By: Michael Oberholzer, PhD and Phil Febbo, MD
The severe acute respiratory syndrome coronavirus SARS-CoV-2
(2019-nCoV) outbreak is an important reminder that the global community must strengthen national and international programs for early detection and response to future disease outbreaks. At Illumina, we will continue to ensure the safety of our employees while encouraging that our global employee workforce skills and expertise are available as a resource to assist in containing and controlling the outbreak. Additionally, Illumina has made our technology available to Chinese health authorities and we are ready to support similar applications and strategies across the globe to improve detection and to enhance our tracking of the epidemiology, evolution, and virulence of SARS-CoV-2.
The role of sequencing in viral outbreaks
Sequencing novel viruses helps remove the fear of the unknown by defining the viral genomic sequence for dissection and interpretation. While we are within the first two months of the first report to the World Health Organization (WHO) of SARS-CoV-21, and there remains much to learn, modern technology has identified and characterized the virus, sequenced its full genome, and started to describe the genetic evolution of the virus over a short time period.
- On January 24, the first SARS-CoV-2 genome was published in the New England Journal of Medicine.2 To our knowledge, this is the first time a complete genome of a novel infectious agent has been publicly available in such a short time after the first case was reported to the WHO.
- As of February 7, over 80 SARS-CoV-2 genomes have been shared through the Global Initiative to Share All Influenza Data (GISAID) and GenBank, which will catalyze the research to understanding of the origin of the new virus, the epidemiology and transmission routes, and facilitate development of diagnostic and treatment strategies.3 Understanding the genome of SARS-CoV-2 early, provided unprecedented insight into dynamics of viral spread and impacted response strategies.
What is known today – insights gained from sequencing the SARS-CoV-2 genome
Within less than 60 days of reporting, global scientists know the likely origin of the virus, how similar it is to related viruses that are better understood, and what therapies may be applicable.
Analysis of the genomic information currently available, indicates SARS-CoV-2 is most closely related to a known bat SARS-like Coronavirus, indicating bats as the likely origin.3,4 Low variability between SARS-CoV-2 genomic sequences available, points toward a recent emergence in the human population in November-December 2019 and rapid detection after initial human infection.3,4 Clusters of related SARS-CoV-2 infections suggest human-to-human transmission and further evolution of the virus. Molecular modeling based on sequencing data reveals diversity in a critical SARS-CoV-2 surface protein in comparison to close related bat Coronaviruses (only 75 percent identical), potentially indicating mechanisms for adaptation to a life in the human host.4 The diversity in this surface protein also has implications for potential vaccine strategies, since SARS vaccine concepts based on the homologous surface protein may not be as effective against the SARS-CoV-2.5
While this is early in the outbreak, there are no specific drugs available to treat SARS-CoV-2. There is high sequence conservation between SARS-CoV-2 and related SARS-CoV in viral drug targets, such as in protease and polymerase enzymes.3,6 This indicates that inhibitors that are active against SARS-CoV protease and polymerase likely have activity against the homologous enzymes in the SARS-CoV-2.4
Unprecedented global collaboration to contain and control the SARS-CoV-2 outbreak – First step of many
The sequence of the SARS-CoV-2 genome has also enabled the development of polymerase chain reaction (PCR) based diagnostics that can be brought to the front lines and leveraged for rapid identification of infected individuals. These tests are essential to both patient management and incidence tracking, so performance must be highly accurate. Illumina previously reported efforts of public health authorities in China who rapidly developed PCR-based tests as well as confirmatory sequencing-based methods to understand the virus spread from Wuhan regionally and across the nation. Just last week, the Centers for Disease Control (CDC) and the Food and Drug Administration (FDA) in the U.S. worked similarly quickly on a PCR diagnostic panel for SARS-CoV-2. The FDA issued emergency use authorization, enabling deployment of the CDC reagents to laboratories across the U.S. In Europe, the European Center for Disease Control (ECDC) also recommends PCR-testing for the SARS-CoV-2.
Reports from Africa indicate no positive cases of SARS-CoV-2 thus far. However, the lack of confirmed diagnoses may be due to a limited capacity for in-country testing rather than the true epidemiology of the virus. Concern remains for the potential risk of introducing SARS-CoV-2 into Africa through expatriates travel, and leaders in the African Union and the CDC Africa had a training session for laboratory directors and personnel in Dakar Senegal last week to establish in-country capacity and capability throughout the African continent.
Virus transmission and virulence - Where do we go from here?
Virus-human interface and viral characteristics such as infectivity, virulence and transmission for SARS-CoV-2 are currently still poorly understood. According to the WHO situation report from February 13, scientists are primarily dependent on reports from China where there were 46,550 confirmed cases and 1,368 deaths. Human-to-human transmission via respiratory route, the pace of spread, and the description of infected individuals suggest that SARS-CoV-2 is quite contagious. However, with the limited information we have available, it is still too early to conclude on the true transmissibility of this novel virus.
Because of suggestions of high transmissibility, health authorities have taken definitive action and restricted day-to-day activities in regions within China and restricted travel to and from China. While only a minority of cases have been reported by WHO outside of China (447 confirmed cases as of February 13), there has been limited access to SARS-CoV-2 testing in many countries, potentially leading to under-estimation of the true epidemiology of the virus. Thus, as the capacity for in-country testing and surveillance is getting established across the globe over the coming weeks, we will have a much better understanding of the true scale and scope of the outbreak and the regional dynamics outside of China.
Similarly, we cannot determine virulence of SARS-CoV-2 or assess how dangerous the virus is to individual patient populations using sequencing information alone. Based on what has been reported, the mortality rate is approximately 2-3 percent (1,369 attributed deaths and 46,997 confirmed infected), although this figure is highly dependent on accurate cause of death attribution and reporting and heavily weighted on information shared by Chinese officials. For the approximate 447 cases reported outside of China, we have two attributed deaths – one in the Philippines and one in Hong Kong. Thus, it is too early to know how dangerous the novel virus is for different patient populations, as well as the role of co-infections on patient mortality. If reporting is accurate, it appears that SARS-CoV-2 might be more similar to what we expect from the annual Influenza viruses rather than what was observed for SARS-CoV outbreaks in the past.
Critical to understanding both transmissibility and virulence, is knowing definitively who is infected with SARS-CoV-2 and what other co-infections may be present. Due to similarities between SARS-CoV-2 and other viruses, and due to the potential for co-infection, Chinese authorities are integrating sequencing in patient diagnostic workups to confirm positive cases and to detect novel mutations. Illumina has made our technology available to Chinese health authorities and are ready to support similar applications across the globe to support strategies to improve detection and to enhance our tracking of the epidemiology, evolution and virulence of SARS-CoV-2.
While we are still early into this outbreak, we know much about the virus: the complete genome, the genetic divergence from previously characterized viruses, the variation of targets for therapy, and we are starting to understand transmissibility and virulence. Rapid identification and sequencing of SARS-CoV-2 enabled characterization of the virus and development of diagnostic methods and initially shed an optimistic light on the global response to SARS-CoV-2. However, it is becoming increasingly clear that it will be very challenging to track and contain the spread of this novel virus due to its often ‘silent’ nature or clinical presentation reminiscent to other respiratory tract infections. Since the virus is now outside of the origin Wuhan, Hubei Province, China, it is expected that novel surveillance strategies are needed to identify clusters of potential infections to guide intervention. Over the next few weeks, we will continue to characterize the virus more deeply, and the scope and impact of the pandemic will be better understood. At Illumina, we remain ready to help ensure access to our technology and to help our global teams of experts to support further understanding of SARS-CoV-2 with the goal of limiting its spread and harm.