Rev. sci. tech. Off. int. Epiz., 2000, 19 (1), 92-97
Monkeypoxvirus infections
S.R. Pattyn
Emeritus Professor of Microbiology, Institute of Tropical Medicine and University Hospital Antwerpen,
Nationalestraat 155, 2000 Antwerp, Belgium
Summary
During and after the smallpox eradication campaign, human cases of monkeypox
appeared in West and Central Africa, as isolated cases or as small epidemics.
Since inter-human transmission has never or only very exceptionally been
documented, monkeypox does not represent a serious threat to humans. The virus
reservoir is among tree squirrels living in the tropical rain forests of Africa and
humans are infected by hunting, killing and skinning these animals. However, the
modernisation of society lessens human contact with the virus reservoir. Since
the eradication of smallpox, stocks of variola virus have been maintained;
whether these stocks should now be destroyed is a political question, which is
seriously compromised by mistrust between countries.
Keywords
Monkeypox - Orthopoxviruses - Public health - Smallpox - Variola - Virus reservoirs Virus stocks-Zoonoses.
Introduction
T h e principal interest of m o n k e y p o x , besides the ecology of
the virus, w h i c h remained an enigma for m a n y years, lies in
the relation of the disease with h u m a n smallpox and smallpox
eradication.
After the last case of smallpox h a d b e e n d o c u m e n t e d o n
2 6 October 1977 in Somalia, the Global C o m m i s s i o n for the
Certification of Smallpox Eradication certified global
eradication in 1980 and advised the discontinuation of
smallpox vaccination. This encountered a great deal of
scepticism and e v e n disbelief in medical circles. Many p e o p l e
found it difficult to admit that a dreadful disease, present since
time immemorial, h a d b e e n eradicated, especially since the
last cases h a d b e e n notified in regions w h i c h w e r e difficult to
access and w e r e not d e v o i d of political turmoil. Moreover,
m a n y feared that smallpox eradication and the a b s e n c e of
smallpox vaccination w o u l d create a form of immunological
void, ready to b e o c c u p i e d b y any n e w threat, as though a
biological rule existed that m a n k i n d should b e plagued b y
dreadful infections. In this view, m o n k e y p o x v i r u s , w h i c h h a d
caused sporadic h u m a n infections in Africa since 1970, was
the m a i n suspect. T h e virus was s e e n as potentially still
m o r e dangerous w h e n , in the Netherlands and in the Union
of Socialist Soviet Republics, viruses
indistinguishable
from smallpox w e r e obtained through manipulations of
monkeypoxvirus in the laboratory (11). However, the latter
threat was r e m o v e d relatively rapidly w h e n
these
m o n k e y p o x - d e r i v e d smallpox strains w e r e s h o w n to b e
laboratory contaminations.
Careful epidemiological studies c o n d u c t e d b e t w e e n 1970 and
1986 confirmed the 1979 thesis of the Global C o m m i s s i o n for
the Certification of Smallpox Eradication that m o n k e y p o x did
not constitute a n e w threat for humans. W i t h the hindsight of
another twenty years, this thesis has b e e n amply confirmed,
although as late as 1996-1997, m o n k e y p o x was active o n c e
again. In the meantime, the virus reservoir of m o n k e y p o x was
discovered, and k n o w l e d g e concerning the virus has
b r o a d e n e d , confirming b e y o n d d o u b t that m o n k e y p o x is not
an emerging disease.
Importance for animal and
public health
M o n k e y p o x occurs sporadically a m o n g m o n k e y s and
n o n - h u m a n primates in captivity in Europe and N o r t h
America. T h e virus gives rise to a b e n i g n eruption, and is m o r e
a nuisance than a disease. Humans m a y also b e infected
sporadically, mainly in Central Africa, from the reservoir in
the wild. W i t h the increasing urbanisation of the h u m a n
population and the decline of traditional ways of life,
m o n k e y p o x is probably a disappearing disease. However,
political unrest in the tropical rain forests of Africa m a y create
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Rev. sci. tech. Off. int. Epiz., 13(1)
conditions favourable for an o u t b r e a k of the disease, as was
the case in 1 9 9 6 and 1997.
Aetiological agent: classification
and characterisation
Poxviruses are the largest vertebrate viruses k n o w n . T h e
virions contain a linear double-stranded deoxyribonucleic
acid (DNA) g e n o m e and e n z y m e s that synthesise messenger
ribonucleic acid (RNA). T h e viruses multiply in the cytoplasm
of the host cells. T h e poxvirus family consists of two
subfamilies, namely:
the Chordopoxvirinae
and
the
Entomopoxvirinae, with the Chordopoxvirinae consisting of
eight genera. M e m b e r s of a genus are genetically and
antigenetically related. T h e genus Orthopoxvirus c o m p r i s e s
c a m e l p o x , c o w p o x , ectromelia, m o n k e y p o x , r a c o o n p o x ,
s k u n k p o x , taterapox, Uasin Gishu, vaccinia, variola and
v o l e p o x . African swine fever viruses share s o m e properties of
the poxviruses. Many poxviruses are associated with a specific
vertebrate species, w h i c h indicates that the transmission of
these viruses occurs preferentially a m o n g o n e particular
vertebrate species. Accidental transmission to another
vertebrate species can occur, but without production of the
necessary clinico-pathological conditions to b e maintained in
this 'aberrant' species (7).
The orthopoxviruses able to infect h u m a n s are variola,
vaccinia, c o w p o x a n d m o n k e y p o x . Variola virus is a virus
w h i c h only infects h u m a n s ; two remaining virus stocks are
maintained: o n e in the United States of America (USA) and
the other in the Russian Federation. Vaccinia virus, the
smallpox vaccine virus, d o e s not exist in nature, the virus
originated in the 18th Century from an u n k n o w n vertebrate
species. C o w p o x is a rodent virus that m a y infect cats, c o w s
and z o o animals a n d through these, h u m a n s . M o n k e y p o x is
also a rodent virus, and occurs only in W e s t and Central
Africa.
The identification of m o n k e y p o x v i r u s is b a s e d o n biological
characteristics and endonuclease patterns of viral DNA. In
contrast to smallpox, m o n k e y p o x v i r u s can infect rabbit skin
and can b e transmitted serially b y intracerebral inoculation of
mice. T h e four orthopoxviruses that m a y infect m a n p r o d u c e
macroscopically characteristic lesions o n the inoculated
chorioallantoic m e m b r a n e of an e m b r y o n a t e d c h i c k e n egg
(4, 11). T h e m a x i m u m , or 'ceiling' temperature at w h i c h the
viruses can proliferate in the chorioallantoic m e m b r a n e differs
for m o n k e y p o x and smallpox. T h e s e viruses differ also in the
ability to multiply in different tissue culture cells. However, at
present the clearest results are obtained b y the endonuclease
restriction patterns of the virus DNA (6). S o m e genetic
variation h a s b e e n found b e t w e e n m o n k e y p o x v i r u s e s from
West and Central Africa. O n the basis of g e n o m e studies,
there is also strong e v i d e n c e that m o n k e y p o x is not ancestral
to variola virus. This m a y b e important in v i e w of the fear
expressed b y s o m e that variola might evolve from
m o n k e y p o x . In the pre-molecular era, great efforts w e r e m a d e
to distinguish the four viruses b y serological reactions. T h e s e
w e r e delicate studies since the viruses share m o s t antigens (8).
S o m e results w e r e obtained through the use of a b s o r b e d sera
in agar gel diffusion tests, but these w e r e rapidly s u p e r s e d e d
b y the study of the biological characteristics a n d DNA
restriction patterns, the latter b e i n g u s e d exclusively at
present. T h e d e v e l o p m e n t of relatively specific antigens h a s
b e e n extremely useful for serological surveys in m a n and
animals.
In the field, rapid presumptive diagnosis of orthopoxvirus
infection is necessary, as is differentiation from c h i c k e n p o x , as
confusion is possible o n clinical grounds. For this p u r p o s e ,
scabs of the lesions are sent, without transport m e d i u m , to t h e
diagnostic laboratory. Electron m i c r o s c o p i c examination of
this material allows the differentiation of o r t h o p o x - and
herpesviruses. T h e poxviruses c a n b e d e t e c t e d in m o r e than
9 5 % of the scabs, w h e r e a s varicella-zoster virus is d e t e c t e d in
only half of the material from cases of c h i c k e n p o x , m e a n i n g
that electron m i c r o s c o p y negative s p e c i m e n s are very unlikely
to b e m o n k e y p o x (11).
Epidemiology
M o n k e y p o x w a s discovered in a m o n k e y in C o p e n h a g e n Z o o
in 1959 (14), a n d w a s later o b s e r v e d sporadically in captive
primate colonies in the industrialised world. In 1970, the first
cases of h u m a n m o n k e y p o x w e r e diagnosed in Central and
W e s t Africa, in areas w h e r e cases of smallpox h a d not b e e n
reported for over a year as a result of the smallpox eradication
campaign. T h e reaction was fear that m o n k e y p o x w o u l d
replace smallpox. Smallpox eradication surveillance was
maintained in Zaire (formerly the C o n g o ) until 1976. Detailed
epidemiological studies w e r e p e r f o r m e d b e t w e e n 1976 and
1 9 8 6 o n 3 0 0 of the 4 0 0 d o c u m e n t e d cases of h u m a n
m o n k e y p o x . All cases occurred in r e m o t e villages in the
tropical rain forest, w h e r e children trap small rodents and
h a v e contact with carcasses of m o n k e y s brought h o m e b y
hunters. In Zaire, 7 2 % of the cases w e r e primary cases
(i.e. possibly infected through contact with small rodents or
m o n k e y s ) , or w e r e co-primary cases (i.e. infected at the s a m e
time b y the s a m e source). Only 2 8 % w e r e suspected to h a v e
b e e n secondary cases, contracted through person-to-person
contact. A small n u m b e r of third, fourth a n d fifth generation
cases w e r e d o c u m e n t e d , but the incidence diminished at e a c h
generation.
Serological surveys w e r e carried out in Zaire (formerly the
Congo) o n p e o p l e without a vaccination scar. A m o n g 5 0 , 0 0 0
p e o p l e spread over 4 0 0 localities in the region of Kole, only
15% of the population did not have a vaccination scar. An
annual crude incidence rate of h u m a n m o n k e y p o x of
0.63/10,000 population was inferred. T h o s e at h i g h risk w e r e
young unvaccinated children (especially b o y s ) and adult
94
w o m e n . Approximately o n e third of the infections w e r e
estimated to b e sub-clinical. Vaccination provided 8 5 %
protection. Since vaccination c e a s e d in 1980, the proportion
of unvaccinated individuals in the population was increasing.
Nevertheless, calculations and computer simulations s h o w e d
that since the basic case reproduction rate of m o n k e y p o x in
h u m a n populations was b e l o w one, the virus could not persist
in h u m a n s (1). All outbreaks w o u l d b e self-limiting, e v e n in
the absence of special sanitary interventions. B e t w e e n 1987
and 1 9 9 2 , thirteen cases of h u m a n m o n k e y p o x w e r e
d o c u m e n t e d ; n o case was reported b e t w e e n 1990 and 1995.
I n 1996, m o n k e y p o x b e c a m e active o n c e again. Between
February 1996 and October 1997, 4 1 9 cases were reported
from the Katako K o m b e and Lodja zones in the Sankuru
region of the Democratic Republic of the C o n g o (5). An
epidemiological investigation revealed 3 0 1 p r o b a b l e , and 115
possible cases. T h e patients w e r e mainly 4 to 8 years old and
presented a m o d e r a t e rash. T h e fatality rate of 1.5% c o m p a r e d
favourably to that r e c o r d e d in the 1980s ( 1 0 % ) . T h e
secondary outbreak rate was 8%, similar to that reported in
the 1980s. T h e increase in cases was ascribed to the effect of
the civil war w h i c h h a d led to increased hunting for forest
animals that carry m o n k e y p o x , particularly squirrels. By the
e n d of 1997, the n u m b e r of cases of m o n k e y p o x h a d
diminished rapidly. Vaccinia vaccination was not considered
b e c a u s e of the possible h i g h prevalence of h u m a n
immunodeficiency virus (HIV) infection in the population.
T h e control measures r e c o m m e n d e d w e r e to limit contact
with patients to those w h o h a d b e e n vaccinated against
smallpox in the past, or w h o h a d b e e n affected b y
m o n k e y p o x , and to avoid handling dead or diseased animals.
W i t h changes in lifestyle d u e to increasing urbanisation, and
intensified agricultural activities replacing hunting and
trapping, the chances of contracting m o n k e y p o x , either from
the primary reservoir or intermediate hosts, will decrease and
m o n k e y p o x will b e c o m e a disappearing disease.
Biology
T h e search for the virus reservoir of m o n k e y p o x was
c o n d u c t e d in different stages. Initially, s e r u m surveys w e r e
performed a m o n g primates in W e s t and Central Africa,
revealing prevalence of antibodies in m o n k e y s (9). However,
since all m o n k e y s live in small troops and n o evidence exists
for either persistent infections or transmission b y flying
arthropods, it was unlikely that this k i n d of population could
constitute the virus reservoir. T h e reservoir was m o s t likely to
b e found a m o n g animals with high population n u m b e r s and
rapid turnover rates. T h e s e factors l e d to the production of
immunologically naïve subjects o n a regular basis, thereby
enabling
enzootic
transmission.
Monkeypox-specific
antibodies w e r e found in m o n k e y and squirrel sera. Hundreds
of kidneys and spleens from animals w e r e screened for the
presence of m o n k e y p o x v i r u s without success. Finally, a
diseased squirrel, Funisciurus anerythrus, was found showing
Rev. sci. tech. Off. int. Epiz., 19 (1)
superficial skin lesions, and virus was isolated from its organs.
More directed s e r u m surveys revealed m o n k e y p o x antibodies
in two species, F. anerythrus and F. rufobrachium and, in
addition, in s o m e species of Heliosciurus.
T h e present
understanding of the ecology of m o n k e y p o x v i r u s is that the
reservoir of the virus is in arboreal squirrels, Funisciurus s p p .
and, to a lesser degree, Heliosciurus spp., living in the
secondary forest surrounding h u m a n settlements and fields.
These animals m a y infect h u m a n s directly or occasionally
through m o n k e y s . Contact with wild animals through
trapping, hunting, skinning and manipulation of carcasses
m a y transmit the virus to humans.
Pathogenesis
Transmission of smallpox is aerogenic, whereas transmission
of the other orthopoxviruses that can infect m a n is through
the skin (3). M o n k e y p o x is therefore also likely to b e
transmitted through the skin, through handling of infected
animals. T h e virus is thought to multiply locally in the
abraded skin, and to b e rapidly transported to the regional
l y m p h n o d e w h e r e it multiplies and then invades the
b l o o d s t r e a m to localise in the skin, producing the
characteristic nodules, papules and pustules.
Diagnosis and surveillance
T h e skin lesions caused b y h u m a n m o n k e y p o x are
indistinguishable
from variola, except for a greater
enlargement of the l y m p h n o d e s . N o haemorrhagic type of
m o n k e y p o x disease has ever b e e n reported, and mortality is
extremely low.
T h e geographic location of the patient is important in the
diagnosis of m o n k e y p o x , as the disease usually occurs in
r e m o t e villages in the tropical African rain forests.
Differentiation from c h i c k e n p o x is important; the latter
appears in successive crops so that lesions at various stages of
d e v e l o p m e n t are visible at any time. In contrast with
smallpox, the distribution of c h i c k e n p o x is 'centripetal' with
m o r e lesions o n the trunk than o n the face and extremities.
For definitive diagnosis, scabs can b e forwarded to a reference
laboratory w h e r e electron m i c r o s c o p y m a y confirm the
presence of an orthopoxvirus and differentiate this virus from
varicella virus. T h e virus can b e cultured in tissue culture and
identified b y DNA restriction analysis.
Prophylaxis and treatment
As h u m a n m o n k e y p o x is a rare disease, with a vanishing
incidence, n o benefit w o u l d b e derived from vaccination with
vaccinia. Furthermore, smallpox vaccination cannot b e
undertaken in populations with high prevalence of HIV
infection b e c a u s e of the risk of serious complications.
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Rev. sci. tech. Off. int. Epiz., 19 (1)
Antiviral c h e m o t h e r a p e u t i c treatment is not a viable o p t i o n in
those r e m o t e places w h e r e the disease is likely to appear. T h e
treatment w o u l d h a v e to b e administered in the very early
stages of the disease and it is unlikely that the treatment could
b e m a d e available in time. In addition, the treatment is not
devoid of side effects.
Arguments for and against destruction
Pro d e s t r u c t i o n
The arguments in favour of destruction of smallpoxvirus
stocks include the following:
- to eliminate the m o s t devastating of h u m a n pathogens
- to prevent accidental release and use b y terrorists
- the virus is t o o dangerous to b e a l l o w e d to live
Destruction of variola virus
stocks
W h e n s m a l l p o x eradication was certified in 1980, the Global
C o m m i s s i o n for the Certification of Smallpox Eradication
p r o p o s e d that all laboratory-maintained smallpoxvirus stocks
b e destroyed to achieve deliberate w o r l d - w i d e elimination of a
biological species. T h e W o r l d Health Organization ( W H O )
m a d e repeated efforts in the s a m e direction (in D e c e m b e r
1990, S e p t e m b e r 1994 and January 1999). At present, two
virus stocks subsist, o n e at the Centers for Disease Control in
Atlanta, USA, and the other at the Russian State Research
Centre of Virology and Biotechnology in Koltsovo,
Novosibirsk Region, Russian Federation. T h e c o m p l e t e
destruction w a s originally s c h e d u l e d for 1 9 9 3 , after the
g e n o m e h a d b e e n c o m p l e t e l y s e q u e n c e d in 1 9 9 1 , but did not
take place. In S e p t e m b e r 1994, the date was set at 30 J u n e
1995, but destruction was again p o s t p o n e d . In 1996, the
W o r l d Health Assembly a d o p t e d a resolution r e c o m m e n d i n g
smallpoxvirus destruction o n 30 J u n e 1999. T h e p e r i o d from
1996 to 1999 was to b e u s e d to achieve a b r o a d e r consensus.
In 1998, the W H O Secretariat c o n d u c t e d a survey o n the
position of 191 m e m b e r states. Seventy-nine r e s p o n d e d ,
seventy-four w e r e in favour, o n e was against and four (the
United K i n g d o m , France, Italy and the USA) w e r e u n d e c i d e d
(2, 10, 12, 13, 15).
In January 1999, the A d H o c C o m m i t t e e m e m b e r s w e r e not
unanimous: five w e r e in favour of destruction, two thought
destruction might b e possible after a review five years later
and two w e r e in favour of retention for scientific reasons,
although the other m e m b e r s expressed greater c o n c e r n at the
risk of the virus b e i n g released. T h e following proposals w e r e
also m a d e :
a) gamma-irradiated killed variola virus s h o u l d b e k e p t for
use as an essential antigen in diagnostic tests;
b) amplification of variola virus DNA b y p o l y m e r a s e chain
reaction, followed b y expression in other orthopoxvirus
vectors, s h o u l d b e prohibited in addition to c h e m i c a l
synthesis of viable virus DNA;
c) w o r k s h o u l d b e a c c e p t e d in only two laboratories;
d) the W H O should appoint a n e w group to establish the
type of research, if any, to b e carried out in order to reach a
global consensus o n the timing of the destruction of viable
virus stocks.
- the study of a virus of a disease that n o longer exists is
pointless
- the g e n o m e h a s n o w b e e n s e q u e n c e d and c l o n e d
- n o research was p e r f o r m e d using the virus during the last
fifteen years (the virus has b e e n g r o w n only twice, to m a k e
m o r e c o p i e s for sequencing studies)
- s o m e information will b e lost b y destroying the virus, but
the value of s u c h information is u n k n o w n
- the biosecurity level 4 (BL4) facilities necessary for the
handling of variola virus are limited and should b e u s e d for
m o r e realistic priorities
- e m e r g e n c y d e v e l o p m e n t of n e w drugs or a n o v e l vaccine in
r e s p o n s e to the u n e x p e c t e d reintroduction of the virus into
the c o m m u n i t y is unrealistic
- a supply of b e t w e e n 60 and 70 million d o s e s of vaccine is
available (this h a s to b e properly stored and tested regularly
for potency)
- it is h o p e d that other infectious agents will b e eradicated in
the not t o o distant future (this leads to the question of
w h e t h e r these agents s h o u l d also b e maintained; e x a m p l e s are
poliovirus and Dracunculus medinensis, the latter can only b e
maintained as a living parasite in humans).
Pro m a i n t e n a n c e
Maintenance of the variola virus s t o c k is supported b y the
following arguments:
- the virus is indispensable for the d e v e l o p m e n t of n e w
antiviral m e d i c i n e s and novel vaccines to protect the
population in the event of accidental or terrorist release of
virus
- officials of the Russian Federation claim that valuable
research remains to b e p e r f o r m e d (without any specifications)
- there is pressure from the Defence Department in the USA
- it is impossible to anticipate the questions w h i c h m a y b e
p o s e d about the virus in the next ten to twenty years, in areas
such as h u m a n i m m u n o l o g y
- the unique specificity of smallpox is justification
preservation of the virus
- the virulence segment of the g e n o m e h a s not
identified
for
been
- destruction is pointless since the virus can b e synthesised
- use b y terrorists is unlikely and vaccine remains available
Rev. sci. tech. Off. int. Epiz., 19 (1)
96
- destruction is illusory b e c a u s e the virus m a y subsist in
cadavers in permafrost
- a wealth of scientific information is to b e gleaned f r o m the
live virus concerning virulence, pathogenic m e c h a n i s m s and
potential for screening drugs.
not destroying the smallpoxvirus stocks is the profound
political mistrust b e t w e e n certain countries. If this distrust
could b e r e m o v e d , the only remaining question w o u l d b e
w h e t h e r the cost of k e e p i n g the virus in a single high-security
environment, with strict rules for its use, w o u l d outweigh the
utility of the virus.
Conclusion on destruction
Although from a purely biological point of view, destruction
of the remaining smallpoxvirus w o u l d i n d e e d signify s o m e
loss of biological diversity, the scientific reasons for
non-destruction are not very pertinent. T h e main reason for
Infections dues au virus de la variole du singe
S.R. Pattyn
Résumé
Au cours de la campagne d'éradication de la variole et dans la période qui suivit,
des cas humains de variole du singe sont apparus en Afrique de l'Ouest et en
Afrique centrale, sous forme de foyers isolés ou de petites épidémies. Comme la
transmission interhumaine n'a été observée que très exceptionnellement, la
variole du singe ne représente pas une menace sérieuse pour l'homme. Le
réservoir du virus est un écureuil arboricole, qui vit dans les forêts ombrophiles
tropicales d'Afrique. C'est en chassant, tuant et dépouillant cet animal que
l'homme contracte l'infection. Cependant, avec la modernisation de la société, les
contacts avec ce réservoir du virus seront moins fréquents. Depuis l'éradication
de la variole, des stocks de virus de la variole ont été conservés. La question de
savoir s'ils doivent être détruits relève d'une décision politique, sérieusement
compromise par la méfiance qui règne entre les pays.
Mots-clés
Orthopoxvirus - Réservoirs du virus - Santé publique - Stocks de virus - Variole - Variole
du singe - Virus de la variole - Zoonoses.
Infecciones por monkeypoxvirus
S.R. Pattyn
Resumen
Durante la campaña de erradicación de la viruela, y también después de ella, se
declararon en el África Central y Occidental casos aislados o pequeñas
epidemias de viruela símica (monkeypox) en el ser humano. Considerando que
nunca o muy rara vez se ha documentado la transmisión de esta enfermedad de
un ser humano a otro, cabe decir que la viruela de los monos no representa una
grave amenaza para el hombre. Las ardillas arbóreas de la pluviselva tropical
africana constituyen el reservorio natural del virus, y el ser humano se infecta al
cazarlas, sacrificarlas y despellejarlas. No obstante, la modernización de la
sociedad está reduciendo el contacto del hombre con este reservorio. Aunque la
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Rev. sci. tech. Off. int. Epiz., 19 (1)
viruela ha quedado definitivamente erradicada del medio natural, se conservan
en laboratorio muestras del virus variólico. La decisión de destruir o no esa
reserva es una cuestión política, cuya resolución se ve comprometida por la
desconfianza existente entre países.
Palabras clave
Orthopoxvirus - Reservas de virus - Reservonos víricos - Salud pública - Viruela - Viruela
símica-Zoonosis.
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