Harvard Medical School

Ragon Institute of MGH, MIT and Harvard

400 Technology Square

Cambridge, MA 02139


Click here to visit the Schmidt Lab Website.


Research Summary

Our research focuses on the development of adaptive immune responses, protein evolution and the interactions between host and pathogen using a combination of biophysical, biochemical and molecular virology techniques. We are structural biologists who bring mechanistic and quantitative approaches to address fundamental problems in virology and immunology. We primarily study orthomyxo- and flaviviruses but our interests extend to emerging viruses (e.g. alpha-, arena-, bunya- and filoviruses) and other pathogens. We are strong believers in collaboration and are always open to pursuing new directions and pathogens.

Therapeutics Discovery
Can novel small-molecules and antibodies be identified to inhibit viral entry?
Antibodies as therapeutics: broadly neutralizing antibodies (bnAbs) against viruses like influenza and HIV are possible therapeutic interventions in the absence of successful vaccines. We use directed evolution to understand bnAb development and to artificially affinity mature bnAbs to optimize specificity and breadth to inhibit viral entry.
Small-molecules as therapeutics: viruses that fuse from internal compartments present a significant hurdle for small-molecule inhibition. Targeting intermediates in the viral fusion pathway requires that the small-molecule be present in the same internal compartment as the fusing virus. We are developing strategies to deliver small-molecules in order to inhibit conformational rearrangements of viral glycoproteins and to target host proteins required for entry. We are also using our understanding of the viral fusion pathway to develop assays to identify small-molecule inhibitors of viral entry.

Protein Engineering
Can viral antigens be manipulated using structure-guided protein engineering to produce a desired immune response?

Traditional vaccination approaches have failed for many viral and parasitic diseases such as dengue, HIV and malaria. New approaches to rational vaccine design are necessary. We use a structure-guided approach for immunogen design in order to direct B-cell populations. We test these immunogens in animal models and analyze resulting B-cell repertoires in order to understand potential “rules” that may govern antigenicity and immunogenicity.

Viral Evolution
Can the evolutionary arms race between host and pathogen be recapitulated in vitro?
Pathogens use antigenic variation of their surface-exposed proteins as an evasion strategy to subvert and avoid host immune surveillance. We are broadly interested in understanding the evolution and co- evolution of pathogens with their hosts. In particular, how the adaptive immune system exerts pressure on viral proteins and how viruses evolve to escape such selective pressures. Understanding these interactions on a structural level may guide therapeutic intervention and vaccine development. We aim to reconstitute the evolutionary arms race between by using directed evolution platforms to evolve both antibodies and viruses.

Key words: Protein engineering, viral evolution, host-pathogen interactions, small-molecule discovery

Selected Publications

McCarthy KR, Watanabe A, Kuraoka M, Do KT, McGee CE, Sempowski GD, Schmidt AG, Kelsoe G, Harrison SC (2017) Human Memory B cells The Cross-React with Group 1 and Group 2 Influenza A Viruses. Immunity. 48: 174-184

Raymond DD, Bajic G, Ferdman J, Suphaphiphat P, Settembre E, Moody MA, Schmidt AG, Harrison SC. (2018) Conserved epitope on influenza-virus hemagglutinin head defined by a vaccine-induced antibody. PNAS 17154711: 1-6.

Raymond DD, Stewart S, Lee J, Ferdman J, Bajic G, Do KT, Ernandes MJ, Suphaphiphat P, Settembre EC, Dormitzer PR, Del Giudice G, Finco O, Kang TH, Ippolito GC, Georgiou G, Kepler TB, Haynes BF, Moody MA, Liao H-X, Schmidt AG, Harrison SC (2016) Influenza immunization elicits hemagglutinin receptor-site antibodies specific for an egg-adapted vaccine strain. Nature Medicine. 10.1038: 1-7.

Kuraoka M, Schmidt AG, Nojima, T, Feng F, Watanabe A, Kitamura D, Harrison SC, Kepler TB and Kelsoe G (2016) B-cell selection in germinal centers elicited by complex antigens. Immunity, 44 1-11.

Schmidt AG, Khoi KT, McCarthy KR, Kepler TB, Liao HX, Moody MA, Haynes BF and Harrison SC (2015) Immunogenic stimulus for germline precursors of influenza-specific antibodies Cell Reports, 13 2842-50.

Schmidt AG, Therkelsen MD, Stewart S, Kepler TB, Liao HX, Moody MA, Haynes BF and Harrison SC (2015) Viral receptor-binding site antibodies with diverse germline origins. Cell 161 1026-34.

Schmidt AG*, Xu H*, Khan AR, O’Donnell T, Khurana S, King LR, Manischewitz J, Golding H, P. Suphaphiphat P, Carfi, A, Settembre EC, Dormitzer PR, Kepler TB, Zhang R-J, Moody MA, Haynes BF, Liao HX, Shaw DE and Harrison SC (2013) Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza antibody PNAS 110 (1) 264-269.

Schmidt AG, Lee K, Yang PL and Harrison SC (2012) Small-molecule inhibitors of dengue-virus entry. PLoS Pathogens 8 (4): 1-10.

Schmidt AG, Yang PL and Harrison SC (2010) Peptide inhibitors of flavivirus entry derived from the E protein stem. J Virol. 2010 Dec; 84 (24):12549-54.

Schmidt AG, Yang PL, and Harrison SC (2010). Peptide Inhibitors of Dengue-Virus Entry Target a Late Stage Fusion Intermediate. PLoS Pathogens (6 ) 4.