Humanity has taken on infectious agents, such as the virus that causes smallpox, and won. But cheer quietly. Smallpox eradication took 200 years, and it's just one of the many diseases out there.

But hey, researchers are nothing if not persistent, right?

That's true for the researchers in Mayo Clinic's Vector and Vaccine Engineering Laboratory. They are taking on some of humanity's biggest medical problems. Lab Director Michael Barry, Ph.D., has worked for almost 30 years on gene and virus therapies, but also on developing new vaccines against infectious diseases and for cancer.

Yes, cancer.

From left, Dr. Barry is the director of Mayo Clinic's Vector and Vaccine Engineering Laboratory. Their projects include working to develop gene therapies for propionic acidemia and kidney diseases and oncolytic virotherapies for cancer. Read more about their projects on the team's website.

Even though vaccines are generally associated with infectious diseases, the definition is broader. A vaccine is any agent that causes the immune system to remember a specific disease-causing entity, thereby preventing future infections. So, a vaccine for cancer might contain a protein specific to the cancer cells; or a protein linked to a bacterial infection with Clostridium difficile; or of course, a protein from a virus. And because the protein is just a small piece of the target organism, the vaccine can't cause that disease, but it's enough to ring alarm bells in the immune system.  

But how to get those proteins into the body safely?

COVID-19 and the power of amplification

Current COVID-19 vaccines deliver mRNA or DNA, but don’t amplify them, and the carrier vaccine, called a vector, dies out. That's called being a “replication defective” vaccine. In this case, one copy of the mRNA or DNA makes a certain amount of vaccine antigen. This antigen protein is what activates the immune system to produce protective antibodies and immune cells. More antigen generally means better protection. Making more antigen can also mean you can use less vaccine to get the same protection.

Dr. Barry and his team have been engineering new ways to get genes into cells and better yet, amplify those genes and the proteins that they produce. They’ve most recently applied this to SARS-CoV-2 using novel vaccine vectors called single-cycle adenoviruses. In contrast to replication-defective vaccines, the single-cycle vector amplifies that one copy of DNA up to 10,000 times in every cell. This can produce as much as 100 times as much antigen as a replication-defective vector.

“A real-world analogy of single-cycle is turning up the volume on your speaker to amplify the sound. If you extend this analogy, one might say current COVID-19 vaccines are set to volume 1 and we've cranked ours up to 11," explains Dr. Barry.

To be used as a vector, the adenovirus genome is altered. For SARS-CoV-2, it is generally the genes for the spike proteins (antigens) that are inserted into the vector genome (top row). When the spike genes are inserted and the vector's own genes for replication and assembly are left intact, that's called a replication-competent adenovirus and results in both the spike protein being made and infectious particles of the carrier virus. When the replication genes are removed, that's called a replication-defective adenovirus and it makes one antigen per vector. Examples of a vaccine using replication defective vector are Ad26.COV2.S from Johnson & Johnson, and the ChAdOx1 NCoV-19 from AstraZeneca. When spike proteins are inserted and just the assembly genes are removed, that's called a single-cycle vector and it 100 times more antigens produced per vector.

Testing Single-Cycle Vaccines

When Dr. Barry’s group saw that the single-cycle adenovirus vector could make 100 times more protein than benchmark replication-defective adenoviruses, they started dropping many different vaccine antigens into the vector and have tested them against infectious diseases and against cancer.

"We’ve tested it against HIV-1, influenza [pandemic in 2009]; Ebola virus [epidemic in 2014-2018]; Zika [outbreak in 2015 and ’16], and now against SARS-CoV-2," says Dr. Barry. "In most cases, we use these single-cycle vaccines as a single immunization. We also focus on delivering them at mucosal sites, because that’s where most pathogens enter your body. For example, SARS-CoV-2 usually enters your body in your nose or lungs. Therefore, delivering a SARS vaccine intranasally makes much more sense than injecting it into your muscle, where the virus rarely goes."

A lab member is purifying an adenovirus vector for preclinical testing.

They've also examined using this vaccine technology for cytomegalovirus, hepatitis C and the challenges hospitals face with MRSA and C. difficile infections. And, Dr. Barry realized, this was more than just useful for one thing, it was a platform — that is, the single-cycle adenovirus was a hub that could address a variety of needs.

To that end, and to advance development of a COVID-19 vaccine, Mayo Clinic Ventures has licensed the single-cycle adenovirus vaccine platform to a pharmaceutical company. Dr. Barry says that while he hopes the work will help bring the COVID-19 pandemic under control, it also lays the foundation for rapid responses to other emerging pathogens and pandemics.

"If single cycle can harness its 100-fold higher power in humans, it might allow one to use 100 times less vaccine per person," Dr. Barry explains. “This might also make it easier to deploy vaccines to other countries that are struggling to get COVID-19 and other vaccines to protect their people.”

— Sara Tiner, March 4, 2021

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