Talking Viral Mutations, Genome Sequencing and Antigenic Drift With Dr Timothy Triche

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Dr Timothy Triche is the co-director of the Center for Personalized Medicine at Children’s Hospital Los Angeles (CHLA), where his team employ a variety of existing and emerging genomic technologies to diagnose and research childhood (and adult) disease, most notably cancer and inherited disease. However, since the COVID-19 outbreak, Triche and colleagues have added a new research focus to their program: SARS-CoV-2 sequencing and analysis.

The CHLA COVID-19 Analysis Research Database (CARD) is a comprehensive genomic resource that provides access to full-length SARS-CoV-2 viral genomes and associated meta-data for over 18,000 (correct as of May 10, 2020) isolates collected from global sequencing repositories and the sequencing performed at the Center for Personalized Medicine at CHLA.

Technology Networks interviewed Triche to gain his perspectives on how analysis of unique strains can help to define the scope and severity of COVID-19, why this is a complex process and the possible negative implications of antigenic drift.

Molly Campbell (MC): What has your research discovered thus far on the ability of SARS-CoV-2 to mutate?

Timothy Triche (TT): We routinely find mutations in every patient sample, but many are trivial and of no biologic consequence. These variants co-exist within one isolate and suggest the virus routinely generates multiple variants at the same time. Why this happens and whether there is any biologic or clinical relevance is not clear. We, like many, are looking for the emergence of strains that could alter patient immune response or efficacy of a vaccine. To date we have not yet seen such an example after sequencing hundreds of samples.

MC: How might this information be useful for identifying vulnerable populations?

TT: More recent data suggest factors like duration of exposure, magnitude of exposure, and host genetic factors are more important than viral clade, or variant, in determining whether the infected person remains asymptomatic, develops typical mild illness, or progresses to severe disease and death. Often, vulnerable populations are more vulnerable because of these factors, more than any relationship to a given viral mutant.

MC: Which analytical methods are superior for studying the mutations of the virus? Are there any challenges here?

TT: Analysis of viral sequence data is not a simple task. It requires sophisticated bioinformatic methods, particularly because of the complexity noted previously. Deciding which variants are significant, when some may only be present in a few percent of the total, and others that have no effect on protein sequence, so-called synonymous variants, or may lead to mis-sense alterations in genes, as opposed to those that change the viral protein structure, so-called non-synonymous variants, is a complicated process.

Further, tracing the origin and spread of the virus requires so-called phylogeny analysis, a very sophisticated process that relies on the quality of those sequence variants. Fortunately, we have a very skilled bioinformatics group that has developed and deployed those tools and skills for broad use via a web site called the CHLA CARD that enables others to analyze their data and share that data.

CHLA CARD, most recently published on bioRxiv, provides the phylogenetic analysis resources and tools that are essential to understand the many complexities of this disease.

MC: What is antigenic drift, and what are the possible negative implications?

TT: Antigenic drift means the virus changes its protein structure due to mutations over time. This is well known with influenza, for example. The concern is that something similar might happen with SARS-Cov-2, which shows remarkable sequence similarity to SARS-CoV, yet shows little cross reactivity with antibodies to SARS-CoV. If this were to happen, of course, it would imply that, like influenza, a vaccine developed for one variant might show little efficacy for an emergent variant, or infection with one variant was not protective against another variant. Fortunately, so far, we have not seen evidence for that; but we are still early in the course of this pandemic and will continue to monitor our isolates for mutations that could result in altered antigenicity.

MC: How is CLHA using sequencing to trace the virus in a healthcare setting?

TT: One of the most useful applications of viral sequencing is our ability to determine whether two individuals were infected by the same virus. When that occurs, as we have seen with a mother and child who were treated in our institution after acquiring the virus via community spread, we can also determine whether anyone they have come in contact with who also develop COVID-19 acquired the virus from an "index case".

In the example we studied early in the course of this pandemic, there was marked sequence dissimilarity between the family and our health care workers, which of course was reassuring that infection was not occurring within the hospital, where rigorous protective measures are routinely employed. If they had been identical, it would have suggested those measure were inadequate. Because they were not identical, it suggested those safety measures were adequate. Similarly, when positive isolates are identified, we can also determine whether workers who are infected with the virus acquired their infections from one another or the community. Such information is of paramount importance as part of infection control measures in a hospital.

Dr Timothy Triche was speaking to Molly Campbell, Science Writer, Technology Networks.