Evolving variants of the SARS-CoV-2 coronavirus are threatening the efficacy of existing COVID-19 vaccines and therapeutics. Now, a group of scientists from Northwestern University and the University of Texas MD Anderson Cancer Center showed that some naturally occurring tiny vesicles isolated from COVID-19 patients could fight off an infection from various subtypes of coronaviruses.
The team identified tiny cell-released lipid particles that expressed a protein called ACE2 from COVID-19 patients’ blood. These circulating extracellular vesicles that express ACE2 (evACE2) blocked infections from different coronavirus variants in lab dishes. Delivered via the nose, the nanoparticles also protected mice from COVID-19. The results were published in Nature Communications.
The researchers believe evACE2 could be developed as a biological product for prevention and treatment of COVID-19 caused by current and future SARS-CoV-2 variants and potentially other coronaviruses as well. Two of the studies’ co-senior authors, Huiping Liu, M.D., Ph.D., and Deyu Fang, Ph.D., at Northwestern University have formed a startup company, Exomira, to pursue that idea. They are currently looking for industry partners to develop the therapy.
The team’s optimism is based on evACE2’s mechanism. SARS-CoV-2, the coronavirus behind the ongoing pandemic, uses the spike (S) protein on its surface to bind to ACE2 on human cells to gain entry and achieve infection. But evACE2, thanks to its strong binding ability, can act as a decoy to lure the virus away from human cells.
The researchers noted the ACE2-expressing extracellular vesicles in blood samples of COVID patients but not in healthy controls. The more severe the disease, the higher the levels of evACE2 detected, suggesting that the production is part of the natural response to an infection in COVID patients.
In lab dishes, evACE2 blocked coronavirus S protein binding to human cells and was 120 to 135 times more efficient than recombinant human ACE2, which has been proposed as potential COVID treatment, the team showed.
By using SARS-CoV-2 pseudoviruses, the researchers showed evACE2 could neutralize the viruses, protecting human cells from infections, while control vesicles without ACE2 expression showed no activity. Similarly, upon SARS-CoV-2 infection, the addition of evACE2 decreased viral loads and stopped the loss of viable human cells, whereas control vesicles failed to do so.
What’s more important, evACE2 showed comparable or greater efficacy in blocking the infection of pseudoviruses mimicking the alpha, beta and delta variants when compared with the original SARS-CoV-2 virus.
The researchers then tested evACE2 in a well-established COVID-19 mouse model with human ACE2 expression. Within a week of a high dose infection, nearly all mice showed severe disease with over 20% weight loss when treated with control vesicles. By comparison, treatment with nasal evACE2 protected 80% of animals, with a significant reduction of viral load detected in lung tissues.
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Existing COVID vaccines and antibody drugs are being challenged by emerging coronavirus variants. A fourth dose of the Pfizer-BioNTech vaccine, Comirnaty, couldn’t protect healthcare workers from infection by the rapid-spreading omicron variant despite the shot being able to trigger increased antibodies, preliminary findings from a real-world study in Israel showed.
The U.S. government in December paused distribution of COVID-19 antibody drugs from Eli Lilly and Regeneron, citing their reduced efficacy against omicron.
evACE2 holds the potential to avoid that pitfall. Almost all existing vaccines and antibody therapies target the S protein, but SARS-CoV-2's variants include mutations to the S protein. Despite the mutation, the coronavirus still needs the ACE2 receptor to infect human cells. By competing with host cell surface ACE2, evACE2 can theoretically act as a bait to attract coronavirus away, regardless of the S protein mutations.
“It remains urgent to identify novel therapeutics,” Northwestern’s Liu said in a statement. “We think evACE2 can meet the challenges and fight against broad strains of SARS-CoV-2 and future emerging coronaviruses to protect the immunocompromised (at least 2.7% of U.S. adults), the unvaccinated (94% in low-income countries and more than 30% in the U.S.) and even the vaccinated from breakthrough infections.”