Whoever lacks the capacity to put on blinders, so to speak, and to come up with the idea that the fate of his soul depends upon whether or not he makes the correct conjecture at this passage of this manucript may as well stay away from science [...] Without this strange intoxication, ridiculed by every outsider; without this passion [...] you have no calling for science and you should do something else.

Science as a vocation

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The second wave of COVID-19

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arrow 31 December 2020. Identification of traces of SARS-CoV-2 in sewage from a housing estate in Hong Kong allowed identification of a previously unsuspected patient. A  resident of Kai Fai House at the Choi Wan Estate in the Wong Tai Sin district of Hong Kong was found to be infected by COVID-19, after a mandatory testing order was issued when sewage samples consistently tested positive for the virus. This is an indication that this way of monitoring the spread of the epidemic will be of considerable interest. In France, the Obepine surveillance system is meant to provide the same kind of service but has not yet been used to allow explicit identification of infected persons.
arrow 29 December 2020. According to the South China Morning post the number of infected people in Wuhan during the first episode was considerably higher than recorded. Over 4 per cent of the 11 million people in the central Chinese city of Wuhan might have been exposed to the coronavirus that causes Covid-19, according to a national study of blood antibodies. This figure is completed by another one, out of the city, that shows that less than 10% of that figure would have affected people in the outskirts of the city. This demonstrates two things: that the lockdown was effective in preventing the spread of the disease, but that it is likely that information about the real situation was not available at the time. Of course it is also possible that tests were overpredicting positive cases, but this would also be true outside of Wuhan. The main conclusion we must draw is likely that we will never really know what happened. In this context, the inquiry launched by the WHO looks like a weird attempt to restore trust, especially because of obvious conflicts of interests affecting some of the members of the committee. This is really unfortunate because this will fuel the spread of inevitable fake news.
arrow 26 December 2020. SARS-CoV-2 had more than a year to evolve, at the significant rate of 21 mutations per genome per year.
This may look a tiny fraction of the ca 30,000 nucleotide long genome sequence of the virus. Yet, knowing that much is considerably constrained by structural features required for the proper folding of the RNA of the virus, as well as for allowing proper catalytic properties of the enzymes it encodes, this is a fairly high rate. New variants have been recorded in UK, South Africa, and at other places in Africa. They appear to have an increased propagation rate, but are apparently not more letal. What is worrying is that many mutations affect the spike protein, which is both involved in helping the virus to attach to its host's cells receptors and in being recognized by the adaptive immune system after vaccination. Knowing that people have already been re-infected after a first contamination this suggests that vaccine protection might sometimes vanish. This is in fact a well known property of common coronaviruses. Worse, we do not know how the immune system will react if a new infection is caused by a significantly different virus: instead of protection people might have been sensitized as is observed with dengue fever. Only time will tell. Let us hope that spontaneous attenuation of the virus will protect, rather than sensitize, as was likely observed in Shanghai in 2003.
arrow 20 December 2020. While mass media trigger panic after mutants of SARS-CoV-2 gained ground in England (and in South Africa) it is time to go back to basics.
Life is based on exploration and competition for resources. While not alive—because they entirely depend on their hosts protein synthesis machinery—viruses are very effective parasites. They draw all their resources from their hosts. Were they to kill their hosts each time they infect them it would require a very complicated strategy to maintain their perennity. As a consequence, widespread viruses will debilitate their hosts but not kill them. By contrast, there will be a strong natural pressure to increase the number of hosts they can infect. This means that there will be a natural tendency to favour all variants that entail a higher contagion rate. This is what we have seen repeatedly with SARS-CoV-2, beginning with the so-called D614G mutation at the beginning of the year. Now, a new variant, carrying several novel mutations, is spreading very fast in England, but, for the time being, its virulence does not appear to have changed much. Yet, as time passes, we may expect—hope in fact—that the virulence will tend to keep decreasing, without entailing that the virus becomes less contagious. And this may even be a hopeful consequence of this type of evolution towards attenuation, as the new form may then act as a natural vaccine. However, for now, the fact that many of the new mutations are in the spike protein suggests that the virus will easily find a way to escape vaccination.
arrow 2 December 2020. A huge cluster of COVID-19 is jeopardizing return to normal in the city of Hong Kong.
Hong Kong has now to fight at COVID-19 surge with venue closures, dining restrictions, and a reporting line for turning in social-distancing violators. A "super spreader" event linked to dancing and singing venues has now swelled to 552 cases of the disease on december 1st and the surge is not abating with infections directly and indirectly linked to the venue spreading to care facilities hospitals and schools. It will likely trigger a city-wide testing for the SARS-CoV-2 virus.
arrow 30 November 2020. It is now more than likely that COVID-19 will become an endemic disease.
Eradicating a disease asks for eradicating it from its reservoirs. Small pox was only infecting mankind and general vaccination succeed eradicating it (at least until the genome sequence had unfortunately been made available, as a genome sequence, which can be used for reconstructing a virus, can no longer be eradicated from the internet...) The same is true for poliomyelitis. Most diseases however have animal reservoirs, and it should be of a considerable concern that domestic animals got infected, by COVID-19 pets, in particular. While these animals usually get only a mild or even asymptomatic disease, they are likely to be able to contaminate back their owners or visitors. Furthermore this implies that the evolutionary landscape of the virus has entered new possibilities which may result in increased propensity for contagion, or even, novel pathogenic traits. This is yet another reason for COVID-19 becoming endemic.
arrow 28 November 2020. Many vaccine candidates claim to have more than 90% success, but is this unequivocally established?
While Astra-Zeneca,  with its "classical" vaccine claimed a 70% success, with possibly a more than 90% success with a subset of older patients undergoing a particular protocol it has reasonably delayed its very positive views until it can rest on better data. This is commendable. By contrast, other suppliers, in particular with vaccines using nucleic acids still claim a very high success rate. Yet, a rational analysis of their allegations does not really support them. It is unfortunate that governments, driven by opinions propagated by ignorant mass media, are unable to resist pressure of the people. Let us hope that this will not result in catastrophic consequences of mismanagement of proper vaccines.
arrow 22 November 2020. Time to recapitulate. First analyses strongly suggest that the use of hydroxychloroquine had a negative impact on the severity of COVID-19.
Because John Ioannidis is an author of this work, it should be taken very seriously. Could this explain why the number of deaths was higher during the first wave than during the present wave? Scientific information is more and more difficult to access because mass media use as references the journals and magazines that promote impact rather than science quality. This has considerable consequences (except perhaps in Asia, despite a deleterious emphasis on impact factors there also) in the way goverments establish their health policies. This has had also a dire consequence in the way essential studies were abandoned. We all knew that coronaviruses were extremely dangerous, but work in the domain was not retained high impact journals, which are only interested in what can provide them with lucrative advertisements. Hence, after the SARS episode in 2003 despite the fact that many published papers warning about a likely recurrence of such epidemics, this was to no avail because media kept looking elsewhere, trying to be the first to cite fancy works retained as relevant or fashionable by high IF journals rather than inform their public! This is yet another explanation for the progressive disappearance of journals published as paper publications, especially in the domain of science. If governments had properly supported research in these non-fashionable domains rather than looked for visibility in media, we would already have antivirals and know much more about vaccines. Even scientific institutions are unable to resist the pressure of advertisement-driven profit, and we pay the price, worldwide. This catastrophic behaviour relayed by mass media has dramatic consequences today.
arrow 19 November 2020. Once again antibodies against SARS-CoV-2 have been discovered in patient cells collected in 2019.
This has been interpreted by some as the proof that the virus was present well before it was detected in Wuhan. However this is certainly no proof of the presence of the same virus as the one which caused COVID-19. We must remember that the immune response does not directly target the genome of a virus, but « antigens », i.e. shapes that are recognized as possible signals of danger for the host. They may or may not be encoded in the genome of a particular pathogen. Often they are caused by natural aging of some components of the host, most often proteins. This accounts for the increasing low grade inflammation associated to aging. Yet, this observation is important as it may indicate that a previous infection (or possibly age: we do not have much information about the age of the patients' cells that produced the antibodies of interest) had features similar to those that are recognized in SARS-CoV-2 by the immune system. This may be protective (as probably happened in Shanghai in 2003 for SARS-CoV-1), or, alternatively might be sensitizing patients and triggering a paradoxical cytokine storm, as in dengue fever. This makes it particularly important to carefully monitor the age-dependent response for the many vaccines claimed at this time to be protective. At this time the excess mortality caused by the second wave is going to be more severe than during the first wave, as illustrated in Switzerland, for example.

arrow 13 November 2020. The FDA has requested that Regeneron's antibody cocktail be discontinued for the treatment of people severely affected by COVID-19.
However, the use of this cocktail, which is part of the European RECOVERY trial, remains for the time being. In addition, RECOVERY will add the use of a daily dose of aspirin (150 mg) to test its effect in the current trial.
arrow 11 November 2020. At a time when Pfizer claims great success of its anti-COVID-19 vaccine, its CEO Albert Bourla sells 60% of his stock at the very high price of $41.94.
Should we be worried by this surprising sell? What does this means in terms of vaccine safety and efficacy? We hope that governments proceed to appropriate due diligence when buying vaccines for millions of people.
arrow 7 November 2020. The eastern Arctic route will close for this year.
The Arctic Ocean remained open on its eastern side for several months. In August 2020, 448 voyages were made by some 193 ships, spanning a range from Spain to Hainan island is Southern China.

The number of COVID-19 cases world wide reached 50 millions.
arrow 5 November 2020. The explosion of anti-COVID-19 vaccination programs will jeopardize work on vaccine safety.
Dozens of vaccine designs are developed worldwide against SARS-CoV-2 without any concerted attempts to check for vaccine safety. This is likely to result in contradictory outcomes that will prevent consistent development of vaccination policies. While vaccination has had considerable successes in the past—small pox and poliomyelitis have been eradicated, while yellow fever, despite its large animal reservoir, can be rapidly tackled when an outbreak appears somewhere—it is neither always successful nor without negative outcomes when not properly tested for safety. In parallel, with vaccines that have to be changed every year, not always with excellent efficacy, it remains essential to maintain widespread vaccination. This is the case of flu, for example. Indeed we may expect that, this year, the number of flu cases in the northern hemisphere will dwindle, simply because of the measures taken to keep COVID-19 in check. This will result in a progressive decline in herd protection against flu and might create conditions, in the near future, of a highly letal flu epidemic if the population does not meet variants of the virus. Vaccination against flu—its usage has been current for many years, and is safe except for very specific cases that we discussed previously—should therefore be maintained at a high level even in the absence of the virus. By contrast it seems difficult, at this time, to decide of the choice of a safe vaccine in the case of COVID-19. Properly designed comparative studies should be organized worldwide before choosing a particular brand of vaccine, in particular with special care used if vaccines of third or fourth generation are preferred (see 28 october figure).
arrow 30 October 2020. While the number of cases and deaths from COVID-19 is exploding governments feign to be surprised.
The present exponential growth of the disease is the direct consequence of the relaxed attitude held by many governments when facing reality. Itr was quite obvious at the end of August that the contagion parameters authorized in France, for example, would lead to the present situation. This can be seen in a figure of an article where we warn against complacency with respect to proper assessment of possible vaccines.
infections icons/earth-biogenome

But this would require real authority, and, possibly reeducation of the majority of people who did not get any civil education (nor simple politeness), for almost 5 decades at this time.
In this context the last day of ICG-15 in Wuhan was refreshing, with Richard Durbin, from the Sanger Centre (UK) giving us plans for the next ten years with sequencing of the genome of all living species on this planet. France, again, is completely out of the picture for reasons that have been often explained.

Later on Zhihua Ou, from the BGI showed us that the gut tropism of SARS-CoV-2 has an important role in reinfection, and she also described how the virus is fought by innate immunity acting against cytidine triphosphate. This epidemic is a source of remarkable discoveries which will extend far beyond virology.
arrow 28 October 2020. At the ICG-15 meeting in Wuhan an afternoon on the contribution of Africa to genome studies, reflection on vaccines and Georges Fu Gao comments on lack of preparedness for COVID-19.
George Gao, the director of the Chinese CDC summarized the presentation of vaccines that have been discussed during the "Africa" session.
vaccines subunit-vaccine

He also showed that, while a variety of organisations were quite aware of the imminence of a pandemic, we were not prepared for it to happen.
In earlier sessions of the conference genetic manipulation using CRISPR-Cas9 (including monitoring off-target accidental modifications) were discussed in relation with plant and animal (pig) genetic manipulation.
Crispr pig-modified

The Global Preparedness Monitoring Board (GPMB) had discussed this previously, and an event 201 exercise à Johns Hopkins University had even prepared an exercise to understand preparedness to a coronavirus infection, but this had not been properly implemented in the world anywhere except perhaps in China.
arrow 27 October 2020. At the ICG-15 meeting in Wuhan Zhengli Shi, director of the Wuhan Institute of Virology, presented the discovery of SARS-CoV-2.

Zhengli-Shi mouse-model

After a morning (in Wuhan) discussion on data collection and availability Zhengli Shi gave an unplanned talk on the origin of COVID-19 from the virologist point of view. She presented interesting data on humanized mice infected by SARS-CoV-2 during the course of the infection, pointing out a possible important role of infection of the brain in unpublished results.
ICG-15-room animal-origin

The afternoon (morning in Europe) is devoted to ethical issues, data sharing and international collaboration. The meeting is held in Wuhan in a largely empty room, but with more than 1,500 persons attending on line, with many distant presentations. This setup works remarkably well.
arrow 26 October 2020. The ICG-15 meeting in Wuhan has started.
Today in Wuhan we had fascinating reports on the first stages of COVID-19 in China.
Huanming    data-sharing2020

The sequence data were submitted to the INSDC (GenBank) on january 5th 2020 and further sequences kept being submitted there, which justified the Gigascience Prize for outstanding data sharing.
5-january-submission  new-viruses

The number of newly discovered viruses is literally exploding, raising multiple questions about their biology, impact and evolution.
arrow 17 October 2020. SARS-CoV-2 infection begins to reveal some human genetic constraints.
Very early on it was suggested that people belonging to the O blood group were less prone to be infected than those belonging to the A group. This observation is certainly not substantiated when considering the severity of COVID-19 infection. It may be that there is some difference in contagion, but the effect is in fact minor for the course of the disease. Also the HLA groups should reveal specific features of the disease: after all the HLA system is used for recognition of pathogens and infected cells killing. However, for the time being no clear picture emerged. Yet we must be open to the corresponding genetic constraints. After all it took a long time to discover that the influenza H1N1 virus was a major cause of narcolepsy in the HLA-DBQ1 genetic locus. Neurological sequels of the infection have now been reported in preliminary studies to be linked to class I and class II specific HLA types (HLA-A33) and  (DRB1*03:01 and DQB1*05:01), respectively. Other studies, also preliminary but progressively gaining weight, suggest that a region of our chromosme 3, that we inherited from Neanderthal ancestors, is also contributing to the severity of the disease. As frequently observed in susceptibility to diseases the corresponding genes are involved in complicated regulatory pathways (controlling interferon synthesis or sensing, for example), but one of those, gene DPP9, corresponds to an enzyme that cleaves the N-terminal dipeptide of proteins ending in a proline or an alanine residue, and this may play a role in the maturation and stability of some of the virus' proteins. For example a maturation protease of the virus begins with an alanine-proline-threonine-lysine sequence which could be sensitive to the product of the DPP9 gene, if recognized. Viral protein Nsp6 which helps the virus to assemble its envelope has a similar N-terminal end. This feature would account for the relative innocuity of the virus in sub-Saharan Africa, but would leave entirely open the increased sensitivity of African-American people in the USA.

arrow 14 October 2020. Vaccination against seasonal flu might provide some protection against COVID-19.
The flu season is beginning. It is likely to be mild because people tend to protect themselves against respiratory diseases when they use protective behaviour against COVID-19. Yet, it remains probably useful to get vaccinated against flu. Indeed several studies tend to support the idea that vaccination in general might be protective. In Italy a general study suggested that, even after taking into account confounding factors, the population that tended to vaccinate against flu had less and milder symptoms of the disease. This is only providing correlations but this is at least consistent with the idea that it may be useful to get a vaccine this year.

arrow 9 October 2020. Understanding how flu spreads in seals may inform us about the way respiratory viruses spread in human populations.
In 2014 ten percent of the European population of seals was killed by an H10N7 strain of the influenza virus. This epidemic was caused by a mutation that allowed the virus—originally from birds as are all influenza viruses—to spread from mammal to mammal. This same mutation allowed the virus to contaminate ferrets. While the H10 subtype is unlikely at this point to lead to a person to person transmission, this is not so of the H3 or H1 subtypes, which are dominating in seasonal flu. In this respect we should be monitoring H3N8 outbreaks that infect dogs and horses. Viruses of the H2 subtype circulate in birds and they should be of particular concern if we remember the letality of the H2N2 epidemic with a virus that circulated 50-60 years ago.

arrow 4 October 2020. Human polymorphism plays a key role in the spread and severity of COVID-19.
To understand this statement, two very different features of sensitivity to the disease must be taken into account, and it should be noticed that Africa escapes the severity of the epidemic, whereas Black Americans are particularly affected and susceptible. We also need to separate the viruses with which we have co-evolved from emerging viruses. Let us go back to the history of mankind. For Neanderthal's man, who came to Europe from Africa probably very early on, the passage from hot Africa to cold Europe in winter required the practice of a specific behavior during the cold season. Individuals were tempted to gather in confined places where it was possible to keep warm. This completely changed the mechanism of contagion of local respiratory diseases, as can be understood. Natural selection led this Hominin to evolve an offspring favoring individuals who possessed all kinds of defense mechanisms (innate and acquired immunity) against these local diseases. When Homo sapiens also arrived from Africa, they lacked these defenses, and mortality in winter must have been considerable. But some of them hybridized with Neanderthals. Their children found themselves better protected, which resulted in keeping a significant part of the Neanderthal genome in the genome of extant Europeans and Asians. These genes were unevenly redistributed, and today there is a significant polymorphism linked to this ancestral DNA, most likely leading to considerable individual variability in modern populations. Of course this is true for diseases that existed in Europe and Palearctic Asia, not for emerging diseases. In particular, for diseases coming from tropical regions, it is expected that the direct descendants of Homo sapiens are best protected, which could partly explain the apparent relative protection against COVID-19 witnessed in Africa. The fact that this continent is hot also means, of course, less contagion from clustering in confined areas. One may have predicted that Black Americans escape the disease, but this is not the case. It is true that a part of their genome often comes from European ancestors, but above all, of course, we must take into account the expression of genetic program: the manifestation of immune capacities depends considerably on the environment, and typically on food and therefore of gut microbiota (it has long been noticed that a bad diet favored tuberculosis, for example). In addition to this—as we have noticed from the beginning of the epidemic—there is also an enormous genetic variability that controls the individual recognition of cells, and in particular allows, or not, the destruction of those infected by SARS-CoV-2. Finally, this virus is new—we are living a full-scale biological experiment—and our response to the infection has not been shaped by thousands of years of co-evolution. This is what will make the creation of a vaccine that is both effective and harmless very problematic. It is not enough to have a strong response, a good vaccine must also protect, and above all it must not sensitize people to future infections (as happened with dengue fever).

arrow 1 October 2020. The SARS-CoV-2 sequence data generated in France are not available to the international community.
Following the evolution of COVID-19 in the world requires following the appearance of mutations world-wide. The usual—and as a principle imposed—pratice is that sequence data should be deposited at the Intenational Nucleotide Sequence Data Collaboration (INSDC) which has three entry points, one in Europe (European Nucleotide Archive) at the EBI in Hinxton (UK); one in Japan (DDBJ) at the National Institute of Genetics in Mishima and one in the USA (GenBank) at the NCBI in Bethesda. Unfortunately, for reasons that should be made transparent, a majority of these sequences are not deposited at the INSDC but at a private structure GISAID, which was initially built up to collect influenza virus sequences. This structure claims to be public and open, but its metadata, sequence choice (sequences appear and disappear from time to time) are not made transparent. Furthermore, public availability of the sequences precludes bulk dowloading, which in effect prevents public access. We must be aware of the fact that this situation allows manipulation of the data in such a way as to mislead governments about the course of the pandemic. In this context the situation in France is even worse: despite the existence of reference centers on specific viral diseases institutions that sequence the genome of virus isolates do not make their sequences public nationally or internationally. This is in line, unfortunately, with the extremely poor governance of France at the highest levels, making that any special interest group, whatever its credentials, whether in contradiction with ethical principles or law, or not, and including utter incompetence, can decide what in its own view is the public good. An important study from India published in Science yesterday suggests that the bulk of COVID-19 propagation comes from a minority of « superspreaders » who contaminate a large number of persons, while most people affected do not contaminate anybody. This same study also demonstrates that children and young adults are efficient propagators of the disease. Taken together these observations plead for publication of detailed maps of the presence of the virus so that people avoid going where the disease has a high prevalence.