The poxviruses are highly relevant to human beings, among which the orthopoxviruses are the best-known. These include the smallpox virus (variola virus, VARV), the monkeypox virus (MPXV), the cowpox virus, and the vaccinia virus.
Background
All of these cause newly emerging endemic diseases, especially in developing countries. Monkeypox (MPX) leaped into the limelight recently with a threatening outbreak of rapidly spreading infections almost completely confined to the community of men who have sex with men (MSM).
A new review published in Viruses sheds light on the origins of this virus and recently acquired knowledge about its disease mechanism and the preventive and therapeutic measures appropriate in this situation.
Introduction
Poxviruses are large viruses with a deoxyribonucleic acid (DNA) genome. The orthopoxvirus genus is especially interesting because its members elicit cross-reactive and cross-protective immunity to each other. Despite the eradication of smallpox, poxviruses can cause emerging endemic diseases.
Several outbreaks have been caused by MPXV, which produces smallpox-like lesions. In 2022, a massive outbreak occurred involving over 30 countries. Not only was this spread by community transmission, but the route was by sexual contact. This was quite unlike earlier, much smaller epidemics confined to endemic regions in western and central Africa, following contact with potentially infected animal hosts.
In July 2022, the MPX outbreak was declared a global health emergency by the World Health Organization (WHO). Orthopoxviruses are a possible bioweapon, with their ability to spread rapidly and their potential mortality risk in the absence of poxvirus immunity ever since smallpox vaccination was stopped almost 50 years ago.
Viral lifecycle
The MPXV infects both animal reservoir hosts and other incidental hosts, including humans, tree squirrels, dormice, and Gambian pouched rats. While first identified in Asian monkeys in a polio research laboratory in Denmark, it was again reported in a captive monkey colony.
The first human infection was documented in 1970 in the Democratic Republic of Congo. The original orthopoxvirus lineage diverged about 3500 years ago into a common ancestor that gave rise to MPXV and VARV. MPXV itself first appeared in West Africa 600 years ago.
Orthopoxviruses develop between 10–5 and 10–6 mutations per replication site. The large genome, containing almost 200, 000 base pairs, changes by 1 or 2 nucleotides a year.
However, the currently circulating strain has changed by about 40 nucleotides over the last 4 years – a 10-fold increase in the mutation rate. This may indicate that it has adapted excellently to its human host, thus permitting the spread of this virus within this species.
Phylogenetically, two clades are distinguished, the West and Central African clades, which are supposed to have diverged between 560-860 years ago. Significant differences in their terminal regions encode proteins responsible for modulating the host immune response distinguish them.
While the West Africa clade (Clade 2) is less virulent and shows a less extensive drift, the Central Africa clade (Clade 1) is more virulent and spreads more rapidly because it prevents T-cell-receptor-mediated T cell activation and resulting cytokine production. This clade has probably expanded by migration, founder effect, or bottleneck events.
Recently a third clade was identified, Clade 3. Both clade 2 and clade 3 belong to the older Western Africa clade. Clade 3 was responsible for the outbreak of 2017/2019, with multiple mutations that seem to indicate adaptation to humans. In fact, there are 47 nucleotides that differ between the currently circulating strain and the 2017/2019 clade 3 strain.
This number is much larger when compared to the expected number of mutations in just 3 years. Some researchers suggest calling the current strain hMPXV1, to emphasize its adaptation to the human host.
Even so, this subclade shows significant variation in genomes. Using the Pango system to name MPXV, it has been suggested that the ancestor of the human strain be called lineage A, with its descendants A.1, A.2, and A.1.1. The current strain would then be called B.1.
Epidemiology
The animal reservoir for this virus remains unknown. Yet, with larger numbers of rodents living near human activity, increasing animal-human interactions, and orthopoxvirus-naïve people interconnecting globally, MPXV was likely to spread to humans at higher rates.
Earlier outbreaks occurred in 1970, 1996–1997, 2003, and 2018, almost always in West Africa. The current outbreak has reached several times the magnitude of any earlier epidemic, at over 28,000 cases. The vast majority of cases are in non-endemic countries in developed regions.
Again, while earlier outbreaks were suggested to be self-terminating, the current epidemic seems to defy such models. The reproductive index has gone up from the earlier calculated value of 0.83 to 1.1-2.4 at present.
Transmission
The virus is spread by contact with infected body fluids, through animal bites, or by handling or eating the meat of an infected animal. Bites or scratches were linked to more severe diseases. Human-human spread was thought to be via infected body fluids and tissues.
In the current outbreak, contact with skin lesions is the probable route of transmission. This explains the lack of travel history to endemic regions in most cases. MPX is not considered a sexually transmitted disease (STD), but in the current outbreak, viral DNA has been identified in semen in some cases.
Congenital MPX is also being reported via transplacental transmission, and unfortunately, in one small case series, most affected babies were malformed. This may make smallpox vaccination of infants in endemic regions a necessity, while MPX effects in pregnancy require to be reassessed urgently.
The period of contagion extends from symptom onset to the point of re-epithelialization of skin lesions. While symptomatic patients are presently isolated from others, the risk of transmission from asymptomatic or subclinical cases is unknown. However, infected patients remain positive for viral DNA on testing for up to 3 weeks.
Clinical features
The illness has an incubation period of 5-21 days, with an initial prodrome consisting of fever, lymphadenitis, body aches, and headache, with tiredness. Characteristically, enlarged lymph nodes occur below the chin, neck, and groin, differentiating this from smallpox.
The maculopapular rash begins 3 days after the prodromal symptoms, spreading outwards from the entry site. In over 90% of cases, the face is involved, and in three-quarters, the palms and soles, and the mucous membranes of the mouth. Genital and conjunctival involvement is less common in below a third of cases.
Passing through successive macular, popular, vesicular, crusting, and scabbing phases, the lesions finally fall off. Complications are more likely in endemic regions but include encephalitis, bacterial infection of the lesions, dehydration, and, less commonly, inflammation of the cornea and conjunctiva, or pneumonia. Up to a tenth of cases die, as estimated from outbreaks in Central Africa. With the current outbreak, the mortality hovers between 3% and 6%.
Much more must be learned about the clinical picture, as some have reported acute illness without prodromal symptoms. Asynchronous lesions have also been reported, contrary to expectations. In one study of over 500 patients diagnosed over the period from the end of April to the end of June, over half had only one lesion in the genital area, and all the patients were MSM.
This suggests viral transmission via close skin-to-skin or mucosal contact.
Diagnosis
Rapid diagnosis is made via a positive real-time polymerase chain reaction (rt-PCR) on swabs from skin lesions. Viremia is transient, limiting the utility of blood tests. Virus isolation and culture, immunochemistry, and immunofluorescence imaging are also potentially useful to confirm the diagnosis.
Specific MPXV antibodies may be detected by enzyme-linked immunosorbent assays (ELISA) after 5 and 8 days of infection onset, respectively. However, cross-reactivity makes this test less useful as a specific tool for MPX diagnosis.
Prevention and treatment
Two smallpox vaccines are available that may confer 85% protection against MPX. Both are live virus-based. One, ACAM2000, is capable of replication and can cause serious complications, such as progressive vaccinia infection, eczema, myocarditis and pericarditis, and encephalitis. ACAM2000 requires a single dose, with peak protection at 28 days.
The second, JYNNEOS, is safer and can be used in immunocompromised individuals and potentially in pregnant women. Two doses are required 28 days apart, with full protection being present only 14 days after the second dose.
Post-exposure prophylaxis with these vaccines has been reported, and ring vaccination is being practiced at present in the USA, UK, and Canada to arrest the MPX epidemic. However, one dose of this vaccine may not be protective against MPX, and data on adverse effects is very limited.
Severe cases may require treatment, including those with severe confluent lesions, hemorrhagic disease, sepsis, encephalitis, immunocompromised individuals, pregnant or lactating mothers, children, those with severe skin disease, and those with secondary bacterial infection of the lesions, and those with dehydration secondary to vomiting, diarrhea or other causes, MPX lesions in the eyes, mouth, genitals or anus. The last category includes almost all patients in the current outbreak.
Drugs like tecovirimat, which inhibits viral replication and has been approved for smallpox treatment, brincidofovir and cidofovir, both of which are DNA polymerase inhibitors, are being used off-label for MPX cases. The first is under a non-research expanded access investigational new drug protocol for non-smallpox orthopoxvirus infections, while the others were approved in 2021 for smallpox. Vaccinia immune globulin intravenous (VIGIV) is approved to treat vaccinia vaccine-related complications and is also under an expanded access protocol for orthopoxvirus infections.
Conclusions
The MPX outbreak seems to be losing force at last. However, its initial rapid spread within the MSM community, despite the known inefficiency of MPXV transmission, exposed some chronic failings of the public health system. It also lends force to the arguments for sticking to a single sexual partner, irrespective of sexual orientation.
The virus has likely acquired beneficial mutations, and new strains have emerged by natural selection to take advantage of a naïve human population. Effective responses to this virus must be implemented, building on experience gained from the coronavirus disease 2019 (COVID-19) pandemic.
