It has been two weeks since the World Health Organization (WHO) designated Omicron as a Variant of Concern (VOC) in the ongoing SARS-Cov-2 coronavirus pandemic. Efforts by researchers from Africa and across the world over this time have provided immense insights into the epidemiology as well as biological properties of the virus. We provide a brief overview of the current understanding on the Omicron variant.
The earliest genome for what is now designated as the Omicron variant was sequenced from a viral isolate collected from Gauteng, South Africa in early November, 2021 and was made publicly available by the National Institute for Communicable Diseases, South Africa through GISAID, a database for sharing genomes of viruses. Further analysis revealed similar genomes deposited from Botswana and Hong Kong, characterised by a large number of mutations, particularly in the spike protein. This led researchers to report the cluster of genomes on the Pango Network, an open community of researchers working together to annotate lineages of SARS-CoV-2, and the lineage was thus designated as B.1.1.529.
The unique cluster, epidemiologically linked with the uptick of cases in Gauteng, and the configuration of mutations, many of which have been previously linked with immune escape and recommendations by the Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE), led to the designation of the lineage as a VOC.
Since its designation, owing to added genomic surveillance and deposits of genomic data from across the world, over 2,700 sequences of the Omicron variant are presently available in GISAID, a database which shares genomic sequences deposited by researchers from across the world. As more sequences were submitted to GISAID, it was observed that a number of genomes did not have the full set of mutations that define Omicron while having many of the characteristic mutations. The originally designated B.1.1.529 lineage was thus split by the Pango Network into two sister lineages, BA.1 and BA.2 (where BA is an alias for B.1.1.529). While both these lineages have almost all important spike protein mutations that were initially defined for Omicron, the lineage BA.2 does not have a deletion in the spike protein which is present in the original lineage (BA.1).
The transmission rate, immune evasion and the proportions of patients developing severe disease and death are the useful parameters which would enable broad assessments on how the variant would impact the population. In the following sections, we detail the evidence on each of these parameters.
The immune system has two arms. The first arm is mediated by antibodies — proteins which can recognise and bind proteins on the surface of microorganisms thereby neutralising them. The second type is mediated by T-cells which can recognise and kill cells infected with viruses.
It is widely believed that the antibody mediated response determines the initial barrier of infection while the cellular response is decisive in the development of disease severity to COVID-19. The corpus of evidence at hand for Omicron is largely based on antibodies and neutralisation.
The Omicron variant has about 32 mutations in the spike protein, many of which have been associated with binding sites of antibodies, indicating that it would escape antibodies from previous infections, vaccines and many monoclonal antibodies used in the treatment.
While clinical estimates of vaccine efficacy can only occur after sufficient number of tracked infections with well-defined vaccination status have occurred, early assessments of immune evasion could be assessed in the lab by performing neutralisation tests. In these experiments, whole virus or virus-like particles (pseudoviruses) are tested with sera from people who have been vaccinated or previously infected. This assesses whether the virus can evade the antibodies present in the sera of these individuals. While these are not surrogates of vaccine efficiency, they can provide early insights.
A total of six studies are now available in public domain from across the world. While the ranges of neutralisation compared with the ancestral lineages as well as Delta provide a wide range, it is unequivocal that the neutralisation of Omicron is significantly less than that of the ancestral lineage (B.1, 20-40-fold lower)) or Delta (about five-fold lower). The only silver lining is that antibodies from individuals with boosters, or individuals with infection prior to vaccination (hybrid immunity), seem to neutralise the virus to some extent.
Early evidence on vaccine efficiency has also emerged from the United Kingdom Health Security Agency, which evaluated efficiency for vaccines against symptomatic infection, that also corroborated quite well with the observations in the laboratory. Two doses of AstraZeneca (ChAdOx1) seemingly provides practically no protection against symptomatic infection, while an added booster with mRNA vaccine seemingly provides much better protection against symptomatic infection. The estimates for protection against severe disease and death would be estimated much later as these are delayed events.
In the perspective of public health, this would mean a significant number of people with pre-existing immunity from COVID-19 infections or from two doses of vaccines could still have symptomatic re-infections and vaccine breakthrough infections.
The rate of transmission is another major parameter which could be useful in understanding how fast the variant would spread in a region, and is critical in making appropriate plans for testing and management, including hospitalisation. One of the useful estimates for assessing the rate of transmission is the doubling time. Early data in this regard has been made available from South Africa, the United Kingdom and Denmark. Early assessments suggest the doubling time for the Omicron variant is approximately 2.5 to 3 days, which is much shorter than the Delta variant. This significant advantage of Omicron over Delta means that in regions where ongoing and high transmission of the Delta variant is occurring, including in the U.K., the Omicron would emerge as the dominant lineage in a very short period of three to four weeks.
From a public health point of view, a higher rate of transmission would mean a large number of people could be infected in a short period of time. This would have implications in the ability of the system to test as well as offer adequate care to the needy. This is important since such a wave of infections can quickly overwhelm established healthcare capacity in no time.
Disease severity is another important parameter for public health and possibly the most difficult to assess accurately, since severity of disease, and deaths, occur late in the course of disease, and therefore, accurate assessment takes time. Additionally, there could be biases such as demographics, reinfections or vaccination, which could make the observations non-generalisable to other settings. Within these limitations, early and preliminary estimates from South Africa suggest that the proportion of patients requiring hospitalisation for the Omicron variant in Gauteng province is much lower than in the previous waves. Similar trends have been observed for oxygen requirements as well as Intensive Care Unit admissions.
While this indeed is a silver lining, a sufficiently high rate of transmission could quickly saturate existing healthcare capacity with consequent more than expected deaths (excess deaths). Such healthcare stress may also increase unnecessary deaths that are not directly related to COVID-19.
Impact in diagnostics
The RT-PCR test widely used in the diagnosis of SARS-CoV-2 infections rely on pieces of DNA (also known as primers) which bind to the genome of the virus to specifically amplify a genomic region. A typical RT-PCR kit has two or more of such sets of primers which target the genome at two or more genes to increase the sensitivity and specificity of diagnosis. Mutations in the virus genome, which could be incidentally where the primers bind, could make these primers inefficient. This is called a target failure or dropout.
This would typically not affect the diagnosis, since the other sites would work as expected. Some of the kits widely used across the world have one such primer targeting, the S gene, and one of the mutations in the Omicron variant is right at this primer binding site. Therefore, the Omicron variant will cause the spike primers to not function as expected. This is called a Spike Gene Target Failure or S-dropout and has been used as a surrogate to look at Omicron variants in surveillance.
The important point to note is that the S-dropout is only applicable to the BA.1 cluster of Omicron as the BA.2 cluster, though presently only a very small fraction of Omicron, does not cause S-dropout and therefore may be missed out. This also highlights the importance of genomic surveillance for accurate assessments for surveillance.
The silver lining
It is reassuring that early evidence suggests that individuals who have attained hybrid immunity (infection as well as vaccination) are likely to be better protected at least against severe disease and deaths. With a significant population in India being infected as suggested by serosurveys, and at least an additional 50% and more of the population having accessed both doses of vaccine, could potentially be the silver lining.
The early evidence from South Africa suggests that the proportion of patients infected requiring hospitalisation is lower than the previous waves. While this does not necessarily mean that the variant is “milder” than other variants, it does imply that populations similar to South Africa — young and with high prior infections — may be less affected this time.
What does this mean for strategies to manage the upcoming wave of infections ?
Evidence at hand suggests that vaccines indeed protect against severe disease and death, and therefore the immediate need is to cover as many eligible people, especially in the high risk groups, with two doses of vaccines.
With a rapid rate of transmission, even a lower proportion of patients requiring hospitalisation can put enormous strain on existing resources — both for testing as well as for provision of care for the needy. On that account, it is important that measures to slow down transmission through appropriate and concerted public health approaches are planned and implemented in advance, thereby minimising the impact of such interventions on livelihoods.
The current scenario also mandates placing a lot of emphasis on time-tested public health measures. The growing corpus of evidence indicates the effectiveness of non-pharmacological interventions, including masks and ventilation, both of which have not been well-appreciated. There is also convincing evidence suggesting that masks especially, good quality masks (FFP2/N95) are extremely efficient in preventing infection. In light of evidence suggesting a high rate of transmission, it is imperative to think of better ways to protect vulnerable populations, including people over 60 years of age as well as with multiple comorbidities and on immunosuppression, with better masks.
Similarly, the importance of ventilation and social distancing cannot be emphasised more, especially in a scenario where a large number of people are likely to congregate over the festive and marriage season. The emphasis on ventilation in places where multiple footfalls are expected, including schools, public offices and marriage halls, which are likely to be lively over the season, would go a long way in limiting transmission.
Molecular surveillance approaches, including whole genome sequencing and the utility of spike-dropouts as surrogates to assess prevalence, come in enormously handy to understand the prevalence in communities, assess growth, and prepare healthcare systems well in advance to handle the onslaught of cases.
In summary, the emerging evidence on the Omicron variant offers too little to comfort. The rapid spread of the Omicron variant is likely to test out public health systems and their ability to plan and implement strategies well in advance, and also their ability to react efficiently and in a timely manner. For the common man, it is possibly the best time to take their pending doses of vaccine, pull up their masks, let a lot more fresh air into their rooms, and avoid crowds. It is always better to be safe than sorry.
(Vinod Scaria and Bani Jolly are researchers at the CSIR-Institute of Genomics and Integrative Biology in Delhi)