Contact

  • Academic
    phamd@stanford.edu
    University - Student Department: BioPhysics Position: Graduate

All Publications

  • Design of Epitope-Focused Vaccines via Epitope Cleavage. ACS central science Pham, D. M., Costello, R. M., Bruun, T. U., Kim, P. S. 2026; 12 (9): 1348-1359

    Abstract

    The design of epitope-focused immunogens that steer serum antibody responses toward epitopes targeted by broadly neutralizing antibodies (bnAbs) is a promising approach to develop broad-spectrum vaccines against pathogens with high genetic variability. Here, we introduce a strategy called epitope cleavage, which involves "cleaving" an epitope to steer antibodies away from it onto other regions of an antigen. We demonstrated the utility of epitope cleavage using two independent approaches: circular permutation and proteolytic cleavage. We first designed a sarbecovirus vaccine candidate by circularly permuting the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein; we next designed broad Ebolavirus immunogens by inserting the TEV protease cleavage site into the glycan cap of Ebola glycoprotein (GP) for site-specific epitope cleavage. By cleaving variable regions on each antigen, both the circular permuted RBD and cleaved GPs elicited antibodies with enhanced cross-reactivity to related viruses compared to unmodified antigen and exhibited a reduction in antibody responses toward the "cleaved" epitope. Our results present epitope cleavage as a vaccine design strategy that redirects antibody responses without compromising immunogenicity.

    View details for DOI 10.1021/acscentsci.6c00476

    View details for PubMedID 42799170

    View details for PubMedCentralID PMC13614085

  • Oriented Multivalent Display Drives Consistent Serum Immunodominance to the Ebola Virus Glycoprotein. ACS central science Zheng, C., Rubio, A. A., Vasquez, S., Pham, D., Pan, Z., Barnes, C. O., Kim, P. S. 2026; 12 (1): 100-110

    Abstract

    Despite the vast diversity of B cell repertoires, serum antibody responses during viral infection often focus on a limited set of epitopesa phenomenon known as immunodominance. This inherent bias establishes a hierarchy of epitope responses, which often facilitates viral immune evasion and presents a major challenge for universal vaccine design. It remains unclear whether serum immunodominance is primarily driven by antigen-intrinsic properties or by the spatial constraints imposed by virion-bound antigen presentation. Here, using Ebola virus glycoprotein (GP) as a model system, we found that trimeric GP elicited varied epitope hierarchies between individual animals during primary immunization. In contrast, multivalent GP presentation on either a vesicular stomatitis virus or ferritin nanoparticlesin the native orientation found on the Ebola viruselicited highly consistent and more refined epitope hierarchies across multiple mice and guinea pigs. These findings reveal a key role of oriented multivalent presentation in shaping serum immunodominance. The striking consistency of epitope hierarchy among individuals suggests that oriented multivalent presentation may promote more uniform immune protection at the population level, beyond increasing the magnitude of antibody binding and neutralizing responses.

    View details for DOI 10.1021/acscentsci.5c01886

    View details for PubMedID 41625225

    View details for PubMedCentralID PMC12856675

  • A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning. Nature communications Kim, S., Radford, C. E., Xu, D., Zhong, J., Do, J., Pham, D. M., Travisano, K. A., Filsinger Interrante, M. V., Bruun, T. U., Rezek, V., Wilder, B., Palomares, M., Seaman, M. S., Kitchen, S. G., Bloom, J. D., Kim, P. S. 2025; 16 (1): 4617

    Abstract

    Antibodies targeting the highly conserved prehairpin intermediate (PHI) of class I viral membrane-fusion proteins are generally weakly neutralizing and are not considered viable therapeutic agents. We previously demonstrated that antibodies targeting the gp41 N-heptad repeat (NHR), which is transiently exposed in the HIV-1 PHI, exhibit enhanced broad neutralization in cells expressing the Fc receptor, FcγRI. To enhance neutralization in cells lacking FcγRI, we here develop a bispecific antibody (bsAb) by fusing an NHR-targeting antibody to an antibody against CD4, the HIV-1 receptor on T cells. The bsAb provides a 5000-fold neutralization enhancement and shows unprecedented neutralization breadth compared to existing broadly neutralizing antibodies. Importantly, the bsAb reduces viral load in HIV-1-infected humanized male mice, and viral envelope sequencing under bsAb pressure revealed an NHR mutation that potentially impairs viral fitness. These findings validate the NHR as a potential HIV-1 therapeutic target, setting the stage for a new class of broadly neutralizing antibodies.

    View details for DOI 10.1038/s41467-025-60035-6

    View details for PubMedID 40383778

    View details for PubMedCentralID 2517140