Diagnostic testing and surveillance are critical, complementary strategies to combat pathogen outbreaks. Illumina’s Chief Medical Officer, Phil Febbo, MD, discusses the important role of sequencing-based surveillance in the fight against COVID-19.

Q: What is the difference between diagnostic testing (PCR) and surveillance testing?

A: At a basic level, diagnostic testing helps clinicians manage patients and surveillance is required to manage populations.

• Diagnostic testing provides important yes/no answers for individual patients so that appropriate management can be provided.
• Surveillance helps public health officials track the path of the epidemic, understand transmission routes, determine the rate of viral evolution, and understand if the virus is changing in ways that impact therapeutic effectiveness.

Q: How might we use sequencing-based surveillance to combat SARS-CoV-2?

A: There are five main ways sequencing-based surveillance has been used to fight SARS-CoV-2:

1. Sequencing identified SARS-Cov-2 as the virus causing the cluster of respiratory illnesses in Wuhan. Deep shotgun sequencing is unbiased and can be performed on nasal swabs and other samples to look for non-host genomic material, which can then be assembled into potential causative agents. The sequence rapidly identified the virus as one closely resembling a coronavirus endemic in bats, but also revealed a mutation in the protein involved in attaching to host cells that helped explain the ability of the virus to infect human cells.¹ Recently, an analysis in Nature provided evidence that SARS-CoV-2 developed through natural selection mechanisms in host species, although the exact path from bats to humans remains uncertain.² The important sequence was required to design PCR probes for diagnostic tests.
2. Sequencing is necessary to track the transmission route of the virus globally. 2434+ genomes have been submitted to the Global Initiative to Share All Influenza Data (GISAID) with the identification of clusters and transmission routes.³ This helps public health entities make decisions on how to control and contain the virus. For example, Trevor Bedford Ph.D., a computational biologist at the Fred Hutchinson Cancer Research Center in Seattle, demonstrated that of the 39 cases he sequenced, 35 came from a single introduction from China and the other four came from Europe and Iran.⁴ Thus, there was not a single introduction into the Seattle area but multiple, suggesting that containment efforts cannot only focus on tracking exposure to the most established cluster, and more aggressive measures are warranted to contain the spread of virus.
3. Sequencing can determine how quickly the virus is adapting as it spreads. It appears that SARS-CoV-2 achieves two mutations per month as it spreads. This information allows public health officials to identify how likely the virus is to avoid detection from established PCR assays and become resistant to therapies.⁵
4.  Sequencing identifies targets to therapies. Knowing the viral genome is essential to understanding therapeutic efficacy from small molecule therapeutics targeting specific viral proteins to vaccines directed against viral antigens. For example, it is clear from the SARS-CoV-2 sequences that drugs developed previously for the SARS infection, targeting the main viral protease, may be effective in SARS-CoV-2 because there is 97 percent overall genetic identity in the protease. However, vaccines are unlikely to work because the highly antigenic surface proteins are very divergent (76 percent identical).^6,7
5. Sequencing-based surveillance is required to understand the role of co-infection. COVID-19 can range from asymptomatic to fatal. Respiratory pathogens can often cause progressive disease by lowering host immunity and fostering a co-infection that results in more severe and life-threatening disease. While still early, we have heard of both common rhinoviruses and less common but more dangerous respiratory syncytial virus (RSV) being identified by sequencing-based surveillance assays of positive cases. If a common co-infection is identified as causing significant disease, therapy may be focused on the co-infection rather than SARS-CoV-2.⁸

These capabilities make surveillance critical to following a disease and determining the best way to control pandemics and manage populations.

For a deeper dive into how we can track the spread of coronavirus mutations, read this National Geographic article, featuring Bedford and Febbo.