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Biancolellaetal. Human Genomics (2022) 16:19
https://doi.org/10.1186/s40246-022-00392-1
REVIEW
COVID-19 2022 update: transition
ofthepandemic totheendemic phase
Michela Biancolella1†, Vito Luigi Colona2†, Ruty Mehrian‑Shai3, Jessica Lee Watt4, Lucio Luzzatto5,6,
Giuseppe Novelli2,7,8,10*† and Juergen K. V. Reichardt9†
Abstract
COVID‑19, which is caused by the SARS‑CoV‑2, has ravaged the world for the past 2 years. Here, we review the current
state of research into the disease with focus on its history, human genetics and genomics and the transition from the
pandemic to the endemic phase. We are particularly concerned by the lack of solid information from the initial phases
of the pandemic that highlighted the necessity for better preparation to face similar future threats. On the other hand,
we are gratified by the progress into human genetic susceptibility investigations and we believe now is the time
to explore the transition from the pandemic to the endemic phase. The latter will require worldwide vigilance and
cooperation, especially in emerging countries. In the transition to the endemic phase, vaccination rates have lagged
and developed countries should assist, as warranted, in bolstering vaccination rates worldwide. We also discuss the
current status of vaccines and the outlook for COVID‑19.
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Introduction
By the end of December 2019, information began to cir-
culate on an alarming form of pneumonia, of unknown
etiology, that was afflicting the district of Wuhan, China.
Two years later, it is of common knowledge that was
the beginning of a pandemic, as declared by the World
Health Organization (WHO) [1], triggered by the new
Severe Acute Respiratory Syndrome Coronavirus-2
(SARS-CoV-2), the causative agent of Coronavirus Dis-
ease 2019 (COVID-19).
While facing the critical times of the manifestation
of a "fourth wave,” amenable to the appearance of new
variants [2–4], there has been exponential growth of
new data. ese data explore the genetics of the virus,
the interaction with the host, as well as short-term and
long-term clinical manifestations. Due to this, we believe
there is need to provide an updated overview to uphold
the commitment made in our latest Editorial [5].
In recent months, we globally experienced a rise in
daily cases, contributing to a total of 527,971,809 cases
and 6,284,871 deaths since the beginning of the pan-
demic (Johns Hopkins University, CSSE, accessed on
2022) [6]. Circulating variants have been supplanted
by the new variant of concern (VOC) SARS-CoV-2
B.1.1.529 (Omicron) and its sub-variants [7, track-
ing website accessed on April 19, 2022], as SARS-
CoV-2 BA.1 and BA.2, which are now dominant in
the USA (Centers for Disease Control and Prevention.
COVID Data Tracker. Atlanta, GA: US Department of
Health and Human Services, CDC; https:// covid. cdc.
gov/ covid- data- track er, accessed on April 19, 2022)
[8] and globally. Characterized by a greater ability to
evade immune responses acquired through infection
with a different strain [9] or through vaccination [10],
this variant seems to be able to change the profile of
current outbreak and, unlike in the previous waves, a
higher rate of reinfections is reported [11, 12]. ese
early data, still under investigation, urge the scientific
Open Access
†Michela Biancolella, Vito Luigi Colona, Giuseppe Novelli and Juergen K.V.
Reichardt contributed equally.
*Correspondence: novelli@med.uniroma2.it
10 Department of Biomedicine and Prevention, School of Medicine
and Surgery, Via Montpellier 1, 00133 Rome, Italy
Full list of author information is available at the end of the article
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Page 2 of 12
Biancolellaetal. Human Genomics (2022) 16:19
community toward the search for therapeutic and
preventive tools that can counter this evolutionary
mechanism.
In our review “COVID-19 one year into the pan-
demic: from genetics and genomics to therapy, vac-
cination, and policy” [13], we strongly claimed the
determining role of vaccines as the most valuable aid
to halt the spreading of SARS-CoV-2. We can now
affirm that the increasing vaccination rate, with a total
of 11.184.961.194 doses administered (Johns Hopkins
University, CSSE, accessed on April 19, 2022) [6], is
contributing to the containment of hospitalizations
and deaths in the population affected by COVID-19
[14–16].
e importance of a homogeneous and universal dis-
tribution of vaccines is becoming more evident and
incisive in hindering the appearance of new variants.
In this regard, the disparities between advanced and
developing countries seem to worsen, and this results
in the inability to cope with new manifestations, as
highlighted by the appearance of the SARS-CoV-2
B.1.1.529 variant [17].
Origin andcurrent state
COVID-19 was first reported in 2019 [18, 19]. It has now
raged worldwide for more than 2years, affecting every
corner of our globe with no clear indication how the pan-
demic started. An intelligible understanding of the ori-
gins of this pandemic is critical to be better prepared in
the future. We lament that a panel proposed by the WHO
in 2021 to achieve this goal has not yet reached signifi-
cant conclusions [20].
While the pandemic is still raging, sprouts of hope
have emerged that we may be transitioning into the
endemic phase [21]. e pervasive Omicron variant, cur-
rently predominant, may lead to this course [22]. How-
ever, overly exuberant enthusiasm must be tempered by
a sense of reality and concern for emerging countries
[21, 23, 24]. Developed countries must remain vigilant
and assist emerging countries in the fight against SARS-
CoV-2, with the aim of detecting new variants of concern
Fig. 1 A comical view of the history of COVID‑19. A few translations: “vorhersehbar” = predictable and “war ja klar” = obviously or sure or of course.
Reproduced with permission (Mira Nagel)
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Page 3 of 12
Biancolellaetal. Human Genomics (2022) 16:19
(Fig.1), investigating animal reservoirs and sharing diag-
nostic tools, surveillance and therapies [25].
Clinical manifestation ofCOVID‑19 andpost‑acute
(long) COVID‑19
It is now known that COVID-19 is a multisystem condi-
tion that largely involves the respiratory system. It starts
as an upper respiratory tract infection that subsequently
affects the lungs and establishes, in the most severe cases,
interstitial pneumonia (showing the diagnostic ground
glass appearance, through CT investigation), severe res-
piratory failure, systemic inflammatory response and
multi-organ dysfunction. Classic symptoms of the dis-
ease are listed as fever, asthenia, dry cough, nasal conges-
tion and breathing difficulties.
Signs and symptoms, however, can affect several
organs. Other systems can be involved, such as the cen-
tral nervous system (hypo-anosmia, loss of the sense
of taste, speech disturbances, dizziness, alterations of
the consciousness and behavior, impaired walking and
maintenance of upright position, impaired hearing and
vision), the cardiovascular system (alterations in hemo-
stasis, arrhythmia, heart failure), the gastrointestinal sys-
tem (nausea, emesis, diarrhea, abdominal pain), the renal
system, neuromuscular (myalgia) and skin adnexa [26].
Clinical manifestation of infection is therefore
extremely heterogeneous, ranging from completely
asymptomatic or paucisymptomatic subjects to criti-
cally ill patients who require hospitalization and venti-
latory support in intensive care unit [27, 28]. Since the
beginning of the pandemic, the medical community has
been aware of the greater susceptibility of patients with
advanced age and comorbidities to the most serious
forms of the disease, but we now know that patients with
a younger age can also be critically affected [29].
Although virus-host interactions have been deeply
investigated [30–32], the mechanisms underpinning a
longer persistence of the symptoms in some patients or
their recurrence (4 to 5weeks, or even 1year) after the
resolution of the disease remain to be understood [33].
e persistence of fatigue, headache, and anosmia, the
onset of anxiety and a depressive state are symptoms that
have recently been included in the so-called post-acute
(long) COVID-19 [26, 33, 34].
Like COVID-19, post-acute (long) COVID-19 is con-
figured as a systemic disease and therefore symptoms
are extremely varied and of difficult clinical interpreta-
tion. ey can occur singly or in combination, they can
be transient, intermittent or constant, and they can even
change over the course of the condition.
e systems involved in post-acute (long) COVID-19
are mainly respiratory, musculoskeletal, cardiovascular
and neurological [35].
Given the predominantly respiratory nature of the con-
dition, lungs are the organs susceptible to the most severe
outcomes, not only on a structural level (e.g., secondary
interstitial fibrosis, pulmonary hypertension) [36, 37], but
also on a functional level (e.g., reduced ventilatory capac-
ity, dyspnea, fatigue) [37–39].
Respiratory sequelae have inevitably been shown to
have repercussions at neuromuscular levels. In fact, dys-
functions of both respiratory and skeletal muscles have
been described in about 40% of patients admitted to
intensive care units, resulting in persistent symptoms of
fatigue, weakness and shortness of breath [40–42]. Fur-
thermore, it has been hypothesized that a direct muscle
affection of SARS-CoV-2 may be responsible for struc-
tural alterations, even in patients who have had an appar-
ently mild disease outcome [43].
e heart has been shown to be a target organ of the
systemic inflammatory response and subject to direct
damage from SARS-CoV-2 [35]. Specifically, the most
described cardiovascular complications refer to heart
failure, arrhythmias, peri-myocarditis, venous and arte-
rial thromboembolism and “reverse Tako-Tsubo” cardio-
myopathy [35, 44, 45].
Approximately 25% of patients who developed
COVID-19 experienced neurological disorders of vari-
ous degrees in the months following diagnosis [46]. e
most common and mild symptoms include headache
[47], disturbances in perception of taste and smell [48–
50], “brain fog” and memory disorders [51]. Among the
major complications, however, those mostly described
were the presence of diffuse brain damage of inflam-
matory [52] or acute metabolic origins (toxic-metabolic
encephalopathies) [53], Guillain-Barré syndrome [54,
55], Miller-Fisher syndrome [56], ischemic vasculitis [57],
dysautonomic dysfunctions [55, 58, 59] and seizures. In
addition to these complications. we urge the scientific
community to deeply investigate mood disorders that
might develop on a psychological substrate in response to
stressors established during the pandemic period [46, 52,
60, 61]. Various mechanisms may underlie the neurologi-
cal implications of SARS-CoV-2 [35, 62]. e systemic
inflammatory response triggered in COVID-19 patients
could potentially accelerate the evolution of neurodegen-
erative processes by exacerbating chronic conditions pre-
sent at the time of infection but not yet manifest [35, 63,
64]. For example, the inflammatory response could exac-
erbate a refractory epileptic condition [65]. Several stud-
ies also reported direct damage of the brain tissue caused
by SARS-CoV-2 infection [35, 66, 67].
In a novel, quantitative, longitudinal imaging study
from Douaud et al. [68], authors analyzed brain scans
of 401 SARS-CoV-2 positive cases, acquired at two time
points (before and after testing positive for infection),
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Page 4 of 12
Biancolellaetal. Human Genomics (2022) 16:19
and 384 matching controls. Following the description of
hundreds of derived phenotypes, the comparison pro-
vided suggestions as to what could be further investigated
as effect caused by, or attributable to, the SARS-CoV-2
infection. A clear involvement of the olfactory cortex has
been detected through variations in tissue damage mark-
ers. e evaluation of gray matter decrease showed FDG
(fluorodeoxyglucose) hypometabolism in the orbitofron-
tal cortex, insula, parahippocampal gyrus, and anterior
cingulate cortex, suggesting a significant implication of
the regions connected to the piriform cortex. In conclu-
sion, the effect of reduction in the gray matter appears to
be generalized, with a greater relevance at the level of the
olfactory system.
However, to date, knowledge of the molecular mecha-
nisms and neurological consequences in the post-acute
(long) COVID-19 is still limited [69, 70].
In a broad sense, it has been hypothesized that post-
acute (long) COVID-19 can be considered a condition
characterized by a chronic persistence of low levels of
inflammatory cytokines [71]. According to this asser-
tion, it is likely that the activation of some cellular tran-
scription factors, including the nuclear factor erythroid
2 (NFE2)-related factor 2 (Nrf2), a possible therapeutic
target in several chronic neurodegenerative conditions
[72–74], may have a role in increasing the expression of
enzymes capable of synthesizing glutathione, therefore
reducing the state of oxidative stress [71, 74, 75]. How-
ever, further data and trials are needed [76].
A recent study highlighted a significant formation
of blood micro-clots, both in the acute phase and in
the post-illness phase. ese micro-clots seem to show
resistance to the body’s fibrinolytic processes in patients
suffering from post-acute (long) COVID-19. Preliminary
results demonstrated the efficacy in reducing the symp-
toms of long COVID-19 patients through the administra-
tion of antiplatelet or anticoagulant therapy [77].
Understanding the signs and symptoms of the disease
and of post-acute (long) COVID-19 represents a major
current therapeutic challenge. is will allow us, in the
near future, not only to better elucidate the molecu-
lar mechanisms of our body’s response to SARS-CoV-2
infection, but also to identify therapeutic targets for an
increasingly personalized medicine.
Genetic susceptibility inthehost
Viruses, like other pathogens, are necessary, but not suffi-
cient, to trigger disease [78]. It therefore appears evident
that the individual host genome plays a fundamental role,
not only in the susceptibility to disease induced by the
infectious agent, but also in the individual response in
terms of severity of the phenotype or resistance to infec-
tion [78]. Numerous host genes have been identified in
the last two years that are active in susceptibility/resist-
ance to infectious diseases [5, 13, 79–81]. Identifying
and qualifying these genes as prognostic and predictive
biomarkers is crucial to optimize patient management
and promote sustainable and rational public health (PH)
interventions. In addition, they contribute to clarify the
mechanisms and variability of the SARS-CoV-2 host–
pathogen interactions [81].
Common and rare variants have been identified in
different studies using a) classical Genome-Wide Asso-
ciation Studies (GWAS) and b) deep sequencing of
genes coding for protein referable to precise biochemi-
cal pathways involved in the pathogenesis of the infec-
tion. ese studies have made it possible to identify
alleles of increased susceptibility and/or partial resist-
ance to the COVID-19, in coding and non-coding
regions of genes. For example, a functional analysis of a
SNP (rs11385942), identified by GWAS on chromosome
3p21.31, demonstrated the involvement of the LZTFL1
protein (leucine zipper transcription factor like 1) [82],
which regulates ciliary localization in the BBSome com-
plex. is gene is mutated in Bardet-Biedl Syndrome
(BBS) (MIM#209,900), a ciliopathy characterized in
part by polydactyly, obesity, cognitive impairment,
hypogonadism, and kidney failure. LZTFL1 is highly
expressed in ciliated cells, including airway ciliated cells.
Its reduced expression leads to fewer airway ciliated
cells with shorter cilia, which could result in inefficient
viral airway clearance in COVID-19 patients. Similarly,
the SNP rs74956615, which maps on the chromosome
19p13.2 in the untranslated 3’ of the RAVER1 gene [82],
has been found to modulate the expression of RAV ER1
itself. is gene encodes for a ribonucleoprotein which
cooperates with cytoskeletal proteins vinculin/metavin-
culin and alpha-actinin to modulate alternative splicing
events. However, RAVER1 is a co-activator of MDA5
(IFIH1), which recognizes nucleic acids associated with
viral infections such as dsRNAs, including SARS-CoV-2,
and activates antiviral response genes, including IFNB1,
ICAM1, TNF and CCL5. A large human genetic study,
involving more than 49,000 COVID-19-affected individ-
uals and 2 million control subjects, identified 13 loci in
the human genome that affect COVID-19 susceptibility
and severity including 6 loci previously not reported [83].
In the regions mapped by this extensive GWAS, authors
identified more than 40 candidate genes, several of which
are involved in immune function or have known func-
tions in the lungs, suggesting that these may have impor-
tant effects on COVID-19. A suggestive susceptibility
locus on chromosome 12q22, has been recently detected
in ai population [84]. Genes mapped in this area
include EEA1 and LOC643339. EEA1 is involved in viral
entry into cells, while LOC643339 is a long non-coding
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Page 5 of 12
Biancolellaetal. Human Genomics (2022) 16:19
RNA. Intriguingly, EEA1 is involved in the entry of Afri-
can Swine Fever Virus via endosomal pathway [85]. Uti-
lizing a Phenome-Wide Association Study (PheWAS)
approach, Regan and Colleagues [86] identified novel
phenotypic associations with genes encoding proteins
active in the antiviral response and inflammatory pro-
cesses. ese genomic biomarkers can have pleiotropic
effects in COVID-19-related comorbidities (cardiovascu-
lar disease, autoimmune disease, arthropathy and endo-
crinopathy), which in turn increase the risk of severe
COVID-19.
Finally, a recent GWAS meta-analysis that considered
125,584 cases and over 2.5 million controls evaluating 60
studies from 25 countries included 11 new significant loci
at the genome level, in addition to those previously iden-
tified. Genes in the new loci include SFTPD, MUC5B and
ACE2, revealing convincing information on the suscepti-
bility and severity of the disease [83].
Candidate-gene approach, on the other hand, made it
possible to confirm and integrate the role of some specific
pathways and proteins in the pathogenesis of the disease.
Among the first candidate genes studied in SARS-CoV-2
infection were those coding for the HLA system, which
plays a crucial role in the immune response [87, 88].
Several studies have highlighted risk alleles capable of
influencing the clinical course of patients infected with
various RNA viruses (e.g., H1N1 influenza virus [89],
Hantaan virus [90] and SARS-CoV-1 [87]). Several stud-
ies have highlighted HLA alleles of susceptibility to
SARS-CoV-2 [28, 91]. However, these studies revealed
discrepancies due to different stratifications of patients
and controls and to the different frequency distribution
of the HLA alleles in the populations analyzed. Recently, a
large and accurate study described a potential association
of HLA-C*04:01 with severe clinical course of COVID-
19. Carriers of HLA-C*04:01 had twice the risk of need-
ing intubation when infected with SARS-CoV-2 [92].
Numerous other candidate genes have been analyzed on
the basis of their biological function during infection,
such as ACE2, TMPRSS2, DPP4, andFurin,involved in
the entry of the virus into cells, or genes active in the viral
egress such as WWP1 and NEDD4 [93–97]. Curiously, an
association of VDR gene polymorphisms with COVID-
19 outcomes has been also detected [98]. e possi-
ble involvement of this receptor is supported by recent
studies that provided evidence for an altered vitamin D
gene signature in CD4 + T lymphocytes in patients with
severe COVID-19. Chauss and colleagues [99] demon-
strated that severe COVID-19 may result from a dys-
function of type I immune response, that involves the
vitamin D receptor (VDR) signaling. Similarly, it is inter-
esting to observe how individuals with African descent,
homozygous for the G1 or G2 variant of apolipoprotein
L1 (APOL1), have an increased risk of acute kidney dis-
ease compared to subjects with low-risk variants [100]. A
recent study revealed an association of phenotype sever-
ity and polymorphisms of the MBL2 gene, which encodes
a mannose-binding lectin (MBL) secreted by the liver
and involved in innate immune defense [101]. Innate
immunity is our immune system’s first line of defense
and plays a central role in SARS-CoV-2 infection [102].
Although studied for over 100years, only in recent years
has significant progress has been achieved, largely due to
the genetic dissection of innate immune pathways [103].
Several clinical and immunological studies have shown
that type I interferons (IFN-I) play critical roles in the
control and pathogenesis of COVID-19 [81, 104–107].
is notion is supported by extensive sequencing of
numerous patients with severe forms of COVID-19 that
identified pathogenic mutations in genes encoding active
proteins in the interferon circuit [81]. e characteriza-
tion of autoantibodies capable of neutralizing IFN-I in
10–15% of severe patients allows us to state that COVID-
19 can be defined as an interferonopathy [108].
Identifying susceptibility alleles in COVID-19 is impor-
tant in order to improve predictive testing and stratify
different subgroups of SARS-CoV-2 positive subjects,
which can be treated in a personalized way. However, it is
possible that in a complex multifactorial and multigenic
disease, such as COVID-19, several genetic, epigenetic
and socio-demographic factors are modulating the phe-
notypic manifestation, thus complicating the analysis of
genotype–phenotype correlations [32].
Interestingly, the CHGE Consortium (Covid Human
Genetic Effort, https:// www. covid hge. com/ about) initi-
ated a study to enroll individuals (referred to as “resist-
ant”) who were not infected with SARS-CoV-2 despite
repeated exposure (e.g., care-givers or familiars of a
patient with severe pneumonia), as evidenced by the
absence of the disease and virus specific antibody titers
in several tests [81, 106, 108–111]. It is conceivable that
these subjects carry monogenic variations that make
them naturally resistant to virus entry, or much more
active in eliminating the virus by activating appropriate
defense mechanisms such as the genes of the interferon
circuit. Interestingly, a splice variant of OAS1 gene, which
appears to have a protective effect, has been identified
frequently in people of African ancestry [112]. OAS1
encodes for an enzyme catalyzing the synthesis of short
polyadenylates, which activate ribonuclease L that in turn
degrades intracellular double-stranded RNA and triggers
several other antiviral mechanisms [113].
Using trans-ancestry fine-mapping approaches,
Huffman et al. [114] recently demonstrated that the
rs10774671-G splice variant determines the length of the
protein encoded by the gene OAS1, which results in an
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Biancolellaetal. Human Genomics (2022) 16:19
enzyme more effective at breaking down SARS-CoV-2.
It is important to clarify that the genes of susceptibility
to pathogens, although of biological and genetic interest,
cannot in any way confer a sort of “natural immunity” to
infection at an individual level and cannot replace the
important protective role offered by vaccines.
Certainly several “resistance” alleles of genes involved
in the different pathways activated by the infection of
SARS-CoV-2 will be identified in the next months [80, 95,
112]. However, until it is possible to develop polygenic
scores programs which must then be validated on large
numbers, it is unlikely that they can be used to identify
resistant subjects and direct them to selective and spe-
cific therapeutic treatments. ese studies have made it
possible to elucidate many aspects of the pathogenesis of
COVID-19 and have provided many biological responses
to the pathogen-host relationship that could prove
important in other viral infections [81]. In this regard, it
seems interesting to report a recent study that correlates
the loss of smell or taste, very frequent in COVID-19, to
variants of the UGT2A1 and UGT2A2 genes expressed in
the olfactory neuroepithelium, which lines the posterior
nasal cavity, and is exposed to a wide range of odorants
and compounds present in the air [115].
e locations of investigated genes of interest are
resumed in Fig.2 [5, 116].
Characteristics ofavailable vaccines
While witnessing an exponential progress in studies
aimed at understanding genetic and molecular mecha-
nisms, we see their direct application in the tools which
are currently the best candidates to lead us out of this
pandemic: vaccines.
Since the beginning, several critical issues emerged
which led to base the development of vaccines on safety,
immunogenicity, durability of the immunity, dosing
schedule, technological platform and ease of manufac-
ture and transport.
Despite a widespread mistrust about safety and speed
of production, nowadays, we can benefit of two types of
vaccines against SARS-CoV-2 and of a growing number
of data that support their efficacy and safety. Two mes-
senger RNA (mRNA) (BNT162b2 and mRNA-1273)
and two viral vector (ChAdOx1 nCoV-19 AZD1222 and
MRPS21
DPP4
IFIH1
ITGA4
SCN5A
SLC6A20
LZTFL1
GYG1
UGT2A1
UGT2A2
TLR3
ERAP2
HLA
complex
NOTCH4
CCHCR1
TREM1
FOXP4
BRF2
WWP1
TMEM65
IFNB1
C9orf72
EXOSC2
ABO
MBL2
SFTPD
UNC93B1
IFITM3
IRF7
MUC5B
VDR
KLRC2
TBK1
LOC643339
EEA1
OAS1
NEDD4
FURIN
ACE
MAPT
CCL5
ALOXE3
APOE
PLEKHA4
IRF3
NR1H2
DPP9
TICAM1
ICAM1
RAVER1
TYK2
IFNAR2
IFNAR1
KCNE1
TMPRSS2
APOL1
TNFRSF13C
TLR7
ACE2
Fig. 2 Chromosome ideogram representing the location of genes of interest investigated for a role in defining susceptibility to SARS‑CoV‑2
infection (generated by ensembl.org [116])
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Page 7 of 12
Biancolellaetal. Human Genomics (2022) 16:19
Ad26.COV2.S) COVID-19 vaccines were developed
[117]. A third type, protein subunit vaccines (NVX-
CoV2373), has been approved by EMA, Indonesia,
Australia and South Korea, while is still lacking a full
approval by the FDA.
Findings show that the Pfizer/BioNTech BNT162B2
vaccine is safe, with very rare incidence of myocardi-
tis and swelling of the lymph nodes while coronavirus
infection is associated with numerous serious adverse
events such as increased risk of pericarditis, arrhythmias,
heart attacks, strokes, pulmonary embolism, deep-vein
thrombosis, acute kidney damage, and others [118]. e
BNT162b2 COVID-19 vaccine has been shown to reduce
viral load of breakthrough infections (BTIs), but its effec-
tiveness declines after the third to fourth month [119].
e appearance of new SARS-CoV-2 variants poses
new challenges for the development of vaccination plat-
forms [120]. As a consequence, mRNA booster vaccines
were developed to restore the viral neutralization activ-
ity that wanes after the initial two-dose vaccination, to
maintain protection against emerging variants and to
increase vaccine effectiveness in low immune response
individuals such as elderly or immune suppressed. e
need for multiple doses of the vaccine has sparked new
debates, but evidence shows that vaccination with two
doses of mRNA-1273 (Moderna) and a booster are safe
and effective [121]. Moreover, the effectiveness of a third
BNT162b2 vaccine booster was demonstrated in both
reducing transmission and severe disease [122].
As previously stated, we are now aware that higher age
and comorbidities are risk factors for poor outcomes,
regardless of vaccination status [123, 124].
Among adolescents aged 16–17 years, 2-dose mRNA
vaccine effectiveness increased to 86% a week days after
booster dose and urgent care hospitalizations were sub-
stantially lower during the Omicron period than dur-
ing the B.1.617.2 (Delta) predominant period among
adolescents aged 12–17 years, with no significant pro-
tection ≥ 150 days after dose 2 during Omicron pre-
dominance [125]. An increasing number of studies are
focusing on the efficacy of multiple doses in fragile cat-
egories: cancer patients receiving at least two doses of
COVID-19 vaccine show reduced risk of COVID-19
[126]. Despite diffused concerns, it has now been estab-
lished that the BNT162b2 and Ad26.COV2.S vaccines
can be safely administered during the third trimester of
pregnancy, reporting excellent results in terms of immu-
nogenicity [127].
e majority of vaccinated patients who required hos-
pitalization due to COVID-19 were elderly with a high
comorbidity burden thus being unable to develop a
proper immune response following vaccination [128].
CDC recommends that all persons aged 12 years and
older receive a booster dose of COVID-19mRNA vac-
cineat least 5months after completing the primary vac-
cination series (at least 2 months after receiving J&J/
Janssen COVID-19 vaccination) and that adults 50years
and older, and moderately or severely immunocompro-
mised people, if eligible, should receive a second booster
dose at least 4months after the previous one.
Vaccines impact on containing the pandemic escala-
tion is evident [129]. eir effectiveness is clearly dose-
dependent as it is higher after administration of a third
dose compared to a second dose administration; how-
ever, vaccine effectiveness wanes with time [129]. For this
reason, and because of the emerging variants that might
overtake the currently available vaccines, the develop-
ment of new vaccines, including variant-specific ones,
should be encouraged and strongly supported. As of
April 15, 2022, 153 vaccines are listed in clinical devel-
opment and 195 in pre-clinical development (WHO,
https:// www. who. int/ publi catio ns/m/ item/ draft- lands
cape- of- covid- 19- candi date- vacci nes, accessed on April
15, 2022) [130].
Outlook
At the official age of about 3years, SARS-CoV-2 is no
longer a baby, but it has proven a rather vicious toddler.
Although ascribing intentions to a virus is naively anthro-
pomorphic, we have to admit that it has managed to cut
short the lives of many fellow-human beings, to change
our ways of relating to each other, to subvert economies,
to shift the priorities of pharmaceutical industry and of
regulatory bodies. With respect to biomedical and pub-
lic health research, as of May29, there are 262,077,248
papers on COVID-19 listed in PubMed, but later tonight
there will be more; and when we wish to discuss science,
we pretend that meeting on line is just as good as being
together in a seminar room – but it is not true.
From the evolutionary point of view, it has been a long-
held tenet of parasitology that for a parasite what is at a
premium is not to kill the host; rather, to have the host
producing the maximum amount of parasite progeny.
SARS-CoV-2 is a perfect illustration. e people infected
have been at least half a billion: Mortality has been there-
fore high in absolute numbers, but at least 98% infected
people have survived and have helped to spread the virus.
Since the beginning of the pandemic, there have been
thousands of mutations in the virus, most of them bio-
logically neutral; at the moment, the predominant Omi-
cron variant seems to be a compromise between high
infectivity and relatively low mortality: Seen from the
vantage point of the virus, the compromise is good, but
not necessarily optimal as yet.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 8 of 12
Biancolellaetal. Human Genomics (2022) 16:19
e wealth of studies that have explored the genetic
variation in host susceptibility to SARS-CoV-2 is impres-
sive. ere seem to be genetic factors that affect the
probability of contracting the infection; and many stud-
ies have naturally preferred to focus on genetic factors
that may allow the disease to become severe and life-
threatening. We must admit that we have not yet hit the
jackpot: Nobody has found a human genotype that bars
infection, as homozygosity for the delta 32 allele of the
CCR5 gene does for HIV [131]. Perhaps this is not alto-
gether surprising: For an infectious agent to select a pro-
tective gene, it requires exposure to be continuous over
the host’s many generations [132], as has been the case
for P falciparum and the hemoglobin S gene [133]. If the
postulated jump of SARS-CoV-2 into the human species
has been very recent, there has been no time for selection
of people having an originally rare mutant gene.
In last year’s update [13], we did briefly speculate about
the apparently low numbers of COVID-19 cases in tropi-
cal Africa, and according to the WHO dashboard, this is
still the case. In the two countries, we know best, there
have been, officially, in Nigeria (population over 200 mil-
lion) 119,322 cases and 1926 deaths to date; in Tanzania
(population around 60 million), which for over a year has
not reported cases, there are now on record 33,726 cases
and 800 deaths. We do not yet know to what extent these
low figures are due to underestimation; but from recent
visits, we know that health workers are vaccinated. As for
people in general, what we have learned to my surprise is
that vaccine availability is not currently a limiting factor:
Even when vaccination is free, uptake is quite low.
Anti-COVID-19 vaccination has been a success of
technology and, in many countries, of public health cam-
paigns. Some of us never thought that an effective vac-
cine could be designed, produced and field-tested within
one year: but we have to stand corrected. In retrospect,
the notion of using RNA to immunize against an RNA
virus seems straightforward: Ugur Sahin and Ozlem
Tureci deserve full scientific credit (in addition to many
€ millions in revenue) for what they have achieved. With
most previous vaccines, peptides derived from the organ-
ism or from the purified protein injected are presented to
T cells by Antigen Presenting Cells (APC). In this case,
instead, nanoparticles that encapsulate the portion of the
viral RNA that encodes the spike protein are endocytosed
by the APCs, whose protein synthetic machinery is taken
over to translate the RNA into the spike protein, peptides
from which are then presented to T cells. A key to the
ultra-fast development of the BioNTech vaccine has been
this clever approach: Since it was unprecedented, nobody
was entitled to predict (i) How it would work in prac-
tice, (ii) What would be the duration of immunity. With
respect to (i) e results have been spectacular; with
respect to (ii) One had to find out the answer empirically,
and it turned out that, even after two doses, the dura-
tion is of the order of months, not years. Only the oldest
among us can remember that when mRNA was discov-
ered, one of its defining properties was a short life span
[134]: It seems not far-fetched to hypothesize that the
takeover of the APC’s ribosomes by SARS-CoV-2 mRNA
is short-lived, and this may be at least one reason why
immunity does not last very long.
Unlike the COVID-19 epidemic, the epidemic of no-
Vax does not lend itself to mathematical analysis: It is
not in the realm of biological science, but rather in the
realm of psycho-patho-sociology [135]. We have all
learnt that evidence-based reasoning does not make a
dent in the hard-core no-Vax. Confrontation fails, and
an approach based on lateral thinking may be better.
Perhaps we should take this on as an intellectual chal-
lenge: If we can largely prevent severe COVID-19 by
immunization, if we can find the molecular basis of
many diseases, if in many cases we can cure leukemia,
we should be able to also address the no-Vax problem.
Abbreviations
ACE2: Angiotensin‑converting enzyme 2; APC: Antigen presenting cells;
APOL1: Apolipoprotein L1; BBS: Bardet‑Biedl syndrome; CCL5: CC‑chemokine
ligand 5; CDC: Centers for disease control and prevention; CHGE: Covid human
genetic effort; COVID‑19: Coronavirus disease 2019; CSSE: Center for systems
and software engineering; CT: Computed tomography; DPP4: Dipeptidyl
peptidase 4; EEA1: Early endosomal antigen 1; EMA: European medicines
agency; FDA: Food and drug administration; FDG: Fluorodeoxyglucose; GWAS:
Genome‑wide association study; H1N1: Hemagglutinin type 1 and neurami‑
nidase type 1; HLA: Human leukocyte antigens; ICAM1: Inter‑cellular adhesion
molecule 1; IFN: Interferon; IFNB1: Interferon beta 1; LZTFL1: Leucine zipper
transcription factor like 1; MBL: Mannose‑binding lectin; MDA5: Melanoma
differentiation‑associated rotein 5; MUC5B: Mucin protein 5B; NEDD4: Neural
precursor cell expressed developmentally down‑regulated protein 4; NFE2:
Nuclear factor erythroid 2; NRF2: Nuclear factor erythroid 2 (NFE2)‑related
factor 2; OAS1: 2’‑5’‑Oligoadenylate synthetase 1; PH: Public Health; PheWAS:
Phenome‑wide association study; RAVER1: Ribonucleoprotein PTB‑binding
1; SARS‑CoV‑2: Severe acute respiratory syndrome coronavirus‑2; SFTPD:
Surfactant protein D; SNP: Single nucleotide polymorphism; TMPRSS2:
Transmembrane serine protease 2; TNF: Tumor necrosis factor; UGT2A: UDP‑
glucuronosyltransferase 2A; VDR: Vitamin D receptor; VOC: Variant of concern;
WHO: World health organization; WWP1: WW domain containing E3 ubiquitin
protein ligase 1.
Acknowledgements
We thank Mira Nagel for permission to reproduce the cartoon presented in
Figure 1. We are grateful for the assistance given by Dr. Francesca Pisanu for
her help with the editing and organization of the manuscript.
Author contributions
JKVR conceived the manuscript, wrote the historical and transition part and
edited the paper. JLW edited the manuscript. VLC wrote the introduction and
clinical manifestations sections, conceived and edited Fig. 2, and revised the
manuscript. GN and MB wrote the genetic susceptibility part, conceived Fig. 2
and revised the paper. LL wrote the outlook section and performed review
and revision of the paper. RMS wrote the characteristics of available vaccines
paragraph. All authors read and approved the final version of the manuscript.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 9 of 12
Biancolellaetal. Human Genomics (2022) 16:19
Funding
This study was also supported in part by a grant of Regione Lazio (Italy, Pro‑
getti di Gruppi di Ricerca 2020 A0375‑2020–36663 GecoBiomark) and Rome
Foundation (Italy, Prot 317A/I) to GN.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or
analyzed during the current study.
Declarations
Competing interests
The authors declare that they have no competing interests.
Author details
1 Department of Biology, Tor Vergata University of Rome, Rome, Italy.
2 Department of Biomedicine and Prevention, Tor Vergata University of Rome,
00133 Rome, Italy. 3 Sheba Medical Center, Pediatric Hemato‑Oncology,
Edmond and Lilly Safra Children’s Hospital, Tel Hashomer 2 Sheba Road,
52621 Ramat Gan, Israel. 4 College of Public Health, Medical and Veterinary
Sciences, James Cook University, Smithfield, QLD 4878, Australia. 5 Depart‑
ment of Haematology and Blood Transfusion, Muhimbili University of Health
and Allied Sciences, Dar es Salaam, Tanzania. 6 University of Florence, Florence,
Italy. 7 IRCCS Neuromed, Pozzilli, Isernia, Italy. 8 Department of Pharmacology,
School of Medicine, University of Nevada, Reno, NV, USA. 9 Australian Institute
of Tropical Health and Medicine, James Cook University, Smithfield, QLD 4878,
Australia. 10 Department of Biomedicine and Prevention, School of Medicine
and Surgery, Via Montpellier 1, 00133 Rome, Italy.
Received: 22 March 2022 Accepted: 26 April 2022
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