Omicron - Current Thinking on December 2, 2021

There are a lot of pending answers on Omicron, such as: Is it more contagious than Delta? (Likely) Is it more deadly? (Probably not) Is prior immunity (through disease or vaccine) still effective? (Yes, but less) Here is my take on it.

The Omicron variant has over 30 mutations on the spike protein (which is about 1200 amino acids long). This is the "key" protein that allows the virus to get into cells. It's what our vaccines target to neutralize the virus the fastest. Unfortunately, mutations at the spike protein help the virus to gain the most evolutionary advantages.

Based on the standard rate of genetic code change of a particular viral lineage, then looking at all of the variety from the sequenced Omicron cases, scientists estimate that the strain spread from one (likely immunocompromised) host about 1-2 months ago. While South African scientists were first to identify the new variant, it's not clear that it evolved there. Looking back at old samples, scientists in Botswana also found it in their country about 4 weeks ago. Other countries in the region have not reported anything, but flights out of Nigeria have also had high rates of infection. It took less than 8 weeks for it to spread around the world to at least 2 dozen countries, many through vaccinated but infected travelers. Rates of cases have dramatically increased in South Africa, and hospitalizations have risen more recently as well.

chart showing how omicron compares to other strains of covid19

In one well-documented case of a traveler in Hong Kong, case 1 tested negative pre-flight, took a plane from South Africa to Hong Kong, and went to his quarantine hotel room. Travelers are tested routinely during their 14 day hotel quarantine. On day 4, his test turned up positive. Although he was not symptomatic, he was sent to a hospital for observation. He left his hotel room and was in the hallway briefly without a mask. A completely unrelated traveler (different flight, different origin country) in the room across the hall then tested positive 4 days after case 1 was in the hallway. Genetic analysis of their viruses show that the first traveler transmitted it to the other person.

Hotel quarantines are extremely strict in Hong Kong. Although there may be variations in implementation, there are standards in quarantine procedure in East Asia. Our supplier who travels frequently has described multiple quarantines to us. Guests are to stay in their hotel rooms the entire time. They get full room service from staff wearing full PPE. Food is delivered 3 times a day and left just outside the door. There are hallway monitors and video cameras. When you poke your head out to get the food tray, they make sure you don't linger. Chatting with others is not allowed. No one is allowed in the halls except for entering and exiting the quarantine. So we have to assume that perhaps case 2 picked up his food tray and was in the hallway briefly after case 1 left or maybe he heard all of the commotion and poked his head out briefly to see what was going on? Was there more interaction than that? Probably not. And that's what makes it all the more concerning. Omicron seems to be super contagious even with brief exposure.

In another crazy case, there were 2 flights that left South Africa for The Netherlands on Black Friday last week. All passengers had shown either negative results or proof of vaccination prior to boarding. During the flight, news about the variant came out. Upon landing the passengers were all required to test again. Surprisingly, 61 people tested positive, 14 with Omicron. To me, this suggests vaccine/immune escape.

Symptoms of Omicron seem to be different from the preliminary reports, but the reports were based on a very small sample in a younger population. There may be less smell/taste loss and more upper respiratory as opposed to lower respiratory symptoms, but let's wait for more comprehensive reporting in the next few days. While it may not be more severe than Delta, Omicron is not benign. Hospitalizations are starting to increase in South Africa due to this new variant, which has quickly out-competed every other strain including Delta in South Africa. Their vaccination rates are low - less than 25% - but they have weathered 3 previous waves of infection including Delta already. While we don't know what percentage of people have had the disease already, it's safe to assume that most people have antibodies either from vaccine or from previous infection. Previous immunity, acquired either through vaccinations or disease, is likely why many cases have been mild - which is somewhat encouraging.

What's most concerning to me is that, within 8 weeks, this virus has spread from a single host to an incredible number of people worldwide. Scientists can model various mutations for theoretical risk based on changes to the spike protein, and this one has a lot of bad traits, like increased contagiousness and regions that decrease effectiveness of the vaccines.

It mutated so much that, in fact, PCR no longer detects the spike protein's genetic sequence. This is good and bad. Bad because it's so mutated that our immune systems may not recognize it as well. Good in that the PCR test can actually "detect" Omnicron without having to do actual genetic sequencing (much more involved and taking several days at minimum). PCR, which stands for polymerase chain reaction, is also called NAAT, which stands for nucleic acid amplification test. The virus's genome is about 30,000 bases long - basically a chain made up of 30,000 RNA (ribonucleic acid) bits. In PCR we look for sections of the genetic code by first amplifying particular sections and then looking for the signal of the amplification. If there were COVID-19 viruses in someone's nose, the PCR would be able to detect tiny parts of it. The CDC has a list of standard PCR primers for the COVID-19 virus. A primer is a section of about 20 bases (RNA bits) that, if matched with the virus sequence, would allow for the signal amplification. The CDC's primer list includes short sequences from various parts of the virus, like the spike protein (S), nucleocapsid (N1, N2), and other regions. One of the more common testing machines (ThermoFisher TaqPath) uses 3 primer sequences to look for COVID-19, and one of the primer sequences is for the spike protein. Because of the mutations, that particular test would only detect 2 of the 3 sequences. If you hear about the "S-gene dropout" in the news, this is it. Because it mutated so much, we can no longer detect the spike protein gene, while still detecting the other two gene sequences, which can actually lead to much faster detection of the Omicron variant.

Not all PCR tests look for the Spike protein's genetic code though. Combination Flu/COVID or Flu/COVID/RSV tests generally do not include the spike protein as one of the sequences. Locally, our doctor's offices use the combination flu/COVID/RSV (GeneXpert) tests when someone arrives for testing due to symptoms, which does not look for the S-gene. For screening tests, like mass testing at schools, the specimens are often sent away to a high-throughput testing lab, which often use the ThermoFisher machines and would detect the "S-gene dropout" indicating Omicron.

Is this whole S-gene dropout/PCR discussion relevant to a patient? Not really. But it's helpful to know about this because it clarifies how and why we can actually track Omicron spread in the US whereas it took so long for us to confirm the Delta variant. We can't easily track Delta spread, and doctor's offices can't tell you which strain you had because it wasn't that different from the Alpha or the original. As Omicron spreads here, we might readily know if you have that or Delta. Note that in the US, 99% of recent infections are all due to the Delta variant, so none of the previous ones are relevant anymore. Now the epidemiologists are tracking exactly how Omicron overtakes Delta to figure out how much more contagious it is. In South Africa, Omicron has overtaken Delta within weeks, which is pretty crazy. It's already the dominant strain there. And we thought Delta was super contagious!

Omicron is so new that we don't have a lot of clear science on it yet. That takes a few weeks. In the meantime, we do have some science on the older strains. The Mu variant has the highest vaccine/immune escape thus far. In a test tube, it takes 10 times the amount of antibodies to neutralize the Mu variant compared with the original. It just so happens that if you get one of the mRNA shots as a booster, you can get at least 10 times the amount of antibodies you had before. If you haven't gotten the booster yet, do so soon before the omicron variant pops up in your community. Once the variant arrives, there will be high rates of transmission within a month. During that time, all of the last-minute/reluctant/hesitant/unvaccinated people will be scrambling to get their doses so the vaccine clinics may be busy and more difficult to schedule. Plus, vaccinators may be sick themselves or need to stay home with kids due to school closures. Currently there are 2 known cases in the US. I predict that by January 1st there will be at least one case in more than 50% of counties in this country. By February 1st we will be in our Omicron surge.

One of the leading scientists looking at immune escape estimates that Omicron will require 10-35 times the amount of antibodies. As a comparison, Delta takes 4 times the amount of antibodies to neutralize. When talking about vaccine effectiveness, Omicron definitely reduces effectiveness by a lot. My best guess is that it would provide half of the amount of protection as before. Twice as many previously immune people would have symptomatic infections, and twice as many will need to be hospitalized. The vaccine developers are most likely gearing up manufacturing of the new strain already, even before they report results of the neutralization assays. As soon as it's approved, there will be a phased rollout of the omicron booster for people 6 months out from their last dose (again, guessing). What does this mean for the "natural-immunity" folks who had the disease? It means that their antibodies are also going to be far less effective. Vaccines can boost immunity all around, even after illness. Make sure that you are maximally protected to reduce the likelihood of severe disease.

The previous two paragraphs are my predictions, which are based on the best evidence we have to date (which is not a lot). I might be wildly wrong, but everyone needs to start somewhere with some operating assumptions when trying to plan for the next few months. This is just what I'm thinking and where I see this going, which you may or may not find valuable. I personally feel pretty safe, having been boosted already and relatively "young." But I'm concerned for the elderly again, the immunocompromised, and the not-yet-immune population. I'm also concerned about healthcare worker burnout. I know many healthcare workers who have retired earlier, changed positions, or decided to travel around for better pay. We have to go back to the "flattening the curve" concept. Even with a "mild" disease, if many people get it all at once, some people will have severe symptoms and overwhelm hospitals. When hospitals are too busy you may not get prompt treatment for anything.

My advice: get maximally vaccinated and then brace for impact.

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