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, Graduate Medical Sciences
- Member, Bioinformatics Graduate Program, Boston University
- Brandeis University, PhD
- University of Massachusetts Boston, BA
- Published on 12/11/2018
Bonsignori M, Scott E, Wiehe K, Easterhoff D, Alam SM, Hwang KK, Cooper M, Xia SM, Zhang R, Montefiori DC, Henderson R, Nie X, Kelsoe G, Moody MA, Chen X, Joyce MG, Kwong PD, Connors M, Mascola JR, McGuire AT, Stamatatos L, Medina-Ramírez M, Sanders RW, Saunders KO, Kepler TB, Haynes BF. Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier. Immunity. 2018 Dec 18; 49(6):1162-1174.e8. PMID: 30552024.
- Published on 7/25/2018
Ferdman J, Palladino G, Liao HX, Moody MA, Kepler TB, Del Giudice G, Dormitzer PR, Harrison SC, Settembre EC, Suphaphiphat P. Intra-seasonal antibody repertoire analysis of a subject immunized with an MF59®-adjuvanted pandemic 2009 H1N1 vaccine. Vaccine. 2018 08 23; 36(35):5325-5332. PMID: 30055967.
- Published on 5/31/2018
Wiehe K, Bradley T, Meyerhoff RR, Hart C, Williams WB, Easterhoff D, Faison WJ, Kepler TB, Saunders KO, Alam SM, Bonsignori M, Haynes BF. Functional Relevance of Improbable Antibody Mutations for HIV Broadly Neutralizing Antibody Development. Cell Host Microbe. 2018 06 13; 23(6):759-765.e6. PMID: 29861171.
- Published on 4/26/2018
Pavlovich SS, Lovett SP, Koroleva G, Guito JC, Arnold CE, Nagle ER, Kulcsar K, Lee A, Thibaud-Nissen F, Hume AJ, Mühlberger E, Uebelhoer LS, Towner JS, Rabadan R, Sanchez-Lockhart M, Kepler TB, Palacios G. The Egyptian Rousette Genome Reveals Unexpected Features of Bat Antiviral Immunity. Cell. 2018 05 17; 173(5):1098-1110.e18. PMID: 29706541.
- 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 01 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 11 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 08 08; 114(32):8614-8619. PMID: 28747530.
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