To follow the unpredictable evolution of the ongoing COVID-19 pandemic, the global sequencing and surveillance capacity for SARS-CoV-2 must be reinforced, as well as multidisciplinary studies of infectivity, virulence, and immune escape.
The World Health Organization (WHO) set up a group to track severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) evolution, as well as monitor the characteristics of the emerging variants and their impact on medical and non-medical remedies in June 2020. In November 2021, this group transitioned into the WHO Technical Advisory Group on Virus Evolution (TAG-VE), responsible for monitoring the global risk of the SARS-CoV-2 variants.
An article published in the journal Nature Medicine examines the unpredictable evolution of the ongoing COVID-19 pandemic.
Study: An early warning system for emerging SARS-CoV-2 variants. Image Credit: NIAID
Tracking of SARS-CoV-2 variants
TAG-VE was responsible for coordinating information exchange from research studies and global surveillance that would help monitor any early warning signs. Furthermore, it assessed whether public health action was needed against emerging variants. The TAG-VE used a Delphi consensus method to determine which variants must be considered as variants of interest (VOIs) and which as variants of concern (VOCs). Additionally, a naming scheme was adopted that followed WHO guidelines and assigned Greek letters to both VOIs and VOCs.
TAGS-VE first analyzed the viral genome sequences and the associated metadata to identify emerging variants. All the available sequences are compared with the index virus that first appeared in late December 2019 since all current VOIs and VOCs originated from the ancestral variants. Gene mutations encoding the viral spike protein are of a high priority since the spike protein comprises the receptor-binding domain that helps in the attachment of the virus to host cells as well as indicates viral transmissibility. However, other gene mutations have also been found to be crucial.
The mutations impact phenotypic features such as immune escape, transmissibility, susceptibility to treatments, detectability, and disease severity. This mutation list is regularly updated and is of importance because similar mutations arise independently in different lines of SARS-CoV-2. These mutations are indicative of both the virus' adaptation to the human host as well as selection pressure brought on by population immunity. However, certain mutations impact the fitness of the virus rather than being a threat to public health. The TAG-VE assesses several indicators regarding a new emerging variant, such as how quickly it emerges, the geographical area and population it spreads in, re-infection rates, disease severity, and vaccine breakthroughs to determine whether the variant will pose a serious threat.
Studies have highlighted that the rate at which new variants spread can outrun the ability of their threat assessment. Although the genomic indicators for increased transmissibility as well as immune escape of VOCs are easy to assess, the comparison of data in real-time is quite challenging. Improvement of physical characterization can be made by working with those viruses that have similar mutations. In this regard, WHO has established a BioHub facility to facilitate the safe, reliable, and transparent exchange of novel biological material among the WHO Member States.
Sequence data analysis
Key challenges include genetic data representativeness, availability, and quality. It is apparent that viral diversification will require sustained, if not increased, investment from governments in reference laboratories to meet public health demands for high-quality sequences and viral characterization for SARS-CoV-2, which can then be used for future threats from infectious diseases.
Analysis of raw reads to verify sequence quality is vital to detect recombination between SARS-CoV-2 genomes. The verified detection of the emerged Omicron VOC has increased mostly since the availability of genomic surveillance has increased along with natural factors. The detection of recombinant forms is easier for Omicron due to many lineage-defining mutations. Additionally, the chances of co-infection and recombination increase on re-infection with immune-escape variants.
Assessment of infectivity and virulence
Infectivity and virulence can be assessed by identifying certain crucial sites and amino acid substitutions which serve as infectivity determinants. Animal models can be useful in the virulence assessment since they can identify specific features and do not take into account the impact of background immunity.
The determination of disease severity in the clinical setting can be challenging, but the interworking of electronic health records, unbiased and systematic collection of epidemiological and clinical data, biological sampling, and virulence characterization are of significant importance in the assessment of the variant threat.
Up until November 2021, the emergence of Delta and Alpha VOCs was associated with heightened transmissibility and modest immunity escape. However, immune escape was found to be the driving force behind the displacement of Omicron VOC over Delta. The increase in population immunity was its selective advantage along with increased transmissibility. Omicron's lesser virulence has been largely attributed to chance. Additionally, hybrid immunity in individuals with breakthrough infections suggests that the continuous evolution of SARS-CoV-2 may be tolerable by population immunity. Nonetheless, because SARS-CoV-2 transmission and virulence are not coupled, it cannot be assumed that the next variant will have the same, or a lower, or a higher virulence than Omicron.
Early warning against emerging variants
According to previous retrospective analyses, some of the key mutations involved in defining variants could have been detected earlier through early warning bioinformatics tools that use globally shared data. In addition, machine learning algorithms are being developed to determine the influence of key mutations. However, epidemiological data and in vivo and/or in vitro experiments are still required to fully assess variants.
It is difficult to predict the future of the pandemic due to factors such as the fact that, unlike other respiratory viruses, SARS-CoV-2 variants do not emerge from the recently dominant circulating virus, chronic viral infections can carry intra-host evolution, animals can function as secondary reservoirs with the potential for reverse zoonoses, and a large percentage of the world's population is not vaccinated.
In light of the uncertainty regarding SARS-CoV-2's trajectory and its continuous evolution, continual monitoring is necessary. The TAG-VE will continue to predict the evolution of future variants and their threat levels. The pandemic is not yet over. It is time to enhance global sequencing capacities and build a global agreement under the leadership of the WHO R&D Blueprint to prevent epidemics and assess the threat that the future variants of SARS-CoV-2 can pose.