On 31 December 2019, the Chinese government notified the World Health Organization (WHO) of an outbreak of severe pneumonia of unknown etiology in Wuhan, Hubei province (1
), a city of approximately 11 million people. Of the initial 41 people hospitalized with unknown pneumonia by 2 January 2020, 27 (66%) had direct exposure to the Huanan Wholesale Seafood Market (hereafter, “Huanan market”) (2
). These first cases were confirmed to be infected with a novel coronavirus, subsequently named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and were suffering from a disease later named coronavirus disease 2019 (COVID-19). The initial diagnoses of COVID-19 were made in several hospitals independently between 18 and 29 December 2019 (5
). These early reports were free from ascertainment bias as they were based on signs and symptoms before the Huanan market was identified as a shared risk factor (5
). A subsequent systematic review of all cases notified to China’s National Notifiable Disease Reporting System by hospitals in Wuhan as part of the joint WHO-Chinese “WHO-convened global study of origins of SARS-CoV-2: China Part” (hereafter, “WHO mission report”) (7
) showed that 55 of 168 of the earliest known COVID-19 cases were associated with this market. However, the observation that the preponderance of early cases were linked to the Huanan market does not establish that the pandemic originated there.
Several lines of evidence support the hypothesis that the Huanan market was the epicenter of the COVID-19 pandemic and that SARS-CoV-2 emerged from activities associated with live wildlife trade. Spatial analyses within the market show that SARS-CoV-2-positive environmental samples, including cages, carts, and freezers, were associated with activities concentrated in the southwest corner of the market. This is the same section where vendors were selling live mammals, including raccoon dogs, hog badgers, and red foxes, immediately prior to the COVID-19 pandemic. Multiple positive samples were taken from one stall known to have sold live mammals, and the water drain proximal to this stall, as well as other sewerages and a nearby wildlife stall on the southwest side of the market, tested positive for SARS-CoV-2 (24
). These findings suggest that infected animals were present at the Huanan market at the beginning of the COVID-19 pandemic; however, we do not have access to any live animal samples from relevant species. Additional information, including sequencing data and detailed sampling strategy, would be invaluable to test this hypothesis comprehensively.
In a related study, we infer separate introductions of SARS-CoV-2 lineages A and B into humans from likely infected animals at the Huanan market (38
). We estimate the first COVID-19 case to have occurred in November 2019, with few human cases and hospitalizations occurring through mid-December (38
). A recent preprint (24
) confirms the authenticity of the CCDC report (
and records additional positive environmental samples in the southwestern area of the market selling live animals. This report also documents the early presence of the A lineage of SARS-CoV-2 in a Huanan market environmental sample. This, along with the lineage A cases we report in close geographical proximity to the market in December, challenges the suggestion that the market was simply a superspreading event, which would be lineage-specific. Rather, it adds to the evidence presented here that lineage A, like lineage B, may have originated at the Huanan market then spread from this epicenter into the neighborhoods surrounding the market and then beyond.
Several observations suggest that the geographic association of early COVID-19 cases with the Huanan market is unlikely to have been the result of ascertainment bias (supplementary text and tables S2 and S3) (39
). These include: (i
) few, if any, cases among Huanan market-unlinked individuals are likely to have been detected by active searching in the neighborhoods around the market – only in hospitals – since all cases analyzed here were hospitalized (7
) public health officials simultaneously became aware of Huanan-linked cases near and far from the Huanan market, not just ones near it (fig. S11) (5
) Huanan-unlinked cases would not be expected to live significantly closer to the market than linked cases if they had been ascertained as contacts traced from those market-linked cases, and (iv
) seroprevalence in Wuhan was highest in the districts around the market (40
). It is also noteworthy that the December 2019 COVID-19 cases we consider here were identified based on reviews of clinical signs and symptoms, not epidemiological factors such as where they resided or links to the Huanan market (7
) and that excess deaths from pneumonia rose first in the districts surrounding the market (42
). Moreover, the spatial relationship with the Huanan market remains after removing the two-thirds of the unlinked cases residing nearest the market.
One of the key findings of our study is that ‘unlinked’ early COVID-19 patients, those who neither worked at the market or knew someone who did, nor had recently visited the market, resided significantly closer to the market than patients with a direct link to the market. The observation that a substantial proportion of early cases had no known epidemiological link had previously been used as an argument against a Huanan market epicenter of the pandemic. However, this group of cases resided significantly closer to the market than those who worked there, indicating that they had been exposed to the virus at, or near, the Huanan market. For market workers, the exposure risk was their place of work not their residential locations, which were significantly further afield than those cases not formally linked to the market.
Our spatial analyses show how patterns of COVID-19 cases shifted between late 2019, when the outbreak began (43
), and early 2020, as the epidemic spread widely across Wuhan. COVID-19 cases in December 2019 were associated with the Huanan market in a manner unrelated to Wuhan population density or demographic patterns, unlike the wide spatial distribution of cases observed during later stages of the epidemic in January and February. This observation fits with the evidence from other sources that SARS-CoV-2 was not widespread in Wuhan at the end of 2019. For example, no SARS-CoV-2-positive sera or influenza-like illness (ILI) reports were recorded among more 40,000 blood donor samples collected up to December 2019 (44
), and none of thousands of samples taken from ILI patients at Wuhan hospitals in October-December 2019 tested for SARS-CoV-2 RNA was positive (7
The sustained presence of a potential source of virus transmission into the human population in late 2019, plausibly from infected live mammals sold at the Huanan market, offers an explanation of our findings and the origins of SARS-CoV-2. The pattern of COVID-19 cases reported for the Huanan market, with the earliest cases in the same part of the market as the wildlife sales and evidence of at least two introductions (38
), resembles the multiple cross-species transmissions of SARS-CoV-2 subsequently observed during the pandemic from animals to humans on mink farms (46
), and from infected hamsters to humans in the pet trade (47
). There was an extensive network of wildlife farms in western Hubei province, including hundreds of thousands of raccoon dogs on farms in Enshi prefecture, which supplied the Huanan market (48
). This region of Hubei contains extensive cave complexes housing Rhinolophus
bats, which carry SARSr-CoVs (49
). SARS-CoV-1 was recovered from farmed masked palm civets from Hubei in 2003 and 2004 (20
). The animals on these farms (nearly 1 million) were rapidly released, sold, or killed in early 2020 (48
), apparently without testing for SARS-CoV-2 (7
). Live animals sold at the market (Table 1
) were apparently not sampled either. By contrast, during the SARS-CoV-1 outbreaks farms and markets remained open for over a year after the first human cases occurred, allowing sampling of viruses from infected animals (20
The live animal trade and live animal markets are a common theme in virus spillover events (21
), with markets such as the Huanan market selling live mammals being in the highest risk category (51
). The events leading up to the COVID-19 pandemic mirror the SARS-CoV-1 outbreaks from 2002-2004, which were traced to infected animals in Guangdong, Jiangxi, Henan, Hunan, and Hubei provinces in China (20
). Maximum effort must now be applied to elucidate the upstream events that might have brought SARS-CoV-2 into the Huanan market, culminating in the COVID-19 pandemic. To reduce the risk of future pandemics we must understand, and then limit, the routes and opportunities for virus spillover.
We thank the researchers who generated the geospatial and environmental sample data and the members of the China team involved in producing the WHO mission report for the maps that made this work possible. We thank Michael Standaert, Bonnie LaFleur, @babarlelephant, Maciej Boni, Florence Débarre and Benjamin Pierce for comments and assistance. We thank worldpop.org for making population density and demographic data from Wuhan freely available. We thank both the patients and the clinicians and researchers whose data made this research possible. We thank five reviewers for insightful comments and feedback.
Funding: This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00015 (MW). JIL acknowledges support from the NIH (5T32AI007244-38). SAG acknowledges support from the NIH (F32AI152341). JEP acknowledges support from the NIH (T15LM011271). JOW acknowledges support from NIH (AI135992 and AI136056). DLR acknowledges support of the Medical Research Council (MC_UU_12014/12) and the Wellcome Trust (220977/Z/20/Z). MAS, PL and AR acknowledge the support of the Wellcome Trust (Collaborators Award 206298/Z/17/Z – ARTIC network), the European Research Council (grant agreement no. 725422 – ReservoirDOCS) and NIH grant R01AI153044. ALR is supported by the Canadian Institutes of Health Research as part of the Coronavirus Variants Rapid Response Network (CoVaRR-Net; CIHR FRN#175622) and acknowledges that VIDO receives operational funding from the Canada Foundation for Innovation – Major Science Initiatives Fund and from the Government of Saskatchewan through Innovation Saskatchewan and the Ministry of Agriculture. MK receives funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 874735 (VEO, Versatile Emerging infectious disease Observatory). RFG is supported by the NIH (R01AI132223, R01AI132244, U19AI142790, U54CA260581, U54HG007480, OT2HL158260), the Coalition for Epidemic Preparedness Innovation, the Wellcome Trust Foundation, Gilead Sciences, and the European and Developing Countries Clinical Trials Partnership Programme. ECH is supported by an Australian Research Council Laureate Fellowship (FL170100022). KGA is supported by the NIH (U19AI135995, U01AI151812, and UL1TR002550).
Contributions: Conceptualization: MW, KGA; Methodology: MW, JIL, AC-C, LM, JEP, MUGK, MAS, ALR, DLR, SAG, AR, JOW, RFG, PL, ECH, KGA; Software: LM, JIL, JEP, JOW, PL, AR; Validation: MW, LM, JIL, JEP, PL, JOW, KGA; Formal analysis: MW, JIL, AC-C, LM, JEP, MUGK, MAS, ALR, DLR, SAG, AR, JOW, RFG, PL, ECH, KGA; Investigation: MW, JIL, AC-C, LM, JEP, MUGK, MAS, MK, ALR, DLR, CN, SAG, AR, JOW, RFG, PL, ECH, KGA; Resources: MW, JOW, KGA; Data Curation: MW, AR, KGA; Writing - original draft preparation: MW, RFG; Writing - review and editing: MW, JIL, AC-C, LM, JEP, MUGK, MAS, MK, ALR, CN, DLR, SAG, AR, JOW, RFG, PL, ECH, KGA; Visualization: MW, JIL, LM, JEP, ALR, AR, JOW, RFG, PL, ECH, KGA; Supervision: MW, JOW, KGA; Project administration: MW, KGA. Funding acquisition: MW, JIL, AC-C, LM, JEP, MUGK, MAS, ALR, DLR, SAG, AR, JOW, RFG, PL, ECH, KGA
Competing interests: JOW receives funding from the CDC via contracts to his institution unrelated to this research. MAS receives funding from Janssen Research & Development, US Food & Drug Administration, and the US Department of Veterans Affairs via contracts and grants unrelated to this research. RFG is a co-founder of Zalgen Labs, a biotechnology company developing countermeasures for emerging viruses. MW, ALR, AR, MAS, ECH, SAG, JOW, and KGA have received consulting fees and/or provided compensated expert testimony on SARS-CoV-2 and the COVID-19 pandemic. MK has participated in the second WHO mission to China to study the origins of the pandemic and has served as scientific advisor on emerging disease preparedness to the Guangdong CDC prior to 2020.
Data and materials availability: Data and code for this manuscript are available from (53). We acquired the Weibo data set from (26).