COVID-19 one year into the pandemic: from genetics and genomics to therapy, vaccination, and policy

Abstract

COVID-19 has engulfed the world and it will accompany us all for some time to come. Here, we review the current state at the milestone of 1 year into the pandemic, as declared by the WHO (World Health Organization). We review several aspects of the on-going pandemic, focusing first on two major topics: viral variants and the human genetic susceptibility to disease severity. We then consider recent and exciting new developments in therapeutics, such as monoclonal antibodies, and in prevention strategies, such as vaccines. We also briefly discuss how advances in basic science and in biotechnology, under the threat of a worldwide emergency, have accelerated to an unprecedented degree of the transition from the laboratory to clinical applications. While every day we acquire more and more tools to deal with the on-going pandemic, we are aware that the path will be arduous and it will require all of us being community-minded. In this respect, we lament past delays in timely full investigations, and we call for bypassing local politics in the interest of humankind on all continents.

Full text

R E V I E W Open Access
COVID-19 one year into the pandemic:
from genetics and genomics to therapy,
vaccination, and policy
Giuseppe Novelli
1,2,3*
, Michela Biancolella
4
, Ruty Mehrian-Shai
5
, Vito Luigi Colona
1
, Anderson F. Brito
6
,
Nathan D. Grubaugh
6
, Vasilis Vasiliou
7
, Lucio Luzzatto
8
and Juergen K. V. Reichardt
9
Abstract
COVID-19 has engulfed the world and it will accompany us all for some time to come. Here, we review the current
state at the milestone of 1 year into the pandemic, as declared by the WHO (World Health Organization). We
review several aspects of the on-going pandemic, focusing first on two major topics: viral variants and the human
genetic susceptibility to disease severity. We then consider recent and exciting new developments in therapeutics,
such as monoclonal antibodies, and in prevention strategies, such as vaccines. We also briefly discuss how
advances in basic science and in biotechnology, under the threat of a worldwide emergency, have accelerated to
an unprecedented degree of the transition from the laboratory to clinical applications. While every day we acquire
more and more tools to deal with the on-going pandemic, we are aware that the path will be arduous and it will
require all of us being community-minded. In this respect, we lament past delays in timely full investigations, and
we call for bypassing local politics in the interest of humankind on all continents.
Keywords: Coronavirus, SARS-CoV-2, COVID-19, Pandemic, Variants, Vaccines, Monoclonal antibodies, Politics
Introduction
The coronavirus disease 2019 (COVID-19), caused at in-
dividual level by the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), has raged for a year now,
as declared by the WHO (World Health Organization)
[1]. By March 31, 2021, more than 125 million cases of
SARS-CoV-2 infection have been reported, causing 2,
816,081 deaths in 192 countries (Johns Hopkins Univer-
sity, CSSE). About the Coronavirus Treatment Acceler-
ation Program (CTAP), there are more than 590 drug
development programs in planning stages (i.e., antivirals,
immunomodulators, cell and gene therapies, compound
combinations and other active principles, vaccines
excluded), more than 430 clinical trials reviewed by FDA
(Food and Drug Administration) with a total of 9
COVID-19 treatments currently approved for use under
Emergency Use Authorization (EUA) (https://www.fda.
gov/drugs/coronavirus-covid-19-drugs/coronavirus-
treatment-acceleration-program-ctap, accessed on
March 31, 2021) [2]. Due to socioeconomic inequalities,
such clinical trials are mainly conducted in/by institu-
tions in high income countries. Disparities also impose
large limitations on low/mid income countries, which
are often unable to cope with high demands for molecu-
lar testing, variant surveillance, vaccine distribution, or
to address the needs of their citizens for financial aid, to
survive amid tough epidemic control measures. This
shows that the effects of this pandemic may well be far-
reaching and long-lasting. The central role and responsi-
bility of the UN (United Nations) and specifically of the
WHO are paramount. The very word pandemic means
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* Correspondence: novelli@med.uniroma2.it
1
Department of Biomedicine and Prevention, “Tor Vergata”University of
Rome, 00133 Rome, Italy
2
IRCCS Neuromed, Pozzilli, IS, Italy
Full list of author information is available at the end of the article
Novelli et al. Human Genomics (2021) 15:27
https://doi.org/10.1186/s40246-021-00326-3
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that it cannot be confronted by measures that are only
at the level of a region, or of a country, or even of a con-
tinent: global measures are absolutely needed.
On the origin of the COVID-19 pandemic
We note that last year already the WHO set up a panel
to investigate the origin, preparedness, and response to
theCOVID-19pandemic(https://www.who.int/news/
item/09-07-2020-independent-evaluation-of-global-
covid-19-response-announced)[3]. Regrettably, there
has been only limited progress and the origin of the pan-
demic has not been definitively pinned down (https://
www.sciencemag.org/news/2021/03/compromise-who-
report-resolves-little-pandemic-s-origins-details-probe-s-
next-steps)[4]. All of us, whether directly affected pa-
tients or not, should be concerned by such astounding
delays, since it is of immense common interest for all to
be best prepared for the next pandemic that will inevit-
ably befall us eventually. We lament these delays and we
call for expeditious, effective, and scientifically rigorous
action by the WHO and the UN. We are not suggesting
that these delays are politically motivated: but we are
anxious for these organizations to show clear evidence
that they are driven at all times by their feeling of re-
sponsibility toward all humankind. As scientists who are
also citizens from around the world, we wish to be able
to say that they are now acting more nimbly and self-
assuredly. We also wish to highlight the importance of
being mindful that emerging nations that will need
thoughtful assistance in order to face the immediate
health crisis, as well as the economic recovery thereafter:
they need improved and more resilient health systems
on a medium to long-term basis, as well as food security.
In this context, a critical role should be played by other
international organizations such as the EU (European
Union) and notably the FAO (Food and Agriculture
Organization of the UN). However, other regional orga-
nizations, such as ASEAN (Organization of Southeast
Asian States), the AU (African Union), and the OAS
(Organization of American States), should also play a
significant and culture-sensitive role in their respective
geographic areas.
Virus variants
An important reason of concern for all countries is the
emergence of virus variants as a result of mutation(s)
during the current pandemic. RNA viruses, such as
SARS-CoV-2, despite being endowed with proofreading
activity during viral replication [5], have a high mutation
rate, and the absolute number of mutations increases
with every round of infection [6]. The average evolution-
ary rate of SARS-CoV-2 is ~0.8 × 10
−4
substitutions per
site per year, which equals about 2 substitutions (“muta-
tions”) per month. Mutations that are deleterious or
even lethal to the virus will be purged from the popula-
tion, and we do not need to worry about those. Many
mutations are essentially neutral, and are maintained in
the population: they may not readily promote functional
changes, but they may facilitate adaptation upon changes
in the environment explored by viruses [7,8]. However,
a few mutations may be beneficial to the virus [9] be-
cause they lead to (i) increased transmissibility; (ii)
higher infectiousness, (iii) higher virulence entailing
higher rate of severe disease; (iv) immune/vaccine es-
cape; or (v) any combination of the above.
Up to March 31, 2021, nearly 1 million (931,463)
SARS-CoV-2 genomic sequences were submitted to the
GISAID, the main database used by researchers in the
field (https://www.gisaid.org)[10] (Fig. 1, Table S1).
SARS-CoV-2 variants identified are heterogeneously dis-
tributed in geographic areas of the world (see https://
nextstrain.org/ncov/global)[11,12]. Variants of SARS-
CoV-2 may adapt differently to the host under individual
selective pressures [7]; some mutations may increase in
frequency, either through genetic drift or through selec-
tion, and become fixed in different populations [6,7].
This is the case of the mutation that led to the amino
acid change D614G (Asp614 →Gly) in the spike glyco-
protein (S), found in the predominant form of SARS-
CoV-2 [13,14]. Patients infected with the D614G variant
often have higher viral loads in the upper respiratory
tract than seen with the ancestral strain, but there seems
to be no difference in disease severity [15]. The D614G
mutation determines an important conformational
change in the spike protein between the S1 and S2 do-
mains, that favors the binding to the angiotensin-
converting enzyme 2 (ACE2) receptor and thus increases
the probability of infection: presumably the key to this
variant having become globally dominant [15]. Recently,
Huang et al. [13] have attributed the selective advantage
of D614G variant to the quantitative differences in
ACE2 expression in different populations. The lower
ACE2 expression observed in the European, North
American, and African populations, compared to Asians,
may have driven positive selection favoring the D614G
mutation.
Many SARS-CoV-2 mutations appeared and were se-
lected for several times, independently, e.g., those that
changes the asparagine residue at spike position 501 (S:
N501Y, S:N501T, S:N501S). This residue is within the
receptor-binding domain (RDB), that is important for
both binding to ACE2 and for antibody recognition. A
variant with S:N501Y, B.1.1.7 (also known as 20B/
501Y.V1), was announced in the South East of England
on December 14, 2020 [14]. Variants from this particular
lineage are associated with multiple amino acid changes
in the spike protein, including a deletion at 69/70 [16],
Y144 deletion, and P681H (adjacent to the furin cleavage
Novelli et al. Human Genomics (2021) 15:27 Page 2 of 13
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site). Rapidly spreading variants were also detected in
South Africa. Viruses belonging to the lineage B.1.351
(also known as 20H/501Y.V2) were detected in Decem-
ber 2020 [17]. These variants are associated with mul-
tiple amino acid changes in spike protein, including S:
N501Y, S:K417N, and S:D80A, but they do not have the
deletion at 69/70 (Table 1). After the detection of these
variants harboring similar genetic changes, genomic sur-
veillance in countries experiencing high COVID-19 inci-
dence started to report more variants with convergent
genetic traits. In late 2020, a new variant was detected in
Manaus, state of Amazonas, northern Brazil [18]. The
new lineage, named P.1 (descendant of B.1.1.28, also
known as 20J/501Y.V3), contains a unique constellation
of lineage-defining mutations, including several amino
acid changes of biological significance known as S:
E484K, S:K417T, and S:N501Y. The P.1 lineage was
identified in 42% (13 of 31) of RT-PCR positive samples
collected between 15 and 23 December 2020, but was
absent in 26 publicly available genome surveillance sam-
ples collected in Manaus between March and November
2020. These results indicate local transmission and pos-
sibly a recent increase in the frequency of a new lineage
from the Amazon region [18]. Finally, two lineages origi-
nated in California, USA, have also emerged and in-
creased in frequency from late 2020 to early 2021,
named B.1.427 and B.1.429, both showing three amino
acid substitutions: S:S13I, S:W152C, and S:L452R [19].
Variants from these two lineages have higher transmissi-
bility (from 18.6 to 24%) when compared with wild type
variants.
Some of the variants of concern have not only been as-
sociated with increased transmission potential but also
with reduced susceptibility to neutralizing antibodies
Fig. 1 SARS-CoV-2 genomic surveillance. aPhylogenetic tree of 19,438 SARS-CoV-2 genomes. Up to December 31, 2020, more than 295,000
complete genomes were submitted to the GISAID database. Each circle in this tree represents a genome that was sequenced over time, since
the beginning of the pandemic. As SARS-CoV-2 establishes new infections, its descendants form lineages of genetically related viruses, which can
circulate more locally, as shown in lineages represented by threads of circles with similar colors (as shown in red, at the top of panel a), or may
have more heterogeneous distributions, as depicted in lineages with multiple colors, highlighting the exchange of viruses between geographic
regions (as shown at the bottom of panel a). bState level distribution of SARS-CoV-2 genomes shown in panel a(see acknowledgement Table
S1). All regions of the world were impacted by the pandemic, some more than others. As a result, an imbalance in the distribution of genomes
worldwide (depicted in panel bas bubbles of distinct sizes) is evident. The differences in genome sampling across continents and countries may
not only be the result of epidemic control via distinct public health strategies (as observed in New Zealand and Australia, for example) but may
also result from socioeconomic disparities at national and international scales, where some regions (e.g., South and Central America, most regions
in Africa), despite being hard hit by the pandemic, are unable to conduct genomic surveillance at a scale comparable to that of rich countries in
North America and Europe. Analyses and illustrations were respectively generated using augur and auspice (by nextstrain.org)[11]
Table 1 Important variants of SARS-CoV-2 that emerged in late 2020
Lineage Other designations Likely origin Key genetic changes
B.1.1.7 20I/501Y.V1 UK 69-70del, 144del, S:N501Y
B.1.351 20H/501Y.V2 South Africa S:E484K, S:N501Y
P.1 20J/501Y.V3 Brazil S:E484K, S:N501Y
Evidence from epidemiological and in vitro assays suggests that variants bearing the key genetic changes listed below are more transmissible
Novelli et al. Human Genomics (2021) 15:27 Page 3 of 13
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from convalescent patients and vaccines (immune scape)
[20]. However, it is important to point out that cellular
response conferred by vaccines is robust, identifies epi-
topes from many proteins beyond the Spike, and major
losses of vaccine efficacy would mainly come as a cumu-
lative effect of several widespread genetic changes that
SARS-CoV-2 undergoes as it continues to spread [21].
Another important consequence of mutations is pheno-
typic changes of virulence. Initial studies have been sug-
gesting that some variants may cause more severe
illness, as already reported for B.1.1.7 [19,22].
The emergence of SARS-CoV-2 variants with concern-
ing phenotypes underscores the importance of genomic
surveillance. The ability to track the spread of variants
differs dramatically across regions, both in international
and national levels [23,24]. To prevent unnoticed viral
spread, and to be able to promptly respond to new vari-
ants as they emerge, genomic surveillance needs to be
incorporated as a routine activity by local departments
of public health, sequencing a minimum percent of re-
ported cases (1-5% of cases or more) per administrative
division (towns, cities, counties, state, etc.).
Human genetic susceptibility
Like in all infectious diseases, while pathogen genetics
plays an important role, host genetics and physiology are
key elements in determining the clinical course of dis-
ease in COVID-19 patients. The main unspecific symp-
toms of the disease are fever, myalgia, fatigue, and dry
cough. As known, SARS-CoV-2 first affects the respira-
tory tract and then activates a systemic inflammatory re-
sponse that can lead to interstitial pneumonia, up to
more critical conditions. The worldwide infection fatality
rate (IFR) is currently estimated around 2-3%, with a
variability depending on different genetic and non-
genetic factors, like sex and age above all [25]. It is a
matter of fact that environmental factors contribute to
the disease severity, but the health status represents a
background that should not be underestimated.
Comorbidities
Virus-host interaction plays a fundamental role in the
disease’s outcome. Although most patients have a favor-
able prognosis, some groups are at higher risk, or “ex-
tremely vulnerable”to severe illness. These include first
and foremost individuals with impaired immune system
function; but also those with cancer, severe lung disease,
such as chronic obstructive pulmonary disease (COPD),
and pregnant women with cardiological disease [26,27].
At “high risk”are also older patients, very obese individ-
uals with obstructive sleep apnea syndrome (OSAS), and
those with diabetes mellitus, neurological disorders, or
heart, lung, liver, and kidney diseases, who are especially
vulnerable to virus-induced acute respiratory distress
syndrome (ARDS) [28]. This general risk stratification
has exceptions: even young people without comorbidity
may develop severe disease that may even become fatal.
In order to explain this, several hypotheses have been
formulated, including breakdown of immunological tol-
erance, the viral load, an innate immune inefficiency,
and the presence of common or rare risk alleles in genes
encoding proteins important for the biological cycle of
the virus [29,30]. A deeper knowledge of the involve-
ment of the alterations affecting these pathways and the
innate and adaptive immune system may represent a
turning point for understanding the pathophysiological
mechanisms of SARS-CoV-2 and the development of
new therapeutic strategies. Variants in the genes that en-
code these proteins could contribute to different re-
sponses to infections.
Genetic factors
Common and rare variants have been identified in differ-
ent studies using different approaches (Table 2): Genome
wide association studies (GWAS) and deep sequencing in
selected cohorts and/or large biobank resources [35,45–
50]. Association studies made it possible to identify in a
number of genes susceptibility alleles for severe disease
phenotypes: however, so far, the risk values are too low
(OR <2) to be regarded as predictive genomic markers
(Table 2). Nonetheless, the additive effects of this low
penetrance alleles might become important in the future
through polygenic scores analysis [51]. On the other
hands, highly penetrance alleles of genes encoding pro-
teins involved in important pathways such as those of in-
nate immunity (e.g., TLR3,IRF7) may be already useful for
risk stratification and potentially useful for prognosis and
treatment [30,31]. A recent (not yet peer-reviewed) study
that has appeared on medRxiv [52], did not find penetrat-
ing rare alleles associated with a severe disease phenotype
in four different cohorts analyzed by whole-exome or
whole-genome sequencing, thus questioning whether the
data by Zhang et al. [31] have general validity. These dis-
crepancies might be attributed at least in part to the het-
erogeneity of biobanks, to how phenotypic stratification is
clinically assessed, and to how functional studies are con-
ducted [31].
Identifying the role of rare variants is important in
order to improve predictive testing, to unravel the
pathogenetic mechanisms in different subgroups of
SARS-CoV-2 positive subjects, and to develop personal-
ized medicine for individual COVID-19 patients tailored
to his or her genetic background. It is possible that, in a
complex multifactorial and multigenic disease, such as
COVID-19, several genetic and epigenetic factors are
modulating the phenotypic manifestation, thus compli-
cating the analysis of genotype-phenotype correlations.
For example, it is known that non-coding RNAs
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(ncRNAs), and in particular microRNAs (miRNAs), are
involved in the pathogenesis of SARS-CoV-2 infection
and in host antiviral immune defense mechanisms [53].
Genes encoding miRNAs, like other genes, show inter-
individual genetic variability, and several studies have
shown that genetic variants in miRNA genes can, in
some cases, affect their expression, maturation, and even
affinity for their target genes [54,55]. Thus, the high
clinical variability of COVID-19 might be influenced by
polymorphisms in microRNA target sites (MTS) or in
miRNA sequences [55]. Genetic and epigenetic differ-
ences in miRNA expression in cells targeted by the virus
during entry could affect the effectiveness of antiviral re-
sponses and therefore disease severity. Interestingly, it
has recently been shown that level of expression of genes
encoding proteins involved in virus attachment and
entry (e.g., ACE2,TMPRSS2) varies with age and may
provide a biological rationale for variability in
Table 2 Genetic risk factors for severe COVID-19
SARS-CoV-2 susceptibility gene variant or haplotype Risk estimated
[OR]
Frequency
[MAF]
References
TLR3,UNC93B1,TICAM1,TBK1,IRF3,IRF7,IFNAR1,IFNAR2 (autosomal-
dominant model)
9 <0.001 Zhang et al. [31]
IRF7,IFNAR1 (autosomal-recessive model) >50 <0.001 Zhang et al. [31]
rs769208985—missense variant of FURIN N.A. <0.001 Latini et al. [32]
rs150892504—missense variant of ERAP2 N.A. 0.002 Hu et al. [33]
rs138763430—missense variant of BRF2 N.A. 0.002 Hu et al. [33]
rs147149459—missense variant of ALOXE3 N.A. 0.002 Hu et al. [33]
rs117665206—missense variant of TMEM181 N.A. 0.006 Hu et al. [33]
rs114363287—missense variant of TMPRSS2 N.A. 0.006 Latini et al. [32]
HLA DRB*27:07 N.A. 0.02 Novelli et al. [34]
rs74956615—3′UTR variant of TYK2 1.6 0.03 Pairo-Castineira et al. [35]
rs73064425—intronic variant of LZTFL1 2.1 0.08 Pairo-Castineira et al. [35], Ellinghaus
et al. [36]
rs11385942—intronic variant of LZTFL1 1.8 0.07 Ellinghaus et al [36]
HLA DQB1*06:02 N.A. 0.08 Novelli et al. [34]
rs143334143—intronic variant of CCHCR1 1.9 0.09 Pairo-Castineira et al. [35]
HLA DRB1*15:01 N.A. 0.10 Novelli et al. [34]
rs6598045—5′UTR variant of IFITM3 N.A. 0.19 Kim et al. [37]
rs429358—missense variant of APOE 2.3-2.4 0.20 Kuo et al. [38]
rs9380142—3′UTR variant of HLA-G 13 0.29 Pairo-Castineira et al. [35]
rs2109069—intronic variant of DPP9 1.4 0.33 Pairo-Castineira et al. [35]
rs75603675—missense variant of TMPRSS2 N.A. 0.36 Latini et al. [32]
rs12329760—missense variant of TMPRSS2 0.9 0.39 Hou et al. [39]
rs657152—intronic variant of ABO 1.3 0.41 Ellinghaus et al. [36]
rs6020298—intronic variant of TMEM189-UBE2V1 1.2 0.58 Wang et al. [40]
rs10735079—intronic variant of OAS1/3 1.3 0.64 Pairo-Castineira et al. [35]
rs2236757—intronic variant of IFNAR2 1.3 0.71 Pairo-Castineira et al. [35]
rs3131294—intronic variant of NOTCH4 1.5 0.9 Pairo-Castineira et al. [35]
HLA B*46:01 2.1 N.A. Lin et al. [41]
HLA-E*0101/0103 2.1/2.7 N.A. Vietzen et al. [42]
KLRC2
del
2.6/7.1 N.A. Vietzen et al. [42]
HLA B*54:01 5.4 N.A. Lin et al. [41]
c.2129_2132del, p.Gln710Argfs*18—frameshift variant of TLR7 N.A. N.A. van der Made et al. [43]
c.2383G>T, p.Val795Phe—missense variant of TLR7 N.A. N.A. van der Made et al. [43]
rs140312271—missense variant of ACE2 N.A. N.A. Novelli et al. [44]
MAF major allele frequency, N.A. not applicable, OR odds ratio
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presentation of COVID-19 [56]. Recently, Blume et al.
[57] identified a new short isoform of ACE2 expressed
in the airway epithelium. Short ACE2 is upregulated in
response to interferon stimulation and rhinovirus, but
not SARS-CoV-2 infection. Its expression is regulated
independently of the primary transcript, with putative
promoter elements identified upstream of the transcrip-
tional initiation site of the short ACE2 transcript. The
characterization of the functional elements of the ACE2
promoter and above all the factors involved in its regula-
tion will help to understand better the mechanisms of
pathology caused by SARS-CoV-2.
Newly the CHGE Consortium (Covid Human Genetic
Effort, https://www.covidhge.com/about) initiated a
study to enroll individuals (referred to as “resistant”)
who were not infected with SARS-CoV-2 despite re-
peated 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. It is conceivable that these subjects carry mono-
genic variations that make them naturally resistant to
virus entry, as previously shown for the DARC gene and
Plasmodium vivax,CCR5 and HIV, and FUT2 and Nor-
ovirus [58–60]. Currently, there are no publications on
this “resistant cluster,”but recently, Zeberg and Pääbo
[61] have identified an haplotype on chromosome 12,
which is associated with a ∼22% reduction in relative risk
of becoming severely ill with COVID-19 when infected
by SARS-CoV-2. Interestingly, this haplotype is inherited
from Neanderthals and it is present at substantial fre-
quencies in all regions of the world outside Africa. The
genomic region where this haplotype occurs encodes
proteins that are important during infections with RNA
viruses.
COVID-19 in Africa and in Latin America
Considering the multifactorial complexity of this disease,
its rapid epidemic spread, and its fast evolving causative
agent, COVID-19 is ravaging emerging countries, and its
impacts in low-resource areas deserves our attention
and action. We focus here on two regions of particular
interest: Africa and Latin America.
On January 1, 2021, J. M. Maeda and J. N. Nkenga-
song published a paper on “The puzzle of the
COVID-19 pandemic in Africa”[62]. The figure in
the paper depicts the two COVID-19 “waves”seen in
Europe are much less evident in Africa: rather, there
has been a peak in July, 2020, followed by a gradual
decrease and in turn by a gradual increase that is still
on-going. The real “puzzle”is that a previous report
(issued on March 26, 2020, by the WHO Collaborat-
ing Centre for Infectious Disease Modeling; MRC
Centre for Global Infectious Disease) had predicted
some 70 million cases and some 3 million deaths in
Africa; in contrast, by November 22, 2020, the official
figures were 2,070,953 cases and 49,728 deaths. The
authors (who are at the Africa Centers for Disease
Control and Prevention—the African CDC—in Addis
Ababa, Ethiopia) mention “challenges with testing”as
one possible reason for this striking discrepancy. This
notion is also supported by a compilation from
Nigeria [63]; according to official data, three-quarters
of African COVID-19 cases are in South Africa and
Egypt. An extreme case is that of Tanzania, where
the COVID-19 epidemic is officially finished, and the
last recorded case was on May 19, 2020. We think
limited testing is a major reason for the paucity of
cases in Africa.
Be that as it may, at least three factors of biological
and epidemiological interest may have contributed to
reducing the impact of the pandemic in Africa. First,
in tropical Africa, sun exposure and UV radiation
may inactivate an RNA virus rather more quickly.
However, this hypothesis is not confirmed in other
countries such as northern Brazil and other regions
ofthetropicswhereCOVID-19isfound.Further-
more, the mode of transmission that occurs through
droplets and aerosols does not fit this hypothesis.
Second, the age distribution of the population is
much younger. Third, a significant fraction of people
(perhaps up to 30%) [64] may have antibodies against
other corona viruses that cross-react with SARS-CoV-
2 (even though only 2-8% have specific anti-SARS-
CoV2 antibodies suggesting there may be, like in Eur-
ope, a large number of asymptomatic infections) [65].
Latin America has also been ravaged by COVID-19
and may be the world’s worst affected region [66].
Vaccinations against the virus are seen as the way
forward and have begun (https://www.as-coa.org/
articles/timeline-latin-americas-race-covid-19-vaccine)
[67]. We must support a path to a world that defeats
COVID-19 in all parts of the world. In fact inter-
national efforts by the Global Vaccine Alliance
(GAVI), Coalition for Epidemic Preparedness Innova-
tions (CEPI), Gates Foundations, WHO, etc. (https://
www.weforum.org/agenda/2020/06/vaccines-
immunization-poor-countries-coronavirus-covid-gavi)
[68] are thankfully ramping up.
New technologies accelerated into clinical
practice
The pandemic has produced an unprecedented shift
in the direction of basic and clinical research. We
think it is remarkable that so many highly qualified
research laboratories have been eager or willing to
bring their experience in other areas to bear on this
impelling worldwide problem, and we think it is com-
mendable that they have had the courage to literally
Novelli et al. Human Genomics (2021) 15:27 Page 6 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

re-purpose their work. There has been also a deluge
of publications: at March 30, 2021, the search item
COVID-19 in PubMed yields 118,065 papers; by the
time this paper is published, there will be several
thousands more publications. At the same time, new
technologies for disease treatment and prevention are
also being developed at unprecedented speed. In gen-
eral, it takes a long time for advances to reach con-
sumers, especially in the areas of biotechnology and
health. However, the pandemic has led to a dramatic
acceleration, including in the development of COVID-
19 vaccines (Table 3)[69].
Monoclonal antibodies
Although there are currently numerous studies to iden-
tify antivirals for SARS-CoV-2, the only compounds with
therapeutic efficacy already in use are monoclonal anti-
bodies (mAbs). mAbs are directed against the binding
site of the SARS-CoV-2 spike protein receptor and they
are able to block virus entry into human cells. mAbs
Table 3 Overview of the worldwide approved different types of COVID-19 vaccines
Vaccine Product
name
Vaccine
type
Phase
III
efficacy
Doses Storage Prize
per dose
Distribution
BioNTech/Pfizer BNT162b2 mRNA 95% 2 doses (0.3
mL) [21
days apart]
−80 and −60 °C
(−112 and −76
°F) for 6
months
+2 and +8 °C
(+36 and +46
°F) for 5 days
19.5 $ USA, EU, UK, Argentina, Australia, Bahrain,
Canada, Chile, Costa Rica, Ecuador, Hong Kong,
Iraq, Israel, Jordan, Kuwait, Malaysia, Mexico,
Oman, Panama, Philippines, Qatar, Saudi Arabia,
Singapore, South Korea, United Arab Emirates
COVAX (COVID-19 Vaccines Global Access)
Moderna mRNA-1273 mRNA 94.1% 2 doses (0.5
mL) [28
days apart]
−20 °C (−4 °F)
for 4 months
+2 and +8 °C
(+36 and +46
°F) for 30 days
32-37 $ USA, EU, UK, Canada, Greenland, Iceland, Israel,
Saudi Arabia, Singapore, Vietnam
COVAX (COVID-19 Vaccines Global Access)
Oxford/
AstraZeneca
ChAdOx1
AZD1222/
Vaxzevria
Viral vector 81.3% 2 doses (0.5
mL) [10-12
weeks
apart]
+2 and +8 °C
(+36 and +46
°F)
1.5-4 $ USA, EU, UK, Australia, Bangladesh, Brazil,
Canada, Greenland, India, Mexico, Nepal,
Pakistan, Philippines, Sri Lanka, Taiwan, Vietnam
COVAX (COVID-19 Vaccines Global Access)
Gamaleya
(Sputnik V)
Sputnik V
Gam-Covid-
Vac
Viral vector 91.6% 2 doses (0.5
mL)
[28 days
apart]
−18 °C (0 °F)
for 24 months
+2 and +8 °C
(+36 and +46
°F) for 3
months
< 10 $ Russia, India, Brazil, China, South Korea, Hungary,
Argentina
Johnson&Johnson JNJ-
78436735
Ad26.COV2.S
Viral vector 72% 1 dose −18 °C (0 °F)
for 24 months
+2 and +8 °C
(+36 and +46
°F) for 3
months
10 $ USA, EU, Greenland, Canada
COVAX (COVID-19 Vaccines Global Access)
Novavax NVX-
CoV2373
Virus-like
particle
89% 2 doses [21
days apart]
−18 °C (0 °F)
for 24 months
+2 and +8 °C
(+36 and +46
°F) for 3
months
16 $ USA, Canada
Sinopharm BBIBP-CorV Inactivated
virus
78% 2 doses [3
weeks
apart]
+2 and +8 °C
(+36 and
+46°F)
Three years in
storage
< 77 $ China, United Arab Emirates, Argentina, Bahrain,
Egypt, Marocco, Pakistan, Perù
SinoVac CoronaVac Inactivated
virus
50% 2 doses [3
weeks
apart]
2-8 °C (36-46
°F)
Three years in
storage
14 $ China, Brazil, Turkey, Chile, Indonesia, Philippines
Covaxin (Bharat
Biontech)
BBV152 Inactivated
virus
81% 2 doses [21
days apart]
2-8 °C (36-46
°F)
Three years in
storage
1 $ India, Iran, Mauritius, Nepal, Zimbabwe
Novelli et al. Human Genomics (2021) 15:27 Page 7 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

have this name because they are produced by one type
of immune cells (plasma cells) that are the progeny of a
single parent cell [70]. mAbs, are laboratory-produced
macromolecules engineered to bind to antigens of se-
lected targets (e.g., cancer cells, microorganisms, viruses)
[71]. The efficacy of mAbs has been successfully tested
in other coronavirus infections (SARS-CoV) [72–74] and
MERS [75]. During the past 12 months, several SARS-
CoV-2 neutralizing mAbs have been isolated and charac-
terized in several clinical studies (NCT04452318,
NCT04497987). Some of these, such as bamlanivimab,
casirivimab, and imdevimab, have been approved for
emergency use in the treatment of mildly ill subjects.
mAbs regarded as good candidates for clinical use have
been derived by cloning B cells from patients who have
recovered from COVID-19, or from other natural
sources [76–82]. Bamlanivimab has been associated with
a decrease in viral load and the frequency of hospitaliza-
tions or emergency department visits in outpatients with
COVID-19 [83]; however, when it was co-administered
with Remdesivir, it did not demonstrate efficacy among
hospitalized patients who had COVID-19 without end-
organ failure [84]. In a double-blind, phase I-III trial in-
volving non-hospitalized COVID-19 patients, Weinreich
et al. [85] investigated two fully neutralizing mAbs used
in combination (casirivimab/imdevimab or REGN-
COV2), in the aim to reduce the risk that treatment-
resistant virus variants may emerge. REGN-COV2, de-
veloped by Regeneron Pharmaceuticals (USA), reduced
viral load, with a greater effect in patients whose im-
mune response to the virus had not yet been initiated, or
who had a high viral replication at baseline. Very recent
and unpublished data show that treatment with bamlani-
vimab (LY-CoV555) and etesevimab (LY-CoV016) to-
gether reduced the risk of hospitalization and death
from COVID-19 by 70% (https://investor.lilly.com/news-
releases/news-release-details/new-data-show-treatment-
lillys-neutralizing-antibodies)[86]. Recently, EMA (Euro-
pean Medicines Agency) has completed review on the
use of an additional mAb, regdanvimab (also known as
CT-P59) to treat COVID-19 patients and concluded that
regdanvimab can be used for the treatment of confirmed
COVID-19 in adult patients who do not require supple-
mental oxygen therapy and who are at high risk of pro-
gressing to severe outcome (https://www.ema.europa.eu/
en/news/ema-review-regdanvimab-covid-19-support-
national-decisions-early-use)[87].
mAbs may be also useful for the prophylaxis of
COVID-19 in persons who are at high-risk (health
workers and first responders, pregnant women, ring-
vaccination-type response to disease outbreak). By apply-
ing an innovative strategy, Miersch et al. [88,89] have
isolated high affinity synthetic mAbs from a phage li-
brary and thus developed a dynamic and rapid
technological platform; this approach has the potential
to identify in a short time mAbs against new virus vari-
ants. Synthetic engineering technologies may prove su-
perior to natural cloning methods, as they offer exquisite
control over the design of mAbs, that can prove more
efficient. Similarly, Rappazzo et al. [90] identified rare
broadly neutralizing antibodies (bnAbs) which can be
engineered for improve neutralization potency and pro-
tection in vivo. Synthetic methods have the added ad-
vantage that they do not depend on natural repertoires,
i.e., they are not limited by the need of accessing in-
fected patients as a source of therapeutic agents.
Andreano et al. [91] have isolated and characterized ex-
tremely potent neutralizing mAbs, suitable for prophy-
lactic and therapeutic interventions of wild-type SARS-
CoV-2 as well as emerging variants. Remarkably, an
international research consortium recently developed a
bispecific monoclonal antibody targeting two different
SARS-CoV-2 sites, thereby preventing the virus from
mutating to resist therapy. A single injection of the bis-
pecific antibody provided protection against disease in
mice. The antibody effectively reduced the viral load in
the lungs and mitigated the typical COVID-19 inflam-
mation [92].
mRNA vaccines
Vaccines against SARS-CoV-2 infection were made in
less than a year (Table 3). This research has undoubtedly
been a great success of modern technology and public
and private investments that have allowed to accelerate
many of the processes required to develop a vaccine.
But, of course, mRNA vaccines represent an epochal sci-
entific and technical breakthrough.
mRNA was discovered in 1961 by Brenner et al. [93]
and its ability to form drugs has been described already
in 1989 [94,95]. Since then, dozens of studies on the
subject have been published, including a study on a vac-
cine against the MERS-CoV, which allowed the acceler-
ated development of the SARS-CoV-2 vaccine [96]. This
technology enables the synthetic production of the
mRNA encoding any protein. mRNA vaccines have ad-
vantages over DNA vaccines. In general, lower doses are
required to induce an immune response. Synthetic
mRNA does not integrate into the cell’s genome, and no
transcriptional step is involved, as the mRNA is directly
translated, and then it undergoes degradation [97]. The
vaccine activates both humoral immune system and cel-
lular immune response, similar to live virus attenuated
vaccine [98–100].
ThesafetydatainadultsonmRNAvaccinesagainst
COVID-19 have been reassuring. The most common side
effects in adults are only local, within 7 days of receiving
the first inoculation, and more common after the second
dose [101,102]. The side effects are mild-to-moderate; no
Novelli et al. Human Genomics (2021) 15:27 Page 8 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

severe-grade local side effects were reported [98,103]. Sys-
temic signs (fever of 38 °C) were reported in 75% of vac-
cine recipients. Subjects over the age of 65 suffered less
systemic symptoms, but reported fatigue and headaches.
During the rollout, some severe allergic reactions were
also observed, but they were rare [104].
RNA-based vaccines efficacy, safety, and the potential
for rapid, inexpensive, and scalable production makes
them a powerful advantageous option to combat
COVID-19, including probably new variants [105–110].
Widge et al. [111] have reported immunogenicity data
119 days after the first dose of vaccine (i.e., 90 days after
the second dose) in 34 healthy adult participants who re-
ceived two injections of 100 μg each. They provided fur-
ther evidence that mRNA-1273, developed by National
Institute of Allergy and Infectious Diseases (NIAID), the
Biomedical Advanced Research and Development Au-
thority (BARDA), and Moderna (ModeRNA Therapeu-
tics, USA) have the potential to provide a durable
humoral immunity, although for how long is of course
not yet known.
Recently, a CDC study of about 4000 healthcare
workers and workers belonging to essential categories
were tested weekly for coronavirus after administration
of the mRNA vaccine. The analyses found that people
who had completed the vaccination course had a 90%
reduced chance of becoming infected. Furthermore, the
study showed that already from the first dose, the per-
centage after 14 days from the first injection was already
close to 80%. Results clearly indicate the vaccine’s ability
to interrupt viral transmission [112].
mRNA-based drugs are a promising novel platform
that might be useful for the development of vaccines
against emerging pandemic infectious diseases [113].
Furthermore, unconventional tools such as Cas13a-
crRNA complex, an RNA-activated RNase, are being ex-
plored as novel therapeutics against SARS-CoV-2 infec-
tion, displaying promising results in reducing viral
replication and symptoms in animal models [114]. RNA
in human cells is susceptible to editing, and the RNA
genome of SARS-CoV-2 is not an exemption. From a
comprehensive sequence analysis of Coronaviridae, nu-
cleotide changes have been identified that may be signa-
tures of RNA editing by both ADAR deaminases and
APOBEC deaminases. It has been suggested that this
process may contribute to shaping the fate of both virus
and patient [115].
Conclusions
We are heartened by the progress in therapeutics and
preventive strategies for COVID-19. Having achieved
within less than 1 year from the start of the pandemic
not only the development of a vaccine but also of several
vaccines; having conducted the necessary clinical trials;
having obtained approval from multiple regulatory agen-
cies around the world; having actually already carried
out mass vaccinations at least in some countries, is noth-
ing short of spectacular [68]. While we can certainly not
relent on the standard preventive measures (rigorous so-
cial distancing, frequent and thorough handwashing,
avoiding poorly ventilated spaces, wearing of face masks
as warranted), we are confident that the vaccines cur-
rently available and those in the pipeline will help defeat
COVID-19 and allow a return to normality in due
course [116,117]. Improved therapies, such as mAbs,
will also be useful in treating the disease. Understanding
the virus entry and egress mechanisms could also open
the door to promising therapeutic perspectives [118,
119]. Molecular testing and genomics will play a critical
role in the detection of newly emerging variants.
Furthermore, we are mindful of our fellow humans in
other countries, particularly in emerging economies. For
many years, the Global Fund has provided funding for
those affected by HIV; it has been a generous gesture,
initially fueled by concerns that from a reservoir in Af-
rica transmission elsewhere could take place. If HIV has
been an epidemic, SARS-CoV-2 has sparked a pandemic,
and it will be in everybody’s interest that it is controlled
on a global scale because, as stated at the beginning of
this paper, otherwise it will continue to affect the world.
We are aware that WHO has launched the COVAX
(COVID-19 Vaccines Global Access) scheme, and that
the GAVI, backed by the Bill & Melinda Gates Founda-
tion, the WHO, the World Bank, UNICEF, and others,
has pledged $8.8 billion to reduce vaccine costs for poor
countries. One possibility is that a good part of these
funds will be absorbed by vaccinating persons from poor
countries and provide immunization certificates to those
who travel to richer countries, so that the latter will be
protected. But we call on international organizations to
set aside this potential narrow-sighted approach: and
make instead vaccines available to all nations on a wide
scale. We look forward to the WHO leading rigorously
and expeditiously, lest their effectiveness is brought into
question more than it has been hitherto. It is legitimate
to hope that the lessons learned with COVID-19 will
help in the future, not only in being more prepared for
other similar emergencies but also in acting as one, for
we have only one planet and only one humankind.
Abbreviations
ARDS: Acute respiratory distress syndrome; ASEAN: Organization of Southeast
Asian States; AU: African Union; BARDA: Biomedical Advanced Research and
Development Authority; CDC: Centers for Disease Control; CEPI: Coalition for
Epidemic Preparedness Innovations; CHGE: Covid Human Genetic Effort;
COPD: Chronic obstructive pulmonary disease; COVAX: COVID-19 Vaccines
Global Access; COVID-19: Coronavirus disease 2019; CTAP: Coronavirus
Treatment Acceleration Program; EMA: European Medicine Agency;
EU: European Union; EUA: Emergency Use Authorization; FAO: Food and
Agriculture Organization; FDA: Food and Drug Administration; GAVI: Global
Vaccine Alliance; GWAS: Genome Wide Association Studies; IFR: Infection
Novelli et al. Human Genomics (2021) 15:27 Page 9 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

fatality rate; mAbs: Monoclonal antibodies; miRNA: micro RNA; MERS: Middle
East respiratory syndrome; NIAID: National Institute of Allergy and Infectious
Diseases; OAS: Organization of American States; ORF: Open reading frame;
OSAS: Obstructive sleep apnea syndrome; SARS-CoV-2: Severe acute
respiratory syndrome coronavirus 2; UN: United Nations; WHO: World Health
Organization
Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1186/s40246-021-00326-3.
Additional file 1: Table S1. List of genomes used in the analysis. We
gratefully acknowledge the following Authors from the Originating
laboratories responsible for obtaining the specimens, as well as the
Submitting laboratories where the genome data were generated and
shared via GISAID, on which this research is based.
Acknowledgements
We are particularly grateful for the assistance given by Dr. Francesca Pisanu
for her continuous help with the editing and organization of the manuscript.
Authors’contributions
G.N. and J.K.V.R. conceived the paper, performed the systematic review,
wrote and edited the manuscript. R.M.S. wrote mRNA vaccines paragraph.
J.K.V.R. is also responsible for the sections on acceleration of technologies
and politics along with some revisions. V.L.C. conceived and edited Table 2,
Table 3, and revised the paper. A.F.B. generated Fig. 1. M.B., V.V., A.F.B., L.L.,
and N.D.G. performed review and revision of the paper. All authors read and
approved the final version of the manuscript.
Funding
This study was also supported in part by a grant of Regione Lazio (Italy,
Progetti di Gruppi di Ricerca 2020 A0375-2020-36663 GecoBiomark) and
Rome Foundation (Italy, Prot 317A/I) to GN and NIH N. AA028432 to V.V.
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
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Department of Biomedicine and Prevention, “Tor Vergata”University of
Rome, 00133 Rome, Italy.
2
IRCCS Neuromed, Pozzilli, IS, Italy.
3
Department of
Pharmacology, School of Medicine, University of Nevada, Reno, NV 89557,
USA.
4
Department of Biology, Tor Vergata University of Rome, 00133 Rome,
Italy.
5
Pediatric Hemato-Oncology, Sheba Medical Center, Tel Hashomer,
Israel.
6
Department of Epidemiology of Microbial Diseases, Yale School of
Public Health, New Haven, CT 06510, USA.
7
Department of Environmental
Health Sciences, Yale School of Public Health, New Haven, CT 06510, USA.
8
Haematology, Muhimbili University of Health and Allied Sciences, Dar-es
Salaam, Tanzania.
9
Australian Institute of Tropical Health and Medicine, James
Cook University, Smithfield, Queensland 4878, Australia.
Received: 8 February 2021 Accepted: 15 April 2021
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