The China part of  COVID-19 global traceability research is announced!

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The China part of  COVID-19 global traceability research is announced!

The China part of  COVID-19 global traceability research is announced!   Recently, the China National Health Commission released the “SARS-CoV-2 Global Traceability Study Convened by WHO: China Part-WHO-China Joint Research Report.”

Through three working groups, the research team reviewed the progress of Chinese experts in the following three fields in the first phase: epidemiology, animal and environment, molecular epidemiology and bioinformatics.

The results of the joint study are as follows:

Epidemiology: 

Early traceability work through incidence monitoring data

Influenza-like illness (ILI) and severe acute respiratory disease (SARI) monitoring combined with appropriate laboratory confirmation are standard measures to measure the impact of influenza and other respiratory viruses on the population. In order to determine the possible impact of the pathogen of COVID-19 on the incidence of the above two diseases in the months before the outbreak of COVID-19, we monitored the adult sentinel surveillance data of ILI in a hospital in Wuhan and SARI surveillance in a provincial hospital in Hubei Province The data was reviewed.

According to the national ILI sentinel monitoring data in Wuhan, Hubei and the surrounding six provinces and influenza activities confirmed by related laboratories, at the end of 2019, there was a significant increase in ILI among children and adults in Wuhan, other cities in Hubei and the surrounding six provinces. Although this may be due to the simultaneous increase in laboratory-confirmed influenza activity, the joint team recommends using time series analysis to further explore the weekly ILI trend in 2019 compared with previous years.

The analysis of antipyretics, cold medicines and cough medicines purchased in retail pharmacies does not indicate early SARS-CoV-2 activities in the community. The joint team recommends reviewing the weekly pharmacy purchases from September to December in 2016, 2017, 2018, and 2019 to look for signs of increased purchases from September to December 2019 compared to the same period in the previous year . If any signal is recognized, it is recommended to continue analyzing the spatio-temporal clusters.

Early traceability work through preserved laboratory samples and other resources

During retrospective testing of more than 4,500 research project samples stored in hospitals in Wuhan, other regions of Hubei Province and other provinces in the second half of 2019, no SARS-CoV-2 was found.

This work can be extended to other blood centers in China and other parts of the world. The time is concentrated within 6 months before the first case is detected locally. It is best to use a systematically designed random selection sample and the same laboratory testing methods. Samples of blood donors from other parts of China who have not found COVID-19 cases before the first few months of 2020 can be used as a control group.

Early traceability work through mortality research

During July-December 2019, the monitoring data of all causes of death and pneumonia death in Wuhan City and Hubei Province except Wuhan did not show evidence of unexpected fluctuations in the death trend, which did not indicate that SARS-CoV-2 occurred in the population before December 2019. In the spread. Nevertheless, it cannot be ruled out that SARS-CoV-2 is spreading at a low level in the population, because population-level mortality changes are unlikely to be sensitive enough to detect this.

In view of the time lag from the start of infection to COVID-19-related deaths, the rapid increase in all-cause mortality and pneumonia-specific deaths in the third week of 2020 indicates that the virus has spread widely among the Wuhan population in the first week of 2020. In the population of Hubei Province outside Wuhan, the sharp increase in mortality occurred after 1-2 weeks, which shows that the epidemic in Wuhan is earlier than that in other areas of Hubei Province and other provinces.

The joint team recommends that the scope of the mortality review be expanded to include other provinces where phylogenetic analysis found early epidemic clusters and compare them with other provinces and cities in China.

Clinical review of potential cases in Wuhan in October and November 2019

A total of 233 medical institutions in Wuhan searched for patients who came to medical institutions for one of the four diseases (fever, acute respiratory disease, flu-like illness, and “unexplained pneumonia) from October 1 to December 10, 2019. A total of 76,253 medical records. At the beginning of December 2019, ARI (as well as ILI and fever) in the age group over 60 years of age increased compared to the previous period. After review by the clinical teams of various medical institutions, 92 of the 76,253 people were considered clinically in line with SARS -Diseases caused by CoV-2 infection. In January 2021, blood was collected from 67 out of 92 cases (excluding death cases, rejected or unavailable cases), and SARS COV-2 was carried out using colloidal gold methods. The antibody test results were all negative. After re-examination by external multidisciplinary clinical experts, it was determined that none of the 92 cases were eligible for SARS-CoV-2 infection.

Based on the fact that there was no evidence of SARS-CoV-2 infection in potential cases in Wuhan in the two months before the outbreak in December 2019, the international joint expert team believes that the possibility of partial transmission cannot be ruled out at this stage. In addition, 12 months after the outbreak, serological testing methods for investigating the possibility of transmission in the months of the end of 2019 also have limitations.

The joint team recommends further review of the methods used to identify and describe the characteristics of cases in retrospective clinical studies, including 92 cases that were initially determined to be consistent with the diagnosis of COVID-19, as well as other cases that may be milder, in order to find The confirmed case may be diagnosed as a characteristic of COVID-19 (such as clustered disease). In view of the increase in ARI in the elderly at the beginning of December 2019, the ARI data should be further reviewed jointly.

The 67 specimens obtained in the clinical review should be further tested and compared with the 174 case samples confirmed since December 2019 and any other relevant samples after re-examination. This should be linked to a new method of serological testing through historical samples collected from blood banks.

A retrospective analysis of cases reported by the National Notifiable Disease Reporting System

In early December 2019, an outbreak caused by SARS-CoV-2 infection occurred in Wuhan. A total of 174 cases of COVID-19 (100 laboratory confirmed cases and 74 clinically confirmed cases) were found with onset in December 2019. Only the more serious cases that went to the medical system were confirmed. Other mild (and asymptomatic) cases co-exist with confirmed cases, but there is currently no information on these milder cases, which may be a supplement to the epidemiology of the early outbreak.

Many early cases are related to the South China Seafood Market, but there are also similar numbers of cases related to other markets, and some cases are not related to any market. The spread in the wider community in December can explain the cases that are not related to the South China Seafood Market. In addition, there are early cases that are not related to the South China Seafood Market, which can indicate that the South China Seafood Market is not the origin of the epidemic. However, other unconfirmed milder cases may provide a link between the South China Seafood Market and early cases, which were previously thought to have no obvious link to the market. Therefore, it is not yet possible to draw definitive conclusions about the role of the South China Seafood Market in the origin of the epidemic or how the infection was introduced to the market.

In view of the limited time during the visit to Wuhan in January and February 2021, a further joint review of 174 confirmed cases should be conducted, including analysis of the clinical and demographic characteristics and risk factors of the cases. Whether to re-examine these patients in person depends on the results of the joint review. The joint team also recommends reviewing the information of other patients who were reported as potential COVID-19 cases in December 2019 to understand whether these cases are previously unconfirmed COVID-19 cases, and whether the SARS-CoV-2 outbreak is being confirmed for the first time Provide any additional information on the infection status of the local population during the period

Molecular epidemiology

Because most of the new viruses are derived from animals, to understand the processes that lead to virus spillover and global spread requires a deep understanding of the diversity and evolution of viruses carried by animal reservoirs, the interaction between animals, the environment, and humans, and the formation of Factors of effective person-to-person transmission. The virus that can cause a global pandemic must be highly adapted to the human environment. This adaptation may be acquired suddenly or gradually through multiple steps, and each step is driven by natural selection.

Therefore, the traceability of SARS-CoV-2 should focus on two stages.

• The first stage involves the circulation of the virus in animal hosts (such as bats, pangolins, or other wild or domestic animals) before zoonotic transfer occurs. In this evolutionary process, various animal species may become reservoirs. The ancestor strain of SARS-CoV-2 may have acquired the ability to infect humans during its cycle. The discovery of a virus with a highly homologous sequence to the SARS-CoV-2 virus indicates that SARS-CoV-2 may originate from zoonotic transmission, but its reservoir remains to be ascertained.

• The second stage involves the evolution of SARS-CoV-2 in the population spread after zoonotic transfer. The probability of this animal-to-human spillage increases with the frequency and intensity of animal-human contact. Spills may occur repeatedly, but if the viral genome in the reservoir needs to be further adapted to achieve effective and sustained transmission, this early spill may not be detected. Once viruses with pandemic potential evolve or overflow, they will gain the ability to spread, resulting in a large number of adaptively mutated virus strains appearing in people in different regions, thus triggering the COVID-19 pandemic.

Genomic data of animals

Evidence from investigations and targeted studies to date shows that the coronavirus most closely related to SARS-CoV-2 has been found in bats and pangolins. The genetic sequence of the sample virus and SARS-CoV-2 is highly similar, suggesting that the mammals mentioned above may be the reservoir of the virus that causes COVID-19.

However, so far, the similarity between the virus found in 99 species and SARS-CoV-2 is not enough to make it the direct ancestor of SARS-CoV-2. In addition to these findings, the high susceptibility of mink and cats to SARS-CoV-2 suggests that there may be other animal species (musteles or cats, among others) as potential reservoirs. Comparing the data in the sequence database with the data in the investigation of potential reservoir species, it is found that the collection of specimens for these potential reservoir species is seriously insufficient.

Analysis of the viral genome and epidemiological data in the early stages of the pandemic

The joint team reviewed the data collected through the China National Center for Bioinformatics in its comprehensive database containing all available coronavirus sequences and metadata. All sequence data of samples collected in December 2019 and January 2020 were selected for in-depth analysis, and the diversity of the virus in the first phase of the pandemic was reviewed. For the cases found in Wuhan, China, after linking the data with the epidemiological background, the cases with onset before December 31 were selected.

The final analysis showed that among the cases exposed to the South China Seafood Market, several cases had the same viral genome, indicating that these cases may be part of a cluster of cases. However, the sequence data also showed that there was a certain amount of virus diversity at the beginning of the pandemic in Wuhan, indicating that there is an unsampled transmission chain outside the South China seafood market group. Judging from the epidemiological parameters of exposure to raw meat or fur animals, there is no obvious clustering of cases.

Estimated time to the nearest common ancestor based on early sequence data

In addition, the time from the SARS-CoV-2 sequence to the nearest common ancestor (tMRCA) in the final data set was estimated through analysis and compared with the results of previous studies. Such a tMRCA analysis can be considered as an estimate and cannot provide a definitive proof of the time of origin. Analysis of molecular sequence data indicates that the start of the pandemic may be a month before mid-December. The estimated time points vary from late September to early December, but most of the estimated points are between mid-November and early December.

Literature review of SAES-CoV-2: early detection

Finally, we reviewed the data in the published literature that showed the early circulation of SARS-CoV-2. These studies from different countries have shown that the circulation of SARS-CoV-2 is several weeks earlier than the initial detection of the case. Some suspected positive samples were tested even earlier than the first case in Wuhan, suggesting that there may be missed diagnosis in other areas. But so far, the quality of research is still very limited. Nevertheless, it is important to investigate these potential early events.

Animal and environmental research People have discovered phylogenetic coronaviruses related to SARS-CoV-2 in different animals, including chrysanthemum bats and pangolins. However, bat samples taken in Hubei Province did not find evidence of the existence of SARS-CoV-2, and samples of wild animals across China have not yet found the existence of SARS-CoV-2. A total of more than 80,000 specimens of wild animals, livestock and poultry were collected in 31 provinces in some countries. No positive results for SARS-CoV-2 antibodies and nucleic acids were found before and after the SARS-CoV-2 outbreak. Through extensive testing of animal products in the South China Seafood Market, no evidence of animal infection was found.

Environmental sampling after the closure of the Huanan Seafood Market showed that 73 of the 923 environmental samples were positive, indicating that SARS-CoV-2 contamination is widespread on the surface, which is consistent with the introduction of the virus through infected persons, infected animals, and contaminated products .

The supply chain of the South China Seafood Market includes cold chain products and animal products from 20 countries. Some of these countries have reported positive SARS-CoV-2 samples before the end of 2019, or have been found to be closely related to SARS-CoV-2 Virus. There is evidence that some farmed wild animal species products sold in the market are susceptible to SARS-CoV-2. However, in this study, none of the animal samples collected on the market had positive results. Cold chain products have not been tested. However, these research results do raise the possibility that there may be different channels of introduction, and emphasize the need for careful traceability and sample testing of these supply chains.

SARS-CoV-2 can survive the conditions of frozen food, packaging and cold chain products. The index cases in the recent outbreak in China are related to the cold chain. Studies have shown that viruses can survive for a long time at low temperatures and can therefore be carried over long distances on frozen products. The viability of the virus at different temperatures is currently being further studied.

There are a large number of stalls selling cold chain products in the South China Seafood Market. Epidemiological studies have shown that the relative risk of cases in stalls with cold chain goods is higher than that of stalls without cold chain goods. Further analysis is needed to determine the spatio-temporal correspondence and correct the potential bias in sampling. Other studies that should be carried out include tracing cold chain goods imported from areas where SARS-CoV-2 positive samples were reported before the end of 2019, and tracing the process of frozen wild animal products from the supply farm to the South China seafood market through interviews with suppliers .

In other countries that supply cold chain products to China, evidence of SARS-CoV-2 has been found on packaging and products. There is evidence that there are early clusters of cases in other countries that provide cold chain products to China. Another issue is to investigate the cold chain or refrigerated supply chain in areas where SARS-CoV-2 positive samples have been reported before the end of 2019 or in countries where SARS-related coronaviruses have been found in animals (such as Southeast Asian countries). At the same time, it is necessary to distinguish the role of cold chain in the imported virus from abroad and the market itself.

The international team made recommendations for the next phase of research to assist in the traceability of SARS-CoV-2 and its closest common ancestor. These studies can include: sequencing and antibody testing of SARS-CoV-2 related viruses in wild animal samples; continuing to investigate chrysanthemum bats in southern China, East Asia, Southeast Asia, and other neighboring countries; sorting out the work that has been completed to Make clear the next step; analyze the possibility of the virus approaching humans. On-site teams working in different countries can sample other wild animal species, or through opportunistic sampling of animals such as pangolins confiscated by customs. The scope of analysis can be extended to other species, including potential intermediate hosts or reservoirs such as civet, mink, ferret, and primates.

Research should be conducted on the edible wild animals raised, visit farmers and suppliers, inquire about their contact, and analyze the transaction and transaction history of animals and products in other markets in Wuhan, especially those related to human infection cases or sequence data. Other work can include the following investigations: animals raised in Southeast Asia and beyond to search for SARS-CoV-2 related viruses; badgers-cultured civet cats/civet cats in Southeast Asia; rabbits and other coronavirus-susceptible animals Livestock farms. It will be very valuable to continue the targeted investigation of SARS-CoV-2 and related viruses on fur animal farms in China and its neighboring countries.

Serological testing should be performed on groups with occupational exposure risks such as animals and cold chain products to determine whether they have abnormally high antibody titers, suggesting that there are risk factors for SARS-CoV-2.

Molecular epidemiology

The main recommendations for future work are:

Expand the comprehensive molecular, clinical and epidemiological database to cover all existing research related to the origin of the new coronavirus. This includes data from animal and environmental surveys. In addition, it is necessary to provide high-quality genomic data solutions for in-depth analysis.

More genome sequencing work will be carried out in areas where the early (December 2019 and before) spread of SARS-CoV-2 is suspected.

Animals and the environment

The main recommendations for future work are:

In the weeks/months before the start of the epidemic, retrospective testing of SARS-CoV-2 products sold in specific batches of cold-chain related products in the South China Seafood Market is still available.

Research and test the viability of the virus and the freeze-thaw cycle that naturally occurs as the product passes through the supply chain.

The investigation of potential wild animal hosts and intermediate hosts should continue, especially in southern China, Southeast Asia, and other regions under the guidance of risk assessment. Species of particular interest are rhino horseshoe bats and related species, pangolins and pangolins, civet cats, ferret badgers, mink and other species known to be susceptible to SARS-related coronavirus infections.

The secondary farms raising domestic wild animals were further traced, and the meat of these farms was related to the epidemic situation in the South China Seafood Market and other markets. This can include interviews with practitioners, farmers and their workers, cold chain suppliers and other related personnel, and can also be combined with serological testing of them, their families and contacts. Investigating and tracing other markets related to early cases may provide key clues.

Before the end of 2019, conduct relevant traceability studies on sewage, serum, human or animal tissue/swabs, and other countries and regions that have tested positive for SARS-CoV-2.

Possible ways for the virus to appear

• The International Joint Expert Group evaluated four introduction situations:
• The direct transmission of zoonotic diseases to humans (spillover);
• Introduced through the intermediate host after overflow;
• Introduced through the cold chain/food chain;
• Introduced through laboratory events.

For each possible path of emergence, the joint expert group conducted a qualitative risk assessment, considered the existing scientific evidence and findings, and stated the arguments for each possibility. The expert group assessed the relative possibilities of these approaches and prioritized further research that might deepen global understanding and understanding.

The joint expert group assesses the possibility of each possible approach as follows:

The direct spillover of zoonotic diseases is seen as a way from possible to more likely;

Introduction through an intermediate host is seen as a way from more likely to very likely;

The introduction of products through the cold chain/food chain is seen as a possible way;

Introduction through laboratory accidents was seen as extremely unlikely.

The international team recognizes the impact of the epidemic on Wuhan, from affected individuals and communities to health workers, scientists, and government officials. The team praised the participation of all professionals who spent a long time analyzing large amounts of data to support the team’s work. Finally, the team called for continued scientific and cooperative methods in tracing the origin of COVID-19.

Sources from the China National Health Commission

(source:internet, reference only)

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