Monkeypox virus (MPXV), a zoonotic pathogen related to smallpox, has garnered significant attention due to its recent outbreaks and the ensuing public health challenges. The virus, which has historically been confined to certain regions of Africa, has seen a global spread that has sparked widespread concern among healthcare professionals and researchers. This article seeks to explore the intricacies of MPXV, from its transmission mechanisms and epidemiology to the implications of its evolution and the ongoing efforts to manage and contain its spread.
| Medical Concept | Simplified Explanation | Relevant Details | Examples |
|---|---|---|---|
| Infectious Dose | The smallest amount of a virus needed to cause an infection. | Infectious dose can vary by how the virus enters the body, such as through the skin, lungs, or mouth. For monkeypox, this dose is not precisely known for humans but is estimated in animals. | If 10 to 10,000 viral particles are needed to infect an animal, the infectious dose for humans might be similar. |
| Median Lethal Dose (LD50) | The amount of a virus required to kill half of the infected population. | LD50 varies depending on how the virus enters the body and is typically higher than the infectious dose. | In animal studies, the LD50 for monkeypox virus can range from 100,000 to 10 million particles, depending on the method of exposure. |
| Transmission Pathways | The ways in which a virus can spread from one person to another. | Monkeypox can spread through direct contact with bodily fluids, respiratory droplets, or touching contaminated objects. It can also spread from animals to humans, especially through bites or handling infected animals. | Touching an infected person’s rash or using their bedding can spread the virus. Droplets from a cough can also transmit the virus. |
| R0 (Basic Reproduction Number) | A measure of how many people, on average, one infected person will spread the virus to in a population with no immunity. | If R0 is greater than 1, the virus can cause an outbreak. If it’s less than 1, the spread will likely stop on its own. For monkeypox, R0 is estimated to be between 1.1 and 2.4 in non-immune populations. | If a monkeypox patient infects two other people, the R0 is 2. This number can change depending on how contagious the virus is and population behavior. |
| Zoonotic Transmission | When a virus spreads from animals to humans. | Monkeypox is zoonotic, meaning it can be caught from animals. The virus was first discovered in monkeys, but it’s more commonly spread by rodents. | Handling a sick monkey or rodent could lead to a person catching monkeypox. |
| Incubation Period | The time between being exposed to a virus and when symptoms start to appear. | For monkeypox, this period can vary from 1 to 31 days, but it is usually around 7 to 14 days. | After exposure to monkeypox, a person might not show symptoms for nearly two weeks. |
| Prodromal Phase | The early stage of an illness when symptoms are just starting to appear but are not yet specific. | During this phase, people might feel like they have the flu, with fever, fatigue, and muscle aches. These are not specific to monkeypox, making diagnosis difficult at this stage. | Before the monkeypox rash appears, a person might just feel very tired and feverish. |
| PCR (Polymerase Chain Reaction) | A laboratory method used to detect the genetic material of a virus in a sample. | PCR tests are very accurate and are the primary method used to confirm monkeypox infection by detecting the virus’s DNA. | Doctors swab a lesion and use PCR to confirm if it’s monkeypox. |
| Post-Exposure Prophylaxis (PEP) | Treatment given after exposure to a virus to prevent it from causing illness. | For monkeypox, this often involves vaccination within a few days of exposure. This can prevent the virus from taking hold or reduce the severity of the disease. | If someone is exposed to monkeypox, they might receive a vaccine to prevent them from getting sick. |
| Smallpox Vaccine | A vaccine originally developed to protect against smallpox, which also provides protection against monkeypox. | The smallpox vaccine is about 85% effective at preventing monkeypox. Since smallpox was eradicated, vaccination against it has declined, leading to reduced immunity in the population. | People vaccinated against smallpox decades ago still have some protection against monkeypox today. |
| Environmental Stability | How long a virus can survive outside the body on surfaces like clothing or bedding. | Monkeypox virus can stay alive for weeks to months on surfaces if not properly cleaned. This makes it important to disinfect areas that infected people have been in. | If an infected person’s bedding is not washed, the virus could survive on it for a long time, potentially infecting others. |
| Ultraviolet (UV) Light Disinfection | Using UV light to kill viruses on surfaces by damaging their genetic material. | UV light, particularly UV-C, is effective in inactivating viruses like monkeypox on surfaces, making it a useful tool for disinfection in hospitals and labs. | Shining UV light on a contaminated surface can kill the monkeypox virus in a few minutes. |
| Gene Loss/Gain in Viruses | Changes in a virus’s genetic material where it loses or gains genes, potentially affecting how it behaves. | These changes can influence how easily the virus spreads or how severe the infection it causes might be. For monkeypox, certain gene losses have been linked to better human-to-human transmission. | A virus that loses genes might spread more easily between people, as seen with some monkeypox strains. |
Infectious Dose and Animal Models
The infectious dose of MPXV in humans remains an enigma, with current estimates drawn largely from animal models, particularly cynomolgus macaques. These animals have proven to be the most accurate models for studying human monkeypox, despite the inherent limitations and differences between species. For instance, various studies suggest that the dose required to cause infection in animal models varies from less than 10 to 10,000 plaque-forming units (PFUs) across different routes of exposure, including intravenous, oral, intranasal, and aerosol methods.
One of the key findings in animal studies is the median infectious dose of MPXV via the aerosol route, which has been estimated to be around 200 PFU in cynomolgus macaques. The median lethal dose (LD50), which represents the dose required to cause death in 50% of exposed animals, is significantly higher, ranging from 100,000 to 10 million PFU depending on the route of exposure. Notably, Clade I MPXV, often associated with higher mortality rates, has a lower lethal dose than Clade II, reflecting the varying pathogenicity of different virus strains.
These findings underscore the importance of determining the infectious dose in humans, which remains a critical gap in our understanding. Human infection studies are ethically unfeasible, leaving researchers to rely on indirect evidence and animal models, which may not fully capture the nuances of human disease.
Transmission Pathways
MPXV transmission occurs through direct contact with infected animals, humans, or contaminated materials. The virus can enter the body through broken skin, the respiratory tract, or mucous membranes such as the eyes, mouth, and genitals. Human-to-human transmission, while historically rare, has become more prevalent, particularly through respiratory droplets, direct contact with bodily fluids or lesion material, and indirect contact via contaminated surfaces.
A significant development in recent outbreaks is the identification of sexual transmission as a major driver of MPXV spread. This has raised concerns about unaccounted community transmission, especially in populations with specific behaviors that increase the risk of exposure. For instance, the virus has been observed to spread efficiently among men who have sex with men (MSM), leading to clusters of cases that challenge traditional containment strategies.
Moreover, the role of droplet transmission remains consistent with previous outbreaks, with no significant changes in transmission rates despite the virus’s increased spread. However, the potential for transmission via other routes, such as mother-to-fetus transmission through the placenta, adds layers of complexity to the epidemiology of MPXV.
| Major Findings by Topic Area | |
| Topic | Overview of Current Knowledge |
| BACKGROUND | – MPXV belongs to the same group of viruses as the Variola major virus, which causes the human disease known as smallpox, which was declared eradicated in 1980. This group also includes vaccinia virus (an attenuated poxvirus used in the smallpox vaccine), horsepox virus, and cowpox virus. These viruses, known as orthopoxviruses (OPVs), are extremely large viruses with DNA genomes. – MPXV causes a disease similar to, but generally less severe than, smallpox. – There are at least two broad groups (clades) of MPXVs. – Virologists use the term “clade” to describe a group of viruses that have extremely similar genetic sequences and are different enough from other viruses of the same species that they form a distinct genetic cluster. – Clade I (formerly Congo Basin clade) is found in Central Africa. About 10% of cases are fatal. – Clade II (formerly West African clade) includes the virus responsible for the current outbreak, and is associated with a lower death rate, about 1%. In the past, viruses of this clade have also been less transmissible than Clade I viruses. |
| INFECTIOUS DOSE | – The infectious dose of MPXV in humans is unknown. – Based upon studies in non-human primates (NHPs), the infectious dose via inhalation is estimated to be between 10 and 10,000 infectious viral particles. Most of these studies were conducted with the Clade I MPXVs. – Clade II MPXVs have generally been found to be less infectious than Clade I MPXVs. |
| TRANSMISSIBILITY | – The virus enters the body through broken skin, the respiratory tract, and other non-respiratory mucous membranes. – Human-to-human transmission is thought to occur primarily through respiratory droplets, direct contact with body fluids/lesion material, and fomites contaminated with lesion material.Rates of droplet transmission in this outbreak appear similar to prior outbreaks. – The current outbreak strain may have accumulated mutations that increase its transmissibility. However, there is not yet enough evidence to suggest that these dramatically increase the basic reproductive number (R0) of the virus. – The R0 of mpox across all clades is generally estimated to be between 0.57 to a maximum of 1.25. The calculated R0 for the current outbreak is 1.10-2.40. This may be related to novel mutations accumulated during prolonged human-to-human transmission. – Evidence suggests that the transmission rate of MPXV has increased over time due to declining immunity in the population after the end of smallpox vaccination. – Direct contact among MSM currently has been cited as a source of a significant numbe of the infections in the current outbreak. |
| HOST RANGE | – Mpox is a zoonotic disease, and outbreaks are initiated by human contact with animals. – NHPs can be intermediate hosts but are not likely to be reservoir hosts.The primary reservoir of the virus is unknown but is likely to be one or more species of rodent. – Domesticated animals in MPXV-positive households have been infected with MPXV by owners. – It is not known if rodent species native to the United States could serve as reservoir hosts, though several can become infected. |
| INCUBATION PERIOD | – The interval between exposure and the development of symptoms ranges from 1 to 31 days, with 7-17 days being the typical range. – Patients are contagious during the first week of the rash and may continue shedding the virus for weeks after symptoms have dissipated. |
| CLINICAL PRESENTATION | – Early presentation consists of fever, fatigue, headache, backache, mild to severe pulmonary lesions, anorexia, dyspnea, conjunctivitis, nasal discharge, swollen lymph nodes, chills and/or sweats, sore throat, cough, and shortness of breath. – Rash presents within 1-4 days upon onset of symptoms and lasts from 2 to 4 weeks. – Rash is typically confined to the trunk but may appear on the palms and soles of feet. Lesions can develop on mucous membranes, in the mouth, on the tongue, and on the genitalia. – In the current outbreak, lesions on the genitalia and the perianal region have been more common due to the role of sexual transmission, and early presentation has not always included fever or other typical early symptoms of mpox. – Some patients in the current outbreak have presented without fever. – These unusual presentations can lead to misdiagnosis as a common sexually transmitted infection such as syphilis, chancroid, or herpes. – Swollen lymph nodes (lymphadenitis) are a feature of mpox disease not seen in smallpox. |
| CLINICAL DIAGNOSIS | – One U.S. Food and Drug Administration (FDA)-cleared test and seven Emergency Use Authorization (EUA) tests are approved for diagnosis of mpox in the United States. All tests require swabs from lesions. – The current Centers for Disease Control and Prevention (CDC) case definition requires positive polymerase chain reaction (PCR), sequencing, or culture to be considered a confirmed case. – Culture-based diagnostics should only be performed by the CDC. |
| FATALITY RATE | – As of 02/15/2023, the fatality rate in the United States for the current outbreak is 0.1%, which is consistent with the global rate. |
| MEDICAL TREATMENT | – There are currently no MPXV-specific antiviral drugs.Tecovirimat (TPOXX) is approved for smallpox and mpox.Brincidofovir (Tembexa), cidofovir (VISTIDE), and vaccinia immune globulin intravenous (VIGIV) are potential treatment options. – Tecovirimat and VIGIV are in the Strategic National Stockpile (SNS). – For post-exposure prophylaxis (PEP), smallpox and JYNNEOS vaccines can be administered at 3 and 4 days post-exposure, respectively. Both vaccines are effective in reducing clinical symptoms up to 14 days post-exposure. |
| VACCINES | – Vaccination with smallpox vaccine (vaccinia virus) is reported to provide protection against 85% of MPXV infections. – JYNNEOS (Bavarian Nordic A/S) is specifically licensed for MPXV by the FDA in addition to licensure for smallpox. JYNNEOS is a two-dose, non-replicating Modified Vaccinia Virus Ankara (MVA) vaccine that can be given to people for whom live vaccina vaccines are not safe. – ACAM2000 (Emergent) is a live vaccinia virus vaccine licensed for smallpox, made available for MPXV under Expanded Access Investigational New Drug (EA-IND) by the FDA. – ACAM2000 and JYNNEOS are maintained in the SNS, along with Aventis Pasteur Smallpox Vaccine (APSV), another live vaccinia vaccine that would be used under an EUA or as an IND in an emergency. |
| ENVIRONMENTAL STABILITY | – The median time of MPXV DNA persistence in various patient samples, like blood, urine, and skin lesions, is from 5.7 days to 13.5 days. – MPXV, like other OPVs can be stable in the environment for days to weeks under some circumstances. – MPXV can survive in scabs for months to years. – MPXV is resistant to desiccation in hot and cold environments.Closely related OPVs may be stable for days to weeks in water, soil, and on refrigerated food. – MPXV is susceptible to inactivation under acidic conditions. |
| DECONTAMINATION | – U.S. Environmental Protection Agency (EPA) recommends bleach and a number of quaternary ammonium reagents for use against emerging viral pathogens. – Data demonstrating effectiveness against MPXV are not available for most common disinfectants, however testing with vaccinia virus (a close relative) suggests that bleach, Virkon, Dettol, and Sanytex are effective. |
| PERSONAL PROTECTIVE EQUIPMENT (PPE) | – Optimal personal protective equipment (PPE) for clinicians caring for infected patients includes disposable gown and gloves, National Institute for Occupational Safety and Health (NIOSH)- certified N95 (or comparable) filtering disposable respirator, and face shield or goggles. – Additional PPE may be required for individuals working with samples or animals known or suspected to be infected with MPXV. – Laboratory studies with MPXV require Biosafety Level 2 or 3 (BSL-2 or BSL-3) precautions. These laboratories have enhanced safety precautions (such as the use of respirators) and higher levels of containment (e.g., high-efficiency particulate air [HEPA] filtration of all exhaust air) to avoid laboratory staff exposure or accidental release of a pathogen. |
| GENOMICS | – MPXV is a DNA virus with a genome more than 10 times larger than that of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). – In August 2022, the World Health Organization (WHO) updated clade nomenclature in which the Congo Basin/Central African clade has been renamed Clade I, and the West African clade was renamed Clade II, with subclades IIa and IIb. – Like related viruses, MPXV evolves slowly. Its genome changes 100-1,000 times slower than that of SARS-CoV-2. – Research conducted in 2022 suggests that the virus responsible for the latest outbreak may be evolving slightly faster than normal, but still significantly slower than other viruses like influenza and SARS-CoV-2. – This faster evolutionary rate may be due to accumulated mutations that enhance transmission of the virus, but more work is needed to clearly demonstrate this finding. – Clade I MPXVs are regulated as U.S. Department of Health and Human Services (HHS) Select Agents by the CDC Federal Select Agents Program. Clade II MPXVs are not Select Agents due to their lower severity/lethality. |
The Global Spread and R0
Since April 2022, MPXV has spread beyond its endemic regions, largely attributed to human-to-human transmission, particularly in non-endemic countries. This shift in transmission dynamics has prompted public health authorities to reassess the virus’s basic reproduction number (R0), which represents the average number of secondary infections generated by one infected individual in a susceptible population.
Estimates of R0 for MPXV during the current outbreak range from 1.10 to 2.40, depending on the population and geographic location. This increase is believed to be linked to the decline in smallpox immunity, as the cessation of smallpox vaccination programs has left populations vulnerable to orthopoxvirus infections. The virus’s potential to spread within communities, particularly through sexual contact, complicates efforts to contain outbreaks and accurately estimate R0.
Additionally, mutations in the current outbreak strain may enhance transmissibility, although these changes are unlikely to dramatically alter the virus’s basic reproduction number. However, the association of MPXV transmission with specific populations, such as MSM, adds complexity to the assessment of R0, making previous estimates potentially unreliable for predicting the virus’s spread in different contexts.
Zoonotic Reservoirs and Potential Hosts
MPXV is primarily a zoonotic virus, with animal-to-human transmission playing a significant role in its epidemiology. The virus was first isolated from monkeys, but non-human primates (NHPs) are likely not the primary reservoir. Instead, small mammals, particularly rodents, are believed to harbor the virus in West and Central Africa. Species such as the Gambian pouched rat, dormice, and various squirrels have been implicated as potential reservoirs.
The risk of MPXV establishing new reservoirs outside Africa, particularly in regions where the virus has recently spread, is a growing concern. The possibility of transmission to domesticated animals, such as dogs, has been documented, highlighting the virus’s adaptability and the potential for new animal reservoirs to emerge in non-endemic regions. This raises questions about the long-term persistence of MPXV in these environments and the implications for ongoing public health efforts.
The potential for MPXV to become an endemic disease outside Africa hinges on its ability to establish reservoirs in native species, which could sustain the virus in the environment. The role of the wild animal trade in facilitating spillover infections and the potential for new host species to emerge also warrant further investigation. These factors could significantly impact the global landscape of MPXV transmission and necessitate revised strategies for surveillance and containment.
Incubation Period and Infectivity
The incubation period for MPXV, which can range from 1 to 31 days, is another critical factor in understanding the virus’s transmission dynamics. The variability in incubation times, influenced by factors such as the route of exposure and the health status of the host, complicates efforts to predict and manage outbreaks. For instance, in the 2003 U.S. outbreak, the median incubation period was 12 days, while in the more recent 2022 outbreak, it ranged from 3 to 20 days.
During the incubation period, individuals may not exhibit symptoms but could still be infectious, posing challenges for public health interventions. The degree of infectivity before symptom onset remains unclear, raising questions about the best strategies for quarantine and isolation, especially in settings where early detection and containment are crucial.
Moreover, the severity of the disease can vary depending on the route of exposure. In some cases, individuals exposed through non-invasive means, such as petting infected animals, experienced a longer incubation period and slower disease progression. This variability underscores the need for tailored public health responses based on specific exposure scenarios.
Clinical Presentation and Complications
MPXV infection typically presents with a prodromal phase, characterized by flu-like symptoms, followed by a rash that may last 2 to 4 weeks. The rash often begins on the trunk and spreads to other parts of the body, including the palms, soles, and mucous membranes. However, the current outbreak has seen a broader range of symptoms, including proctitis and tonsillitis, particularly in cases linked to sexual transmission.
Misdiagnosis of MPXV is a significant concern, as the rash can resemble other conditions such as varicella (chickenpox) or sexually transmitted infections like syphilis and herpes. The absence of lymphadenopathy, a hallmark of MPXV, in some cases further complicates accurate diagnosis. Additionally, individuals with underlying health conditions, such as HIV or cancer, may exhibit atypical symptoms, leading to delayed or incorrect diagnoses.
Complications from MPXV infection can be severe, including ocular infections that may result in vision loss, and the risk of miscarriage or fetal death in pregnant women. These potential outcomes highlight the importance of early detection and appropriate medical management to prevent severe complications.
Diagnostic and Therapeutic Advances
The recent outbreak has accelerated the development and deployment of diagnostic tools for MPXV. As of February 2023, several FDA-cleared and EUA-approved tests are available, primarily utilizing PCR-based methods to detect the virus in lesion samples. These tests are critical for confirming cases and guiding public health responses, although challenges remain in resource-limited settings where access to advanced diagnostic tools may be restricted.
Therapeutic options for MPXV are currently limited, with no specific antiviral drugs approved for the virus. However, existing antiviral treatments for other poxviruses, such as tecovirimat (TPOXX), have shown efficacy in treating MPXV in clinical settings. The availability of such treatments, particularly for severe cases or immunocompromised individuals, is a crucial component of the response to the outbreak.
Post-exposure prophylaxis (PEP) with smallpox vaccines, such as JYNNEOS and ACAM2000, offers another line of defense. These vaccines, particularly when administered within 3 to 4 days of exposure, can prevent or mitigate the severity of MPXV infection. However, the optimal use of these vaccines, particularly in different population groups and exposure scenarios, remains an area of ongoing research.
Public Health Strategies and Vaccination
The resurgence of MPXV, particularly in regions where smallpox vaccination has been discontinued, underscores the importance of vaccination as a key public health strategy. The cessation of smallpox vaccination has left large populations vulnerable to orthopoxvirus infections, contributing to the current outbreak’s spread. Vaccination strategies now focus on high-risk populations and those with known or suspected exposure to MPXV.
JYNNEOS, a non-replicating Modified Vaccinia Virus Ankara (MVA) vaccine, has emerged as a critical tool in the fight against MPXV. It is particularly suited for individuals who are at increased risk of severe disease, such as those who are immunocompromised. The vaccine’s two-dose regimen, with the second dose administered four weeks after the first, provides substantial protection, although the duration of immunity remains under investigation.
The challenges associated with vaccine deployment, including limited supply and the need for targeted vaccination strategies, highlight the complexities of managing the outbreak. The decision to vaccinate, particularly in non-endemic regions, must balance the benefits of protection against the risks of adverse events and the logistics of vaccine distribution.
Environmental Stability and Disinfection
MPXV, like other orthopoxviruses, is known for its environmental stability, particularly in dried scabs and on contaminated surfaces. Studies have shown that the virus can remain viable for extended periods under certain conditions, which has implications for infection control in both healthcare and community settings. The persistence of MPXV DNA on various surfaces, including PPE and household items, underscores the importance of rigorous disinfection protocols.
Effective disinfection methods include the use of EPA-registered chemicals with emerging viral pathogen claims, such as sodium hypochlorite (bleach) and quaternary ammonium compounds. These disinfectants have been validated against a wide range of viruses and are recommended for use in environments where MPXV is present. Ultraviolet (UV) light and heat treatments have also proven effective in inactivating the virus, providing additional tools for decontamination.
The stability of MPXV in different environments, including its resistance to desiccation and repeated freezing and thawing, highlights the need for comprehensive infection control measures. These measures are particularly important in healthcare settings, where the risk of nosocomial transmission is high, and in homes where infected individuals are isolating.
Evolutionary Dynamics and Genomic Insights
MPXV’s genome, a double-stranded DNA molecule approximately 197 kilobases in length, is relatively stable compared to RNA viruses like SARS-CoV-2. However, recent outbreaks have revealed an accelerated evolutionary rate, potentially driven by human-to-human transmission and interactions with host RNA editing enzymes such as APOBEC3. This accelerated evolution may have contributed to the virus’s enhanced transmissibility and the emergence of new variants.
The World Health Organization (WHO) has updated MPXV variant nomenclature, classifying the virus into Clade I (formerly Congo Basin/Central African clade) and Clade II (formerly West African clade). Clade II is further subdivided into subgroups IIa and IIb, with the latter being associated with the current outbreak. These distinctions are important for understanding the virus’s pathogenicity and guiding public health responses.
The potential for MPXV to adapt further to human hosts, through gene loss or gain and nucleotide changes, is a critical area of research. The progressive loss of non-essential genes, observed in some MPXV strains, may facilitate human-to-human transmission, raising concerns about the virus’s long-term evolution and its implications for public health.
The Rise and Resurgence of Monkeypox: A Comprehensive Examination of a Global Health Threat
| Medical Concept | Simplified Explanation | Detailed Description | Example/Application |
|---|---|---|---|
| Monkeypox Virus (MPXV) | A virus that causes a disease similar to smallpox but less severe. | MPXV is a member of the Orthopoxvirus family and is primarily found in Central and West Africa. It can spread from animals to humans and between humans. | In 2003, MPXV caused an outbreak in the U.S. when infected rodents were imported from Africa. |
| Orthopoxvirus Genus | A group of viruses that includes smallpox and monkeypox. | The Orthopoxvirus genus belongs to the Poxviridae family and includes viruses that cause diseases in both humans and animals. | Smallpox and cowpox are also part of this genus, with smallpox being the most famous due to its historical impact. |
| Gamma Interferon (IFN-γ) | A protein that helps the body’s immune system fight off infections. | IFN-γ is a cytokine that plays a crucial role in activating immune cells and directing the immune response against pathogens like viruses and bacteria. | IFN-γ levels increase during viral infections, helping to control the spread of the virus in the body. |
| Inbred Mouse Strains | Types of mice that are genetically similar, used for research. | Inbred strains like BALB/c and C57BL/6 are commonly used in research to study diseases because they have consistent genetic backgrounds, making results more reliable. | Researchers use these mice to understand how different strains react to diseases like MPXV, helping to develop treatments. |
| CAST/EiJ Mice | A special type of mouse that is more susceptible to monkeypox. | CAST/EiJ mice are derived from wild mice and are used in research because they have a higher sensitivity to certain diseases, making them useful for studying infections. | These mice are particularly useful for studying how the body’s immune system responds to severe MPXV infections. |
| Virulence | How harmful or severe a disease-causing organism is. | Virulence refers to the ability of a pathogen to cause damage to its host. Higher virulence means a more severe disease. | The Central African strain of MPXV is more virulent than the West African strain, meaning it causes more severe disease. |
| Cytokines | Proteins that signal the immune system to respond to infection. | Cytokines are molecules that help regulate the immune response by signaling between cells. They can increase or decrease inflammation and immune activity. | IFN-γ is an example of a cytokine that plays a key role in fighting viral infections. |
| Smallpox Vaccination | A vaccine that protects against smallpox, and also provides some protection against MPXV. | The smallpox vaccine was used globally until smallpox was eradicated. It also helps protect against other related viruses, like monkeypox, due to cross-protection. | Routine smallpox vaccination stopped in 1980 after smallpox was eradicated, which may have led to increased susceptibility to MPXV. |
| Zoonotic Diseases | Diseases that spread from animals to humans. | Zoonotic diseases are infections that are transmitted from animals to humans, often through direct contact or through vectors like insects. | MPXV is a zoonotic disease that can spread to humans from infected animals like rodents and primates. |
| Bioterrorism | The use of biological agents, like viruses, to cause harm or fear. | Bioterrorism involves the deliberate release of viruses, bacteria, or other germs to cause illness or death in people, animals, or plants. | MPXV, like smallpox, could potentially be used as a bioterrorist agent due to its ability to cause disease in humans and its potential for transmission. |
| Immunodeficient Mice | Mice with weakened immune systems, used in research to study diseases. | Immunodeficient mice, like SCID mice, lack certain components of the immune system, making them more susceptible to infections and useful for studying immune responses. | These mice are often used to test how well new vaccines or treatments work, particularly in cases where the immune response is a key factor. |
| Vaccinia Virus (VACV) | A virus related to smallpox, used in the smallpox vaccine. | VACV is a live virus used in the vaccine to protect against smallpox. It is part of the Orthopoxvirus genus and can also provide protection against MPXV. | The smallpox vaccine, which contains VACV, was crucial in eradicating smallpox and offers cross-protection against other orthopoxviruses like MPXV. |
| Interleukin-10 (IL-10) | A protein that regulates the immune response, often reducing inflammation. | IL-10 is a cytokine that helps to limit immune responses, preventing excessive inflammation that can damage tissues during infections. | In some cases, high levels of IL-10 can be harmful if they suppress the immune response too much, allowing infections to persist or worsen. |
| Onchocerciasis | Also known as river blindness, a parasitic disease caused by infection with a worm. | Onchocerciasis is caused by the parasitic worm Onchocerca volvulus and is spread by the bites of infected blackflies, leading to severe itching and vision loss. | Ivermectin is widely used to treat onchocerciasis, reducing the burden of the disease in affected regions. |
| Ivermectin | A medication used to treat parasitic infections, with potential effects on the immune system. | Ivermectin is an antiparasitic drug commonly used in mass drug administration programs to control diseases like onchocerciasis and lymphatic filariasis. | While effective against parasites, long-term use of ivermectin may impact the immune response, potentially influencing susceptibility to other infections like MPXV. |
| Mass Drug Administration (MDA) | Public health campaigns that distribute medications to large populations to control diseases. | MDA is used in areas where diseases like onchocerciasis are common, aiming to reduce or eliminate the disease by treating the entire at-risk population, often with ivermectin. | These campaigns have been successful in reducing the prevalence of diseases like river blindness but may have unintended effects on other aspects of public health. |
Monkeypox virus (MPXV), a zoonotic pathogen first isolated in 1958 from lesions on laboratory monkeys imported to Denmark from Singapore, belongs to the Orthopoxvirus genus of the Poxviridae family. While initially thought to be confined to non-human primates, subsequent investigations identified rodents, particularly squirrels, as the primary reservoir. The first human cases of Monkeypox were reported in Africa in the early 1970s, though retrospective analysis suggests that earlier cases were likely misdiagnosed as smallpox, given the close clinical resemblance between the two diseases.
The eradication of smallpox in 1980 marked a turning point in the global health landscape. However, it also inadvertently set the stage for the emergence of other orthopoxviruses, including MPXV. With the cessation of routine smallpox vaccination, populations worldwide have become increasingly susceptible to MPXV, a concern that has been magnified by the recent surge in cases across non-endemic regions.
MPXV is endemic in the rainforested regions of Central and West Africa, where it causes a disease that clinically resembles smallpox but with reduced morbidity and mortality. The virus exists in two distinct clades: the Central African (Congo Basin) clade, associated with more severe disease and higher mortality rates, and the West African clade, which is less virulent and has not been observed to sustain human-to-human transmission effectively. The Central African clade, with a case fatality rate of up to 10%, represents a significant public health threat, particularly in regions where access to healthcare is limited.
The 2003 outbreak of Monkeypox in the Midwestern United States, linked to imported Gambian pouched rats from Ghana, underscored the ease with which MPXV could be transported and introduced to non-endemic regions. This outbreak, which involved human cases arising from contact with infected prairie dogs, highlighted the vulnerability of North American rodents to MPXV and the potential for geographic spread.
In addition to its public health implications, MPXV, like the variola virus (the causative agent of smallpox), is considered a potential bioterrorist agent. The absence of smallpox vaccination in much of the current global population heightens the risk, as does the demonstrated capability of MPXV to infect a range of hosts, including non-human primates and rodents.
The Susceptibility of Animal Models: Insights into MPXV Pathogenesis
Over the years, various animal species have been utilized to study MPXV pathogenesis, each with differing degrees of susceptibility. Primates, such as cynomolgus and rhesus monkeys, are highly valued for their close genetic relationship to humans. However, high input doses are required to induce significant morbidity and mortality in these models, and unnatural routes of infection are often employed to achieve desired outcomes.
Small animals, including prairie dogs, ground squirrels, and African dormice, have shown sensitivity to MPXV infection at lower doses, making them attractive candidates for modeling the disease. However, these animals present several challenges: they are outbred, resulting in considerable variation in disease susceptibility; many must be caught in the wild, complicating their use in controlled studies; and there is a notable lack of immunological reagents available for these species.
Inbred mouse strains, such as BALB/c and C57BL/6, have been less susceptible to MPXV, prompting researchers to explore alternative models. Notably, the CAST/EiJ strain, derived from wild mice, has shown a higher susceptibility to MPXV-induced disease and death, making it a valuable model for studying the virus. CAST/EiJ mice have a low 50% lethal dose (LD50) for MPXV, both via intranasal and intraperitoneal routes of infection, and develop both humoral and cellular immunity to MPXV following non-lethal orthopoxvirus infection.
Comparative studies between CAST/EiJ mice and more classical inbred strains, such as BALB/c and C57BL/6, have uncovered significant differences in the host response to MPXV infection. Notably, while virus replication in the lungs of BALB/c and CAST/EiJ mice proceeds similarly, the virus spreads rapidly to other organs in CAST/EiJ mice, leading to high titers in the liver, spleen, kidney, and brain by days 6 to 8 post-infection—coinciding with the time of death.
In contrast, BALB/c mice exhibit minimal viral spread beyond the lungs and subsequently recover fully. This resistance in BALB/c mice has been linked to the induction of gamma interferon (IFN-γ) in the lungs, a response that is notably absent in CAST/EiJ mice following MPXV infection.
Gamma Interferon and the Innate Immune Response: A Double-Edged Sword?
Gamma interferon (IFN-γ) is a critical component of the host’s innate immune response, playing a multifaceted role in combating viral infections. It not only promotes a Th1 immune response but also exhibits direct antiviral activity. Previous studies have demonstrated that the susceptibility of inbred mouse strains to ectromelia virus (ECTV), another orthopoxvirus, correlates with their ability to produce IFN-γ in the spleen. For example, BALB/c mice, which produce low levels of IFN-γ, are highly susceptible to ECTV, while C57BL/6 mice, which produce higher levels of IFN-γ, are relatively resistant.
The lack of IFN-γ production in the lungs of CAST/EiJ mice in response to MPXV infection was unexpected, particularly given that CAST/EiJ mice can mount a robust IFN-γ response in the spleen following virus spread. This suggests that the defect in IFN-γ production is localized to the lungs, potentially due to a failure to activate or recruit IFN-γ-producing cells, such as natural killer (NK) cells and T lymphocytes, to the site of infection.
Further investigation revealed significant differences in the immune cell profiles of CAST/EiJ and BALB/c mice. For instance, the percentage of NK cells in the peripheral blood of CAST/EiJ mice is markedly lower than that in BALB/c mice, which may contribute to the observed deficiency in IFN-γ production in the lungs. Additionally, CAST/EiJ mice exhibit lower percentages of CD8 T cells, although the percentage of CD4 T cells is similar between the two strains.
The role of IFN-γ in the host response to poxvirus infections is well established. Many poxviruses, including MPXV, encode a soluble IFN-γ binding protein that can counteract the host’s immune response. This protein, which bears homology to the extracellular part of the IFN-γ receptor, is thought to help the virus evade the immune system. However, the binding affinity of these viral proteins for IFN-γ varies across species. For example, the vaccinia virus (VACV) IFN-γ binding protein inhibits IFN-γ from humans, cows, rabbits, rats, and chickens but has a low affinity for mouse IFN-γ. This could explain why deletion of the B8 gene, encoding the VACV IFN-γ binding protein, did not significantly affect VACV virulence in mice, although a reduction in virulence was reported by another group.
In contrast, the ectromelia virus (ECTV) homolog of the IFN-γ binding protein binds mouse IFN-γ more effectively, and deletion of the gene reduces virulence in mice. MPXV encodes a homolog of the B8 protein with high sequence identity to the VACV and ECTV proteins, but its binding properties have yet to be fully characterized.
The administration of exogenous IFN-γ to CAST/EiJ mice prior to and following MPXV infection has been shown to reduce viral titers in the lungs, decrease morbidity, and prevent mortality entirely. These findings suggest that CAST/EiJ mice can respond effectively to IFN-γ when it is provided externally, highlighting the importance of timely IFN-γ production in the lungs for controlling MPXV infection.
To further explore the role of IFN-γ in MPXV resistance, researchers have conducted experiments using IFN-γ knockout and IFN-γ receptor knockout C57BL/6 mice. These mutant strains were found to be more susceptible to MPXV than their wild-type counterparts, though they remained less sensitive than CAST/EiJ mice or STAT1-deficient C57BL/6 mice, which lack a key signaling molecule downstream of the IFN-γ receptor. This indicates that while IFN-γ is a crucial factor in MPXV resistance, other components of the immune response also play significant roles.
The Broader Implications of Innate Immunity and the Re-Emergence of Monkeypox
The recent resurgence of Monkeypox, particularly in regions outside its endemic range, has prompted renewed interest in understanding the factors that contribute to its spread and severity. Some researchers have proposed that the discontinuation of routine smallpox vaccination, which provided cross-protection against MPXV, has played a significant role in the re-emergence of the virus. As more time passes since the last smallpox vaccinations were administered, the proportion of the population that lacks immunity to orthopoxviruses increases, creating a larger pool of susceptible hosts.
Another factor that may be contributing to the increase in Monkeypox cases is the widespread use of ivermectin in certain regions, particularly in Africa, where it is employed as part of mass drug administration (MDA) campaigns to control onchocerciasis (river blindness) and other parasitic diseases. Ivermectin, while highly effective in reducing the burden of parasitic infections, has been shown to have immunomodulatory effects, including the suppression of cytokine responses such as IFN-γ production.
A recent commentary published in the Indian Journal of Pharmacology suggested that the long-term use of ivermectin could potentially weaken the innate immune response to Monkeypox infection by reducing levels of IFN-γ. This hypothesis is based on observations that ivermectin treatment is associated with decreased production of IFN-γ and interleukin-10 (IL-10), another cytokine involved in immune regulation. Given the importance of IFN-γ in controlling MPXV infection, a reduction in its production could theoretically make individuals more susceptible to severe disease.
However, this connection remains speculative and requires further investigation. The relationship between filariasis, ivermectin treatment, and susceptibility to Monkeypox is complex, and many variables must be considered. For example, the impact of ivermectin on immune responses may vary depending on the dose, duration of treatment, and the presence of other co-infections or underlying health conditions. Additionally, while the immunomodulatory effects of ivermectin are well documented, the extent to which these effects translate into increased susceptibility to viral infections like Monkeypox is not yet fully understood.
The Global Health Perspective: Preparing for the Future
The re-emergence of Monkeypox as a global health threat has underscored the need for vigilant surveillance, rapid response, and comprehensive public health strategies. The spread of MPXV to non-endemic regions, including Europe, the Americas, and Asia, has highlighted the ease with which zoonotic diseases can cross borders and establish themselves in new environments.
In response to this emerging threat, public health authorities have ramped up efforts to monitor and control the spread of Monkeypox. This includes enhanced surveillance in both endemic and non-endemic regions, increased availability of diagnostic testing, and the development of targeted vaccination campaigns for at-risk populations. Additionally, research into antiviral treatments and other therapeutic interventions is ongoing, with the goal of providing effective tools to combat Monkeypox outbreaks.
The lessons learned from the COVID-19 pandemic are particularly relevant as the world grapples with the resurgence of Monkeypox. The importance of early detection, international collaboration, and the equitable distribution of medical resources cannot be overstated. As global travel and trade continue to expand, the risk of zoonotic diseases spreading across continents will only increase, making it imperative that the global community remains prepared to respond to these threats swiftly and effectively.
Looking ahead, the development of new vaccines and treatments for MPXV and other orthopoxviruses will be critical in preventing future outbreaks. Advances in genomic sequencing and molecular biology have provided researchers with powerful tools to study the virus’s evolution and identify potential targets for intervention. Additionally, efforts to improve public health infrastructure in endemic regions, where the burden of Monkeypox is highest, will be essential in reducing the risk of future outbreaks.
The rise and resurgence of Monkeypox serve as a stark reminder of the interconnectedness of global health. As the world becomes increasingly interdependent, the need for a coordinated, multidisciplinary approach to infectious disease control has never been more apparent. By leveraging the knowledge gained from past experiences and applying it to the challenges of the present and future, the global community can hope to mitigate the impact of emerging infectious diseases and safeguard the health of populations worldwide.
Conclusion
The global spread of monkeypox virus presents a complex challenge that requires a multifaceted response. From understanding the infectious dose and transmission dynamics to developing effective diagnostics, treatments, and vaccines, the fight against MPXV is ongoing. The virus’s potential to establish new reservoirs, its environmental stability, and its evolutionary dynamics add layers of complexity that must be addressed through continued research and public health efforts.
As the world grapples with the resurgence of orthopoxviruses, the lessons learned from MPXV will be critical in preparing for future outbreaks. The integration of advanced genomic insights, robust public health strategies, and targeted vaccination programs will be essential in controlling the spread of the virus and mitigating its impact on global health.
reference :
- https://www.dhs.gov/sites/default/files/2023-12/23_1220_st_monkeypox_MQL_cleared_for_public_release.pdf
- https://journals.asm.org/doi/full/10.1128/jvi.00162-12
- https://journals.lww.com/iphr/fulltext/2023/55050/annual_ivermectin_treatment,_interferon_gamma,_and.12.aspx
