New antibodies with an extra fragment overcome malaria parasite diversity

A publication in the renowned journal Nature describes a new groundbreaking mechanism that generates super-antibodies that can broadly target malaria parasites. The study was conducted at IRB, in collaboration with the KEMRI-Wellcome Trust Research Programme in Kenya and the University of Oxford. The study was partially funded by the Swiss National Science Foundation (SNSF) and the European Research Council (ERC).

Background

The most deadly malaria parasite, Plasmodium falciparum, has been engaged in a struggle with the human immune system for thousands of years. To evade the immune response, the parasite uses the chameleon-like technique of continuously changing its protein coat. Infants are susceptible to severe disease, but become protected as they grow older by producing a large collection of antibodies that match the parasite’s diverse protein coats. Antibodies that simultaneously target many different parasites would potentially lead to the development of new interventions against malaria, but have not been discovered so far.

The discovery

An international team of researchers from the Institute for Research in Biomedicine, the KEMRI-Wellcome Trust Research Programme in Kenya, and the University of Oxford has discovered a new class of antibodies that can target different malaria parasites and also identified the target proteins as members of the RIFIN family. Upon binding to RIFINs, the antibodies could act as beacons to signal the immune system to remove and destroy the parasite-infected cells. These antibodies represent a new tool to fight malaria, and the RIFINs recognized are candidates for the development of a vaccine that protects from disease. The antibodies described in this study were not only special for their broad reactivity, but also for their novel and surprising structure characterized by the presence of a large extra fragment. Unlike conventional antibodies that are made by assembling DNA segments present on chromosome 14, the new antibodies contain an additional large piece of DNA derived from a gene called LAIR1, which is found on chromosome 19. Remarkably, this extra piece alone is sufficient to bind to malaria parasites. In conclusion, the study illustrates, with a biologically relevant example, a novel mechanism of antibody generation that relies on the transfer of a piece of non-antibody DNA derived from a different chromosome. It also demonstrates the existence of conserved antigens that may be suitable candidates for the development of a malaria vaccine.

Comments from the researchers

Antonio Lanzavecchia, director of the IRB, Professor of Human Immunology at ETH Zurich, as well as senior author of the study, says: “It is amazing that after more than 100 years of research in this field we can still find a new type of antibody. This shows how human studies can advance our understanding of basic mechanisms of defence and open up new avenues for therapy and vaccination."

Joshua Tan, a first co-author of the paper says: "Given the amount of energy Plasmodium uses to escape from the immune response, it is interesting to see that the immune system can fight back by creating antibodies that target many different parasites. In the long struggle with malaria, it looks like the immune system may have an extra card to play."

Kathrin Pieper, another first co-author of the paper says: "The unusual structure of these antibodies came as a surprise. It will be important to find out how many other antibodies use the new mechanism."

Luca Piccoli, another first co-author of the paper says: "It is interesting that the extra piece is the only element required for binding to the parasite. In this respect, these antibodies belong to a completely new class."

Peter Bull, group leader at KEMRI and a senior author of the study says: "A vaccine against the variant parasite proteins on the surface of infected red blood cells has long been considered impractical due to their diversity in structure. With the discovery of RIFIN targets that are expressed by many parasite isolates, it would be worth investigating these proteins as potential candidates for a new malaria vaccine."

Further information

Antonio Lanzavecchia
[email protected]
tel +41 76 578 15 08

Peter Bull
[email protected]
tel +44 78 10 15 87 24

About the Institute for Research in Biomedicine (IRB)

The Institute for Research in Biomedicine (IRB) was founded in 2000 in Bellinzona and was affiliated to the Università della Svizzera Italiana (USI) in 2010. Financed by private and public institutions, and by competitive grants, the IRB currently hosts 10 research groups and 105 researchers that investigate the mechanisms of host defence against infectious agents, cancer and degenerative diseases. With more than 450 publications in leading scientific journals, the IRB has gained an international reputation as a centre of excellence in human immunology.

Article reference

A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens. Joshua Tan, Kathrin Pieper, Luca Piccoli, Abdirahman Abdi, Mathilde Foglierini, Roger Geiger, Claire Maria Tully, David Jarrossay, Francis Maina Ndungu, Juliana Wambua, Philip Bejon, Chiara Silacci Fregni, Blanca Fernandez-Rodriguez, Sonia Barbieri, Siro Bianchi, Kevin Marsh, Vandana Thathy, Davide Corti, Federica Sallusto, Peter Bull & Antonio Lanzavecchia.

DOI: doi:10.1038/nature16450.
Advance Online Publication (AOP) on http://www.nature.com/nature