Major Areas of Research
Biology of antibody response to Plasmodium falciparum
Characterization of human monoclonal antibodies to infectious pathogens
Human monoclonal antibodies are emerging as powerful tools in combating infectious disease, both as direct prophylactics and as reagents to identify vulnerable sites on pathogens to guide vaccine design. At the Antibody Biology Unit (ABU), we aim to use cutting-edge technology to study B cells at the single cell level and to identify and characterize human monoclonal antibodies against a range of pathogens. We have two major aims:
- To study basic antibody biology. The sequences of monoclonal antibodies isolated from a vaccinated or naturally infected individual provide a high-resolution portrait of the antibody response to a given pathogen. Information revealed includes the predominant antibody isotype that is generated, the degree of somatic mutation and affinity maturation required for the development of a potent neutralizing response, and the preferential usage of specific VH genes to mount a response against a given antigen.
- To investigate the use of monoclonal antibodies for prevention of infection and as tools for vaccine design. Monoclonal antibodies that are isolated will be screened in in vitro and in vivo assays to determine their potency in preventing infection. Their affinity for their targets will be measured using biophysical assays. In collaboration with structural biologists, we will identify the specific epitopes targeted by the most potent antibodies and develop these sites as novel vaccine candidates. The most potent antibodies will also be considered as candidates to prevent infection in early-phase clinical trials.
The primary focus of the unit will be on malaria. Plasmodium falciparum causes approximately 400,000 deaths a year and remains a serious global health threat. Antibodies have been shown to be key mediators of protection against different stages of the P. falciparum life cycle, but the antibody response to malaria has only recently been studied at high resolution. The biology of the antibody response to P. falciparum is complex and fascinating. Recently, we identified broadly reactive antibodies from individuals living in malaria-endemic areas that contain a LAIR1 insert (an extra immunoglobulin-like domain) that is originally encoded in a different chromosome. This insert confers broad reactivity and is somatically mutated along with the rest of the antibody. This insertion event appears to be quite common in individuals living in different malaria-endemic regions (5-10% of individuals). In a separate study, we identified potent human monoclonal antibodies targeting a novel epitope on the P. falciparum circumsporozoite protein, the major sporozoite coat protein. This site is now being investigated as a new vaccine candidate.
Our platform is adaptable to any target. This unit will also study human monoclonal antibodies against other infectious agents, including Mycobacterium tuberculosis and SARS-CoV-2, as well as non-infectious targets.
Joshua Tan, Ph.D., is a Stadtman Tenure-track Investigator and an NIH Distinguished Scholar in the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. He received his Ph.D. from the University of Oxford, England. Prior to joining the NIH, he was awarded the Pfizer Research Prize for his malaria work and the Sir Henry Wellcome Postdoctoral Fellowship to investigate human monoclonal antibodies that target the malaria-causing parasite P. falciparum.
Cherrelle Dacon, Ph.D., Postdoctoral Fellow
Divya Mohan, Biologist
Lauren Purser, Lab Manager
Lawrence Wang, Visiting PhD Student
Cho H*, Gonzales-Wartz KK*, Huang D*, Yuan M*, Peterson M*, Liang J, Beutler N, Torres JL, Cong Y, Postnikova E, Bangaru S, Talana CA, Shi W, Yang ES, Zhang Y, Leung K, Wang L, Peng L, Skinner J, Li S, Wu NC, Liu H, Dacon C, Moyer T, Cohen M, Zhao M, Lee FEH, Weinberg RS, Douagi I, Gross R, Schmaljohn C, Pegu A, Mascola JR, Holbrook M, Nemazee D, Rogers TF, Ward AB, Wilson IA, Crompton PD, Tan J. 2021. Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants. bioRxiv
Tan J*, Cho H*, Pholcharee T*, Pereira LS, Doumbo S, Doumtabe D, Flynn BJ, Schön A, Kanatani S, Aylor SO, Oyen D, Vistein R, Wang L, Dillon M, Skinner J, Peterson M, Li S, Idris AH, Molina-Cruz A, Zhao M, Olano LR, Lee PJ, Roth A, Sinnis P, Barillas-Mury C, Kayentao K, Ongoiba A, Francica JR, Traore B, Wilson IA, Seder RA, Crompton PD. 2021. Functional human IgA targets a conserved site on malaria sporozoites. Sci Transl Med, in press
Tan J, Piccoli L and Lanzavecchia A. 2019. The antibody response to Plasmodium falciparum: cues for vaccine design and the discovery of receptor-based antibodies. Annu Rev Immunol 37, 225-246.
Tan J*, Sack BK*, 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 and Lanzavecchia A. 2018. A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein. Nat Med 24, 401-407.
Pieper K*, Tan J*, Piccoli L*, Foglierini M, Barbieri S, Chen Y, Fregni CS, Wolf T, Jarrossay D, Anderle M, Abdi A, Ndungu FM, Doumbo OK, Traore B, Tran TM, Jongo S, Zenklusen I, Crompton PD, Daubenberger C, Bull PC, Sallusto F and Lanzavecchia A. 2017. Public antibodies to malaria antigens generated by two LAIR1 insertion modalities. Nature 548, 597-601.
Tan J*, Pieper K*, Piccoli L*, Abdi A, Foglierini M, Geiger R, Tully CM, Jarrossay D, Ndungu FM, Wambua J, Bejon P, Fregni CS, Fernandez-Rodriguez B, Barbieri S, Bianchi S, Marsh K, Thathy V, Corti D, Sallusto F, Bull P and Lanzavecchia A. 2016. A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens. Nature 529, 105-109.