In a paper published in the journal Frontiers in Microbiology, a team of researchers at the University of North Carolina at Chapel Hill review possible strategies against SARS-CoV-2, SARS-CoV-1, MERS-CoV as well as future coronaviruses; the authors propose that the most promising approaches for fast progress are selected antivirals such as remdesivir, and gene therapy.
Colorized scanning electron micrograph of a VERO E6 cell (blue) heavily infected with SARS-COV-2 virus particles (orange), isolated from a patient sample. Image credit: NIAID.
“Coronaviruses represent a true threat to human health and the global economy,” said senior author Professor Ralph Baric, a researcher the Department of Epidemiology and the Department of Microbiology and Immunology at the University of North Carolina at Chapel Hill.
“We must first consider novel countermeasures to control the SARS-CoV-2 pandemic virus and then the vast array of high-threat zoonotic viruses that are poised for human emergence in the future.”
“To help focus the global search for a treatment, we here aim to provide a comprehensive resource of possible lines of attack against SARS-CoV-2 and related coronaviruses, including the results from all preclinical and clinical trials so far on vaccines against SARS and MERS.”
Professor Baric and colleagues discuss one-by-one the possible strategies against the coronavirus.
First and most effective are vaccines. In the present case, the most successful are likely to carry the spike protein of the virus, which allows it to bind to and fuse with host cells.
Besides the traditional live attenuated, inactivated, and subunit-based vaccines, modern types such as DNA/RNA-based and nanoparticle- or viral vector-borne vaccines should be considered.
Because the amino acid sequence of the spike protein is very different across coronaviruses (e.g., 76-78% similarity between SARS-CoV and SARS-CoV-2), vaccines against one strain typically won’t work against another.
But because the development and testing of new vaccines takes one to several years, other approaches are essential in the meantime.
The second-most likely effective are broad-spectrum antivirals such as nucleoside analogs, which mimic the bases in the virus’ RNA genome and get mistakenly incorporated into nascent RNA chains, stalling the copy process.
But because coronaviruses have a so-called proofreading enzyme which can cut such mismatches out, most nucleoside analogs don’t work well. Exceptions seem to be β-D-N4-hydroxycytidine and remdesivir, proposed by the authors as good candidates against SARS-CoV-2.
Schematic of the coronavirus replication cycle and key steps for antiviral targets. White text boxes indicate the subtype of antivirals that work either extracellularly or intracellularly. Different steps of the coronavirus replication cycle are illustrated in cartoon form, including receptor binding, membrane fusion, viral RNA replication, sub-genomic RNA transcription and translation. Image credit: Tse et al, doi: 10.3389/fmicb.2020.00658.
Third, convalescent blood plasma from patients who recovered, with low levels of a range of antibodies against the virus; or preferably (but slower to develop), monoclonal antibodies, isolated and mass-produced through biotechnology. Such ‘passive immunization’ can give short-term immunity.
The scientists discuss a range of options from fusion inhibitors, to inhibitors of human proteases, to immune modulators such as corticosteroid hormones, and others.
Finally, and in the authors’ view the most attractive alternative until a vaccine is produced, is gene therapy delivered through the adeno-associated virus (AAV).
This would entail the fast, targeted delivery of antibodies, immunoadhesins, antiviral peptides, and immunomodulators to the upper airways, to give short-term protection. Because the rapid turnover of cells here, risks of toxicity are minimal.
They estimate that such tools can be developed, adapted, and tested within a month.
“AAV-based passive immunization can be used as a quick alternative,” said first author Dr. Longping Victor Tse, a researcher in the Department of Epidemiology at the University of North Carolina at Chapel Hill.
“It is straightforward and only contains two components, the viral vector and the antibody.”
“Multiple AAV vectors have been proven to be safe and effective for human use.”
“In theory, a single dose could mount a protective response within a week and last for more than a year.”
“The currently high price could be reduced when treating infectious diseases, which have a larger market.”
“It may or may not already be too late to use AAV to treat SARS-CoV-2, but it is certainly not too late for future outbreaks.”
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Longping V. Tse et al. The Current and Future State of Vaccines, Antivirals and Gene Therapies Against Emerging Coronaviruses. Front. Microbiol, published online April 24, 2020; doi: 10.3389/fmicb.2020.00658
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