Omicron And Perhaps A Return To Basic Principles

With a primer in basic evolutionary biology

I had been writing about Covid on my personal Facebook page ever since the pandemic became an American issue in March of 2020. I recently stopped doing that for a variety of reasons. One of those is simply that it has become almost impossible to truly know what is happening all of the time. I had become a primary source for information for a number of people, and I did not want anyone to think that I was always right. I also felt that I was at risk of not being perfectly up to date with the information that I was presenting. This does not represent an attempt to start routinely writing about Covid again in a predictable manner.

I have decided to try out this platform as a place to publish opinions. I want to be clear that there are still many interpretations of what is happening. I want to be clear that I am not always right. This is not going to be done in a way that attempts to publish information in a purely unbiased manner. I don’t believe that is honestly possible in the current environment. As always, I will do my best to be as honest as I possibly can.

With that said, let’s get started:

A Primer In Evolutionary Biology

Throughout the pandemic, we’ve had a tendency to treat The SARS-CoV-2 virus as though it were the first virus to ever plague humanity. We’ve had a tendency to throw out even the most basic principles of biology in favor of either panicked modeling or short term studies that appear to lean away from those principles. What we’ve learned however over time is that this virus is actually rather boring. It is also becoming very predictable. To understand what is happening one has to understand some of the basic principles underlying viral evolution.

A virus survives because it can replicate faster than the organisms that it infects can destroy it. Period. A virus cannot and will not spread through a hard, a community, a pack, or any other cluster of creatures without following this basic principle. It is because of this, that we can predict how a virus is likely to evolve over time. The following give a virus an advantage:

1. It replicates very rapidly. A virus that is able to make copies of itself quickly is more likely to go on to infect others than one that replicates slowly.

2. It spreads very easily. Viruses that are more contagious are more likely to survive than those that don’t spread easily. An airborne virus has an advantage over a virus that spread via droplets. A virus that spreads via droplets has an advantage over a virus that spreads via blood or sex.

3. It produces mild symptoms. Contrary to the panic we are seeing, the evolutionary advantage goes to an organism that produces fewer symptoms. In fact, a virus that produced no symptoms would have an absolute advantage. Humans tend to self isolate more when symptomatic, and they tend to avoid other humans that are symptomatic.

4. It doesn’t kill its host. The majority of viruses are NOT lethal. Lethal viruses with rapid transmission tend to become less lethal over time. A dead host rarely effectively spreads the virus. Killing your host is a disadvantage. Those that do kill their hosts have an advantage if they don’t do so quickly.

5. It leads to chronic infections. A number of viruses that lack some of the transmission advantages we note above survive by producing long and chronic infections (think HIV or Hepatitis B).

This list is not comprehensive, but it gives us an idea as to where viral evolution is likely to trend over time. The perfect virus from an evolutionary perspective would spread through the air with no symptoms, rapidly replicate, and then cause widespread chronic infections that produced no symptoms. Those blissfully unaware hosts would then spread the virus far and wide while they lived perfectly normal lives.

Now, that doesn’t mean that we never see a virus pop up that doesn’t have these advantages. One of the ways a virus can spread that I didn’t mention above is that it can jump between species. When a virus first jumps to a new species, it is likely not well adapted to spread in that species.

More Complex Is Often Less Adaptive

We have a tendency to think that more complex organisms are harder to contain, but the opposite is typically true. If we were attempting to create an analogy, imagine that you decided that you wanted to go in to the woods near my home and kill all of the bears. If we made a coordinated attempt to do so, it is highly likely we could entirely eliminate bears from the ecosystem. Please note that I’m not suggesting we do such a thing.

After you’ve envisioned how one might eliminate all of the bears, now imagine eliminating all of the ticks. I suspect you cannot imagine achieving this. The bear is a complex, slow developing, slowly evolving creature. The ticks are more simple, rapidly multiplying, and more rapidly mutating creatures. The ticks are actually harder to control. Now, a single bear may be more likely to do more damage to you in a fight over a single tick, but that doesn’t mean that ticks overall don’t have the survival advantage if you go to war to eliminate them.

Viruses are like this as well. A virus like Smallpox is very complex. It mutates slowly. It actually spreads with relatively less ease than Covid. It can only spread after infecting a person and generating viremia (widespread circulation in the bloodstream). Thus, a single intervention may be sufficient to eliminate it.

There is a spectrum of viral complexity. Viruses with more interdependent parts mutate more slowly. Viruses formed of DNA mutate more slowly than viruses formed of RNA. Influenza is an RNA virus. Smallpox is a DNA virus.

Similarly, a simpler infectious mechanism is an advantage. A virus like Smallpox requires a systemic infection to spread effectively. A virus like Rhinovirus or Influenza can often replicate and spread in the respiratory tract before the body mounts any type of adaptive immune response. Thus, even a person with substantial immunity that would likely prevent any serious illness to that virus may still be able to become a vector to spread it to others.

Coronaviruses, including beta coronaviruses to which SARS-CoV-2 belongs, are rapidly replicating RNA viruses that do not require obligate viremia. This means that they rapidly mutate AND have a relatively simple mechanism of infectiousness that is both more adaptable and harder to control. There is a reason why we’ve never been able to cure the common cold.

SARS-CoV-1 Versus SARS-CoV-2

The original SARS infection was much more lethal. It was much more symptomatic. It also spread less efficiently. When it made its jump to humans, these features put it at a distinct disadvantage. Despite early transmission, every single chain of transmission was ultimately identified. Without shutting down the world, and implementing just a few inconvenient interventions, this virus was completely contained and then ultimately eliminated.

On the other hand, SARS-CoV-2 (The virus that causes COVID) has been so difficult to control in part because it is nowhere near as severe. The majority of cases have always had mild symptoms. This means that the majority of people spreading it don’t know they are doing so. It means that people don’t avoid infected people, because they don’t show signs of being infected.

The virus also spreads through the air. This means that in a poorly ventilated space, it can infected people who aren’t in close proximity. It can even spread through ventilation systems with suboptimal filtration and infect people who were never even in contact with the source of the infection.

These features are critically important to understanding what is happening. Despite a lot of people getting very sick, the virus has spread precisely because the overwhelming majority of people didn’t get very sick. This is why this virus has eluded unprecedented public health interventions, while the original SARS was controlled through much less aggressive efforts.

The Virus Is Still Not Perfectly Adapted

While no virus is ever perfectly adapted, the Achilles Heel of SARS-CoV-2 is that it is killing too many people. This has given it a distinct disadvantage. While our efforts have not been successful at containing it, the virus clearly still has been slowed to a degree by those efforts. While the long term public health benefits of that slowing remain unclear, the short term evolutionary disadvantages to the virus are.

In light of this, we would expect any forms of the virus that have more advantages over the current version to ultimately take over. These advantages as I’ve pointed out give the virus a greater advantage when spreading form person to person, and that version that spreads more easily will ultimately outcompete versions that don’t have those advantages.

Thus, we would expect that over time, future versions of the virus would become both more transmissible and less lethal. That said, not every variant is going to be both. When we see variants emerge that begin to take over, it does suggest that the variant has one of these features as it applies to the local population where it occurs. For example, we saw a variant that appears more transmissible with Delta, but it did not manifest any obvious declines in lethality.

Transmissibility and Immune Escape

None of these adaptations occur in a vacuum. The population within which the virus is evolving helps to shape these changes. If a certain population has some degree of immunity for example, the variants that escape that immunity will be more transmissible. Thus, over time, we expect the virus to try and adapt away from immunity. This does NOT mean the virus is likely to become more lethal. That’s not an advantage. Rather, it will select for versions that are less impacted by pre-existing immunity to transmission.

We’ve seen certain prior versions of SARS-CoV-2 show evidence of immune escape. The Beta, Gamma, and Lambda variants in South America and South Africa both had this feature. It is important to remember that the majority of the world was not immune at that time. When Delta first appeared in India, it rapidly took over, likely as its’ ability to replicate more quickly gave it a transmission boost that was more advantageous than immune escape. We will note however, that some of those escape features appeared on the Delta Plus Variant, allowing it to gain both advantages.

Unless you can create true herd immunity, we’d expect escape from any intervention over time in any virus with the capacity to mutate frequently. This doesn’t just apply to viruses. It’s why we see antibiotic resistant bacteria. If you give someone an antibiotic, and a bacteria has a mutation that allows it to escape the impacts of that antibiotic, that bacteria will start to beat out the other bacteria that are susceptible. Similarly, if a certain type of antibody is prevalent in a population that neutralizes a virus, viruses with mutations that escape that antibody are going to have an advantage. That advantage becomes a transmission advantage that allows it to take over.

Applying All Of This To SARS-CoV-2

With the push toward evidence based medicine, we’ve had a tendency to ignore some of these really basic principles when applying interventions to COVID. I am not arguing against evidence based medicine, but the problem is that this virus is new. As it is new, we have no idea how any study will hold up over time. We also don’t know how the virus is going to change over time.

We’ve learned a few things about the virus over the last couple of years that should make us very skeptical of short term data. This virus is rapidly mutating. Each version of the virus has features which change the efficacy of just about everything we are doing. We can create studies that look at how effective something we did was. It’s very hard to know how effective it will remain going forward.

As we attempt to determine how things are likely to play out over time, it’s important to lead with principles, allowing the data to fill in the details over time. So far, this virus has not violated any basic principles. We did mischaracterize it against those principles early on, and that has led to a number of the errors we’ve made.

Complexity And Herd Immunity

For true herd immunity to develop in a population, that population has to have sufficient immunity to a virus that each individual can on the average spread the virus to fewer than one additional person. We look at something called the Reproductive Rate (R). When we look at a population with no immunity, we infer what that rate would be an call it R0. When we look at current immunity, the predicted rate is called Re. When Re is less than 1, a virus should burn out. It is important to note that herd immunity can change over time. Changes in immunity or the virus can take a population that had herd immunity and allow it to become susceptible again.

Early on, it was believed that the spike protein was a complex protein that would no longer be able to make the virus infectious if it were substantially mutated. This led to the idea that we could achieve herd immunity by generating the presence of a substantial amount of antibody to that spike protein within the general population. When we moved beyond “flatten the curve” strategies and on to suppression strategies, the idea was that we keep the virus at bay for long enough to produce a vaccine that was effective at generating antibodies to that spike protein.

Similarly, strategies that did not get as much press, such as those put forth in The Great Barrington Declaration, also focused on herd immunity. Suppression wanted to achieve it via vaccination. The alternative was protecting vulnerable people while allowing it to move more rapidly through low risk people. The goal there was also herd immunity. I admit that I personally pushed for strategies that involved herd immunity.

Here’s the issue. We are never going to develop herd immunity to COVID. It is time to admit that we are never going to develop it. Before the current surge, over 80% of Americans had antibodies. Over 90% of Brits had antibodies.

If we want to understand what happened, we need to go back to principles. The development of herd immunity was based on two premises that have both proven to be objectively untrue:

1. The virus wouldn’t be able to remain infectious with significant mutation to the spike protein

2. Those who had antibodies wouldn’t be able to spread the virus to others

I think that it’s important to point out that this doesn’t mean that the individual may not retain substantial protection against becoming critically ill with antibodies. How that evolves over time also remains to be seen. However, it is VERY clear that herd immunity in the sense that the virus disappears is never going to happen. Covid clearly spreads from individuals with antibodies, and the spike protein can clearly remain infectious with mutation. It has in fact become MORE contagious with mutation.

Sustainable Intervention And Sunk Costs

If we are being honest with ourselves, we are now sitting at a point where the entire world has engaged in an unprecedented response to a virus that is based on bad predictions. If we’d truly understood these properties of the virus back in 2020, it is highly doubtful we’d have chosen the path we are on. The problem of course is that we are already almost two years down this path.

Antibodies wane after vaccination. This is NORMAL. Immune memory remains. The original goal was to vaccinate a substantial portion of the population. That population would remain immune. If they did encounter the virus again, they would rapidly generate new antibodies to fight it.

The problem is that those antibodies may come in time to prevent the most severe illness, but they do NOT happen with the speed necessary to prevent the spread of the disease. In this way, only those with very high antibody titers may suppress the disease sufficiently to prevent spread. These are of course titers at levels that are NOT sustainable over time.

Obligate Viremia And Why The Current Strategy Is Going To Fail

What we’ve discovered is that each new variant requires a progressively higher quantity of antibodies (higher titers) to neutralize it. This may be theoretically blunted by the development of a vaccine that focuses on a new spike configuration, but the odds are overwhelming that we’d begin to see variants that outran that new configuration as well.

The current strategy is to push boosters. I want to be clear that there is currently no evidence that boosters do anything for long term immunity. They do rapidly increase antibody titers, so in the short term, they do reduce acute infections. At the very least, they reduce infections that are identified. It remains unclear whether they reduce secondary transmission to others, although it’s possible.

If the virus needed to invade the body in a widespread fashion to be contagious, this might still work to some degree. Those who avoided serious illness would also be less contagious. The problem of course is that an infection limited to the respiratory tract, and functionally causing a head cold, is still sufficient to spread the virus.

In addition to this, vaccination alone has a fatal flaw in the long term control of this virus. Antibodies aren’t always expressed in high volumes on mucosal surfaces (like in your nose or throat or GI tract). They also tend to last for shorter periods of time on those surfaces, which is why a virus can spread if it avoid obligate viremia. The vaccine flaw however is the dependence on IgG antibodies.

IgG is expressed on mucosal surfaces, and it is highly effective in the blood stream. The real powerhouse however of those surfaces isn’t IgG. It’s IgA. IgA isn’t stimulated by an injection in to your muscle, as this skips the mucosal surface. Perhaps the addition of an intranasal vaccine would overcome this weakness to a degree, but that’s not what we are doing right now.

In light of this, it is inevitable that over time, every booster is going to reduce the ability to spread the virus at best temporarily. Similarly, as the virus mutates, it is going to be effective in all likelihood for shorter periods of time. This strategy is a band aid at best if the goal is to slow transmission.

The Effectiveness Of Prior Infection

All of the issues that I’ve addressed with vaccination are also issues with prior infections. However, a prior infection does potentially have two advantages against vaccination in terms of being able to spread to others:

1. The immune response (both antibodies and T cell responses) is aggressively generated to the entire virus. This means that it likely requires more mutations before immune escape.

2. The body will likely develop immune memory involving not just IgG, but also IgA. This means the mucosal response is likely to be stronger.

As the body sees reinfections however, the immune response will adapt to the new configuration of the virus. This is what already happens with influenza. We have some memory to most strains. When those strains partially escape our memory, we still have partial neutralization from those prior infections. We tend to have more mild illness, and the body then develops immune memory to the new strain. When we have a new strain that jumps from an animal species to which we have more limited crossover immunity, that tends to be when we see pandemic influenza (like the Spanish Flu).

As SARS-Co-V-2 evolves in a highly immune environment, we would anticipate that the illness will be more mild, and the body will naturally evolve its’ immune responses to adapt to the new variant. The virus will then mutate in a way that again allows for more mild illness. The body will then further adapt its’ immune response to those mutations. I’ve previously referred to this as “the immortal dance.” This is why in spite of what you would think by watching the news, we’ve actually ended all prior pandemics without a vaccine. That doesn’t mean a vaccine is bad or can’t have benefits, but the idea that the pandemic won’t end until everyone is vaccinated is inconsistent with all of history. The disease will survive, but severity of illness will decrease.

What Happened With Omicron

I’m attaching two news article that give us some early insights in to this variant:

https://www.bloomberg.com/news/articles/2021-12-17/s-africa-says-hospitalizations-in-omicron-wave-much-lower?utm_source=facebook&utm_medium=news_tab&fbclid=IwAR05NhKZ7Q7XafzbWEyOHO0zPdmZOR7wQqjpzB9LZN5McO68DawPs1qmA-Q

https://www.cnbc.com/2021/12/16/omicron-lung-infection-less-severe-replicates-faster-than-delta-in-human-airways-study.html

You can copy and paste the above links in to a separate window if you would like to read the articles.

More Contagious, Immune Escape, Likely Less Lethal

In South Africa right now, new cases of Omicron Variant are exploding. Really, new cases are exploding everywhere, but it was identified in South Africa first. The article looks at what is happening there, and this really shows the rest of us what the implications are for the broader pandemic.

Cases are rising much faster than prior surges with other variants. It is likely we will see rapid increases in cases once Omicron takes hold in a place. It is notable however, that there are FAR fewer hospitalizations compared to cases at the same time in this surge than compared to prior surges. Also, a substantial portion of hospitalizations have been incidental and for other things. This suggests strongly that the average infection there is much less severe than in prior surges.

The second article gives us a potential explanation as to why. The virus replicates very quickly in the bronchial tree. That means it explodes in your airway before it really reaches the lungs. This likely has two impacts. It means that it more rapidly becomes contagious, and it likely produces higher viral loads while becoming contagious. That virus is also closer to the mouth, and thus we may see higher viral loads entering the surrounding environment to infect other people.

On the other hand, the virus is replicating more slowly in the lungs. The virus actually enters the body and causes severe illness through the lungs. This one mutation may very well set the stage for a more contagious, but less lethal variant. This movement of the replication to the bronchial tree from the lungs themselves may actually confer multiple separate evolutionary advantages to the virus.

There are also many mutations that have allowed this to happen. Those mutations have changed the configuration of the spike protein. That has allowed immune escape. So far, this appears to be the worst with vaccine acquired immunity, but it also has a legitimate amount of immune escape against naturally acquired immunity as well. As I previously noted, immune escape is also an evolutionary advantage.

In this way, Omicron has in a fascinating (and yet entirely in line with principles) way begun to take over. These mutations appear to have conferred on Omicron immune escape, more contagiousness, less lethality, and more mild overall symptoms. It is not surprising that it is starting to win.

Pitfalls To Watch Out For

We can’t state with absolute certainty that the lower apparent lethality is related to the high degree of prior immunity in South Africa from prior infection. While there is a clear mechanism by which the variant may be less severe, we can’t entirely rule out this mechanism of partial protection from prior immunity. While not as high as South Africa, it is important to note that prior infections are also quite high in the US, so this mechanism may still apply here.

Right now, the impacts around the world still haven’t entirely declared themselves. In Denmark, hospitalizations began to drop right as Omicron spiked. In the UK, they rose. Denmark was dealing with a significant Delta surge and has low prior immunity. UK has had a harder to explain case pattern with slow steady mortality. Omicron isn’t completely dominant in either yet, but it almost certainly will be in the near future. I will say that as of now, we’ve still had fewer officially documented Omicron deaths worldwide than I saw Delta related deaths in my own hospital last month. That may change, but it is still the case as of now.

Omicron in America

For a brief period, the worst documented Omicron outbreak in The US was in Ithaca, NY at Cornell. This is currently being supplanted by…Manhattan. It will likely soon be everywhere.

I’m attaching the links to the CDC vaccination website and the NY State Department of Health:

https://coronavirus.health.ny.gov/positive-tests-over-time-region-and-county

https://covid.cdc.gov/covid-data-tracker/#vaccinations_vacc-total-admin-rate-total

The other information I will reference on here can be found at https://CovidActNow.com

First things first. In spite of national rhetoric, it is very clear that no amount of vaccination is going to control an Omicron outbreak. The initial documented outbreak was on the Cornell Campus, which had a 97-99% vaccination rate. Tompkins County, where Ithaca, NY is located, is 80% vaccinated. There is substantial booster uptake in the region as well.

Notably, it is also the MOST vaccinated place in the region. It was in fact the example pointed to before this by the state as to what everyone should be doing. The outbreak happened very rapidly. It also notably led to zero cases of severe illness as of now. The outbreak was over 900 people. I don’t believe that all cases were sequenced, but of those that were, over 100 were documented to be Omicron.

The current worst outbreak is in NYC, with the worst borough being Manhattan. It is notable that Manhattan had the fewest cases per capita of the boroughs during the initial outbreak in March of 2020. It is also notable that in Manhattan has seen almost 100% of the population receive at least one dose of vaccine, with 80% fully vaccinated. While we don’t get official data on booster dose rates from the CDC in real time per county, it does appear that the city is also boosting roughly 100,000 people per week if one digs in to the numbers.

It is notable that New York has certain vaccine rules for schools, vaccine passports to enter businesses, vaccine mandates on business, mandates on public workers, the extraordinarily high vaccination rate, some of the nation’s most aggressive contact tracing, and some high profile police enforcement of those cases where people tried to enter a business without being vaccinated. Despite this, the city rapidly developed the worst outbreak in the country. This suggests that all of these things have not prevented Omicron transmission to any degree that is sufficient to meaningfully slow the issue. These policies are both becoming popular worldwide, and they are clearly not working.

Also notable however, is that there is currently no spike in hospitalizations from COVID within the city. Whether this is because of the high vaccination rate, a lower severity of illness, or we just haven’t seen the cases hit the hospital yet remains to be seen.

Let’s Be Realistic About Our Responses

Short of a complete lockdown in a way unlikely to happen in the US, we will likely not see substantial slowing of Omicron transmission. There is some evidence that disease severity may be mitigated by booster doses, but that evidence is really still dependent on a lot of assumptions. It is very likely that booster doses will not be sufficient to stop transmission. Any more aggressive interventions will likely only delay transmission.

At the astonishing rate of transmission we are seeing, the odds are quite high that almost everyone in America is going to be exposed to Omicron within the next month or two. It is extremely unlikely we will prevent that. It is unclear if this will be a crisis at the hospital level, or a blessing in which a less severe Omicron displaces a more severe Delta as the dominant variant. I don’t know.

At the very least, lets do things that are in line with those same evolutionary principles I discussed. Any closure or lockdown will stop working the moment it stops. Any vaccine mandate is likely to lose effectiveness at preventing transmission. An individual choice to be vaccinated or boosted MAY prevent some infections and likely prevents severe disease in some who are high risk or haven’t had a prior infection.

Let’s otherwise be realistic in the understanding that we are NOT going to stop this. We certainly aren’t going to stop it by doubling down on the same things that didn’t stop it last time. We certainly aren’t going to stop it by engaging in unsustainable interventions that will not see any long term compliance. Mandates and vaccine passports are clearly insufficient to meaningfully slow this, and we have strong evidence of that from New York and Ithaca.

I fear we are caught in this narrative where we are so invested in a suppressive strategy, that we cannot come off of it even when it makes sense. This applies to both politicians and many of my colleagues. We don’t stop doing things even when they are both divisive and ineffective.

To prepare, we need appropriate triage processes in hospitals in case we see a hospital surge. This includes a better definition of futility when resources are strained. We need to strongly reconsider policies being pushed that are causing healthcare workers to flee in some of the hardest hit areas. Vaccine mandates in Central and Western New York have brought the healthcare workforce to a pandemic low right as Omicron is hitting. We really ought to consider rapidly expanding production of antivirals with potential and the monoclonal antibodies that we have which are likely to still have some efficacy against Omicron. There are some, but they are in shorter supply than would be ideal.

I think the most important thing is to stop panicking. That is not helping, and panicked people are making bad decisions in which they double down on things that aren’t as effective as we’d like for them to be. They are also fighting with others, which is diminishing compliance with any intervention at all. This could lead to another crisis. If this variant however maintains the properties it seems to have, in which it is less severe, it could also be the beginning of the natural end of the pandemic. We don’t know, but we shouldn’t simply assume the worst.

Regardless, it seems like it’s time to stop flip flopping our responses around short term data. This is a virus that is following the rules we’d expect from similar viruses. Unless proven otherwise, let’s start treating it like its’ going to follow the expected patterns we’d expect according to basic scientific principles.