs to design new immunogens based on their cryo-EM images is something the team is keen on pursuing. “If we can learn how to focus the immune response on the key structural and functional features of the malaria antigen, we can really make a difference in trying to control this disease,” says Wilson.