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Kevin O'Neil Saunders, PhD

Associate Professor in Surgery
Assistant Professor in the Department of Immunology
Assistant Professor in the Department of Molecular Genetics and Microbiology
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

Gobeil, Sophie M-C, Rory Henderson, Victoria Stalls, Katarzyna Janowska, Xiao Huang, Aaron May, Micah Speakman, et al. “Structural diversity of the SARS-CoV-2 Omicron spike.” Mol Cell 82, no. 11 (June 2, 2022): 2050-2068.e6. https://doi.org/10.1016/j.molcel.2022.03.028.

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Lucier, Amanda, Youyi Fong, Shuk Hang Li, Maria Dennis, Joshua Eudailey, Ashley Nelson, Kevin Saunders, et al. “Frequent Development of Broadly Neutralizing Antibodies in Early Life in a Large Cohort of Children With Human Immunodeficiency Virus.” J Infect Dis 225, no. 10 (May 16, 2022): 1731–40. https://doi.org/10.1093/infdis/jiab629.

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Casazza, Joseph P., Evan M. Cale, Sandeep Narpala, Galina V. Yamshchikov, Emily E. Coates, Cynthia S. Hendel, Laura Novik, et al. “Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial.” Nat Med 28, no. 5 (May 2022): 1022–30. https://doi.org/10.1038/s41591-022-01762-x.

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Whitley, Jill, Christopher Zwolinski, Christian Denis, Maureen Maughan, Leonie Hayles, David Clarke, Meghan Snare, et al. “Development of mRNA manufacturing for vaccines and therapeutics: mRNA platform requirements and development of a scalable production process to support early phase clinical trials.” Transl Res 242 (April 2022): 38–55. https://doi.org/10.1016/j.trsl.2021.11.009.

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Li, Dapeng, Simon Brackenridge, Lucy C. Walters, Olivia Swanson, Karl Harlos, Daniel Rozbesky, Derek W. Cain, et al. “Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity.” Commun Biol 5, no. 1 (March 28, 2022): 271. https://doi.org/10.1038/s42003-022-03183-5.

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Mu, Zekun, Kevin Wiehe, Kevin O. Saunders, Rory Henderson, Derek W. Cain, Robert Parks, Diana Martik, et al. “mRNA-encoded HIV-1 Env trimer ferritin nanoparticles induce monoclonal antibodies that neutralize heterologous HIV-1 isolates in mice.” Cell Rep 38, no. 11 (March 15, 2022): 110514. https://doi.org/10.1016/j.celrep.2022.110514.

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Martinez, David R., Alexandra Schäfer, Sophie Gobeil, Dapeng Li, Gabriela De la Cruz, Robert Parks, Xiaozhi Lu, et al. “A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice.” Sci Transl Med 14, no. 629 (January 26, 2022): eabj7125. https://doi.org/10.1126/scitranslmed.abj7125.

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Saunders, Kevin O., Norbert Pardi, Robert Parks, Sampa Santra, Zekun Mu, Laura Sutherland, Richard Scearce, et al. “Author Correction: Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates.” Npj Vaccines 6, no. 1 (November 6, 2021): 136. https://doi.org/10.1038/s41541-021-00397-2.

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Williams, Wilton B., Kevin Wiehe, Kevin O. Saunders, and Barton F. Haynes. “Strategies for induction of HIV-1 envelope-reactive broadly neutralizing antibodies.” J Int Aids Soc 24 Suppl 7 (November 2021): e25831. https://doi.org/10.1002/jia2.25831.

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Martinez, David R., Alexandra Schäfer, Sarah R. Leist, Gabriela De la Cruz, Ande West, Elena N. Atochina-Vasserman, Lisa C. Lindesmith, et al. “Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice.” Science 373, no. 6558 (August 27, 2021): 991–98. https://doi.org/10.1126/science.abi4506.

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