COVID-19 coronavirus has killed hundreds of thousands of people, sickened millions and crippled the word economy since emerging from Wuhan, China in 2019. Now a team at UNC Chapel Hill is undertaking a massive review of all available research data to find a way to beat it.
Never before in human history has so much scientific and research ammunition been aimed at a single target. Researchers, clinicians and other scientists are working feverishly to develop better diagnostic tests, treatment protocols, cures and vaccines for COVID-19 and its underlying cause, SARS-CoV-2.
To date, there are nearly 1,700 scholarly articles and research studies already listed in databases, many available to the public in places like Science Direct and Google Scholar. According to one source, over 450 clinical trials (you know, the serious kind) are underway at this moment. All of them are focused squarely on COVID-19 and SARS-CoV-2. With this wealth of information floating around out there, someone had to take on a systematic review of this stuff.
A team headed by Dr Ralph Baric, William R. Kenan, Jr. Distinguished Professor in the Department of Epidemiology and Professor in the Department of Microbiology and Immunology at UNC Chapel Hill is doing just that. They’ve published a new study in Frontiers in Microbiology that, while aimed at the research folks, is understandable by non-specialists as well.
In the study they take on SARS-CoV-2. But they also review ways to combat other coronaviruses, including SARS-CoV (which causes SARS) and MERS-CoV (which causes MERS.) They believe their work may give us a leg up in dealing with yet unknown strains which may arise in the future, too.
In their findings, they say the most promising treatments are antivirals, like Remdesivir, and gene therapy.
“Coronaviruses represent a true threat to human health and the global economy. 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,” says Dr Ralph Baric, William R. Kenan, Jr. Distinguished Professor in the Department of Epidemiology and Professor in the Department of Microbiology and Immunology at UNC Chapel Hill.
“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 pre-clinical and clinical trials so far on vaccines against SARS and MERS.”
The authors break down the possible strategies against the coronavirus one by one. First, and most effective, they believe, are vaccines.
For SARS-CoV-2, it’s likely the most effective vaccine will carry the virus’s Receptor Binding Domain. This allows it to bind to and fuse with host cells. Most commonly, live attenuated, inactivated and subunit-based vaccines would be most widely used. However, the team believes that more modern vaccine types like DNA/RNA-based and nano-particle- or vector-borne vaccines ought to be considered as well.
Because the amino acid sequence of the S-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.
Since the lead time on effective vaccines is typically from 12 to 30 months, other weapons must be found. This is where broad-spectrum antivirals like nucleoside analogs come in. Nucleoside analogs mimic the bases in a virus’s RNA genome, allowing them to be mistakenly incorporated into the RNA chains. Once inside, they stop the genomic copy process.
These have one big problem to overcome, though. Coronaviruses have a so-called “proofreading” enzyme. This allows them to locate and eliminate mismatches. Two drugs which seem to get around this process are Remdesivir and a drug known as ?-D-N4-hydroxycytidine. These may be good choices for treatment of the virus.
Convalescent blood plasma (CBP) gets good grades from the team as well. This is plasma taken from patients who’ve recovered from COVID-19. Their blood has low levels of a variety of antibodies against the virus. The researchers think that convalescent plasma spiked with monoclonal antibodies would be even better, but developing that is a much slower process. CBP would give recipients at least short-term immunity via “passive immunization.”
The authors also discuss a variety of other possible options. These run the gamut from corticosteroid hormones to immune modulators to human protease inhibitors.
Deemed the most effective (and possible most fascinating) of the studied options is gene therapy using the adeno-associated virus, or 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 of 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. 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,” says author Dr Long Ping Victor Tse.
“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.”
This research team did a mountain of work in a short period of time. Time and treatment of patients will tell if they are right in their conclusions. For everyone’s peace of mind, let’s hope they are.
Keep the faith and keep after it!
Journal Reference – Longping V. Tse, Rita M. Meganck, Rachel L. Graham, Ralph S. Baric. The Current and Future State of Vaccines, Antivirals and Gene Therapies Against Emerging Coronaviruses. Frontiers in Microbiology, 2020; 11 DOI: 10.3389/fmicb.2020.00658