In recent days, the increasingly dire news about the global spread of COVID-19 has featured little glimpses of charming optimism. Specifically, many internet commenters, a couple biotech companies, and also the president of the United States, have been circulating the claim that repurposed antiviral drugs and new vaccines will be arriving shortly to save us all from the worst the virus can throw at us.
Are these claims realistic?
No. They are not.
We are not going to see either a widely available antiviral treatment or working vaccine before the first wave of SARS-COV-2 has had a chance to spread across the globe this year.
While it’s certainly possible that we’ll know how effective repurposed antivirals and first-generation RNA vaccines are in weeks or a few months, these therapies are unlikely to be available soon at the scales needed to address the growing numbers of patients and areas where the disease has spread.
The repurposed drugs that have survived the initial in-silico and in-vitro screening efforts and are probably going to make it to human trial results have included protease inhibitors (lopinavir and ritonavir), reverse transcriptase inhibitors (remdesivir), and Chloroquine an antimalarial drug which appears to function by altering the chemistry of the cell surface rather than via a molecular mechanism against SARS2-COV specifically.
Remsdesivir and Chloroquine have shown evidence of reducing viral replication in in-vitro assays. Chloroquine has even done so in some clinical studies, while remdesivir and protease inhibitors have only been the subject of case reports so far. In mice, Remdesivir inhibits viral replication of the MERS coronavirus, while the protease inhibitor cocktail helps lung function but doesn’t inhibit replication. Thus, expert assessments have been more positive about remdesivir than protease inhibitors in recent days.
Remdesivir and protease inhibitors are already in human trials, and some reports indicate Chloroquine will soon be tried. Other drugs may be added to the coterie of experiments at any time, of course, and may surprise us.
Because of the fast-moving character of the epidemic, it’s possible that clinical trials may be carried out and yield results in a matter of weeks, and very likely that regulatory authorities around the globe will be eager to act quickly on any positive results. Preliminary reports from trials initiated weeks ago in Wuhan could theoretically be published any time now, depending just how fast they’ve been moving and how definitive the results were (in either direction). But it would be surprising if we didn’t have a pretty good read on things in a matter of months.
RNA vaccines and others
As we’ve reported before, the effort to produce a vaccine for SARS2-COV has centered on RNA vaccines, a new flavor of vaccines that can in theory be designed and produced more quickly than traditional protein or whole-virus vaccines.
Accordingly, at least two companies have already synthesized prototype samples of their SARS2-COV vaccines: Moderna Therapeutics, in Cambridge, MA, and Greffex, located in Houston. Both companies are proceeding to animal testing. Moderna has shipped samples to the NIAID arm of the US NIH for use in an imminent phase one trial, while Greffex has announced it will trial its vaccine in affected countries abroad, who have more cases to contend with.
Additional trials may be announced for one or both vaccines, and other vaccine efforts are in the works from companies around the world. One of them, an Israeli company, hasn’t yet produced samples of a SARS2-COV vaccine suitable for trial use, but its vaccine is a protein vaccine which may be able to more rapidly scale using the established supply chain for protein vaccines.
These trials may read out pretty quickly. Clinical trials of Ebola vaccines and therapies have been carried out and published in as short as a few months, and it’s possible that trials of SARS2-COV vaccines may happen faster.
So once we know these things work, is everything solved? Well, no.
In theory, we might know in mere weeks that some repurposed drugs are effective, or that an RNA vaccine is effective. But that doesn’t mean that everyone who needs these drugs could get them, because of the matter of scale.
Right now there are about fifty thousand active, not-recovered cases of COVID-19, a number which is still growing rapidly and could be in the millions a few months from now if the worst scenarios play out.
Vaccination campaigns range from requiring several times as many doses as the numbers of current patients (i.e. in ring-fencing strategies), up to population scale (i.e. in saturation strategies). Thus, to really play a large role in determining the course of a pandemic, a drug or vaccine would need to be produced and distributed in quantities ranging from millions to billions of doses.
There seems to be little hope of this happening soon (e.g. this year) with most or all of the promising therapies currently being considered:
Remdesivir is a prototype drug which is not FDA approved and is not being produced in volume. We’ve been unable to find estimates of quantities, but one analyst estimated that Gilead could make $2.5 billion by selling its current and nearterm supply of remdesivir. If this estimate assumes Gilead’s usual strategy of high pricing for antivirals, it could mean that these analysts estimate as little as a few tens of thousands of courses of remdesivir may be available near term, which will probably be overwhelmed by case numbers soon enough, and may be an overestimate to begin with.
One bright spot (other than for Gilead’s finances, possibly) is that generic Chinese pharmaceutical companies are working around the clock to copy remdesivir, and may be able to scale up production faster than Gilead itself (with or without an appropriate license).
There are currently no RNA vaccines approved for human use anywhere in the world, and there appear to be no large RNA vaccine factories either. Vaccine manufacturers have been known to put commercial concerns aside (or negotiate them very quickly and reasonably) to cooperate in the case of epidemics and pandemics, but right now, it may be that no one in the world has the needed facilities already working.
While nucleic acid vaccines are easier to convert from producing one type of vaccine to another than other forms, the facilities themselves have to be built first, and it’s not clear how fast the scaleup from prototypes could happen.
The protease inhibitor cocktail is approved and used in third-world countries all over the world. As far as our research has been able to indicate, it is only used in tens of thousands of patients worldwide, but this may be enough to allow hundreds of thousands of coronavirus patients to be treated, since courses for coronavirus would be short and HIV patients who take protease inhibitors usually take them continuously. The timeline to increase production further is unclear.
Chloroquine may be a bright spot, since it is widely used for malaria and already produced cheaply in very large quantities in countries around the globe. If it bears out clinically the way it has in vitro and in early reports, it may actually be possible to treat millions of COVID-19 patients with it in the near term.
There’s discussion of some drug repurposing to make a difference in the mortality rates of critical cases, e.g. corticosteroids like dexamethasone for use in patients with cytokine storm, or other drugs for respiratory distress. If this bears out, it’s possible dexamethasone could be used at scale, since it is already produced at scale.
How long until we produce these drugs at pandemic scales?
It’s hard to know, but responsible estimates have not been shorter than a year for widespread deployment of the RNA vaccines or large increases in the production of remdesivir.
Most likely, wave one of the COVID-19 pandemic will play out without new therapies making a dramatic entrance in quantity to save the day.