image title

ASU Biodesign scientists develop improved, potentially safer Zika vaccine

ASU takes a major step forward in boosting Zika prevention efforts.
August 9, 2017

Tobacco plant-produced vaccine could also be less costly, targeted for developing world

The worldwide Zika threat first emerged in 2015, infecting millions as it swept across the Americas. It struck great fear in pregnant women, as babies born with severe brain birth defects quickly overburdened hospitals and public health care systems.

In response, there has been a flurry of heroic scientific efforts to stop Zika.  Whole governments, academic labs and pharmaceutical companies have raced to develop Zika vaccines ever since global health experts first realized the dangers wrought by the mosquito-borne virus.

Now, Arizona State University has taken a major step forward in boosting Zika prevention efforts.

ASU Biodesign Institute scientist Qiang “Shawn” Chen has led his research team to develop the world’s first plant-based Zika vaccine that could be more potent, safer and cheaper to produce than any other efforts to date. 

“Our vaccine offers improved safety and potentially lowers the production costs more than any other current alternative, and with equivalent effectiveness,” said Chen, a researcher in the Biodesign Center for Immunotherapy, Vaccines and Virotherapy and professor in the School of Life Sciences. “We are very excited about these results.”

Rapid response network

Several potential Zika vaccines have had promising results in early animal and human tests. Last year, the Food and Drug Administration approved the first human testing of a Zika vaccine candidate, and this summer, a $100 million U.S. government-led clinical trial is underway.

But currently, there are no licensed vaccines or therapeutics available to combat Zika.

Several dedicated ASU scientists heeded the call to action, wanting to use their special know-how to find a way to overcome the pandemic crisis.

First, ASU chemist Alexander Green, along with collaborators at Harvard, developed a more rapid and reliable Zika test, an achievement highlighted by Popular Science in its “Best of What’s New” of 2016.

Now, Chen may have come up with a better vaccine candidate based on a key Zika protein. Chen is a viral expert who has worked for the past decade on plant-based therapeutics and vaccines against West Nile virus and dengue fever, which come from the same Zika family, called flaviviruses.

He honed in on developing a vaccine against a part of a Zika viral protein, called DIII, that plays a key role for the virus to infect people. 

“All flaviviruses have the envelope protein on the outside part of the virus. It has three domains. The domain III has a unique stretch of DNA for the Zika virus, and we exploited this to generate a robust and protective immune response that is unique for Zika,” Chen said.  

They first grew the envelope protein in bacteria, then switched to prepare the DIII protein domain in tobacco plants.

After developing enough material for the new vaccine candidate, Chen’s team performed immunization experiments in mice, which induced antibody and cellular immune responses that have been shown to confer 100 percent protection against multiple Zika virus strains in a mouse challenge.

Producing plant-based vaccines, especially in tobacco plants, is old hat for ASU researchers like Chen. For more than a decade, they’ve been producing low-cost vaccines in plants to fight devastating infectious diseases in the developing world.

It’s the same approach ASU plant research pioneer Charles Arntzen used when he played a key role in developing ZMapp, the experimental treatment used during the Ebola outbreak.

Artntzen’s Biodesign colleagues, including Chen, Hugh Mason and Tsafrir Mor, have continued to pursue plant-based vaccines and therapeutics to combat West Nile virus, dengue fever, nerve agents and even cancer.

Effective but not foolproof

While Chen has been cheering on Zika vaccine progress from other researchers, in each case there can be side effects.

To date, other scientists have tested several kinds of vaccines on mice — including one made from DNA and another from an inactivated form of the virus. With just one dose, both vaccines prompted the creation of antibodies that shielded the animals from becoming infected when they were exposed to the virus.

Any heat-killed vaccine runs the risk of accidentally injecting a live version of the virus if there is an error made in the vaccine production protocol. This tragic scenario happened occasionally with the polio vaccine.

For the second research group, they used the complete Zika envelope protein for their vaccine. Since envelope protein domains I and II are similar to West Nile and dengue viruses, this can cause a dangerous cross-reactive immune response.

“When you make the full native envelope protein as the basis for a vaccine, it will induce antibodies against DI, DII and the DIII domains of the protein,” Chen explained. “Those who have been prior exposed to DI and DII of other members of the Zika virus family may be prone to developing very bad symptoms, or in some cases, fatalities for dengue.”

In fact, animal experiments have shown that prior exposure to dengue or West Nile virus makes the Zika infection and symptoms much worse, suggesting a similar risk for people who had prior exposure to dengue (especially in South America, where it is more common).

“If you have prior exposure to dengue, and then have Zika exposure, the Zika infection may be much worse, and for men, may increase the likelihood of sexual transmission,” Chen said.

Chen’s protein-based vaccine uses the smallest and most unique part of the Zika virus that can still elicit a potent and robust immune response.

“In our approach, we make what we call a pseudovirus. It’s a fake virus. The pseudovirus displays only the DIII part of the envelope protein on the surface. This is at least as potent as previous vaccine versions.”

And he is very confident that his DIII-based protein vaccine will be safer.

“We did a test to make sure that the vaccine produces a potent protective immune response, but also, that it does not produce antibodies that may be cross-reactive for dengue, West Nile, yellow fever or others,” Chen said.

Fast track to the clinic

During the height of the Zika pandemic, whole countries of women were told not to become pregnant, due to babies born with a severe brain defect called microcephaly, in which the head and brain don't develop properly.

There have also been vision and hearing defects and learning disabilities associated with less severe infections.

To make matters worse, in adults, a debilitating nervous system condition called Guillain-Barre syndrome has also been shown to be caused by Zika.

While the most severe wave of the Zika pandemic has ebbed, it won’t go away anytime soon, and a vaccine still offers the best hope.

Tens of millions more could still be infected in the Americas in the coming years (see WHO fact sheet).

The ASU scientists were able to mobilize quickly from idea to proof-of-concept because they could leverage funds from an NIAID grant and seed funds from the Biodesign Institute.  

These are all made possible by generous federal, state and public support, including sales tax generated from the longtime Arizona innovation booster, voter-approved Proposition 301.

“This is a great example of the brightest minds quickly coming together, with public support, to take on one of the most significant public health challenges of our time,” said Josh LaBaer, executive director of the Biodesign Institute.

“That’s the essence of Biodesign at its best, and we hope this important proof-of-principal of a Zika vaccine can be translated quickly into the clinic.”

With the successful proof-of-principle, Chen hopes to partner with the medical community to begin the first phase of a human clinical trial in the next two years.

“Above all, we have to ensure the utmost safety with any Zika vaccine, especially because the people who will need it most, pregnant women, have the most worries about their own health, and the health of the fetus,” Chen said. “This has to be 100 percent safe and effective.”

Along with Chen, the research team included Ming Yang, Huafang “Lily” Lai and Haiyan Sun.

The research was published in the online version of Scientific Reports - Nature.

 

Top photo: ASU Biodesign Institute scientist Qiang “Shawn” Chen has led his research team to develop the world’s first plant-based Zika vaccine that could be more potent, safer and cheaper to produce than any other efforts to date.  

Joe Caspermeyer

Managing editor , Biodesign Institute

480-258-8972

 
image title

ASU grad student leads study estimating oxygen loss in ancient ocean

August 9, 2017

Oceanic extinction event 94 million years ago may be able to tell us about the future of today's seas, researchers say

A loss of oxygen in global ocean seawater 94 million years ago led to a mass extinction of marine life that lasted for roughly half a million years.

Scientists have found several potential explanations for how the loss of oxygen happened. These could include enhanced volcanic activity, increased nutrients reaching the ocean, rising sea levels, and warming sea and surface temperatures. But to point a finger at any one cause (or several of them) requires knowing how fast the oxygen loss happened.

A new technique, developed by Arizona State University graduate student Chad Ostrander (pictured above, right) with colleagues at Wood Hole Oceanographic Institution (WHOI) and Florida State University (FSU), has put a timetable on the oxygen loss associated with this major ocean extinction event, which is known to science as Oceanic Anoxic Event 2.

Their research was published today in the journal Science Advances.

"The project began when I was an undergraduate Summer School Fellow at Woods Hole," said Ostrander, a doctoral student at ASU's School of Earth and Space Exploration. His co-authors on the paper are Jeremy Owens at Florida State and Sune Nielsen at Woods Hole.

"We were able to track changes to the oxygen content of ancient seawater by measuring isotopes of thallium in ancient seafloor sediments," Ostrander explained. "Since the oxygen in the rocks we measure wouldn't really give any valuable information, we use thallium and other elements as stand-ins, or proxies."

This exposure of sediments in Italy includes a record in the black shales (dark diagonal layers) of the 94-million-year-old Oceanic Anoxic Event 2. Although these shales were analyzed by the team, the ocean-oxygen study focused primarily on core samples taken at sea because they preserved better the chemical evidence for ancient oxygen loss. Photo by Jeremy Owens/Florida State University

Sediments preserve the thallium isotope composition of seawater, which changes depending on the amount of oxygen in the deep ocean at the time they were deposited. The sediments pile up over time, with deeper levels corresponding to times further in the past.     

The sediments the team studied were organic-rich black shales collected as core samples by deep ocean drilling in 2003. The site was the Demerara Rise, a submarine plateau in the Atlantic Ocean off the coasts of Suriname and French Guiana.

"We dissolved the rocks in our lab," explained Ostrander, "and then chemically separated everything but thallium, the element we needed for analysis."

Then using mass spectrometry, the team measured variations in thallium within sedimentary rocks as a proxy for changes in oxygen levels over tens of thousands of years.

Based on the analysis, the researchers suspect that up to half of the deep ocean had become oxygen-depleted during Oceanic Anoxic Event 2, and remained so for about half a million years before it recovered.

"The loss of oxygen took 43,000 years to occur, plus or minus about 11,000," Ostrander said. "Call it 50,000 years or less."

The primary cause of Oceanic Anoxic Event 2 may have been increased nutrient delivery to the oceans, the researchers said. An increase in nutrients fuels the production of organic matter, and subsequent remineralization by bacteria feeding on it.

"It's this remineralization that is specifically responsible for the oxygen loss, because these bacteria consume oxygen in order to oxidize the organic, or carbon-bearing, matter," Ostrander said. "We see a similar scenario in the modern ocean, again due to increased nutrient delivery, but largely driven by fertilizers used in farming."

In fact, he said, "the largest 'dead zone' observed in the Gulf of Mexico is occurring right now for this very reason."

Adding nutrients to the ocean causes increased production of organic matter such as phytoplankton. When these die, they sink to the bottom as "marine snow" and decompose, consuming oxygen in the process. This is thought to be primarily responsible for large-scale oxygen loss in ancient oceans, leading to mass extinctions in the marine environment. The modern ocean exhibits similar symptoms. Image by Natalie Renier/WHOI

The researchers draw a distinct parallel between the rate of deoxygenation back then and modern trends in oceanic oxygen loss.

Said co-author Nielsen, "Our results show that marine deoxygenation rates prior to the ancient event were likely occurring over tens of thousands of years, and are surprisingly similar to the 2 percent oxygen depletion trend we're seeing induced by human-related activity over the last 50 years."

He added, "We don’t know if the ocean is headed toward another global anoxic event, but the trend is, of course, worrying."

Ostrander said, "At this point, we are only just beginning to understand how oxygen levels in the ocean have changed in the past. But with our new tool, we’ve already learned that one of the most extreme climate events in the sedimentary record provides an uncomfortably reasonable analog for possible future ocean oxygen loss and subsequent ecological shifts."

He added, "We hope to use this information to gain a better look into the short-, medium- and long-term future for oxygen content in today's oceans."

 

Top photo: Co-authors Sune Nielsen (left) of Woods Hole Oceanographic Institution and Chad Ostrander from Arizona State University working in the lab. Photo by Matt Barton/WHOI

Robert Burnham

Science writer , School of Earth and Space Exploration

480-458-8207