Inventors take portfolio strategy to combat next virus outbreak

April 4, 2021
A new drug to treat EEE is showing a lot of promise. (AP Photo/Rick Bowmer)

A new drug to treat EEE is showing a lot of promise. (AP Photo/Rick Bowmer)

The nightmare of COVID-19 spurred a wake-up call among immunologists, leading several experts to band together and create a list of 100 organisms most likely to cause the next pandemic. Having steadily conjured treatment and prevention routes for dozens, their most recent achievement surrounds a protein molecule that targets the deadly virus Eastern equine encephalitis.

The molecule, which has been tested in mice, could make for a three-fold solution: preventing infection in healthy individuals, preemptively protecting those who were exposed and treating others who fully exhibit symptoms.

"Part of the beauty of these molecules is, for people who are already infected, they can be used as treatments; and for people who are at risk, they can be used as prevention," said James E. Crowe Jr., director of the Vanderbilt Vaccine Center, a professor in Vanderbilt University's pathology, microbiology and immunology department and the lead of the initiative Ahead 100

The initiative, which was started in Crowe's lab, led to the molecule he says could protect against and treat Eastern equine encephalitis, or EEE. An application to patent the molecule was published March 4 by the World Intellectual Property Organization.

Referencing foundational research published in August 2020 in Cell Host & Microbe, Crowe relayed to The Academic Times that in mice, "treatment was very effective and prevention was 100% effective." 

Fatal and often the cause of debilitating consequences such as lasting brain damage, Eastern equine encephalitis is primarily a concern only in the U.S. and manifests in about 10 cases per year. Its variants, Western equine encephalitis and Venezuelan equine encephalitis, also don't affect a significant number of people. 

But the numbers may not paint a full picture of the virus' potential impact in the future. Crowe noted the way the pathogens behind COVID-19 were thought of a few years ago, before the pandemic hit.

"We knew about SARS and MERS, and we knew about viruses like SARS-CoV2," he said. "And yet, we did not invest in them."

Crowe and his fellow researchers aren't only advocating that the medical community devote more focus to the mosquito-borne virus, but also requesting that it be viewed in the context of the other 99 organisms on their ledger of pandemic-prone pathogens. 

The team has filed more than 30 additional patent applications regarding potential therapies for diseases such as Hendra virus, Nipah virus, Rift Valley fever and Crimean-Congo hemorrhagic fever.

"We've spent some time working through the literature and assessing which types of pathogens have the potential to cause epidemics," Crowe said. "Instead of waiting until an epidemic occurs, and then scrambling as fast as we can to find a solution, we're thinking to be proactive instead."

Despite the miraculous speed with which scientists were able to address COVID-19, Crowe argues that it was still too slow: While the medications and vaccines were being processed and distributed, 2.79 million people worldwide lost their lives to the disease.

The researchers hope to receive funding for their entire swath of patented molecules at once, increasing the likelihood of having a viable drug available to scale up whenever the next pandemic arrives, and for whichever virus causes it.

"The philosophy is very similar to investing," Crowe said. "If you look at investment strategies, people who try to pick individual stocks — no matter how smart they are — they always lose money, or virtually always lose money." But with a mutual fund index, which involves multiple stocks, the value typically goes up. 

"It's a much more successful way to predict an uncertain future outcome," Crowe said. Betting simultaneously on so many potential epidemic- and pandemic-starters would make the investment worth it when the time comes, he argues.

It would take approximately 18 months to conduct safety and toxicity tests, then make the drug available for humans, Crowe said. Those tests are vital, as human or non-human primate toxicity testing is much more indicative of safety for human use than are tests on mice.

Because of Eastern equine encephalitis' potential as a biological weapon, the U.S. Department of Defense offered some funding to the team, Crowe noted, prior to its receipt of funding from the National Institutes of Health.

In the 20th century, nation-states such as the Soviet Union and the U.S. were working on developing spreadable viruses for bioterrorism. Eventually, the virus was turned into an aerosolized spray and tested on animals. It threatened immediate death, as the spray would enter through nasal pathways of victims that breathed it in, going directly to the brain.

"The DOD is concerned about the biowarfare, bioterrorism applications, and the NIH is concerned about the normal route where people get infected just living in the northeast United States," Crowe explained.

Some experimental vaccines exist for the virus and its variants, but are only available for soldiers in high-risk areas or academics working on studying the diseases. They aren't available commercially.

Crowe's new molecule-based treatment would theoretically work in people by placing synthetic, lab-generated antibodies into a human. First, an individual who has been infected with Eastern equine encephalitis would be identified and asked to be a volunteer. Because this person already battled the disease, their body would be in fight-mode thanks to the possession of many antibodies, which are like the body's weapons against viruses.

Then, scientists could extract immune cells containing those antibodies, called B-cells. They would use next-generation sequencing to locate the genes from those antibodies, copy them and make identical antibodies in huge amounts. It's like using a printer, but with DNA.

"We can actually make — in the lab or in a factory — the same antibody that the person was making in their body," said Crowe. "Instead of having to harvest over and over from the person … we can make as much as we want, forever. And it's always the same."

After being synthesized, these antibodies could be injected into someone who needs treatment, prevention or a prophylactic option to stop the virus in its path. Because the antibodies are ready-made, patients wouldn't have to create any on their own, meaning the effect would happen very quickly.

"They get instant immunity, so you don't have to wait six weeks to become immune," Crowe said. "Within a few hours, the antibody circulates in your body and your immune system." 

The team is using monoclonal antibodies, which are designed by researchers to mimic the body's immune response, in the same way natural antibodies would. In contrast, a vaccine would prompt the body to generate its own natural antibodies.

"The word vaccine is a complicated word, but most people do not consider what we do vaccines," Crowe said. "We are working on antibodies."

To the team's surprise, it turned out that Eastern equine encephalitis was not the only target for its molecule. Some of the antibodies were cross-reactive for the Venezuelan variant, and other members of the alphavirus group it belongs to. 

This offers promise that one of these molecules could be used as a broad-spectrum agent, targeting several viruses at once and grounding Crowe's belief that a large-scale solution for the next inevitable pandemic is possible. 

"We're saying, let's do all 100 most likely [organisms], and then the next one that happens is highly likely to be on our list," he said. "And we'll be ready."

The application for the patent, "Human antibodies to Alphaviruses," was filed Aug. 31, 2020 to the World Intellectual Property Organization. It was published March 4, 2021 with the application number WO 2021/042021. The earliest priority date is Aug. 31, 2019. The inventor of the pending patent is James E. Crowe Jr. The applicant listed is Vanderbilt University.

Parola Analytics provided technical research for this story.

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