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Meng B, Abdullahi A, Ferreira IATM Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity. Nature. 2022; 603:706-714 https://doi.org/10.1038/s41586-022-04474-x
Bojkova D, Widera M, Ciesek S Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant of SARS-CoV-2 isolates. Cell Res. 2022; 32:319-321 https://doi.org/10.1038/s41422-022-00619-9
Fonager J, Bennedbæk M, Bager P Molecular epidemiology of the SARS-CoV-2 variant Omicron BA.2 sub-lineage in Denmark, 29 November 2021 to 2 January 2022. Euro Surveill. 2022; 27 https://doi.org/10.2807/1560-7917.ES.2022.27.10.2200181
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Global infections with the Omicron variant of SARS-CoV-2 have now superseded all other similar variant infections we have witnessed thus far. The current global wave mainly caused by a descendant of the SARS-CoV-2 Omicron variant, called BA.2, is the most prevalent in UK, and has a natural history somewhat different from its predecessors. It also appears, that the so-called COVID-19 variant infections, in varying guises, are the harbingers of the post-COVID-19, ‘new normal’ world of the future, we have to live in. Here, we look at key features of SARS-CoV-2 variants, particularly BA.1 and BA.2, and the reasons for their phenomenal spread, vaccine efficacy against them, as well as the unfolding short-term outlook for the pandemic.
CPD/Clinical Relevance: To describe the reasons for the high global prevalence of SARS-CoV-2 Omicron variant, particularly its BA.2 subvariant, and discuss the attendant implications for the dental profession.
Article
Variants of viruses emerge incessantly, and it is the nature's way of preserving a species, and in our context, the SARS-CoV-2 viral progeny. As Charles Darwin explained in his postulate of ‘survival of the fittest’, in order to survive, a living being must be ‘endowed with phenotypic characteristics which improve chances of survival and reproduction’. We see this explicitly in the case of SARS-CoV-2. The original strain of SARS-CoV-2, over a short period of 2.5 years has undergone many genetic reincarnations ranging from Alpha, to Lambda and the latest, the Omicron variant, which in turn has evolved into the intractable, sublineages BA.1 and BA.2 (Table 1).
: Vaccine effectiveness, after three doses of almost all current vaccines range from 85% to 90%;
: initial data are promising, but more research is required. Data from various sources.
The ravenous spread of the current global wave of Omicron has been phenomenal and breathtaking. For instance, there were 125 million Omicron infections per day worldwide in January 2022 alone, which is more than ten times the peak of the Delta wave of April 2021.1 In a recent article in Lancet, Murray from the International Health Metrics and Evaluation Foundation in US, opined that: ‘The unprecedented level of infection suggests that more than 50% of the world will have been infected with Omicron variant between the end of November 2021 and the end of March 2022’. Although the number of global daily SARS-CoV-2 infections has increased over 30 times in such a short time, the reported number of overt COVID-19 cases has only increased only by six times. This is mainly due to the proportion of asymptomatic or mild Omicron infections, compared with previous variant infections.1 Murray also opined that, due to such a widespread global infection, the end of the pandemic may be near.
Historically, the Omicron subvariants of SARS-CoV-2 were detected almost simultaneously in November 2021 in South Africa. These new and profoundly different lineages2 were a surprise to many virologists who had anticipated that the next major variant would descend incrementally from the Delta variant, which was the most widely circulating variant worldwide at that time.
Immediately thereafter, the BA.1 sub lineage of Omicron quickly overtook Delta as the dominant strain. Subsequently, as we have witnessed, the BA.2 variant has stolen a march over BA.1, and has spread faster in many communities the world over, implying that it has a significant selective advantage over its sibling. The former currently accounts for over three-quarters of all new SARS-CoV-2 infections in the UK and USA.
Incidentally, scientists are continuing to discover Omicron subvariants/sublineages BA.3, BA.4 and BA.5, but these have not taken off as rapidly as BA.2. To add to the confusion, a BA.1/BA.2 recombinant strain has now arisen and this is termed XE (a major proportion of its genome, including the Spike gene, belonging to BA.2). As of April 2022 there is some evidence of XE community transmission within England, but less than 1% of total sequenced cases. Emerging data indicate that the growth rate of XE strain is similar to BA.2, although not its transmissibility.
What is the societal impact of the currently circulating viral variants?
Before we discuss the various viral variants, it is instructive to evaluate their societal impact. Not the least because we may have to confront various, yet to emerge SARS-CoV-2 variants or subvariants or their siblings in the immediate future:
Ability to spread more quickly
As mentioned, there is ample data now to indicate that the new variants spread extremely rapidly within the community compared to the ancestral parental strains. This property was first noted in laboratory studies where the BA.2 strain spreads almost three to four times faster in cultured cell lines (within flasks), in comparison to the parental strains. Simply, the virus is becoming smarter and more efficient in evolutionary terms.
Causing mainly milder and/or asymptomatic disease
The current BA.2 variant causes milder infection in most people infected. Most who are affected are asymptomatic, and are ‘virtual super spreaders‘ of infection. This has implications for the practice of dentistry as the disease is likely to become endemic in many regions of the world, including UK.
Detection by viral diagnostic tests
According to authorities, most commercial reverse-transcription polymerase chain reaction (RT-PCR)-based rapid tests should detect the variants as these tests have, built in, multiple targets to detect the virus. Again, the logistics of incorporating such tests into routine dental practice is a matter that needs urgent consideration.
Effective vaccine-induced immunity
Either natural infection with SARS-CoV-2, or full vaccination with the currently available major vaccines appear to provide over 90% effective protection against severe COVID-19 infection. However, a small proportion of cases, up to 2–5% (depending on the age) may exhibit so-called ‘breakthrough infections’, which may either be symptomatic or asymptomatic. Recent data indicate that full vaccination with all three doses, or indeed a fourth dose, of the mRNA or other vaccines, leads to virtually full protection.3 Some jurisdictions, such as UAE, are currently administering a fifth dose, 4–6 months after the fourth does, despite the fact that there is no consensus on its need.
The frequency of COVID-19 booster vaccines for healthcare professionals is yet unclear. It is likely that in the short term, 6-monthly vaccinations may be required, although in the longer term, if there is established regional endemicity with herd immunity in the community, a longer period between booster vaccines is likely. This may take the form of annual vaccinations similar to the seasonal flu vaccine prescribed for healthcare workers, including dental professionals. Indeed, COVID–influenza-combination (CIC) vaccines, now in Phase 2 trial stages, have shown much promise.
BA.1 and BA.2 compared
The BA.2 variant is known to be 30–50% more infectious than BA.1. What is the reason for this? In general, the infectivity of SARS-CoV-2 variants is dependent on three major reasons. The first, is the increased transmissibility, second, the evasion of vaccine-induced or post-infection immunity, so called ‘immunological escape’, leading to breakthrough illness, and finally the temporal waning of vaccine-induced or natural immunity in the community.
It is now known that the increased infectivity of the BA.2 variant is due to unique mutations in the spike proteins. For instance, it is known that BA.1 possesses 60 mutations that are not found in the ancestral SARS-CoV-2, first detected in Wuhan, China. Of these, 32 genetic changes are located specifically in the spike or the S-protein of the virus. In comparison, BA.2 shares many similar mutations, but 28 are unique to the variant itself, four of which are in the spike protein.4 As the spike proteins are the major targets for immune cells and vaccines, the high infectivity of BA.1 and BA.2 are not surprising.
In terms of transmissibility, researchers in the UK have noted that it took less time on average for someone with BA.2 to infect another person, accelerating its spread through communities.5 This was reinforced by a study in Hong Kong, where researchers estimated that during an outbreak of BA.2 in a public housing complex, infections with the virus doubled every 1.28 days.6
These data on the BA.2 variant indicate that it is probably the fastest-spreading virus in human history. Prior to the emergence of SARS-CoV-2, the measles virus was known to be one of the fastest, if not the fastest, spreading respiratory viruses. However, compared to a person with the measles virus who might infect 15 others in 12 days, a single case of the Omicron BA.2 variant infection may lead to 216 cases in a similar period. Hence, the reason for the exponential case surge worldwide.
Why the Omicron variants spread faster
It appears that Omicron and its variants exhibit significant immune-evasion strategies compared with their predecessors. One of the major strategies appears to be the method by which they gain entry into host cells. Whereas other variants rely on two major proteins on the surface of human cells, TMPRSS2 and ACE2, to cross the cell membrane, Omicron seems to require only ACE2 to inject its genome into a cell, to be enclosed within an endosome that is then carried to the innards of the cell for subsequent viral replication (Figure 1).7 This means that the TMPRSS2-independent endosomal pathway provides Omicron with a larger array of cells (up to10 times more) that are conducive to infection (as many cells do not have TMPRSS2 on their exterior). This certainly provides a selective survival advantage for the variant compared to its sibling/s.
Figure 1. One reason for the high transmissibility of the Omicron sublineage, BA.2, is its selective requirement for only ACE2 receptors on host cells for viral entry (lower panel) as compared with previous variants, such as the Delta variants, which required two different receptors (TMPRSS2 as well as ACE2) for cellular entry and multiplication (upper panel). (Figure created using Biorender.com software.)
Another major reason for its fast spread appears to be the predilection of BA.2 to the upper, rather than the lower respiratory tract, as in the case of the original Wuhan strain or its derivatives, such as the Delta strain (Figure 2). Clearly, the ability to replicate and profusely colonize the upper respiratory tract implies that BA.2 dissemination may occur through routine daily activities such as talking, rapid breathing, sneezing and coughing.
Figure 2. Another major reason for the extraordinary spread of Omicron subvariant BA.2 is considered to be its greater affinity for the cellular receptors in the upper, rather than the lower respiratory tract, in comparison to its ancestral lineage such as the Delta variant (illustrated above). Colonization of the upper respiratory tract facilitates viral spread through routine daily activities such as talking, sneezing and coughing. This also has profound implications for clinical dental practice. (Figure created using Biorender.com software).
It is also known that BA.2 replication in lung tissue is nearly 10 times less than the original strain, which may be the reason for its lower disease severity. This is thought to be due to the fact that the lungs have a more pronounced interferon response than the upper respiratory tract and BA.2 being more susceptible to interferon, lingers and multiplies in the upper respiratory tract.8 (Interferon is a common antiviral chemical that interferes with cell-to-cell spread of viruses, hence its name.)
Disease severity after BA.1 and BA.2, and reinfections
Current evidence indicates that the classic COVID-19 symptoms due to the BA.2 variant are not more severe than those due to BA.1, either in vaccinated people or those who were previously infected with SARS-CoV-2. For instance, British4 and Danish9 researchers have found that BA.2 infection does not carry a higher risk of hospitalization than BA.1.
According to early data, there is only a rare possibility of reinfection with BA.2 after BA.1 infection. 10 For instance, in South Africa, where BA.1 was the earlier infection in a vast proportion, BA.2 reinfection has been relatively uncommon.
On the other hand, spread of BA.2 is common among those in unvaccinated groups, as was recently shown in the fifth wave of the pandemic in Hong Kong, where a dramatic surge in BA.2 infection occurred with a record number of deaths in the elderly. Conversely, the current BA.2 spike in UK is thought to be due to the result of easing COVID restrictions, such as lifting mask mandates and social distancing restrictions.
A note on drugs against BA.1 and BA.2 variants
As far as the currently available major drugs for COVID-19 are concerned, the antiviral Paxlovid (a combination antiviral of nirmatrelvir and ritonavir), molnupiravir and remdesivir all remain effective against both BA.1 and BA.2, provided they are taken in the early stage of the disease, soon after a positive test (Figure 3). However, most monoclonal antibody treatments authorized by the Food and Drug Administration seem to be ineffective against the variants.11
Figure 3. The antivirals nirmatrelvir and ritonavir (sold as a combination drug Paxlovid, shown above), molnupiravir and remdesivir are extremely effective against both BA.1 and BA.2 subvariant infections (in all age groups), provided they are taken in the early stage of the infection, soon after a positive test.
Viral variants, endemicity and future prospects
The full capacity of SARS-CoV-2 to evolve, through both antigenic shifts and drifts, and to produce radically new variants is unclear. However, the consensus is that it has a fair degree of genetic flexibility, as it were, to produce variants that could skirt the human immune assault and infect human cells. The current view of the scientific community is that Omicron BA.1- and BA.2-like variants will continue to emerge, driven primarily by immune selectivity, as more and more people receive effective vaccines, thereby reaching herd immunity in many regions of the world.
There is much speculation that SARS-CoV-2 will turn into a virus similar to the influenza and the common cold virus and hit a plateau owing to vaccines and infection-associated immunity, akin to the coronaviruses that cause the common cold. However, because of the many unknowns about SARS-CoV-2 behaviour, this remains speculative, as yet. New vaccines against the Omicron variants are currently in large-scale Phase 1 and 2 human vaccine trials, and it is hoped that they will provide longer-lasting immunity than the initial crop of vaccines.
A notable silver lining in this dark cloud is the technological advances in vaccine production, including predictive tools linked to artificial intelligence. For instance, predicting how various pathogens evolve, and change their surface antigenic structure, and priming the human immune system for the next wave of combatants is a possible pro-active path for success. One such approach, called ‘deep mutational scanning’, entails observing evolutionary changes in the pathogens' surface antigen ‘drifts and shifts’ in silico using artificial intelligence and machine learning.12 This means that vaccines for the next viral variant, or indeed a new pathogen, could be predicted far in advance and the infection nipped in the bud, prior to becoming a full blown pandemic. If such ambitious, technologically driven programs bear fruit, then the COVID-19 pandemic could be relegated to history as the last great pandemic which humankind has endured.
