on March 19, 2018
BELLINZONA and BASEL (Switzerland) – A Swiss team of researchers from the Institute for Research in Biomedicine, affiliated to the Università della Svizzera italiana, and from the Swiss Tropical and Public Health Institute, associated Institute of the University of Basel, has discovered a new class of antibodies that potently block malaria parasites in the initial phase of the infection thus, conferring a sterilizing immunity. These antibodies bind to the surface of the sporozoites, the infectious form of the malaria parasite which is injected into the blood by the mosquito. The new study describes antibodies able to directly neutralize the parasites injected by the mosquito and therefore to stop the infection in the bud. This work, published in the renown scientific journal Nature Medicine, was carried out in collaboration with researchers at the Scripps Research Institute in La Jolla and the Center for infectious disease research in Seattle and was partially funded by the Swiss National Science Foundation (SNSF), the European Research Council (ERC), Swiss Vaccine Research Institute and the Fondazione Aldo e Cele Daccò.
Background
The most lethal form of malaria is caused by the protozoan parasite Plasmodium falciparum, which is responsible for approximately 400,000 deaths yearly. Only a small number of Plasmodium parasites (10-100) is delivered during each infectious mosquito bite. These Plasmodium parasites, also called sporozoites, quickly reach the liver where they expand and give rise to a massive infection of the red blood cells that causes a severe pathology. Antibodies can therefore protect at two levels: in the initial phase, by blocking sporozoites, and in the acute phase of the disease, by blocking the infected red blood cells. The same Swiss team had reported, in two papers published previously in the prestigious journal Nature, a new molecular mechanism that generates broad-spectrum antibodies able to bind red blood cells infected by the parasite and therefore to keep the infection under control.
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| Structure of an antibody (blue) binding to the novel region of the malaria parasite protein (yellow) (courtesy of Luca Piccoli; structure provided by Ian Wilson and David Oyen). |
The discovery
A portion of the surface protein of sporozoites (CSP) is the basis of the current vaccine (RTS, S), which unfortunately has only a modest effectiveness in preventing the infection. For this reason, experimental vaccines based on attenuated whole parasites were tested. The Swiss team isolated a series of monoclonal antibodies from individuals who were protected from one of these experimental vaccines (Sanaria PfSPZ Vaccine) and found that the most effective antibodies recognized a distinct region within the surface protein of the sporozoites that has not been considered in malaria vaccines so far. Further testing performed in Seattle revealed that these antibodies were highly potent in reducing malaria infection. In summary, this study has identified a novel part of the parasite surface protein that is a key target of inhibitory antibodies and represents a candidate for a second generation malaria subunit vaccine.
Comments from the researchers
Antonio Lanzavecchia, director of the IRB, and senior author of the study, says:
“A vaccine that blocks the parasites as they enter the body has the potential to eradicate malaria. Our finding that humans can produce these blocking antibodies suggests that this long-sought goal is finally within reach”.
“This has been a great team work initiated by the two Swiss teams with complementary expertise in antibody biology and clinical trials. I am looking forward to engage in the next step of vaccine development.”
Luca Piccoli, a co-author of the paper says: “It’s amazing to find that such a small region in the malaria protein can trigger such potent neutralizing antibodies in different individuals. This is very encouraging for vaccine design”.
Joshua Tan, a co-author of the paper says: “Many antibodies that bind to this surface protein have been isolated before, but these potent antibodies target a novel site on the protein that may be a potentially exploitable weakness of the malaria parasite.”
Claudia Daubenberger, Head of Clinical Immunology Unit of SwissTPH and co-senior author says: The long-term collaboration between the SwissTPH, running experimental vaccine trials, and IRB that conducted detailed analyses of basic immunology, provides unprecedented and exiting insight into the humoral immunity against malaria”.
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 13 research groups and 110 researchers that investigate the mechanisms of host defence against infectious agents, cancer and degenerative diseases. With more than 560 publications in leading scientific journals, the IRB has gained an international reputation as a centre of excellence in human immunology. www.irb.usi.ch
About the Swiss Tropical and Public Health Institute (SwissTPH)
The Swiss Tropical and Public Health Institute (Swiss TPH) is a world-leading institute in global health with a particular focus on low- and middle-income countries. Associated with the University of Basel, Swiss TPH combines research, services, and education and training at the local, national and international level. Over 800 people from more than 70 nations work at Swiss TPH focusing on infectious and non-communicable diseases, environment, society and health as well as health systems and interventions. www.swisstph.ch
Article reference
A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein. Joshua Tan, Brandon K Sack, David Oyen, Isabelle Zenklusen, Luca Piccoli, Sonia Barbieri, Mathilde Foglierini, Chiara Silacci Fregni, Jessica Marcandalli, Said Jongo, Salim Abdulla, Laurent Perez, Giampietro Corradin, Luca Varani, Federica Sallusto, Betty Kim Lee Sim, Stephen L Hoffman, Stefan H I Kappe, Claudia Daubenberger, Ian A Wilson, and Antonio Lanzavecchia. DOI: 10.1038/nm.4513
Advance Online Publication (AOP) on https://www.nature.com/nm/
