The Kepler laboratory develops computational tools and applies them in the context of systems-level experimentation to address outstanding questions in immunology and vaccine development. Much of their work is centered on antibodies and the cells (B cells) that produce them.
Antibodies are genetically extraordinary: their genes are encoded only as fragments in the genome. The B cell’s genome must be cut, rearranged and re-ligated in several places to make the genes required for antibody production. Furthermore, after a B cell has encountered a molecule that binds its antibody (whether on a pathogen, an infected cell, a cancerous tumor, or, in the case of autoimmune disease, normal tissue) the B cell directs mutations into its rearranged antibody genes, and is then subject to competitive selection for improved ability to bind the eliciting molecule. In this Darwinian process, known as affinity maturation, the antibody response is rapidly improved and prepared as the memory response that confers long-term immunity and serves as the basis for vaccination.
The Kepler group works with multiple collaborating laboratories to generate and integrate data from many different assays, each of which provides one perspective on the workings of affinity maturation. By using computational means to coordinate the integration of these diverse data, a comprehensive picture of the process at a systems level emerges.
Professor Kepler, in partnership with colleagues at Duke and Harvard Universities, has developed a new approach to vaccination that uses computational methods to select combinations of immunogens to use in vaccines that drive affinity maturation in specific directions. These methods are being used to develop vaccines against HIV, influenza, and anthrax.
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Division of Graduate Medical Sciences
- Member, Bioinformatics Graduate Program, Boston University
- Brandeis University, PhD
- University of Massachusetts Boston, BA
- Published on 1/16/2018
McCarthy KR, Watanabe A, Kuraoka M, Do KT, McGee CE, Sempowski GD, Kepler TB, Schmidt AG, Kelsoe G, Harrison SC. Memory B Cells that Cross-React with Group 1 and Group 2 Influenza A Viruses Are Abundant in Adult Human Repertoires. Immunity. 2018 Jan 16; 48(1):174-184.e9. PMID: 29343437.
- Published on 11/23/2017
Williams WB, Zhang J, Jiang C, Nicely NI, Fera D, Luo K, Moody MA, Liao HX, Alam SM, Kepler TB, Ramesh A, Wiehe K, Holland JA, Bradley T, Vandergrift N, Saunders KO, Parks R, Foulger A, Xia SM, Bonsignori M, Montefiori DC, Louder M, Eaton A, Santra S, Scearce R, Sutherland L, Newman A, Bouton-Verville H, Bowman C, Bomze H, Gao F, Marshall DJ, Whitesides JF, Nie X, Kelsoe G, Reed SG, Fox CB, Clary K, Koutsoukos M, Franco D, Mascola JR, Harrison SC, Haynes BF, Verkoczy L. Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations. Nat Commun. 2017 Nov 23; 8(1):1732. PMID: 29170366.
- Published on 11/1/2017
Breden F, Luning Prak ET, Peters B, Rubelt F, Schramm CA, Busse CE, Vander Heiden JA, Christley S, Bukhari SAC, Thorogood A, Matsen Iv FA, Wine Y, Laserson U, Klatzmann D, Douek DC, Lefranc MP, Collins AM, Bubela T, Kleinstein SH, Watson CT, Cowell LG, Scott JK, Kepler TB. Reproducibility and Reuse of Adaptive Immune Receptor Repertoire Data. Front Immunol. 2017; 8:1418. PMID: 29163494.
- Published on 10/27/2017
Ramesh A, Darko S, Hua A, Overman G, Ransier A, Francica JR, Trama A, Tomaras GD, Haynes BF, Douek DC, Kepler TB. Structure and Diversity of the Rhesus Macaque Immunoglobulin Loci through Multiple De Novo Genome Assemblies. Front Immunol. 2017; 8:1407. PMID: 29163486.
- Published on 10/13/2017
Han Q, Williams WB, Saunders KO, Seaton KE, Wiehe KJ, Vandergrift N, Von Holle TA, Trama AM, Parks RJ, Luo K, Gurley TC, Kepler TB, Marshall DJ, Montefiori DC, Sutherland LL, Alam MS, Whitesides JF, Bowman CM, Permar SR, Graham BS, Mascola JR, Seed PC, Van Rompay KKA, Tomaras GD, Moody MA, Haynes BF. HIV DNA-Adenovirus Multiclade Envelope Vaccine Induces gp41 Antibody Immunodominance in Rhesus Macaques. J Virol. 2017 Nov 01; 91(21). PMID: 28794027.
- Published on 7/26/2017
Hwang JK, Wang C, Du Z, Meyers RM, Kepler TB, Neuberg D, Kwong PD, Mascola JR, Joyce MG, Bonsignori M, Haynes BF, Yeap LS, Alt FW. Sequence intrinsic somatic mutation mechanisms contribute to affinity maturation of VRC01-class HIV-1 broadly neutralizing antibodies. Proc Natl Acad Sci U S A. 2017 Aug 08; 114(32):8614-8619. PMID: 28747530.
- Published on 6/14/2017
Kepler TB. Unconventional Interrogation Yields HIV's Escape Plan. Cell Host Microbe. 2017 Jun 14; 21(6):659-660. PMID: 28618264.
- Published on 6/8/2017
Bradley T, Pollara J, Santra S, Vandergrift N, Pittala S, Bailey-Kellogg C, Shen X, Parks R, Goodman D, Eaton A, Balachandran H, Mach LV, Saunders KO, Weiner JA, Scearce R, Sutherland LL, Phogat S, Tartaglia J, Reed SG, Hu SL, Theis JF, Pinter A, Montefiori DC, Kepler TB, Peachman KK, Rao M, Michael NL, Suscovich TJ, Alter G, Ackerman ME, Moody MA, Liao HX, Tomaras G, Ferrari G, Korber BT, Haynes BF. Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge. Nat Commun. 2017 Jun 08; 8:15711. PMID: 28593989.
- Published on 5/16/2017
Cale EM, Gorman J, Radakovich NA, Crooks ET, Osawa K, Tong T, Li J, Nagarajan R, Ozorowski G, Ambrozak DR, Asokan M, Bailer RT, Bennici AK, Chen X, Doria-Rose NA, Druz A, Feng Y, Joyce MG, Louder MK, O'Dell S, Oliver C, Pancera M, Connors M, Hope TJ, Kepler TB, Wyatt RT, Ward AB, Georgiev IS, Kwong PD, Mascola JR, Binley JM. Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop. Immunity. 2017 May 16; 46(5):777-791.e10. PMID: 28514685.
- Published on 3/15/2017
Bonsignori M, Kreider EF, Fera D, Meyerhoff RR, Bradley T, Wiehe K, Alam SM, Aussedat B, Walkowicz WE, Hwang KK, Saunders KO, Zhang R, Gladden MA, Monroe A, Kumar A, Xia SM, Cooper M, Louder MK, McKee K, Bailer RT, Pier BW, Jette CA, Kelsoe G, Williams WB, Morris L, Kappes J, Wagh K, Kamanga G, Cohen MS, Hraber PT, Montefiori DC, Trama A, Liao HX, Kepler TB, Moody MA, Gao F, Danishefsky SJ, Mascola JR, Shaw GM, Hahn BH, Harrison SC, Korber BT, Haynes BF. Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies. Sci Transl Med. 2017 Mar 15; 9(381). PMID: 28298420.
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