2022 Article 775

REVIEWS
Monkeypox: disease epidemiology,

host immunity and clinical
interventions
Fok-Moon Lum1, Anthony Torres-Ruesta 1, Matthew Z. Tay 1, Raymond T. P. Lin2,3,4,
David C. Lye3,5,6,7, Laurent Rénia1,5,8 and Lisa F. P. Ng 1,9,10 ✉
Abstract | Monkeypox virus (MPXV), which causes disease in humans, has for many years been
restricted to the African continent, with only a handful of sporadic cases in other parts of the
world. However, unprecedented outbreaks of monkeypox in non-endemic regions have recently
taken the world by surprise. In less than 4 months, the number of detected MPXV infections has
soared to more than 48,000 cases, recording a total of 13 deaths. In this Review, we discuss the
clinical, epidemiological and immunological features of MPXV infections. We also highlight
important research questions and new opportunities to tackle the ongoing monkeypox outbreak.
Monkeypox is a zoonotic viral disease caused by the rates in patients vaccinated against smallpox4. Recently,
monkeypox virus (MPXV), an orthopoxvirus belong- a study on 528 infections diagnosed during this current
ing to the Poxviridae family of viruses1. MPXV was outbreak reported that only 9% of the individuals who
first identified in 1958 in research monkeys that were were infected received prior smallpox vaccination8.
shipped from Singapore2, which is the likely reason for Interestingly, one characteristic of the recent outbreaks
the disease being called ‘monkeypox’. However, the nat- is a disproportionate number of infections in men who
ural hosts of MPXV are more likely to be rodents and have sex with men (MSM)8,9.
other small mammals3. The Orthopoxvirus genus also Phylogenetically, MPXV can be divided into two dis-
includes variola virus (VARV), the causative agent of tinct clades — Central African (also commonly known
lethal smallpox disease. The symptoms of monkeypox as Congo Basin) and West African. Depending on the
in humans are relatively similar to those of smallpox, but source of the West African MPXV, sequence similarity of
with a lower mortality rate1,4. ~95%10 or >99% between the two clades11 was reported.
Sporadic cases of MPXV in humans were first iden- The Central African clade is generally considered to be
tified in the 1970s in several African countries, but the more virulent, with an average fatality rate of 10.6% (95%
virus became more widespread within the African con- CI 8.4–13.3%) compared with the 3.6% (95% CI 1.7–6.8%)
tinent over the past 20 years (see Box 1 for details). Since reported for the West African clade12. MPXV of the
May 2022, there has been a drastic increase in the num- Central African clade has been identified in cases appear-
ber of MPXV cases worldwide (Fig. 1), leading the World ing in the Democratic Republic of the Congo (DRC) and
Health Organization (WHO) to declare the monkeypox South Sudan12, whereas cases in Nigeria between 2010
outbreak a global health emergency5. and 2019 appeared to be due to the West African clade12.
Possible reasons for this current outbreak could be Cases reported outside Africa, including those currently
attributed to waning smallpox immunity in the general in circulation, have all been caused by the West African
population and termination of the smallpox vaccination clade9,13. Whether genetic changes in the MPXV genome
regime6. Vaccination against smallpox has been shown could be responsible for this current outbreak is currently
to offer protection against monkeypox. An early study being investigated14 (see Box 2 for details).
from Zaire in 1988 (ref.7) reported that individuals vac- Here, we discuss our current understanding of the
cinated against smallpox (during a national smallpox transmission and immunopathogenesis of MPXV and
vaccination campaign beginning 12 years before the the unique epidemiological and pathological character-
start of data collection) were approximately 85% less istics observed in this outbreak. Specifically, we exam-
✉e-mail: Lisa_Ng@ likely to contract monkeypox than those who were not ine the potential mechanisms of host immunity against
idlabs.a-star.edu.sg vaccinated. In another study, severe complications and MPXV, drawing parallels from other poxviruses where
https://doi.org/10.1038/ long-term effects of MPXV infection were found to necessary. We also discuss vaccines and therapeutics,
s41577-022-00775-4 be less common (39.5% versus 74%) with lower death and highlight remaining critical gaps in our knowledge.
NAture RevIeWS | IMMuNoloGy volume 22 | October 2022 | 597
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Of note, nomenclature for- orthopoxviruses gene/pro- report from Portugal suggested that inguinal lymphad-
tein orthologues is very complex. In this Review, we enopathy was more common than cervical and axillary
refer to orthopoxvirus genes and proteins according to lymphadenopathy24. Rashes appear following the onset
publicly available reference genomes: NC_063383 for of fever, beginning on the face, tongue and oral cavity
the West African MPXV strain, NC_003310.1 for the (enanthem) before spreading across the body. In the later
Central African MPXV Zaire strain and NC_006998 stages of infection, lesions in the oral cavity can cause
for the vaccinia virus (VACV) Western Reserve strain. difficulties in drinking and eating4. However, in the
MPXV genes/proteins are referenced to the Central recent outbreaks, several atypical clinical observations
African MPXV Zaire strain, unless otherwise stated. have been reported. In patients who are MSM, these
include the presence of genital lesions that subsequently
MPXV genome and phylogeny spread to other sites in the body, as well as anal ulcers,
Computational analysis of the Central African MPXV and it appears that skin lesions may be more limited in
Zaire strain revealed the presence of at least 190 open distribution than reported in previous outbreaks24–26.
reading frames (ORFs)15–17. Genes known to be impor- Disease severity can be classified using the lesion
tant for orthopoxviruses are present within the central count, as higher lesion counts correlate with increased
region of the MPXV genome (between ORFs C10L and risk of severe complications4. Patients with severe com-
A25R)16,17. However, a subset of ORFs are either missing plications may experience respiratory and gastrointes-
or truncated in the MPXV genome compared with the tinal issues27, encephalitis4, septicaemia27,28 and ocular
genomes of other orthopoxviruses11,16,18. Disruptions to infections leading to permanent vision loss29. Skin
several ORFs that code for genes involved in immune lesions also increase the likelihood of dermal bacterial
evasion have been reported in the West African clade, infections, especially in patients who are not vaccinated
and these may be responsible for this clade’s lower against smallpox4.
virulence relative to the Central African clade6,11,18. Lesions typically progress through four stages —
The virus exists in two distinct infectious forms, the macular, papular, vesicular and pustular — before
intracellular mature virus and the extracellular enveloped falling off as scabs 1. Patients are typically consid-
virus, which differ in their surface glycoproteins and ered non-contagious once lesions have crusted over.
infect cells via different mechanisms19. MPXV replication However, scabs have been reported to contain significant
is a complex process but is generally thought to be identi- quantities of MPXV DNA even after falling off30, which
cal to other orthopoxviruses19. Entry receptors for MPXV may indicate the presence of infectious viral material.
have not been clearly identified, although it was suggested Of note, viable VARV has been isolated from scabs of
that viral entry is dependent on the viral strain and host patients with smallpox31.
cell type and involves multiple surface receptors, includ- During pregnancy, MPXV can be vertically transmit-
ing chondroitin sulfate20 or heparan sulfate21,22. In VACV, ted from the mother to the fetus32. In one study involving
surface proteins H3, A27 and D8 have been associated four pregnant women who were infected with MPXV in
with viral binding20–22. Following binding, VACV gains the DRC, only one gave birth to a healthy infant. Two
entry into the cell through 11 conserved proteins, which women experienced miscarriage in the first trimester
form a complex known as the entry fusion complex23. and one had a stillbirth. In the stillborn, skin lesions
were observed across the body32. In another study, four
Monkeypox pathology out of five women who were infected with MPXV in the
MPXV infection has an incubation period of 5–21 days, DRC had fetal demise and lesions were observed on
and common symptoms include fever (between the maternal surface of the placenta30. The studies did
38.5 °C and 40.5 °C), headache and myalgia. A distin- not report which clade of MPXV these patients were
guishing feature of MPXV infection is the presence of infected with, although given the location of the studies
swelling at the maxillary, cervical or inguinal lymph it is very likely the Central African clade30.
nodes (lymphadenopathy)1,4. In the recent outbreak, a A study conducted in Zaire during 1980–1985
reported a higher incidence of fatal disease in young chil-
Author addresses dren infected with MPXV, with a case fatality rate of 14.9%
1
A*STAR Infectious Diseases Labs, Agency for Science, Technology and Research in children aged between 0 and 4 years compared with
(A*STAR), Singapore, Singapore. a rate of 0% in individuals aged 10 years or older4. This
2
National Public Health Laboratory, Singapore, Singapore. disparity could potentially be due to differences in their
3
National Centre for Infectious Diseases, Singapore, Singapore. immune responses4. Currently, data on severity of infec-
4
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, tion in children infected with the West African clade are
National University of Singapore, Singapore, Singapore. lacking33. Nevertheless, the severe outcomes of monkey-
5
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, pox in pregnant women and in young children highlight
Singapore. the importance of future public health efforts to limit the
6
Tan Tock Seng Hospital, Singapore, Singapore. spread of MPXV and minimize the risk of adverse events.
7
Yong Loo Lin School of Medicine, National University of Singapore, Singapore,
Singapore.
8
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. MPXV pathogenesis
9
National Institute of Health Research, Health Protection Research Unit in Emerging and The clinical outcome of orthopoxviral infection in a
Zoonotic Infections, University of Liverpool, Liverpool, UK. vertebrate host is strongly dependent on the entry route
10
Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, used by the virus to establish the primary infection34
Liverpool, UK. (Fig. 2). For several orthopoxviruses, such as the highly
598 | October 2022 | volume 22 www.nature.com/nri
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Box 1 | History of monkeypox tissues. Clinical studies of human monkeypox suggest

that lymphoid tissues in the neck and throat are areas
Epidemiological surveys to identify residual clusters of smallpox in the 1970s also led of primary MPXV replication37. This was supported by
to the identification of the first cases of monkeypox virus (MPXV) in humans212. A total studies in a cynomolgus macaque model of aerosolized
of 48 confirmed and/or suspected cases were reported across six African countries: the MPXV infection, where the tonsils and the mandibu-
Democratic Republic of the Congo (DRC), Cameroon, Liberia, Nigeria, Sierra Leone
lar and mediastinal lymph nodes were active areas of
and Côte d’Ivoire12,213–215. Between 1980 and 2000, MPXV was confined to the African
continent, with no reports of infection or transmission in other parts of the world. The early virus replication36. Poxvirus tropism in lymphoid
number of MPXV cases in Africa continued to climb, mainly in the DRC (>800 confirmed tissue has been associated with infection of monocyte/
and/or suspected cases), with sporadic cases reported in Gabon, Cameroon, Côte macrophages, dendritic cells, B cells and activated
d’Ivoire and the Central African Republic (CAR)12,216–222. Between 2000 and 2020, MPXV T cells, which could also be targets for MPXV48. The
became more widespread within the African continent, with cases reported in the processes leading to abnormal lymph node swelling
Republic of the Congo29,223,224, Liberia12,215, South Sudan225, Sierra Leone226, Nigeria, upon natural MPXV infection have not been elucidated;
Cameroon222, the CAR227,228 and the DRC1,12. During this period, Nigeria229 reported 181 however, during experimental infection of non-human
confirmed and/or suspected cases, and the DRC reported more than 20,000 suspected primates (NHPs) with MPXV, massive proliferation and
cases12. The first report of MPXV infection outside Africa was in 2003, when an outbreak accumulation of natural killer cells was observed in the
of 47 confirmed and/or suspected cases was reported in the United States27,230. This
lymph nodes surrounding the site of inoculation37.
outbreak was caused by human exposure to prairie dogs that had been infected by
imported Gambian pouched rats27. Other countries with reported MPXV infections were After the development of low-grade primary virae-
Israel (2018; one case)231, the United Kingdom (2018–2021; seven cases)28,232–234, Singapore mia resulting from the infection of the lymphoid tissues,
(2019; one case)235 and the United States (2021; two cases)236,237 (reviewed in ref.12). orthopoxviruses can disseminate to distant organs via
As described above, MPXV was largely restricted to endemic regions prior to the the lymphohaematogenous route36,49. In experimental
current outbreak12,238. Particularly, it is noteworthy to highlight that between 2017 and mousepox models, the spleen and liver are the main
2022, Nigeria reported more than 650 confirmed cases, where nine patients eventually targets for infection after primary lymphatic spread50.
succumbed to the infection. The majority of the infected patients were male and aged Virus infection in these organs releases a second major
between 21 and 40 years239. viraemia wave (believed to be through infected cells)
Since May 2022 there has been a drastic increase in the number of MPXV cases that results in viral dissemination to the lungs, kidneys,
reported from Europe, the Americas, the Middle East and Australia9,13,240 (see Fig. 1). The
intestines, skin and other organs50. Similarly, in an NHP
current spread of MPXV is unprecedented, with outbreak clusters expanding each day.
By 28 August 2022, close to 50,000 confirmed and suspected cases were reported from model of aerosolized MPXV infection, viral antigen was
more than 100 countries240, with 13 deaths240. Recently, Singapore confirmed several observed in the liver, particularly in highly specialized
imported and local cases of monkeypox, which are the first reported in Southeast Asia macrophages such as Kupffer cells36. Antigen was also
during this recent outbreak241 and the first time that monkeypox has reappeared in detected in hepatocytes, although to a lower extent.
Singapore since 2019 (ref.235). On 23 July 2022, the World Health Organization (WHO) Enlarged spleen and liver have also been reported dur-
declared the monkeypox outbreak a global health emergency5. ing MPXV infection in humans30. In VARV infection, it
is believed that lymphoid organs such as the spleen and
bone marrow support virus replication, but there is less
contagious VARV and MPXV, the respiratory/oral cavity evidence for hepatic involvement51.
is a possible common entry route following the inhala- The presence of orthopoxviruses in the small dermal
tion of aerosolized respiratory secretions or the ingestion blood vessels marks the start of skin infection and devel-
of bodily fluids from individuals who are infected35. The opment of skin lesions51. However, how the virus reaches
virus then infects the oral and respiratory tract mucosae, the upper skin layers, which lack blood and lymphatic
with the upper, middle and lower airway epithelium as vessels, is not well understood. It is possible that infected
main targets for primary infection36. This phase of infec- migratory skin dendritic cells such as Langerhans cells
tion is asymptomatic, with no signs of oropharyngeal might be responsible, as they are known to be susceptible
lesions34. Virus spread progresses with the infection to VACV infection36. Infiltration of macrophages, den-
of nearby tissue-resident immune cells, potentially dritic cells and CD3+ T cells has been observed around
including antigen-presenting cells such as monocytes, the infective pustule52. The role of skin-infiltrating
macrophages, B cells and dendritic cells37–41. The mecha- CD3+ T cells in the context of MPXV infection requires
nisms whereby orthopoxviruses relocate from the initial characterization; this is particularly true for cytotoxic
site of infection to nearby draining lymph nodes are a T lymphocyte responses, which have been associ-
matter of debate. It has been observed, for example, that ated with better virus control in vaccinated rhesus
VACV-infected murine dendritic cells migrate from the macaques53. Importantly, epithelial lesions (enanthema)
lung epithelium to draining lymph nodes, likely con- also appear during MPXV infection in the oropharyn-
tributing to virus dissemination42. Conversely, VACV geal mucosa, tongue, pharynx, larynx, trachea and
infection of human monocyte-derived dendritic cells has oesophagus51, eventually evolving into ulcers which
been shown to be abortive, affecting dendritic cell mat- release infectious viral particles into the saliva51.
uration and their migratory potential39,43–45, and arguing Infection can also occur via the skin. It has been
against a role of dendritic cells supporting the initial postulated that infection of the dermal keratinocytes,
lymphatic spread of VACV. Importantly, the rapid relo- fibroblasts and tissue-resident antigen-presenting
cation of VACV to draining lymph nodes within hours of cells such as monocytes, macrophages, Langerhans cells
inoculation46,47 indicates direct viral access to lymphatic and dendritic cells might occur and migratory
vessels as a dissemination mechanism. antigen-presenting cells could contribute to virus dis-
Following the infection of nearby draining lymph semination through the lymphatics46,54,55. Nonetheless,
nodes, orthopoxviruses replicate extensively in lymphoid recent evidence from a mouse model of orthopoxvirus
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Number
of cases
50
100
250
500
1,000
2,000
3,000
4,000
5,000
Fig. 1 | Geographical distribution of confirmed and suspected monkeypox cases during the outbreak between
May and August 2022. Data presented as of 5 August 2022 were obtained from Global.health. Diagram generated with
Datawrapper.
skin infection suggested that dendritic cell migration form of close contact with the infectious pustules that are
from the skin to draining lymph nodes is impaired on symptomatic of monkeypox.
VACV56. The relocation of the virus from the skin to the
lymphatics might also be supported by other mecha- Immunity to MPXV
nisms such as direct lymphatic vessel access, as observed Even though the virus was identified decades ago, human
in skin infection models of Zika virus57. immunity to MPXV infection has not been extensively
Sexual transmission of monkeypox has been characterized. As such, inferences on MPXV interaction
speculated52, and MPXV was recently identified in the with the host immune system are often drawn from
semen of three male patients in Italy26. Cases of mon- studies performed with VACV and related orthopoxvi-
keypox with exclusive genital lesions have also been ruses. In the following sections, we highlight the poten-
reported58, which might indicate preferential MPXV tial mechanisms of host immunity against MPXV and
tropism into the testes. Being an immune-privileged discuss the immune evasion strategies utilized by MPXV
tissue59, the testes could act as a site for latent MPXV during active infection.
infection, but this requires further investigation.
Nonetheless, recent animal studies showed that the Innate immune responses to MPXV. Innate immune cells
related VACV exhibits tropism for testicular and ovar- typically act as the first line of defence following active
ian tissues60,61. Viral shedding was also reported in faeces viral infection, but these cells also serve as targets for
and contact with the rectal mucosa might increase the some viruses. Numerous in vitro and in vivo studies have
likelihood of MPXV transmission35. It was previously demonstrated that monocytes are the initial targets of
noted in patients with human immunodeficiency virus poxviruses36,65–68. Early detection of poxvirus antigen in
1 (HIV-1) that these tissues could act as a reservoir for both monocytes and neutrophils has been suggested to
the virus62. A recent study63 determined that the rectal be a strong predictor of MPXV lethality69. Susceptible
mucosa immune environment in MSM was significantly monocytes are actively recruited to sites of infection, with
different compared with individuals who are heterosex- marked expansion of CD14+ monocytes in the lungs of
ual, with a higher presence of immune activities indic- cynomolgus macaques experiencing viral pneumonia fol-
ative of mucosal injuries. This condition could lead to lowing MPXV infection70. Mouse CD45+CD11b+GR-1int
the recruitment of immune cells, which could then be inflammatory monocytes have also been shown to be
easily targeted by infectious agents, such as observed permissive to VACV replication and may be plausible
with HIV-1 (ref.64). This could similarly apply to MPXV vehicles for virus dissemination47. It was also reported
transmission and infection in MSM. However, this does that human primary M2-like macrophages allowed
not indicate that monkeypox has become a sexually VACV replication and dissemination71. Following VACV
transmitted disease, as MPXV can spread through any infection, these primary macrophages formed actin tails,
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Genetic accordions
cell linkages, lamellipodia and branching structures asso- chemokine receptors such as CXCR3, CCR5, CCR6
Multistep events involving gene ciated with the VACV virions, indicating that these cells and CCR7 on these cells was also reported37. Moreover,
application and mutations that might participate in virus spread71. However, it was also natural killer cells isolated from both lymph nodes and
allow poxviruses to subvert reported that depletion of phagocytic cells did not abol- blood were reported to lose their ability to degranulate
host antiviral responses.
ish spread of VACV72 in infected mice, suggesting that and to secrete IFNγ and TNF37. Although no correlation
monocytes and macrophages are not the only immune between viral clearance and natural killer cell numbers
cells that are capable of facilitating virus dissemination. and activities was reported in this NHP model37, the
Nevertheless, Ly6G+ innate immune cells (both neutro- importance of natural killer cells in controlling MPXV
phils and Ly6G+ monocytes72) were responsible for infil- viral load was demonstrated in CAST/EiJ mice. This
trating and controlling virus-infected cells, thus limiting strain is exceptionally susceptible to orthopoxvirus
viral tissue damage47,72. These results were indirectly infection76 owing to low numbers of natural killer cells.
confirmed by a study that found an association between IL-15 treatment protected CAST/EiJ mice from lethal
low numbers of blood neutrophils with moribundity in MPXV infection even when both CD4+ and CD8+ T cells
MPXV-infected animals73. It is also worth noting that were depleted76. This implies that the expanded natural
immune cells recruited to the site of infection control killer cells were responsible for the protective effect as
only local pathogenesis and tissue pathology, but not treatment with IL-15 is known to transiently increase
virus dissemination, and a systemic immune response the numbers of IFNγ-secreting natural killer cells and
is required to prevent widespread infection74. CD8+ T cells77.
Natural killer cells are an important component of Similarly, natural killer cells are also needed to con-
innate immunity and, similar to monocytes, are capa- trol both Ectromelia virus (ECTV) and VACV infection
ble of shaping the adaptive immune response75. In in C57BL/6 mice78,79. ECTV is a natural orthopoxviral
MPXV-infected rhesus macaques, numbers of natural pathogen of mice, and is often used to induce experi-
killer cells expand significantly in both peripheral blood mental mousepox as a model for other clinically impor-
(a mean 23-fold increase by day 7 post infection) and tant orthopoxviruses80. Interestingly, it was suggested
lymph nodes (a mean 46.1-fold increase by days 8–9 that the expression of CD94 on natural killer cells in
post infection)37. Prior to this rapid proliferation, the C57BL/6 mice is absolutely essential for conferring
migratory capacity of the various natural killer cell resistance to ECTV infection81. This is mediated by
subsets was significantly impaired by MPXV infection, the NKG2E and CD94 receptors on natural killer cells,
which severely affected their recruitment into the lym- which bind complexes of MHC class I with the peptide
phoid and/or inflamed tissues37. A downregulation of Qa-1b, which are expressed by infected cells81. NKG2D
has also been reported to participate in natural killer
cell-mediated protection against ECTV infection79 and
Box 2 | Genetic changes in current circulating MPXV it was postulated that CD94-NKG2E and NKG2D may
Understanding whether the recent monkeypox outbreaks are a result of genetic have synergistic activity in inducing optimally protec-
changes in monkeypox virus (MPXV) remains a research challenge. The 2022 tive natural killer cells81. However, the exact mecha-
outbreak is caused by lineage B.1 of the West African clade (MPXV Clade 3)242. At least nisms behind this apparent synergism remain to be
46 single-nucleotide polymorphisms have been found to be specific for this lineage, elucidated, and further studies will be required to better
including 24 non-synonymous single-nucleotide polymorphisms243. Recent molecular understand the roles of natural killer cells in mousepox
epidemiology studies have shown a higher than expected rate of genomic variance infections. Given that CD94 and NKG2 are highly con-
among the outbreak sequences, suggesting accelerated evolution242 and, potentially, served between humans and rodents82, these receptors
APOBEC3 editing244. One preprint publication (not peer reviewed) reports the presence may also play a protective role against MPXV infection
of insertions and deletions in the DNA of the MPXV strain that is circulating in the
in humans.
2022 outbreak compared with MPXV strains that were circulating prior to 2017 and
suggests that these changes may be responsible for the current outbreak14. However,
In humans infected with MPXV, the roles of many innate
it remains unclear whether and how these genetic differences drive the epidemiological immune cells — including monocytes/macrophages,
phenotype. A leading hypothesis proposes that the three non-synonymous single- neutrophils, natural killer cells, conventional dendritic
nucleotide polymorphisms (D209N, P722S and M1741I), which are found in the surface cells, plasmacytoid dendritic cells and innate lymphoid
glycoprotein B21R, a key antibody target, are enhancing the transmissibility of the cells — are currently unknown. The characterization and
virus243,245. However, MPXV is a complex virus, with a DNA-based genome that is profiling of these immune cells during MPXV infection
approximately six times as large (~197 kb) compared with the RNA-based genome of will be essential for understanding their functions and
SARS-CoV-2. It encodes more than 190 open reading frames (ORFs), many of which identifying important biomarkers for disease prognosis.
do not have well-defined functions15–17. Identifying the potential impact of particular VARV infection in animal models triggers systemic
genetic mutations on the viral phenotype is therefore complex and time-consuming.
cytokine responses that correlate with disease outcomes.
That said, the DNA-based genome of MPXV has a much greater capacity to repair
errors incurred during viral replication246 compared with the RNA-based coronaviruses.
In unvaccinated cynomolgus macaques, significant
However, the related orthopoxvirus vaccinia virus (VACV) is capable of ‘phenotypic changes in host gene expression were detected follow-
mutations’ in the form of genetic accordions (multistep events involving gene application ing infection with VARV66. In particular, transcription
and mutation(s) that allow poxviruses to subvert host antiviral responses)247. Specifically, of a cluster of interferon-associated genes was upreg-
a variant of VACV was identified that has a significant amplification of the K3L gene, ulated; this cluster was enriched for genes regulated
which, together with a beneficial point mutation in the same gene, allows the virus by both type I and type II interferons, including PKR,
to largely overcome the host protein kinase R (PKR)-mediated antiviral responses247. STAT1, STAT2, MX1, MX2, IP10, OAS1, OAS2 and OAS3
Such genetic accordions have not been reported in MPXV and further investigations (ref.66). The animals that succumbed to the infection
are needed to investigate whether such a phenomenon could be a plausible mechanism (two out of seven) had minimal interferon responses,
for MPXV evolution and spread.
indicating that this early interferon response protects
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a Respiratory route g Infective ulcers
MPXV
Ciliated cells
Mucosa
Dendritic Macrophage
cell
Infected
macrophage
h Aerosolized MPXV
Direct virus
Infected access?
dendritic cell
Lymphatic
vessel
Infected
macrophage
Infected
Dendritic cell
c Draining f Infective pustules
lymph node
Natural
killer cells
b Skin route
e Sexual route
Wound MPXV
detected
in semen
Langerhans cell
Epidermis
Infected
ﬁbroblast
d
Hepatocyte
Direct
virus
access?
Macrophage
Dendritic
cell
Lymphatic
Dermis vessel
Kupﬀer cell
against fatality66. Human IFNβ has been demonstrated VARV and other orthopoxviruses harbour genes that
to inhibit MPXV replication and spread83. However, can modulate TNF84,85 and NF-κB86,87 pathways.
MPXV does not robustly activate TNF-regulated and Although host immunity is required to combat infec-
NF-κB-regulated genes, especially in animals that suc- tions, aberrant immune signalling can adversely affect
cumb to infection66. This is not surprising, given that infection outcomes. In another study of VARV-infected
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◀ Fig. 2 | Immunopathogenesis of human monkeypox. a–h | Monkeypox virus (MPXV) B cell and antibody protection. The importance of B cells
might enter the body via the respiratory (panel a) or skin (panel b) route. In the respiratory and immunoglobulins against poxviruses was first
tract, the virus can infect airway epithelial cells such as ciliated cells. Antigen-presenting demonstrated with the successful global vaccination cam-
cells such as dendritic cells and macrophages (MΦ) are also susceptible to MPXV paign that eradicated smallpox, which used a live VACV
infection. Upon inoculation in the skin, the virus infects keratinocytes and fibroblasts.
vaccine94,95. It was further demonstrated that treatment
Skin-resident immune cells such as Langerhans cells, dendritic cells and macrophages
are also targeted. In both scenarios (panels a and b), it is hypothesized that infected
with vaccinia immune globulin (VIG) isolated from the
antigen-presenting cells travel to nearby draining lymph nodes and facilitate its spread serum of vaccinees successfully protected close contacts
through the lymphatic system (panel c). Direct viral access to the lymphatics has been of patients with smallpox from infection96. In rhesus
also speculated. A common feature of human monkeypox is swelling of lymph nodes macaques, VACV-specific B cell responses were instru-
(lymphadenopathy). The abnormal proliferation and retention of natural killer cells might mental in protecting against a lethal MPXV infection53.
be one of the causes. Following its spread through lymphoid tissue, MPXV may target Importantly, epidemiological studies have further
other large organs such as the spleen and liver (panel d). Of note, MPXV antigens have demonstrated that the VACV vaccine confers protection
been previously been detected in both hepatocytes and Kupffer cells in non-human against other poxviruses, including MPXV97. The VACV-
primate (NHP) models. The viraemia wave could then allow the virus to further spread to specific memory B cells and antibody levels induced by
distant organs such as the skin and gonads. Recently, MPXV was isolated from semen of
vaccination were exceptional, in some cases lasting longer
infected individuals, highlighting the possibility of sexual transmission (panel e). The
infection of skin and mucosae leads to the appearance of infective pustules (panel f) and than 50 years98,99. However, only ~50% of vaccinated indi-
ulcers (panel g). The latter release high quantities of virus into the saliva, which viduals at >20 years after vaccination65 had neutralizing
potentially leads to aerosolized transmission of MPXV (panel h). antibody titres greater than 1:32, a correlate of protec-
tion suggested to confer protective immunity against
smallpox100. It is likely that cross-protective immunity
cynomolgus macaques, the levels of IL-8, CCL2 (also against monkeypox may similarly wane over time.
known as MCP1), CCL4 (also known as MIP1β), Fourteen MPXV proteins have been shown to be
IL-6 and IFNγ were significantly increased during recognized by cross-reactive VACV-induced immuno
the first 4 days post infection67. These cytokines drive globulins from human vacinees101. Three proteins in
monocytosis88, which might facilitate enhanced virus particular — MPXV (Zaire-1979_005) proteins D8, H3 and
dissemination through monocytic cell-a ssociated A26 — were targeted by neutralizing antibodies against
viraemia67. Importantly, the macaques eventually suc- MPXV in infected macaques101. In VACV, orthologue D8
cumbed to VARV infection, where high levels of these and H3 proteins are involved in the attachment of mature
cytokines might have contributed to a ‘cytokine storm’ virions22, whereas A26 associates with A27 (ref.102) to
leading to their demise67. Likewise, the levels of IL-1RA, bind surface laminin103. MPXV (Zaire-1979_005) pro-
IL-2, IL-6, IL-8, IFNγ, CCL2, CCL5 (also known as teins C19, A33 and A44 were also prominent antigens
RANTES), G-CSF, GM-CSF and sCD40L were found to for IgM isolated from MPXV-infected macaques dur-
be elevated in MPXV-infected cynomolgus macaques70. ing the acute phase of infection — these proteins could
Furthermore, a relative expansion (0.97-f old to thus be further developed as antigen-based serological
16.3-fold) of CD14+ monocytes was reported during diagnostic tools101. In another study, prophylactic treat-
acute infection, suggesting that the general immune ment with a cocktail of two mAbs — c7D11 and c8A —
milieu promoted the development and recruitment of successfully protected marmosets against lethal MPXV
monocytes following MPXV infection70. infection104. C7D11 and c8A target the VACV proteins L1
In reported cases of human MPXV infection, numer- (ref. 105) and B5 (ref. 106) , respectively, and have been
ous cytokines are elevated following infection (regard- recently formulated as a potential mRNA vaccine encap-
less of disease severity) — these include IL-1β, IL-1RA, sulated in lipid nanoparticles107. Gilchuk et al.108 showed
IL-2R, IL-4, IL-5, IL-6, IL-8, IL-13, IL-15, IL-17, CCL2 that a mixture of human-derived mAbs targeting the
and CCL589. However, in patients with serious disease VACV proteins D8, H3, A33, A27, B5 and L1 effectively
(defined as having >250 lesions), concentrations of cross-neutralized four clinically relevant orthopoxvi-
IL-2R, IL-10, GM-CSF and CCL5 were higher compared ruses, including MPXV and live VARV. However, despite
with those in patients with less severe disease, whereas knowledge of the MPXV proteins that are recognized by
the concentration of pro-inflammatory IL-6 was lower89. neutralizing antibodies, MPXV-specific epitopes (both
This cytokine profile suggests a dominant T helper conformational and linear) have not been extensively
2 cell response characterized by higher levels of IL-4, characterized.
IL-13 and IL-10. Likewise, the reduced levels of IL-2, The isotype composition of the anti-MPXV response
TNF, IFNα and IFNγ also suggest an anti-inflammatory may provide an important clue to pre-existing immunity
microenvironment involving regulatory T cells89. and protection, as IgM antibodies typically dominate in
VACV can evade immune responses by downregulat- primary immune responses, whereas IgG antibodies
Monocytosis ing inflammatory and antiviral immune responses44,90,91, dominate in secondary immune responses. In a cohort
An elevated number of
and MPXV may use a similar strategy to subvert host of 200 patients infected with MPXV who were recruited
infection-fighting monocytes in
the blood circulation. immunity 92. Given that immune mediators often between March 2007 and August 2011 in the DRC, indi-
facilitate crosstalk between immune cells 93, future viduals with both IgM and IgG responses were 5.09 times
Cytokine storm studies should identify the functional relationships more likely to develop severe lesions compared with
A sudden increase in levels of between cytokine profiles and immune cells in order individuals who had IgG-only responses30. Similarly, in a
circulating cytokines leading to
an over-activated immune
to clarify the mechanisms of pathogenesis and deter- cohort of infected individuals from the 2003 MPXV out-
response, which can be mine immune correlates of protection during MPXV break in the United States, patients with moderate/severe
life-threatening. infection. disease had an overall higher titre of anti-orthopoxvirus
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IgM 109 compared with those with mild disease, activation of CD8+ T cells114. In a mouse model of VACV
and anti-orthopoxvirus IgG responses were much respiratory infection, IFNγ secretion by primary acti-
reduced and less frequent in patients with moderate/ vated effector CD8+ T cells was shown to protect against
severe disease109. It is plausible that an IgG-only response lethality115. Indeed, CD8+ T cell-derived IFNγ was suffi-
reflects robust levels of cross-protective IgG+ memory cient for protection even in the absence of CD4+ T cells
B cells that produce a dominant secondary antibody and B cells115, highlighting the possibility that CD8+
response, whereas the lack of such memory necessitates T cells also confer protection against infection with other
an IgM-dominated primary response that is less effec- orthopoxviruses. Likewise, memory CD8+ T cells, which
tive at preventing disease. Thus, IgM responses may be a are induced following VACV immunization, were also
biomarker for disease severity. This also emphasizes the demonstrated to protect against lethal ECTV infection
critical and immediate need to extensively characterize in mice116. These memory CD8+ T cells execute their
the antibody profile of patients with MPXV in different protective effects via a combination of IFNγ and per-
cohorts. Likewise, VACV vaccine correlates of protection forin secretion, and work concomitantly with primary
must be determined to explain why certain vaccinated effector CD8+ T cells to achieve optimal protection116.
patients experience breakthrough infections. In humans, standard smallpox vaccine administered by
scarification117 was also able to induce primary cyto-
T cell immunity. CD4+ T cells, particularly T follicular toxic CD8+ T cells and IFNγ-producing T cells118. This
helper cells, play a role in enhancing recall and differ- observation was supported by another study, in which
entiation of memory B cells into antibody-secreting participants received live vaccinia smallpox vaccine
cells110. Memory CD4+ T cells were found to persist for (Dryvax)119. High levels of IFNγ-producing CD8+ and
up to 50 years or longer following VACV vaccine, with an CD4+ T cells were detected following immunization119.
estimated half-life of 8–15 years99. These VACV-specific In humans infected with VACV, activated CD4+ T cells
CD4+ T cells were capable of producing IFNγ and TNF were shown to upregulate genes related to cytolytic
following stimulation99. However, no direct correlation activities120. Interestingly, MHC class II-restricted cytol-
was reported between numbers of virus-specific CD4+ ytic CD4+ T cells have also been reported in individuals
T cells and anti-VACV antibody titres99. By contrast, immunized with VACV121. These cells could be respon-
the number of CD4+ T cells was shown to be critically sible for virus clearance in vaccinees with reduced or
important in inducing a protective antibody response missing memory CD8+ T cell responses99. In the experi-
against lethal MPXV infection in VACV-vaccinated mental mousepox model, perforin-dependent cytolytic
rhesus macaques53. Simian immunodeficiency virus CD4+ T cells have been reported122. Taken together, these
(SIV)-infected macaques with CD4 + T cell counts observations highlight the importance of T lymphocytes
<300 cells mm–3 were not able to produce VACV-specific in controlling orthopoxviral infections.
IgG following vaccination and died when challenged with Across the orthopoxvirus proteome, numerous
MPXV53. This observation is of high concern to both CD4+ and CD8+ T cell epitopes have been identified
VACV-vaccinated and unvaccinated individuals with in humans, mice and NHPs123–125. Many are conserved
uncontrolled HIV-1 infection, as their CD4+ T cell counts among the major orthopoxviruses and bind to human
are typically very low111. This group of individuals is there- MHC class I and class II molecules126–128. In particu-
fore at high risk of developing severe MPXV infection if lar, CD8+ T cells specific for two identified epitopes
exposed112. They might also experience a more compli- (MHC class II-restricted GRVFDKADGKSKRDA
cated pathology and provide the virus with an opportu- and MHC class I-restricted NPVTVINEY) in the immediate-
nity to acquire mutations that result in higher virulence early E3 protein of VACV were capable of killing infected
or transmission potential113. By contrast, a recent patient cells and halting the spread of VACV129. Both epitopes are
infected with MPXV who was on antiretroviral treat- conserved in the MPXV homologue, which is encoded
ment for HIV-1 had a CD4+ T cell count >700 cells mm–3 by the MPXV F3L gene130. An earlier study showed that
and did not experience a severe disease outcome25. VACV missing the E3 protein did not protect cynomol-
This may suggest an important role for CD4+ T cells gus macaques from subsequent MPXV infection131. As E3
in regulating monkeypox severity. Nevertheless, more protein is detected within 30 min of VACV infection132,
studies will need to be carried out to fully understand it should be readily processed and presented by infected
the role of CD4+ T cells during MPXV infection. cells, allowing T cell-mediated lysis at an early infection
In addition to supporting antibody development, stage before virion production and release. These prop-
T cells can play direct antiviral roles. Given that erties make E3 an excellent possible candidate for future
orthopoxviruses, including MPXV, infect and dissem- vaccine designs targeting all major orthopoxviruses.
inate in macrophages36,65–68, cytolytic T cells can be Despite the potential importance of T cells in dis-
instrumental in killing infected macrophages to prevent ease protection, smallpox vaccination does not neces-
viral spread. CD8+ T cells have been shown to eradicate sarily provide robust T cell-mediated immunity against
virus-infected monocytes and minimize virus dissemi- MPXV. In two out of five vaccinated individuals who
nation in a mouse model of VACV infection47. In fact, subsequently contracted MPXV, orthopoxvirus-specific
activation of CD8+ T cells in response to VACV infection CD4+ and CD8+ T cells were not detectable throughout
has been shown to be dependent on γδT cells, which convalescence 109 . Furthermore, similar levels of
present VACV peptides via MHC class I molecules114. orthopoxvirus-specific CD4+ T cell reactivity were
Moreover, γδT cells also upregulate co-stimulatory mol- observed in vaccinated and unvaccinated patients, and
ecules CD80 and CD86 and secrete IL-1 and IFNα for orthopoxvirus-specific CD8+ T cell responses were in
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factors such as NF-κB and interferon regulatory factors

(IRFs)137,138. Numerous orthopoxviral proteins can antag-
onize these signalling processes18,84,85,133. For example, the
VACV genome encodes numerous B cell lymphoma 2
(BCL-2)-like proteins that inhibit NF-κB and IRF3 acti-
vation by interacting with cofactors that are recruited
Preventing IFNα/β Reducing cellular
signalling activation following PRR binding85,139–141. BCL-2-like proteins are
generally conserved across orthopoxviruses — A47,
B13, P1, C6 and D11 are orthologues of BCL-2-like pro-
teins in MPXV17,84. VACV also encodes the E3 protein,
Targeting cytokines which binds to double-stranded RNA (dsRNA)142 that is
and chemokines produced late in its replication cycle143, and prevents the
dsRNA from being detected by host intracellular PRRs54.
This leads to complete inhibition of the protein kinase R
Escaping apoptosis (PKR)-mediated pathway54, which can otherwise block
protein synthesis by phosphorylating the eukaryotic
translation initiation factor subunit 2α (eIF2α)144. The
F3 protein of MPXV is a homologue of the VACV E3
NF-κB protein with a 37 amino acid truncation at the amino
Blocking activation
of complement terminus130. Unlike a similarly truncated recombinant
cascade VACV (VACVΔ37N), MPXV can still inhibit host
Preventing NF-κB activation
immune responses130. Interestingly, another recombinant
P IRF3 VACV expressing the MPVX F3L gene (VACV-F3L) did
not inhibit host PKR activation, suggesting that MPXV
P IRF3
has evolved to encode for yet undiscovered proteins that
Blocking of PRR compensate for the missing N-terminal amino acids of F3
Blocking IRF3 signalling signalling cascade in limiting host antiviral activities130.
One of the most important transcription factors
Fig. 3 | Immune evasion by MPXV. Monkeypox virus (MPXV) is known to encode downstream of PRR binding is IRF3, which controls
numerous viral proteins that are involved in evading the host immunity. These can be the expression of the crucial antiviral molecules IFNα
involved in interfering with the signalling cascade of pathogen recognition receptors,
and IFNβ145. The VACV B19 protein directly interacts
disrupting key transcription factors for the expression of inflammatory genes, such as
interferon regulatory factor 3 (IRF3) and NF-κB. MPXV can also interfere with interferon
with soluble interferons and inhibits their binding
signalling by blocking IFNα/β binding or suppressing IFNα/β production and by blocking to receptors146. Although deletion of the B19R gene
protein kinase R (PKR)-mediated pathways. In addition, MPXV secretes proteins that can in VACV did not affect its virulence, deletion of B19 in
target key inflammatory molecules such as TNF, IFNγ, IL-1β, IL-18 and IL-6. Moreover, ECTV did severely attenuate its ability to establish
MPXV can prevent apoptosis in infected cells by expressing numerous viral proteins that infection147. The MPXV orthologue B16 can inhibit IFNβ
target the apoptotic pathways. The Central African MPXV Zaire strain also expresses D14 signalling83,148. Interestingly, the interferon response is
which blocks the activation of the complement cascade. However, this viral protein is not known to be stronger in children and has been shown to
expressed in the West African MPXV strain. Lastly, MPXV can also downregulate the protect against severe SARS-CoV-2 (ref.149) and RSV150
activities of natural killer cells and T cells by interfering with their activation processes infections, but the reverse was observed in children
(see also Table 1). PRR, pattern recognition receptor.
infected with MPXV1,4. This emphasizes the need to bet-
ter understand host–pathogen interactions and further
fact higher in unvaccinated patients109. The association characterize the mechanisms of MPXV pathogenesis.
of CD4+ and CD8+ T cell responses with the severity of The activation of NF-κB is controlled by proteins of
MPXV infection remains inconclusive in human studies. the IκB family, which contain ankyrin repeats151. NF-κB
consists of two subunits (p65/p50), and in its inactive
MPXV immune evasion form the p65 subunit is bound by the inhibitory protein
Orthopoxviruses have accrued an arsenal of genes that IκBα (which contains six ankyrin repeats). During NF-κB
encode proteins which interfere with host cell signalling activation, IκBα is phosphorylated by IκBα kinase (IKK),
pathways that are involved in virus recognition, apopto- followed by ubiquitination and subsequent degradation151.
sis and immune regulation18,84,85,133–136 (Fig. 3). Here, we To prevent NF-κB activation, orthopoxviruses express
discuss some of the evasion mechanisms used by MPXV ankyrin-like proteins that compete with IκBα for phos-
during active infection (Table 1). For a more in-depth phorylation by IKK84,85. Eight ankyrin-like genes (J3L,
review of orthopoxvirus immune evasion strategies, see D1L, D7L, D9L, O1L, C1L, B5R, B17R, N4R and J1R) are
refs.85,133–136. encoded by the MPXV genome84 — J3L and J1R as well
as D1L and N4R are duplicated ORFs in left and right
Preventing cellular signalling. Mammalian cells can inverted terminal repeats within the viral genome84.
detect the presence of microbial infection through pat-
tern recognition receptors (PRRs). These can trigger Regulation of apoptosis. Another mechanism of
intracellular signalling cascades involving numerous orthopoxvirus immune evasion involves regulat-
host cofactors such as MYD88, TRAM, TIRAP and TRIF, ing apoptosis. The BCL-2-like proteins encoded by
eventually activating important immune transcription orthopoxviruses may interfere with the BCL-2-mediated
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Table 1 | Virulence and immune evasion genes of monkeypox virus (MPXV)

Protein function VACV (Western Reserve) MPXV (Central African) MPXV (Western African)
Accession No. NC_006998 Accession No. NC_003310 Accession No. NC_063383
Genea Size, amino Gene Size, amino Gene Size, amino
acids acids acids
Inhibitor of NF-κB activation; BCL-2-like protein A46R 240 A47R 240 OPG176 240
Inhibitor of NF-κB activation; BCL-2-like protein B15R 149 B13R 149 OPG200 149
Inhibitor of IRF3 and NF-κB activation, apoptosis N1L 117 P1L 117 OPG035 117
inhibitor; BCL-2-like protein
Inhibitor of IRF3 NF-κB activation; BCL-2-like K7R 149 C6R 149 OPG044 149
protein
Inhibitor of IRF3 and IRF7 activation; BCL-2-like C6L 151 D11L 153 OPG029 155
protein
Double-stranded RNA-binding protein, inhibitor E3L 190 F3L 153 OPG065 153
of interferon signalling, apoptosis inhibitor
IFNα/β binding proteins B19R 351 B16R 352 OPG204 351
IFNγ binding proteins B8R 272 B9R 267 OPG193 267
Dephosphorylation of STAT1; phosphatase H1L 171 H1L 171 OPG106 171
Ankyrin-like protein C19L 112 J3L 587 OPG003 588
Ankyrin-like protein – – D1L 437 OPG015 437
Ankyrin-like protein VACWR017 71 D7L 660 OPG023 660
Ankyrin-like protein C9L 634 D9L 630 OPG025 630
Ankyrin-like protein M1L 472 O1L 442 OGP037 442
Ankyrin-like protein K1L 284 C1L 284 OPG039 284
Ankyrin-like protein B4R 558 B5R 561 OPG189 561
Ankyrin-like protein – – B17R 793 OPG205 787
Ankyrin-like protein – – N4R 437 OPG015 437
Ankyrin-like protein B25R 112 J1R 587 OPG003 588
Apoptosis inhibitor, caspase 1 and caspase 8 inhibitor, B13R 345 B12R 344 OPG199 344
SPI-2
Apoptosis inhibitor, SPI-1 C12L 353 B19R 357 OPG208 357
Apoptosis inhibitor F1L 226 C7L 219 OPG045 219
Apoptosis inhibitor VACWR013 181 D5R 242 OPG021 242
TNF and chemokine binding protein, CrmB C22L 122 J2R 348 OPG002 349
IL-1β binding protein VACWR197 326 B14R 326 – –
IL-18 binding protein VACWR013 126 D6L 126 OPG022 126
Inhibitor of complement enzyme C3L 263 D14L 216 – –
CC chemokine binding protein C23L 244 J3R 246 OPG001 246
CC and CXC chemokine binding protein A41L 219 A41L 221 OPG170 221
OMCP, inhibitor of natural killer cell-mediated – – N3R 176 OPG016 176
NKG2D-dependent cell lysis
Inhibitor of intracellular trafficking of MHC class I B9R 77 B10R 221 OPG195 221
molecules
Inhibitor of MHC class II antigen presentation A35R 176 A37R 176 OPG163 176
Viral growth factor; EGF-like protein C11R 140 D3R 142 OPG019 142
Data obtained from refs.18,84,85,133–136. Size of each protein encoded by the displayed genes shown as number of amino acids. BCL-2, B cell lymphoma 2;
EGF, epidermal growth factor; IRF3, interferon regulatory factor 3; MPXV, monkeypox virus; OMCP, orthopoxvirus MHC class I-like protein; SPI-2, serine protease
inhibitor 2; VACV, vaccinia virus; –, no corresponding gene can be identified in the respective virus genome. aName or Gene ID is provided. Locus tags are provided
in the event that name or Gene ID is not available.
regulation of the intrinsic apoptotic pathway. Numerous VACV is considered the virus’s most potent inhibitor of
orthopoxvirus-encoded serine protease inhibitors (SPIs; apoptosis154. CrmA interferes with granzyme B155, which
serpins) have also been reported85,133,152,153, such as CrmA is secreted by cytotoxic T cells to initiate cell death in
in cowpox virus (CPXV)153; its homologue SPI-2 (B13) in the virus-infected target cells156. It also inhibits caspase 1
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and caspase 8, thereby interfering with their respective Vaccines

pyroptotic or apoptotic pathways152. In MPXV, an SPI-2 Vaccines against smallpox are known to have cross-
orthologue is encoded by the B12R gene84. protective activity against monkeypox. Two vaccines
TNFR orthologues are also commonly used by are approved by the US Food and Drug Administration
orthopoxviruses to interfere with host inflammation (FDA) for pre-exposure vaccination against orthopox-
and apoptotic events85,86. Decoy viral TNFRs, which viruses including monkeypox: a second-generation
lack signalling domains, are secreted and compete for live VACV vaccine, ACAM2000, and an attenuated
the binding of TNF157. Five orthopoxviral viral TNFRs third-generation vaccine based on modified vaccinia
— CrmB, CrmC, CrmD, CrmE and vCD30 — have Ankara (MVA), JYNNEOS174,175. National stockpiles
been identified 84,85,157. The MPXV genome encodes of second-generation vaccines such as ACAM2000 are
only CrmB, which is reported to bind to both TNF and most common176. However, these vaccines are associ-
TNFβ based on investigations performed with the CPXV ated with several rare side effects including myocar-
CrmB158. Interestingly, CrmB from VARV is extremely ditis and pericarditis176, with higher risks for certain
potent and exhibits an affinity for TNF159 that is stronger groups of individuals, such as those with eczema and
than etanercept, a commercially available competitive those who are pregnant. Nevertheless, a study demon-
inhibitor of TNF160. strated the efficacy of ACAM2000 smallpox vaccination
in eliciting VACV-specific T cell responses by report-
Antagonism of immune mediators. Orthopoxviruses ing the presence of activated CD4+ and CD8+ T cell
also evade host immune responses by secreting proteins responses at 1, 3, 6 and 12 months post vaccination177.
that antagonize the functions of host IFNγ, CC and CXC Following VACV stimulation, activated CD8+ T cells
chemokines, IL-1β and the complement system161–166. expressed much higher levels of the degranulation
Interestingly, the West African MPXV clade does not marker CD107, as well as IFNγ, TNF, IL-2 and CCL4
express any complement-m odulating proteins 11,18, (ref.177), indicating the presence of robust memory T cell
whereas the Central African strains encode the mon- responses. The elevated CD8+ T cell responses were
keypox inhibitor of complement enzyme (MOPICE) also observed in another study that compared the effi-
from the D14L gene11,167. Despite truncation in one of cacy of the MVA vaccination with the first-generation
its short consensus repeat (SCR) domains, MOPICE Dryvax immunization178. In both vaccination groups,
inhibits complement activation by binding to C3 and VACV-specific CD8+ T cells were observed to secrete
C5 convertases11,168. However, deletion of MOPICE did IFNγ, TNF, IL-2 and CCL4 following stimulation178.
not affect MPXV virulence in rhesus macaques infected Moreover, both ACAM2000 and Dryvax also triggered
with a Central African isolate, although it did dampen the production of VACV-neutralizing antibodies in the
the adaptive immune response169. vaccinees177,179, despite apparent differences in the viral
proteins being targeted179.
Reduction of cellular activation. Orthopoxviruses also In unvaccinated individuals, post-exposure vacci-
evade T cell-mediated and natural killer cell-mediated nation can be effective both for preventing disease and
cytotoxicity. T cells identify virus-infected cells by for reducing disease severity. Protection is strongest if
detecting foreign peptides loaded on surface-expressed vaccination is carried out immediately after exposure,
MHC class I. Meanwhile, natural killer cells continually and decreases with increasing time since exposure, with
survey cells via NKG2D for the absence of MHC class I, most studies agreeing that vaccination up to 3 days post
thereby ensuring that the MHC system is not compro- exposure provides significant clinical benefit180. In ani-
mised. MPXV overcomes this system first by secreting the mal studies, post-exposure vaccination against monkey-
orthopoxvirus MHC class I-like protein (OMCP) encoded pox varies in efficacy depending on the animal model
by the N3R gene, which resembles the MHC class I used, the challenge dose and the timing of post-exposure
molecule and binds to NKG2D. This suppresses the typi- vaccination181. Notably, vaccination with ACAM2000 at
cal NKG2D-dependent natural killer cell lysis of infected 1–3 days after a 50× median lethal dose MPXV challenge
cells that do not express MHC class I170. Evasion of natural in prairie dogs resulted in survival for 50–62% of the
killer cell surveillance allows the virus to reduce MHC animals, compared with only 25% survival in the unvac-
class I expression, thus reducing T cell recognition171. cinated group181. Human clinical studies are currently
In addition, CPXV also expresses proteins D10 and B8 in progress to determine the efficacy of post-exposure
that impair peptide loading and MHC class I trafficking vaccination against monkeypox182.
within the endoplasmic reticulum172. In MPXV, the B10R Third-g eneration attenuated vaccines such as
gene encodes for an orthologue of the CPXV B8 protein84. JYNNEOS have a better safety profile compared with
Orthopoxviruses also directly modulate natural killer cells earlier vaccines 183. However, because JYNNEOS is
and T cells in a paracrine fashion. For instance, orthopox- given in two doses 28 days apart, the second dose
viruses produce an IL-18-binding protein that further would likely be too late to help protect from disease in
blocks the cytotoxic activities of natural killer cells173. cases of post-exposure vaccination, and it is not known
MPXV also suppresses T cell-mediated immunity by whether the first dose is sufficient for therapeutic effi-
triggering a state of T cell unresponsiveness via an MHC- cacy. However, at 2 weeks post vaccination, neutralizing
independent mechanism65. Subversion of T cell responses antibody titres from one dose of JYNNEOS were equiv-
may explain why orthopoxvirus-specific memory T cells alent to those from ACAM2000, although they subse-
in vaccinated NHPs failed to protect against lethal MPXV quently became inferior to those of the ACAM2000
infection in the absence of neutralizing antibodies53. group183. Thus, if viral neutralization correlates with
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Box 3 | Ring-fencing vaccination against monkeypox little supporting clinical data from humans. The anti-
viral drug tecovirimat does not affect the intracellular
To halt the potential spread of monkeypox virus (MPXV) globally, ring vaccination has form of the virus (the intracellular mature virus), but
been implemented in several countries including the United Kingdom, the United targets the VP37 membrane protein of MPXV to prevent
States and Canada. This usually involves vaccinating people who may have been the formation of enveloped virions that are capable of
exposed to the virus through interactions with an infected person. Vaccination is
cell egress, thus disrupting viral spread188. Tecovirimat
performed using smallpox vaccines, which are thought to offer protection against
MPXV. Some of the challenges facing a successful ring vaccination are discussed below. was effective at reducing monkeypox severity in NHP
• Contact tracing: to identify all individuals who are potentially exposed, extensive models189,190, but its effectiveness is reduced if treatment
contact tracing and robust testing needs to be carried out. For logistic reasons this may is given more than 5 days post challenge191. This sug-
not be possible in every country. Furthermore, given the current characterization of gests a caveat if tecovirimat is given based on the onset
non-endemic monkeypox as a disease that spreads primarily within the community of symptoms, which may appear much later following
of men who have sex with men (MSM), patients may be reluctant to come forward for infection1,4. Nevertheless, a small study used tecovirimat
diagnosis, especially in countries where homosexuality is stigmatized or criminalized248. in a single patient infected with monkeypox, who then
• Efficiencies of second-generation and third-generation vaccines: past data showed showed a shorter duration of viral shedding and illness
that smallpox vaccination was 85% protective against MPXV60. However, this compared with six untreated patients28.
value was obtained from individuals vaccinated with the first-generation vaccine. Another smallpox therapeutic is brincidofovir, which
Nevertheless, currently available second-generation and third-generation vaccines
is approved by the FDA but not the European Medicines
were also reported to be approximately 85% protective against MPXV in animals
models249,250, but there are no data on their efficacy in humans exposed to MPXV.
Agency (EMA). Brincidofovir inhibits orthopoxvi-
rus DNA polymerase-mediated DNA synthesis. It has
• Willingness to comply: not everyone identified will be willing to receive the vaccine.
In a recent report, only ~14% of community contacts and ~69% of potentially exposed shown efficacy against monkeypox in prairie dog and
health-care workers in the United Kingdom were willing to be vaccinated40. Moreover, mouse models192,193. In the same small study discussed
the stigmatization of potentially being associated with the community of MSM might above28, three patients were treated with brincidofovir,
further deter vaccination efforts. but all three ceased therapy owing to toxicity (elevated
liver enzymes). Cidofovir28, the active drug form of brin-
protection, the efficacy of a single dose of JYNNEOS cidofovir, also shows anti-poxvirus activity in vitro and
may be similar to ACAM2000 within the first critical in animal studies194, but it is nephrotoxic195–197.
weeks of post-exposure prophylaxis. In the same prairie VIG showed promising activity in preventing
dog study referenced above, post-exposure vaccination smallpox in exposed individuals198 and has exhibited
with JYNNEOS resulted in 38–88% survival181. cross-neutralizing activity against MPXV in rhesus
A critical aspect of vaccine development is under- macaques53. However, neither VIG nor other mAbs
standing the mechanisms by which different vaccines or antibody cocktails have yet been studied against
elicit immune responses, as different formulations can monkeypox in the clinic.
induce either specific B cell-mediated or T cell-mediated
immunity184. Likewise, the immunocompetency of vac- Concluding remarks
cine recipients as well as the route of immunization Immunotherapeutics and preventive strategies are
will also affect the quality of the immune response184. important public health tools that complement strin-
Given the frequent mucosal route of infection, the spe- gent contact tracing in curbing the spread of monkey-
cific induction of mucosal immunity may be crucial in pox. Similarly, serology-based diagnostics are valuable
the context of MPXV, as documented for other infec- surveillance tools for contact tracing and understanding
tious pathogens that transmit via the mucosal route185. exposure history. However, such serological diagnostic
Currently, it is not well understood whether any of the tools must be specific for MPXV, given the baseline
available vaccines are able to induce mucosal immunity, of vaccine-induced poxvirus immunity199. Expansion of
and this remains a key future research need. surveillance networks and identification of surveillance
Another research need is to understand whether there gaps are also critical for a successful ring-fencing strat-
is a risk of creating new virus strains when individuals egy (see Box 3 for details). Notably, there is a major need
infected with monkeypox are vaccinated. Co-infecting in public health to better inform potentially exposed
poxviruses can evolve by exchanging genetic information persons of the benefits and risks of vaccination.
via homologous or non-homologous recombination186. Historically, the collection of clinical data on mon-
It is currently unknown how frequently genes from live keypox has been hindered by the sparseness and unpre-
or attenuated poxvirus-based vaccines may recombine dictability of cases in endemic countries, impeding
with monkeypox. accurate risk–benefit calculations in managing mon-
In addition to the VACV or MVA-based vaccines, keypox. The current outbreaks provide an opportunity
newer genetically engineered VACV or other poxvirus to evaluate current and novel treatments and vaccine
strains such as NYVAC and ALVAC have also been experi- options and to establish correlates of vaccine protection.
mented with as potential vaccine vectors for other diseases. Notably, the ring vaccination trial design can provide high
Ring vaccination trial design However, they generally induce lower antibody titres187, statistical power with relatively few subjects owing to
A recently developed approach and their effectiveness against monkeypox is unclear. the high potential attack rate200. However, in generaliz-
that recruits subjects linked to ing such findings, caution must be taken to account for
an infected case and allows Therapeutics variance in the route of transmission.
for the simultaneous evaluation
of vaccine efficacy and
Several therapeutics that were developed for smallpox Several key research questions remain to be answered.
effectiveness during ongoing are available for monkeypox, but their effectiveness Studies of the human systemic and mucosal immune
outbreaks. for monkeypox is based on preclinical evidence with responses during MPXV infection are currently limited
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and will be required to better understand the mecha- recommended by the UK Health Security Agency that
nisms of immune defence against MPXV. Importantly, vaccination should be given to men who are homosexual
it is not currently known whether prior infection with or bisexual who are at a higher risk of exposure to help
VACV or MPXV, or smallpox vaccination, induces any control the current outbreak205.
form of mucosal immunity. It will be critical to char- Many other infectious diseases are endemic to
acterize the mucosal immune responses given that Africa206, and co-infection with MPXV is possible.
MPXV and other poxviruses can be transmitted via For instance, co-infection of alphaviral infections and
respiratory aerosols1. Knowledge of the roles of IgA malaria can significantly modulate host immunity
and tissue-resident memory T cells in MPXV infection and affect infection outcomes207–209. Given the current
would be particularly critical, enabling a deeper under- transmission among MSM in non-endemic countries,
standing of MPXV-related respiratory complications22. there is also a need to understand monkeypox disease
Likewise, the preputial mucosal immunity should also and vaccination in the context of co-infection with other
be characterized, as MPXV DNA has been identified in diseases that have a disproportionate burden in the com-
semen26. munity of MSM; this is especially true for HIV-1, which
Defining the immunological correlates of protection can severely impair adaptive immune responses210.
is also an important goal for the evaluation of newer Risk factors for severe MPXV should also be identi-
vaccines, especially those targeted towards the vul- fied. Pregnant women, young children and unvaccinated
nerable populations of pregnant women and children. individuals are known to be especially susceptible1,4,30,32.
Therefore, other than being unvaccinated, what other However, other populations also need characteriza-
factors (for example, behavioural, geographical, nutri- tion, including older people, individuals on long-term
tional, medical, immunological or genetic factors) are medications and individuals with underlying metabolic
involved? It was recently reported that the quality of diseases who may manifest the disease differently.
innate immune responses in young children determines Long-term disease sequelae should be tracked in
the severity of respiratory viral infection201. Likewise, patients, including children born to mothers infected
as reported for SARS-CoV-2 infections, children who with MPXV. Experience with the Zika outbreak showed
are infected tend to have reduced B cell202 and T cell203 that children with in utero exposure can develop some
responses compared with adults. The characterization developmental issues later in life211. This research focus
of adaptive immune responses in children infected with should be given more urgency, given that available data
MPXV could clarify why children tend to exhibit a more suggest that only 20–25% of pregnant women infected
severe disease and lower vaccine effectiveness1,4,7. It is with MPXV would successfully give birth30,32. Moreover,
also important to understand the risks of vaccination young children are apparently more susceptible to severe
in vulnerable populations, especially young children monkeypox4. Currently, data on fetal development follow-
and pregnant women1,4,30,32. Clinical studies are lacking ing congenital MPXV infection are lacking. In addition,
in these populations for most of the available thera- longitudinal monitoring of patients with MPXV would
peutics and vaccines. Furthermore, some important also allow the determination of whether infection with
vaccines and therapeutics (for example, ACAM2000 MPXV can lead to long-term effects, as observed after
and brincidofovir) are not recommended or are even infection with SARS-CoV-2 during the current pandemic.
contraindicated for these populations due to increased
potential risk of side effects204. Nevertheless, it was Published online 5 September 2022
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occurrences of MPXV infection globally. accordions to adapt rapidly against host antiviral Author contributions
241. Channel News Asia. Singapore confirms imported case defenses. Cell 150, 831–841 (2012). All authors contributed equally to all aspects of the article.
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and rashes. CNA https://www.channelnewsasia.com/ using genomic accordions as a mechanism of Competing interest
singapore/monkeypox-singapore-imported-case-flight- evading host antiviral responses. The authors declare no competing interests.
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242. Isidro, J. et al. Phylogenomic characterization and Monkeypox: avoiding the mistakes of past infectious Peer review information
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outbreak of monkeypox virus. Nat. Med. https:// org/10.7326/M22-1748 (2022). co-reviewed with Bertram Jacobs, Sathesh Panayampalli and
doi.org/10.1038/s41591-022-01907-y (2022). 249. Centers for Disease Control and Prevention. the other, anonymous, reviewer(s) for their contribution to the
This recent article characterizes the MPXV outbreak Monkeypox and smallpox vaccine guidance. CDC peer review of this work.
genome sequence and highlights the involvement of https://www.cdc.gov/poxvirus/monkeypox/clinicians/
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243. Luna, N. et al. Phylogenomic analysis of the 250. Kimball, S. U.S. has more than 36,000 Jynneos Springer Nature remains neutral with regard to jurisdictional
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of a novel viral lineage. Travel. Med. Infect. Dis. https:// national stockpile. CNBC https://www.cnbc.com/2022/
doi.org/10.1016/j.tmaid.2022.102402 (2022). 06/06/us-has-36000-doses-of-jynneos-monkeypox- Springer Nature or its licensor holds exclusive rights to this
244. Gigante, C. M. et al. Multiple lineages of monkeypox vaccine-immediately-available-in-national-stockpile. article under a publishing agreement with the author(s) or
virus detected in the United States, 2021–2022. html (2022). other rightsholder(s); author self-archiving of the accepted
Preprint at bioRxiv https://doi.org/10.1101/2022. manuscript version of this article is solely governed by the
06.10.495526 (2022). Acknowledgements terms of such publishing agreement and applicable law.
245. Hammarlund, E. et al. Multiple diagnostic techniques The authors thank D. Ackerman of Insight Editing London for
identify previously vaccinated individuals with his valuable inputs on an early draft. This work was supported © Springer Nature Limited 2022
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REVIEWS

Monkeypox: disease epidemiology,

NAture RevIeWS | IMMuNoloGy volume 22 | October 2022 | 597

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Box 1 | History of monkeypox tissues. Clinical studies of human monkeypox suggest

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a Respiratory route g Infective ulcers

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factors such as NF-​κB and interferon regulatory factors

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Table 1 | Virulence and immune evasion genes of monkeypox virus (MPXV)

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and caspase 8, thereby interfering with their respective Vaccines

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