key: cord-0974779-fjhofgwf authors: Focosi, Daniele; Casadevall, Arturo; Maggi, Fabrizio; Antonelli, Guido title: Reflections after 2 years of COVID‐19 pandemic date: 2022-04-05 journal: Rev Med Virol DOI: 10.1002/rmv.2351 sha: 37a91e9df1aeacddb6015756c75bfe754be7baea doc_id: 974779 cord_uid: fjhofgwf nan as part of the call to action required to "win the war against the virus". Systematic contact tracing and massive deployment of screening tests only make sense when the incidence of novel cases is low, 3 and was successfully implemented in multiple instances in China [4] [5] [6] ), but the majority of westernised countries have instead pretended to continue non-automated contact tracing approaches while having more than 3% of the general population affected at a given time: this is nonsense given that manual tracing has been shown to miss up to two out of 3 contacts. 7 On the other side, automated tracing with smartphone apps is not affordable in low-to-middle income countries (LMIC) and requires compliance from 56% to 95% of the population 8 : in a perfect oxymoron, this countermeasure is hence mostly available for countries who are too concerned for their privacy to adopt it. Furthermore, massive testing by high-priced molecular or antigenic assays is very costly even for robust economies and, after a certain level of contagion has been reached, produces only marginal benefits for the public. Part of the justification for this effort was the need to understand viral evolution and ecology. Under peak pandemic waves, random sampling of symptomatic cases might be a better approach for real-time monitoring of viral evolution, so that fund allocation could be shifted to more cost-effective programs and strategies (e.g., antiviral research, healthcare staff, or intensive care unit beds). Since a novel VOC could emerge anywhere, those virological surveys are relevant at any location, and WHO should promote random sequencing efforts to LMIC. (2) The unpredictability of modern pandemics. Mark Twain is often suggested as the originator of the quote "It's difficult to make predictions, especially about the future". Every pathogen is different. Consequently, the trajectory of modern pandemics from low-grade respiratory viruses cannot be predicted based on past examples (including past coronavirus outbreaks). Even for well-known and highly predictable viral threats, like influenza, we have very limited ability to prevent severe seasonal disease (such as the last flu pandemic). While on the one hand, globalisation leading to faster circulation has the potential to accelerate the year-long process of spontaneous viral attenuation/adaptation, on the other hand, chronic replication in an unprecedented number of immunocompromised hosts (a growing slice of the population in Westernised countries) and selective pressure from antibody-based therapeutics (e.g., monoclonal antibodies) and vaccine-elicited antibodies have the potential to alter such trajectory by facilitating the emergence of otherwise rare viral variants that are fit enough to spread. 9 Predictive models so far have only been validated retrospectively. 10 (3) The peculiarities of SARS-CoV-2. Several factors peculiar to coronaviruses make the trajectory of the SARS-CoV-2 pandemic even less predictable. First, SARS-CoV-2 is not a pandemic -it is a panzootic event 11 -and numerous other species (including pets) are being infected. 12 Confinement of mammals from human lives is not possible worldwide, increasing the chances for reverse zoonoses. Accordingly, reverse zoonosis from mice currently represents a likely explanation for the emergence of the Omicron VOC, 13, 14 as suggested by mouse adapted mutation sites. 15 Second, the SARS-CoV-2 genome is prone to recombination, with two recombinant sublineages (dubbed XA and XB in PANGO phylogeny) already described, and multiple recombination events (either with seasonal coronaviruses or human transcripts 16 ) likely also the basis of the Omicron VOC. 17 There are reasons to believe this may happen again in the coming months. During the COVID-19 pandemic, we have seen a progressive growth in the basic reproductive number of subsequent VOCs (from 2.4 to 3.4 for the original Wuhan strain to 4-5 for Alpha to 5-8 for Delta to eight for Omicron). Higher viral loads leading to higher reproductive numbers are generally considered a proxy for viral adaptation to host, although this is not universally true. 18 Paradoxically, with Omicron approaching the asymptote of reproductive number for human respiratory viruses, this VOC could be our best insurance against the dominance of another novel VOC, and the steadiness of pandemic lineages should offer manufacturers much-needed stability to develop novel therapeutics and vaccines. Sotrovimab, the only pansarbecovirus antibody approved to date, has not been combined with a different mAb and is hence prone to immune escape in up to 10% of recipients. 20 ACE2 decoys, which by definition are less dependent on Spike mutations, should also be further investigated as therapeutics for the current and for future coronavirus pandemics. [21] [22] [23] (5) The illusion of herd immunity. The fact that SARS-CoV-2 can replicate in individuals vaccinated with the currently available vaccines means that herd immunity sufficient to stop the pandemic cannot be achieved with the current generation of systemically administered vaccines. Those vaccines prevent severe disease (which represents an extraordinary goal) and partly hasten viral clearance, but lead to viral load peaks similar to those seen in unvaccinated subjects, 24, 25 which is enough to maintain the transmission chain. This is evident in the widespread circulation of the Omicron VOC in regions with vaccine coverages higher than 90%. Sterilising and herd immunity might be eventually achieved more easily by deploying mucosal vaccines, but even in that case animal reservoirs might prevent virus eradication. 26 While it is clear that COVID-19 is mostly a disease of the frail elderly, which is an underrepresented category in LMIC compared to westernised countries, this cannot be used as a justification to deny vaccine access at all, also considering the limited resilience of healthcare systems in LMIC. The same reasoning applies to therapeutics. Both antibodies and small chemical antivirals are not affordable to LMIC and come in short supplies. b. Secondly, investigator-initiated studies for off-label drug usage typically suffer from poor economic support compared to company-sponsored trials for novel drugs. Additionally, many high-impact factor journals profit on reprint sales to drug manufacturers, which could favour acceptance for publication of company-sponsored trials. 27 In the current pandemic, this conflict of interests has translated into better echo for novel antivirals and immunosuppressive drugs, which have been advertised as magic bullets for every patient, while real-world evidences have instead shown modest benefits in more selected populations. Noninferior benefits are achievable with far cheaper, old-fashioned approaches, which have often been dismissed by opinion leaders. for example, it has taken 2 years before well-designed trials have convinced the US Food and Drug Administration 28 By nature, humans often get bored with chronic situations, and even the most scaring novelties tend to become under-evaluated in time. We authors are concerned about how the ending of the pandemic will be managed. At the time of writing, many governments are proposing solutions that do not match biological realities, such as "green passes" with unlimited validity, or suddenly removing face mask mandates for indoor activities while the virus is circulating at unprecedented rates, just because the peak of the current wave seems to have passed. Such transition from black to white, without any shade of grey, seems supported more by mental tiredness than by factual science, and the complete and sudden removal of nonpharmaceutical interventions comes with the risk of flares that would diminish the achievements made so far. While some modelling studies suggest that high viral transmission amongst populations with high vaccination coverages paradoxically accelerates the endemic transition of COVID-19 with reduced numbers of severe cases, 30 caution is needed to avoid leaving frail patients behind. In two years we should have learnt that the old adage about "the possible becoming probable and the probable becoming inevitable" has become consistent. 17 Time has come to look behind us and learn lessons. COVID-19 infodemics: the role of mainstream and social media The impact of the COVID-19 "Infodemic" on drug-Utilization behaviors: implications for Pharmacovigilance Public health effectiveness of digital contact tracing in the COVID-19 pandemic: a systematic review of available data Chinese city of Tianjin to test 14 million people after Covid outbreak. The Guardian China's Wuhan Completes Mass Covid Testing After Cases Return China is Testing an Entire City of 9 Million for COVID-19 after it Found 12 Cases Connected to a Hospital There COVID-19 case investigation and contact tracing in the US Automated and partly automated contact tracing: a systematic review to inform the control of COVID-19 Analysis of immune escape variants from antibody-based therapeutics against COVID-19: a systematic review Predicting the mutational drivers of future SARS-CoV-2 variants of concern Mutations Arising in SARS-CoV-2 Spike on Sustained Humanto-Human Transmission and Human-to-Animal Passage Severe acute respiratory syndrome coronavirus-2 natural animal reservoirs and experimental models: systematic review Evidence for a Mouse Origin of the SARS-CoV-2 Omicron Variant Where did Omicron come from? Three key theories Evidence for a mouse origin of the SARS-CoV-2 Omicron variant Putative Host Origins of RNA Insertions in SARS-CoV-2 Genomes SARS-CoV-2 Coronavirus Omicron is a Multiply Recombinant set of Variants that Have Evolved Over Many Months A highly virulent variant of HIV-1 circulating in The Netherlands An mRNA Vaccine Candidate for the SARS-CoV-2 Omicron Variant Resistance Conferring Mutations in SARS-CoV-2 Delta Following Sotrovimab Infusion Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry. Science Design and Development of Potent H-ACE2 Derived Peptide Mimetics in SARS-CoV-2 Omicron Variant Therapeutics High Activity of an Affinity-Matured ACE2 Decoy against Omicron SARS-CoV-2 and Pre-emergent Coronaviruses Vaccinated and unvaccinated individuals have similar viral loads in communities with a high prevalence of the SARS-CoV-2 delta variant. medRxiv Viral Loads of Deltavariant SARS-CoV2 Breakthrough Infections Following Vaccination and Booster with the BNT162b2 Vaccine Omicron is bad but the global response is worse Conflicts of interest at medical journals: the influence of industry-supported randomised trials on journal impact factors and revenue -cohort study Clinical memorandum Re: EUA 26382. Product: COVID-19 convalescent plasma IDSA Guidelines on the Treatment and Management of Patients with COVID-19 Increasing Viral Transmission Paradoxically Reduces Progression Rates to Severe COVID-19 during Endemic Transition