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Updates on Rabies virus disease: is evolution toward
“Zombie virus” a tangible threat?
Giuseppe Lippi1, Gianfranco Cervellin2
1Section of Clinical Biochemistry, University of Verona, Verona, Italy; 2Academy of Emergency Medicine and Care, Pavia, Italy
Abstract
Human rabies disease is caused by Rabies Lyssavirus, a virus belonging to Rhabdoviridae family. e more
frequent means of contagion is through bites of infected mammals (especially dogs, but also bats, skunks,
foxes, raccoons and wolves) which, lacerating the skin, directly inoculate virus-laden saliva into the underly-
ing tissues. Immediately after inoculation, the Rabies virus enters neural axons and migrates along peripheral
nerves towards the central nervous system, where it preferentially localizes and injuries neurons of brainstem,
thalamus, basal ganglia and spinal cord. After an initial prodromic period, the infection evolves towards
two distinct clinical entities, encompassing encephalitic (i.e., “furious”; ~70-80% of cases) and paralytic (i.e.,
“dumb”; ~20-30% of cases) rabies disease. e former subtype is characterized by fever, hyperactivity, hydro-
phobia, hypersalivation, deteriorated consciousness, phobic or inspiratory spasms, autonomic stimulation,
irritability, up to aggressive behaviours. e current worldwide incidence and mortality of rabies disease are
estimated at 0.175×100,000 and 0.153×100,000, respectively. e incidence is higher in Africa and South-
East Asia, nearly double in men than in women, with a higher peak in childhood. Mortality remains as high
as ~90%. Since patients with encephalitic rabies remind the traditional image of “Zombies”, we need to think
out-of-the-box, in that apocalyptic epidemics of mutated Rabies virus may be seen as an imaginable menace
for mankind. is would be theoretically possible by either natural or artificial virus engineering, producing
viral strains characterized by facilitated human-to-human transmission, faster incubation, enhanced neuro-
toxicity and predisposition towards developing highly aggressive behaviours. (www.actabiomedica.it)
Key words: rabies virus; rabies disease; epidemiology; zombie
Acta Biomed 2021; Vol. 92, N. 1: e2021045 DOI: 10.23750/abm.v92i1.9153 © Mattioli 1885
Review
The Rabies virus
Rabies disease is mostly sustained in humans by
Rabies Lyssavirus, a virus belonging to the large family
of Rhabdoviridae, comprised within the Mononega-
virale order (1). It is conventionally assumed that the
original virus shall have evolved in Old World bats,
which then shifted to carnivores and spread globally.
e virus is characterized by a bullet-shaped struc-
ture, sizing approximately 75×200 nm, and is substan-
tially divided in two parts, encompassing a structural
(i.e., the viral envelope) and a functional (i.e., the
ribonucleoprotein; RNP) unit. e ~12 kd RNA of
the virus contains five major genes, encoding five cor-
responding viral proteins (1). Briefly, (i) the N gene
encodes the nucleoprotein encapsulating both viral
and unsegmented negative-stranded RNA, (ii) the P
gene encodes a phosphoprotein involved in transcrip-
tion and replication activities, as well as in mediating
interplay with cellular proteins during neural transpor-
tation (see below), (iii) the M gene encodes a matrix
protein, (iv) the G gene encodes a transmembrane
glycoprotein, which mediates binding during initial
infection and seems to be the major antigenic domain
Acta Biomed 2021; Vol. 92, N. 1: e2021045
2
follow a prevalent intra-neuronal localization, and a
clear viraemia is hence probably absent in mammals
(13). Moreover, the Rabies virus can be very rapidly
inactivated by sunlight (i.e., ultraviolet rays) and heat
exposure, so that its chances of survival outside the
host are extremely limited. It seems reasonable to con-
clude that the cumulative risk of human-to-human
infection appears definitely low, except in the case of
direct inoculation of human saliva (e.g., through vol-
untary or involuntary bite) of infected individuals (13).
Immediately after inoculation, the virus enters
neural axons of sensory and motor nerves with an
endosomal transport pathway, and then migrates
along peripheral nerves (through fast axonal trans-
port system) towards the CNS, with a speed esti-
mated at approximately 8-20 mm/day (4). According
to this velocity of propagation, the incubation period
of rabies disease depends on the site of inoculation,
whereby in patients who have been infected at distant
sites (i.e., arms or legs) the virus would need longer
time to reach the CNS than in those bitten on face or
neck. Although no clear receptor mechanism has been
elucidated so far, it seems that nicotinic acetylcholine
receptor (nAchR) and neural cell adhesion molecule
(NCAM) may play a role in concentrating virus par-
ticles at the neuromuscular junction and providing a
more efficient transportation within the intracellular
space. Once the intact virions have reached the CNS
(thus producing pathognomonic cytoplasmic inclu-
sions, known as “Negri bodies”), viral replication starts
by transcription of viral genome by P-L polymerase
and further assembly of new viruses, especially in dor-
sal-root ganglia and anterior-horn cells. e virus then
propagates throughout the CNS, principally through
plasma-membrane budding, cell-to-cell direct infec-
tion or trans-synaptic dissemination, with preferential
localization in brainstem, thalamus, basal ganglia and
spinal cord (3). Importantly, major damages to the lim-
bic system are those responsible for onsets of the typical
emotional and motivational symptoms characterizing
patients with viral encephalopathy (2). e cumulative
neurotoxicity is perhaps the result of a combination
of direct cell damage due to virus replication, as well
as to development of immune response and autoim-
mune reactions against infected neurons. Importantly,
the huge cytokines production that accompanies CNS
responsible for generation of neutralizing antibodies
and, finally, (v) the L gene encodes a RNA polymer-
ase (1). e viral capsid is typically surrounded by host
cell-originating plasma membrane, strictly interacting
with the matrix protein and the transmembrane gly-
coprotein. Overall, Rabies viruses are divided into two
major phylogroups, accounting for a total number of
up to 14 different genotypes (2). Among these, geno-
type 1 seems to be the most prevalent, and also that
causing the largest number of human infections (3).
Physiopathology of Rabies virus infection
Although all the precise mechanisms involved in
the physiopathology of Rabies virus infection have not
been thoughtfully discovered and defined so far, several
important aspects can be summarized. e more fre-
quent means of Rabies virus transmission in humans
is through bites of infected mammals which, lacerat-
ing the skin, directly inoculate virus-laden saliva into
underlying tissues. Dogs are the most frequent vehicles
of infection in poor countries, whilst virus inoculation
by other mammals such as bats, skunks, foxes, raccoons
and even wolves has been reported in developed coun-
tries (4). e risk of virus inoculation through bites
is highly variable (i.e., between 5-80%), depending
on bite severity, animal species, virus concentration,
amount of saliva inoculation and so forth, but remains
consistently higher than after simple scratchs (i.e., 0.1-
1.0%) (1). In particular, a recent study reported that
the risk of virus inoculation by animal bite exposure is
the highest for skunks, followed by bats, cats and dogs
(5). In general, bites involving the face, neck or hands
expose the patient to the highest risk of contagion,
especially when the lesion is accompanied by profuse
bleeding (1). Since Rabies virus is actively present in
many human biological fluids, especially cerebrospinal
fluid (CSF), saliva, urine and tears, as well as at the
nape of neck containing hair follicles (6), an acciden-
tal and involuntary human-to-human transmission is
theoretically possible (7,8), as also revealed by publica-
tion of a number of paradigmatic case reports (9-12).
Nonetheless, cases of rabies contamination through
direct contact with blood of infected humans have
not been described so far, whereby the virus seems to
Acta Biomed 2021; Vol. 92, N. 1: e2021045 3
nearly half of the patients few hours before death, which
can also occur for respiratory, cardiac and circulatory
arrest during severe spasm episodes (4). Taken together,
these signs and symptoms would contribute to associate
a rabid patient with the traditional image of a “Zom-
bie”, as originally depicted by George A. Romero in his
notorious 1968 movie “e Night of the Living Dead”
(17), where humans were transformed into aggressive,
flesh-eating cannibals after being exposed to radiations
of space probe which exploded in the atmosphere while
coming back from Venus.
e paralytic, and less frequent form of rabies, is
mostly characterized by weakness due to peripheral
nerve dysfunction attributable to the combined effect
of an autoimmune reaction against the infected cells
and activation of immune response against the viruses
within the axons (4). Unlike the encephalitic subtype,
where brain stem, cerebrum and limbic system are
especially affected, this form mainly involves medulla
and spinal cord (18). is mostly leads to appearance
of symptoms like muscular paralysis and facial dipare-
sis. e CNS involvement develops later in the course
of disease, evolves towards coma and is then usually
followed by death (4).
Epidemiology of rabies
e most updated statistics on rabies epidemiol-
ogy can be garnered from the database of the Global
Burden of Disease (GBD) Study 2017 (19), which is
currently considered the most comprehensive world-
wide repository of health-related information (20).
e trends of incidence and mortality of this condition
over the past 3 decades are reported in figure 1, which
clearly shows that both these epidemiologic meas-
ures have considerably declined, by approximately
80%, between the years 1990-2017. In 2017 (i.e.,
the last accessible year in the GBD database), rabies
disease has an estimated incidence and mortality of
0.175×100,000 and 0.153×100,000, respectively (i.e.,
~13200 cases and ~11500 deaths around the world).
Notably, the mortality rate has also contextually
declined during the past 30 years, from 96% to 87%,
thus mirroring the combination of improved diagnosis
and better therapeutic care.
infection generates a strong impact on hippocampus
and other limbic-system functions, thus impairing
electrical cortical activity, hypothalamo-pituitary-
adrenal axis and serotonin metabolism (4). Later in the
course of disease, Rabies virus returns to the periphery
by means of intra-axonal transport, with enhanced tro-
pism for salivary and lacrimal glands (14).
Pathology and clinics of Rabies virus infection
e so-called prodromal stage typically initiates
when the virus propagates from peripheral nerves to
dorsal-root ganglia (i.e., triggering neuropathic pain),
up to the CNS. Along with prickling or itching sensa-
tion at the site of the original bite, the initial symptoms
appear relatively non-specific, mimicking an influenza
syndrome, and thus encompassing fever, general weak-
ness and headache (1). After this initial period, whose
length is somewhat variable (i.e., between 2-10 days),
the infection can then evolve towards two distinct
clinical entities, encompassing encephalitic (i.e., “furi-
ous”; ~70-80% of cases) and paralytic (i.e., “dumb”;
~20-30% of cases) rabies (4).
e former subtype (i.e., encephalitic) of rabies is
also the most severe, whereby the vast majority of these
patients die within 1 week of onset, and display fever,
hyperactivity aggravated by thirst, fear, light, noise
and other external stimuli. Within 24 hours from the
onset of the first symptoms the patients also develop
hydrophobia, hypersalivation, fluctuating conscious-
ness, hallucinations, phobic or inspiratory spasms
(often accompanied by fearful facial expressions), along
with signs of autonomic stimulation. Importantly, the
impaired serotonin neurotransmission due to injured
brainstem cells is frequently accompanied by marked
agitation and irritability, and can occasionally evolve
toward aggressive behaviours (15). roughout this
period, patients shall be preferably isolated and sedated,
to prevent that they may involuntarily injury, or even
contaminate, relatives and/or the healthcare staff (16).
e mental status varies, characterized by almost normal
periods alternated with severe agitation or depression,
up to consciousness deterioration and coma. Seizures
are not very frequent, but can occasionally develop in
pre-terminal stage. Hematemesis may be present in
Acta Biomed 2021; Vol. 92, N. 1: e2021045
4
e geographic distribution of rabies disease in
the year 2017 is shown in figure 2. e worldwide area
with the highest incidence and mortality is Africa, fol-
lowed by South-East Asia, Eastern Mediterranean and
Western Pacific, whilst the values of both these epi-
demiologic measures is <0.01×100,000 in Europe and
Americas. e highest burden of rabies disease cases
described in Africa (i.e., 0.40×100,000) and South-
East Asia (0.34×100,000) is clearly dependent on
insufficient infrastructure for preventing, diagnosing
and rapidly establishing post-exposure prophylaxis, as
well as on ubiquity of wild and domestic animals, which
enormously magnifies the risk of human contagion (2).
Notably, the incidence of rabies disease in Romania
(which is - incidentally - the ancestral vampires’ home-
land) is over 2-fold higher than in the rest of Europe
(i.e., 0.011×100,000 vs. 0.005×100,000). e distinc-
tive geographical localization of rabies disease mirrors
that of the socio demographic index (SDI), since the
incidence in countries with low SDI (0.445×100,000)
is nearly 4-fold higher than in medium SDI countries
(0.102×100,000), being approximately 300-fold higher
than in high SDI countries (0.002×100,000).
e age and sex distribution of rabies disease is
then summarized in figure 3, showing that the overall
Figure 1. Epidemiology of Rabies virus disease during the past
three decades.
Figure 2. Geographical distribution of Rabies virus disease.
Figure 3. Sex- and age-related epidemiology of Rabies virus
disease.
incidence is nearly double in men than in women
(i.e., 0.22×100,000 vs. 0.13×100,000). e epidemi-
ology in men is characterized by an almost triphasic
curve, with peaks of incidence in the childhood (i.e.,
between 0-14 years), in the middle age (i.e., between
40-54 years) and in the elderly (i.e., after 75 years of
age), whilst the epidemiology in women seems more
homogenous, with an initial peak in childhood, a fur-
ther decline between 10-29 years and a final (virtually
stable) increase throughout adulthood.
Acta Biomed 2021; Vol. 92, N. 1: e2021045 5
Could Rabies virus become a “Zombie virus”?
e term “rabies” most likely derives from the
old Indian root word “rabh”, which stands for “mak-
ing violence” (21). It is hence not surprising that the
most devastating phenotype of encephalitic (“furi-
ous”) rabies disease is that of an individual displaying
hypersalivation, hydrophobia, paranoia, hyperactiv-
ity, hyperirritability and abnormal aggressiveness (4).
Interesting evidence has recently been published by a
team of scientists from the University of Alaska Fair-
banks (22), who demonstrated that a specific sequence
within the Rabies virus glycoprotein, which has partial
homology with snake toxins, is capable to inhibit the
nAchR in the CNS, thus modifying animal behaviours
and triggering high excitability and hostility.
e hypothesis of viral infection as primary cause
of a “Zombie” transformation (i.e., “zombification”) is
not new, since it has already been proposed in both the
“Resident Evil” movie series and by “Walking Dead”
comics, nearly 20 years ago (23). In the former case,
the so-called “Tyrant Virus” (also known as “T-Virus”)
was originally developed by the imaginary pharma-
ceutical company “Umbrella Corporation” in the late
1970s, with the primary scope of eradicating some
genetic diseases. Nevertheless, the innate characteris-
tics of the T-Virus persuaded some scientists to pro-
mote its conversion into a biological weapon, whereby
the pathogen would have been capable to almost irre-
versibly damage the CSF (especially neurons in frontal
lobe, somatosensory cortex and hypothalamus), thus
generating a dramatic decline in intelligence and motor
functions in the host, but preserving many elementary
function, reducing pain responsiveness and amplify-
ing psychotic rage, persistent hunger, and increased
aggressiveness (i.e., “zombification”) (17).
Some intriguing cases of “pseudo-zombification”
have also been reported in the scientific literature,
mostly occurring in Haiti (where the original term
“Zombie” was coined), as result of tetrodotoxin and/
or Datura stramonium intake (24), or more recently
in the US, after mass intoxication with synthetic can-
nabinoids such as AMB-FUBINACA (25). e risk
of a “Zombie emergency” has also been seriously con-
templated by the US Centers for Disease Control and
Prevention (CDC), issuing an official manual entitled
“Preparedness 101: Zombie Pandemic” (26) (Fig. 5),
which aims to prepare healthcare and civil resources to
handle epidemic threats, among which Zombie infes-
tation is perhaps the most paradigmatic example. is
document has then been followed by another guide,
endorsed by the US Government, and specifically
called “Counter-Zombie Dominance” (27). is sec-
ond document contains the thoughtful description of
how a military strategy shall be established for defend-
ing the nation against an imaginable Zombie alert,
thus encompassing detailed information on biological
characteristics of “enemy force”, on available means for
preventing pathogen transmission, as well as on con-
ceivable strategies that shall be planned for prevent-
ing collapse of civilized society (27). erefore, some
discernible questions would follow. Specifically, how
much human rabies disease overlaps with “zombifica-
tion”? And, would it be possible that a mutated Rabies
virus epidemics (or pandemic) will transform mankind
into Zombies?
e first important aspect is defining the risk of
human-to-human transmission, the mainstay of the
imaginary Zombie contagion (28). It has been previ-
ously highlighted that bloodborne transmission is very
unlikely for rabies disease, whereby viraemia does not
seemingly occur with this type of infection. e sur-
vival of Rabies virus outside the host is also frankly
poor, so that the most probable means of human-to-
human transmission would need direct inoculation of
the pathogen through bites from infected people (13).
Rabies virus detection in saliva of infected humans has
been reported as being the highest 2-3 days after the
onset of symptoms, remains apparently stable for 2-7
days afterwards, and then apparently declines (29).
roughout the contagious window, it shall hence be
assumed that patients with overt rabies disease would
be so aggressive against their own kind to feel the
uncontrollable instinct to bite them. Although there
is only sporadic evidence of rabid patients biting other
humans (e.g., a 41-year-old woman died of rabies dis-
ease after being bitten by her 5-year-old son, who in
turn had developed the pathology after being bitten
by a rabid dog) (9), this possibility cannot be straight-
forwardly excluded. e real incidence of human
bites is largely underestimated due to under-report-
ing, and also because affected people tend to avoid
Acta Biomed 2021; Vol. 92, N. 1: e2021045
6
medical care. Nevertheless, current evidence suggests
that mammalian bites would account for almost 1% of
all emergency department visits, up to 20% of which
are attributable to human bites (i.e., 0.2% of all emer-
gency department admission) (30). erefore, the
suggestion that extremely aggressive rabid patients
would suffer from an incontrollable instinct to bite
other humans, and thus transmitting the infection,
remains actual. Interestingly, the Advisory Committee
on Immunization Practices of the CDC suggests that
post-exposure prophylaxis shall be planned for all peo-
ple with mucous membranes or non-intact skin expo-
sure to potentially infectious body fluids from rabid
patients (31), thus implicitly confirming that the risk
of human-to-human transmission of rabies disease is
not irrelevant.
e comparison of the current image of a Zombie
with that of a rabid patient is a second import aspect
that needs to be accurately scrutinized. As already
emphasized, conventional Zombies, as depicted in
comics and movies (23), share some similar behaviours
with patients infected by Rabies virus. Both undergo a
variable degree of consciousness deterioration, which
tends to be almost identical in the last stages of rabies
disease. Both individuals display also fearful facial
expressions, increased hyperirritability and aggressive-
ness, which can be both substantially accentuated by
external stimuli (thirst, fear, light and noise) in rabid
patients (Figure 4), and may ultimately evolve toward
violent and ferocious behaviours.
at said, it is now widely acknowledged that
many viruses are characterized by naturally occurring
Figure 4. Clinical similarities between encephalic rabies disease and imaginary “zombification”.
Acta Biomed 2021; Vol. 92, N. 1: e2021045 7
Figure 5. e Centers for Disease Control and Prevention (CDC) manual “Preparedness 101: Zombie Pandemic”.
Acta Biomed 2021; Vol. 92, N. 1: e2021045
8
high mutation rates, which induce constant changes
as reliable means for escaping host defences or facili-
tating their transmission to other susceptible hosts.
Rabies virus makes no exception to this rule, as
recently described by Wang et al (32), who found a vast
array (up to 100) of antigenic variants of this pathogen
in a wide range of animal hosts and geographic loca-
tions. Notably, even single amino acid mutations in the
proteins of Rabies virus can considerably alter its bio-
logical characteristics, for example increasing its path-
ogenicity and viral spread in humans, thus making the
mutated virus a tangible menace for the entire man-
kind (33). Beside the natural evolution of Rabies virus,
an equal threat may come from the science of genetic
engineering, which would reproduce the theatrical
scenario depicted in the movies of the Resident Evil
saga (23). By means of genetic engineering, scientists
have already developed innovative biological weapons,
which would appear more powerful and destructive
than their natural counterparts (34). e outbreak of
severe acute respiratory syndrome (SARS) in 2003, in
China, is perhaps the most paradigmatic example (35),
whereby many biological features of the pathogen
have led some eminent scientists to conclude that the
SARS virus might have been produced under labora-
tory conditions (36). Would a mutated Rabies virus,
bearing one or more mutations such as those described
by Hueffer et al (22), and hence characterized by facil-
itated human-to-human transmission, faster incuba-
tion, enhanced neurotoxicity and predisposing towards
aggressive highly behaviours, become the most lethal
biological agent that humans have ever faced?
Conclusions
e Rabies virus, like the vast majority of other
pathological microorganisms, attempts to perpetuate
itself with general and reservoir host-specific mecha-
nisms, which ultimately confer a considerable epide-
miological plasticity. e pace and phenotype of rabies
infection are mostly written in the virus genome,
whilst transmission is strongly favoured by aggres-
sive behaviours (i.e., a biting inclination) of rabid
hosts (37). Despite incidence and mortality of rabies
disease have both markedly declined during the past
three decades (Fig. 1), and irrespective of whether the
genetic code of Rabies virus can be naturally (i.e., by
ecological opportunities and viral adaptation) or arti-
ficially (i.e., by genetic engineering) modified, we need
to think “out-of-the-box”, in that the generation of a
“Zombie virus” cannot be firmly excluded according to
the currently available biological evidence (38). Wave-
front velocity of rabies disease propagation has been
calculated in wild animals (e.g., foxes, skunks, raccoons
and vampire bats) at around 10-40 km per year (37).
However, in densely populated towns, where natural
landscape barriers would be minimal, the human-to-
human contagion may increase by several orders of
magnitude, thus easily assuming apocalyptic propor-
tions and creating a new generation of pseudo-human
creatures, who have completely unleashed their already
existing part of zombie within (39). In keeping with
this conjecture, an interesting simulation of an imag-
inary Zombie outbreak reveals that most of the US
population would turn into Zombies within one week
from appearance of the first case, whilst only some
remotes zones in Montana and Nevada would remain
infestation-free one month afterwards (40).
In conclusion, what has become rather clear so
far is that rabies disease is entirely preventable, while
encephalomyelitis has never been described in people
who had received pre-exposure vaccination or post-
exposure booster (41). erefore, although the trans-
formation of Rabies virus into a “Zombie virus” will
always remain a tangible threat surrounding human
future (Fig. 1), further efforts shall be made for dis-
seminating a culture of widespread knowledge, preven-
tion and surveillance against this and other potentially
devastating viruses (42).
Conflict of interest: Each author declares that he or she has no
commercial associations (e.g. consultancies, stock ownership, equity
interest, patent/licensing arrangement etc.) that might pose a con-
flict of interest in connection with the submitted article.
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Correspondence:
Received: 10 January 2020
Accepted: 15 January 2020
Prof. Giuseppe Lippi. Section of Clinical Biochemistry,
University Hospital of Verona, Piazzale LA Scuro, 37134
Verona, Italy. Email: giuseppe.lippi@univr.it
