key: cord-1050197-rsog0thm
authors: Alexandridi, Magdalini; Mazej, Julija; Palermo, Enrico; Hiscott, John
title: The Coronavirus Pandemic – 2022: Viruses, Variants & Vaccines
date: 2022-02-12
journal: Cytokine Growth Factor Rev
DOI: 10.1016/j.cytogfr.2022.02.002
sha: b5b38808914837e45171da425ba78aba7967c17a
doc_id: 1050197
cord_uid: rsog0thm

Since the beginning of the COVID-19 pandemic in 2019-2020, Cytokine & Growth Factor Reviews has published several Special Issues focused on the biology, pathogenesis and therapeutic options in the treatment of COVID-19 infection, including articles on the involvement of the chemokine system in the cytokine storm in COVID-19, intervention in the early stages of COVID-19 pneumonia, the therapeutic value of corticosteroid treatment, early clinical intervention with type 1 interferons, progress in vaccine development, and organ specific complications of COVID-19. By 2022, multiple highly efficacious vaccines are available and are being administered in countries around the world, therapeutic options have been clinically evaluated and approved, and SARS-CoV-2 has arguably become the most thoroughly studied virus in history. But, with progress has also come unanticipated problems - misinformation, anti-vaxxers, opposition to protective masks, and politically motivated interference disguised as knowledge. With this issue of CGFR, we continue to document the global coronavirus pandemic and provide an update on the emergence of viral variants, the global effort to administer vaccines and the impediments to progress posed by misinformation and anti-vaccine sentiment.

In June of 2020, Cytokine & Growth Factor Reviews published a Special Issue of the journal entitled The Coronavirus Pandemic 2020 (volume 53), featuring reviews from China, Italy, Russia and America, early ground zero countries hit by the pandemic; this issue reflected our early understanding of SARS-CoV-2 biology, pathogenesis, immune response and treatment strategies. Subsequent Special Issues of CGFR -August 2020, volume 54; April 2021 volume 58 and this issue February 2022, volume 63 -continue to highlight reviews focusing on the global spread of the COVID-19 pandemic. Along the way, CGFR has published articles on the involvement of the chemokine system in the cytokine storm in COVID-19 [1] - [3] , intervention in the early stages of COVID-19 pneumonia [4] , the therapeutic value of corticosteroid treatment [5] early clinical intervention with type 1 interferons [6] - [9] , progress in vaccine development [10] and organ specific complications of COVID-19 [11] .

By now, we all recognize that the origins of the COVID-19 pandemic began in December 2019, with the first known cases detected in Wuhan, China. By March 2020, the global spread of the virus prompted the World Health Organization (WHO) to declare the outbreak a pandemic [12] . As of February 3, 2022, more than 385 million cases have been identified and almost 6 million deaths reported, both numbers likely a gross underestimate of the extent of SARS-CoV- J o u r n a l P r e -p r o o f Today, multiple highly efficacious vaccines have been generated and are being administered in countries around the world, therapeutic options have been clinically evaluated and approved, and SARS-CoV-2 has arguably become one of the most thoroughly studied viruses in history.

But with progress has also come unanticipated problems -misinformation, anti-vaxxers, opposition to protective masks, and political interference disguised as knowledge. This Introduction to our Special Issue provides an update on the emergence of viral variants, the global effort to administer vaccines and the impediments to progress posed by misinformation and anti-vaccine sentiment.

The origins of SARS-CoV-2 have been extensively debated since the beginning of the pandemic, with two main theories proposing either a laboratory escape or a natural emergence of the virus. While no evidence of a laboratory origin has been reported so far, accumulating genetic and epidemiological data indicate SARS-CoV-2 outbreak as the result of a zoonotic event [13] - [16] .

In January 2020, the first whole-genome sequence of SARS-CoV-2 was published on GISAID which helped to start the production of diagnostic tests against COVID- 19 genome sequence submissions of SARS-CoV-2 data were shared via GISAID.

Genetic alterations into viral genome have been cataloged as it multiplies, spreads and mutates within the human population (Figure 2 ) [17] , [18] . The emergence of new variants continues to fuel the pandemic -since the genetic differences in viral properties, particularly in Genome sequencing demonstrated that Omicron contained 60 genetic mutations compared with the original SARS-CoV-2 isolates [29] . Omicron was found to be highly transmissible, with estimates that it can multiply in the lung cells 70 times faster than the Delta variant [30] , [31] , while the overall binding of Omicron Spike to ACE2 receptor remained comparable to Delta.

The combination of two mutations in the Spike protein -Q498 and N501Y -have been reported to increase the binding affinity to ACE2 in in-vitro studies [32] , but other Omicron mutations seem to have the opposite effect, most notably, the K417N substitution. Mutations that are more likely responsible for enhanced Omicron transmissibility act by increasing the evasion of the antibody response to a greater degree, thus partly explaining the number of "breakthrough" infections in previously vaccinated individuals. A better immune evasion was linked with the acquisition of an N-linked glycan in RBD residue N370, which drives neutralization escape as it sits in the binding footprint common to many antibodies [33] , [34] . Severe and critical symptoms include multiorgan dysfunction, respiratory failure, chronic kidney impairment, heart complications, stroke, Guillain-Barre syndrome, and others [37] , [41] .

The majority of patients recover from the acute phase of the disease. Nevertheless, some patients continue to suffer from a range of symptoms months after recovery, a recognized medical condition that is now termed 'Long Covid'. Long Covid is characterized by long term complications or persisting symptoms after the typical COVID-19 recovery period. Nearly every organ system can be affected by Long Covid -most common effects are observed in the J o u r n a l P r e -p r o o f respiratory, nervous and cardiovascular systems [42] . Symptoms include fatigue, malaise, musculoskeletal pain, headaches, shortness of breath, parosmia, anosmia, low fever, anemia and cognitive dysfunction. Some patients experience multisystem inflammatory syndrome,

where severe damage to organs has been observed [37] , [43] . WHO released a clinical case definition in October 2021: "Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19

with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis" [12] .

In a recent study from the UK Office for National Statistics, it was concluded that approximately 14% of people who tested positive for SARS-CoV-2 suffered from one or more symptoms consistent with Long Covid for longer than three months [44] . Another study from the University of Oxford showed that 37% of COVID-19 patients experienced at least one symptom three to six months after diagnosis [45] . Long Covid risk factors include: age (especially those above 50 years old), obesity and asthma, coupled with the development of more than five symptoms during the first week of acute SARS-CoV-2 infection [46] - [49] .

Moreover, other studies suggested that women are more likely to develop Long Covid than men, even though they are less likely to develop severe acute COVID-19 [49] .

Numerous hospitals and clinics have initiated special multidisciplinary programs, with specialists from a wide range of departments in order to offer comprehensive care and help with Long

Covid recovery [50] . The treatment is individualized according to the grouping of clinical signs and symptoms and includes numerous clinical, functional, cognitive, psychological, and nutritional aspects.

The development, manufacture, testing and distribution of vaccines against SARS-CoV-2, essentially in the space of a year, will surely be viewed as one of the most remarkable accomplishments in the history of modern medicine. Prior to 2020-2021, the pharmacological 'dogma' stated that several years of effort were required to develop a vaccine against an infectious disease; however, an unprecedented collaboration between government, academia and the pharmaceutical industry accelerated the scope of vaccine development [51] , [52] .

The rapid development of COVID-19 vaccines was not a consequence of hastily conducted research, inadequate clinical trials or blind luck, but rather the result of decades of public and private vaccine research that for the most part flew 'under the radar' of the general public.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f Likewise, in those individuals previously infected with SARS-CoV-2, immunization provides strong protection against disease (up to 90% protection). Because antibody titer and immunity decrease over time, especially in individuals aged 65 years or older, booster vaccine shots are strongly recommended, especially with the mix and match method. It has been proven that fully vaccinated status prevents serious COVID-19 illness, hospitalization and death [71] , [72] . 

Mild side effects, like soreness, redness, rash, and inflammation at the injection site have been reported for all the vaccines and they are related with the introduction of a foreign compound into the body. Other reported side effects, that last only a few days, include headache, fatigue, myalgia and arthralgia [74] , [75] . A very rare event is hypersensitivity to one or more ingredients of the vaccines that in even rarer cases can lead to anaphylaxis [76] - [78] . A few rare blood clotting syndromes had been reported in small numbers of individuals who had received the AZD1222 -Oxford/AstraZeneca or the Janssen vaccines (Johnson & Johnson). These vaccines were suspended in some countries until their safety profile had been reassessed, finally demonstrating that the rate of blood clotting problems was not higher in vaccinated individuals than the whole population. Currently, both vaccines are approved for use by WHO and EMA [79] , [80] . An association between mRNA vaccine and the onset of myocarditis and pericarditis has also been reported; the highest incidence was detected in young male patients, with mild to moderate disease severity and symptoms resolution in most of the cases [81] - [84] . There is a multitude of factors that can influence the immune response after vaccination or after exposure to the virus, including the infection history of each individual, the severity of disease, age and others. Nevertheless, J o u r n a l P r e -p r o o f vaccination is recommended even after natural infection, since it offers stronger immunological protection [85] , [86] .

One of the most unexpected and bewildering consequences of the SARS-CoV-2 pandemic has been the extreme level of misinformation emanating from the individuals, groups and media.

Misleading information, ranging from conspiracy theories that the virus does not exist, to theories that vaccines can alter the human DNA have spread almost as rapidly as the virus [87] .

WHO proposed the term 'Infodemic' to describe the overabundance of information including false or misleading information in digital and physical environments during a disease outbreak [12] . Misinformation has led to mistrust in health authorities that threatens the public health response and has undoubtedly contributed to low vaccination rates in some areas of the world [88] .

To address this problem, governments, universities and private organizations have taken measures to disrupt the spread of misinformation. More than 130 UN member states signed a cross regional statement on the COVID-19 'infodemic' and the UN task force initiated the "Verified" campaign to deliver life-saving information on COVID-19 [89] , [90] . Additional efforts have included a collaboration between WHO and the UK government in an awareness campaign named "Stop the Spread" to counteract the consequences of false information.

Cambridge University partnered with the UK Cabinet Office and developed an online game called "Go Viral!" [12] . European Commission in the Joint Communication to the European Parliament titled 'Communication on the Global EU response to COVID-19' highlighted all the EU actions against COVID-19 disinformation and mobilized significant resources to fund projects regarding information veracity [91] .

Moreover, leading social media platforms also stepped up to introduce new policies against posting alarmist rhetoric or false narratives. Twitter announced that will block repeat fake news offenders from the social media, while Facebook and Instagram launched a fact-checking initiative; by April 2020, Google announced a $6.5 million investment to fight misinformation, with an urgent focus on coronavirus. Many other platforms like TikTok and Snapchat have also introduced new policies to counter the spread of misinformation [92] , [93] .

The reluctance of a portion of the population to get vaccinatedvaccine hesitancy -was a major health concern long before the COVID-19 pandemic; in the age of COVID-19, vaccine hesitancy has been characterized as "a leading global health threat" J o u r n a l P r e -p r o o f by WHO [12] . The basis for these low rates of vaccine acceptance within a specific cultural and/or geographic group is usually multi-factorial, and often linked with misinformation or lack of sufficient information regarding vaccines and vaccination, issues related to vaccine efficacy and safety, distrust in government and health organizations, or the sense that personal freedom supersedes the societal need to respond to a global threat [94] - [96] .

Promoting vaccination, especially against COVID-19, requires an understanding of the reasons contributing to such hesitancy. Leading drivers of acceptance of an approved COVID-19

vaccine include individual health concerns, as well as trust in the national health authorities and scientists [97] . Vaccine hesitancy remains a particularly intractable problem and further evaluation, education and research on vaccine acceptance needs to be prioritized, together with efforts to maintain trust in health and political authorities.

Activists against vaccinations, known as anti-vaxxers, have spread a range of conspiracy theories and fake news about vaccines and vaccination, based on distorted information, prior prejudices, lack of scientific knowledge or understanding, and even religion.

These theories include misguided claims about lethal side effects of vaccination, spread of COVID-19 by 5G networks, implantation of 'microchips' during vaccination, or vaccines used as tracking devices. Since anti-vaxxer theories lack any scientific support, protests in many places (Los Angeles, New York, London, Paris, Zagreb, Madrid, Canada and several US states) have ended with physical intimidation and violence. In Los Angeles, a man was stabbed and a reporter attacked at a protest against COVID-19 vaccines; in Canada, Prime Minister Trudeau was hit with gravel thrown by an anti-vaccine protester at a campaign event [98] . Similarly, in Germany and other European countries, doctors have experienced increased abuse in clinics, as well as threats of violence by mail. As a consequence, healthcare workers all over the world are addressing the need for more protection against harassment and threats to their unions [95] , [99] .

Many countries that struggle with low rates of vaccination or vocal anti-vaccination movements have introduced laws that enforce mandatory vaccination. Italy, Hungary, France, Greece, UK, New Zealand, and other countries announced that all health workers need to be vaccinated, and whoever refuses will be suspended. In countries such as Austria, Greece, Italy and Indonesia, vaccination for older people became mandatory and whoever refuses will receive a monetary fine from the local governments. In Singapore, the government will no longer cover the COVID-19 medical bills of unvaccinated people. The

Canadian government announced that unvaccinated workers in the public service and transportation sectors will be placed on administrative leave without pay. In the US vaccination became mandatory for health care workers (to be vaccinated by 4 January 2022), federal J o u r n a l P r e -p r o o f government employees (to be vaccinated by 22 November 2021) and military personnel [100] , [101] . Figure 5 depicts the global distribution of vaccinations throughout the world -the total number of people who are completely vaccinated as described in the initial protocols, divided by the total population of the country. A major discrepancy between developed wealthy Western countries and underdeveloped nations becomes clearly evident. 

Two years into a pandemic that has caused almost 6 million deaths and globally affected all clinical evaluation of a new Omicron-specific mRNA vaccine has already been announced by Pfizer/BioNTech [73] .

Optimism for the future must be tempered however with the realization that a new SARS-CoV-2 variant could appear that evades host antiviral immunity to B cell generated antibodies and T cell-directed adaptive responses. Such a scenario would be devastating to an exhausted population, but a sufficiently high level of global immunization could intervene to mute the emergence and the degree of severity of such a novel variant. At the individual level, two-shot immunity has been shown to protect against Omicron to the level of 68%; recent work indicates that a third booster shot provides maximal protection (>90%) against the risk of severe illness [103] ; as illustrated by Figure 4 , it is unvaccinated individuals that make up the vast majority of current hospitalizations.

Despite the availability of safe and effective vaccines against COVID-19, access to these vaccines remains unequal. High income countries, although representing only 14% of the global population, had purchased 51% of all pre-sold doses by the end of 2020. Some countries bought more vaccine doses than necessary to inoculate 100% of their population. According to the WHO, if the doses were distributed in an equal way, there would be enough vaccine to protect the elderly and health workers worldwide [12] .

WHO had set a goal for all countries to vaccinate at least 10% of their populations by September 2021. Altogether, 56 countries -most of them in Africa -were not able to reach this target. Likewise, many countries remain at risk of missing the WHO target of vaccinating 70% of the population of each country by the middle of 2022. In late November 2021 the WHO published that 'it is vitally important that inequities in access to COVID-19 vaccines are urgently addressed to ensure that vulnerable groups everywhere, including health workers and older persons, receive their first and second doses, alongside equitable access to treatment and diagnostics [12] . Inequalities in vaccine distribution facilitate the emergence of new J o u r n a l P r e -p r o o f variants like SARS-CoV-2 Omicron variant'. As noted countless times in the media over the past two years, vaccination remains the one sure way out of this pandemic. Health care workers, activists, politicians and individuals all need to continue to convey this vital information. At the time of writing, some European countries were beginning to loosen or abandon their lockdown restrictions, with many other countries to follow soon. The sense that we are reaching an endpoint in the pandemic is unmistakable, although it remains to be determined if this is the final curtain or simply an intermission.

The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

SARS-CoV-2 infection: The role of cytokines in COVID-19 disease

COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons

Cytokine storm intervention in the early stages of COVID-19 pneumonia

A critical evaluation of glucocorticoids in the management of severe COVID-19

Are we fully exploiting type I Interferons in today's fight against COVID-19 pandemic?

Interferon, restriction factors and SUMO pathways

Type I and III IFN-mediated antiviral actions counteracted by SARS-CoV-2 proteins and host inherited factors

Interferons and other cytokines, genetics and beyond in COVID-19 and autoimmunity

SARS-CoV-2: Targeted managements and vaccine development

Understanding novel COVID-19: Its impact on organ failure and risk assessment for diabetic and cancer patients

World Health Organization

On the origins of SARS-CoV-2

The origins of SARS-CoV-2: A critical review

The proximal origin of SARS-CoV-2

Identification of novel bat coronaviruses sheds light on the evolutionary origins of SARS-CoV-2 and related viruses

A Novel Coronavirus from Patients with Pneumonia in China

A new coronavirus associated with human respiratory disease in China

SARS-CoV-2 variants, spike mutations and immune escape

Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand, the human ACE2 receptor on binding affinity and kinetics.," eLife

Nextstrain: real-time tracking of pathogen evolution

Nextstrain

The mutation that helps Delta spread like wildfire

Progressive Increase in Virulence of Novel SARS-CoV-2 Variants in Ontario, Canada," medRxiv

How does Omicron spread so fast? A high viral load isn't the answer

SARS CoV-2 Delta variant exhibits enhanced infectivity and a minor decrease in neutralization sensitivity to convalescent or post-vaccination sera

Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation

Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization

Heavily mutated Omicron variant puts scientists on alert

Lab studies, animal studies, and epidemiological data all indicate that Omicron may cause less severe disease than previous variants

From delta to Omicron: S1-RBD/S2 mutation/deletion equilibrium in SARS-CoV-2 defined variants

SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution

Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2

Structural basis for continued antibody evasion by the SARS-CoV-2 receptor binding domain

Some reduction in hospitalisation for Omicron v Delta in England: early analysis

Title: Clinical outcomes among patients infected with Omicron (B.1.1.529) SARS-CoV-2 variant in southern California

Centers for Disease Control and Prevention

Food & Drug Administration

Global Percentage of Asymptomatic SARS-CoV-2 Infections Among the Tested Population and Individuals With Confirmed COVID-19 Diagnosis: A Systematic Review and Meta-analysis

The proportion of sars-cov-2 infections that are asymptomatic: A systematic review

Severe Covid-19

More than 50 Long-term effects of COVID-19: a systematic review and meta-analysis.," medRxiv : the preprint server for health sciences

High-dimensional characterization of post-acute sequelae of COVID-19

Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK

Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19

Attributes and predictors of long COVID

Long covid -Mechanisms, risk factors, and management

Long COVID -metabolic risk factors and novel therapeutic management

Immune determinants of COVID-19 disease presentation and severity

Meeting the challenge of long COVID

Measles

The Global Alliance for Vaccines and Immunization--a millennial challenge

Next-generation peptide vaccines for advanced cancer

Cold Spring Harbor perspectives in medicine

Vaccines for the 21st century

A guide to vaccinology: from basic principles to new developments

Development of SARS vaccines and therapeutics is still needed

Effects of a SARS-associated coronavirus vaccine in monkeys

Immunogenicity of an adenoviral-based Middle East Respiratory Syndrome coronavirus vaccine in BALB/c mice

Tozinameran (BNT162b2) Vaccine: The Journey from Preclinical Research to Clinical Trials and Authorization

The Johnson & Johnson Vaccine for COVID-19

Advances in gene-based vaccine platforms to address the COVID-19 pandemic

Next-generation vaccine platforms for COVID-19

COVID-19 Vaccine Tracker

An interactive website tracking COVID-19 vaccine development

COVID-19 vaccines: key facts

10 Vaccines Approved for Use by WHO

Mix-and-match COVID vaccines ace the effectiveness test

Heterologous prime-boost vaccination

Could mixing COVID vaccines boost immune response?

Association between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity

How COVID vaccines shaped 2021 in eight powerful charts

COVID-19 vaccine makers chase variant-ready vaccines

Efficacy and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection

Potential mechanisms of anaphylaxis to COVID-19 mRNA vaccines

Pfizer's vaccine raises allergy concerns

mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested Approach

Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination

COVID vaccines and blood clots: five key questions

Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From

Myocarditis and Pericarditis After Vaccination for COVID-19

Myocarditis after Covid-19 Vaccination in a Large Health Care Organization

Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection.," Nature medicine

Heterologous Immunity: Role in Natural and Vaccine-Induced Resistance to Infections

Had COVID? You'll probably make antibodies for a lifetime

COVID: Top 10 current conspiracy theories

Infodemics: A new challenge for public health

United Nations

United Nations (UN)

Fighting disinformation

Social-media companies must flatten the curve of misinformation

The COVID-19 social media infodemic

Trust in science, social consensus and vaccine confidence

Self-inflicted wounds

Understanding COVID-19 vaccine hesitancy

Public acceptance of COVID-19 vaccines: cross-national evidence on levels and individual-level predictors using observational data

Trudeau, facing 'anti-vaxxer mobs' on election trail, is met with flying gravel at campaign stop

COVID vaccines: time to confront anti-vax aggression

The case for mandatory vaccination

COVID-19 vaccine mandate for healthcare workers in the United States: a social justice policy

Will Omicron end the pandemic? Here's what experts say

Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel

Our World in Data

Her research is focused on the effect of virus infection on metabolic pathways and the activation of the oxidative stress response. She earned her B.Sc

Julija Mazej is a PhD student in the Department of Molecular Medicine at the University of Sapienza in

Angela Santoni on the research project centering around innate lymphoid cells and their responses in the context of viral infections. She is also an early-stage researcher in the innovative training network INITIATE (innate-immunometabolism as antiviral target) funded by Marie Skłodowska-Curie Actions

The authors thank the students of INITIATE, the Marie Curie International Training Network