To meet that pressure, we need to understand what’s possible in the short-term, and how best to mobilize for future large-scale production of an as-yet-undiscovered vaccine in the long term. The lessons we learn from this staggered offensive will help us draft a better plan for defeating COVID-19 in the long run, and similar threats that may arise in the future.
In the Near-Term: Immunoglobulin
Two to three months
Of those with a COVID-19 diagnosis, more than 80% will recover without medical intervention and with mild symptoms. The other 20%, whose immune systems aren’t up to the task of fighting off this disease, face a difficult struggle unless they receive appropriate medical intervention.
One solution for immediate and effective treatment is immunoglobulin (Ig). Using technology and processes already well-established in the fights against other indications, we can harvest the blood plasma of donors who have fully recovered from COVID-19, purify the Ig and distribute it to those in need, quickly and with dramatically improved patient outcomes.
- The technology behind harvesting and purifying Ig is well understood and will likely need little or no modification for redeployment against COVID-19.
- We know from established Ig products that they pose little risk to patients, which could help to streamline regulatory approval.
- The product itself is relatively stable, which indicates a moderately long shelf life (when stored correctly in a refrigerated environment, Ig will remain stable for up to 36 months). This could be useful in the event of an annual occurrence of the outbreak.
- This approach depends on the availability of a pool of plasma donors who have recovered from the virus. A near-term lack of availability in the donor pool could limit a manufacturer’s ability to scale up quickly.
In the Middle-Term: Monoclonal Antibodies
One to three years
Although COVID-19 is a novel enemy, the coronavirus battlefield is familiar to us. In 2003, a coronavirus triggered the Severe Acute Respiratory Syndrome (SARS) epidemic; an outbreak of Middle East Respiratory Syndrome (MERS), also caused by a species of pathogenic coronavirus, erupted ten years later.
As we face our third highly pathogenic coronavirus threat of this century, researchers are racing to develop a prophylactic strategy against this persistent group of related viruses. Monoclonal antibodies (mAb) could be part of the solution. Because each of these three coronaviruses shares certain genetic features, it’s possible that an antibody designed to neutralize today’s COVID-19 threat could be effective against a related instance of coronavirus in the future. Should MERS threaten us again, for example, or should a fourth species of pathogenic coronavirus emerge, today’s mAb research could be our most valuable tool in protecting human health.
- Like Ig, mAb presents relatively little risk to patients, which means a mAb product could move quickly through the regulatory pipeline.
- The historic threats of SARS and MERS generated a wealth of valuable clinical research which helped to identify a few antibodies with activity against SARS and/or MERS. Because each of these three coronaviruses shares certain genetic features, it’s possible that an antibody designed to neutralize today’s COVID-19 threat could be effective against a related instance of coronavirus in the future.
- Unlike antibodies harvested from patients in Ig production, mAb is produced in bioreactors by genetically modified mammalian cells, which means that manufacturers could ramp up production more easily in the event of a future outbreak.
- While focused initially on development, drug companies must simultaneously ready themselves for commercialization the moment a candidate mAb product shows promise.
In the Long-Term: A Vaccine
18 months to three+ years
We don’t know when or if SARS-CoV-2 will surge back after this pandemic is under control, or when another pathogenic coronavirus is on the horizon. Our best long-term defense is prevention through vaccination.
The pathway towards vaccine development is long, with many branching paths. The historical approach is to propagate a mammalian cell culture, infect it with the actual SARS-CoV-2 virus under appropriate biosafety containment conditions, then isolate and chemically inactivate the virus. This is followed by purification, formulation and filling to produce the final dose form of the vaccine. Another “live viral” vaccine approach is to genetically modify the virus itself, attenuating and rendering the virus non-pathogenic throughout its lifecycle. Both approaches could trigger the necessary immune response in healthy individuals. Both have their advantages and disadvantages. Both are commonly used in producing today’s vaccines.
Using the actual virus is a faster and more straightforward process, but that speed could levy a high cost. For one thing, a chemically inactivated virus is potentially riskier than one that’s been attenuated. Manufacturing personnel could be susceptible to harmful exposure, and patients are more likely to develop injection site reactions and other adverse effects, including the risk of enhancing the course of the disease rather than protecting against it. A genetically modified virus, on the other hand, is relatively toothless; lab researchers and operators can handle it safely, and it’s more likely to prove safe and efficacious in patient populations. There’s a catch, though: it takes more time to develop the scientific understanding necessary to manipulate a virus so precisely, making certain that it can’t evolve back to the virulent form—and time is hard to come by when trying to respond as quickly as possible to an acute threat like this one. At this point, no one has publicized that they have initiated the development of a live viral vaccine approach for COVID-19.
A third prevalent approach is a subunit vaccine, in which a non-pathogenic fragment of the virus, typically a surface protein without any DNA or RNA, is used to trigger an antigenic immune response and stimulate acquired immunity against the virus. Recombinant microbial or insect cells can be enlisted as host organisms for producing these subunit vaccines. In some cases, the surface protein of the subunit vaccine assembles into virus-like-particles (VLP) with improved recognition by the immune system, but with no nucleic acids and hence no pathogenicity.
New innovative approaches to vaccines are also under development and showing promise. Not long after Chinese scientists published the SARS-CoV-2 sequence, researchers developed an mRNA vaccine candidate and initiated a Phase 1 clinical trial.
Other possible strategies include DNA plasmid vaccines and recombinant vector vaccines.
- If SARS-CoV-2 persists as a long-term threat, an effective vaccine could accelerate the herd immunity gained from this pandemic and prevent future outbreaks.
- Despite tremendous pressure to accelerate vaccine production, there’s only so much that we can do to collapse the timeline required for necessary safety and efficacy testing. Since most vaccine candidates fail in the clinic, it’s crucial to test multiple strategies.
COVID drug development strategies timeline
With few certainties to guide us through this complex situation, experience and leadership matter more than ever. Those who understand the science, the technology and the challenges of commercial scale-up that you face on the COVID-19 battleground will become your most valuable assets.