Kevin O'Neil Saunders, PhD

Assistant 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

Wee, Edmund G., Nathifa A. Moyo, Kevin O. Saunders, Celia LaBranche, Filippo Donati, Silvia Capucci, Robert Parks, et al. “Parallel Induction of CH505 B Cell Ontogeny-Guided Neutralizing Antibodies and tHIVconsvX Conserved Mosaic-Specific T Cells against HIV-1..” Mol Ther Methods Clin Dev 14 (September 13, 2019): 148–60. https://doi.org/10.1016/j.omtm.2019.06.003.

PMID
31367651
Full Text

LaBranche, Celia C., Rory Henderson, Allen Hsu, Shay Behrens, Xuejun Chen, Tongqing Zhou, Kevin Wiehe, et al. “Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies..” Plos Pathog 15, no. 9 (September 2019). https://doi.org/10.1371/journal.ppat.1008026.

PMID
31527908
Full Text

Han, Qifeng, Julia A. Jones, Nathan I. Nicely, Rachel K. Reed, Xiaoying Shen, Katayoun Mansouri, Mark Louder, et al. “Difficult-to-neutralize global HIV-1 isolates are neutralized by antibodies targeting open envelope conformations..” Nat Commun 10, no. 1 (July 1, 2019). https://doi.org/10.1038/s41467-019-10899-2.

PMID
31263112
Full Text

Francica, Joseph R., Richard Laga, Geoffrey M. Lynn, Gabriela Mužíková, Ladislav Androvič, Baptiste Aussedat, William E. Walkowicz, et al. “Star nanoparticles delivering HIV-1 peptide minimal immunogens elicit near-native envelope antibody responses in nonhuman primates..” Plos Biol 17, no. 6 (June 2019). https://doi.org/10.1371/journal.pbio.3000328.

PMID
31206510
Full Text

LaBranche, Celia C., Andrew T. McGuire, Matthew D. Gray, Shay Behrens, Xuejun Chen, Tongqing Zhou, Quentin J. Sattentau, et al. “Correction: HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies..” Plos Pathog 15, no. 3 (March 2019). https://doi.org/10.1371/journal.ppat.1007646.

PMID
30913265
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Henderson, Rory, Brian E. Watts, Hieu N. Ergin, Kara Anasti, Robert Parks, Shi-Mao Xia, Ashley Trama, et al. “Selection of immunoglobulin elbow region mutations impacts interdomain conformational flexibility in HIV-1 broadly neutralizing antibodies..” Nat Commun 10, no. 1 (February 8, 2019). https://doi.org/10.1038/s41467-019-08415-7.

PMID
30737386
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Kisalu, Neville K., Azza H. Idris, Connor Weidle, Yevel Flores-Garcia, Barbara J. Flynn, Brandon K. Sack, Sean Murphy, et al. “Author Correction: A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite..” Nat Med 25, no. 1 (January 2019): 188–89. https://doi.org/10.1038/s41591-018-0315-0.

PMID
30552419
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Cheng, Cheng, Kai Xu, Rui Kong, Gwo-Yu Chuang, Angela R. Corrigan, Hui Geng, Kurt R. Hill, et al. “Consistent elicitation of cross-clade HIV-neutralizing responses achieved in guinea pigs after fusion peptide priming by repetitive envelope trimer boosting..” Plos One 14, no. 4 (2019). https://doi.org/10.1371/journal.pone.0215163.

PMID
30995238
Full Text

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