WHO-Convened Global Study of Origins of SARS-CoV-2: China Part (Text Extract)
Zhao, Wei
Abstract
Summary In May 2020, the World Health Assembly in resolution WHA73.1 requested the Director-General of the World Health Organization (WHO) to continue to work closely with the World Organisation for Animal Health (OIE), the Food and Agriculture Organization of the United Nations (FAO) and countries, as part of the One Health approach, to identify the zoonotic source of the virus and the route of introduction to the human population, including the possible role of intermediate hosts. The aim is to prevent both reinfections with the virus in animals and humans and the establishment of new zoonotic reservoirs, thereby reducing further risks of the emergence and transmission of zoonotic diseases. In July 2020, WHO and China began the groundwork for studies to better understand the origins of the virus. Terms of Reference (TORs) were agreed that defined a phased approach, and the scope of studies, the main guiding principles and expected deliverables. The TORs envisaged an initial Phase 1 of short-term studies to better understand how the virus might have been introduced and started to circulate in Wuhan, China. The joint international team comprised 17 Chinese and 17 international experts from other countries, the World Health Organization (WHO), the Global Outbreak Alert and Response Network (GOARN), and the World Organisation for Animal Health (OIE) (Annex B). The Food and Agriculture Organization of the United Nations (FAO) participated as an observer. Following initial online meetings, a joint study was conducted over a 28-day period from January 14 to February 10, 2021 in the city of Wuhan, People's Republic of China. The team agreed on a workplan and established working groups to review the progress made in Phase 1 studies in the areas of epidemiology, animals and the environment, and molecular epidemiology and bioinformatics. During the course of the discussions, the international experts gained deeper understanding of the methods used and data obtained. In response to requests during the visit, further data and analyses were generated, reflecting a productive iterative approach to refining the design and interpretation of complex studies in all areas. In addition to group work, the team shared scientific and thematic presentations on relevant topics to help inform its work, undertook a series of site visits to important locations, and conducted interviews with key informants. Main findings Epidemiology The overall focus of the studies was to determine: (1) whether there was evidence of transmission of SARS-CoV-2 in Wuhan or Hubei Province in the period preceding the recognized outbreak in Wuhan in December 2019 using routine disease and death surveillance data, review of clinical records and targeted SARS-CoV-2 laboratory testing; (2) whether there was evidence of transmission of SARS-CoV-2 in the wider population of Wuhan or Hubei Province at the time the outbreak was recognized in Wuhan in December 2019 using information from the cases reported with onset in that month; and (3) whether the epidemiological characteristics of the early cases associated with the Huanan market pointed to a specific time, location or source of the introduction of infection into the market at the beginning of the outbreak. The joint international team concluded that: Morbidity surveillance, pharmacy purchases, and mass gatherings 1. Based on the national sentinel surveillance data for ILI, and the associated laboratory-confirmed influenza activity, in Wuhan as well as Hubei and six surrounding provinces, there is a marked increase in ILI in both children and adults at the end of 2019 in Wuhan. This may be explained by a contemporary increase in laboratory-confirmed influenza activity but whereas the data provided no evidence for substantial SARS-CoV-2 transmission in the months preceding the outbreak in December 2019, sporadic transmission or minor clusters of SARS-CoV-2 cannot be ruled out 2. Analysis of aggregated retail pharmacy purchases for antipyretics, and cough and cold medications did not provide a useful indicator of early SARS-CoV-2 activity in the community. 3. No appreciable signals of clusters of fever or severe respiratory disease requiring hospitalization were identified in association with mass gatherings during September to December 2019. Mortality surveillance 4. During the period August–December 2019, a review of all-cause and pneumonia-specific mortality data provided little evidence of any unexpected fluctuations that might suggest the occurrence of transmission of SARS-CoV-2 in the population in the period before December 2019. This does not exclude, however, the possibility that some circulation of SARS-CoV-2 was occurring in the population at a low level, as changes in mortality at the population level would be unlikely to be sufficiently sensitive to detect this. 5. In view of the time lag from the onset of disease to COVID-19-associated death, the documented rapid increase in all-cause mortality in week 3 of 2020 and pneumonia-specific deaths in week 4, suggest that virus transmission was widespread among the population of Wuhan by the first week of 2020. The steep increase in mortality occurred 1–2 weeks later among the population in the Hubei Province outside Wuhan, suggesting that the epidemic in Wuhan predated the spread in the rest of Hubei Province. Identification of early cases and role of Huanan market among early cases 6. An explosive outbreak began in Wuhan in early December 2019. Only more severe cases with contact with the healthcare system were recognized. Other milder (and asymptomatic) cases will have been occurring at the same time as the recognized cases but no information is currently available on these milder cases that could add to the epidemiological picture of the early outbreak. 7. Many of the early cases were associated with the Huanan market, but a similar number of cases were associated with other markets and some were not associated with any markets. Transmission within the wider community in December could account for cases not associated with the Huanan market which, together with the presence of early cases not associated with that market, could suggest that the Huanan market was not the original source of the outbreak. 8. Other milder cases that were not identified, however, could provide the link between the Huanan market and early cases without an apparent link to the market. No firm conclusion therefore about the role of the Huanan market can be drawn. Case-searching 9. The retrospective search for cases compatible with COVID-19 illness identified 76,253 episodes with one of four indicator conditions. A rise in one of these conditions, ARI (as well as ILI and fever), was seen in this group of individuals in the over 60-year age group in early December. The clinical assessment of the 76,253 individuals revealed 92 cases clinically compatible with COVID-19. It is possible that the clinical review, resulting in the identification of only 92 clinically compatible cases, may have decreased the possibility of identifying a group or groups of cases with milder illness. 10. All 92 cases identified by the clinical retrospective review of morbidity surveillance episodes were rejected as cases of SARS-CoV-2 infection on further clinical review. None of these cases (where blood could be obtained) was positive on SARS-CoV-2 serological testing performed on samples collected more than 12 months later. The use of retrospective serological testing so long after the illness cannot be relied on to exclude the possibility of SARS-CoV-2 infection at the time of the presenting illness, given the possible drop in SARS-CoV-2-specific antibody over time and the associated reduced sensitivity of commercial assays. The possibility that earlier transmission of SARS-CoV-2 infection was occurring in this community cannot be excluded on the basis of this evidence. Laboratory testing 11. Blood donor screening surveys for SARS-CoV-2 antibodies are used in many countries to understand community prevalence of SARS-CoV-2 and monitor the increasing proportion of the population being infected over time. The Wuhan Blood Centre offers the opportunity to undertake a serosurvey for SARS-CoV-2 in blood donors in the latter part of 2019. 12. Testing of convenience samples collected in 2019 from research study biobanks did not provide any indication of earlier SARS-CoV-2 circulation. 13. Given the outstanding questions and the potential for limited clusters that would not be detected through the studies done so far, access to systematically collected historic samples, including routinely stored blood bank samples, would be of great added value for the studies of the origin. Recommendations The joint international team made the following recommendations: Morbidity surveillance, pharmacy purchase, and mass gathering events 1. The joint team recommends further exploration of the weekly ILI trends (especially in adults) in 2019, in comparison to the earlier years, using time-series analyses. 2. The joint team recommends a review of pharmacy purchases by week during the period of September to December in 2016, 2017, 2018, and 2019 to look for any signals of increased purchases in the weeks of September to December 2019 as compared with the same weeks during the previous years. If any signals are identified then proceed with analyses for spatial-temporal clusters. 3. The joint team recommends that consideration be given to further joint review of the data on respiratory illness from the on-site clinics at the Military Games in October 2019. Mortality surveillance 4. The joint team recommends augmenting the mortality review by broadening the approach to include other provinces where phylogenetic analyses (Fig. 5, Molecular Epidemiology section) have revealed early epidemic clusters and comparison with other provinces and cities in China. Identification of early cases and role of Huanan market among early cases 5. The joint team recommends that further testing of the 67 specimens obtained in the retrospective clinical review of the 92 cases identified by the clinical retrospective review be carried out and compared with retesting of a subsample of the 174 confirmed cases from December 2019, and any other groups of specimens of relevance. This should be linked with the investigation of new approaches to serological testing using historic samples collected through the blood bank. 6. In view of the limited time available during the visit to Wuhan in January and February 2021, further joint review (including the data and analyses in Annex E4) should be carried out, including analyses of clinical and demographic characteristics, as well as risk factors, of the 174 notified cases. Consideration of re-interviewing these cases should be based on the findings of the joint review. Case-searching 7. The joint team recommends further review of the methods used to identify and characterise the cases in the retrospective clinical search for patients presenting with relevant conditions to the 233 Wuhan medical institutions, to search for features (such as clustering) that could be suggestive of occurrence of previously unrecognized cases of SARS-CoV-2 infection. 8. This review should include the 92 cases initially identified as being compatible with a possible COVID-19 diagnosis, as well as other cases with potentially milder illness. 9. It should also include the increase in ARI in older adults in late 2019, seen in the retrospective search from the 233 Wuhan medical institutions. Acknowledging the constant progress in understanding the broad spectrum of COVID-19 illness over time and the insight into mild and/or atypical clinical presentation of the infection, the joint team recommends review of all NNDRS COVID-19 discarded cases (potential or confirmed) registered in Wuhan city during the weeks of December 2019 in the search for early cases. Laboratory testing 10. No further work is required on the convenience clinical sample collection already investigated, as all SARS-CoV-2-specific laboratory results were negative. 11. The joint team recommends a collaborative study with the Wuhan Blood Center for the presence of SARS-CoV-2-specific antibodies in blood samples from adult blood donors in Wuhan collected during the months of September to December 2019, and further back in time until there are two successive months without any evidence of SARS-CoV-2-specific antibodies among the tested samples. This could be expanded to include other blood centres in China and other locations worldwide, focusing on the 6 months (at least 3–4 months) period before the first cases in each location were identified and ideally using a common laboratory testing approach. Contemporary samples from blood donor populations in other regions of China where COVID-19 cases were not detected before the early months of 2020 could serve as a control group. 12. The joint team recommends investigation of new approaches to serological testing to revisit testing performed from cases initially identified in the retrospective clinical review, the early confirmed cases and any other groups of interest. There may be potential for international collaboration on such work. Molecular epidemiology Most emerging viruses originate from animals. Understanding the process that may lead to a cross-species transmission event, also known as “spillover,” and global spread requires a deep understanding of both the virus diversity and evolution in an animal reservoir, the interactions between animals, their environment and humans, and the factors contributing to efficient human to human transmission. A virus causing a global pandemic must be highly adaptive to human environments. Such adaptation may be gained suddenly or may have been evolving through multiple steps with each step driven by natural selection. The search for the origin of SARS-CoV-2, therefore needs to focus on two phases. (1) The first phase involves viral circulation in animal hosts (such as bat, pangolin, mink, or other wild animals) before zoonotic transfer. During this evolutionary process, various animal species may serve as reservoir hosts. Upon circulation, SARS-CoV-2 progenitor strains may have acquired increased ability to infect humans. Finding viral sequences nearly identical to SARS-CoV-2 helps the elucidation of the origin of SARS-CoV-2 from zoonotic transmissions from intermediate host species. The second phase involves radiative evolution of SARS-CoV-2 during its global spread in human populations following zoonotic transfer. Animal–human contacts permit a progenitor of SARS-CoV-2 to switch its host to humans, and the likelihood of such spillovers increases with the frequency, nature, and intensity of contact. (2) Spillovers may have occurred repeatedly, if the genomic features of the virus in the reservoir require further adaptation for efficient onward transmission, and such early spillovers may go undetected. In addition, the evolution or spillover of viruses with pandemic potential may have resulted in substantial clusters in different geographical regions before factors converged and led to the pandemic of COVID-19. Evidence from surveys and targeted studies so far have found the most highly related viruses in bats and pangolins, suggesting they may be the reservoir of SARS-CoV-2 according to the high sequence similarity between the sampled viruses and SARS-CoV-2. Viruses identified so far from neither bats nor pangolins are sufficiently similar to SARS-CoV-2 to serve as the direct progenitor of SARS-CoV-2. (3) In addition to these findings, the high susceptibility of mink and cats suggests the potential of species of animals to the or as well as other as potential of virus presence and diversity in potential reservoir species have not been and potential reservoir hosts are The joint international team concluded that: 1. genomic data with epidemiological data is for molecular in of 2. control of is important to provide 3. Viruses from some Huanan market cases were suggesting a 4. Analysis of early also some suggesting and unrecognized circulation. 5. of the time to most common the and suggest that virus transmission or circulation might be in late 2019. 6. to the most closely related genomic sequences have been found in 7. of of SARS-CoV-2 in cases and samples before January 2020 in different of the require Animal and environment studies In this and surveillance studies and surveys conducted in China were according to defined studies that the origin of SARS-CoV-2 from that aim to identify potential infection of animals by surveys and animal as part of the initial outbreak investigation and a review of the of the Huanan market. testing of samples from and animals in China was also conducted and the results were 1. that are related to SARS-CoV-2 were identified in different animals from different countries, including bats and and testing of bats in Hubei however, been conducted but were positive for viruses to SARS-CoV-2. of China been conducted but no samples were positive for SARS-CoV-2. 2. The Huanan market evidence of the of and animals and and limited All the samples during the outbreak investigation tested for the SARS-CoV-2 3. SARS-CoV-2 can in conditions found in and cases in in China have been linked to the cold This a possibility of transmission of SARS-CoV-2 through The to the markets in Wuhan (including animal and from provinces in China and other countries and regions where SARS-CoV-2 and tested positive before the outbreak of SARS-CoV-2, countries where cold were provinces where were and where the of SARS-CoV-2 are found in bats and There is evidence that some species in the Huanan market are to SARS-CoV-2 or but of the animal sampled in the market tested from in Huanan market were not tested in early 2020. findings however, the possibility for different potential of the for of these and sample 4. and testing at other markets in Wuhan and to the Huanan market during 2020 did not evidence of SARS-CoV-2 in animals. Evidence was not found of presence of SARS-CoV-2 among animal in the Huanan market and 5. in the Huanan market widespread of with SARS-CoV-2, compatible with the virus from infected in the market at the end of December 2019. through testing of animal in the market, no evidence of animal was One sample collected on January 2020 on a second market tested from the patients in the 6. No evidence was found of circulation of SARS-CoV-2 among and wild animals before and after the SARS-CoV-2 outbreak in China. Recommendations The joint international team made the following recommendations: Recommendations for work related to the of emergence from to a SARS-CoV-2 been conducted in animals in no positive samples were found so the origin of the SARS-CoV-2 in relevant species to through international should be conducted for the viral of in emerging disease surveys of in China for there are to the of for populations over areas. further surveys to identify related to SARS-CoV-2 are in bats and pangolins in China as well as in is and in bats in other countries where this is This should focus in on regions where been done and where analyses spillover to is most of other wild animals known to be infected by should be conducted where they such as mink and Recommendations for work related to the of emergence intermediate hosts at the that previously Huanan market and other Wuhan markets linked to positive cases, including interviews and serological testing of and their and other relevant and their The surveys of and in this are but to and animal there are to the to detect positive surveys for in or that have potential to be including species for such as and and for such as mink and in in in and in other of the samples from the Huanan market to identify more species and potential intermediate hosts or of that might have been in the Recommendations for work related to the cold global retrospective testing for SARS-CoV-2 from in 2019 to the Huanan market and virus and at different to the that would as are from one to then through the the different of the cold in the possible introduction of the virus in a market and the possible spread within a market following the introduction of the virus in a market by an infected of emergence The joint international team and four main for introduction 1 and direct zoonotic transmission introduction through an intermediate host by zoonotic transmission introduction through the and introduction through a laboratory for possible of a for possible for SARS-CoV-2 The are to be in a and the location and are not The animals animal species that have been in to potential infection but can be by other species as of possible transmission. The are to any to ability to infect other species and/or each of these possible of the joint team conducted a risk assessment the available scientific evidence and The team the likelihood of these using an of through to and further international and national phase scientific studies as in the The are to be used as a risk assessment and can be new information or studies In the joint team the following of potential introduction from to (1) through an intermediate (2) direct zoonotic (3) introduction through and introduction resulting from a laboratory from the evidence for the studies conducted so far, research studies were for the first The and these are for each in the zoonotic transmission In this there is the transmission of SARS-CoV-2 closely related progenitor from an animal reservoir host to by direct transmission with of human or without the for adaptation of the virus to humans (Fig. The of will on events such as events by the for the market, and for direct zoonotic transmission. relevant for this are in through intermediate host by zoonotic transmission SARS-CoV-2 is from an animal reservoir to an animal by spread within that intermediate host and then to humans. The through an intermediate host can be without of animals, or with of animals, virus adaptation (Fig. for introduction of SARS-CoV-2 through an intermediate host by transmission. relevant for this are in through the transmission can direct zoonotic transmission or spillover through an intermediate cold may be a of transmission between humans. This would also to events in addition to The focus of this is on and their as potential route of introduction of SARS-CoV-2. is important to between of cold to in 2020 and the potential for cold as the for the origin of the pandemic in for introduction of SARS-CoV-2 through the relevant for this are in through a laboratory SARS-CoV-2 is introduced through a laboratory reflecting an infection of from laboratory the relevant did not the of or of SARS-CoV-2 for the latter been ruled out by other following analyses of the for introduction of SARS-CoV-2 through a laboratory relevant for this are in The international team recognized the of the epidemic on Wuhan, from individuals and to and The team the of all the long of data to its work. 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