Does blood type influence COVID-19 symptoms?

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Review

ABO Blood Types and COVID-19:

Spurious, Anecdotal, or Truly

Important Relationships? A Reasoned Review of
Available Data

Jacques Le Pendu 1,*, Adrien Breiman 1,2 , Jézabel Rocher 1, Michel Dion 3 and Nathalie Ruvoën-Clouet 1,4

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Citation: Pendu, J.L.; Breiman, A.;

Rocher, J.; Dion, M.; Ruvoën-Clouet,

N. ABO Blood Types and COVID-19:

Spurious, Anecdotal, or Truly

Important Relationships? A Reasoned

Review of Available Data. Viruses

2021, 13, 160. https://doi.org/

10.3390/v13020160

Academic Editor: Shan-Lu Liu

Received: 18 December 2020

Accepted: 19 January 2021

Published: 22 January 2021

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4.0/).

1 CRCINA, INSERM, Université de Nantes, F-44000 Nantes, France; Adrien.Breiman@univ-nantes.fr (A.B.);
jezabel.rocher@univ-nantes.fr (J.R.); Nathalie.Ruvoen@univ-nantes.fr (N.R.-C.)

2 CHU de Nantes, F-44000 Nantes, France
3 Microbiotes Hosts Antibiotics and Bacterial Resistances (MiHAR), Université de Nantes,

F-44000 Nantes, France; michel.dion@univ-nantes.fr
4 Oniris, Ecole Nationale Vétérinaire, Agroalimentaire et de l’Alimentation, F-44307 Nantes, France
* Correspondence: Jacques.le-pendu@inserm.fr

Abstract: Since the emergence of COVID-19, many publications have reported associations with
ABO blood types. Despite between-study discrepancies, an overall consensus has emerged whereby
blood group O appears associated with a lower risk of COVID-19, while non-O blood types appear
detrimental. Two major hypotheses may explain these findings: First, natural anti-A and anti-B
antibodies could be partially protective against SARS-CoV-2 virions carrying blood group antigens
originating from non-O individuals. Second, O individuals are less prone to thrombosis and vascular
dysfunction than non-O individuals and therefore could be at a lesser risk in case of severe lung
dysfunction. Here, we review the literature on the topic in light of these hypotheses. We find that
between-study variation may be explained by differences in study settings and that both mecha-
nisms are likely at play. Moreover, as frequencies of ABO phenotypes are highly variable between
populations or geographical areas, the ABO coefficient of variation, rather than the frequency of each
individual phenotype is expected to determine impact of the ABO system on virus transmission.
Accordingly, the ABO coefficient of variation correlates with COVID-19 prevalence. Overall, despite
modest apparent risk differences between ABO subtypes, the ABO blood group system might play a
major role in the COVID-19 pandemic when considered at the population level.

Keywords: COVID-19; ABO blood groups; natural antibodies; thrombosis; attack rate; susceptibility

1. Introduction

Since the first description of COVID-19 in Wuhan, China, the emergence of the new
SARS-CoV-2 coronavirus led to a global public health crisis due to massive morbidity and
a burden of mortality that rapidly overwhelmed health systems worldwide. However, the
disease impact shows considerable variation between countries and geographic areas for
reasons that are poorly understood. Besides differences in the economical, sociological,
behavioral, and political response to the pandemic, genetic factors might also play a role in
their own right. Thus, soon after the beginning of the pandemic a publication from Wuhan,
China, reported a higher risk of infection for people of blood group A, and inversely a lower
risk for people of blood group O [1]. Since then, associations with the ABO blood groups
have been described in several additional publications from China as well as many other
locations from Asia, the Middle East, Europe, and North America [2–36]. Associations
between ABO phenotypes were described with either the risk of infection or disease
severity, although most studies did not explicitly separate these two aspects. Moreover,
the ABO phenotypes that appeared associated with either a higher or a lower risk were
not always identical across studies, and several studies failed to uncover any significant
association [37–41]. Finally, if there is an effect of ABO blood groups on SARS-CoV-2

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Viruses 2021, 13, 160 2 of 20

infection or the outcome of COVID-19, its impact on the evolution of the pandemic in
different regions of the world and its potential importance in terms of patients care remain
to be assessed. The purpose of this work is therefore to provide a reasoned review of the
literature in order to assess the extent of the potential role and usefulness of the ABO blood
group system in the COVID-19 pandemic.

2. The ABO Blood Group System at a Glance

The ABO blood group system was discovered more than a century ago and its un-
derstanding allowed the development of blood transfusion. However, the corresponding
antigens are expressed on a large number of cell types in addition to erythrocytes [42]. They
are of the carbohydrate type, constituting terminal motifs of either N-linked or O-linked
chains of glycoproteins as well as of glycolipids. Their synthesis proceeds by addition of
monosaccharide units to precursor glycan chains through specific glycosyltransferases. It
first requires the synthesis of the histo-blood group H precursor antigen, which is catalyzed
by alpha1,2fucosyltransferases that add a fucose in α1,2 linkage to a terminal β-galactose
of the subjacent glycan chain. The FUT1 enzymes are responsible for this activity in ery-
throblasts, megakaryocytes, vascular endothelial cells, and several other cell types, while it
is the FUT2 enzyme that catalyzes synthesis of the H antigen in most epithelial cells such
as the upper airways, the digestive tract, and the lower genito-urinary tracts. Once the H
antigen is produced, addition in α1,3 linkage of an N-acetylgalactosamine or of a galactose
to the same subjacent galactose unit by the A or B blood group enzymes generates the A
and B antigens, respectively (Figure 1). The A and B enzymes are coded by distinct alleles
of the ABO gene, whereas the O alleles correspond to null alleles unable to generate any
active enzyme. These three major types of alleles generate the four major phenotypes O,
A, B, and AB [43]. Both the FUT1 and FUT2 genes also present null alleles that lead to a
lack of precursor H antigen synthesis in the corresponding cell types and therefore to a
lack of A and B blood group antigens expression in these cells [44]. FUT1 null alleles are
responsible for a rare red cell phenotype called “Bombay”. Given its rare occurrence, it will
not be discussed any further. By contrast, null alleles of the FUT2 gene are common and
their frequency varies across populations. These alleles are responsible for the so-called
“nonsecretor” phenotype which by contrast with the “secretor” phenotype is characterized
by a lack of A, B, and H antigens in many secretions such as saliva and in epithelia. In the
Western world, the secretors represent around 80% of the population and nonsecretors, the
remaining 20% [44].

In addition to its antigens, the ABO system is characterized by the presence of anti-
bodies against the A and B antigens. Thus, blood group O individuals possess anti-A and
anti-B antibodies, blood group A individuals possess anti-B antibodies, and blood group B
individuals have anti-A antibodies. Only blood group AB individuals are devoid of both
anti-A and anti-B antibodies. This system of antigens and their cognate antibodies defines
the basic rules of transfusion where blood group O constitutes a universal donor, whereas
blood group AB represents a universal receiver [45]. The origin of the natural anti-ABO
antibodies is still debated. Nonetheless, it seems that most of these antibodies appear
during the first year of life under stimulation of microorganisms either pathogenic or
from the microbiota that carry similar antigens [46,47]. Their amounts are highly variable
between individuals and some data suggest that they may decrease with improved hygiene
conditions [48,49].

Viruses 2021, 13, 160 3 of 20

Figure 1. Description of the major characteristics of the ABO blood group system. Biosynthesis of the
A and B antigens starts from a precursor structure constituted by a galactose residue in beta linkage
to a subjacent sugar located at the termini of either N- or O-glycans as well as glycolipids. In red
blood cells (RBC), vascular endothelial cells (VE) and other cell types such as megakaryocytes that
give rise to platelets, addition of a fucose in α1,2 linkage by the FUT1 enzyme gives rise to the H
blood group antigen. In most epithelial cells, synthesis of the H antigen is performed by the FUT2
enzyme. Blood group A antigen is then synthesized by the A enzyme coded by A alleles of the ABO
gene, while blood group B antigen is synthesized by the B enzyme coded by B alleles. O alleles are
unable to generate a functional enzyme; therefore, O/O individuals leave the H antigen unchanged.
Relationships between genotypes, phenotypes, antigens, and the corresponding natural antibodies
are shown.

The ABO gene and the FUT2 gene, which controls expression of ABH antigens in
epithelia, are among the few human genes clearly under frequency-dependent balanced
selection, suggesting important roles in interactions with environmental factors [50–55].
Histo-blood group antigens, including ABO blood groups, have previously been implicated
in the genetic susceptibility to several infectious diseases, including viral diseases. This has
been particularly well documented for human noroviruses and rotaviruses that together
are responsible for the majority of gastroenteritis cases worldwide. These non-enveloped
RNA viruses attach to the carbohydrate antigens expressed in the gastrointestinal mucosa.
They have evolved so that distinct strains recognize preferentially different carbohydrate
motifs, resulting in a strain-dependent susceptibility in accordance with the person’s
blood type [56]. Rabbit Hemorrhagic Disease Virus (RHDV) is a highly pathogenic rabbit
calicivirus related to noroviruses also attaches to blood group antigens expressed in the
rabbit respiratory and gut epithelia. The rabbit-RHDV pair allowed the documentation of
a natural example of host–pathogen co-evolution involving the recognition of A, B, and H
blood groups antigens by the virus [57]. These co-evolving host–pathogen pairs explain, at
least partly, the maintenance of the ABO polymorphism. Nevertheless, using mathematical
modeling, it has been argued that its maintenance would additionally require the role of
the anti-ABO antibodies to be taken into account [58]. It has additionally been argued
that viral-mediated selection may explain why South American native populations are
exclusively of blood group O [59].

3. Hypotheses Linking ABO Types and COVID-19 and Their Consequences on the
Interpretation of Reported Associations

Soon after the first report of an association between ABO phenotypes and the risk of
COVID-19, several hypotheses were proposed about the underlying mechanisms [60–63].
Prior to presenting the results of the various studies reporting associations, or the lack of

Viruses 2021, 13, 160 4 of 20

association, we will explain the bases and rationale of these hypotheses as they have distinct
consequences that may explain discrepant outcomes stemming from variable designs of
the association studies. Because of their crucial importance for blood transfusion ABO
blood groups are generally perceived as red cell markers. Their potential role in COVID-19
is therefore not obvious. The mechanisms that have been proposed to account for their
implication in the disease can be broadly divided into two major groups; those affecting
the risk of infection and of SARS-CoV-2 transmission, on the one hand, and those affecting
disease severity, on the other hand.

3.1. The Anti-ABO Antibodies

As described above, histo-blood group antigens, including the ABH antigens, are
synthesized by many epithelial cell types, including those of the respiratory and digestive
tracts that are known to emit large amounts of viral particles [64–67]. The SARS-CoV-2 main
envelope protein, the Spike or S protein harbors many glycosylation sites. It is therefore
heavily glycosylated and structural analyses of the recombinant glycoprotein produced in
HEK293 cells revealed a large panel of glycans, mostly of the N-glycan type, but also of O-
glycans [68–71]. As the enzymatic machinery required for their synthesis is that of the host
cell, the exact structures present on virions will depend on the infected cell type. Glycans
detected on the recombinant S protein from HEK293 cells or on the virus produced in Vero
cells therefore do not fully represent those that are synthesized on viral particles emitted
from either respiratory or digestive epithelial cells from infected persons. Most importantly
they cannot be decorated by ABH antigens as HEK293 cells and Vero cells do not synthesize
these epitopes [72]. To uncover whether the S glycoprotein carries A, B, or H antigens when
produced in cells that have the ability to synthesize these glycan motifs, in a recent work,
we produced the recombinant S1 domain in CHO cells expressing the FUT2 enzyme and
either the A or the B enzymes. This showed that H, A, or B epitopes can be present on the
viral S protein in accordance with the glycosyltransferase repertoire of the cells [72]. It is
therefore to be expected that authentic infectious virions produced by respiratory epithelial
cells also carry the antigens in all individuals of the “secretor” phenotype. Consequently,
applying the rules of blood transfusion, SARS-CoV-2 viral particles transmitted in ABO
incompatible situations might be neutralized by the anti-A and anti-B antibodies. As blood
group O individuals possess both types of antibodies, they might benefit from a better
protection than blood group A or B individuals who possess only one of these types of
antibodies and even more so than blood group AB people who have none of them. As
previously discussed, this kind of protection will only be partial as it can only take place
in incompatible ABO situations and likely requires sufficient amounts of the anti-A and
anti-B antibodies [60]. Because these are highly variable, it follows that individuals who
possess low titers of anti-A or of anti-B antibodies are expected to be at a higher risk of
infection than people with high titers. This was indeed recently observed in a study where
agglutination scores of patients were compared to those of a control group. Patients’ anti-A
and/or anti-B scores were lower than those of non-COVID-19 controls. By contrast, no
differences were observed for antibodies directed against similar carbohydrates, including
the αGal antigen (see below), which cannot be synthesized by human cells, indicating that
the lower scores of anti-ABO antibodies observed in patients did not result from a general
decrease of anti-carbohydrate antibodies following infection [72].

Earlier observations additionally support the anti-ABO antibodies hypothesis. Follow-
ing an outbreak of SARS-CoV in Hong Kong hospital in 2003, it was observed that blood
group O hospital staff members in contact with the initial patient had been largely spared
by the disease in comparison with non-O blood group staff members [73]. It could then be
showed using an in vitro cellular model that the interaction between the virus S protein
and the ACE2 protein, its receptor like that of SARS-CoV-2, could be specifically inhibited
by anti-A antibodies when the S protein was produced by cells able to synthesize the blood
group A antigen [74]. Additionally, Measles virus grown in cells expressing either the A
or B blood group antigens was neutralized by human serum anti-B or anti-A antibodies,

Viruses 2021, 13, 160 5 of 20

respectively, in a complement-dependent manner [75]. Likewise, the αGal xenoantigen,
similar to the human B blood group antigen, but not present in humans due to mutations
in the GGTA1 gene that encodes a closely-related specific α1,3galactosyltransferase, is
present in enveloped virus particles produced by animal cells possessing the enzyme [76].
A large body of evidence indicates that expression of the αGal carbohydrate epitope on
viral envelopes leads to the elimination of viruses through anti-carbohydrate natural anti-
bodies. Various mechanisms appear to be involved in the phenomenon, including blocking
of receptor engagement, complement-dependent neutralization and amplification of the
specific immune response through targeting of the opsonized virus particles to antigen
presenting cells (reviewed in [77]).

In light of all these data, the involvement of natural anti-ABO antibodies in COVID-
19 infection is a serious possibility that needs careful attention. It should be stressed
that if these antibodies play any role, they can only act by preventing infection or by
decreasing the viral load. As soon as virus replication has taken place in the new host,
newly formed virions will carry autologous glycans that can no longer be recognized by
the allogeneic anti-ABO antibodies. Another critical consequence of a potential protection
effect of anti-ABO antibodies is that, as protection exclusively takes place in situations of
ABO incompatibility, the final number of infected individuals cannot be affected to a great
extent, because more and more ABO compatible encounters will take place as the epidemic
progresses. Yet, it can still have a major impact on the epidemic by significantly slowing
down its progression which will enhance the efficacy of non-pharmaceutical measures of
protection, such as social distancing. This was modeled using data from a SARS-CoV 2003
outbreak [74]. The model showed that in case of a strong protection afforded by a sufficient
amount of anti-ABO antibodies in ABO incompatible transmission events, the epidemic
would be very strongly delayed.

3.2. The ABO Effect on Thrombosis

A large number of studies show associations between ABO blood groups and throm-
boembolic diseases as recently reviewed [78]. This has been shown for myocardial in-
farction, atherosclerotic vascular disease, venous thromboembolism, and cardiovascular
ischemic events. In all instances, people with non-O blood groups proved at a higher
risk than O blood group individuals. One of the explanations rests on the observation
that plasma levels of coagulation factors, most notably von Willebrand’s factor (vWF), are
~30% higher in non-O blood group individuals than in blood group O. Synthesis of vWF
takes place in megakaryocytes and vascular endothelial cells that express ABH antigens.
As it is heavily N- and O-glycosylated, it carries the antigens depending on the person’s
ABO phenotype. Its clearance, largely glycan-driven and mediated by lectins such as the
Ashwell hepatic lectin or CLEC4AM, is reduced in the presence of either the A, the B
antigen, or both, leading to higher plasma levels of non-O individuals. In addition to their
effect on hemostasis, there is evidence that ABO blood groups also affect vascular function,
although the exact underlying mechanisms are not fully elucidated. In this context, it is
noteworthy that the levels of vascular adhesion molecules such as the soluble forms of
ICAM, P-selectin, and E-selectin correlate with ABO blood groups, with higher levels of
these factors detected in blood group A individuals in comparison with blood group O [79].
Regardless of the precise underlying mechanisms, these observations suggest that ABO
blood groups modulate leucocyte–endothelial interactions and influence the magnitude of
the inflammatory response.

Severe COVID-19 is characterized by an inflammatory state damaging the alveolar–
capillary barrier and thereby compromising gas exchange. Intracapillary thrombosis
and endothelial dysfunction are essential components of the severe form of the disease.
Considering that ABO blood groups modulate both hemostasis and endothelial function,
including its interactions with inflammatory cells, this has been suggested as an explanation
of the reported associations between COVID-19 and ABO blood types [61,62]. Within the
framework of this hypothesis, it appears that ABO blood groups would only influence

Viruses 2021, 13, 160 6 of 20

the outcome of the disease at a late stage when ARDS or severe lung dysfunction has
taken place.

3.3. ABO Blood Groups and the Furin Cleavage Site

Cell entry of SARS-CoV-2 involves pre-activation of the S protein by the proprotein
convertase furin or furin-like proteases [80]. The furin cleavage site is surrounded by
O-glycosylation sites, which represents a unique feature of SARS-CoV-2 among coron-
aviruses. As ABH antigens are largely present on O-glycans of epithelial cells [81], the
distinct versions of O-glycans thus generated on the virions may impact the ability of furin
to cleave the S protein. In a recent publication, Abdelmassih et al. also suggested potential
relationships between ABO blood groups and furin [62]. They proposed that furin levels
might be reduced in blood type O individuals based on a reported negative relationship
between blood type O and furin-related proprotein convertases [82]. In addition, they
suggested that furin levels modulated by the ABO phenotypes could play a role in the en-
dothelial pathogenicity of SARS-CoV-2. In these conditions, the impact of ABO phenotypes
on furin could take place both at the infection level and at the late stage of severe disease.

3.4. ABO Blood Groups and Susceptibility to Other COVID-19-Associated Risk Factors

Besides cardiovascular diseases, a large number of COVID-19 comorbidity factors
have been described, some of which could also be associated with ABO blood groups.
Although many studies looking for associations between ABO phenotypes and inflamma-
tory conditions or autoimmune diseases have been conducted, they have often generated
conflicting results. Nonetheless, a recent phenomic study involving a very large number of
subjects from independent cohorts replicated some of these associations [83]. Thus, levels
of C-reactive protein and alkaline phosphatase appear higher in blood group A individuals
in comparison with blood group O, which may indicate a higher inflammatory state in
the former group. Blood group O has also been reported to represent a protective factor
for Crohn’s disease and ulcerative colitis, type I diabetes, and multiple sclerosis, although
replications studies are lacking (reviewed in [62]). ABO blood groups additionally show
associations with markers of the general metabolism. PSK9 levels appear higher in non-O
blood group people, consistent with their higher levels of total cholesterol, LDL-C, and
HDL-C [82,83]. Blood group A also appears associated with a lower forced vital capacity
and forced expiratory volume in 1 s [83]. Although the mechanisms behind these various
associations are unknown, they might contribute to increase the risk of severe COVID-19
or to worsen the disease.

3.5. ABO Blood Groups and the Microbiota

As bacteria of the microbiota trigger the synthesis of anti-A and anti-B antibodies,
composition of the gut microbiota might be critical to explain the large inter-individual
variations in levels of these antibodies. The microbiota is also known to play a major role
in controlling immunity and inflammation and since recent reports showed that the gut
microbiota signature of COVID-19 patients appears distinct from that of healthy controls
(reviewed in [84]), it is worth mentioning two studies that related ABO phenotypes to
the composition of the gut microbiota. Mäkivuokko et al. observed that the overall
microbiota composition of blood group B individuals differed from that of the other blood
groups and showed increased levels of Actinobacteria in group A healthy individuals [85].
These bacteria are reportedly increased in Crohn’s disease and ulcerative colitis and may
contribute to facilitate the development of the inflammatory state associated with severe
COVID-19. Another study reported lower levels of Blautia in blood group A secretors than
in non-A secretors [86]. A decreased level of these bacteria had previously been described
in several inflammatory, autoimmune conditions, and aging [87], it may also reveal a higher
risk of uncontrolled inflammation among blood group A COVID-19 patients than among
other ABO blood types.

Viruses 2021, 13, 160 7 of 20

Strikingly, all hypotheses linking ABO blood groups to COVID-19 predict a protective
effect of the O blood type in comparison with non-O blood groups. Disentangling their
relative importance is therefore not straightforward. Nonetheless, those that concern
susceptibility to infection and the likelihood of transmission have different consequences
than those predicting an impact on late events associated with the cytokine storm, ARDS
and severe lung dysfunction. These differences help in analyzing the reported studies as
discussed below.

4. Studies Linking ABO Blood Types to COVID-19
4.1. Case–Control Studies Designed to Observe Associations

At the time of writing, 34 case/control studies reporting associations between ABO
phenotypes and the risk of COVID-19 have been reported, while only four studies failed to
uncover a significant association (Table 1). Importantly, not all of the reports have been
peer-reviewed as yet. As immediately apparent from Table 1, the data show a lower risk for
O blood group people and/or inversely a higher risk for people with non-O blood types,
most often blood group A. The reported significant odd ratios (ORs) generally revealed
a modest influence of the ABO blood groups, although some reports suggested stronger
effects. Thus, ORs for blood group O ranged from 0.53 to 0.9 and ORs for non-O blood
groups ranged from 1.12 to 3.7. Meta-analyses of the earliest available data have already
been conducted, confirming the effect [88–92].

The majority of these studies were hypothesis-driven. Yet, six of them concerned
genome-wide association studies (GWAS) that looked for genetic associations without
a priori [5,20,23,26,27,37]. Of the latter, only one failed to observe a significant signal at
the ABO locus on the long arm of chromosome 9 (9q34) [37]. The fact that the majority of
both agnostic GWAS and hypothesis-driven studies found the same significant associations
with the ABO blood types indicates that these did not derive from biases due to the a priori
search for a link between ABO blood groups and COVID-19.

The various studies also differ in many other aspects, including the number of patients
included, the definition of cases and the types of controls to whom patients were compared,
as well as the relative ABO frequencies in the diverse studied populations. These different
settings can seriously affect outcomes. Thus, in studies where the patients’ group was
compared to blood donors, a bias might be introduced as blood group O is over-represented
among regular blood donors because group O blood representing the universal donor is
more widely demanded. In such studies, there is a risk of finding a false apparent increase
in non-O blood types or a decrease of the O type among patients. Nonetheless, other
studies using anthropological data of the frequency of ABO phenotypes obtained from
large fractions of the local population alleviate this potential bias, as long as the population
is sufficiently homogeneous and has not changed in composition since the acquisition of the
anthropological data. In this respect, data from Asian and Middle-East countries are quite
safe at the local level, with population ancestries being rather homogeneous. This is not so
in the USA or European countries. Higher risks of COVID-19 have been reported for some
disadvantaged subgroups from these countries [93]. The variations in ABO blood group
frequencies between populations of different geographical origins and ancestries represent
another important source of potential bias. In order to take this bias into account, in several
studies, groups of patients and controls were stratified for ancestry [7,20,21,26,37]. Again,
with the exception of one study discussed below [37], they consistently documented a lower
risk of COVID-19 for blood group O, although not visible in all ethnic groups as illustrated
by the study of Leaf et al. who uncovered a significant ABO effect in the white American
population, but not in minorities of African Americans or Latin Americans [7]. This is
likely due to the impact of the relative frequencies of ABO phenotypes in populations as
discussed below. The effect of population admixture also likely explains why a study from
New York, USA, failed to reveal any significant association between ABO blood types and
the risk of COVID-19 [38]. In that study, no stratification for ancestry was performed even
though the control group was composed of historical non-COVID-19 hospitalized patients.

Viruses 2021, 13, 160 8 of 20

Table 1. Case–control studies reporting data on ABO blood groups and COVID-19.

Country
Cases Controls ABO Effect a

Ref.
Definition b Number Definition c O A B AB

China I 1775 I Risk ns ns [1]
USA I 682 I Risk ns ns [2]

China II 2153 I Risk ns ns [3]
Turkey I 186 III Risk ns ns [4]

Spain/Italy d III 1610 III + IV Risk ns ns [5]
China I 187 IV Risk ns ns [6]
USA V 3239 V Risk ns ns [7]

China III + IV 97 I Risk ns ns [8]
Turkey I 179 IV Risk ns ns [9]

Iran VII 76 I Risk ns ns [10]
China V 134 I Risk ns ns [11]
Spain VIII 854 VI Risk ns ns [12]
Spain IX 965 III Risk ns ns [12]
UK I 86 II Risk ns ns [35]

Turkey II 1667 I Risk ns ns [36]
Iran VI 93 I Risk >Risk >Risk [13]
USA I 1289 II Risk >Risk [14]

Canada I 7071 II Risk >Risk [15]
India I 8102 I Risk ns [16]
Spain II 226 I Risk ns [17]

Saudi-Arabia II 72 III Risk [18]
Iran I 397 IV Risk [19]

USA + UK I 15,434 II

Denmark V 7422 I Risk [23]

Italy I 447 III Risk ns ns [25]
USA I 2417 I ns >Risk ns ns [26]

Italy/Spain III 505 VI ns >Risk ns >Risk [27]
Bahrain V 2334 III ns ns >Risk

UK V 2244 I ns ns ns ns [37]
Brazil I 2037 II ns ns ns ns [41]
USA II 957 IV ns ns ns ns [38]

a All relevant studies in published or prepublication (not peer reviewed) formats as of 14 December 2020 are included. Significant
associations are marked in green to indicate a decreased risk relative to the other blood types or in red to indicate an increased risk; ns:
non-significant. b I: all diagnosed patients (RT-PCR), II: hospitalized patients, III: severely ill patients, IV: mildly ill patients, V: critically ill
patients (ICU patients), VI: ICU admitted patients < 45 y/o with no previous history, VII: deceased patients, VIII: convalescent plasma donors (previously blood donors), IX: transfused patients. c I: regional anthropological data, II: regional SARS-CoV-2 RT-PCR negative people, III: blood transfusion donors, IV: non-COVID-19 hospitalized patients, V: non-COVID-19 hospitalized patients stratified by ethnic group, VI: first-time transfusion blood donors. d Genome-wide association studies (GWAS) studies are marked in bold.

The number of patients included in the various studies has been highly variable,
ranging from several thousands to less than one-hundred. Yet, they generated very similar
results regardless of their high apparent differences in statistical power. This may be
explained if the effect of ABO phenotypes was stronger in some geographical areas as
discussed below. In that case, significant between-groups differences can be obtained with
a lower number of cases. Inversely, in some geographical areas where the effect is weaker
because of the relative frequencies of the ABO phenotypes, in particular a high frequency of
blood group O, it takes very high numbers of patients to document a significant distortion
of the ABO blood groups distribution in the patient groups, as illustrated by the lack of
association reported from Brazil [41].

When only data on severe hospitalized patients are analyzed very important risk
factors such as sex, age, obesity, cardiovascular, and metabolic underlying diseases are

Viruses 2021, 13, 160 9 of 20

involved. As discussed above, the ABO polymorphism is known to associate with some of
these COVID-19 risk factors, which might explain the link between blood group O and a
lesser risk of COVID-19. However, analyses evaluating the potential confounding effect of
these known risk factors showed that they cannot explain associations with ABO blood
groups [2,12]. This conclusion is reinforced by a study from Iran where young patients
(<45 y/o) without known underlying condition were enrolled. It showed a lower risk for blood group O in comparison with non-O types in absence of any strong comorbidity factor [13]. Inversely, one can also argue that the combined weight of these important risk factors is so high that it could mask any genetic effect on susceptibility to COVID-19 that would be more easily visible in the less severely affected patients who fortunately constitute the majority of patients. This could be the reason why one GWAS study failed to reveal a signal of association between COVID-19 and the ABO locus [37]. In that study, the control group was based on population data adjusted for ancestry, but the patient group was exclusively composed of patients under intensive care, excluding all non-severe cases and other hospitalized patients. Observing an effect on the risk of infection with this study design is therefore very difficult, unless the effect is very strong. Nonetheless, observing an effect on severity remains possible if a careful analysis of clinical data is performed within the patient group, which was not done in that particular study. In contrast, it was done in the study of Hoiland et al. [29] who also first compared ABO frequencies of patients requiring intensive care to those of the regional population and similarly failed to observe any difference between the patient and control groups. However, in a second analysis, even though it was based on a limited number of patients, the authors were able to uncover a clear effect of ABO phenotypes on severity by a careful analysis of ABO frequencies within the patient groups [29].

As the majority of COVID-19 infections result in a relatively mild disease, or even
remain asymptomatic, studies taking into account all diagnosed patients (RT-PCR+), re-
gardless of symptoms are well suited to find an effect on infection while inversely being
unable to observe associations with severity. It is worth noting that such studies consis-
tently observed either a lower risk for blood group O and/or an increased risk for non-O
groups, in particular blood group A (Table 1). It therefore seems quite clear that blood
group O individuals have a lower risk of SARS-CoV-2 infection relative to non-O blood
types. The only exception comes from a study conducted in Bahrain where, in addition to
the commonly observed increased risk for the A blood group, a significantly decreased risk
was found for blood group AB [28]. It should nevertheless be kept in mind that the AB
blood group is always the least represented and therefore that the data of that particular
study rest on a rather limited number of cases.

4.2. Studies Designed to Observe an Effect on Severity

Considering the consistent associations found between the risk of COVID-19 infection
and ABO blood types, observing potential associations with disease severity requires
comparison of blood group frequencies between patient subgroups presenting with dis-
tinct clinical characteristics. As shown above, comparing patients to non-infected controls
mainly reveals an effect on infection that will be diluted off when the disease has pro-
gressed to high severity. Revealing any effect on severity requires the comparison of blood
group frequencies between patients suffering from more or less severe forms of the dis-
ease. Several studies of this type were performed and their design and results are briefly
summarized in Table 2. Thus, Sardu et al. [30] reported that non-O Italian hypertensive
COVID-19 patients had higher values of prothrombic indexes, cardiac injury, and rates of
death than blood group O patients, consistent with the known effects of ABO blood groups
on thrombosis and cardiovascular diseases. Likewise, a very careful clinical analysis of
critically ill Canadian patients revealed that blood groups A and AB patients presented
a higher risk of requiring mechanical ventilation, continuous renal replacement therapy,
and prolonged admission to intensive care units than blood groups O and B patients [29].
In another study from Canada, the O blood group was also found associated with lower

Viruses 2021, 13, 160 10 of 20

severity, whereas the B and AB blood groups were associated with higher severity [15]. In
that study involving a large series of patients, the frequencies of ABO blood types were
compared between cases with severe illness or death and all other cases, severe illness
being defined as requirement for admission to intensive care unit. Independent data from
a very interesting approach were reported from Spain. In their work, the authors com-
pared hospitalized patients who required blood transfusion for their risk of death [12]. In
this group of patients, blood group A and a non-O blood group were associated with a
higher risk of death. Finally, a study on patients who had undergone transcatheter aortic
valve replacement showed that having blood group A was the only independent predictor
of COVID-19, but also predicted disease severity and death in this group of high-risk
patients [31]. Therefore, although it appeared more difficult to evidence than its effect
on infection, the association of blood group O with lower disease severity, or inversely
the harmful consequence of having A or non-O blood groups, also appears now well
established by these convergent studies, in accordance with the previously known effects
of ABO blood types on thrombosis and the vascular function.

Table 2. Studies specifically analyzing an effect on disease severity a.

Country Type of Study
ABO Effect b

Ref.
O A B AB

Italy
Analysis of clinical and biological criteria among hypertensive

COVID-19 patients

Canada
Analysis of clinical and biological criteria among critically ill

COVID-19 patients
risk risk [29]

Spain
Analysis of the risk of death among COVID-19 patients

requiring transfusion

Canada Separate analyses of patients with or without severe illness risk >risk [15]

France
Comparison between patients who underwent transcatheter

aortic valve replacement
ns >risk ns ns [31]

a Studies including patients of various severity degrees, not specifying clinical criteria and comparing with non-COVID-19 control groups
were not taken into account; b Significant associations are marked in green to indicate a decreased risk relative to the other blood types or
in red to indicate an increased risk; ns: non-significant.

4.3. Other Study Designs

In addition to the studies presented in Tables 1 and 2, several additional reports ana-
lyzed the risk of COVID-19 in relation to ABO blood types using quite distinct approaches.
These are listed in Table 3. Thus, two studies compared the frequencies of ABO blood
groups to COVID-19 prevalence between countries. The first one observed an association
between the frequency of blood group A and prevalence of the disease, while the other ob-
served an inverse relationship between the frequency of blood group B (including B + AB)
and prevalence of the disease [32,33]. This approach is very interesting but suffers from
two major weaknesses that will be discussed below. At this point, suffice it to say that they
concern the low accuracy of prevalence data and, most critically, the fact that it is not the
frequency of each blood type considered individually that matters at the population level.

Two other studies looked at the ABO types of blood samples collected for transfusion
that proved SARS-CoV-2 seropositive. The selection of blood donors implies that all of
these seropositive individuals had been free of symptoms during the two weeks preceding
donation. In the study from France, these cases represented 3% of blood donations and
presented an important deficit of blood group O in comparison with the remaining blood
donors who did not have SARS-CoV-2-neutralizing antibodies [34]. Although the approach
was similar, the study from Italy failed to find any bias in ABO blood types among the 1%
of SARS-CoV-2 blood donors who had antibodies against the viral N protein [39]. Whether
the discrepancy between the outcomes of these two studies is due to the different methods
used to assess infection, the different percentage of seropositive blood samples, or the
overall small number of concerned cases remains unclear.

Viruses 2021, 13, 160 11 of 20

Table 3. Other study settings reporting data on ABO blood groups and COVID-19.

Country Type of Study
ABO Effect a

Ref.
O A B AB

Europe, Africa,
Middle-East, Asia

Association between frequency of the A allele and
COVID-19 prevalence across countries

>Risk [32]

Europe, Africa,
Asia, America

Correlation between frequency of B+AB blood types
and COVID-19 prevalence across countries

France
Comparison of ABO phenotypes of blood donors

with SARS-CoV-2 neutralizing antibodies
Risk ns ns [34]

Italy
Comparison of ABO phenotypes of blood donors

with SARS-CoV-2 anti-N antibodies
ns ns ns ns [39]

France
Comparison of ABO phenotypes of COVID+ vs.

COVID− aircraft carrier crew members ns ns ns ns [40]

a Significant associations are marked in green to indicate a decreased risk relative to the other blood types or in red to indicate an increased
risk; ns: non-significant.

Finally, another publication reported the analysis of a large outbreak that occurred on
a French aircraft carrier [40]. While the vessel was in operation at sea, an outbreak occurred
unabated for two weeks before confinement measures were taken. A large number of
crew members were infected since the attack rate was 76%, but only 1.6% of the infected
sailors could be considered as severe cases, that is, requiring oxygen therapy or admission
to an intensive care unit. By comparing these 76% infected to the remaining 24%, no
difference in ABO blood group frequencies could be observed. At first sight, this negative
result appears to strongly contradict all the other reports discussed above that showed
significant associations between the risk of COVID-19 and ABO phenotypes. Yet, when
considered within the framework of the anti-ABO antibodies hypothesis, this result was
predictable. Anti-ABO antibodies lower the risk of transmission at the group or population
level, slowing progression of the epidemic [60,74]. In a confined situation such as that of
an aircraft carrier where the outbreak lasted until the virus infected over three quarters of
the personnel on board, nearly all susceptible individuals have been infected because of
multiple contacts. It should be remembered that O blood group individuals are susceptible
to transmission from other O blood group individuals. If the outbreak had been stopped
early, then blood group O crew members might have proven less represented among the
infected than among the non-infected crew members.

5. Consequences of between-Populations Differences in ABO Blood
Types Frequencies

Frequencies of the A, B, and O alleles and of the respective ABO phenotypes are quite
variable across human populations [50]. Overall, on the Eurasian continent, there exists a
gradient of blood group B whose frequency increases as one moves from west to east. This
increase takes place at the expense of both blood groups A and O that are less frequent in
East Asia than in Western Europe, the Middle East presenting intermediate frequencies [94].
The African continent is characterized by a rather large and complex diversity of ABO blood
groups frequencies between geographic locations and ethnic groups [33]. The American
continent is characterized by an extremely high frequency of the O blood type among
Amerindian populations, most notable in its Central and Southern parts [94]. Considering
these large differences between geographical areas and human populations, variation in
the impact of ABO phenotypes on COVID-19 is to be expected. Documenting an effect is
more difficult in ethnically mixed populations such as those of Western Europe or of the
Americas. As already mentioned, special care should therefore be given to alleviate biases
introduced by the population admixture as the risk of COVID-19 is clearly associated with
socioeconomical conditions, themselves associated with the ethnic background.

For all hypotheses raised to explain the links between ABO phenotypes and COVID-
19, variations in relative frequencies represent a basic statistical issue. Obviously, it is
more difficult to observe significant associations for less well represented phenotypes

Viruses 2021, 13, 160 12 of 20

and this may contribute to explain some of the divergences observed between studies.
In addition, and quite distinctly, within the framework of the anti-ABO hypothesis, the
variation in ABO phenotypes frequencies affects the outcome in a more complex manner.
Thus, anti-B antibodies from blood group A individuals may be protective from viral
particles emitted by blood group B individuals. Reciprocally, anti-A antibodies from blood
group B individuals can only be protective in the case of an ABO incompatible transmission
event originating from a blood group A person [60]. The relative proportion of blood group
A and B in the population will therefore be critical. This may explain why blood group
A appears as a risk factor more often than blood group B. Indeed, many studies were
performed on population showing a higher representation of blood group A than of blood
group B. Likewise, O blood group individuals if protected from transmission from non-O
individuals, cannot be protected from transmission by other O blood group individuals.
Consequently, the frequency of the O blood type in a population will be critical. At the
individual level, the maximal protection of O blood group individuals will take place when
they only represent a small fraction of the population. Inversely, when present in a large
proportion their protection by anti-ABO antibodies will vanish and completely disappear
if all individuals of the population were of the O blood type. With this in mind, we looked
for a correlation between the reported odd ratios of O versus non-O blood types to the
frequencies of blood group O in the studied population listed in Table I. To do this, we used
studies that reported the O blood group odd ratios in comparison with all other groups
and we also used the frequency of blood group O in the studied populations as reported by
the authors or deduced from previously published data. Figure 2A shows the results of the
analysis, indicating that, as predicted by the hypothesis involving anti-ABO antibodies, O
blood group individuals may benefit from a more important protection from SARS-CoV-2
infection in locations where blood group O frequencies are lower.

As the above observation suggested that the variable ABO frequencies across pop-
ulations may differentially impact the outcome of the pandemic between countries, we
looked for a potential correlation between ABO frequencies and SARS-CoV-2 attack rates
worldwide. As already mentioned above, the relationship between an ABO blood type
and susceptibility to COVID-19 is not straightforward, therefore individually relating each
ABO blood type to the virus attack rate may be misleading. At the population level, the
optimal protection that anti-ABO antibodies may provide should be attained when A, B,
and O phenotypes are more or less evenly distributed because protection should occur
only in ABO incompatible transmission events. In extreme situations, where one or two of
these three major phenotypes largely dominate, incompatible events will be less frequently
encountered. Thus, rather than looking for correlations between each ABO phenotype
and SARS-CoV-2 attack rates, we looked for correlations between ABO coefficients of
variation in different countries or geographical locations and SARS-CoV-2 attack rates.
Protection conferred by anti-ABO antibodies should be optimal in populations presenting
low coefficients of variation and inversely it is expected to be far less efficient or even not
efficient at all in populations where they are elevated. ABO coefficients of variation were
calculated using published frequencies of ABO blood types in different regions or coun-
tries. However, obtaining reliable SARS-CoV-2 attack rates that can be compared between
countries is rather complex. Rates of detection obtained following RT-PCR testing are
particularly unreliable since testing strategies have been very different between countries
and within countries during the unfolding of the pandemic. Using data such as the number
of COVID-19-related deaths/106 inhabitants may appear easier to compare. Yet, these may
be greatly affected by variable reporting strategies between countries and most importantly
by the age structure of the population as the risk of death increases exponentially with
age [95]. Older populations will therefore appear disproportionately affected, regardless
of other parameters. More reliable data were recently provided by O’Driscoll et al. [95]
using seroprevalence analyses from 45 countries or regions. Using these published median
values of proportions of SARS-CoV-2 seropositive individuals as of September 2020, we
found 41 countries with reliable published national ABO frequencies. As depicted on

Viruses 2021, 13, 160 13 of 20

Figure 2B, a strong positive relationship can be detected between infection rates and the
ABO coefficients of variation. It is noteworthy that countries of Central and South America
where blood group O is highly prevalent show the highest SARS-CoV-2 attack rates, as pre-
dicted by the hypothesis on anti-ABO antibodies protection limited to ABO incompatible
transmission events. Looking at a more homogeneous group of countries, both in terms of
ABO coefficient of variation and of socioeconomic status, European countries also show a
clear relationship between the distribution of ABO blood groups and infection attack rates
(r2 = 0.29, p = 0.012).

Figure 2. Relationship between ABO blood groups and the impact of COVID-19 across countries.
(A) Blood group O odd ratios (ORs) of COVID-19 relative to the other blood groups and blood
group O frequencies at various geographical locations. Odd ratios were obtained from the works
in [1–3,6,9–11,14,17–19,22,24], and the frequencies of blood group O were those reported in the
groups of controls of the corresponding studies, representing frequencies in the local populations.
OR values in populations where frequencies of blood group O are below and above 40% (O < 0.4 and O > 0.4, respectively) were compared by a two-tailed Mann–Whitney test. (B) Regression
analysis between coefficient of variation calculated from the distribution of ABO for each country and
attack rates represented by median estimates calculated by O’Driscoll et al. [95] from seroprevalence
studies. (C) Regression analysis between ABO coefficients of variation of each country and the
2018 IHDI (inequality-adjusted human development index) obtained from the UNDP (United Nation
Development Program). (D) Regression analysis between COVID-19 attack rates of each country and
the 2018 IHDI. Countries are labeled by geographic area. Cyan: Central and South Americas; blue:
Africa; green: Europe; yellow: North America; red: Asia.

Infection attack rates are very dependent on demographic and geographic variables,
the national policies of protection that have been set up by governments, as well as
by the socioeconomic conditions and inequalities [96–98]. To determine whether the
observed associations between ABO coefficient of variation and SARS-CoV-2 attack rates
actually revealed underlying covariation with historical between-population socioeconomic
inequalities, we looked for a potential relationship between the ABO coefficient of variation
and the inequality-adjusted human development index (IHDI). This index has been created
by the United Nation Development Program (UNDP) in order to best define the degree
of human development by taking inequalities into account. As shown on Figure 2C, we
controlled that there was no relationship between ABO coefficient of variation and the
IHDI. As unfavorable socioeconomic and demographic conditions have been discussed as

Viruses 2021, 13, 160 14 of 20

important drivers of the epidemic [99], we also tested whether the IDHI was associated
with the attack rates for the 41 countries that could be included in our analysis. This was
indeed the case (Figure 2D), but the correlation was not as strong as that observed between
attack rates and the ABO coefficients of variation. More refined indexes might be able to
better capture the effect of inequalities and poverty on the impact of COVID-19, but that is
beyond the scope of this article. Regardless, these observations suggest that the distribution
of ABO blood groups strongly impacts development of the COVID-19 pandemic when
looking at the level of populations. They suggest that the protective effect of anti-ABO
antibodies is particularly high in Asian countries, important in Europe and North America,
but unfortunately less important in countries of Central and South Americas where the
frequency of blood group O is disproportionately high in comparison with those of blood
groups A and B. This highly ABO-biased distribution is due to the large American Indian
populations in these countries as American Indians are almost exclusively of blood group
O [100]. Interestingly, in the USA, the impact of COVID-19 is extremely high among non-
Hispanic American Indians and Alaska Natives with attack rates 3.5 times higher than in
the white population [101]. It is also high among Hispanics (3 times higher compared to
whites) [21], followed by African-American (2.3 times higher compared to white) in parallel
with the frequencies of blood group O in these subgroups [21,102]. Similarly, a study from
the UK aimed at relating ABO phenotypes to the risk of COVID-19 in pregnant mothers,
reported the results of separate analyses of White and BAME (Black, Asian, Minority
Ethnic) women, the latter being overrepresented among the COVID-19 positive cases [35].
The ABO coefficients of variation were widely different between the two subgroups, 60%
and 28% for the White and BAME women groups, respectively. In accordance with the anti-
ABO hypothesis, in the White COVID-19+ group, O blood group was modestly decreased
in comparison to the White COVID-19− group (37% vs. 43%), but in the BAME cohort, the
effect was much more pronounced (25% vs. 40%). It is thus tempting to hypothesize that
the disproportionately high COVID-19 impact on the disadvantaged subgroups as well as
in some countries might be explained by a synergistic effect between ABO blood group
distribution and socioeconomic factors.

Although correlative and potentially influenced by other demographic covariates that
cannot be ruled out, the data presented in Figure 2 suggest that the protective effect of
anti-ABO antibodies could greatly contribute to the large COVID-19 disparities between
countries and population subgroups. It seems that non-pharmaceutical interventions, such
as population confinement and social distancing, are efficient when the ABO coefficients of
variation are low, as seen in some Asian countries that remarkably succeeded in controlling
the epidemic. However, when they are high, the non-pharmaceutical interventions fail
as illustrated by the examples of Latin American countries. When intermediate, as in
Europe, they work to some extent, but are still affected by the West–East gradient of ABO
frequencies, Eastern European countries tending to fare better, as of September 2020. All
this seems to indicate that when the frequency of blood group O is below 40% and blood
groups A and B are well balanced, the situation remains manageable, but when blood
group O frequency increases above 40% and that the frequencies of blood groups A and
B are unbalanced, management of the epidemic in absence of a vaccine turns out to be
more difficult.

6. Conclusions

Collectively, the data presented above indicate that ABO blood groups influence the
risk of SARS-CoV-2 infection and several studies additionally allow to ascertain an effect
of the ABO phenotypes on disease severity. In both situations, blood group O appears
protective in comparison with non-O types. As discussed above, the protective effect
on infection could be mediated either by natural anti-A and anti-B antibodies or by a
lower efficiency of furin cleavage in blood group O individuals. Both could lead to either
a complete protection or to lowering the initial viral load, which may have important
consequences by facilitating viral clearance by the immune system and preventing the

Viruses 2021, 13, 160 15 of 20

cytokine storm and ensuing ARDS. The observation of a link between ABO coefficient of
variation in different geographical areas and the odds ratios of blood group O relative to
other blood types as well as the COVID-19 attack rates suggest that anti-ABO antibodies
play a prominent role in protection against infection but that their impact is heavily
influenced by the relative frequencies of ABO phenotypes in the population.

The previously well-documented influence of ABO phenotypes on hemostasis and
vascular function, likely contributes to the lower severity of the disease observed among
already severely affected patients of blood group O in comparison with non-O blood
group patients. Other mechanisms could also contribute, including effects of the ABO
polymorphism on inflammation and immune functions as well as on lipid metabolism.

At the individual level, the increased risk of severe COVID-19 symptoms associated
with non-O blood groups is generally modest. Therefore, it is not clear if that information
can be useful at the clinical level. Nonetheless, in selected groups of patients, such as
patients with underlying cardiovascular diseases it may be of importance, as illustrated by
the study of Sardu et al. on hypertensive patients which detected a 3.7 times increased risk
of death in non-O blood group patients [30]. Special attention could be important for such
high-risk patients who may need early anticoagulant therapies in order to reduce cardiac
injury, as suggested by the authors.

Until recently, the only evidence that natural anti-ABO antibodies played any sig-
nificant biological role, besides their importance for blood transfusion and organ trans-
plantation, came from artificial in vitro observations and indirectly from the association
between ABO phenotypes and SARS [74]. The new data accumulated on COVID-19 point
to a role of these antibodies in the control of outbreaks at the population level. Anti-ABO
antibodies could also help controlling infection by other coronaviruses as these viruses
are highly glycosylated and replicate in epithelial cells of the upper respiratory tract that
strongly express ABH antigens in accordance with the ABO and FUT2 genes polymor-
phisms. There is evidence that anti-A and B titers are decreasing in relation with improved
living conditions [49]. This phenomenon could contribute to facilitate virus transmission in
contemporary societies with high standards of living. Moreover, COVID-19 patients have
lower levels of anti-ABO antibodies than control individuals, suggesting that these anti-
bodies are protective only when present in sufficient amounts [72]. Interestingly, levels of
natural anti-glycan IgM, including anti-ABO, decrease with aging, which may contribute to
the increased risk of infection in the elderly [103]. Acting to increase these antibodies titers
at the population level would thus be desirable in order to take full profit of this natural
antiviral defense mechanism. Although a detailed discussion of the means by which anti-
ABO antibodies could be raised at the population level is beyond the scope of this article, a
possibility would be to use selected probiotic bacterial strains that express the A and/or
B antigens as it is largely under stimulation of bacteria from the microbiota that these
antibodies are naturally raised. A transfusion accident was reported where a platelet donor
had an extremely high anti-B titer following ingestion of a probiotic preparation containing
several species of harmless bacteria [104]. Similarly, pediatric patients developed anti-B
in association with probiotic use [105], suggesting that this could be a broadly applicable
strategy as a complement to the SARS-CoV-2 vaccine strategy. Populations where ABO
coefficients of variation are low or intermediate could slow down the virus transmission to
a large extent, making it easier to control the epidemic. Even populations that present high
ABO coefficients of variation could benefit from the anti-ABO protective effect, albeit to a
lesser degree. That would increase the efficacy of both non-pharmaceutical interventions
and of vaccines if used as a complementary tool in the fight against COVID-19.

Author Contributions: Conceptualization, J.L.P., A.B., J.R., M.D., and N.R.-C.; Data analysis, J.L.P.;
Writing—Original Draft Preparation, J.L.P.; Writing—Review and Editing, J.L.P., A.B., J.R., M.D.,
and N.R.-C.; Supervision, J.L.P. All authors have read and agreed to the published version of the
manuscript.

Funding: This research received no external funding.

Viruses 2021, 13, 160 16 of 20

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Data used to generate Figure 2 are available upoin request.

Acknowledgments: This work was supported by institutional funding from Inserm (Institut National
de la Santé et de la Recherche Médicale), l’Université de Nantes, and the CHU de Nantes. The authors
thank Dorian McIlroy for careful editing of the manuscript and insightful comments. The funders
had no role in conceptualization, synthesis, or decision to submit this work for publication.

Conflicts of Interest: The authors declare no conflict of interest.

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    • Introduction
    • The ABO Blood Group System at a Glance
    • Hypotheses Linking ABO Types and COVID-19 and Their Consequences on the Interpretation of Reported Associations
    • The Anti-ABO Antibodies
      The ABO Effect on Thrombosis
      ABO Blood Groups and the Furin Cleavage Site
      ABO Blood Groups and Susceptibility to Other COVID-19-Associated Risk Factors
      ABO Blood Groups and the Microbiota

    • Studies Linking ABO Blood Types to COVID-19
    • Case–Control Studies Designed to Observe Associations
      Studies Designed to Observe an Effect on Severity
      Other Study Designs

    • Consequences of between-Populations Differences in ABO Blood Types Frequencies
    • Conclusions
    • References

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