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Human Monkeypox

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Human monkeypox is a zoonotic Orthopoxvirus with a presentation similar to smallpox. Clinical differentiation of the disease from smallpox and varicella is difficult. Laboratory diagnostics are principal components to identification and surveillance of disease, and new tests are needed for a more precise and rapid diagnosis. The majority of human infections occur in Central Africa, where surveillance in rural areas with poor infrastructure is difficult but can be accomplished with evidence-guided tools and educational materials to inform public health workers of important principles. Contemporary epidemiological studies are needed now that populations do not receive routine smallpox vaccination. New therapeutics and vaccines offer hope for the treatment and prevention of monkeypox; however, more research must be done before they are ready to be deployed in an endemic setting. There is a need for more research in the epidemiology, ecology, and biology of the virus in endemic areas to better understand and prevent human infections.
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EMERGING INFECTIONS
Mary E. Wilson and James M. Hughes, Section Editors
Human Monkeypox
Andrea M. McCollum and Inger K. Damon
Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases,
Centers for Disease Control and Prevention, Atlanta, Georgia
Human monkeypox is a zoonotic Orthopoxvirus with a presentation similar to smallpox. Clinical differentia-
tion of the disease from smallpox and varicella is difcult. Laboratory diagnostics are principal components to
identication and surveillance of disease, and new tests are needed for a more precise and rapid diagnosis. The
majority of human infections occur in Central Africa, where surveillance in rural areas with poor infrastructure
is difcult but can be accomplished with evidence-guided tools and educational materials to inform public
health workers of important principles. Contemporary epidemiological studies are needed now that popula-
tions do not receive routine smallpox vaccination. New therapeutics and vaccines offer hope for the treatment
and prevention of monkeypox; however, more research must be done before they are ready to be deployed in an
endemic setting. There is a need for more research in the epidemiology, ecology, and biology of the virus in
endemic areas to better understand and prevent human infections.
Keywords.monkeypox; Orthopoxvirus; smallpox.
Monkeypox virus is an Orthopoxvirus, a genus that in-
cludes camelpox, cowpox, vaccinia, and variola viruses.
The virus is the foremost Orthopoxvirus affecting
human populations since smallpox eradication, con-
rmed by the World Health Organization in 1980.
Clinical recognition, diagnosis, and prevention still
remain challenges in the resource-poor endemic areas
where monkeypox is found. Monkeypox epidemiology
is informed by studies conducted at the end of small-
pox eradication, but new assessments are needed now
that routine smallpox vaccination has ended and there
is associated waning herd immunity. Additionally,
foundational ecological studies are necessary to better
understand the animal species involved in transmission
and maintenance of the virus, and to further inform
prevention measures.
CLINICAL PICTURE
Human monkeypox was not recognized as a distinct in-
fection in humans until 1970 during efforts to eradicate
smallpox, when the virus was isolated from a patient
with suspected smallpox infection in The Democratic Re-
public of the Congo (DRC) [1]. The majority of the clini-
cal characteristics of human monkeypox infection mirror
those of smallpox (discrete ordinary type or modied
type, Table 1)[24]. An initial febrile prodrome is ac-
companied by generalized headache and fatigue. Prior to,
and concomitant with, rash development is the presence
of maxillary, cervical, or inguinal lymphadenopathy (1
4 cm in diameter) in many patients (Figure 1). Enlarged
lymph nodes are rm, tender, and sometimes painful.
Lymphadenopathy was not characteristic of smallpox.
The presence of lymphadenopathy may be an indication
that there is a more effective immune recognition and re-
sponse to infection by monkeypox virus vs variola virus,
but this hypothesis requires further study [5].
Fever often declines on the day of or up to 3 days after
rash onset. Often, the rash rst appears on the face and
quickly appears in a centrifugal distribution on the body.
The distinctive lesions (Figure 2) often present as rst
macular, then papular, then vesicular and pustular [6].
The number of lesions on a given patient may range
Received 15 March 2013; accepted 18 October 2013; electronically published 24
October 2013.
Correspondence: Andrea M. McCollum, PhD, MS, Centers for Disease Control
and Prevention, Poxvirus and Rabies Branch, 1600 Clifton Rd NE, MS A-30, Atlanta,
GA 30333 (amccollum@cdc.gov).
Clinical Infectious Diseases 2014;58(2):2607
Published by Oxford University Press on behalf of the Infectious Diseases Society of
America 2013. This work is written by (a) US Government employee(s) and is in the
public domain in the US.
DOI: 10.1093/cid/cit703
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from a few to thousands [7]. Lesions are often noted in the oral
cavity and can cause difculties with drinking and eating.
Given the distinctive presentation of lesions, digital photographs
and the Internet are 21st-century tools for clinical consultation.
The extensive perturbation of the skin raises concerns about
secondary bacterial infections of the skin, and this has been ob-
served to be present in 19% of unvaccinated monkeypox pa-
tients [7]. The skin of patients has been noted being swollen,
stiff, and painful until crusts appeared [4]. The occurrence of a
second febrile period occurring when skin lesions become pus-
tular has been associated with deterioration in the patients
general condition [4].
Severe complications and sequelae were found to be more
common among unvaccinated (74%) than vaccinated patients
(39.5%). Patients have been observed with pulmonary distress
or bronchopneumonia, often late in the course of illness, sug-
gestive of secondary infection of the lungs. Vomiting or diar-
rhea can occur by the second week of illness and can contribute
to severe dehydration. Encephalitis was observed in one patient
and septicemia in another patient with > 4500 lesions [7].
Ocular infections can occur and may result in corneal scarring
and permanent vision loss [8]. Pitted scarring is the most
Table 1. Key Clinical Characteristics of Smallpox, Monkeypox, and Varicella
Characteristic Smallpox Monkeypox Varicella
Time period
Incubation period 717 d 717 d 1021 d
Prodromal period 14d 14d 02d
Rash period (from the
appearance of lesions
to desquamation)
1428 d 1428 d 1021 d
Symptoms
Prodromal fever Yes Yes Uncommon, mild fever
if present
Fever Yes, often >40°C Yes, often between 38.5°C
and 40.5°C
Yes, up to 38.8°C
Malaise Yes Yes Yes
Headache Yes Yes Yes
Lymphadenopathy No Yes No
Lesions on palms
or soles
Yes Yes Rare
Lesion distribution Centrifugal Centrifugal
a
Centripetal
Lesion appearance Hard and deep, well-
circumscribed, umbilicated
Hard and deep, well-
circumscribed, umbilicated
a
Superficial, irregular borders,
dew drop on a rose petal
Lesion progression Lesions are often in one stage
of development on the body;
slow progression with each
stage lasting 12d
Lesions are often in one stage
of development on the body;
slow progression with each
stage lasting 12d
a
Lesions are often in multiple
stages of development on
the body; fast progression
a
Differences in the appearance of rash have been noted in vaccinated (vaccination <20 years prior to illness) vs unvaccinated individuals. Vaccinated individuals
were noted to have fewer lesions, smaller lesions, and better presentation of regional monomorphism and centrifugal distribution of rash.
Figure 1. Cervical lymphadenopathy in a patient with active monkeypox
during a monkeypox outbreak in Zaire, 19961997. Photograph credit: Dr
Brian W. J. Mahy; provided by the Public Health Image Library, Centers for
Disease Control and Prevention.
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common long-term sequelae of those who survive an infection.
The average case-fatality rate of unvaccinated patients has been
recorded as high as 11%; children are often more prone to
severe forms of disease [7]. In these clinical studies, prior vacci-
nation was 319 years preceding monkeypox disease.
Varicella, caused by the varicella zoster virus (VZV) in the
Herpesviridae family, is another febrile rash illness that is often
confused with monkeypox, but several features help distinguish
the 2 illnesses (Table 1). Varicella rarely has a prolonged febrile
prodrome (12 days if present) and the fever is generally mild
during this phase. The rash exhibited by VZV generally pro-
gresses more quickly than monkeypox and smallpox, and the
lesion presentation can be quite different [2]. Additionally, al-
though varicella patients rarely present with lesions on the
palms and/or soles, lesions have been noted on the palms and/
or soles of 5 household contacts initially thought to have had
monkeypox infections, but who tested positive for VZV, in the
Republic of the Congo (ROC) [9]. The lymphadenopathy in
monkeypox patients has been noted to be a dening differenti-
ating characteristic of the disease from varicella [7]. Additional
vesiculopustular rash illnesses included on the differential are
other herpetic infections, drug-associated eruptions, syphilis,
yaws, scabies, and, more rarely, rickettsialpox.
Clinical distinction between rash illnesses is difcult in the
absence of a diagnostic test. Given the similarities between small-
pox and monkeypox, an existing smallpox algorithm (http://
www.bt.cdc.gov/agent/smallpox/diagnosis/riskalgorithm/) that
takes into account major smallpox criteria (febrile prodrome,
classic lesions, lesions in the same stage of development) and
minor criteria [10] could be modied for monkeypox and used
for diagnostic management. Namely, the inclusion of lymph-
adenopathy as a major criteria would allow for the addition of
monkeypox in the algorithm, retaining smallpox in the differ-
ential. This will be an important consideration in the light of
biosecurity concerns and the need to consistently rule out suspect
smallpox disease. The implementation of such a protocol will
be possible with the analysis of clinical and surveillance data
from an endemic area. Public health ofcials should be contact-
ed immediately upon clinical suspicion of an Orthopoxvirus in-
fection. State health departments and the US Centers for Disease
Control and Prevention offer consultation and diagnostic testing.
DIAGNOSTIC CONFIRMATION
Diagnostic assays are important components to the identica-
tion of an Orthopoxvirus infection. Table 2lists the diagnostic
assays that may be used to classify monkeypox or Orthopoxvi-
rus from clinical specimens. These tests are most powerful
when they are combined with clinical and epidemiological in-
formation, including a patients vaccination history. Given the
limited cold chain and diminished resources for sample collec-
tion and storage, lesion exudate on a swab or crust specimens
still remain some of the best and least invasive acute patient
specimens. Viral DNA present in lesion material is stable for a
long period of time if kept in a relatively dark, cool environ-
ment, an important factor to consider when cold chain is not
readily available. Conventional tests such as viral isolation from
a clinical specimen, electron microscopy, and immunohisto-
chemistry remain valid techniques but require advanced tech-
nical skills and training, as well as a sophisticated laboratory.
Specimens can be analyzed using real-time polymerase chain
reaction (PCR) to assess the presence of Orthopoxvirus or mon-
keypox virus in a lesion sample [1114]. These assays are
highly sensitive and can efciently detect viral DNA. Real-time
PCR is currently best used in a major laboratory, thus limiting
its use as a real-time diagnostic in rural, resource-poor areas.
Advances in technologies may make diagnostic use of real-time
PCR more feasible outside of major laboratories.
Determining the cause of cases identied retrospectively
requires antibody-based diagnostics. Anti-Orthopoxvirus im-
munological assays have cross-reactivity to a variety of Ortho-
poxviruses, and these assays may be useful in areas where there
is prior evidence as to what virus is causing illness. Anti-
Orthopoxvirus immunoglobulin G (IgG) alone will not provide
adenitive diagnosis for retrospective patients who have been
exposed to an Orthopoxvirus, including by vaccination, during
their lifetime. Alternatively, serological assays that assess anti-
Orthopoxvirus immunoglobulin M (IgM) are more applicable
Figure 2. A patient with monkeypox showing characteristic lesions.
Photograph credit: Dr Marcel Pie Balilo.
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to diagnose recent retrospective infections, including in indi-
viduals with prior vaccination [15].
Aeld-deployable point-of-care test is ideal, but there are
few developments in this area. A recent pilot of the Tetracore
Orthopox BioThreat Alert provided promising results using
lesion specimens from acute Orthopoxvirus infections. This
assay reliably detected vaccinia and monkeypox viruses in prep-
arations with 10
7
plaque-forming units/mL, and correct identi-
cation of clinical specimens occurred in 5 of 6 specimens
tested [16]. Although not specic for monkeypox virus, this
assay could be used in monkeypox-endemic areas for Ortho-
poxvirus conrmation by proxy, and it will be important to test
this in endemic settings. Patients with monkeypox virus often
seek diagnosis and care at rural clinics or hospitals without
electricity; thus, there is a need for the development of assays
that can be tested in very basic environments with limited
training of personnel.
THE CHANGING FACE OF MONKEYPOX
EPIDEMIOLOGY
Historically, there have been reports of human monkeypox in-
fections in West Africa, but since 1981 most reported infections
have occurred in the Congo Basin of Central Africa [17]. DRC
continues to report the majority of human monkeypox cases
each year. Recently, infections also were noted in the Central
African Republic, ROC, and Sudan [8,18,19], but it is unclear
if these infections were the result of movement across the DRC
border or the occurrence of indigenous disease. Improved phy-
logeography and georeferencing of human cases will aid in a
better understanding of the distribution of cases, and these data
can be used to develop more accurate ecological models of
monkeypox distribution [20,21].Domestically, the United States
experienced a monkeypox outbreak among humans and cap-
tive prairie dogs in 2003, and traceback studies identied a
Table 2. Diagnostic Tests for Monkeypox or Orthopoxvirus
Test Pros Cons
Viral culture/isolation: Live virus is
grown and characterized from a
patient specimen.
Can yield a pure, live culture of virus for definitive
classification of the species. Orthopoxviruses
produce distinctive pockson chorioallantoic
membranes; and other cell-based viral culture
methods can be used. Patient specimens from
lesions are the most reliable for this method, as
viremia is not present the entire duration of
illness.
The assay takes several days to complete. Patient
specimens may contain bacteria, hampering
culture attempts. Further characterization must
be done for viral identification. Must be
performed at a major laboratory with skilled
technicians.
Electron microscopy: Negative
staining produces a clear image
of a brick-shaped particle,
allowing for visual classification
of a poxvirus, other than
Parapoxvirus
Can be used to identify viral particles in a biopsy
specimen, scab material, vesicular fluid, or viral
culture. Can differentiate an Orthopoxvirus from
Herpesviridae.
Orthopoxviruses are morphologically
indistinguishable from each other. Must be
performed at a major laboratory with skilled
technicians and an electron microscope.
Immunohistochemistry: Tests for
the presence of Orthopoxvirus-
specific antigens.
Can be used to identify antigens in biopsy
specimens. This technique can be used to rule
out or identify other suspect agents.
Not specific for monkeypox virus. Must be
performed at a major laboratory with skilled
technicians.
PCR, including real-time PCR:
Tests for the presence of
monkeypox-specific DNA
signatures.
Can diagnose an active case using lesion material
from a patient. The assay uses viral DNA, which
is stable if a specimen is kept in dark, cool
conditions. Designed to be specific for
monkeypox virus.
Highly sensitive assays where concerns about
contamination are warranted. These assays
require expensive equipment and reagents. Must
be performed at a major laboratory with skilled
technicians.
Anti-Orthopoxvirus IgG: Tests for
the presence of Orthopoxvirus
antibodies.
Can be used to assess a previous exposure to an
Orthopoxvirus, including a pathogen or smallpox
vaccination.
Requires the collection of blood (serum) and a cold
chain. This assay is not specific for monkeypox
virus. Results will be affected by prior smallpox
vaccination. The duration of response is variable.
Must be performed at a major laboratory with
skilled technicians.
Anti-Orthopoxvirus IgM: Tests for
the presence of Orthopoxvirus
antibodies.
Can be used to assess a recent exposure to an
Orthopoxvirus, including a pathogen or smallpox
vaccination. This assay could be used as a
diagnostic for suspect Orthopoxvirus patients
with prior smallpox vaccination.
Requires the collection of blood (serum) and a cold
chain. This assay is not specific for monkeypox
virus. Must be performed at a major laboratory
with skilled technicians.
Tetracore Orthopox BioThreat
Alert: Tests for the presence of
Orthopoxvirus antigens.
Can rapidly diagnose an active case using lesion
material from a patient; a point-of-care diagnostic
test. Can be performed at ambient temperature
with little expertise.
This assay is not specific for monkeypox virus.
Needs to be tested in endemic settings. Less
sensitive than PCR.
Abbreviations: IgG, immunoglobulin G; IgM, immunoglobulin M; PCR, polymerase chain reaction.
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shipment of wild rodents from Ghana as the probable source
[22,23].
Monkeypox can infect a taxonomically wide variety of mam-
malian species; however, the virus has only been isolated once
from a wild animal, a Funisciurus squirrel in DRC [24]. The
extent of viral circulation in animal populations and the precise
species that may harbor the virus is not entirely known, al-
though several lines of evidence point to rodents as a likely res-
ervoir [25]. Human infections have been linked to contact with
animals, but the precise exposure of a human case can be dif-
cult to pinpoint in areas where contact with animals via house-
hold rodent infestations and the hunting or preparation of
bushmeat from a variety of species is common. Transmission is
believed to occur via saliva/respiratory excretions or contact
with lesion exudate or crust material [26,27]. Viral shedding
via feces may represent another exposure source [26]. Although
human-to-human transmission of monkeypox is apparently
less efcient than that observed in smallpox, it did occur in up
to 11.7% of household contacts of patients who did not have
prior smallpox vaccination; evidence indicates that household
members or those who care for a monkeypox patient are at
increased risk for acquiring an infection [27]. The longest unin-
terrupted chain or sequential transmission events of human-
to-human spread is posited to be 6 individuals, and clusters of
patients have been commonly noted [8,18,27]. Transmission
in hospital settings has also been documented [8], and may be
prevented with standard precautions, as well as vaccination of
those at risk, including healthcare workers [28]. In the United
States, vaccination is recommended for any persons who are at
risk of exposure to an Orthopoxvirus species, including occupa-
tional exposures [29].
Surveillance for human monkeypox infections in endemic
areas is a challenge. Poor infrastructure, scarce resources, inap-
propriate diagnostic specimens and/or lack of specimen collec-
tion, and clinical difculties in recognizing monkeypox illness
are some of the challenges encountered by surveillance systems.
As more information is gained from contemporary monkeypox
cases, together with the data from past efforts, it will be impor-
tant to reassess the characteristics of the disease that help
identify monkeypox from other rash illnesses. Current case def-
initions may be sensitive and broadly identify rash illnesses, but
the renement and use of a more specic case denition will
provide better detection of actual monkeypox cases, aiding in
patient care and isolation to prevent human-to-human trans-
mission. Continued training of healthcare workers is needed to
maintain knowledge, vigilance, and support for monkeypox sur-
veillance. Ultimately, a broader laboratory-based surveillance
network will augment our knowledge of disease burden.
Smallpox vaccination (using vaccinia virus) provides protec-
tion against Orthopoxvirus infections, including monkeypox.
Smallpox vaccination ended around 1982 in DRC. As a result,
(1) there is waning vaccine immunity in the individuals who
were vaccinated by 1982, and (2) there are large numbers of
people who have never been vaccinated and, in the absence of a
previous exposure and development of immunity, are susceptible
to an Orthopoxvirus infection. The question of how this changing
Orthopoxvirus immunity via the absence of a vaccination will
alter the incidence of human monkeypox is one that is difcult
to answer but is nevertheless concerning based on the available
data.
There is a wealth of human monkeypox epidemiological data
from patients and their contacts in Equateur Province of DRC
from 1981 to 1986, in the days following smallpox eradication.
The attack rate of household members was signicantly lower
among those who had prior vaccination than those without
vaccination. At the time of these studies, approximately 70% of
all case contacts were vaccinated (319 years previously), and
prior vaccination conferred 85% protection against monkey-
pox. The average annual incidence of monkeypox in the
Bumba Health Zone was 0.63 per 10 000 persons [27,30]. A
more recent assessment of a cohort of patients from Sankuru
District, DRC, showed a dramatic increase in average annual
incidence to 5.53 per 10 000. An obvious hypothesized factor
affecting this increase in incidence is the lack of vaccination;
indeed, only 24% of the local population and 4% of the mon-
keypox patients had prior vaccination. These recent data
suggest that vaccination >25 years prior may still protect indi-
viduals against an Orthopoxvirus infection and, also, that the
lack of vaccination in these populations may contribute to an
increased incidence of infection [31]. In the US outbreak,
however, 24% (6/29) of the cases had received prior childhood
smallpox vaccination, indicating that childhood vaccination
was not entirely protective against disease [32]. These observa-
tions deserve further study, accounting for additional virologic,
anthropologic, and ecological variables to more effectively
parse the factors affecting this increase in incidence and the
role of vaccination, or lack thereof.
VIRUS DIFFERENCES: WEST VS CENTRAL
AFRICAN MONKEYPOX
There are 2 distinct phylogenetic clades of monkeypox viruses:
those that exist in West Africa and those in Central Africa. Ex-
perience during the 2003 US outbreak with the West African
clade suggested that disease severity also differed across
clades [33]. There are very few documented cases of West
African monkeypox: Liberia, Sierra Leone, Nigeria, and Côte
dIvoire have each reported <10 cases between 1970 and 2005,
and the US outbreak had 47 cases [17]. Generally, West African
monkeypox infections exhibit a less severe illness in humans and
nonhuman primates [5,33,34]. The US outbreak had a number
of hospitalized patients and severe disease, but no fatalities [35].
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Genome comparisons of West and Central African strains
yielded a set of candidate genes that may be involved in the dif-
ferentiating clade virulence. These open reading frames are pre-
dicted to be involved in alterations to the viral life cycle, host
range, or immune evasion, or are virulence factors [17]. Central
African monkeypox prevents T-cell receptormediated T-cell
activation, prohibiting inammatory cytokine production in
human cells derived from previously infected monkeypox pa-
tients. These results suggest that monkeypox may produce a
modulator that suppresses host T-cell responses [36]. Several
immune evasion candidates have been identied in Central
African monkeypox virus [17].
The monkeypox virus inhibitor of complement enzymes, a
gene that inhibits complement enzymes and is absent in West
African strains, has been implicated as an important immune-
modulating factor contributing to the increased virulence of
Central African strains [37,38]. Additionally, Central African
monkeypox strains selectively downregulate host responses
compared to West African strains, specically apoptosis in the
host [39]. Multiple loci may be involved in the observed patho-
genicity differences [17,34,38,39]. Furthermore, transcription-
al studies have shown that Central African monkeypox appears
to selectively silence transcription of genes involved in host im-
munity during an infection [40]. Determining the range of
effects produced with these different viruses will require a mul-
tifaceted effort.
THERAPEUTICS AND VACCINES
Several compounds have shown promise as antiviral therapeu-
tics against Orthopoxvirus species; 3 of the most promising
compounds are summarized in Table 3. Cidofovir has antiviral
activity against a variety of viruses by inhibiting viral DNA po-
lymerase. CMX-001 is a modied cidofovir compound that
Table 3. Promising Therapeutics for the Treatment of Orthopoxvirus Infections
Antiviral
Therapeutic Mechanism of Action Clinical Considerations Stage of Development or Use
Cidofovir Inhibits DNA polymerase Intravenous administration with hydration
and probenecid; nephrotoxicity has
been seen
Licensed for the use of cytomegalovirus
retinitis in AIDS patients. Has been
used to treat other poxvirus infections
(molluscum contagiosum and orf
virus).
CMX-001 Modified cidofovir compound;
inhibits DNA polymerase
Lacks nephrotoxicity seen with cidofovir;
oral administration
In development.
ST-246 Inhibits release of intracellular
virus
Oral administration Is maintained in the United States in the
Strategic National Stockpile. Available
for other Orthopoxvirus infections
under an investigational protocol.
Table 4. Smallpox Vaccines
Vaccine Pros Cons Stage of Development or Use
ACAM2000: Live
vaccinia virus
Single-dose administration. A
successful take is noted by
observation of a lesion at the
vaccination site. Lyophilized
preparation for long-term
storage.
Live viral vaccine that replicates in
mammalian cells; autoinoculation and
contact transmission are risks. In low-
disease-risk situations, should not be
used for individuals with
immunocompromising conditions,
history of eczema or atopic dermatitis,
or pregnant females. Cardiac events
postvaccination have been noted to
occur.
Licensed vaccination in the United
States. Currently available to
specific populations from the
Strategic National Stockpile.
Modified vaccinia
Ankara; IMVAMUNE
(US); IMVANEX
(Europe): Attenuated
vaccinia virus
The virus has limited replication
in mammalian cells. No lesion
produced at the vaccination
site.
Two-dose administration by injection. European Commission has authorized
marketing for immunization of the
general adult population, including
those who are
immunocompromised. Maintained
in the United StatesStrategic
National Stockpile.
LC16m8: Attenuated
vaccinia virus
Single-dose administration.
Exhibits a safer profile and
less adverse events than
ACAM2000 in human and
animal vaccinations.
Attenuated virus that can still replicate in
mammalian cells.
Licensed for use in Japan.
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lacks the extent of nephrotoxicity seen with cidofovir. Antiviral
activity of CMX-001 has been demonstrated with a variety of
Orthopoxvirus species. The drug ST-246 blocks the release of
the intracellular virus from the cell, and has shown promising
results against a variety of Orthopoxvirus species, including
variola virus [41]. These compounds have been used in varying
combinations, also with vaccinia immune globulin, investiga-
tionally, to treat severe vaccine-associated adverse events [42,43].
Development of strategies to use these drugs in endemic areas to
treat disease will need to be considered.
Smallpox vaccines, comprised of fully replicative vaccinia
virus, are currently not in use in monkeypox-endemic areas given
concerns about severe adverse events in a population with an un-
certain immunocompromised prole. The risk of pathogenic
monkeypox disease must be balanced with the risk of adverse
events from replicative vaccines such as ACAM 2000 (Table 4)[29].
An ideal vaccine for use in monkeypox-endemic areas would
be one that does not have these risk groups and could be ad-
ministered readily to children, as well [17]. There is no vaccina-
tion that meets all of these criteria, but some next-generation
vaccines take one step closer to reaching that goal (Table 4).
Modied vaccinia Ankara (MVA) is an attenuated vaccinia
virus that cannot achieve complete replication in mammalian
cells. MVA has shown protection in primate models challenged
with lethal doses of monkeypox virus [4446]. However, this
vaccine has not conferred protection in primates with severely
diminished T-cell function [47]. LC16m8 is another vaccine
that has been altered to prevent viral replication and has shown
protection against severe monkeypox illness in nonhuman pri-
mates [48]. LC16m8 was used to vaccinate >50 000 schoolchil-
dren in Japan with few reported adverse events [49].
CONCLUSIONS
Human monkeypox has the potential for spread via zoonotic
reservoirs, as was demonstrated by the US outbreak. Civil con-
ict and displacements cause concerns for movement of the
virus into an area without monkeypox [50,51], or movement of
individuals to more heavily forested areas more prone for inter-
action with wildlife and a range of zoonoses. The documented
rise in incidence of human disease needs further evaluation and
consideration with additional studies to better understand the
range of factors involved in disease transmission and spread.
There are still many unanswered questions about human
disease, animal reservoirs, and the virus itselfadvances in our
understanding of this important zoonosis will help better guide
prevention strategies and mitigate human disease.
Notes
Acknowledgments. The authors appreciate comments by anonymous
reviewers that improved this manuscript.
Disclaimer. The ndings and conclusions in this report are those of
the author(s) and do not necessarily represent the views of the Centers for
Disease Control and Prevention.
Financial support. This work was supported by the Centers for Disease
Control and Prevention.
Potential conicts of interest. Both authors: No reported conicts.
Both authors have submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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... Due to the difficulty of a differential diagnosis between smallpox and human monkeypox infection, the CDC created a specific protocol, named the "Acute, Generalized Vesicular or Pustular Rash Illness Protocol" [48]. Lymphadenopathy was used as the primary criteria to discriminate which patients are sent to second-level tests, because, as mentioned above, this was an MPV characteristic symptom [49]. However, in the present outbreak, this symptom may be absent [50]. ...
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The commercially available Orthopox BioThreat(®) Alert assay for orthopoxvirus (OPV) detection is piloted. This antibody-based lateral-flow assay labels and captures OPV viral agents to detect their presence. Serial dilutions of cultured Vaccinia virus (VACV) and Monkeypox virus (MPXV) were used to evaluate the sensitivity of the Tetracore assay by visual and quantitative determinations; specificity was assessed using a small but diverse set of diagnostically relevant blinded samples from viral lesions submitted for routine OPV diagnostic testing. The BioThreat(®) Alert assay reproducibly detected samples at concentrations of 10(7)pfu/ml for VACV and MPXV and positively identified samples containing 10(6)pfu/ml in 4 of 7 independent experiments. The assay correctly identified 9 of 11 OPV clinical samples and had only one false positive when testing 11 non-OPV samples. Results suggest applicability for use of the BioThreat(®) Alert assay as a rapid screening assay and point of care diagnosis for suspect human monkeypox cases.