Photo: Anna Shvets/Unsplash.
As the COVID-19 pandemic rages on, researchers around the world have turned to two of the most reliable treatment strategies to counter the virus: vaccines and antivirals. Both vaccines and antivirals can be designed to target SARS-CoV-2 but the way they do so are different – with very different implications for the control of the disease as well.
Vaccines: The prevention model
Vaccines are one of humanity’s greatest healthcare achievements. A vaccine is simply the administration of parts of a deactivated virus into humans. White blood cells (immune cells) in the body respond to these parts by making antibodies while also developing an “immune memory” against it. So the next time an active virus enters the body, the immune cells remember the previous infection (the vaccine) and know what to do: they quickly make antibodies to beat the virus, and prevent it from entering our cells and establishing an infection. No virus entry = no virus infection = no disease.
To prevent viruses from entering the cells, researchers have to carefully pick the virus’s protein that our immune system has to make antibodies against, a.k.a. the target. The target of choice with SARS-CoV-2 coronavirus is its spike protein, which the virus uses to enter human cells.
Since the vaccine uses a ‘fake’ virus, researchers have to deliver the CoV-2 spike protein alone, not the whole virus. This is easier said than done and is the subject of multiple COVID-19 clinical trials. The vaccine furthest along is the mRNA vaccine developed by the US National Institutes of Health and Moderna, a private medical research company. In this vaccine, the genetic material of the CoV-2 spike protein is encased in a thin double-layer of fat – quite like a tiny soap bubble. When this bubble is injected into our cells, the cellular machinery reads the genetic code like a recipe to make the CoV-2 spike protein alone, which in turn provokes the immune system to make antibodies against it.
This is not the only approach. Researchers in China, the UK, and Germany as well as at a host of other companies are using DNA and microneedle patches to deliver the coronavirus spike protein payload. In India, the Serum Institute of India, Bharat Biotech and Seagull Biosciences have all announced that they will be developing COVID-19 vaccines using the same spike protein. There are also alternative approaches that attempt to isolate antibodies against the spike protein from patients who have recovered from COVID-19, and then administer them in large quantities to patients who are currently critically ill.
Because vaccines and antibody therapies have never been deployed against the new coronavirus, we don’t know how safe and effective they can be in humans. So researchers have to monitor volunteers for safety. This is an important point: most vaccines are preventative, not therapeutic. The original 2002 SARS virus vaccine seems to work pretty well, so we are pretty confident that the CoV-2 vaccine will work as well given how similar they are. But to make sure that the new CoV-2 vaccine is safe and immunogenic (i.e. makes antibody memories) will require at least a year’s follow-up before we can be sure it’s safe to manufacture enough doses for the population.
Antivirals and inhibitors: The treatment model
So what do we do until then? Clearly there are no signs of the disease slowing across countries until clinical trials end. We need drugs that can manage the disease in people who have already been exposed to the virus, and save them. This is where antivirals and inhibitors come into play.
The drug that has received the most attention is hydroxychloroquine, a compound of chloroquine that has been successfully used to treat malaria and some other infections. Chloroquine is a broad-spectrum drug that acts on infected cells to reduce viruses’ ability to spread. Although early data from a controversial pilot study in France showed some promise, a bigger trial from Brazil yielded conflicting results suggesting that hydroxychloroquine could actually make things worse at higher doses. So for now we are unsure if hydroxychloroquine derivatives will be useful.
Other promising drugs include those that specifically fight dangerous adverse events that actually kill patients. For example, the IL-6 inhibitors specifically mitigate the cytokine storm, an aggressive immune system overreaction that happens in patients critically ill with COVID-19. Inhibiting IL-6 protein levels in patients could reduce inflammation often associated with lung failure.
Another class of drugs, the antivirals, are like antibiotics but for viruses. Remdesivir, made by Gilead Sciences, Inc., is a type of antiviral called a nucleoside analog. It has been previously shown to work against other coronaviruses. It creates DNA-like molecules (that are not really DNA) that an unsuspecting virus incorporates into its genes as it tries to grow and replicate within our cells. But because the analogs have messed up the new viruses’ genetic code, they are born with defects and become unable to spread to other cells.
Late last week, the first results from a study in which researchers administered Remdesivir among severely ill COVID-19 patients in the US and Japan were published. They seem promising, with clinical improvement in close to 70% of the participants. However, the trial was not placebo-controlled. Other antiviral candidates have not worked well against COVID-19, and we need bigger randomised control trials to understand if this and many other antivirals have any effect. A nice advantage here is that since many antivirals have already been approved to treat other diseases, they have been through regulatory requirements, so they can be repurposed faster if they show a response against COVID-19.
Which is better?
Our goal is to end this pandemic, which means preventing the virus from creating new outbreaks. So it’s not either-or with vaccines and antivirals. It’s both. The only way to prevent people from ever contracting SARS-CoV-2 in the first place is to generate protective immunity by vaccination. But even if we accelerated all clinical trials (and optimistically anticipate safe and effective vaccines), it will be 2021 before they enter mass production. Until then, we can’t stay on stand-by as patients struggle through severe respiratory distress. At the same time, we can’t shut everything down and maintain physical distancing forever while what many consider to be the worst economic crisis in a century plays out.
We have to reduce the number of people who succumb to the worst of COVID-19’s symptoms, or keep people with mild symptoms from progressing towards the worst stages of the disease using antivirals and inhibitors. A short-term strategy of continued social distancing, disease management by repurposed antivirals or inhibitors with a long-term goal of vaccines seems to be, at least in my view, our most promising way out of this disaster.
Dr Sri Krishna is an immunology researcher at the National Institutes of Health, USA. The views expressed are his own and do not necessarily represent the views of the National Institutes of Health or the US government. He tweets at @tellkrish.