Omicron Variant and Endemic SARS-CoV-2 Unknowns
Updated: Jan 4, 2022
A SARS-CoV-2 variant, with a high number of mutations, has the potential to block our escape from the COVID-19 pandemic. Omicron is one such variant with many mutations. It is even infecting those with existing immunity.
Vaccinated and naturally immune individuals have been infected by Omicron. Data shows breakthrough infections can happen for those who recently received a booster. If Omicron were just as lethal as Delta, then we could be right back at square one: No effective vaccine, no pre-existing immunity.
Fortunately, Omicron causes a mild infection in most people. The UK National Health Service (NHS) reported emergency room visits and hospitalizations for Omicron infections are much lower than the Delta variant.
"An individual with Omicron is estimated to be between 31 and 45% less likely to attend A&E [emergency room] compared to Delta, and 50 to 70% less likely to be admitted to hospital." - UK NHS
An Ontario, Canada pre-print (not yet-peer reviewed study) reported out of 6,312 Omicron infections there were 21 (0.3%) hospitalizations and 0 (0%) deaths, compared to 116 (2.2%) hospitalizations and 7 (0.3%) deaths in the 8,875 people from the Delta group (N=8,875). The Omicron and Delta infected cohorts were matched among demographics and adjusted for vaccination status.
However, it is important to remember there is a non-zero number of Omicron hospitalizations. So even with a less severe variant, if the transmissibility is high enough, that variant might still stress the healthcare system.
Omicron's reduced infection severity can be attributed to intrinsic characteristics of the variant, and existing immunity from vaccination or previous infection.
The intrinsic factors relate to the variant's poor ability to infect the lungs and spread from cell to cell. Reduced Omicron infectivity in lung tissue appears to be due to 3 specific mutations in the spike protein. These 3 mutations inhibit the formation of syncytia, which are fusions of human cells. Syncytia help viruses pass directly from one cell to another while shielded from neutralizing antibodies.
Reduced fitness in lung tissue is only part of the reason Omicron infection is less severe. Another reason being the high prevalence of existing immunity in the population. While the vaccines were not designed against Omicron, diversity in the immune response helps protect against the variant. The same is true for those with natural immunity.
Clonal Response and Immune Memory
When your immune system responds to a virus or a vaccine antigen, many T and B cell clones specific to that virus or antigen are activated. These clones divide, giving you trillions of foot soldiers to fight an infection.
Each clonal population responds to a different epitope on the virus. An epitope is about a 5-15 amino acid sequence from a full-length protein. To put the size of an epitope in perspective, SARS-CoV-2 uses the 1,273 amino acid long spike protein to infect human cells. You can read our explanation of epitopes in the Protein Background section here.
After beating the first infection by a virus (primary infection), most of the T and B cell foot soldiers go into apoptosis, which is programmed cell death. But a small representative fraction of the clonal population become long lived memory cells.
Collectively these memory cells are your memory repertoire. Cells from the memory repertoire are activated and rapidly divide if their epitope is encountered again, as in secondary infection. This time the process of viral neutralization is much faster. As a result, there is reduced risk for severe breakthrough infection or reinfection.
SARS-CoV-2 variants have specific amino acid mutations, or changes, compared to the virus's original spike protein sequence. For example, in the spike protein, the Delta variant contains ~13 amino acid mutations, and Omicron has ~30 amino acid mutations. These changes allow the virus to occasionally escape from antibody binding.
The memory repertoire covers a very broad collection of viral epitopes. Which makes it less likely that all epitopes on new variants will completely escape your immune memory.
Omicron can escape most neutralizing antibodies but many T-cell clones from vaccination or previous infection still bind the virus.
A recent pre-print from Adaptive Biotechnologies (Adaptive Biotechnologies have the only T-cell test in the USA with an FDA EUA) reported 70-80% of T-cell clones from previous infection or vaccination recognize Omicron's spike protein. A separate research group in South Africa also found 70-80% of T cells from vaccination or past infection are active against the Omicron's spike protein. In people with natural immunity, other, less mutated parts of SARS-CoV-2 are also targeted by T and B cells.
T-cells act after other cells are infected. This is why a breakthrough or reinfection by Omicron usually leads to mild symptoms. Fortunately, immune memory allows your immune system to take the upper hand. T-cells are among the fastest dividing cells in your body, which helps beat viral replication.
Despite having symptoms, the likelihood of a severe reinfection or breakthrough infection is low. The below charts demonstrate how antibody evasion and partial T cell evasion affect relative immunity.
Life With Endemic SARS-CoV-2
The reduced severity and partial immune recognition of Omicron are good news for our future with SARS-CoV-2 endemic virus. While a very mutated variant like Omicron can escape antibody-mediated immunity, it struggles to escape T-cells. This is a great demonstration of the diversity of an adaptive immune response.
Immunity is on a continuum and can be defined a number of ways. For example, you can independently consider immunity to colonization, symptomatic infection, severe disease, critical disease or death.
Omicron's lesson is that even with a breakthrough infection by a mutated variant, preexisting immune recognition of SARS-CoV-2 can protect you against severe disease. This will likely apply to current and future variants.
Fortunately, you can develop immune recognition through vaccination, so you don't have to be infected when your immune system is SARS-CoV-2 naive. In the USA there are 3 approved vaccines (Pfizer, Moderna and Johnson & Johnson).
On December 31st, 2021, Novavax submitted an FDA approval application for their protein subunit vaccine. People wary of the existing mRNA vaccines might find comfort in Novavax's more traditional approach. So, there are options for those who want to be vaccinated. Which is a very wise choice if you are at risk for severe disease.
Importantly, despite the partial immune escape, recovery from Omicron likely protects against other variants, such as Delta.
Cure-Hub's antibody array data also shows a more diverse immune response in those with natural immunity. Hybrid immunity, which is from infection recovery and vaccination, appears to have the strongest response in our neutralizing antibody data. Typically, a strong immune response leads to strong immune memory.
Taken together this shows the vaccines provide you with partial lasting immunity, then if a natural infection occurs, you may get the added diversity of a natural immune response. With a comprehensive immune response like this, future variants may escape some of your immune system but severe disease is less likely. This might be the path taken by existing endemic coronaviruses like OC43 and HKU1.
While the data presented here paints an optimistic picture SARS-CoV-2's future as an endemic virus, there are reasons to reserve judgement.
An immune phenomenon called Original Antigenic Sin (OAS) needs to be carefully evaluated. In OAS the immune system responds to new pathogen variants unproductively. This is due to its reliance on memory of similar, past variants. The new variant might have some conserved epitopes which induce the memory response, but the response to those epitopes is not able to neutralize the virus. Due to preference for a memory response over a new response, the immune system is inhibited from redirecting the immune system away from an unproductive response.
OAS is a known risk with the flu virus. Over a period of years, the flu virus mutates away from its original antigen, then we have a severe flu year.
In bad flu years, there is often a generational divide for disease severity. Where a specific generation is more at risk because their immune memory was established against a flu strain that does not overlap with the circulating strain.
For example, during the Swine Flu epidemic, middle aged people were most at risk, while those over the age of 60 were more protected due to exposure to some ancestral strain.
The below figure does a good job of explaining how OAS works in practice. Although the figure is labeled for antibody responses, OAS has been observed in T-cells.
The phenomenon of OAS calls into question repeat vaccination with the same exact vaccine. Or vaccinating after natural immunity has been established. This is because continually boosting the immune system with the same antigen may select for the specific T and B cell clones best able to neutralize the antigen, at the cost of clonal diversity.
There is uncertainty about OAS and its effects on vaccine boosters. Much of OAS foundational research is in the influenza virus and will need to be examined in SARS-CoV-2. Not all of the influenza research is negative for repeat vaccination. For example, a 2015 paper from Norway shows enhanced antibody response with yearly vaccination.
Another unknown involves the genetics of future SARS-CoV-2 variants. Omicron has mutations that stop it from infecting the lungs, but the virus could recombine or naturally drift back to a version that infects the lungs. It is worth noting the pathology also involves thrombosis, or clotting. This may still occur with Omicron.
In many corners it is assumed viruses mutate towards a less lethal version, but HIV and Ebola are examples of this not happening.
These unknowns are meant to be honest about our reality with endemic SARS-CoV-2. There continue to be uncertainties you should be aware of. This is especially true at a time of mandated health behaviors, such as vaccine boosters.
At Cure-Hub we are cautiously optimistic that Omicron signals a pandemic off-ramp. A less severe variant that provides protection against more lethal variants is a good thing. Especially when so many people have some immune recognition of SARS-CoV-2.
Last and not least we need to finish with a disclaimer. Cure-Hub does not recommend purposeful exposure to any SARS-CoV-2 variant, even one with less severe infection. The fact is, more severe variants are still circulating. Even though someone you know might have a weaker infection, you probably won't know if their weaker infection is actually caused by Omicron. The weaker infection could simply be due to their pre-existing immune status. That means purposeful exposure is taking a substantial risk with your health. As the NHS report showed, even Omicron can cause hospitalization.
If you are interested in getting a COVID-19 antibody test and participating in the amazing Cure-Hub antibody survey, then sign up today! We can even ship a collection kit to your door.
By signing up you'll find more information about yourself and help everyone better understand COVID-19. Eligibility: Adults in the USA who are non-pregnant and non-incarcerated.
Also, keep an eye out for our Omicron neutralizing antibody data. Should be published by the end of the month (January 2022).