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Principal Investigator: SCOTT W WONG
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2024
Award: $1,212,634
Funding agency: National Cancer Institute
SUMMARY
The overall goals of this U01 application are two-fold. First, to investigate two potential KSHV targets, one
structural and one non-structural, to determine if these two targets are capable of protecting vaccinated animals
from infection. And, the second, to compare two vaccine strategies to stimulate immune responses to the KSHV
antigens. The first approach utilizes mRNA-lipid nanoparticles (mRNA-LNPs) vaccines, the widely used vaccine
strategy that has proven capable of inducing protective immunity against SARS-CoV2. The second approach
employs a novel vaccine strategy that targets CD180, a toll-like receptor (TLR) expressed on antigen presenting
cells (APCs) that can stimulate robust immune responses to conjugated antigens, even in the context of immune
suppression. To accomplish these goals, we will utilize the rhesus macaque rhadinovirus (RRV)/rhesus macaque
(RM) model of KSHV-like infection to evaluate the KSHV targets and compare the immune responses induced
by the mRNA-LNPs and targeted CD180 vaccine platform. The innovation and strengths of this application are
several and include the collaboration formed amongst the principal investigator, and co-investigators from the
biotechnology sector (Abacus Bioscience), whose company's focus is on a novel targeted CD180 vaccine
platform (anti-CD180) capable of inducing robust immune responses to conjugated antigens in rodents and
nonhuman primates (NHPs), and academic co-investigator, whose expertise is on the characterization of primate
antibody-mediated function. Importantly, data presented in the preliminary studies section supports this
application as 1) CD180 is expressed on multiple B cell lineages, dendritic cells and monocytes, similar to that
shown in humans. 2) fusion of an antigen to agonist anti-CD180 antibody (aCD180) provides the simultaneous
antigen delivery and activation of the APC, resulting in a potent antigen-specific IgG production and expansion
of activated antigen-specific T cells in immunocompetent and immune suppressed animals. 3) we have
successfully expressed two recombinant aCD180-KSHV antigen complexes (aCD180-K8.1 ectodomain and
aCD180-KSHV vIL6) to evaluate in vitro and in vivo. 4) we have established an oral challenge model for RRV
infection, that results in virus infection. 5) we have created the necessary chimeric KSHV/RRV recombinants
pseudotyped with KSHV glycoprotein K8.1 or a recombinant RRV encoding KSHV vIL-6 in place of RRV vIL-6.
These chimeric RRV recombinants can infect and establish latent infections in RM, identical to wild-type RRV.
Thus, the overall goals are to compare state-of-the-art mRNA-LNPs to the novel anti-CD180 platform to
stimulate an anti-K8.1 and anti-vIL6 immune responses in immune competent and SIV-infected RM prior to oral
RRV challenge/infection. The overall hypothesis is immunization targeting KSHV proteins will develop cell and
humoral immune responses against viral antigens. This direct head-to-head comparison serves as a necessary
prerequisite to evaluating either vaccine platform in RM prior to clinical evaluation in humans.
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