How long will the next pandemic last?
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Before our memories of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) fade, the coronavirus's third attack on humans has already begun. Since the first case of pneumonia caused by the novel coronavirus (SARS-CoV-2) was reported in Wuhan, Hubei Province, in December 2019, the outbreak has spread rapidly around the world. In March 2020, the World Health Organization declared that COVID-19 had become a global pandemic. As of 3 May, the outbreak has spread across the globe, causing 3.4 million infections and 240,000 deaths[1], with more than 100,000 confirmed cases reported in eight countries.
Both SARS-CoV and MERS-CoV originated in bats, and the novel coronavirus (SARS-CoV-2) may be the same. Sequencing results showed that SARS-CoV-2 had 96.2 percent identity at the genome-wide level with bat coronavirus BatCoV RaTG13 found in Yunnan, suggesting that bats may be natural hosts of SARS-CoV-2 sources[2]. In the cross-species spread of viruses, some mammals act as intermediate hosts, promoting recombinant and mutant events and expanding genetic diversity. SARS-CoV and MERS-CoV cross the species barrier through intermediate hosts civets and dromedary camels, respectively, and enter the population. For SARS-CoV-2, it has been found that the coronavirus carried by pangolins is highly similar to the genome sequence of SARS-CoV-2, so it is suspected that pangolins may be intermediate hosts for SARS-CoV-2 [3]. But so far, the highest match with SARS-CoV-2 is still the RaTG13 found in bats, and the currently obtained data do not fully clarify whether the virus is transmitted directly from bats to humans or indirectly through intermediate hosts, and we still need more sequence data to confirm the specific origin of SARS-CoV-2.
What have past respiratory viral epidemics brought us?
The outbreak of covid-19 has once again brought respiratory viruses into the sights. Despite the deepening understanding of biomedicine, when the virus hits, we still fall into panic, and in the face of the raging virus, we only have weapons but science and technology and accumulated experience. In recent decades, respiratory infectious diseases have emerged in an endless stream, and most of them have the potential to cause a pandemic, and the threat of respiratory viruses to human health cannot be underestimated.
Influenza is an acute respiratory infectious disease caused by influenza virus infection. Influenza viruses repeatedly infect people with their characteristics of easy mutation and strong transmission ability. There have been four influenza pandemics in the past century: 1918 (H1N1), 1957 (H2N2), 1968 (H3N2) and 2009 (H1N1). Each pandemic has caused a large number of infections worldwide, with the 1918 "Spanish flu" being the most severe, with more than half of the world's population estimated to have been infected, killing about 50 million people.
Including the new crown virus this time, human beings have encountered three "attacks" of the coronavirus. In 2002, SARS-CoV caused 8,422 infections worldwide and killed 916 people (11% mortality rate) [4]. People with SARS infection develop flu-like syndrome and pneumonia within a week or so of infection, and in severe cases, respiratory failure. In 2012, MERS-CoV emerged in Saudi Arabia, infecting 2,494 people and killing 858 people (34% mortality rate) [5]. People infected with MERS develop severe pneumonia and quickly lead to respiratory failure, resulting in a higher mortality rate.
Because respiratory viruses spread rapidly and have a huge impact on society, we need to adopt effective strategies to prevent and respond to every link of the spread of the virus and cut off the chain of transmission.
1. Source of infection
In the emerging respiratory infectious diseases of modern times, most of the pathogens come from mammals and birds that are closely related to humans, such as bat-borne coronaviruses and bird-borne avian influenza. Wild animals, as rich "reservoirs of viruses", have the ability to spread viruses to humans. Viruses can break through species barriers and spread between different animals through constant mutation, and although most of them have no obvious effect on humans, a pandemic may begin once a virus infects humans and humans lack immunity to such viruses.
The virus continues to spread from natural hosts to populations, largely due to human activities, including urbanization and modern agricultural production. Humans destroy the territory of other animals while also increasing the risk of contact with diseased wild animals, and trafficking and eating wild animals directly exposes themselves to the risk of contracting the virus.
In the face of a virus that is about to invade at an unknown time, all we can do is protect ecosystems and restore natural habitats, fundamentally banning the wildlife trade. Only by maintaining the barrier between humans and the virus's natural host can the chain of infection be severed from the root cause and the attack of the virus stopped at the "first step".
2. Monitoring and diagnosis
The emergence of novel epidemic pathogens is often unpredictable, so early detection and timely response are essential to control infectious diseases. Rapid detection of possible pathogen infections in the future requires surveillance systems that can detect abnormal symptoms, while the rapid identification and exclusion of known pathogens requires effective diagnostic systems.
The devastating influenza pandemic of 1918 left an indelible memory on the world and made people aware of the importance of global influenza surveillance. The main purpose of influenza surveillance is to grasp the distribution, spread, mutation and other conditions of the virus in real time, and to estimate the epidemic trend. The first global surveillance system, the Global Influenza Surveillance and Response System (GISRS), established in 1952, was able to report and share emergency information on influenza in a timely manner, playing a key role in the management of subsequent influenza epidemic crises, including the response to the three influenza pandemics of 1957, 1968 and 2009. Since then, national influenza centers and specialized laboratories have been established in various countries to analyze the strains of influenza that are constantly spreading in the population to provide detailed information on seasonal influenza vaccines [6].
Surveillance of infectious diseases requires the collection of abnormal cases over a long period of time and without interruption, and the causes and transmission routes are analyzed and summarized from them. Efficient surveillance and reporting systems enable early detection and identification of epidemics and next steps of control. For example, in the second half of 2002, unexplained respiratory diseases were discovered and reported in Guangdong Province, China, and the syndrome was later named "Severe Acute Respiratory Syndrome" (SARS).
Accurate and rapid diagnosis of pathogenic pathogens is critical to selecting appropriate treatments and epidemiological control strategies, but similar clinical symptoms produced by different pathogens can hinder the identification of potentially endemic viruses. In the early days of the SARS outbreak, a bacterial microbial anaplasm was mistakenly regarded as a pathogen of SARS, and SARS patients were treated with antibiotics that treated the amorphous body, and the misdiagnosis and misjudgment of the pathogen may exacerbate the spread of the virus. In the face of unknown diseases, how to quickly and accurately identify pathogens is very critical, rapid diagnostic detection techniques, such as next-generation sequencing, serological testing, RT-PCR, etc. can help accurately identify pathogens [7]. Future work should focus on developing inexpensive, accurate, and rapidly delivering molecular methods for identifying novel pathogens in resource-constrained environments.
3. Interventions
When the virus has begun to spread, how to intervene in the outbreak becomes urgent. Known interventions include antiviral therapy, vaccination, and public health measures.
Antiviral drugs can interfere with the life cycle of the virus and reduce the replication of the virus. For example, viral neuraminidase inhibitors zanamivir and oseltamivir, used to treat influenza, can significantly reduce the duration of symptoms and reduce the severity of the condition. But the underlying problem with antiviral drugs is that they can lead to the emergence of drug-resistant viruses, such as a seasonal influenza virus carrying a single mutation in the neuraminidase gene, creating resistance to oseltamivir [8], suggesting that the virus can avoid the effects of the drug through mutations. For now, the best option for combating a pandemic remains to reduce the number of susceptible people through vaccination. But vaccine effectiveness depends on the time it takes to develop it, and unless there is a fundamental change in manufacturing techniques or methods, vaccines that take months or more to develop can only be used later in the outbreak.
Given that both drugs and vaccines take a long time to develop, we still rely heavily on public health measures to combat emerging infectious diseases. Public health measures mainly include non-pharmacological interventions such as closing schools, shopping malls and other public places, restricting public transportation, canceling assemblies, and paying attention to personal hygiene. The fundamental purpose of public health measures is not to prevent or stop epidemics, but to slow down the spread of the virus, limit the spread of the virus locally and internationally, reduce individual infections, thereby containing the epidemic within a controllable range, preventing the collapse of the health system, and buying time for the development of antiviral drugs and vaccines.
Strict public health measures require not only government decision-making, but also the conscious cooperation of the public and a lot of work at the grass-roots level. Therefore, the intensity of public health intervention needs to be appropriately grasped and flexibly adjusted in combination with the current social situation.
4. Treatment and intervention of new crown pneumonia
With no approved antiviral drugs or vaccines and a lack of effective antiviral treatments for COVID-19, current treatment modalities are essentially respiratory support and symptomatic treatment.
After the SARS-CoV-2 gene sequence was published, a large number of laboratories began to develop vaccines. As of April 30, in addition to 94 vaccines under preclinical development, eight vaccine candidates have entered clinical trials. Among them, the adenovirus vector vaccine developed by the Academy of Military Sciences of China carries the spike protein gene of SARS-CoV-2 and has taken the lead in entering the clinical phase II. In addition, the inactivated vaccine developed in China, the mRNA vaccine and DNA vaccine developed in the United States, and the adenovirus vector vaccine developed in the United Kingdom have also entered the clinical stage [9].
The development of antiviral drugs is also being carried out intensively, and the focus of drug development is to find targets specific to viruses. Antiviral drugs currently being tested include the RNA-dependent RNA polymerase inhibitor remdesivir and the protease inhibitor lopinavir/ritonavir [10]. The study found that remdesivir can shorten the recovery time of patients by 31%, and the US Food and Drug Administration (FDA) has officially approved the emergency use authorization of remdesivir for the treatment of new crown pneumonia on May 1. In addition, the intervention routes being explored include convalescent plasma therapy, monoclonal antibodies, interferon therapy, and small molecule drugs [11].
At the beginning of the outbreak, in the absence of specific drugs and vaccines, China quickly adopted strict public health measures. At the national level, wuhan has been "locked down", and all provinces and cities across the country have entered a first-level response state for major public health emergencies, which has minimized the export of cases from Wuhan to the outside world, won valuable time for other provinces and cities to fight the epidemic, and also enabled the whole country to help Wuhan and the entire Hubei province on a large scale. At the public level, people across the country have actively responded to national epidemic prevention measures, minimized interpersonal interactions, strengthened personal hygiene, and consciously worn masks. As a result, in just two months, China has rapidly contained the epidemic through strict and effective non-drug interventions. However, the epidemic is still spreading around the world, and we cannot predict the final scope and impact of the epidemic.
The 3 coronavirus pandemics in the past 20 years have made us wonder: Will there be a new coronavirus?
Coronaviruses are RNA viruses with a higher rate of variation than DNA viruses, but not the same mechanism of mutation as influenza viruses that are also RNA viruses.
In the case of influenza A virus, for example, its genome contains eight negative strands of RNA, each encoding a different viral protein. When two or more influenza strains infect the same cell, they can interchange genomic fragments, and fragments of genomes from different sources wrap into a single viral particle and genetic rearrangement occurs, resulting in new fragment combinations. Pigs can be infected with both swine flu, avian flu and human influenza strains, which makes pigs an ideal "container" for influenza virus recombination. And when a newly emerging virus gains the ability to infect humans, a new pandemic could occur.
Coronaviruses undergo RNA recombination. When at least two viruses co-infect the same host cell and exchange genetic segments, there is a chance that a recombinant virus will be produced. At present, it is believed that the mechanism by which reorganization occurs is mainly template conversion. When the viral genome is replicated, the RNA polymerase jumps from one template to another while maintaining the binding of the nascent nucleic acid chain. After the RNA polymerase is shed from the original template, it can bind to the same or different locations of the same template, or to different templates, resulting in strands of RNA with mixed parents [12]. Non-replicating recombination also occurs at lower frequencies, during which RNA strands are broken at specific sites and then join to other RNA strands to form hybrid molecules [13]. The high frequency of RNA recombination of coronaviruses is an important factor in altering the host range. Communication between different coronaviruses is more frequent through template switching and rupture connections, and the highly diverse coronaviruses in bat populations also facilitate the evolution of viruses.
Coronaviruses are constantly evolving, breaking through barriers between species to capture new hosts, so it's not hard to imagine that it's only a matter of time before the next coronavirus outbreak breaks out. In the face of a new virus that is destined to emerge, we need to think about how to fight it. Past outbreaks have also pointed to several key research needs: strengthening surveillance of wildlife, developing rapid and accurate diagnostic measures, and developing drugs with broad-spectrum antiviral activity. At the same time, preparations for the outbreak need to start early and cannot wait until the next crisis comes.
Infectious diseases appeared before humans, but not before humans ended. It has not only been, but will certainly be, one of the important factors affecting the development of human civilization. COVID-19 will not be the last infectious disease to threaten human safety, but the experience of prevention and control and medical advances gained from the COVID-19 pandemic and past epidemics can help us better cope with the next pandemic.
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About the Author
Cheng Gong, a long-term professor at tsinghua university school of medicine, is mainly engaged in the research of mosquito-borne virus infection transmission mechanism and antiviral immunity. Professor Cheng Gong and his team have conducted long-term exploration in related fields, achieved a series of innovative and internationally influential research results, promoted the development and improvement of the knowledge concept system of virulent mosquito-borne virus infectious diseases, and represented an important breakthrough in China's hot field of mosquito-borne virus infectious diseases. The above research results have been published in mainstream journals such as Nature, Cell and its sub-journals, and have obtained a number of invention patents and applied for international patents. He has won the first prize of Beijing Science and Technology Award (the first completer), the National Outstanding Youth Science Foundation, the Ministry of Education Young Yangtze River Scholar, the Royal Medical Association of the United Kingdom "Newton Senior Scholar", the Tan Jiazhen Life Science Award, the Shulan Medical Youth Award, WuXi AppTec Life Chemistry Research Award and other awards and honors.
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This article was published with the permission of Teacher Cheng Gong.
Editor-in-charge: Zhang Yisong
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