Malaria is one of the oldest and deadliest diseases in human history. Each year it takes the lives of 3 times as many children as cancer and puts nearly half the world’s population at risk of infection. The parasite which causes malaria, Plasmodium, is more complex than the viruses and bacteria for which we have developed vaccines thus far. This, combined with the fact that Plasmodium has been evolving to escape our immune defenses for millennia, has stymied scientists from developing a vaccine using traditional approaches. If we are to develop a vaccine capable of preventing and eliminating such a competent foe, we will need to use even more sophisticated weapons.

A Plasmodium infection starts when an infected mosquito injects tens to hundreds of parasites into the skin. The parasite then actively crosses through a blood vessel and enters the blood circulation with the goal of reaching the liver. Once in the liver, it will traverse through multiple liver cells before settling in a single one where it will grow to form roughly 50,000 parasites over 7 days. During this time there are no actual symptoms of infection. After this week, the 50,000 parasites emerge in a radically changed life stage which cyclically infects and kills red blood cells as parasite numbers expanding into the billions. It is at this stage when all malaria-associated disease and death occurs. A subset of parasites will develop into sexual stages that can then be taken up by a new mosquito to spread the infection.

Such a prolonged and complex life cycle allows for multiple points where the immune system can intervene and stop the infection. Using unconventional approaches such as genetically-weakened parasites that infect but do not cause disease, Brandon Wilder and colleagues have uncovered several mechanisms by which the immune system can overcome malaria infection or prevent it all together—ideally before the disease-causing blood stages. The Wilder group is focused on how to turn these observations into vaccines or interventions which can be used for both the prevention and eventual elimination of the disease altogether.

This includes combining human studies, non-human primate models of malaria and the use of humanized mice to develop and optimize such interventions. For example, working with researchers from across the globe, Brandon Wilder has helped uncover a unique kind of antibody made by the body after vaccination. These particular antibodies are extremely potent at preventing infection from the point of mosquito bite and this is now being pursued both as a vaccine and as a monoclonal antibody therapy. In addition, the T-cells of the immune system can track and kill liver cells infected with parasites. In collaboration with established researchers at OHSU, the Wilder group also aims to harness the potent T-cell response induced by cytomegalovirus viruses to better understand how we can develop a vaccine which generates T-cells capable of killing the parasite before it can cause and spread disease.

Biography

Brandon Wilder attended the University of Florida where he received his B.S. in 2006 and his Ph.D. in Immunology and Microbiology in 2012. He then did his postdoctoral fellowship with Stefan Kappe at the Center for Infectious Disease Research in Seattle, WA where he studied protective immune responses to malaria and eventually finished as a Research Assistant Professor in 2018. He then joined the OHSU Vaccine and Gene Therapy Institute in as an Assistant Professor. He also splits his time serving as the Unit Head of Immunology and Vaccine Development in the Department of Parasitology at the Naval Medical Research Unit-6 in Lima, Peru.

Selected publications

1. Sack BK*, Tan J*, Oyen D*, Zenklusen I*, Piccoli L, Barbieri S, Foglierini M, Fregni CS, Marcandalli J, Jongo S, Abdulla S, Perez L, Corradin G, Varani L, Sallusto F, Sim BKL, Hoffman SL, Kappe SHI, Daubenberger C, Wilson IA, Lanzavecchia A. A public antibody lineage that potently inhibits malaria infection by binding to the N-terminal junction of the circumsporozoite protein. Nature Medicine. 2018. 24(4): 401-407. *equal contribution PMID: 29554084
2. Kisalu NK, Idris AH, Weidle C, Flores-Garcia Y, Flynn BJ, Sack BK, Murphy S, Schön A, Freire E, Francica JR, Miller AB, Gregory J, March S, Liao HX, Haynes BF, Wiehe K, Trama AM, Saunders KO, Gladden MA, Monroe A, Bonsignori M, Kanekiyo M, Wheatley AK, McDermott AB, Farney SK, Chuang GY, Zhang B, Kc N, Chakravarty S, Kwong PD, Sinnis P, Bhatia SN, Kappe SHI, Sim BKL, Hoffman SL, Zavala F, Pancera M, Seder RA. A human monoclonal antibody prevents malaria infection and defines a site of vulnerability on Plasmodium falciparum circumsporozoite protein. Nature Medicine. 2018. 24(4): 408-416. PMID: 29554083
3. Isabelle Zenklusen, Joshua Tan, Antonio Lanzavecchia, Stephen L. Hoffman, Jongo Said, Salim Abdulla, Claudia Daubenberger*, Brandon K. Sack*. Immunization of malaria pre-exposed Tanzanian adults with aseptic, purified, irradiated Plasmodium falciparum sporozoites elicits long-lived sporozoite-specific IgM antibodies which are capable of inhibiting sporozoite invasion in vitro. Journal of Infectious Diseases. 2018. Apr 23;217(10):1569-1578. *Equal contribution PMID: 29438525
4. Vaughan AM, Sack BK, Dankwa D, Minkah N, Nguyen T, Cardamone H, Kappe SHI. "A Plasmodium parasite with complete late liver stage arrest protects against pre-erythrocytic and erythrocytic stage infection in mice." Infect Immun. 2018. Apr 23;86(5). PMID: 29440367
5. Sack BK, Mikolajczak SA, Fishbaugher M, Vaughan AM, Flannery EL, Nguyen T, Betz W, Jane Navarro M, Foquet L, Steel RWJ, Billman ZP, Murphy SC, Hoffman SL, Chakravarty S, Sim BKL, Behet M, Reuling IJ, Walk J, Scholzen A, Sauerwein RW, Ishizuka AS, Flynn B, Seder RA, Kappe SHI. Humoral protection against mosquito bite-transmitted Plasmodium falciparum infection in humanized mice. 2017. npj Vaccines 2(1): 27. PMID: 29263882
6. Sack BK, Keitany GJ, Vaughan AM, Miller JL, Wang R, Kappe SH. Mechanisms of stage-transcending protection following immunization of mice with late liver stage-arresting genetically attenuated malaria parasites. PLoS Pathog. 2015 May 14;11(5):e1004855. PubMed PMID: 25974076; PubMed Central PMCID: PMC4431720. 

Complete bibliography