Bob

The human papillomavirus (HPV) vaccine was a landmark first in cancer prevention, protecting women against the virus that causes cervical cancers. Yet this life-saving vaccine and many others remain inaccessible to a large part of the developing world due to their high cost and need for refrigeration. Many have tried to overcome these barriers to universal vaccination, but thus far, all have fallen short.

Now BioFrontiers scientist Bob Garcea and collaborator, Ted Randolph, promise to finally break down these barriers with a fresh, cross-disciplinary approach. Blending their expertise in virology and chemical engineering, with a dash of ingenuity, they are redesigning low-cost, heat-stable vaccines with unprecedented success. Starting with HPV, their revolutionary vaccine designs could transform vaccine programs worldwide to serve regions that need them most.

VIROLOGY GURU

Bob Garcea

Bob Garcea has been a transformative force in vaccine development since the 1980s. By studying viral structures, he has discovered new ways to simplify vaccines that drastically reduce their cost and increase their reach. His discovery of virus-like particles (VLPs) led to next-generation vaccines that are more affordable and safer than traditional live attenuated or heat-killed virus vaccines, and have since become the new gold standard in vaccine design.

Now, Bob promises to revolutionize vaccines once again with his discovery of viral capsomeres. “You don’t need the whole VLP to elicit an immune response,” says Bob. “Building blocks of the viral shell, termed capsomeres, are just as good at sensitizing the immune system against HPV.” These capsomeres are so simple they can be churned out en masse by bacteria, whereas VLPs require more complex biological production systems that are four times as costly. In addition, complex VLP vaccines are unstable, requiring liquid suspension and refrigeration for preservation. Meanwhile, simple capsomeres are much more stable, lending themselves to a new heat-tolerant formulation.

While Bob had no experience with vaccine formulations himself, he knew someone in a neighboring lab who did. “Our BioFrontiers lab happened to be next to chemical engineers. They come at problems in a very different way than we do. For them, it’s about practicality,” says Bob. “In particular, Ted Randolph had developed a technique for thermo-stabilizing proteins in powder form.”

CHEMICALLY ENGINEERING DRUG FORMULATIONS

Ted Randolph

Ted Randolph specializes in the practical matters of converting molecular discoveries into viable treatments. Biological proteins are notoriously unstable, particularly when exposed to heat. Ted’s job is to prevent them from degrading throughout the manufacture, storage, and distribution processes. The stakes are high—any failures can compromise drug safety or efficacy, putting patients’ lives at risk.

“Meeting the stringent requirements for chemical and conformational stability during shelf life is a daunting task,” says Ted. Exploring how and why proteins go bad, he stabilizes them with chemical engineering solutions. His cutting-edge technique to freeze-dry proteins into powder form has achieved unprecedented heat-stability, enduring temperatures as high as 120 degrees Fahrenheit for 3 to 4 months.

“We brought our capsomeres over to Ted’s lab, and his team quickly made thermostable capsomere powders that equaled the ability of the current HPV vaccine to sensitize the immune system,” Bob says.

FROM DISCOVERY TO THE REAL-WORLD

Recognizing the revolutionary nature of their breakthrough, and its potential to finally overcome barriers to universal vaccination, the duo teamed up with Al Weimer of the Department of Chemical and Biological Engineering in a unique collaboration that secured a $1.1 million grant from the Bill & Melinda Gates Foundation in 2016. The three investigators work in the Jennie Smoly Caruthers Biotechnology Building (JSCBB) at CU Boulder, but their research areas have very different emphases, and the grant has helped them work together and collaborate to translate their discovery into real-world vaccines. “It’s really merging three different people with three different sets of expertise into one project,” Garcea says. Ted adds, “This formulation represents a breakthrough technology previously unattainable for vaccines, allowing for safe and effective distribution wherever needed.”

Bob and Ted also founded the spin-off company VitraVax Inc., turning to CU’s Technology Transfer Office in conjunction with the Innovation Center of the Rockies to get up and running. Offering essential guidance in identifying business drivers, finding equity support and licensing intellectual property, among other new challenges, these resources were instrumental in successfully launching the new venture.

IMPACTING GLOBAL HEALTH

With low-cost, heat-stable vaccines in a single dose, this BioFrontiers inspired team is aiming for the holy grail of vaccination. Their revolution in vaccine design would overcome the barriers to universal vaccination and save millions of lives, particularly in developing nations.

Current disparities in access to HPV vaccination deprive millions of women and men worldwide of this life-saving breakthrough in cancer prevention. “In cancer, an ounce of prevention is worth a pound of cure,” says Bob, explaining that HPV vaccination offers a more realistic strategy to save lives in areas without the resources for cervical cancer screening or treatments.

In addition, the team’s new technique could lead to new, more protective HPV vaccines by lowering R&D costs. “Although a majority of HPV-related cancers result from HPV16 and 18 infections, another 15 different strains can be oncogenic,” Bob says, “Our ability to fight this disease is currently limited by manufacturing and distribution costs as well as the breadth of coverage.”

Beyond HPV, the team is laying the foundation for an entirely new paradigm in vaccinology that could impact all vaccines. “Our decades of work aimed at better HPV vaccines may become more about a process than a product—a way of making many types of vaccines rather than a single vaccine itself,” Bob explains. With their elegant combination of virology and chemical engineering, Bob and Ted’s next-generation vaccines have the potential to rewrite the book on disease prevention worldwide. Their admirable work exemplifies the BioFrontiers mission to drive medical advances through innovative cross-disciplinary science.


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Vaccines are crucial to the health of millions in developing countries, but timely delivery of these lifesaving immunizations has always been hindered by the need for refrigeration.  Now, a unique interdisciplinary collaboration at CU Boulder’s BioFrontiers Institute aims to change that.

Professors Robert Garcea, Theodore Randolph and Al Weimer specialize in different areas of biochemistry; but recently, the trio banded together on a multiyear effort to develop shelf-stable, nonperishable vaccines that can be stored at high temperatures for months rather than days.

If successful, such an advancement would radically ease the difficult task of distributing immunizations to rural hospitals and population centers.

The magnitude of the challenge requires a wide range of skill sets and ideas, something that the researchers were all too happy to take on.  “It’s really merging three different people with three different sets of expertise into one project,” Garcea said.

In Garcea’s lab, investigators work on new vaccines such as those for human papillomavirus (HPV), a leading cause of cervical cancer that is particularly devastating to women in developing countries.

One corridor away, Randolph’s team, which focuses on creating stable dosage forms for therapeutic proteins and vaccines, developed a process for making vaccines thermostable, or resistant to damage from heat or cold. In its final form, this vaccine resembles a glassy powder.

The two began collaborating about two years ago and even formed a spinoff company, Vitravax Inc., which has seen encouraging results in mice thus far.

Weimer contributed the final piece of the puzzle.  His lab coats the vaccine microparticles with protective layers of aluminum oxide, a process known as atomic layer deposition.  This nanometer-thick barrier shields the vaccine particles while helping trigger the body’s immune response.

The trio are now forming extended-release vaccine dosage forms.  When the formulation is injected, the outer layer provides an initial vaccine dose.  Next, the aluminum oxide layer slowly dissolves, eventually releasing the inner core, which acts as a second dose of vaccine.  Patients receive their second or third “dose” without ever knowing it and without a return trip to the doctor.

Individual results have been promising, but scaling from test batches in the lab to manufacturing millions of vaccines for public use is a challenging process that might not succeed quickly—or at all.  “We’ve done many of the individual parts of this project,” Randolph said.  “Now we’ve got to put those pieces together and have it work.”

Still, the professors say they are optimistic about the collaboration, which might never have happened if not for their proximity on CU Boulder’s East Campus and the interdisciplinary mission of the BioFrontiers Institute, which drives innovation by combining researchers from different fields.

“One of the hopes of the BioFrontiers Institute is that investigators will, by their proximity, do new and interesting things,” Garcea said.  “In a sense, we’ve fulfilled the mission. If the technology works, we’ve really fulfilled the mission.”

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The University of Colorado Boulder has received a $1.1 million grant from the Bill & Melinda Gates Foundation to develop next-generation vaccines that require no refrigeration and defend against infectious diseases with just one shot.

If successful, those advancements could radically transform the difficult task of dispensing life-saving immunizations in developing countries — and improve convenience in every part of the world.

Professor Bob Garcea of the Department of Molecular, Cellular and Developmental Biology and the BioFrontiers Institute has teamed up with Professors Ted Randolph and Al Weimer of the Department of Chemical and Biological Engineering in a unique collaboration that applies a wide range of skillsets and ideas to the pressing challenge of delivering vaccines to patients in developing countries.  All three investigators work in the Jennie Smoly Caruthers Biotechnology Building (JSCBB) at CU Boulder, but their research areas have very different emphases.

“It’s really merging three different people with three different sets of expertise into one project,” Garcea said.

In Garcea’s lab, located in the Jean and Jack Thompson Vaccine Research Laboratories of the JSCBB, investigators work on new vaccines such as those for human papillomavirus, a leading cause of cervical cancer that is particularly devastating to women in developing countries.

One corridor away, Randolph’s team, which focuses on creating stable dosage forms for therapeutic proteins and vaccines, developed a process for making vaccines thermostable, or resistant to damage from heat or cold.  In this glassy powder state, the vaccine can be stored at temperatures as high as 120 degrees Fahrenheit for three to four months without losing efficacy, Randolph said.

The two began collaborating about two years ago and even formed a spinoff company, Vitravax Inc., which is seeing successful results in vaccine studies conducted in mice.

The Gates Foundation grant will take these innovations a step further by combining the thermostable vaccine powders with techniques developed in the Weimer lab that allow uniform nanoscopic protective layers of aluminum oxide to be applied to vaccine microparticles.  This coating process, called atomic layer deposition, not only provides a nanometer-thick protective barrier for the vaccine particles but also helps trigger the body’s immune response.

The trio is now forming extended release, multilayer microparticulate vaccine dosage forms, composed of an inner core of stabilized vaccine coated with aluminum oxide layers and an outer layer of vaccine, all embedded in a glassy powder. When the formulation is injected, the outer layer provides an initial vaccine dose.  Next, the aluminum oxide layer slowly dissolves, eventually releasing the inner core which acts as a second dose of vaccine.  Patients receive their second or third “dose” without ever knowing it and without a return trip to the doctor.

Although each step of the process has worked independently, researchers cautioned that moving from small test batches in the lab to manufacturing millions of vaccines for public use is a challenging process that may not succeed quickly – or at all.

“We’ve done many of the individual parts of this project,” Randolph said.  “Now we’ve got to put those pieces together, and have it work.”

Still, investigators say they’re optimistic about the collaboration, which might never have happened if not for their proximity on CU-Boulder’s East Campus and the interdisciplinary mission of the BioFrontiers Institute, which seeks to drive innovation by combining researchers from different fields.

“One of the hopes (of the BioFrontiers Institute) is that investigators will, by their proximity, do new and interesting things,” said Garcea, who is a member of the Institute.  “In a sense, we’ve fulfilled the mission. If the technology works, we’ve really fulfilled the mission.”

The Randolph and Weimer Labs are part of the Department of Chemical and Biological Engineering.  The Garcea lab is part of the Department of Molecular, Cellular and Developmental Biology at CU Boulder and the BioFrontiers Institute.  At the University of Colorado BioFrontiers Institute, researchers from the life sciences, physical sciences, computer science and engineering are working together to uncover new knowledge at the frontiers of science and partnering with industry to make their discoveries relevant.

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