Much like everyone else, I have spent the last couple of weeks constantly bombarded by news of COVID-19. Wherever I look — Twitter, WhatsApp, or TV — there seems to be a new headline every few minutes. Unfortunately, many of these articles, especially the ones related to potential treatments, generate catchy headlines by overly simplifying nuanced scientific results. As someone with a strong interest in biotech and whose PhD research relies heavily on immunology, I’ve made an effort to stay on top of the literature related to the pandemic. In hopes of spreading reliable information, I’m summarizing some of my favorite sources of knowledge for COVID-19 as well as a quick description of some potential treatment approaches.
First, some nomenclature: even though most news outlets refer to the virus as COVID-19, this is actually the name for the disease; the virus itself is named SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). This name comes from its similarity to the virus that caused the SARS outbreak in the early 2000s, which is named SARS-CoV. Both of these viruses, along with MERS-CoV (responsible for the MERS outbreak in 2012), are all part of the same family — coronaviruses.
Throwing it back to high school biology, viruses replicate by infiltrating our cells and “hijacking” our own machinery to create copies of their genetic code. This is an important difference in comparison to bacterial infections, in which the pathogenic bacteria can replicate on their own. From a treatment perspective, this provides a significant challenge: drug development is often based on leveraging differences between human and pathogen cells, allowing us to generate therapies that specifically target the latter. In the case of a virus, because they have breached our own cells, accomplishing this is more difficult. Nonetheless, there are ways to target and disrupt the virus’s life cycle to prevent further infection.
Below, I’ve explained some of the biology behind the most common approaches for potentially treating COVID-19. After that, I’ve added a link to an exhaustive list of compounds and vaccines currently being tested.
Vaccines:
In terms of preventing viral infections, vaccines have proven very successful. Though there are a few different types, they all function under the same principle. In vaccination, you present the body with an antigen for the virus you want to immunize against. An antigen is generally a small fragment of the virus that your body can recognize and use to build an immune response against it. One type of immune response comes in the form of neutralizing antibodies, which are highly specific molecules your body makes to bind to the virion (a mature virus particle) and physically prevent it from interacting with your cells.
Two of the most common vaccine types are live-attenuated and inactivated whole-cell vaccines. In the former, you administer a weakened but live version of the virus, allowing the patient to build a robust response while remaining asymptomatic. These vaccines are highly immunogenic but have the downside of the need for a cold-chain (supply chain with controlled temperature) and potential safety issues. In the latter, the virus is entirely inactivated and given to patients. Here, while there are fewer safety risks, the immune response may be dampened.
A third category of vaccines is called a subunit vaccine, in which you only deliver the antigenic part of the virus. The challenge here lies in knowing a suitable antigen for that virus. Because we’ve done a lot research on the similar MERS-CoV and SARS-CoV, scientists had a good sense of what the ideal antigen might be for SARS-CoV-2 — the Spike (S) protein that allows the virus to enter our cells. The Spike protein sits in the viral envelope and protrudes outward making a crown or “corona” around the particle (check out the red molecules in the first image I posted). Within the Spike protein, there is a specific section, called the receptor binding domain (RBD), that is specifically responsible for binding to our cells and allowing the virus to infect us. SARS-CoV-2 (and SARS-CoV) do this by binding to ACE2, a receptor on the surface of our cells (if you’d like to know its normal role in the body, check out this review). In fact, a critical difference between SARS-CoV and SARS-CoV-2 seems to be mutations in the genetic code of the RBD, giving SARS-CoV-2 an increased ability to fuse and enter our cells (paper showing this can be found here).
Therefore, the simplest reasoning behind a subunit vaccine would be one in which we would give patients recombinantly produced Spike protein and allow our body to build up an immune response by generating neutralizing antibodies against it (anti-Spike antibodies).
Of course, it’s not that simple. After a protein is made in a cell, it is decorated with specific sugars in a process called glycosylation. Until recently, these sugars were mostly ignored and considered to not affect protein behavior; however, it’s becoming very clear that they are critical. This entire field of glycobiology, led by pioneers like Carolyn Bertozzi at Stanford, has been blossoming as we realize just how important carbohydrate patterns on proteins are (more on that here). Therefore, in thinking of making a SARS-CoV-2 subunit vaccine, not only do we have to match the genetic code of the Spike protein in the virus (this is easy), we have to have the relevant glycosylation pattern on it for our body to make an antibody that will recognize the true virus.
Another aspect of vaccine development to consider is the adjuvant, which is a co-administered compound that helps drive the immune response against the antigen. While there is a “gold-standard” that many vaccines employ (alum), this, and alternatives, will still have to be tested and optimized. Lastly, there is the issue of the production scale needed for an effective COVID-19 vaccine campaign. The entire glycosylated Spike (S) protein is a large molecule which could prove hard to manufacture at the necessary scale. An alternative approach is a vaccine in which just the RBD serves as the antigen. Only time will tell which will work.
The last, and most novel, type of vaccine is called a nucleic acid vaccine. In this strategy, you deliver the genetic building blocks — DNA or RNA — that code for the antigen (e.g. S protein) and let your own body create it. In this way, you are taking a lot of the “guess work” out of it and allowing your body’s own immune system to build the correct response. Even though this sounds promising, the platform as a whole has yet to be validated. That being said, Moderna Therapeutics, the leader in mRNA vaccines, cashed in the largest biotech IPO ever in 2018, so there is a lot of money and hope behind this technology.
Antibodies:
Another train of thought that might naturally arise is, “Can’t we skip the vaccine altogether and just take antibodies from COVID-19 survivors and administer those?” The quick answer is “yes” and many people are trying that. The idea here is that survivors have built up the neutralizing antibodies that ultimately defeated the virus, so we could isolate them from their blood and use them as a potential treatment. Hospitals like Mount Sinai and Houston Methodist are planning on doing this. Another approach is to biomanufacture these antibodies recombinantly, even engineering them to have more desired behaviors. This approach, which would allow for more controlled and at-scale production, is being carried out by multiple companies.
It’s worth mentioning a cautionary note on this. A paper published in 2018 showed that in a study with non-human primates infected with SARS-CoV, certain antibodies against the Spike protein actually led to more respiratory complications by overactivating immune responses. By no means does this study invalidate antibody-based therapies, it just brings light to the complexity of the situation. Inducing a balanced, well-timed immune response is critical.
Small Molecules:
The last commonly used treatment approach is antiviral small molecule drugs, which can work similarly to antibodies in that they bind to the virus and try to disrupt the life cycle. This could be done by preventing attachment to the host cell, as we’ve mentioned, but also by preventing the virus from re-assembling once it’s inside our cells or inhibiting the release of the virus as it tries to move from one cell to the next. An example of this is Tamiflu, which works by binding and inhibiting the special protein on the flu virus that allows new viral particles to exit our cells (neuraminidase). A benefit of small molecule approaches is that, given their size, they can enter our cells, opening up additional avenues for targeting the virus. In comparison, antibodies are too large to enter cells and therefore are limited to neutralizing the virus by preventing its entry. Furthermore, small molecules can be easier to manufacture at the necessary scale.
Resources:
Knowing this, we can take a look at what people are currently testing. The Menkin Institute frequently updates a treatment and vaccine compilation that is worth checking out. To get a sense, on March 31st, there were on the order of ~50 vaccines, ~25 antibodies, and ~15 small molecules being tested. You can find it here.
In terms of reliable sources, my go-to is Twitter. Three of my favorites accounts relating to evidence-based Coronavirus news are:
- David Liu, (Harvard + Broad Institute): one of the leading chemical biologists in the world, working on developing gene editing capabilities for new therapeutics. Though his research doesn’t focus on COVID-19, he does a fantastic job of retweeting and compiling important knowledge about the pandemic.
- Akiko Iwasaki (Yale): her research focuses on immune responses to viral infections and her feed has a ton of threads with great information and papers.
- Eric Topol (Scripps): he is the founder and director of Scripps, a translational research institute. Because he is also a physician, many of his COVID-19 tweets have a unique perspective.
Another great website is from the University of Washington’s Institute for Health Metrics and Evaluation (IHME). They have state-specific projections for hospital resource use as well as deaths. You can find that here.
