SARS-CoV-2 and Monkeypox Virus: Structure and Evolution
Structure and Genome
Structurally speaking, SARS-CoV-2 (the cause of COVID-19) and monkeypox virus (MPV) are very different. SARS-CoV-2, like all coronaviruses, is an enveloped single-stranded RNA virus. It is small (~100 nm in diameter), spherical and decorated with a porcupine-like sheath of spike (S) proteins. S proteins bind to host cells via angiotensin-converting enzyme 2 (ACE2), a protein ubiquitously expressed by organs throughout the human body, to initiate infection.
MPV is a member of the Poxviridiae family-the virus is enveloped, brick shaped and large (220-450 nm long). Its double-stranded DNA genome is encapsulated in a core containing enzymes needed for replication and evasion of host immune defenses. Like SARS-CoV-2, MPV has surface proteins that facilitate its entry into host cells. However, rather than a single protein, poxviruses use 11 to 12 transmembrane proteins to fuse with host cells, likely binding glycosaminoglycans or laminin on the cell surface.
Evolution and Variants
The differences in the genomes of SARS-CoV-2 and MPV have important evolutionary ramifications. RNA viruses, like SARS-CoV-2, can be sloppy replicators. RNA polymerase, which copies the viral genome, lacks the ability to catch and fix replication errors. Unlike other RNA viruses, coronaviruses do have an enzyme (i.e., an exoribonuclease) with some proofreading ability. However, while this may slow the acquisition of mutations in SARS-CoV-2, it does not stop them altogether. As a result, random mutations develop that can, if beneficial for viral fitness, quickly become widespread. This has been apparent throughout the COVID-19 pandemic. In 2021, the SARS-CoV-2 Delta variant dominated the pandemic landscape. When 2022 rolled around, Omicron, which spreads easier from person- to- person, replaced Delta as the most dominant variant. The increased transmissibility of Omicron is tied to a slew of S protein mutations that regulate binding to ACE2 and promote the ability to evade host antibodies.
There are 2 known viral clades of MPV: the Congo Basin clade and the less virulent West African clade, which underlies current outbreaks in non-endemic countries. DNA viruses, like MPV, do not mutate as freely as RNA viruses. The enzymes involved in DNA viral replication (i.e., DNA polymerase) are better at proofreading and fixing errors than those in RNA viral replication (i.e., RNA polymerase). Poxviruses typically acquire about 1-2 mutations per year. However, evidence suggests that MPV has acquired nearly 50 mutations compared to strains detected in 2018-2019. If/how these genetic changes influence the spread of monkeypox is unclear. What researchers do know is that most of the mutations bear the mark of a human antiviral enzyme, APOBEC3, which edits base pairs in viral genomes. The mutations, therefore, do not reflect the virus's random mutation rate, but seem to be indicative of time spent in humans (indeed, data suggest MPV may have been circulating among human populations in Africa and Europe for several years before the influx of cases began in May 2022). This differs from mutation patterns in SARS-CoV-2, which are largely tied to replication errors that may or may not become fixed in a population.
Reservoirs
Monkeypox and COVID-19 are both zoonotic diseases, meaning they are transmitted from animals to humans. SARS-CoV-2 is thought to have originated in bats, potentially hopping to another animal, such as pangolins or minks, before making the leap into humans. However, direct evidence supporting this chain of transmission events is still lacking.
MPV is endemic to countries in central and western Africa. Although monkeypox was first discovered in monkeys kept for research in the Democratic Republic of the Congo (DRC), they are not the main, or only, reservoir of the virus. Rodents, including rope squirrels and Gambian pouch rats, are believed to be reservoirs of MPV. Yet, MPV has only been isolated from wild animals on 2 occasions, including a rope squirrel in the DRC and a sooty mangabey in Côte d'Ivoire in 2012. As with SARS-CoV-2, more research is needed to understand the origins, reservoirs and circulation of MPV among animal populations.
Transmission
SARS-CoV-2 is a respiratory virus-it spreads when an infected person breathes out small virus-laden droplets. If someone else inhales these droplets, or they land on their eyes, nose or mouth, the exposed individual can become infected. Because SARS-CoV-2 spreads efficiently through the air, it is particularly challenging to control-a single person has the potential to infect many others just by breathing. Moreover, people can spread COVID-19, even if they are asymptomatic.
While MPV can be transmitted through respiratory secretions, it is not a respiratory virus. Rather, it primarily spreads through direct (usually prolonged) contact with monkeypox rash, scabs or body fluids from someone who is infected. It can also be spread congenitally, or by touching objects and surfaces that have been used by someone with monkeypox. Activities like trying on clothing at a store, however, pose a low risk-an individual would need to have extended contact with clothing that had come into prolonged contact with monkeypox lesions or sores to increase their risk of infection. This is more likely when living with a person with a confirmed case of monkeypox, but less relevant to the usual clothes-on, clothes-off routine of the fitting room.
Though MPV is transmitted through sexual contact, scientists are still investigating whether the virus spreads specifically through sexual transmission routes (i.e., semen or vaginal fluids), as well as whether the virus can be transmitted prior to symptom onset. What is clear is that, because MPV spreads primarily through close, prolonged contact, monkeypox is far less transmissible than COVID-19.
Symptoms and Disease Severity
COVID-19 symptoms appear anywhere from 2 to 14 days after exposure to SARS-CoV-2. They can include fever, chills, headache, sore throat and loss of taste or smell, among others. People usually feel better after a few days to few weeks, though some people have prolonged symptoms that continue for 3+ months (i.e., long COVID). COVID-19 can be fatal. Since the beginning of 2020, COVID-19 has caused over 6,400,000 deaths across the world, though rate of deaths has declined, in part due to the availability of vaccines and treatments. Risk for severe COVID-19 depends on several factors, including the SARS-CoV-2 variant causing the infection, vaccination status, age and whether a person has underlying conditions or is immunocompromised.
For monkeypox, it can take up to 3 weeks after exposure to MPV for symptoms to develop. Though it varies on a case-by-case basis, symptoms may mirror those of COVID-19 during the early stages of infection (e.g., fever, headache, chills). Clinically speaking, monkeypox differs from COVID-19 in that it is characterized by the development of a rash, which can be painful and itchy, and tends to be distributed on the face, extremities and genitals.
Most people recover from monkeypox after 2-4 weeks. It can be severe, even fatal, but the mortality rate is nowhere near that of COVID-19. According to WHO, there have been 12 deaths from monkeypox since January 2022, 5 of which occurred outside of the African region. Disease severity is tied, in part, to the strain of MPV causing infection. Like COVID-19, monkeypox severity also depends on age (young children are more likely to develop severe disease) and the presence of underlying conditions.
Diagnosis
Due to rapid antigen tests, people can test themselves for COVID-19 at home. Nucleic acid amplification testing (NAAT), such as polymerase change reaction (PCR), is also available. These methods are performed in laboratories or point-of-care facilities (e.g., pharmacies, school health clinics, among others) and involve isolating and amplifying the genetic material from patient specimens to detect SARS-CoV-2 RNA.
Currently, there are fewer options for diagnosing monkeypox. Confirmatory testing is only conducted via PCR on fluid from pustules or dry crust from scabbed lesions. Moreover, samples must be sent to a public health laboratory or 1 of 5 commercial labs for analysis-there are currently no options for testing at home or at point-of-care facilities. As monkeypox outbreaks evolve, and case counts rise, other diagnostic tools may be developed that promote the ease, accessibility and/or diagnostic capabilities of monkeypox testing.
Prevention and Treatment
There were no vaccines for COVID-19 at the beginning of the pandemic because SARS-CoV-2 was a novel virus when it was discovered in late 2019. Now, 4 vaccines have been approved for use in the U.S. COVID-19 vaccination, which protects against severe disease and hospitalization, is approved by the U.S. Food and Drug Administration (FDA) for people 6 months of age and older. There are also several antiviral and monoclonal antibody treatments available to treat COVID-19.
Unlike the early days of 2020, when COVID-19 first came onto the scene, there are already vaccines that protect against monkeypox. A live-attenuated vaccine, trademarked JYNNEOS, is currently being used for widespread vaccination efforts. JYNNEOS was developed to prevent smallpox and is also protective against monkeypox in adults 18 years and older (as of August 9, 2022, people younger than 18 years old, and at high risk for monkeypox infection, may also receive the vaccine under an Emergency Use Authorization).
While JYNNEOS is the preferred vaccine for monkeypox, according to the Centers for Disease Control and Prevention (CDC), there is a second smallpox vaccine, ACAM2000, that may be used as an alternative. ACAM2000 can be considered for people 1 year of age and older. However, because ACAM2000 has the potential for more adverse side effects, particularly people with weakened immune systems, the CDC recommends that individuals consult with their healthcare provider to determine which vaccine is best for them.
Monkeypox vaccination efforts are currently focused on people who have been exposed to monkeypox or who are more likely to get monkeypox, such as members of the men (i.e., people assigned male at birth) who have sex with men (MSM) community, who have been disproportionately affected by the disease. Right now, there are no specific treatments for monkeypox. However, tecovirimat, a drug that treats smallpox, may be considered for people with, or at risk for, severe disease.
For both COVID-19 and monkeypox, isolating infected individuals and maintaining proper hygiene (i.e., handwashing) and disinfection practices are important for preventing and slowing the spread of infection.
Monkeypox Outbreaks vs. The COVID-19 Pandemic
There are several important differences between monkeypox outbreaks and the COVID-19 pandemic. For one, SARS-CoV-2 was a novel virus when it emerged in late 2019, meaning it had never been seen before. As a result, the world didn't have vaccines or immunity to the virus, which allowed it to spread like wildfire. The rise of new SARS-CoV-2 variants, coupled with the virus's ability to transmit efficiently from person to person through the air, only fueled (and continues to fuel) this fire.
Monkeypox is not a new disease. Scientists know more about MPV than they did about SARS-CoV-2 at the beginning of the COVID-19 pandemic. Importantly, given that MPV spreads primarily through close contact, it is less efficient at spreading between humans. Vaccines are also already available and, while there have been supply chain challenges, are being administered to at-risk communities.
Still, MPV is spreading in ways not previously seen (i.e., through sexual networks). The virus has also acquired mutations with unclear function and significance-if MPV continues to circulate, it could develop mutations that help it better infect humans. As such, the world must remain vigilant and put the lessons learned from the COVID-19 pandemic to good use. According to a recent letter issued by ASM and partner organizations to the Department of Health and Human Services, this includes:
- Ensuring adequate and equitable distribution and administration of monkeypox diagnostics, vaccines and treatments.
- Using transparent, timely, non-alarmist and fact-based messaging to educate communities about monkeypox spread and prevention.
- Increasing testing capacity and accessibility.
- Bolstering public health infrastructure, including strengthening the workforce and collecting, sharing and summarizing data to inform the development of effective disease control measures that promote health equity and support.
