India is facing an epidemic wave of Omicron disease presenting mostly with sore throat, nasal discharge – without cough or high fever. Pneumonia is uncommon. Blood oxygen level remains normal.
Some senior citizens and those with diseases or therapies that weaken the immune system do get severe disease requiring hospitalisation. Altogether, Omicron disease is a milder version of COVID-19 with Wuhan-D614G or Alpha, Beta, Gamma and Delta variants.
Mutational changes
All previous variants had few mutational changes of the spike protein, Omicron has many more, particularly in the ‘receptor-binding domain’ (RBD), the ligand that binds to host cell receptor, ACE-2. While earlier variants have 8-9 mutations on the S1 portion, Omicron has 32-37 in different studies. On RBD, Omicron has 15 mutations, while others have only 1 to 3. This many mutations have resulted in several alterations in the virus-host cell interactions. For example, the viral load in saliva is high, allowing high sensitivity in RT-PCR of saliva samples. Much virus is broadcast into air even without cough. Obviously, the need for face masks cannot be overemphasised, to block virus shedding (by the infected) and to prevent inhaling air-borne virus (by others).
Coronaviruses have two cell entry processes – the major one by fusion of virus envelope with the cell membrane and the minor one by fusion with the endosomes within the cytoplasm. Virus multiplication is far more efficient with major than minor process. All previous variants use the major cell entry process.
Omicron uses the second process, as elucidated in laboratory experiments. After receptor-binding the receptor–virus complex is ‘swallowed up’ by the cell through ‘endocytosis’ without affecting the cell membrane. The endocytotic vesicle (invagination of cell membrane) then fuses with subcellular organelle called endosome, a normal process. The virus coat now fuses with endosome membrane, releasing the virus genome into the cytoplasm.
In the first process with cell-surface fusion, all adjacent cells also fuse with the infected cell and form a ‘syncytium’ – giant cell with multiple nuclei. Syncytia are closely associated with disease severity, particularly with lung pathology. In laboratory experiments with Omicron, syncytium formation does not occur. This change presumably leads to less virus production in the body, less invasion of organs and tissues, lower severity and duration of symptoms, decreased need for hospitalisation and low case-fatality ratio – altogether a watered down 2021 version of COVID 2019. Omicron resembles influenza virus infection that remains mostly confined to upper respiratory tract.
Immunity evasion
Omicron has a propensity for immunity evasion. Virus neutralising antibodies induced by infection by all earlier variants or any of the available vaccines are far less effective against Omicron disease. Most monoclonal antibodies that were effective to treat COVID-19 are no longer effective to treat Omicron disease. However, the world over, high degree of protection against severe disease requiring hospitalisation by enhanced antibody levels achieved by a booster dose, is observed. Experience from the U.K. is instructive. Vaccine effectiveness against Omicron disease requiring hospitalisation was 72% during 2-24 weeks after second dose, but only 52% after 25 or more weeks – significantly increasing to 88% two weeks after a booster dose.
Even when antibody fitness to the virus (affinity) is low, the sheer magnitude of antibody level enables antibody-binding to more viruses, thus enhancing functional effectiveness as shown in the U.K. Had India gone on a massive public education on the importance of two doses of vaccine to mitigate the impact of Omicron wave, and also on the value of booster doses to increase protection, we could have had a relatively normal life in India during January–February of 2022 – many scientific meetings and other events scheduled for these months could have proceeded unhindered, instead of getting postponed.
These many changes – genetic, fundamental cell–virus interactions, pathology, virulence, disease characteristics, immunity evasion – set Omicron apart from all other variants. To emphasise its greater deviation than other variants, imagine the term ‘deviant’.
The term deviant indicates the high degree and abruptness (non-continuum) of change – in virology, the terms used to represent substantial genetic differences are: lineage, sub-type or serotype – depending on the degree of deviation. We expect the International Committee of Taxonomy of Viruses will address this question without delay, as we have already alerted the WHO and the International Society of Infectious Diseases.
If we consider Omicron disease sufficiently different from Coronavirus disease of 2019 (COVID-19), perhaps it deserves the name COVID-21. If it is considered a deviant with antigenic shift, rather than drift, as is the case in all variants, the current upsurge of disease overcoming high population immunity can be considered a new pandemic, not simply a wave of the COVID-19 pandemic.
Influenza pandemic
Analogy with Influenza Type A virus epidemiology is interesting. The 1957 pandemic due to a subtype H2N2 emerged when the H1N1 of 1918 pandemic was still circulating as endemic/seasonal. H2N2 with antigenic shift not only spread globally, but it also displaced H1N1 from circulation – why? Immunity induced by H2N2 was sufficient to prevent H1N1 circulation. In 1968, the next pandemic started with H3N2 subtype; it displaced H2N2, presumably due to cross-immunity. The 2009 pandemic was with a new variant of H1N1, with borrowed genes from swine influenza, and named H1N1pdm09 to distinguish it from the earlier H1N1. Antigenic cross-reactivity with H3N2 was not strong – hence both H3N2 and H1N1pdm09 are in co-circulation globally as endemic/seasonal.
While Delta variant overshadowed all earlier variants that are nowadays infrequently found anywhere, we anticipate that Omicron with antigenic shift and compromised cross-reactivity may not displace Delta. Omicron being more transmissible than Delta, we speculate: (1) In 2022, both Delta and Omicron might co-circulate, and (2) we may need vaccines against all variants of SARS-CoV-2 as well as against Omicron and its future variants, if any.
(T Jacob John and M S Seshadri are former (retired) Professors of Virology and Endocrinology, respectively, at Christian Medical College, Vellore and Dhanya Dharmapalan is a pediatric infectious diseases specialist in Navi Mumbai.)
