A (literally) multi-pronged viral vaccine approach

From the McGuire Lab, Vaccine and Infectious Disease Division

In today’s world of fast-paced scientific and medical innovation, it’s easy to forget that some of the most widespread pathogens affecting humanity still lack effective treatments or prevention strategies. Epstein-Barr virus (EBV), a double-stranded DNA herpes virus, epitomizes this reality. If you aren’t familiar with EBV, your body most likely is—the virus infects over 95% of people worldwide, and while it commonly causes relatively benign cases of mononucleosis (‘mono’), classic and emerging research has linked EBV to various cancers, rheumatoid arthritis, and even multiple sclerosis. Despite this, no treatment or vaccine for EBV exists. The McGuire Lab in the Vaccine and Infectious Disease Division at Fred Hutch has taken on this challenge, using state-of-the-art approaches in their efforts to develop a vaccine against EBV. In a recent paper published in Cell Reports Medicine, they present exciting progress towards this goal.

Among the different vaccine technologies available, so-called subunit vaccines—those that use pieces of pathogens (‘antigens’) as opposed to intact, attenuated pathogens to induce protective immunity —are valued for their safety and efficacy. Given the potentially oncogenic nature of EBV, most efforts at developing an EBV vaccine—including those of Dr. McGuire’s lab—are focused on this vaccine technology. However, this immediately presents an important consideration: which of the several EBV antigens would make for the most potent and effective vaccine? In their recent study, led by graduate student Harman Malhi, the team focused on gH/gL, a glycoprotein complex which the virus expresses on its surface and employs to induce fusion with host cells. Although this represents a departure from most previous and current vaccine trials, which focus instead on an EBV attachment protein called gp350, the team was confident in their choice of antigen primarily because of previous encouraging findings. More specifically, Dr. McGuire’s lab had isolated and characterized a host-produced antibody called AMMO1 which binds to gH/gL and prevents EBV from infecting both epithelial cells and B cells—its two target cell types. The fact that hosts produced such a potent antibody against gH/gL thus provided evidence that this could be a viable antigen for an EBV vaccine.

Armed with a vaccine strategy and a promising viral antigen, the McGuire team could have gone the ‘traditional’ route: produce a lot of gH/gL protein, use that protein to immunize animal models of EBV, and determine the vaccine’s efficacy at preventing EBV infection. Instead, they went a step further, leveraging state-of-the-art advances in protein engineering to design protein nanoparticles which display multiple copies of gH/gL in various three-dimensional arrangements. Collaborating with the labs of Dr. Barry Stoddard at the Hutch, Dr. Jim Olson at Seattle Children’s, and Dr. Neil King at the University of Washington, among others, Malhi et. al designed four such particles, displaying four, seven, 24, or 60 copies of gH/gL. After a monumental effort to produce and purify these gH/gL nanoparticles, the team appeared to have the odds stacked in their favor: a solid vaccine strategy, a new and promising viral antigen, and a state-of-the-art nanoparticle technology. But the most important question remained: would this be an effective vaccine?

Monochrome electron microscopy images show collections of EBV vaccine nanoparticles, which display different amounts of 'spokes' (gH/gL proteins) radiating from a central core.
Negative-stain electron micrographs of nanoparticle EBV vaccines from the McGuire Lab Image taken from the spotlighted study.

In this regard, the McGuire team report exciting results. Not only do their designed gH/gL nanoparticles induce EBV-neutralizing antibodies in mice, but they appear more effective at doing so than monomeric gH/gL. Moreover, when the researchers took their nanoparticle-elicited antibodies and transferred them into engineered EBV-susceptible mice, mice that received antibodies elicited by 60-mer gH/gL were protected from lethal doses of EBV, while those receiving monomer-elicited antibodies were not! Their findings thus solidify gH/gL nanoparticles as a promising EBV vaccine candidate and serve as a foundation for ongoing work testing the efficacy of these nanoparticles in a primate model of EBV.

This study also serves as an illustration that—even when things appear to have worked out in scientists’ favor—mother nature always has another curveball to throw. Specifically, when Malhi et al. identified the specific neutralizing antibodies elicited by their nanoparticle vaccines, they were surprised to find that AMMO1—the anti-gH/gL antibody previously identified by Dr. McGuire as being incredibly effective at neutralizing EBV infection—was only present in trace amounts. “I think this really highlights the complexity of host immune responses and opens new questions into how exactly these nanoparticle vaccines work,” mentions Dr. McGuire, “but it also gives us hope that these vaccines could be further improved by encouraging the production of AMMO1-like antibodies in response to gH/gL nanoparticles.” If I were EBV, I'd start getting nervous now. 

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member Dr. Andrew McGuire contributed to this study.

The spotlighted research was funded by the National Institutes of Health, the Bill & Melinda Gates Foundation, the Audacious Project, the Washington Research Foundation, and Project Violet.

Malhi, H., Homad, L. J., Wan, Y., Poudel, B., Fiala, B., Borst, A. J., Wang, J. Y., Walkey, C., Price, J., Wall, A., Singh, S., Moodie, Z., Carter, L., Handa, S., Correnti, C. E., Stoddard, B. L., Veesler, D., Pancera, M., Olson, J., King, N. P., McGuire, A. T. Cell Reports Medicine. 3(6).