Our goal is to make a lasting impact on human health and to continue being thrilled and challenged by our jobs. Biomedical research allows us to satisfy both goals. We wish to translate our skills and understanding of structural biology and immunology into vaccines for diseases. Particularly, we are enthusiastic about investigating the molecular basis of host-pathogen interactions and humoral immunity, with the goal of understanding how alterations in structure of particular antigens are linked with infection/disease and in taking advantage of this knowledge to develop novel prophylactic and therapeutic interventions. Identification of novel effective human antibodies against pathogens is revolutionizing our understanding of pathogen inhibition by the humoral immune system.

Structure of wild type 426c gp120 core with glVRC01 reveals molecular details with glycans surrounding the CD4BS, including N276.

HIV Vaccine

We aim to determine structures of the HIV-1 Env in complex with antibodies from infection or immunization/vaccination to better understand the immune response at the molecular level and to use the structural information to advance HIV vaccine design, which is a leading cause of mortality worldwide. Different approaches are being proposed to obtain an HIV-1 vaccine and we are focusing on using a germline-targeting approach. ~20% of HIV-1 infected patients can develop bNabs after years of infection. The VRC01-class bNabs target the conserved receptor CD4 binding site (CD4BS) on HIV-1 Env. Although isolated from distinct HIV-1-infected subjects, these bNabs share common features: gene usage, mode of recognition and use principally the Vgene encoded region for molecular recognition. As such, a germline targeting approach has been proposed to elicit these class of bNabs, where immunization with Env constructs designed to bind germline (gl) precursors of bNabs will initiate their development followed by booster immunizations with different recombinant Envs to guide their maturation. 426c is a unique strain of HIV that can bind glVRC01-class bNabs after removal of the N276 glycan, which has been proposed to be a major roadblock to elicit VRC01-class bNabs. Immunization strategies are needed to guide the immune response to recognize that glycan. My objective is to understand why inferred glVRC01-class antibodies bind the 426c strain, which is currently considered as a clinical product for HIV vaccine and to improve this immunogen and identify a booster immunogen. In collaboration with Dr. Stamatatos (Fred Hutch) and Dr. Veesler (UW), we determined that naturally occurring reduction of oligosaccharide near the CD4BS and sequence specific features were responsible for the unique ability of 426c Env to engage glVRC01. Our structural data showed that glVRC01 can bind short glycan (Man5) at residue N276 of HIV-1 gp120 (Borst et al, ELife, 2018). These results constitute a paradigm shift for the field and suggest that priming of VRC01-class bNabs might be initiated through interactions with Env proteins featuring a short glycan at position Asn276. We will be testing this hypothesis in collaboration with Dr. Stamatatos. We used a combination of cryo-EM and X-ray crystallography to determine the structures.

Graphic of structure-based vaccine approach.
Structural comparison of junctional epitope (new site of vulnerability) bound to a protective (CIS43) and a non-protective (CIS42) antibody targeting the PfCSP.

Malaria Vaccine

Recent discoveries that antibody can protect against malaria infection, at different stages of its life cycle, open new possibilities for structure-based vaccine approach. A candidate vaccine under development by GlaxoSmithKline, RTS,S-AS01, targets the pre-erythrocytic stage of the parasite (before it infects the hepatocytes in the liver). It is the most advanced malaria vaccine candidate to date, showing ~30% reduction in disease. RTS,S-AS01, contains a truncated version of the Plasmodium Falciparum (Pf) Circumsporozoite protein (CSP), the most abundant protein present at the surface of the Pf sporozoites (SPZ), essential for motility and entry into hepatocytes, fused to the hepatitis B surface antigen (HBsAg) (a multimer). The vaccine induces high antibody titers against the PfCSP and a moderate CD4+ T cell response. The correlates of protection remain unknown although it appears that antibody responses to the CSP repeat region prevented malaria sporozoites from infecting hepatocytes, its target cells. The structure of that vaccine candidate is at present unknown.

In collaboration with Dr. Seder at the VRC, NIH and other scientists, we described a new human protective antibody against PfCSP. We isolated protective and non-protective antibodies from a vaccinated individual with irradiated PfSPZ who was protected from controlled human malaria infection challenge. Our goals were to understand the host/pathogen interactions in the context of the humoral immune response that lead to protection after vaccination and to guide further immunogen improvement. We characterized a new site of vulnerability on PfCSP that is currently not included in the RTS,S vaccine. Structures of a protective and non-protective antibodies were obtained with peptides of the epitopes. We observed the antibodies bound different conformations of the same epitope. These molecular details are now being used to design immunogens, focusing on stabilizing the conformation of the peptide bound by the protective antibody, for a next generation CSP-based vaccine as part of a bigger consortium, which includes myself, Dr. Seder and collaborators at University of Washington (Dr. Baker, Dr. King and Dr. Pepper), funded by the Bill and Melinda Gates Foundation. The immunogens are being tested in an in vivo malaria challenge model in mice. My lab will structurally characterize the humoral immune response with their epitopes as well as obtain structural information of the designs.