SARS-CoV-2 Vaccines
Given the worldwide pandemic of COVID-19, caused by SARS-CoV-2 infection, and its devastating impact on public health, the economy, and our society, we are actively contributing to the development of a vaccine to prevent disease as well as transmission. We are working on a number of vaccine candidates designed to induce T cell and antibody responses to regions of SARS-CoV-2 important for mounting protective immunity. To do so we are utilizing a number of different platform approaches including DNA and RNA, as well as protein, the latter in collaboration with the Veesler and King labs at the UW. For delivery of DNA vaccines encoding SARS-CoV-2 antigens, we are using the gene gun technology described below. For delivery of RNA vaccines, in addition to evaluating gene-gun delivery, we are also using a lipid nanocarrier formulation developed by HDT Bio, a Seattle biotech startup. In order to enable rapid immune response to RNA-encoded antigens, we use replicating or self-amplifying RNA derived from the alphavirus, Venezuelan equine encephalitis virus. Upon delivery to the host cell, the amplification of messenger RNAs encoding the antigen-of-interest results in significantly higher protein production, allowing for dose sparing as well as rapid and robust immunogenicity. The Fuller lab is also evaluating heterologous DNA, RNA, and protein prime/boost regimens. An early front-runner in our preclinical vaccine development efforts, termed repRNA-CoV2S, is advancing into phase I clinical trials later this summer under the name HDT-301. Read more about the phase I clinical trials here.
Prophylactic & Therapeutic HIV Vaccines
The Fuller lab is focused on investigating therapeutic and prophylactic vaccines for HIV. These studies employ novel vaccines with an emphasis in DNA vaccines as well as delivery technologies, and new adjuvants designed to stimulate both systemic and mucosal antibody and T cell responses. Using the SIV macaque model for AIDS, we are investigating the ability of these vaccines to either prevent vaginal or rectal infection (prophylaxis) or reduce residual virus in the gut mucosa and provide a functional cure from AIDS when administered to chronically infected animals in combination with short-term treatment with antiretroviral drugs (immunotherapy). These studies also endeavor to define the role of mucosal responses, in particular, and other immune mechanisms underlying the response to vaccination, protection from infection, or induction of viral control.
Influenza Anti-virals & Vaccines
The Fuller laboratory is collaborating with the Baker lab at the Institute of Protein Design in two exciting projects: 1) Development of novel influenza antivirals and 2) investigating computational designed proteins as new immunogens for a universal influenza vaccine. For both projects, the overall goal is to achieve broad spectrum protection against a wide range of influenza variants including emerging strains with pandemic potential. Working closely with the Baker lab, our laboratory has shown that novel computationally designed proteins can potently inhibit influenza infection (antivirals) or when expressed as DNA vaccines, induce broadly reactive antibody (vaccines) in vivo. These projects are iterative and cutting edge with computational designed proteins generating unexpected and exciting effects on the control of influenza replication in vivo and results in vivo driving refinement and optimization of the protein design. Using both the mouse and ferret models of influenza infection, new projects include investigating a wider range of protein designs and defining the immunological and virological mechanisms underlying efficacy including the effects of the antivirals on resistant viruses and immune mechanisms of cross-protection induced by the computationally designed DNA vaccines.
Gene Gun Delivery of Nucleic Acid Vaccines
We developed the first Particle-Mediated Epidermal Delivery (PMED) device (or gene gun) to deliver plasmid DNA directly into cells in the highly immunocompetent skin tissue as a more effective approach for DNA vaccination. The Fuller lab has shown that PMED consistently induces strong immune responses and protection against HIV and a wide range of other viral infections. Furthermore, our lab was the first to show the ability of a DNA vaccine to induce protective levels of immunity in 100% of the vaccinated subjects in a human clinical trial. Previously, DNA vaccines administered by a needle and syringe uniformly failed in the clinic. Our findings showed the importance of efficient DNA vaccine delivery and prompted the field to develop other efficient DNA vaccine delivery approaches that are now showing significant promise in the clinic. To date, however, only PMED has consistently achieved induction of both T cell responses and protective levels of antibody in 100% of vaccinated subjects in a human clinical trial. The PMED device was optimized in my lab for use in both NHPs and humans. The device is needle-free, painless and produces only a mild, transient reaction at the delivery site.
Currently our research is focused on investigating novel engineering modifications to build upon the desirable aspects of the gene gun, as well as evaluating novel nucleic acid formulations to enhance vaccine gene expression and immunogenicity. To these ends, the Fuller lab has teamed up with Orlance Inc. in a long-standing collaboration on gene gun and NA vaccine technology research.
Zika Pathogenesis
The Fuller lab is also investigating Zika virus (ZIKV) pathogenesis in a non-human primate model to understand more about ZIKV infection in humans. These studies focus on evaluating immune responses elicited during ZIKV infection and their relationship to persistence or viral clearance in the host. Using the SIV macaque model, we are also investigating the impact that HIV co-infection may have on ZIKV pathogenesis, to determine if there is any risk to immunocompromised individuals. In addition, using these infection models we aim to evaluate potential therapeutic/prophylactic vaccine strategies for ZIKV. This research area is a key component of Dr. Megan O’Connor’s research program.
CD180-targeted Vaccines and Immunotherapy
The Fuller lab is collaborating with Abacus Bioscience, a local biotech company, on a vaccine platform targeting antigens to CD180. CD180 is a toll-like receptor expressed on antigen presenting cells B cell and dendritic cells. Ligation of CD180 induces B cell activation, resulting in proliferation, germinal center formation, affinity maturation, and rapid antibody production. We take advantage of this powerful signaling mechanism to develop vaccines that rapidly and robustly generate antibody and T cell responses through enhanced antigen presentation by CD180-activated antigen presenting cells. These vaccines consist of antigen-antibody conjugates produced through chemical conjugation of antigens to agonistic anti-CD180 antibodies. We have observed anti-CD180 conjugate vaccines to be more effective not only in young, immunocompetent mice and non-human primates, but also in aged and immunocompromised models, demonstrating the versatility of this vaccine platform. We are investigating CD180-targeted vaccines for protection from infectious disease, such as HBV, WNV, and SARS-CoV-2, as well as for cancer immunotherapy.