The Evolving Pandemic

Introduction           

While there is a great deal that we don’t know about SARS-CoV-2, the virus that causes COVID-19, there is a lot that we do know thanks to the efforts of countless scientists, researchers, and clinicians around the world. As a biotech investor and someone who worked in a virology lab many moons ago during the days of my otherwise misspent youth, I continue to believe there are myriad of reasons for optimism amidst the otherwise dark cloud of the COVID-19 pandemic.

Let’s first start with a quick primer on viruses and the immune system, then we’ll dive into a review of what we know, what we’ve learned, what we don't know, and what you can do to help in the fight against SARS-CoV-2.

The “Evil Genius” of Viruses

While viruses are not technically alive – since they can’t replicate on their own – they have developed an evolutionary sleight-of-hand to hijack the machinery of a host cell. A virus enters a host cell via binding to a specific cellular receptor (or receptors) located on the surface of a cell. In the case of case of HIV, for example, the virus binds to two different receptors called CD4 and CCR5. All cells in the human body express surface receptors, although different types of cells within your body expresses different, and often times unique, receptors.

A useful analogy is to think of a virus as a key and the receptor as a lock. Each key fits uniquely into its respective lock, turning the host cell’s receptor into a cellular doorway for the virus. Once a virus enters the cell, the virus hijacks the cell’s infrastructure to replicate until there are enough copies of the virus that the cell bursts, releasing the newly created copies of itself which go on to infect nearby cells, at which time the process repeats itself.

This brings us to the concepts of viral load and viral shedding, which you’ve undoubtedly heard in the media a lot recently. To ensure we’re all using the viral vernacular in the same way, viral load relates to the number of viral particles being carried by an infected individual (also referred to as titer), while viral shedding relates to the number of viral particles that are released into their environment (like shedding hair from a dog), which in turn can infect people nearby. 

Evidence suggests there is a proportional correlation of viral load with the damage a virus is capable of inflicting on it host; the higher the viral load of an infected individual, the greater the severity of the course of infection. This helps explain why healthcare workers and others on the front-lines who are otherwise young and healthy have developed severe infections from SARS-CoV-2 – they are often exposed to numerous infected individuals and experience higher viral loads then people who are exposed to one, or a limited number of, infected individuals. Higher viral loads also typically correspond to higher shedding and vice versa. 

Nature vs. “Nurture”

All organisms must constantly protect themselves from the onslaught of harmful pathogens like viruses and bacteria. It’s the job of our immune system to deliver this protection, which happens via two major pathways: the innate immune system, which we’re all born with, and the adaptive immune system, which we acquire over time following exposure to specific pathogens.

The first line of defense is your innate immune response, which is by evolutionary design fast-acting and non-specific. It’s indiscriminate and does not differentiate between unique pathogens. When a virus first enters a host cell, the infection triggers the innate immune response, which triggers the production of interferons and cytokines (among a variety of other chemical signals). Interferons are a group of signaling proteins made and released by the host cell in response to the presence of pathogens, whereas cytokines are small proteins released by cells that have a specific effect on the interactions and communications between other cells. These signaling molecules – specifically interferons – continue to drive activation of the innate immune response, but also signal the adaptive immune system that your body is under attack by foreign invaders. 

The adaptive immune response, in turn, has two major arms: T cells and B cells. One of primary functions of T cells is immune-mediated cell death, which is carried out by CD8+ T cells, also known as "killer T cells" or cytotoxic T lymphocytes (or CTLs). CTLs are akin to the marines of the immune system and directly kill virus-infected cells, as well as cells that have been damaged in other ways (such as cancer cells, hence why CAR-Ts are so effective against certain types of cancer).

 The B cell arm of the adaptive immune system is responsible for developing the memory of your immune system. For example, let’s say you are infected with an influenza virus. Small pieces of the virus (or antigens) are presented to your B cells, which in turn have receptors on their surface, some of which recognize the virus as “not you” and bind very weakly the virus (this B cell is now termed an antibody). 

This binding then stimulates the B cell to divide, which is a highly error prone process. Some of the copying errors cause your antibodies to bind more weakly to the antigen. Those antibodies will die off. The antibodies that bind more tightly to the antigen are the ones that survive, replicate, neutralize the virus, and go on to create the “memory” within your immune system. So, if you encountered the same virus later in life your pre-made antibodies will bind to the virus and neutralize it (i.e. prevent it from binding and entering your cells) and protect you from infection. This is the basis of how vaccines work – your expose B cells to a virus (typically attenuated or inactive virus) so that when you encounter the virus in the future you already have circulating antibodies. 

The Scary Biology of SARS-CoV-2

In the case of SARS-CoV-2, the virus enters a host cell by way of a receptor called ACE2. The ACE2 receptor is present in many cell types and tissues including the lungs, heart, blood vessels, kidneys, liver and gastrointestinal tract. Most clinically relevant, however, is that ACE2 is present in epithelial cells. ACE2 is present in epithelium in the nose, mouth, throat – the upper respiratory tract – where its symptoms are general no worse than the common cold.

In particular, the presence of ACE2 in the upper respiratory tract explains why many people who are infected with SARS-CoV-2 remain asymptomatic – the virus may remain there and never travel further down to the lungs where the infection becomes more severe. It’s only after the virus infects the lower respiratory tract, where it leads to more severe symptoms - such as trouble breathing - that patients infected with SARS-CoV-2 end up on a ventilator.

This is also explains the difference between SARS-CoV-1 and SARS-CoV-2. SARS-CoV-1, which first emerged in 2002-2003 and never progressed beyond Southern China (except for a few isolated cases), bypassed the upper respiratory tract (because it lacked the ability to infect those cells) and headed straight to the lungs, where it immediately made its presence known. Patients could then be immediately isolated and quarantined to contain further spread of the virus.

SARS-CoV-2’s nifty little evolutionary slight-of-hand – remaining in a person’s upper respiratory tract while the person remains asymptomatic – is largely responsible the transmissibility and spread of the virus. Patients who are asymptomatic are much more likely to spread the virus unknowingly by coughing or even just breathing near an uninfected individual (can you guess where this is heading?)

Furthermore, how SARS-CoV-2 hijacks the cell is unique, even in the world of viruses. As virologist Benjamin tenOever of the Icahn School of Medicine at Mount Sinai said, “it's something I have never seen in my 20 years of studying viruses.” What Dr. tenOever is referring to is SARS-CoV-2 unique ability to activate the innate immune system, but not the adaptive immune system. SARS-CoV-2 induces cells to produce cytokines (i.e. to call for reinforcements from the adaptive immune system), but it blocks their “call-to-arms” genes, that part of the immune system that attacks the virus’ ability to replicate. 

The result is runaway viral replication coupled with an inflammatory storm that is never answered by the adaptive immune system. These inflammatory molecules, largely cytokines, are what in turn lead to the respiratory issues and trouble breathing that are hallmarks of a severe infection.

Vaccines, Monoclonals, and Heard Immunity, Oh My!

If we haven’t developed a vaccine against the common cold, why should we believe we’ll be successful in developing a vaccine against SARS-CoV-2, after all, the coronavirus shares several features with viruses that cause the common cold? And if we are successful, will we need to vaccinate ourselves every year like we do against influenza? Furthermore, can’t we just wait for heard immunity to kick in and then we’ll all be set to get back to business as usual?

The answer to the first questions is almost certainly a resounding yes, we are indeed capable of developing a vaccine against SARS-CoV-2. We haven’t developed a vaccine against the common cold because there are so many varieties of the common cold is would take dozens of vaccines, each specifically developed for a particular virus, to significantly reduce your risk of getting the common cold. Unlike the common cold which is caused by a large variety of different viruses, SARS-CoV-2 is a single virus. It also has a very limited ability to “escape” the immune response, compared to HIV for example (this is why we haven’t been successful at developing a vaccine against HIV…its not technically feasible, at least not yet).

They key question is what percentage of the antibodies generated against SARS-CoV-2 are neutralizing? If you remember how antibodies are created, they are not all created equal – some are “born” with the ability to neutralize the virus (these are called neutralizing antibodies), while others only impair the virus but don’t completely neutralize the virus. Furthermore, what’s duration of any neutralizing antibody to protect us against a future infection? The answers to these two critical questions remain largely unknown as of this writing. 

In addition to having a limited ability to “escape” the immune system, SARS-CoV-2 has a low mutation rate. Influenza viruses, for example, have eight unique genomic segments that can be mixed and matched with other flu viruses. This feature of the influenza virus is what allows it to constantly mutate and change, which is why we must get vaccinated every year (we encounter a unique form of the virus every year). On the other hand, SARS-CoV-2 has a single unsegmented genome. So even when replication errors occur, they seldom lead to significant mutations like what we encounter with the influenza virus. This is another feature of SARS-CoV-2 that makes it an ideal target for developing a vaccine.

The absolute earliest a vaccine may be available is toward the tail end of 2020, so why can’t we simply open the economy back up and wait for heard immunity? Once 70% or so of the population gets infected, won’t we get this whole debacle behind us?

Sure, this is a great idea if you want an additional hundreds of thousands or potentially millions of Americans to die. Let’s be realistic here, the ones most susceptible to SARS-CoV-2 are mainly the old and the weak anyway, and truth be told, are probably only a few years away from the grave, right?

I don't actually feel the need to defend my position here, but I will anyway, albeit breifly. First, we can’t actually predict who will get a severe infection and die and who won’t. Second, we don’t yet know the long-term consequences of the virus - remember SARS-CoV-2 infects many tissues within the body so it’s highly probable some people who recover will have lasting organ damage. Third, are we - as a society - really okay with letting countless of our friends, family members, colleagues, and people in our communities die unnecessarily?

So how do we bridge the gap between getting the “heard” vaccinated and where we are today? Here’s where monoclonal antibodies come into the picture. You can think of a monoclonal antibody as the Olympic gold medalist of the antibody world. Monoclonals are the best of the best of the best when it comes to competing as a neutralizing antibody. Long story short, we could create a monoclonal against SARS-CoV-2 by identifying those individuals who generate the strongest immune response and clone their best neutralizing antibodies. These can then be manufactured at scale and used for prevention and treatment until a vaccine is available. 

Case Fatality and Infection Fatality Rates

The Case Fatality Rate (CFR) is the number of people who die as a percentage of people who are confirmed as being COVID-19 positive. Current evidence suggests the risk of death from COVID-19 is estimated to be ~1% overall, possibly lower, when factoring in everyone who has been infected but not formally diagnosed as having COVID-19. However, the CFR rises with age, from <0.2% among children aged nine years or younger to nearly 8% for seniors aged 80 years or older.

The Infection Fatality Rate (IFR) is the number of individuals who die of the disease among all infected individuals (symptomatic and asymptomatic). The IFR is likely lower than the CFR given the unknown number of people that probably didn’t have a severe enough infection to warrant hospitalization or testing. This is a challenging number to calculate given the unknowns, but recent studies suggest the IFR for COVID-19 is in the 0.5-1% range overall.

Are We Disciplined?

Remember all the viral load and viral shedding discussion from earlier? Well, turns out that masks can reduce how much virus an infected person sheds into their surrounding environment very effectively by stopping the particles that carry the virus. Furthermore, if you’re not infected, a mask can help reduce the number of particles you breathe in. There's no mystery how we can drop the R0 (naught) to below one and burn out the spread of the virus: masks, social distancing, and hand-washing. However, the major outstanding question that remains is...are we, as a society, disciplined enough to do it?

And while we should all be grateful to the efforts of countless scientists, researchers, and clinicians around the world who are battling SARS-CoV-2 on the scientific front, we should also be grateful for everyone around us who is practicing social distancing and who takes the time and makes an effort to wear a mask. Less we forget the stark reality we find ourselves living in: we are all on the front lines in the fight against SARS-CoV-2 and we all have our part to play.