A Lack of COVID-19 Genomes Could Prolong the Pandemic

Researchers in China and Australia analysed the genome of the coronavirus taken from one of the first patients in the Wuhan outbreak before the COVID-19 pandemic got international attention. The first genetic blueprint for the SARS-CoV-2 virus was made public on January 10, 2020. The publishing of that genome, and subsequent ones, contributed in the rapid construction of a solid international scientific response to the pandemic, including the prompt development of diagnostic tests, monitoring systems, immunizations, and other new tools for outbreak control.

Because technology can now analyse the genome of a viral sample collected from a patient in a matter of hours, the World Health Organization (WHO) declared in a research that “for the first time, real-time genomic sequencing has been enabled to advise the public health response to a pandemic.”

Despite this, countries continue to fall well short of these standards, according to the Global Initiative on Sharing Avian Influenza Data (Gisaid), which supervises the most widely used global collection of SARS-CoV-2 genomic data, and other sources. Globally, over 180 million confirmed COVID-19 infections have been reported; however, only around 2,042,000 viral genome sequences have been submitted, accounting for less than 1% of all cases. In a handful of countries, sequencing rates are increasing, but not quickly enough. The figures are especially concerning for the countries with the highest infection rates: the US has sequenced 1.7 percent of its 33.2 million cases, while Brazil has sequenced less than 0.1 percent of its nearly 18.2 million infections and India has sequenced less than 0.1 percent of its 30.1 million infections.

Medical researchers are concerned that a lack of understanding of how COVID-19 mutations can intensify and extend the pandemic. “The greater the gaps in our knowledge of the variants circulating globally, the more likely it is that we will miss the evolution of a critical variant and find ourselves taking steps backward in the fight to contain the pandemic,” said Justin O’Grady, former deputy director of the COVID-19 Genomics UK Consortium (COG-UK) and now senior director of translational applications at Oxford.

If the existing impediments to viral surveillance are not overcome, we may see more uncontrolled viral outbreaks in the future. “If there are major ‘blind spots’ in virus sequencing surveillance, then you cannot avoid pandemics,” said David Haussler, scientific director of the Genomics Institute at the University of California, Santa Cruz. “It is therefore vital that virus genomes be sequenced globally and that knowledge be communicated as soon as possible.”

Why is it critical to collect viral genomic data?
Scientists utilise genetic sequences gathered during an epidemic to determine how a virus evolves. While it is very easy to estimate the rate at which a viral genome mutates in the laboratory, this is not the same as the virus’s rate of evolution, which is determined by how quickly and successfully a mutation spreads throughout a population. A more precise estimate of the evolutionary rate can be obtained by comparing the genomes of viral samples collected from different patients at different times. According to research, it is best to collect samples for SARS-CoV-2 at least every two months, with more samples taken over longer periods producing better results.

Observing the evolution of SARS-CoV-2 is, of course, useful for improving and maintaining the accuracy of COVID-19 diagnostics: If tests are designed to detect viral features that have been displaced by evolution, they may become unreliable over time or in different places. Vaccine design is closely related to genetic data, and this is more true now that clinical medicine is employing mRNA vaccines.

“We need to be able to develop a vaccine for a disease before it spreads globally,” Haussler explained. “With mRNA vaccines, we may start as soon as we know the genetic sequence of the infectious agent. This shows that getting genome sequences early in a novel strain’s outbreak, before it spreads, is the most critical issue at the moment.”

The genomic material from SARS-CoV-2 has also offered light on the complicated biology that underpins COVID-19. It let scientists discover the cellular receptor protein to which SARS-CoV-2 attaches, showing which cell types in the body are most vulnerable to infection.

Keeping a precise record of the virus’s evolution during the pandemic, on the other hand, is important in a more subtle sense since it can reveal information about the disease’s epidemiology. Because the viral genome acquires approximately one random mutation every two weeks, the number of genomic variants among samples can be utilised to determine whether the COVID-19 patients being tested are part of the same viral transmission network.

“The virus’s genome acts as a molecular fingerprint,” said David O’Connor, a pathology and laboratory medicine professor at the University of Wisconsin, Madison, whose lab studies SARS-CoV-2 genomes. “At first, we were concerned that health-care workers would become infected while caring for COVID patients.” The genomes of the viruses obtained from medics and patients were rarely similar, he noted, “suggesting that the health care staff were infected outside of the hospital.”

Similar sorts of genetic epidemiology aided researchers in determining early in the pandemic that an outbreak in Connecticut was produced by a mix of home and foreign sources, rather than by direct international travellers. It also helped researchers determine that non-pharmaceutical measures like masks and social separation lowered sickness spread within states but were less efficient at decreasing disease transfer between states in Brazil.

The patterns of viral diversity in the population can be used to calculate crucial COVID-19 epidemiological metrics such as its reproduction number, R0. They can also give information on pandemic dynamics that epidemiological data alone cannot identify; for example, they can shed light on what happened during an outbreak before any cases were detected.

Furthermore, investigations can reveal subtle differences in the epidemiological behaviour of different virus lineages or variations. Health officials around the world are concerned about a number of significant SARS-CoV-2 mutations that are more easily transmitted. B.1.1.7 (alpha), which was first identified in the United Kingdom and may pose an increased risk of death; B.1.351 (beta), which was first identified in South Africa and may exhibit increased resistance to certain vaccines; B.1.617.2 (delta), which was first identified in India and has since become a leading cause of new cases; P.1 (gamma), which was first identified in Japan; and Britain.

Additional variants are likely to emerge over time, and it is unclear how much they will complicate, or possibly impede, attempts to end the pandemic. “Continuous genome sequencing is crucial for detecting the emergence of ‘vaccine escape’ variants,” Moi explained. This simply adds to the worry that the majority of countries have not even begun to approach the levels of genome sequencing that may be required.

The situation is particularly serious in 38 countries where COVID-19 infections have been identified but no sequencing data has been shared with Gisaid. These countries include Chad and Burundi, both of which are among the poorest in the world. Africa had reported more than 5.3 million infections (3.9 million of which were confirmed) as of June 27, but its governments had only sequenced and exchanged roughly 22,700 genomes, accounting for less than 0.6 percent of its infections. Over 40% of those genome sequences (roughly 9,600) come from a single country, South Africa.

The consequences of a data shortage in Africa could be devastating for individuals all across the world. “Africa, with its human population diversity, is a likely source of even more severe and refractory strains,” said Muntasar Ibrahim, a Sudanese geneticist and professor of molecular biology at Khartoum University, where he also runs the Institute of Endemic Diseases.

Strategic and structural planning flaws
Sequencing flaws cannot be blamed only on a lack of funding. (Sequencing costs about $120 per SARS-CoV-2 genome, but Haussler emphasises that sequencing the genomes in large quantities can significantly lower expenses.) Those of the poorest countries had more cases than some of the richest, demonstrating that income cannot be the main determinant. Gambia, for example, has sequenced more than Germany (3.6%), a country with 60 times Gambia’s GDP per capita.

Low rates do not just reflect how hard the pandemic has hit countries. Despite the fact that the United States has sequenced the most SARS-CoV-2 genomes, only about 10% of the population in the United States carries COVID-19, resulting in a low sequencing rate (1.7%). However, the United Kingdom, where the disease has affected around 7% of the population, has sequenced more than 10% of its caseload: It has the 13th highest rate of virus genome sequencing in the world, yet it has sequenced more virus genomes than the countries ahead of it combined.

The performance of countries’ genome sequencing efforts during the epidemic appears to have been dictated by a mix of their strategic choices and biomedical infrastructure.

COVID-19 surveillance in the United States has been hampered, according to Tom Maniatis, CEO of the New York Genome Center (NYGC), by a systemic lack of connections between facilities that have virus samples — hospitals, public health laboratories, and commercial testing facilities — and facilities that have the capacity to sequence them. “While the situation has improved, logistical challenges remain,” he stated.

The most important issue in the United States, according to Maniatis and Soren Germer, who heads the sequencing and analytics teams at NYGC, has been getting samples. “During the early days of the pandemic, when New York was exceptionally hard hit, even the most research-oriented hospitals usually lacked the resources required to collect study samples,” they wrote in an email. “We have heard reports of very heroic efforts to save some of these samples for research and surveillance,” but in chronically understaffed institutions, patient care and staff safety must take precedence. Maniatis and Germer also emphasised the absence of coordinated support in the United States, which has been inconsistent at the state and municipal levels and has only just begun at the federal level.

According to Rolf Apweiler, director of the European Bioinformatics Institute, the countries donating SARS-CoV-2 sequences to his organization’s specialised genomic data platform have a wide range of goals. While some countries set low targets or do not conduct SARS-CoV-2 genomic surveillance, “countries such as Denmark, Iceland, Australia, and the United Kingdom aim to sequence between 10% and 100% of all positive samples during periods of high infection rates and all positive samples technically feasible during periods of low infection rates,” he explained.

Some of the countries that are investing the most significantly in genome sequencing may already be reaping the benefits. COG-UK is a collaboration of genetic experts entrusted with identifying, tracing, and managing the SARS-CoV-2 virus in the United Kingdom. It was formed when the country’s experts worked early in the epidemic to assure large-scale genetic sequencing, with government support of £20 million. Within weeks of its launch in March 2020, the project made the first sampled genomes publicly available; it has already sequenced over 450,000 viral genomes.

O’Grady attributes that work to assisting in the containment of the UK outbreak. “Genome sequencing discovered the B.1.1.7 variant, which explained why case numbers were rapidly increasing near the end of 2020 and allowed us to implement effective control measures,” he explained. When other variants were discovered in South Africa and elsewhere, UK authorities increased testing and contract tracing operations, essentially stopping the variants’ introduction into the country.

Preparing to Carry on the Fight
Several countries are actively working to increase the scale of their sequencing initiatives. In February, the CDC proposed $200 million as a “down payment” for genetic surveillance. In April, the Biden administration pledged $1.7 billion to accelerate sequencing efforts and tackle SARS-CoV-2 mutations. “The United States is now investing heavily in sequencing, acknowledging that the gains we have made are fragile and may be undone by viral variants,” O’Connor added.

In January, the Indian government created the Indian SARS-CoV-2 Genomics Consortium to expedite the genome sequencing initiative by using an expanding network of institutions. Anurag Agrawal, a senior scientist with the consortium and director of the CSIR-Institute of Genomics and Integrative Biology in New Delhi, one of the participating institutions, stated that the consortium’s nationally coordinated genome-sequencing programme has sequenced over 15,000 genomes in about three months. “I expect the stats to continue to improve,” he said.

Africa’s standing is improving as well. Segun Fatumo, an assistant professor of genetic epidemiology and bioinformatics at the Medical Research Council/Uganda Virus Research Institute, emphasised the critical importance of African governments funding critical research and infrastructure. He did note, however, that Africa has been quite efficient in its fight against the coronavirus, an accomplishment made possible by genome sequencing.

“The WHO has established a network of COVID-19 genomic sequencing laboratories in 18 African countries,” he stated. “Because Africa is important for human origin and illness vulnerability, large-scale genomic study in African-ancestry populations may give novel therapeutic strategies.”

Apweiler believes that only global cooperation and effort can successfully control a pandemic. “A deadly new lineage of SARS-CoV-2 in one location might very quickly become a global problem,” he cautioned. “Our global response to the epidemic will be as successful as the weakest link in the chain.”

Moi agrees that sequencing is vital, but adds that it will always be necessary to balance that effort against other local objectives in order to maximise public health benefit. “Sequencing massive volumes of virus [genomes] may not be practical, especially during large outbreaks,” she said, adding to the strain on laboratories and medical facilities. She is confident, however, that “important insights can still be achieved through well-planned sampling and testing with effective sequencing methods in place.”

Detecting and Avoiding Future Pandemics
“If the pandemic had occurred even five years earlier, creating large-scale genetic surveillance programmes would have been substantially more difficult,” O’Connor added. “The technologies required to democratise sequencing and make it accessible to small labs and public health authorities simply did not exist.”

The infrastructure and technology used to map COVID-19 could be beneficial for other applications. “Our secondary goal is that the precise observation of viral evolution throughout the pandemic, as well as the study, will hasten the development of targeted medications for future pandemics,” Maniatis explained.

According to him, the fundamental question is whether information networks and infrastructure will allow for routine viral surveillance, such that detecting the next potential pandemic virus becomes a routine component of the public health system. The WHO has indicated that incorporating genome sequencing into the normal activities of the global health community is “important” in order to prepare for future risks.

Haussler recognised that developing worldwide capabilities for pathogen sequencing and genome exchange could help avert future viral epidemics. “At this point in time,” he continued, “it is one of the most critical investments that the world can make.” “It is projected to save thousands of lives and trillions of dollars over time.”

Source:
1.COVID research: a year of scientific milestones.doi: https://doi.org/10.1038/d41586-020-00502-w
2.https://www.quantamagazine.org/a-lack-of-covid-19-genomes-could-prolong-the-pandemic-20210628/