A new study published in the journal Frontiers in Microbiology in April 2020 discusses the most attractive approaches among the broad spectrum of experimental and theoretical strategies being worked on to counter the COVID-19 pandemic.
The importance of being prepared
There have been pandemics before, notably the Black Death in the Middle Ages and the Spanish flu pandemic of 1918-20. However, this time around, people are looking to science to actually find a way out of the desperate situation, not just to save lives but to save the global economy.
In every country, eager investigators and medical workers are locking hands to find some way to restore health to those stricken by the virus faster and better, without their having to go into respiratory failure. Diagnostic testing, vaccine development, and therapeutic drugs are all on the agenda for these thousands of researchers.
Within the last 3.5 months, hundreds of scientific papers on COVID-19 have already been published, as Google Scholar shows. Clinical trials currently in progress for various aspects of medical management of the pneumonic illness already number 460, the majority in the very first phases. These cover a wide range of experimental approaches.
It is against this background that the current study was performed. The researchers aim to provide a systematic review of the promising discoveries and proposals among the plethora being held up to public view. While aimed at scientists, it can also be a useful overview for laypeople.
What is the current study about?
The study covers all possible lines of attack against the virus, also summarizing results from all vaccine trials that have reached the preclinical or clinical stages for vaccines against the SARS or MERS viruses.
The review addresses feasible policies and action plans not only to counter the SARS-CoV-2 but other dangerous coronaviruses such as the SARS and the MERS CoV, both of which also caused severe respiratory illness. The researchers predict that as yet unknown strains will most probably emerge in the years to come.
According to investigator Ralph Baric, “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.”
Hence, they stress the need to identify and focus on those approaches which promise the greatest success. Their prime candidates are, of course, vaccines, and then some antiviral drugs like remdesivir, and gene therapy.
.jpg "Novel Coronavirus SARS-CoV-2 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 captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID")
Novel Coronavirus SARS-CoV-2 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 captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
Vaccines
Vaccines occupy a unique place in the antivirus armamentarium. They are easy to administer, produce durable immunity, and can be highly successful in breaking the chain of transmission by providing ‘herd immunity.’
The most promising vaccines against human coronaviruses are probably going to attack the Receptor Binding Domain of the spike (S) glycoprotein of the virus, which gives them their name by forming a ‘corona’ or ‘crown’ around it. This is the part of the S protein that binds to the ACE2 receptor on the human host cell, allowing it to fuse with the cell membrane and enter the cell.
Both traditional types of vaccines (live attenuated, inactivated, and subunit-based), as well as the newer types such as those based on DNA or RNA, are considered. There are also still more creative approaches, such as inserting the vaccine by attaching it to a nanoparticle or non-pathogenic virus that will enter the cell and produce an immune reaction.
The S protein is very different in the different coronavirus species, with only 78% or less of the genome being similar in the SARS-CoV-2 and the earlier SARS-CoV viruses. Thus a vaccine directed against the S protein of one type won’t be effective against another coronavirus. In other words, a specific vaccine will need to be developed.
These typically take years, if not decades, to be developed due to the stringent approval processes. In the meantime, other plans must be conceived and executed to arrest the pandemic.
Antivirals
The next best option is to find an antiviral drug that acts on a broad variety of viruses because it inhibits some fundamental viral process. For instance, there are drugs called nucleoside analogs used in the treatment of HIV, among other things. A nucleoside is a building block of the building block of DNA.
In other words, a nucleoside is a nitrogen-rich DNA or RNA base, to which a sugar group has been added. This forms the backbone of the growing DNA or RNA strand. When a phosphate group is also added, it becomes a nucleotide.
The genome normally gives precise instructions about what to add next to the strand of nucleic acid. Nucleoside analogs get around this roadblock by simulating the structure of a normal nucleoside very closely until the cell is fooled into including the analog into the nucleic acid strand.
Only this is the wrong base. Its incorporation into the new strand stops the strand from growing and hence prevents the replication of the virus, stopping it in its tracks.
One issue with relying on this method alone is the presence of DNA proofreading and repair enzymes whose sole job is to recognize such impersonators and cut them out with magic scissors, allowing the right base to take its place and thus restore the strand to normalcy. Thus, coronaviruses don’t usually respond well to nucleoside analogs.
Except, of course, for a few. These include β-D-N4-hydroxycytidine and remdesivir, both of which are considered to have a high potential for activity against the SARS-CoV-2.
Passive immunization
The third alternative is to use the good old-fashioned way of finding blood plasma from convalescents – people who have had COVID-19 and recovered – which contains low levels of multiple antibodies against the virus. Another and better way, though more tedious, is to synthesize monoclonal antibodies, using microbes.
This is the field of biotech, where humans harness yeasts and bacteria to do their work for them – in this case, to produce just one specific type of antibody against just one antigen. The mass-produced monoclonal antibody is then isolated and purified and is ready for use. The administration of antibodies directed against the virus is meant to produce a short-term passive immunity, which protects the person against infection for a time.
Other developing procedures and therapeutic agents include inhibitors of virus-membrane fusion, human protease blockers, and immunomodulators, including corticosteroids.
Viral vector-delivered therapeutics could be the answer
According to the study, in the absence of a vaccine, the best option currently is gene therapy. Scientists already use the innocuous virus called the adeno-associated virus (AAV) to deliver therapeutic substances into a cell. This can enable all kinds of molecules, including antibodies, antiviral peptides, and immunomodulators, to be delivered straight into the upper airways, to protect the cells there against infection. Since these cells mature and die, to be replaced by new cells growing up from the deeper layers of the epithelium, the chances of toxicity are very low.
The researchers think that such a system could be ready, from scratch, through development, modification, and testing, within a month. The delivery of antibodies could protect the airways via passive immunity, as described above. Antibodies could be developed to attack not just SARS-CoV-2 but a broad range of related viruses. It is likely that more zoonotic coronaviruses will break out, and resist existing vaccines and drugs because of their dissimilarity with the SARS and MERS CoV.
The advantages are twin: there are only two parts, the AAV and the antibody. AAVs are already established as safe and effective vectors in humans. Thus this could be an ‘instant’ means of providing passive immunity, with a single dose, that begins to confer protection within a week of administration and lasts for a year or more, theoretically.
The pricing of this tool is high, which is a considerable hindrance. This could be brought down if the platform was adapted to infectious diseases because of the much higher market volume.
The researchers sum up, “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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