The most mutated variant
CLINICAL MATTERS
On Nov. 26, 2021, the World Health Organization (WHO) announced the designation of a new COVID-19 Variant of Concern (VOC) named Omicron. This followed the observation that a SARS-COV-2 lineage B.1.1.529 was driving an increase in cases in the Gauteng province of South Africa. While the variant most likely originated elsewhere, South Africa was able to characterize this lineage and raise the alarm due to its extensive genome sequencing capabilities.
B.1.1.529, now known as the Omicron VOC, is the most mutated form of SARS-CoV-2 to emerge to date. It has over 50 mutations, 32 of which are on the spike protein. The spike protein is the part the virus that sticks to human cells and allows it to gain entry into the host cells. The spike protein is also the main target of our COVID-19 vaccines. Past mutations in the spike protein have sometimes resulted in increased transmission (Alpha, Delta) and decreased vaccine efficacy (Beta). This is, however, not an automatic phenomenon. Other variants such as P.3 (formerly variant of interest Theta) had some scary mutations on the spike protein, but did not turn out to be more transmissible or more vaccine resistant. With double the number of mutations on the spike protein compared to Delta, Omicron does have an increased potential for escaping vaccines, along with a higher potential for increased transmissibility. This is likely why WHO decided to designate it as a variant of concern even before a clear clinical picture has been confirmed.
Omicron is showing some indications of becoming the dominant variant in South Africa based on recent sequencing data. This implies a survival advantage over other circulating variants. This, however, needs to be cautiously interpreted because when active contact tracing is done the proportions of any variants can be unduly magnified as a result of super spreader events. In other words, you find what you are looking for if you are looking harder for something, particularly in places where Omicron was detected. It remains to be seen if this variant will take over completely, similar to what Delta did, in the coming weeks.
While the sheer number of mutations in Omicron is scary, it also means a bigger risk of deleterious effects for the virus as it develops more mutations downstream. Too many mutations can render essential parts of the virus dysfunctional or non-functional. Omicron might very well mutate itself out of existence since some mutations come at a cost in viral fitness and reproductive stability. Some scientists think this contributed to the demise of Delta in Japan, where an initial increase in cases was extinguished very rapidly. With double the number of mutations compared to Delta, the potential to “burn out” is also increased for this variant.
It is unlikely that Omicron will become completely vaccine resistant. Current COVID-19 vaccines may eventually show some reduced defense against infection. Significant protection against severe disease, however, is likely to persist. Even if there is breakthrough infection in fully vaccinated individuals due to Omicron, the disease course is likely to be mild. Even though spike protein antibody epitopes (the part of the spike protein that is recognized by the immune system) are limited, the immune system has other components that ensure it can continue to protect against severe infection. T-cells, which are the body’s soldiers that seek and destroy viruses that are already inside cells, are also induced by current vaccine epitopes. These epitopes are less likely to be affected by the mutations on the spike protein which reduce antibody effectiveness. Moreover, vaccine manufacturers are already working on tweaked vaccines against the spike protein. These modified vaccines may restore vaccine-induced antibody effectiveness and protection from infection. Pfizer has said it can formulate a modified vaccine against Omicron in 100 days. Preventive non-pharmacologic measures such as masks, face shields, and physical distancing will remain effective as long as these are used correctly and consistently.
There is currently no evidence that Omicron is deadlier than the other SARS-CoV-2 variants. Preliminary clinical data indicates just the opposite. From initial reports by doctors from South Africa, many confirmed Omicron COVID-19 infections have been mild. Many of these infections, however, occurred in young individuals. Younger people tend to have less serious disease, so it is difficult to make general conclusions about just how deadly Omicron is. There has been a concomitant increase in hospitalization in some areas reporting Omicron infections, but it is unclear if this is due to the overall increase in cases or from more virulent disease. Many deaths do occur when the healthcare systems are overwhelmed, regardless of the circulating variant. The priority should always be to control the spread of the virus. This can be done through public health measures, accelerating vaccination programs, and enhancing border control. Strengthening healthcare capacity is key to managing spikes in cases. Since the treatment of COVID-19 has substantially improved since the start of the pandemic, ensuring the availability of hospital beds for the sickest patients during a surge in cases can minimize mortality.
Most treatment options for COVID-19 will still work against Omicron. Dexamethasone, tocilizumab, baricitinib, and remdesivir will remain effective if used in the appropriate patients. Newer therapeutic options like molnupiravir and Paxlovid should still remain active since their mode of action isn’t impacted by the genetic changes. The one group of medicines that may lose potency against Omicron are the monoclonal antibodies. Casirivimab/imdevimab and other monoclonal antibody preparations may not work as well against Omicron since these drugs target the spike protein.
Tests for COVID-19 such as RT-PCR and antigen will continue to detect Omicron without any problems. RT-PCR kits, with the possible exception of tests that detect the S (spike) gene, will not be impacted. Not very many RT-PCR kits use the S gene. The ones that do use the S gene also simultaneously detect other genes, which will not be affected by Omicron’s mutations. In fact, the TaqPath kit, which detects the S gene and two other COVID-19 genes (ORFa/b and N), is being used as a screening tool for detecting Omicron. Since the S gene will not amplify for Omicron using this test kit (a phenomenon known as S gene dropout), a positive COVID-19 test with the other two genes but not the S gene suggests that Omicron is present. Another variant of concern, Alpha, also exhibits S gene dropout so it isn’t a unique property. Since Delta is the current dominant variant and it doesn’t show S gene drop out, a Taqpath test showing an S gene dropout can be treated as a possible Omicron case in places where genome sequencing is limited.
The biggest takeaway from the rise of Omicron is that neglecting vaccination in the poorer parts of the planet will come back to haunt us all. While many first-world countries are racing to already give vaccine boosters to their general population, resource limited countries are still struggling to give primary series COVID-19 vaccines to their population. Vaccination, even if there is breakthrough infection, decreases viral diversity. This means highly mutated variants are less likely to emerge in highly vaccinated settings. Therefore, unless we all work toward globally equitable distribution of vaccines, we will just prolong this pandemic and undermine our own public health efforts.