Viruses From Plants/Bacteria Key Ingredient for New COVID-19 Vaccine Candidates

These fridge-free COVID vaccines are grown in plants and bacteria

Nanoengineers at the University of California San Diego have developed COVID-19 vaccine candidates that can withstand the heat. Their main ingredients? Viruses from plants or bacteria.

The new refrigerator-free COVID-19 vaccines are still in the early stages of development. In mice, the vaccine candidates caused a high production of neutralizing antibodies against SARS-CoV-2, the virus that causes COVID-19. If proven safe and effective in humans, the vaccines could be a big game changer for global distribution efforts, including those in rural areas or poor communities.

“The exciting thing about our vaccine technology is that it is thermally stable, so it can easily reach places where it is not possible to fit ultra-low-temperature freezers or drive trucks with these freezers,” said Nicole Steinmetz, a nanoengineering professor and director. from the Center for Nano-ImmunoEngineering at UC San Diego Jacobs School of Engineering.

The vaccines are detailed in an article published today (Sept. 7, 2021) in the Journal of the American Chemical Society.

The researchers created two COVID-19 vaccine candidates. One is made from a plant virus called the cowpea mosaic virus. The other is made of a bacterial virus, or bacteriophage, called Q beta.

Both vaccines are made with similar recipes. The researchers used cowpea plants and E. coli bacteria to grow millions of copies of the plant virus and bacteriophage, respectively, in the form of spherical nanoparticles. The researchers collected these nanoparticles and then attached a small piece of the SARS-CoV-2 spike protein to the surface. The finished products look like a contagious virus for the immune system to recognize, but they are not contagious in animals and humans. The small piece of spike protein attached to the surface stimulates the body to mount an immune response against the coronavirus.

The researchers note several advantages of using plant viruses and bacteriophages to make their vaccines. First, they can be easily and cheaply produced on a large scale. “Growing plants is relatively easy and requires a not-too-advanced infrastructure,” says Steinmetz. “And fermentation with bacteria is already an established process in the biopharmaceutical industry.”

Another major advantage is that the plant virus and bacteriophage nanoparticles are extremely stable at high temperatures. This allows the vaccines to be stored and shipped without having to be kept refrigerated. They can also undergo manufacturing processes that use heat. The team uses such processes to package their vaccines into polymer implants and microneedle patches. These processes involve mixing the vaccine candidates with polymers and fusing them together in an oven at temperatures around 100 degrees Celsius. Since the plant virus and bacteriophage nanoparticles can be mixed with the polymers right from the start, it is easy and straightforward to make vaccine implants and patches.

The goal is to give people more options to get a COVID-19 vaccine and make it more accessible. The implants, which are injected under the skin and slowly release the vaccine over the course of a month, only need to be administered once. And the microneedle patches, which can be worn on the arm without pain or discomfort, would allow people to administer the vaccine themselves.

“Imagine if vaccine patches could be sent to the mailboxes of our most vulnerable people, instead of leaving their homes at risk,” said Jon Pokorski, a professor of nanoengineering at the UC San Diego Jacobs School of Science. Engineering, whose team developed the technology to make the implants and microneedle patches.

“If clinics could offer a single-dose implant to those who would have a really hard time getting their second injection, that would protect a larger segment of the population and we’d have a better chance of stopping the transmission.” Pokorski added. , who is also a founding member of the faculty of the university’s Institute for Materials Discovery and Design.

In tests, the team’s COVID-19 vaccine candidates were administered to mice via implants, microneedle patches, or as a series of two shots. All three methods produced high levels of neutralizing antibodies in the blood against SARS-CoV-2.

Potential Pan-Coronavirus Vaccine

Those same antibodies also neutralized against the SARS virus, the researchers found.

It all comes down to the bit of the coronavirus spike protein attached to the surface of the nanoparticles. One of these pieces Steinmetz’s team chose, called an epitope, is nearly identical between SARS-CoV-2 and the original SARS virus.

“The fact that neutralization is so profound with an epitope so well conserved under another deadly coronavirus is remarkable,” said study co-author Matthew Shin, a nanoengineering Ph.D. student in Steinmetz’s lab. “This gives us hope for a potential pan-coronavirus vaccine that could protect against future pandemics.”

Another advantage of this particular epitope is that it is not affected by any of the SARS-CoV-2 mutations reported to date. That’s because this epitope comes from a region of the spike protein that doesn’t bind directly to cells. This is different from the epitopes in the currently administered COVID-19 vaccines, which come from the binding region of the spike protein. This is a region where many of the mutations have occurred. And some of these mutations have made the virus more contagious.

Epitopes from a non-binding region are less likely to undergo these mutations, explains Oscar Ortega-Rivera, a postdoctoral researcher in Steinmetz’s lab and the study’s lead author. “Based on our sequence analyses, the epitope we chose is highly conserved among the SARS-CoV-2 variants.”

This means the new COVID-19 vaccines could potentially be effective against the variants of care, Ortega-Rivera said, and tests are currently underway to see what effect they have against, for example, the Delta variant.

Plug and play vaccine

Another thing that makes Steinmetz really excited about this vaccine technology is the versatility it offers to create new vaccines. “Even if this technology has no impact on COVID-19, it can be quickly adapted for the next threat, the next virus X,” Steinmetz said.

Making these vaccines, she says, is “plug and play:” grow plant virus or bacteriophage nanoparticles from plants or bacteria, then attach a piece of the target virus, pathogen, or biomarker to the surface.

“We use the same nanoparticles, the same polymers, the same equipment and the same chemistry to put it all together. The only variable is actually the antigen we stick to the surface,” says Steinmetz.

The resulting vaccines do not need to be kept cold. They can be packaged in implants or microneedle patches. Or they can be administered directly in the traditional way via shots.

Steinmetz and Pokorski’s labs have used this recipe in previous studies to create vaccine candidates for diseases such as HPV and cholesterol. And now they’ve shown that it also works for making COVID-19 vaccine candidates.

Next steps

The vaccines still have a long way to go before they enter clinical trials. In the future, the team will test in vivo whether the vaccines protect against infection by COVID-19, as well as its variants and other deadly coronaviruses.

Reference:: “Trivalent Subunit Vaccine Candidates for COVID-19 and Their Delivery Devices” September 7, 2021, Journal of the American Chemical Society.
DOI: 10.1021/jacs.1c06600

Co-authors include Angela Chen, Veronique Beiss, Miguel A. Moreno-Gonzalez, Miguel A. Lopez-Ramirez, Maria Reynoso and Joseph Wang, UC San Diego; Hong Wang and Brett L. Hurst, Utah State University.

This work was funded in part by a National Science Foundation, both through a RAPID grant (CMMI-2027668) and through the UC San Diego Materials Research Science and Engineering Center (MRSEC, grant DMR-2011924).

Disclosure: Nicole Steinmetz and Jon Pokorski are co-founders of and have a financial interest in Mosaic ImmunoEngineering Inc. All other authors declare no competing interests.