Geneticists see the “improbability” of the coronavirus circulating massively in Spain before February

Author: Mónica G Salomone

Was the coronavirus in Europe as late as 2019, before China even alerted of the presence of a new infectious agent? Last week, a scientific magazine published the case of COVID – 19 from Amirouche Hammar, a neighbor in the French municipality of Bobigny, near Paris. Its positive dates from 27 of December, one month before until now first confirmed in there, and days before China's alert to WHO.

The case has reactivated key questions: How long has the coronavirus been circulating silently among us? And, if it really came so soon, how could it have gone unnoticed and why didn't the epidemic explode earlier here?

In the case of Spain, geneticists who analyze the evolution of the pandemic, consulted by SINC, do not rule out the possibility that SARS-CoV-2 arrived before the first confirmed cases, from 31 of January in La Gomera and beginning of February in mainland Spain. But they consider “very improbable” that before February there was an extended asymptomatic transmission. The first known case of local contagion, with no known relationship to any trip, was detected in Seville in a patient who began to have symptoms on 12 February.

Both Fernando González Candelas, from the Universitat de València and FISABIO, and María Iglesias , from the Laboratory of Respiratory Viruses of the National Center for Microbiology (CNM) , consider it difficult to retrospectively follow up on the origin of the epidemic in Spain.

If you really arrived in Europe at the end of 2019 How could it go unnoticed and why did the epidemic not explode here before?

The first thing that is not clear is that the positive of 27 December detected in France really is. The work has several technical weaknesses, which the authors themselves recognize in the publication.

That explains, thinks González Candelas, that it has been published in a low-impact scientific journal, the International Journal of Antimicrobial Agents. “ What they are saying is that the coronavirus was already in France before China alerted the WHO. A finding like this would deserve to be in a publication with a greater impact , ”says González Candelas, and if he is not, according to this expert, it is surely due to the doubts he has raised in its scientific reviewers.

The first information from China to the WHO about pneumonia of unknown cause occurred on 31 from December to 2019. The first case detected outside of China occurred on 13 January in Thailand. The first cases in France, which were also the first Europeans, are from 25 from January.

Everyone waiting for the genome

A point that makes González Candelas and, in general, the geneticists consulted quite uncomfortable, is that the authors have not sequenced the genome of that supposed first European coronavirus, a test that gives information about the origin of the virus.

Both the genome sequencing and the antibody search for the French patient is now being done, but many geneticists are surprised that they have not been done before

This patient's sample was kept frozen; The analysis of the genome would allow, for example, to rule out that it was contaminated with a virus from now when they went to recover it. Neither have antibodies been sought in relatives of the patient, who are said to have had mild symptoms.

One of the authors of the work, Jean Ralph Zahar, from the Infectious Risk Prevention Unit of the GH Paris Seine Saint-Denis, confirms to SINC that both genome sequencing and the search for antibodies is now being done .

But experts are surprised that they haven't done it before. For Ignacio González Bravo, director of Research at the CNRS (French National Center for Scientific Research), expert in viral evolution at the MIVIGEC Laboratory in Montepelier, “the only way to prove that this sample is truly positive, and that it is not a contamination of a more recent sample would be to sequence the viral genome, ”he explains to SINC. “ Probably the sample was not of sufficient quality to do a complete genome sequencing, after many freeze-thaw cycles, but I'm sorry they didn't try ”.

The genomes of viruses accumulate mutations each time they multiply. By looking at the repertoire of mutations in a viral genome, you can identify the lineage to which it is most likely to belong and the moment in which the infection took place: you must have the repertoire of mutations from previous samples (their ancestors) but not from samples most recent (their descendants).

Disconnection between China and the French fishmonger

Another point that makes experts doubt is the lack of connection between the French positive for December and the origin of the epidemic, in China. The patient in question is a fishmonger that on December 27 He felt too bad about the flu he had and went to the emergency room. You have no recent travel history.

Another point that makes experts doubt is the lack of connection between the French positive of December and the origin of the epidemic, in China

In the published work it is not said, but the authors – and the patient himself, who was discharged in just two days and who is now well and granting interviews – have shared his hypothesis with the media for the contagion: the patient's wife, who claims to have had a cough, works in a supermarket next to the Charles de Gaulle airport, frequented by travelers.

Yves Cohen, one of the main authors, from Avicenne Hospital, has told The New York Times that “ the lack of recent trips [del paciente] suggests that the disease was already circulating among the French population at the end of December 2019 ”. “For us there is no doubt” .

On the other hand, for other experts there are doubts. Even if the analysis of the viral genome confirms the case of the 27 of December, that does not automatically mean that the virus has been around for a long time. That outbreak of infection could have been a dead end to the coronavirus, as, as confirmed, there were several in France.

Was the virus already established in France at the end of 2019?

The country initiated symptom-based surveillance on 10 January 2020 and two weeks later the first three were diagnosed COVID cases – 19. They were all related to Chinese travelers and therefore did not point to a settled local transmission.

The phylogenetic analysis of these and a hundred more genomes from French patients sampled among the 24 January and 24 March has revealed several initial introductions to SARS-CoV-2. Only one of them spread.

It is known that four of the early introductions of the virus in France had hardly any infections around them. Only one curdled and expanded, associated with demonstrations of evangelical churches in Alsace

As González Bravo explains, “ the initial events of a zoonosis are random ”. In fact it is known that “ four of the early introductions of the virus in France had practically no contagions around them ” . Only one of these events “caught on and expanded, associated above all with mass demonstrations of evangelical churches in Alsace.”

That is why “ the epidemic in France is considerably less genetically diverse than in Spain, in which there have also been at least four and probably six or seven introductions, and most have curdled in the population ”, adds this expert.

Thus, the answer to whether or not there was local transmission in France as late as December is – again – in the genome of the patient of Yves Cohen and Jean Ralph Zahar.

As viruses in France are less diverse, if the genome of this December sample were sequenced, it would be possible to know if it belongs to the main lineage detected in France or if it is close to the initial strains in China ”, says González Bravo.

He would bet – if the positive is confirmed – for the closeness with the Chinese strains. Otherwise, if by then there were already established local infections, the epidemic in France would have been noticed earlier: “The alarms should have gone off much earlier, with a peak of atypical pneumonia that has not been identified, at least so far” .

And in Spain?

The announcement of the possible French positive of 27 December has caused the WHO to recommend reviewing atypical pneumonia cases even since November last year. It is not the first time that the WHO recommends looking back. It also did so in February, with the first suspicions of asymptomatic transmission .

Then the Spanish Ministry of Health changed the criteria to investigate possible cases of coronavirus, and it was confirmed, after an autopsy, a positive deceased on 13 February in Valencia . He had made a recent trip to Nepal. It was the first known case of flight under the radar, a patient treated in a hospital without being diagnosed with COVID – 19.

González-Candelas, who investigates the evolution of the pandemic in Spain and aspires to analyze viral genomes of thousands of patients, has not yet analyzed the case of the 13 February. You will get the sample these days.

It is unlikely that the virus was spreading in Spain with stable transmission before the end of February, the specialists who work with it agree

He does not rule out anything, but he is inclined to the hypothesis that no, “it is not at all probable” that the coronavirus had been circulating in Spain for a long time, with stable transmission, before the end of February.

Iglesias, in Madrid, coincides with him. His laboratory at the CNM is the reference center for all of Spain and has already received samples from all over the country. The oldest sequenced genomes are from mid-February. None of the samples that came to them with the change of criteria, which urged a retrospective search, have tested positive for the moment.

It is not impossible, of course, that the virus was. Iglesias recalls that with the first SARS, that of 2003, it was discovered that it had been circulating for months before its detection. .

Having a clear answer is going to be difficult, both González Candelas and Iglesias believe. For starters, samples of all pneumonia without cause are not saved. And “ must be taken into account that this has been a wave that has overwhelmed the system ,” says Iglesias. In such a situation, it is difficult for all centers to keep the day to day in the registers.

González Bravo also points out that “ expeditions to the refrigerator” in search of samples “are normally made once the tension on the system has relaxed ”.

And it recalls a famous result of these reconstructions of epidemics: the search in the pathological anatomy archives for evidence of HIV in samples prior to the epidemic of the 70 revealed two blocks of tissue with remains of the virus, and the oldest was 1959.

We know that HIV has been circulating since the beginning of the 20th century and that it spread from the populations of the rain forest to the cities with the extension of the railway, but the epidemic did not arrive until the end of 70 and the pandemic until 80 ”, explains González Bravo. It is possible that the initial strains were poorly transmitted between humans and that there was a period of adaptation to the new host.

With the flu of 18 the same thing happened: it was already circulating in the European battlefields at least a year before and it continued to make two or three trips around the world with the annual temperature cycles ”, he concludes.

A bottleneck prior to global expansion

Actually, discovering that a virus has been circulating among humans for a long time without being seen is quite common. Viral evolution expert Ignacio González Bravo explains this to SINC: “ It is probably the common pattern to all zoonoses: we see the outbreak of an epidemic and think that it corresponds to the time with the jump from an animal host to the human host, but it is not ”.

The ancestors of the first coronavirus, SARS-VOC-1 probably circulated between five and ten years before the SARS episode of 2002. Also the MERS coronavirus.

Looking only through the glass of the SARS-CoV-2 genomes we can already know that its ancestor dates from November 2019, at least a month before the excess of atypical pneumonias was so great that not even the Chinese gag could cover it ”, adds González Bravo.

According to this expert, the best current estimates give a common ancestor to all SARS-CoV-2 strains towards 17 November – between 27 August and 19 from December-.

There is no doubt that there was a very restricted initial event, a bottleneck in the spread of the virus, which we can date back to the beginning-mid-December in China. All the lineages of this SARS-CoV-2 in the world descend from this event ”, says González Bravo.

For France, with the genomes currently sequenced, the ancestor dating common to all the strains detected is 27 December (between 29 November and 15 January), and the dating of the common ancestor to the most frequent strain in France is February 3 (between 18 January and 13 of February).

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