Engineering a Smart Messenger

This story originally appeared in Stanford Magazine.

smart messenger
SPECIAL DELIVERY: Swartz with a model of a VLP prototype. Photo: Linda Rice.

NEARLY 30 YEARS AGO, scientists began experiments on what seemed a promising pathway to vaccines of the future: virus-like particles (VLPs). By mimicking the mechanisms of a virus—organisms that actively navigate a host’s body and target specific cells inside—they believed they could engineer “smart” vaccine templates that could be tweaked to fight any number of maladies. But without any vaccines making it out of testing, the concept remained something of a laboratory pipe dream.

Until now. In a paper published last fall, Stanford chemical engineering and bioengineering professor James Swartz detailed how his lab has finally developed a functioning prototype.

Over the years, many trials used a design based on hepatitis B. That virus contains three layers, the innermost of which is called a capsid. Shaped like a spiky ball, the capsid is a hollow protein shell that carries the virus’s genome; once the virus infects a host cell, the capsid unfolds to release its payload and hijack the host.

Scientists reasoned that they could copy the capsid’s design but use it to human benefit.

However, as Swartz explains, “We saw a lot of variation from animal to animal when we tested [earlier] vaccines. We also saw a lot of weird things when we observed those particles we were making.” Trial vaccines were falling apart, becoming useless.

As it turns out, the capsid’s very ability to unfold made it unstable in the body. “I think that wasn’t fully appreciated,” muses Swartz. A natural virus’s two outer layers hold the capsid together until it’s inside a host cell, but the VLP lacked that structure.

After evaluating 10 possible strategies, Swartz and his lab identified a solution: By adding a reagent to their VLPs, they could build networks of stabilizing disulfide bonds across the particle’s surface. Once the capsid enters its target, the host cell will break apart those disulfide bonds, allowing the capsid to unfold and release its medical cargo. “That’s why we call this a smart particle,” Swartz says.

The other “smart” feature is the VLP’s guidance mechanism. Scientists had theorized that they could attach various molecules to a capsid’s spikes—either molecules to direct the VLP to find tumorous cells, or antigens (disease markers) to teach a person’s immune system to recognize and kill foreign bodies carrying those markers (as in a vaccine). But poor attachments between spike and antigen stymied their efforts, as did the immune system’s tendency to react to the VLP itself instead of the antigens. By altering the molecules at the tips of the capsid’s spikes and attaching a separate protein, Swartz engineered a VLP that circumvents both issues.

The resulting particle is stable, reproducible and versatile. Swartz is designing VLPs that attach to cancerous cells and then either emit light for diagnostic testing or release a tiny cargo of drugs to kill the malignant cells, leaving the surrounding area unharmed. The VLP also functions as a vaccine scaffold—a template to which scientists can attach any antigen they want. Swartz is using them to develop a vaccine against all known strains of the flu and for an HIV vaccine that’s almost ready for animal testing.

“In the meantime, there’s this Zika virus,” he adds. “We’ll probably be making a trial vaccine for that in the next few months as well.”