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Kevin O'Neil Saunders, PhD

Assistant Professor in Surgery
Assistant Professor in the Department of Immunology
Office: 2 Genome Court, 4074 Medical Science Research Building 2, Durham, NC 27710
Campus Mail: DUMC Box 3020 Med Ctr, Durham, NC 27710

The Saunders laboratory aims to understand the immunology of HIV-1 antibodies and the molecular biology of their interaction with HIV-1 envelope (Env) glycoprotein. Our overall goal is to develop protective antibody-based vaccines; therefore, the laboratory has two sections–antibody repertoire analysis and immunogen design. Our research premise is that vaccine-elicited antibodies will broadly neutralize HIV-1 if they can bind directly to the host glycans on Env. However, Env glycans are poorly immunogenic and require specific targeting by a vaccine immunogen to elicit an antibody response.

Anti-glycan HIV-1 antibody biology. The laboratory utilizes single B cell PCR to probe the antibody repertoire during natural infection and after vaccination. Using this technique we identified two monoclonal antibodies from HIV Env vaccinated macaques called DH501 and DH502 that bind directly to mannose glycans and to HIV-1 envelope (Env). We have characterized these antibodies using glycan immunoassays, antibody engineering, and x-ray crystallography to define the mechanisms of Env-glycan interaction by these antibodies. Glycan-reactive HIV antibodies are rarely elicited with HIV-1 vaccination; therefore we have studied the ontogeny of DH501 using longitudinal next generation sequencing and reversion of somatic mutations within the antibody variable regions. DH501 and DH502 antibodies are mostly found in the repertoire as IgG2 and IgM isotypes—similar to known natural glycan antibodies. Therefore we are examining whether vaccines mobilize antibodies from the natural glycan pool that affinity mature to interact with HIV-1 envelope. The results of these studies inform us about the similarities and differences between vaccine-induced glycan-reactive antibodies and known broadly neutralizing HIV-1 antibodies from human natural infection. These comparative studies define the molecular biology of glycan-reactive antibodies as well as determine how close current vaccines are to inducing glycan-dependent broadly neutralizing antibodies.

HIV-1 Env immunogen design. The discovery of lineages of broadly neutralizing antibodies in HIV-infected individuals has provided templates for vaccine design. With knowledge of the antibodies we desire to elicit we can engineer the HIV-1 Env to preferentially bind to those antibodies. We discovered that Man9GlcNAc2 is the glycan preferred by early precursors in broadly neutralizing antibody lineages. We translated this finding into a vaccine design strategy that we have termed “glycan learning.” This approach modifies the glycosylation of HIV-1 Env immunogens to be the optimal glycan type for engagement of the precursor antibody of glycan-reactive broadly neutralizing HIV-1 antibody lineages. The Env glycosylation sites and glycan type are then modified on subsequent Env immunogens to select antibodies that are maturing towards a broadly neutralizing phenotype. We have developed cell culture procedures and purification strategies combined with mass spectrometry analyses to create Env immunogens with specific glycosylation profiles. While the overall goal is to elicit protective neutralizing antibodies in vivo, we use these Env antigens in vitro to investigate the biology of B cell receptor engagement. More specifically, we investigate the effects of various immunogen delivery platforms, such as protein or gold nanoparticles, nucleic acid, or recombinant viral vectors on B cell activation.

Taken together, our research program is an interdisciplinary approach to understanding the molecular biology underlying antibody recognition of glycoproteins in order to produce protective vaccines.

Education and Training

  • Ph.D., Duke University, 2010

Publications

Saunders, KO, Santra, S, Parks, R, Yates, NL, Sutherland, LL, Scearce, RM, Balachandran, H, Bradley, T, Goodman, D, Eaton, A, Stanfield-Oakley, SA, Tartaglia, J, Phogat, S, Pantaleo, G, Esteban, M, Gomez, CE, Perdiguero, B, Jacobs, B, Kibler, K, Korber, B, Montefiori, DC, Ferrari, G, Vandergrift, N, Liao, H-X, Tomaras, GD, and Haynes, BF. "Immunogenicity of NYVAC Prime-Protein Boost Human Immunodeficiency Virus Type 1 Envelope Vaccination and Simian-Human Immunodeficiency Virus Challenge of Nonhuman Primates." Journal of virology 92, no. 8 (April 2018).

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Saunders, KO, Verkoczy, LK, Jiang, C, Zhang, J, Parks, R, Chen, H, Housman, M, Bouton-Verville, H, Shen, X, Trama, AM, Scearce, R, Sutherland, L, Santra, S, Newman, A, Eaton, A, Xu, K, Georgiev, IS, Joyce, MG, Tomaras, GD, Bonsignori, M, Reed, SG, Salazar, A, Mascola, JR, Moody, MA, Cain, DW, Centlivre, M, Zurawski, S, Zurawski, G, Erickson, HP, Kwong, PD, Alam, SM, Levy, Y, Montefiori, DC, and Haynes, BF. "Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models." Cell reports 21, no. 13 (December 2017): 3681-3690.

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Williams, WB, Zhang, J, Jiang, C, Nicely, NI, Fera, D, Luo, K, Moody, MA, Liao, H-X, Alam, SM, Kepler, TB, Ramesh, A, Wiehe, K, Holland, JA, Bradley, T, Vandergrift, N, Saunders, KO, Parks, R, Foulger, A, Xia, S-M, 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, and Harrison, SC et al. "Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations." Nature communications 8, no. 1 (November 23, 2017): 1732-.

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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, and Haynes, BF. "HIV DNA-Adenovirus Multiclade Envelope Vaccine Induces gp41 Antibody Immunodominance in Rhesus Macaques." Journal of virology 91, no. 21 (November 2017).

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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, S-L, Theis, JF, Pinter, A, Montefiori, DC, Kepler, TB, Peachman, KK, Rao, M, Michael, NL, Suscovich, TJ, Alter, G, Ackerman, ME, Moody, MA, Liao, H-X, Tomaras, G, Ferrari, G, Korber, BT, and Haynes, BF. "Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge." Nature communications 8 (June 8, 2017): 15711-.

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Alam, SM, Aussedat, B, Vohra, Y, Meyerhoff, RR, Cale, EM, Walkowicz, WE, Radakovich, NA, Anasti, K, Armand, L, Parks, R, Sutherland, L, Scearce, R, Joyce, MG, Pancera, M, Druz, A, Georgiev, IS, Von Holle, T, Eaton, A, Fox, C, Reed, SG, Louder, M, Bailer, RT, Morris, L, Abdool-Karim, SS, Cohen, M, Liao, H-X, Montefiori, DC, Park, PK, Fernández-Tejada, A, Wiehe, K, Santra, S, Kepler, TB, Saunders, KO, Sodroski, J, Kwong, PD, Mascola, JR, Bonsignori, M, Moody, MA, Danishefsky, S, and Haynes, BF. "Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide." Science translational medicine 9, no. 381 (March 2017).

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Bonsignori, M, Kreider, EF, Fera, D, Meyerhoff, RR, Bradley, T, Wiehe, K, Alam, SM, Aussedat, B, Walkowicz, WE, Hwang, K-K, Saunders, KO, Zhang, R, Gladden, MA, Monroe, A, Kumar, A, Xia, S-M, 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, H-X, Kepler, TB, Moody, MA, Gao, F, Danishefsky, SJ, Mascola, JR, Shaw, GM, Hahn, BH, Harrison, SC, and Korber, BT et al. "Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies." Science translational medicine 9, no. 381 (March 2017).

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Easterhoff, D, Moody, MA, Fera, D, Cheng, H, Ackerman, M, Wiehe, K, Saunders, KO, Pollara, J, Vandergrift, N, Parks, R, Kim, J, Michael, NL, O'Connell, RJ, Excler, J-L, Robb, ML, Vasan, S, Rerks-Ngarm, S, Kaewkungwal, J, Pitisuttithum, P, Nitayaphan, S, Sinangil, F, Tartaglia, J, Phogat, S, Kepler, TB, Alam, SM, Liao, H-X, Ferrari, G, Seaman, MS, Montefiori, DC, Tomaras, GD, Harrison, SC, and Haynes, BF. "Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial." PLoS pathogens 13, no. 2 (February 24, 2017): e1006182-.

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Saunders, KO, Nicely, NI, Wiehe, K, Bonsignori, M, Meyerhoff, RR, Parks, R, Walkowicz, WE, Aussedat, B, Wu, NR, Cai, F, Vohra, Y, Park, PK, Eaton, A, Go, EP, Sutherland, LL, Scearce, RM, Barouch, DH, Zhang, R, Von Holle, T, Overman, RG, Anasti, K, Sanders, RW, Moody, MA, Kepler, TB, Korber, B, Desaire, H, Santra, S, Letvin, NL, Nabel, GJ, Montefiori, DC, Tomaras, GD, Liao, H-X, Alam, SM, Danishefsky, SJ, and Haynes, BF. "Vaccine Elicitation of High Mannose-Dependent Neutralizing Antibodies against the V3-Glycan Broadly Neutralizing Epitope in Nonhuman Primates." Cell reports 18, no. 9 (February 2017): 2175-2188.

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McCurley, NP, Domi, A, Basu, R, Saunders, KO, LaBranche, CC, Montefiori, DC, Haynes, BF, and Robinson, HL. "HIV transmitted/founder vaccines elicit autologous tier 2 neutralizing antibodies for the CD4 binding site." PloS one 12, no. 10 (January 2017): e0177863-.

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