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
Member of the Duke Human Vaccine Institute
Campus mail 2 Genome Court, 4074 Medical Science Research Building 2, Durham, NC 27710
Phone (919) 684-1503
Email address kevin.saunders@duke.edu

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

LaBranche, Celia C., Andrew T. McGuire, Matthew D. Gray, Shay Behrens, Peter D. Kwong, Xuejun Chen, Tongqing Zhou, et al. “HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies.” Plos Pathog 14, no. 11 (November 2018): e1007431. https://doi.org/10.1371/journal.ppat.1007431.

PMID
30395637
Full Text

Wiehe, Kevin, Kevin O. Saunders, Todd Bradley, Willam J. Faison, Connor Hart, Cindy Bowman, Ashley Trama, et al. “Targeted Selection of an Improbable HIV-1 Antibody Mutation Critical for Broadly Neutralizing Reactivity With a Designed Immunogen.” In Aids Research and Human Retroviruses, 34:58–58. MARY ANN LIEBERT, INC, 2018.

Scholars@Duke

Verkoczy, Laurent, Chuancang Jiang, Raiees Andrabi, Jinsong Zhang, Amanda Newman, Devin Sok, Ge Song, et al. “Mechanistic Insights Into Vaccine Induction of V2 Apex-directed, Heterologous Tier 2 Neutralizing Responses in CH103 UCA Knock-in Mice.” In Aids Research and Human Retroviruses, 34:110–110. MARY ANN LIEBERT, INC, 2018.

Scholars@Duke

Bonsignori, Mattia, Eric Scott, Kevin Wiehe, David Easterhoff, S Munir Alam, Kwan-Ki Hwang, David C. Montefiori, et al. “Dual Maturation Pathways from the Unmutated Common Ancestor of HIV-1 Envelope Broadly Neutralizing Antibodies Overcome Glycan Barriers.” In Aids Research and Human Retroviruses, 34:111–111. MARY ANN LIEBERT, INC, 2018.

Scholars@Duke

Williams, Wilton Bryan, R Ryan Meyerhoff, Hui Li, Priyamvada Acharya, Guillaume B. E. Stewart-Jones, Kevin Wiehe, Thomas B. Kepler, et al. “Macaque SHIV Induction of 2G12-like Broadly Neutralizing Antibodies.” In Aids Research and Human Retroviruses, 34:38–38. MARY ANN LIEBERT, INC, 2018.

Scholars@Duke

Wiehe, Kevin, Todd Bradley, R Ryan Meyerhoff, Connor Hart, Wilton B. Williams, David Easterhoff, William J. Faison, et al. “Functional Relevance of Improbable Antibody Mutations for HIV Broadly Neutralizing Antibody Development.” Cell Host Microbe 23, no. 6 (June 13, 2018): 759-765.e6. https://doi.org/10.1016/j.chom.2018.04.018.

PMID
29861171
Full Text

Pardi, Norbert, Michael J. Hogan, Martin S. Naradikian, Kaela Parkhouse, Derek W. Cain, Letitia Jones, M Anthony Moody, et al. “Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses.” J Exp Med 215, no. 6 (June 4, 2018): 1571–88. https://doi.org/10.1084/jem.20171450.

PMID
29739835
Full Text

Wang, Lingshu, Wei Shi, James D. Chappell, M Gordon Joyce, Yi Zhang, Masaru Kanekiyo, Michelle M. Becker, et al. “Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape.” J Virol 92, no. 10 (May 15, 2018). https://doi.org/10.1128/JVI.02002-17.

PMID
29514901
Full Text

Wang, L., W. Shi, J. D. Chappell, M. G. Joyce, Y. Zhang, M. Kanekiyo, M. M. Becker, et al. “Importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on the Middle East respiratory syndrome coronavirus spike glycoprotein to avoid neutralization escape.” Journal of Virology 92, no. 10 (May 1, 2018). https://doi.org/10.1128/JVI.002002-17.

Full Text

Kisalu, Neville K., Azza H. Idris, Connor Weidle, Yevel Flores-Garcia, Barbara J. Flynn, Brandon K. Sack, Sean Murphy, et al. “A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite.” Nat Med 24, no. 4 (May 2018): 408–16. https://doi.org/10.1038/nm.4512.

PMID
29554083
Full Text

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