The following is a guest post by Daniel Lucey, M.D. MPH, FIDSA, FACP, and Kristen Kent, MPhil

The origin of the SARS-CoV-2/COVID-19 pandemic is still not publicly known. It was initially proposed that the virus spilled over to humans from an animal in December 2019 in the Huanan seafood market in Wuhan, then explosively spread outwards. Subsequent data, however, supports an alternative hypothesis that the original human infections began before December, and not in this seafood market.

We interpret these data to be most consistent with a naturally-occurring spillover infection from an animal species to humans at a different location in September-November. Once human-to-human transmission occurred, then infected persons brought the virus into the seafood market where other persons were then infected and brought it out of the market.

Due to the initial definition of a “probable case” of this new viral pneumonia in late December that focused explicitly on an epidemiological link to the seafood market, the presumably zoonotic novel coronavirus was thought to have originated there.

We have not found evidence to support any theory that the origins of SARS-CoV-2 among humans occurred in a laboratory either intentionally or by accident. The closest, but still distant, match to the SARS-CoV-2 is a bat coronavirus. The crucial part of this bat virus that binds to the human receptor used by SARS-CoV-2, however, is notably different than that same part of the human SARS-CoV-2.

Although virus-positive environmental specimens were found in the market after sampling on Jan. 1 when the market was closed, no infected animal has ever been reported. These infected samples, including those from sewage, may have come from infected persons in the market. According to the China CDC on Jan. 21: “Despite extensive searching, no animal from the market has thus far been identified as a possible source of the infection” (Ref 1).

This month, after experiments in an animal biosafety level 4 laboratory in Harbin (Ref 2 ) China reported that cats and ferrets could be infected with SARS-CoV-2. Thus, it would be prudent for the search for the virus to include cats and ferrets.

In order to advance global solidarity against this pandemic in both hemispheres, we call for a full sharing and discussion of all data related to the origin of this pandemic at the upcoming 73rd World Health Assembly scheduled for May.

Daily human cases since Nov. 17 in Hubei province

The earliest person known to be infected became ill Nov. 17, in Hubei province (not stated if in Wuhan, let alone having any link to the Huanan seafood market), according to an article in the March 13 South China Morning Post by Josephine Ma, citing an unpublished China government report (Ref 3). She wrote that from Nov 17, “one to five new cases were reported each day”. A total of 266 cases had occurred by Dec. 31, and 381 cases by Jan. 1. (We note that the diagnostic test for the virus became available after the virus was sequenced Jan. 3, and thus the above lab-confirmations would have to be in retrospect).

The Director of the China CDC in Beijing, Dr. George Fu Gao, was asked by Jon Cohen in an interview published March 17 in Science: “What do you think of the report in the South China Morning Post that says data from the Chinese government show there were cases in November 2019, with the first one on 17 November?” Dr. Gao replied: “There is no solid evidence to say we already had clusters in November. We are trying to better understand the origin” (Ref 4). (We note, however, the South China Post article did not use the term “clusters”).

Definition of a “probable case” of the pneumonia focused on epi-link to the market

How did December 2019 and the seafood market come to be believed as the time and place for the origin of this presumably zoonotic pandemic? The initial observation of an unusual pneumonia in four persons with an epidemiological link to the seafood market, was attributed by Chinese officials to an astute clinician, Dr. Jixian Zhang, at the Hubei Integrated Chinese and Western (HICWM) hospital on Dec. 26, as reported in JAMA by Wu et al. (see Figure 1 text, page 1240). (Ref 5).

According to the official China CDC outbreak investigation, by Dec. 31 the Wuhan CDC, Hubei provincial officials, and experts from the main China CDC in Beijing were all in Wuhan working together on the investigation. (Ref 1). The Director of the China CDC, Dr. Gao, was reported by the US media to have called his United States Centers for Disease Control and Prevention counterpart in the first week of January to convey information on the novel coronavirus pneumonia.

As a result of Dr. Jixian Zhang’s observation of an epi-link with this seafood market, the initial case definition included an epi-link to the market. Before any laboratory confirmation test existed, the initial “probable case” of what officials termed ‘Viral Pneumonia of Unknown Etiology (VPUE)” required “a history of exposure to the Huanan Seafood Wholesale Market in Wuhan or any other VPUE case” (Ref 1). In addition, the initial suspected cases were transferred to a designated referral hospital called Jin Yin-tan, where from the beginning patients were isolated using airborne precautions (Ref. 6, page 2).

Thus, there was an understandable initial bias toward identifying patients with an epi-link to the market, and excluding patients without an epi-link to the market unless they also had exposure to another person with this new pneumonia. (We are aware of comparisons to the United States in January and February where the initial focus for lab-testing at the U.S. CDC was on persons with an epi-link to China, or exposure to another person with this new pneumonia).

On Jan. 17, a date that will be long-remembered, a total of 17 new patients were diagnosed, well after the maximum 14-day incubation period since the seafood market presumed epi-link for the outbreak had been closed on Jan. 1. In a release that will long be remembered, the Wuhan Municipal Health Commission stated:

”An analysis of the epidemiological data of new coronavirus-infected pneumonia cases released in the previous period found that some cases have no history of exposure to the South China Seafood Wholesale Market. On the basis of standardizing pre-examination and triage and fever diagnosis, the optimized detection kit was used to sample and monitor unexplained pneumonia cases isolated from fever diagnosis and treatment in the city, and 17 new coronavirus nucleic acid positive cases were detected” (Ref 7).

Over Jan. 18 to 19 a total of 136 additional new cases were diagnosed as the epi-link to the market was no longer required, and cases were subsequently found in multiple hospital and clinics across Wuhan.

In retrospect, before Jan.17 and even Jan. 1, there were already many patients with SARS-CoV-2 COVID-19. The China CDC reported in their CDC Weekly publication (Feb. 17) that there had been 104 confirmed patients with onset of symptoms before Dec. 31. In addition, there were also clinically-diagnosed patients in December. Then from January 1 to Jan. 10: there were 653 confirmed cases and 102 deaths. Between Jan. 11 and Jan. 20: 5,417 confirmed cases and 310 deaths, and between Jan. 21 and 31: 26,468 confirmed cases and 494 deaths. (Ref. 8, Table 1, page 116).

In a Jan. 24 paper online in the Lancet by Huang et al. (Ref 6) the initial 41 lab-confirmed cases transferred to the designated hospital “Jin Yintan”. Importantly, the initial patient had no exposure to the seafood market and his onset of illness was Dec. 1. Thus, he must have been infected in November. In fact, three of the initial four patients in this report had no exposure to the market and overall 14 of the 41 patients were reported to have no exposure to the market. Further details about this initial patient were provided in a BBC interview of one of the senior physicians at Jin Yin-tan hospital. She noted that he did not live close to the seafood market, and he had underlying neurologic conditions that would have made it unlikely he was exposed to any animals outside the home. (Ref. 9).

We infer he was most likely infected by another person. Although none of his family members reported being ill, transmission by an asymptomatic person is certainly possible. Antibody testing of family members and other persons in contact with this patient might help explain his source of infection.

In a paper published Jan. 29 in The New England Journal of Medicine, reporting on the initial 425 patients in Wuhan, a total of five of the initial 6 patients had no exposure to the seafood market. (Ref 10). The 45 co-authors, including Dr. George F. Gao of the China CDC, concluded from their data that human to human transmission by close contact was underway as early as “ the middle of December 2019 .”

Indeed, the initial Weibo account messages in late December by the courageous 34 year-old Dr. Li Wengjiang, Dr. Ai Weng, and multiple other health workers, warned colleagues of a SARS-like contagious pneumonia. Dr. Li Wengjiang died of SARS-Cov-2 on February 6.

“Extensive searching” for infected animals since January but none reported

On Jan. 21 the official China 2019 nCoV outbreak investigation team and Qun Li, reported in the China CDC Weekly that:

“Huanan Seafood Wholesale Market has western and eastern sections and 15 environmental specimens collected in the western section were positive for 2019-nCoV virus through RT-PCR testing and genetic sequencing analysis. Despite extensive searching, no animal from the market has thus far been identified as a possible source of the infection ” (Ref 1, page 79, bottom right side).

In a Jan. 26 China Daily online newspaper reporting on a China CDC press conference stated that: On the morning of Jan. 1st, 515 environmental samples were obtained from the closed market. Then on Jan. 12 an additional 70 samples were obtained from unspecified locations within the closed and disinfected market. Of these total 585 samples, 33 were positive for the virus, 31 from western market and one from a garbage truck. (Ref. 11).

The exact source within the market for these positive samples has not been officially disclosed. In an interview with Jon Cohen of Science published March 3, Dr. H. Clifford Lane of the NIAID/NIH and a member of the 25-person WHO-China Joint Mission on COVID-19 in China Feb.16-24, stated that he was under the impression that the source of samples was “sewage” (Ref 12). Of note, however, Dr. Lane was not part of the Joint Team when they travelled to Wuhan, according to his interview in the NIH Record April 3. (Ref 13).

China has been searching for an animal source in other markets as well as a priority, as reported in the Chinese Journal of Epidemiology by Feng Zhijian from the China CDC titled: “Urgent research agenda for the novel coronavirus epidemic: transmission and non-pharmaceutical mitigation strategies. Strategy and Policy Working Group for NCIP Epidemic Response. (Ref 14, page 137 bottom right).

In an April 17 story on the origins of the epidemic in the Financial Times, the WHO Canadian official Dr. Bruce Alyward was cited as saying “he was told China had collated four key data streams: Vendor records of animal sales, samples kept from swabbing the whole market, including gutters where urine and feces collect; freezers still full of animal parts, and tracking the earliest patients”. (Ref. 15).

We interpret this information to corroborate that animal specimens were available to test for the virus, and to corroborate the initial January 21 statement by China CDC that “ Despite extensive searching, no animal from the market has thus far been identified as a possible source of the infection ” (Ref 1).

In addition, Dr. Aylward wrote in the WHO Joint Mission Report Feb. 28 that it was important to determine the “destination” of the animals from the market. (Ref. 16 page 8):

“However, three important areas of work are already underway in China to inform our understanding of the zoonotic origin of this outbreak. These include early investigations of cases with symptom onset in Wuhan throughout December 2019, environmental sampling from the Huanan Wholesale Seafood Market and other area markets, and the collection of detailed records on the source and type of wildlife species sold at the Huanan market and the destination of those animals after the market was closed.”

In the “ Knowledge Gaps” section (page 36): the first gap was “Source of Infection”: “Source of infection: Animal origin and natural reservoir of the virus. Human-animal interface of the original event. Early cases whose exposure could not be identified”.

Dr. Gao, Director of China CDC was interviewed by Science reporter Jon Cohen as published March 27. When asked: “Do you think the seafood market was a likely place of origin, or is it a distraction—an amplifying factor but not the original source?” Dr. Gao answered: “That’s a very good question. You are working like a detective. From the very beginning, everybody thought the origin was the market. Now, I think the market could be the initial place, or it could be a place where the virus was amplified. So that’s a scientific question. There are two possibilities.” (Ref. 4).

A One Health map of the market: humans, environment, animals

In an effort to help clarify what occurred in the seafood market, we propose the use of superimposed maps of the market, overlaid with areas from which samples were taken from people, the environment, and animals.

On this map, positive viral samples should be marked for three categories: those from (1) environmental samples, (2) humans, and (3) animals. If the 27 human positives, who had links to the market, overlap with many of the 33 positive environmental samples, and any positive animal specimens, then support could be given to hypotheses that: 1) infected humans account for positive environmental samples, 2) infected animals account for positive environmental samples, or 3) positive environmental samples can be attributed to both humans and animals.

In the China Daily News January 26, Tan Wenjie, a researcher within China’s CDC, reports that as of Jan. 26 they had already found the 22 possible stalls in the market from which the spill over event originated. He was further quoted in the China Daily News as saying, “We are close to finding the source of the virus.” (Ref. 11) Three months have passed since this statement, and no information has been shared publicly regarding data on animal testing or mapping of the location in the Market of positive, and negative, environmental, human, and animal specimens.

Call to share and discuss all data at 73rd World Health Assembly scheduled for May 2020

We have hypothesized since Jan. 25 here on Science Speaks that the virus did not originate in this market, as discussed in a Jan. 26 interview with Jon Cohen of Science (Ref 17-19). The evidence presented above, over 115 days since the market was closed and still without the virus being found in any animals, highlights why the origin of this virus must be discussed transparently and comprehensively at the World Health Assembly in May 2020.

Daniel Lucey, M.D. MPH, FIDSA, FACP, is an infectious diseases physician and adjunct professor of infectious diseases at Georgetown University Medical Center, a senior scholar at the Georgetown University O’Neil Institute, Anthropology Research Associate, Smithsonian Museum of Natural History and a member of the Infectious Diseases Society of America Global Health Committee.He has served as a volunteer medical responder to outbreaks that included the West Africa Ebola crisis. He has collected information on outbreaks starting in 2001 with cases of anthrax in 2001, and including smallpox vaccination 2002, SARS 2003, H5N1 Flu 2004, MERS in 2013, and Ebola in April, 2014, He has gathered, and updated information on the spread of the coronavirus here since Jan. 6.

Kristen Kent, MPhil, is a medical student at Georgetown University School of Medicine.

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