Why are Viral Surveillance Systems Struggling to Monitor SARS-CoV-2 Variants?

New variants
Objectives of surveillance
Surveillance cracks
Patchy surveillance
Areas for correction​​​​​​​
Conclusion
References 
Further reading

The coronavirus disease 2019 (COVID-19) broke out in 2020, following the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019.

As of now, it has caused well over 525 million cases and 6.2 million deaths in 2.5 years. The unprecedentedly rapid development of several vaccines and their efficacy against symptomatic disease failed to end the pandemic; however, both due to the very uneven pattern of vaccine deployment and to the emergence of several variants of concern (VOCs) of the virus in quick succession.

As the virus replicates in the human target cells, the ribonucleic acid (RNA) genome undergoes duplication. Despite the impressive proofreading capacity of the virus, mutations continue to occur, and these may affect the biology of the virus. However, the majority do not increase viral fitness.

​​​​​​​Image Credit: Andrii Vodolazhskyi/Shutterstock.com

New variants

A VOC is a variant that shows either increased transmissibility, pathogenicity, or the ability to evade immunity induced by the earlier strain of the pathogen.

The major VOCs, beginning with D614G, where experiments testing the effect of this mutation on infectivity, suggested that it was associated with increased transmissibility, perhaps because it infected the upper respiratory tract infection more efficiently.

Multiple variants with a host of mutations followed, apparently by natural selection in a partially immune environment.

The Alpha variant was first reported in the UK, with spike gene target failure in the gold standard diagnostic polymerase chain reaction (PCR) tests. With eight mutations in the spike gene, of its 22 total mutations, it was 40% more transmissible than older viruses, with some degree of immune escape and increased viral shedding.

The Beta VOC reported first from South Africa at almost the same time also had eight spike mutations that increased receptor binding and conferred immune escape. The Gamma was reported from Brazil and was more transmissible.

The Delta also showed several spike mutations at key sites that might promote receptor binding, enhance transmissibility via increased spike cleavage at the furin cleavage site, and escape antibodies to prior variants. 

Objectives of surveillance

Public health surveillance includes the work of public health agencies at various levels, healthcare providers, and the public to collect and record data on the locations and timing of outbreaks and their rate of spread in an accurate and timely manner.

The aims of surveillance have been:

• To find the routes of viral entry into a locality, institution, or other facility
• To identify the routes of spread
• To examine the patterns of infection and disease at local, national, and international levels through an epidemiological lens
• To look for evidence of immune escape
• To analyze the effect of non-pharmaceutical interventions (NPIs) on the course of the outbreak.

As of now, it is known that over 50,000 mutations have occurred that changed the genetic sequence of the viral RNA. As the virus spreads, these mutations are replicated and become part of a unique strain or variant.

Surveillance cracks

The spread of the virus has been monitored from the earliest days of the outbreak by epidemiologic techniques.

Case detection, contact tracing, isolation, and quarantine were all used to help track the outbreak's progress and predict future local epidemics before they became large-scale.

Epidemiological surveillance

Epidemiologic surveillance is carried out in an uncertain situation, where things keep changing rapidly and resources are limited.

With rising pressures, it is difficult for an epidemiological system to keep operating efficiently, as many fall victim to the disease, and technical crises also arise due to the lack of personnel and resources. Political, financial, and media-related factors also play a role in this instability.

Changing disease detection criteria and methods, the emergence of new variants, and different restriction levels on the movement of people across international and national boundaries all led to varying degrees of confusion about whether and how many cases of the disease could be attributed to COVID-19 at any point.

Genomic surveillance

Genomic surveillance also began to be deployed, though the scale was much smaller initially. Intensive genomic surveillance began to come into favor when the Alpha VOC emerged and shot to dominance over the earlier D614G variant within a few weeks.

The immune escape Beta variant demonstrated the potential impact of genomic differences on the future spread and toll of the virus. While the Beta and Gamma were relatively localized in their spread, the Delta VOC led to a devastating upsurge in infections, hospitalizations and deaths worldwide that left countries reeling.

A little later, the Omicron VOC arose, with the greatest ever number of mutations of known viral variants. It was also the most highly infectious of all known variants, close in transmissibility to the measles virus. However, it was clinically milder than the Delta variant.

Immunologic and phenotypic study

It is necessary to understand the behavior of the variants in the presence of neutralizing antibodies, their transmissibility, pathogencity and immune escape. The right tools to analyze this data and draw the right inferences are also necessary.

Patchy surveillance

Why, then, did so many variants swamp the world, taking it by surprise? Taking the Global Initiative for Sharing Avian Influenza Data (GISAID) database as an example, it is clear that genomic surveillance was inherently biased. All these variants, and others, were first reported in countries with an active genomic surveillance program.

Limited resources

Genomic sequencing takes time, effort, sophisticated facilities and technology, all of which require money. In developing countries, this is in short supply.

Thus, genomic surveillance was largely carried out in high-income countries, with much fewer sequences from low- and middle-income countries (LMICs), despite the fact that the major chunk of the earth's population lives in these countries. Europe sequenced a much higher percentage of diagnosed cases by July 5, 2021, compared to the <2% of the Americas, though both were struck hard by the disease.

Origin of VOCs in immunocompromised hosts

The origin of these variants has not yet been identified, say the researchers, even though almost one in a hundred cases with the infection have been sequenced by now. One hypothesis is that they arose during prolonged infection in immunocompromised patients.

Host range

Secondly, the wide host range of this virus makes it likely that animal reservoirs exist and need to be identified and monitored, since the virus has been shown to infect mink, dogs, cats, ferrets, deer, lions and some other animals.  

Escape variants

Again, the rapid spread of the virus encouraged natural selection in an immune setting. In countries that have limited genomic surveillance, this would then cause the emergence of new variants that escaped detection and spread rapidly as they resisted neutralization by existing immune barriers.

The issue at present is therefore the ability to predict and detect VOCs as they occur. This requires the ability to pinpoint the biological effects of each mutation, singly and in various combinations. On the other hand, differences in the spread, morbidity and mortality need not always be the result of mutation-induced increased viral fitness.

For this reason, good-quality epidemiological surveillance data must be coupled with the genomic data to understand how the genotype affects the phenotype. As Layne and Taufenberger say, "Global COVID-19 surveillance efforts have been a patchwork that is not organized to address time-sensitive and mounting demands. At present, assorted international organizations, government institutions, and academic centers operate independently with entirely different approaches and methods that lack uniform standards."

Areas for correction

Strengthen resources

In many countries, epidemiologic surveillance performs poorly, with low funding, and isolation of available information in different, unrelated repositories.

To avoid this, the following measures have been suggested: the networking of local and state public health laboratories; introducing genomic sequencing extensively over an appropriate window of time; proper funding for physical and information technology infrastructure more widely; staff acquisition and training.

Improved tests

The priority areas for genomic surveillance remain to be defined. The ability of pseudovirus neutralization assays to determine the presence and extent of escape from vaccine- and infection-induced immunity is important, since it shapes public health responses. These have a long turnaround time, however.

New assays are required to quantify the risk arising from different mutations in time to take preventive action against new escape variants. The lack of these assays at the right time may lead to the loss of value of sequencing data. Tests assessing both humoral and T cell immunity are essential, besides monitoring vaccine efficacy.

Collaboration

Global sharing of epidemiologic, virologic, and genomic data is also essential to properly analyze the pathogen and antiviral drug properties. Isolated non-standardized data stored in outdated silos is useless in addressing global outbreaks.

For this to occur, genomic data standardization must be ensured. This cannot be done overnight and may take years.

Cooperation

Moreover, academic and public health efforts need to be aligned in fighting such crises, each contributing to the other and thus promoting research that can improve health status.

Finally, genomic surveillance must be performed promptly, and the data must be made open access to help policymakers and drug manufacturers to make proper decisions.

Conclusion

"What are the reasonable options for establishing a WHO [World Health Organization] Global COVID-19 Response Program? The many questions include the who, what, why, where, and when of the organizers, the agreements, the stakeholders, the finances, and the rollout. But as we ponder these questions, one point is very clear: The variants of concern of the COVID-19 pandemic are relentless."

Resources

• Munnink, B. B. O. et al. (2021). The Next Phase Of SARS-Cov-2 Surveillance: Real-Time Molecular Epidemiology. Nature Medicine. doi:10.1038/s41591-021-01472-w. https://www.nature.com/articles/s41591-021-01472-w
• Becker, S. J. et al. (2021). Identifying and Tracking SARS-CoV-2 Variants — A Challenge and an Opportunity. New England Journal of Medicine. DOI: 10.1056/NEJMp2103859. https://www.nejm.org/doi/full/10.1056/NEJMp2103859
• Layne, S. P. et al. (2021). Increasing Threats From SARS-Cov-2 Variants: Time to Establish Global Surveillance. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.abj6984. https://www.science.org/doi/full/10.1126/scitranslmed.abj6984

Further reading

• Role of Glycoscience in Viral Surveillance
• How to Prevent Pandemics
• Monkeypox Epidemiology
• Importance of Wastewater Surveillance of SARS-CoV-2

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.