A. Evolution of the virus

It is fair to claim that the sars-Cov-2 development of 2021 has provided us with the largest experiment in evolution we have ever witnessed in the history of humankind. As it always happens with evolution, we know the rules and we can predict the outcome but the actual mechanisms are always an unpredictable black box. Evolution, if you want a bit of a nerdy quote, evolution is akin to deep-learning in computer science: we know the starting point and we can guess the final outcome but it is very difficult to predict and often even to recapitulate how we go from one point to the next.

A1. The most important variants have not developed linearly.

All of the most important variants – certainly all of those who became dominant – have not developed linearly from each other. Delta did not arise from Alpha and Omicron did not arise from Delta (or Beta). That was not a

predictable development by any means but it does carry some important implications in terms of vaccinology. We knew Delta had acquired some decent properties of immune escape towards all the vaccines and in the Autumn of 2021 most scientists would have welcomed a vaccine update based on Delta’s Spike sequence, based on the assumption that any future variant would have evolved on Delta’s backbone. However, given how omicron evolved, it is now reasonable to assume that a Delta specific vaccine would not have helped towards omicron – in fact, it is even possible to speculate the opposite: a Delta specific vaccine may confer less protection toward omicron than the vaccines currently available! Looking at the early epidemiological findings from South Africa – where exposure to previous variants was rampant – it appears that the highest number of omicron re-infection were detected in people who had previously come in contact with Delta (Pulliam et al – Fig. 2b and pg 14). Other explanations for this observation are certainly possible (and in vitro data do not necessarily corroborate it: eg Ikemura et al) but it is something worth considering.

In general, it is clear that we cannot expect future variants to build on the backbone of the circulating one. In fact, from the immunological point of view, it makes sense to expect the opposite! Future variants will benefit from being as different as possible from the variant that just preceded them. The implications for future vaccines are important. We should probably enrich the antigen repertoire we will be using for future vaccines, to bet on multiple horses.

A2. The fitness landscape is large and dynamic.

This is something that comes as no surprise to anyone who has been looking at Sars-CoV-2 development from an evolutionary standpoint.

The first variants (Alpha, Delta) were selected against a very different landscape. Pressure for those was linked to their sheer contagious ability, not on immune escape. Omicron (with Lambda and Beta) on the other hand evolved in a different setting in which pressure was mostly towards immune evasion. Some had proposed that Delta represented “peak fitness” of the virus (Burioni et al) but, as population geneticists know well, it is not appropriate to talk about peak fitness when the fitness landscape changes continuously. What should we expect then? Given that immunity seems to be extremely short lasted, we should expect a continuous change of fitness landscape that will select new escape variants. The scenario is conceptually similar to what we see with flu but complicated by the outstanding evolutionary rate of this virus (see Kistler et al). Evolutionary rate is a function of population size and a month ago it would have been reasonable to assume that vaccines and

immunity built by contagion would have slowed the pace of evolution. However, omicron spectacularly changed that prediction, considering that – at least for the sheer number of cases – the pandemic has never been as large as it will be with this variant. We should certainly expect that the virus now has a much larger evolutionary pressure towards immune escape and the evanescent nature of immune protection, with waining manifesting itself after a few weeks, creates perfect conditions for further selection.

A3. We cannot dismiss future reverse-zoonosis.

Where will future variants come from? Considering the molecular characteristics of omicron’s Spike and its likely geographical genesis, it is easily tempting to opt for its evolution in a chronically infected immunocompromised subject. However, the discovery of BA.2 (a sister branch of the original omicron sequence, now named BA.1) opened new perspectives. BA.1 and BA.2 are too different from each other for being vertical products of evolution; they have got to be horizontal. In lay terms: they are “sister variants” rather than “mother and daughter”. The implication is therefore for a “primordial broth of omicron” simmering in a wide reservoir. This reservoir is unlikely to be a single individual: it could be a group of immunocompromised patients or – equally possible – an animal reservoir. We know the Spike protein is extremely versatile when it comes to species affinity and animal reservoirs were identified both in captivity and in the wild: future reverse-zoonosis should not be dismissed with ease.

I would also command extreme caution towards the idea that the evolutionary landscape is restricted to ACE2 binding. We have multiple solid evidence of co-receptors and/or alternative receptors involved in cell entry of Sars-Cov-2 and we do know that other beta-coronaviruses do not use ACE2 at all (MERS-CoV, for instance, uses DPP4 as its main receptor). The unprecedented evolutionary pressure toward Spike implies that tropism could change and, with it, the disease profile (including symptomatology and the age/severity profile). The remarkable number of residues changes in the RBD of omicron’s Spike is an alarming sign that this could happen.

A4. The evolution of severity is a random walk.

We know the severity of the disease takes an unjustified level of attention with media and the public. Mathematically speaking, a more contagious variant is way more problematic than a more virulent one and yet we’ve seen with Alpha and Omicron the public being distracted by the red herring of severity. One aspect of omicron’s severity was not discussed as required: omicron descends from the original strain and therefore its severity should be compared to the original strain, not to Delta. Is omicron’s virulence higher or lower than the original Wuhan strain? Alpha doubled the risk of hospitalization compared to the original strain and Delta doubled the risk of hospitalization compared to Alpha. Omicron has evolved from the original strain, not from Delta, so the narrative of the virus getting milder is rather unsupported if we compare omicron severity to Delta’s severity.

B. Evolution of human response to the virus.

It is not just the virus to have evolved in this year. Our response has too – or at least it should have.

B1. Technology is paramount but wise politics is the most important tool.

Omicron has found most of the world incredibly unprepared. Many scientists spent the last two years explaining how important surveillance was, and yet most countries were completely in the dark when it came to identifying and monitoring omicron’s spread – and this despite the convenient and fortuitous fact that omicron BA.1’s contagion could be observed without sequencing, through SGTF. In Europe, only the UK and Denmark had a good understanding of omicron’s growth in December, with almost all other countries absolutely unaware of its pace and location. This was unfortunate for multiple reasons: different countries had different control measures in place and a comparison of omicron’s speed among different conditions could have hinted at whether some measures were more or less likely to dent its impressive growth.

Having said this, information about omicron itself did not influence dramatically the containment taken by the UK, mostly for political reasons. Little did it matter that the UK had daily data on omicron’s growth and the best epidemiological analysis of its spread and virulence with state of the art weekly reports and impressive numerology throughout.

While technology is paramount, politics is clearly the bottleneck.

B2. Easy vaccination vs difficult vaccination.

We would certainly be in a very different place had not been for vaccines and we have heard repeatedly how vaccines are the only way out from this mess. Paradoxically, however, very little effort has been placed toward extending vaccine protection to as many people as possible and most countries found themselves completely unprepared when facing vaccine sceptics. Positive persuasive efforts were extremely limited and/or based on outdated methods (for instance: no country has adopted a door-to-door salesman strategy) and punitive measures were preferred instead, with limited results. Judging on what we have witnessed so far, I am afraid we will probably see a wave of vaccine coercion in 2022 and there is no guarantee that will work at all; in fact, it may even lead to the opposite effect.

B3. What is the equilibrium we are seeking?

We will not be able to eradicate this virus and for years to come, we must accept some kind of equilibrium between its damage and what we intend as our normal routine. Where is that equilibrium? Do we measure it in terms of deaths of hospital capacity? Should the equilibrium be built on a potentiated health system? Should this threshold be decided democratically?

Containment measures with limited cost do exist and must be considered seriously. They range from increasing remote work to the widespread use of facemasks during the winter season. Many Asian countries have shown that while eradication is an impossible chimaera, containment is not.

What I would like to see in 2022.

Testing.

Omicron clearly showed that we cannot possibly win the rat race between viral evolution and human countermeasures. The virus is simply too fast. What we have not realised yet, however, is that the black swan of this pandemic is not the virus itself, but the unprecedented level of human connectivity we are experiencing at this time and age. It is absolutely possible and even likely that humankind has met in the past viruses with similar or even greater transmissibility but never in the history of humanity have connections been so immediate and widespread. Connectivity between countries and continents is what makes this pandemic unique and therefore those are the aspects we must try to curb. In all likelihood, it will be impossible to completely halt the spread of future variants but we must at least try to contain them. We have all learned to remove our shoes and laptops at security just before boarding a plane: we consider that normal routine (and even expected), so why not adopt something similar for covid? A LAMP test at the airport should be an integral part of the ticket we buy and we should make testing before travel and before social events more effortless and accessible.

Tracing.

As for tracing, we have not even tried. We have foregone any attempt of tracing technology in the name of perceived privacy and that was, in my opinion, a huge mistake. When it comes to movements and meetings, we have already surrendered most of our rights to privacy to advertising agencies, phone companies, and credit card providers so the choice of not even attempting digital tracing of contagion strikes me as a particularly irrational one.

A more genuine communication.

This is probably the least likely of my wishes but I would really love to see a more sincere scientific communication. I would like to see patronising and optimistic claims give way to sincere and realistic statements, about the virus, the vaccines, the political strategies and containment plans. Everything really has to start from here.