Are we in a pandemic, or not? “Pandemic yes, pandemic no?” These two questions are being fiercely debated now, posing a global dilemma. The reality is the SARS-CoV-2 (Covid virus) has met the two basic definitions of a pandemic. The first is that the newly identified virus has caused prolonged community-wide outbreaks in two or more countries in more than one region (defined by the WHO). The second is that human-to-human transmission of the new virus has been proven and already caused more than 900,000 deaths and nearly 30 million confirmed cases, in virtually orally every country in the world. Yet paradoxically, for many, this is not the case as thousands of people still seem to doubt that this dramatic situation is a "true pandemic", and some experts even continue to sow dangerous doubts about the situation we now face. Therefore, it is essential to clarify the real potential of SARS-CoV-2, then to hypothesize the evolutionary potential of the virus and the pandemic in progress.

To clarify the problem, a "pandemic" virus is not a pathogen like the others, but a possible "agent of chaos". As such, SARS-CoV-2 was able to penetrate our species starting from its spillover or “species leap” from its natural animal natural reservoir of bats in China. It was able to evolve rapidly (through mutations of its genome) to better adapt to our cells (for its replication and diffusion) to become extremely contagious, invasive and virulent. Being unknown to our immune system, it is also able to trigger in our organism, a violent potentially lethal immune-inflammatory reaction.

From these first, simple observations, evaluating SARS-CoV-2 by its evolution and spread in the human sphere, leads to the conclusion it must be considered as a true pandemic and extremely dangerous virus. On the other hand, we can assert that those who continue to propose reassuring versions have not yet recognized SARS-CoV-2 as a pandemic virus, nor the specific, alarming characteristics of the long-awaited "first great pandemic of the third millennium" now in progress.

In the early years of this century, for virologists and pandemic hunters, the scenario has changed completely. For over a century, the pandemic risk linked to respiratory viruses had been exclusively attributable to influenza viruses. The two epidemic outbreaks of SARS (2002) and MERS (2012) literally changed the rules of the game. Also because these two new unexpected Coronaviruses (potentially lethal to humans unlike those that normally circulate around the world causing common colds) emerged from an animal that had been under close surveillance for several decades: the bat.

The bat is a natural reservoir1 much more dangerous than wild waterfowl and other wild birds that are the primary reservoir for influenza Orthomyxoviruses2. This is because of the increasing promiscuity between men and bats on the outskirts of the megalopolises. Because the bat has been shown to be the reservoir for some of the deadliest viruses that have emerged in recent decades (Ebola, Marburg, Nipah, Hendra, etc.). But above all because the bat, being a mammal, is an animal genetically much closer to us, and its viruses can more easily adapt to the receptors of human cells, especially those present on the cells of our upper airways, which makes the “species leap” much easier. Which increases the contagiousness and, subsequently, the virulence. For all these reasons, it is not surprising that virus hunters from all over the world have dedicated themselves (i.e. after the SARS epidemic) to the study of the Coronaviruses of Asian bats that are capable of infecting the man. This research paid off quite soon, if it is true that already in 2005 in the caves of Yunnan, China numerous strains of bat-Coronavirus similar to SARS-CoV-1 were isolated. It should not be surprising that these viruses were the subject of research and experiments. Virologists created highly contagious, invasive strains in the laboratories3 to better understand the genetic characteristics so they could then design vaccines capable of counteracting them: a type of research disputed by many, but clearly necessary even if dangerous4.

The numerous alarms from scientists of an imminent pandemic originating in China should not arouse suspicion because for some years the discoveries of this looming threat represented by the Asian bat-Coronaviruses had been known and voiced. International laboratories characterized by the highest levels of biosecurity (BSL-3 and 4) were installed, in the areas at greatest risk, to isolate such dangerous biological agents. Pre-pandemic plans and preventive exercises were also put in place. Yet, these plans often have proved useless, at least in Western countries.

So, at this point, can we say with enough evidence that this outbreak is a pandemic? First of all, do we have enough epidemiological data, to say that this expanding epidemic is the first true great pandemic (long awaited and foretold) of the 21st century? Secondly, may we state that SARS-CoV-2 has the dreaded characteristics (contagiousness and virulence, essentially understood as the ability to trigger severe immune-inflammatory responses in a substantial portion of affected individuals) typical of a true pandemic virus?

Pandemic yes, pandemic no?

The mounting evidence is clear. One of the most fundamental characteristics of a pandemic agent is the ability to rapidly adapt to the new species. The transmissibility and high contagiousness of this new virus is documented. The discovery of the first clusters across the entire world and the different trend of outbreaks in various countries clearly depended on the containment strategies implemented (in timing and effectiveness)5. In Italy, during the first two months, nearly 20,000 deaths were recorded in Lombardy alone. Over 180 doctors died in Italy and approximately 7000 health workers passed away across the globe. The speed in which the virus spread from China to Europe and then to all continents was dramatic. News of the first 100,000 American deaths was published on May 24 by the New York Times. Images of mass graves in countries such as Brazil and Ecuador proved shocking. Nearly 30 million cases and over 920,000 deaths were documented in the first 6 months of the pandemic (March 15 – September 15, 2020). Official lethality rate is close to 3%. This epidemiological data allows us to answer the first question. We can now confirm that this is the first phase of the “much feared and uselessly foretold” first great pandemic of the third millennium6.

But then, how can we explain that clinicians and even experts of infectious diseases have often taken diametrically opposed positions to the virologists and leading national and international health institutions, primarily the WHO? They are absolutely certain that this is a health crisis like so many others, but they argue it has been considerably overestimated and deliberately amplified, for speculative business purposes and government surveillance programs.

It is important to underline this extremely concrete issue, not only because these different positions have caused dangerous disorientation in public opinion. But, also because the contrasts between virologists and clinicians is becoming more radicalized. Even non-experts, like news commentators, and ordinary citizens have formed into opposing antagonistic factions.

Understanding the origin of these different interpretations is essential to avoid the growing confusion which will provoke risky and irresponsible behavior in people. We must also better understand and predict the evolution of the pandemic to deal with it in the best way. The fact remains that most virologists are convinced that we are facing an epochal tragedy that risks taking on apocalyptic dimensions if we do not convince both institutions and citizens to behave with precautionary strategies. And, with each passing day, such measures are becoming progressively unpopular. The conflict has been drawn between failing economies and failing health.

The two “camps”

Interestingly, the two "camps" did not change during the pandemic. The proponents of the pandemic thesis and the drama of the situation are on one side. Meanwhile, supporters of an easily controllable parainfluenza virus outbreak are facing each other on the other side and both have been stuck since the start of the crisis. Furthermore, from this position of denial, some have become heroes of a large movement of public opinion that sees the pandemic as an invention, the product of a vast media campaign in a global plot designed by Big Pharma. In short, both sides have a radically different interpretation of the ongoing drama and, more specifically, of the nature and potential of the pathogen involved.

The supporters of a softer line evidently do not recognize SARS-CoV-2 as a true pandemic virus and consider it like other common pathogens, going so far as to theorize that it could rapidly weaken and that the new host (us) may acquire in a short time a stable and effective immune memory. On the contrary, virus hunters, as already mentioned, tend to view these viruses as "time bombs" whose evolutionary path should be slowed immediately, at any cost and for a long time, at least until the majority of the human population has acquired a stable immunity (either naturally or through global mass vaccination strategies).

At this point, we must try to answer the second key question, the one concerning the new virus. Is it possible to say with absolute certainty that SARS-CoV-2 is the feared and awaited new pandemic Coronavirus, or it is still possible to argue that it is a “common influenza virus” destined to weaken and quickly disappear, as some experts still claim7?

Is SARS-CoV-2 the new (and expected) pandemic virus?

Coronaviruses are a group of single-stranded RNA viruses found in a wide range of vertebrates. Currently, there are four common kinds of Coronaviruses (alpha, beta, gamma and delta) that cause mild respiratory tract diseases in humans as well. But over the last twenty years, 3 highly pathogenic beta-Coronaviruses for humans have emerged from “zoonotic events” 8, when a pathogen passes from animals to humans. In 2002 SARS-CoV-1 infected about 8000 people with a mortality rate of 10%, causing a first pandemic alert (SARS). In 2012, MERS-CoV, related to Middle Eastern Respiratory Syndrome (MERS), infected about 2,500 people with an even higher lethality rate (about 35%). In the fall of 2019, the current coronavirus, SARS-CoV-2, made the feared leap from bat to man9.

The sequencing of the new virus was completed very quickly, thanks to the significant technological advances that had taken place in the last decade. At the beginning of 2020, Chinese researchers made the sequence of the new Coronavirus available to the international scientific community. A few days later, the Pasteur Institute also announced that it had completed the sequencing, starting from samples of three suspected cases (two patients in Paris and one in Bordeaux). The complete sequences were filed on January 30 on the GISAID (Global Initiative on Sharing All Influenza Data) platform10.

The rapid sequencing and timely discovery of cases all over the world could have been an enormous advantage in addressing the current situation, because nowadays it is possible, by crossing genetic and phylogenetic data, to predict the potential evolution of a virus. Starting from the first analysis of the master sequence, it was possible to see that SARS-CoV-2 had acquired some key mutations in the first months. These mutations occurred in two sections of the sequence that gave it greater invasive, contagious potential and a marked tendency to attack tissues of the new host, not only the upper airways and lungs, but also arteries, gastrointestinal tract, and the central nervous system. It was also evident that the genetic sequence of the new virus was only 70% similar to that of the SARS Coronavirus and over 95% to that of one of the bat Coronaviruses discovered and registered in the Yunnan caves11. This confirmed the hypothesis that it was a virus that had made the “spillover” from bats to man and had all the credentials to become a serious threat to human health on a global level12.

The first in-depth analysis of the sequence13 revealed that SARS-CoV-2 had acquired some key mutations in the genes encoding the spike protein that allows the virus to attach to ACE-2 receptors present in the human upper airways14. The attack of the virus on the cells is the first step of any viral infection and is also a determining factor of the tropism for the tissues of the new host. It is important to note that a high binding capacity to the ACE2 receptor had already been seen in SARS-CoV-115, but the first modeling of the new spike protein seemed to suggest a further increased affinity16.

In particular, some mutations (N493Q and T499P) appeared to result in greater binding site (RBD) affinity for ACE217. This was acquired by SARS-CoV-2 through a complex evolutionary process rather than through a progressive accumulation of mutations18. Indeed, these new mutations were not present in the original bat-Coronavirus (RaTG13). For this reason, it has been hypothesized that the recombinatory process occurred in another mammal, the pangolin, which acted as an intermediate host19.

This was an intriguing fact, though controversial20. Furthermore, two other mutations in the cleavage site, fundamental in determining the ability of the virus to spread in the tissues (thanks to the interaction with an enzyme called furin21 that is present in our lungs, liver and small intestine) were supposed to have the same origin. It is even more interesting to note that a similar polybasic cleavage site, which can be easily processed by furin-like proteases, is also typical of highly pathogenic avian influenza viruses, distinguishing them from “seasonal” influenza viruses22. The expression in various human organs of furin and similar proteases could then explain the increased tropism of SARS-CoV-2 for human tissues23.

In February, the international scientific community had therefore evidence that SARS-CoV-2 was a virus that had recently made the "spillover" and was extremely contagious and dangerous for humans: a real pandemic and not an ordinary parainfluenza virus24. But to conclude this brief analysis of the reasons why SARS-CoV-2 should be definitively recognized as the agent of the first great pandemic of the third millennium, we must at least mention the other fundamental factor that determines the particular virulence of a pandemic virus ( a new pathogen completely unknown to our immune system): the ability to trigger a life-threatening systemic inflammatory reaction in the new host. The most specific clinical picture is Acute Respiratory Distress Syndrome (ARDS) with rapid pulmonary fibrosis25. But there are also other inflammatory reactions: Macrophage Activation Syndrome (MAS), Disseminated Intravascular Coagulation (DIC), Cytokine Storm, and cardiovascular failure. In the great historical pandemics and the more recent outbreaks - from H5N1 (Avian flu), SARS-CoV-1 and MERS-CoV - the high lethality rates even among young subjects were due to the same pathogenic mechanisms. Defining the transcriptional response is the best way to decipher them.

The body's recognition and response to a virus takes place inside the cells, where a family of intracellular receptors detects the exogenous RNA that forms during the replication of the virus itself. The cell reacts by activating some transcription factors, in particular the interferon regulatory factors (IRF) and the nuclear factor kB (NF-kB) that trigger two basic antiviral programs. IRFs induce the transcription of first and third type interferons (IFN-I and IFN-III) and the subsequent upregulation of genes stimulated by IFNs (ISG). On the other hand, NF-kB, is the main transcription factor that activates inflammatory programs. It recruits and coordinates specific subgroups of leukocytes by secreting chemokines and cytokines. Over millions of years, these responses have exerted a strong selective pressure on viruses and determined in them the deployment of innumerable molecular countermeasures in a sort of (co-evolutionary) arms race26. Well, it is possible to state that all the studies published so far show that in SARS-CoV-2 infections characterized by a strong viral load, despite the almost complete lack of IFN expression, the chemotactic and inflammatory response documented by the expression of CCL20, CXCL1, IL6, IL-1B, CXCL3, CXCL5, CXCL6 and TNF represent the key feature and is able to explain the possible critical evolution affecting approximately 5-10% of Covid patients27.

Now that we have established SARS-CoV-2 as a pandemic virus in the first great pandemic of the third millennium, is it possible to predict the evolution of this virus? Also in this case, the question is twofold. Is it possible on the basis of both genetic and phylogenetic monitoring of the virus to predict how SARS-CoV-2 will evolve? On the basis of data and above all of current epidemiological trends, can we predict the evolution of the pandemic?

The possible second wave: the worst possible scenario

These two questions are closely interconnected. We know that a new virus evolves by acquiring adaptive mutations. The most plausible model is that the more the virus circulates, infecting a high number of individuals of the new "host species", the more it develops mutations. The progressive adaptation of the virus, producing more cases, inevitably produces more deaths. This coevolution should last until a balance is reached between the new virus and the human immunocompetent system. Although these simple rules have been shared for decades within the international scientific community, contrary hypotheses are proposed every day: very rare mutations that weaken the virus28 could explain the frequency of mild cases in countries such as Italy where the dramatic initial phase has been overcome. Which leaves room for optimistic forecasts about the evolution of the epidemic.

Some authors have even hypothesized that it would be "cheaper" for the virus to develop mutations that make it less virulent to spread more easily. However, we must remember that on a scientific level, at least in the context of the classical model, mutations are essentially stochastic events and selection rewards those most advantageous for the virus, that is, the most adaptive ones: as confirmed by one of the few mutations so far proved to be stable and frequent, D614G in the Spike protein, which would have favored in Europe, since February, a faster transmission of the virus than in Asian countries29.

Finally, the scenario most similar to the current crisis is the Spanish Pandemic. This was the only modern pandemic due to a completely new respiratory virus introduced to our immune system. This does not mean that the second epidemic will have catastrophic consequences like a century ago. It simply requires us to take the worst-case scenario into consideration and organize health systems around the world accordingly to avoid the second pandemic wave.

Zoonosis and pandemics: are prevention strategies still possible?

We have long known that most of the infectious diseases that have ravaged the life of Homo Sapiens for millennia and of the most terrible epidemics in history are “zoonoses” – diseases due to a pathogen that jumps from an animal to human. According to the well-known thesis by the Anthropologist Jared Diamond zoonoses were a "gift", but we could also say almost a "revenge" by millions of animals we have imprisoned, tortured, exploited and forced into unnatural ways of life since the Neolithic Age30. We know that the ecological disasters caused by man - eco-systemic upheavals, wars, deforestation, forced migrations, and the construction of immense megacities close to degraded and violated natural areas - today represent the major factor favoring "species leaps" and pandemics. And there are immense markets of thousands of species animals kept artificially in contact with each other that adds to the problem.

Perhaps it has always been like this. The great pandemics of the recent past like the Spanish Flu were the consequence of natural or social disasters (primarily migrations, wars, and famines). But the current movement of human beings, animal, and microbial species is unprecedented in history. This is why the cause of Covid is rooted in on the rapid degradation of ecosystems31.

International agreements aimed at protecting or restoring damaged ecosystems are urgently needed. Countermeasures must be taken to slow down the emergence of such animal-based diseases that pass to man. Like the climate crisis and biodiversity crisis, the degradation of the ecosphere represents an urgent global challenge. And, we now know, these crises have provoked the current biological crisis. This awareness should lead to a radical cultural, political and economic change. We can only hope there is still time ...

(Article written by Ernesto Burgio and Terence Ward, author and cultural consultant, ambassador for Religions for Peace, member of PEN International and ISMEO - International Association for Mediterranean and Oriental Studies.)


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