mpox

Paul G. Auwaerter, M.D.

MICROBIOLOGY

DNA virus and a member of the orthopoxvirus genus of the Poxviridae family, monkeypox is similar to smallpox (variola virus), smallpox vaccine (vaccinia virus), and cowpox virus.
- In November 2022, the WHO renamed "monkeypox" to "MPOX," with some using the lowercase "mpox," allowing for a one-year transition during which both names would be recognized.
  - The idea was to reduce the stigma and discrimination associated with the "monkeypox" name and ensure that the infection is not associated much with non-human primates.
- WHO is using Roman numerals for MPXV variants.
  - The former Congo Basin (Central African) clade is now referred to as Clade I.
    - Has high reported human-to-human transmission rates and mortality (up to 10%).
    - It tends to affect children > adults, with higher mortality than Clade II.
  - The former West African clade is Clade II.
    - Clade IIa
      - It causes a mild illness with limited human-to-human transmission and low mortality (~1-3%).
    - Clade IIb refers to variants that circulated during the 2022 global outbreak.
Although initially named monkeypox, the animal reservoir is believed to be African rodents; however, this has not been fully defined.

CLINICAL

Previously, an uncommon zoonotic disease spread between infected animals, humans, and contaminated materials.
- First isolated in 1958, with the first human case in 1970, most human cases are seen in Central and West Africa.
  - Before 2022, cases in the U.S. were predominantly imported or due to contact with animals.
  - Progressively, more cases have been reported annually in Africa (particularly in the DRC and West Africa) since the 1970s.
- It resembles smallpox but is milder and less transmissible.
- A large number of cases in Nigeria since 2017 can be traced as the basis of the current WHO global public health emergency.
Outbreaks in the U.S.
- 2003: 71 confirmed or suspected cases.
  - The first U.S. outbreak was traced to the importation of Gambian giant rats, squirrels, and dormice, which spread to prairie dogs sold as pets.[33]
    - Eighteen were hospitalized, and no deaths.
- 2022 outbreak: low-level transmission of Clade II continues worldwide.
  - The U.S. has had the highest number of cases from this outbreak through 2024. CDC case counts have not been updated since January 2025.
  - Numbers are likely to underestimate actual cases.
    - Cases have decreased significantly in the U.S.; a recent cluster of cases in Chicago has heightened concerns that they could re-emerge with less vigilance and immunization among high-risk groups.
      - New cases continue to be found in the U.S. and other countries, suggesting this may be here to stay as an ongoing disease in humans outside Africa.
      - This is likely due to both behavioral changes and immunization.
  - Spread within social networks implicated, reported in men who have sex with men (MSM), bisexual; few reports in women or children.
  - Deaths are rare in the U.S. and other non-endemic countries during this outbreak. This clade of the mpox virus appears milder than the disease acquired in Africa.
    - The CDC report of deaths in October 2022 found that the majority are Black MSM with advanced HIV, not on ART.
  - 2025: Low levels of clade II cases continue worldwide.
- The 2023 outbreak continues to the current (2025) in the Democratic Republic of the Congo (DRC). Due to Clade I or Ib, the country has the highest recorded cases, and most provinces report cases.
  - WHO declared a Public Health Emergency of International Concern in August 2024 based on >15,000 cases and 537 deaths in the DRC.
    - Much of the spread appears to be within Congolese households and children.
    - Subtype clade 1b, which emerged in eastern DRC and is now found in nearby countries, including Kenya, Rwanda and Uganda, is causing increased concern.
  - Travel-related cases have been seen in Europe since the summer of 2024.
  - Clade 1 in the U.S.: patients with a travel history with infection confirmed first in California (2024), Georgia (Jan 2025).
    - The CDC judges the risk of widespread clade 1 transmission in the U.S. as currently low.
Transmission
- The virus may be acquired through contact, including intact skin and mucous membranes. Most human infections are believed to be acquired through respiratory droplets.
  - Animal-to-human transmission is seen following an infected animal bite or scratch, butchering bush meat, direct contact with body fluids or lesions, or contaminated materials.
  - Acquisition by human-to-human is believed to be predominantly large respiratory droplets among African cases, although they may also be sexually transmitted or through social networks.
    - As a large pox virus, it is not believed to be aerosolizable but can be spread by droplets.
    - The virus enters the body via broken skin, the respiratory tract or the mucous membranes.
    - Household and nosocomial transmission are described
    - Fomite transmission occurs via contaminated clothing or bed sheets.
  - From acquisition to the first symptoms, the duration may range from 5 to 21 days, with an average of 1 to 2 weeks.
Human-to-dog transmission has been documented, which is not unexpected since this poxvirus can be spread among mammals, especially small mammals.
- The virus’s worrisome aspect of entering other animal populations makes control difficult.
Symptoms: Note that some individuals initially develop a rash, followed by other symptoms, while others experience only a rash.
- Initial viral prodrome
  - Fever, chills, headache, myalgia, back pain, fatigue
    - Occasionally, a sore throat with lesions on the tongue and oral mucosa
- Rash phase, typically 1 to 3 days after symptom onset.
  - Viral exanthem, flat/red, becomes nodular, umbilicated, and pox-like with fluid/pus before crusting.
    - Lesions, described as painful, appear in the same stage of development on a single site of the body.
    - Lymphadenopathy often accompanies this phase.
  - For example, in Africa, the rash often begins on the face [Fig. 1], and then spreads [Fig. 2], including the palms [Fig. 3].
    - Skin lesions do not develop in all individuals who are infected.
  - 2022 outbreak: nodular, pustular, pox-like, and may have eschar, [Fig. 4] and [Fig. 5]
    - Consider all oral, genital and anal (proctitis, too) lesions potentially due to mpox.
      - The rash may appear as pustules, blisters or pimples that may be pruritic or painful.
      - Rectal involvement may cause bloody stools (tenesmus), rectal bleeding, severe rectal pain, and local purulence.
      - Rash onset and evolution are not synchronous; lesions may range from several stages.
        Lesion(s) may range from a single spot to a grouping to disseminated cutaneous lesions across the body.
        Lesions may produce pain, which is often pruritic when they are crusted.
        The rash is not always on the palms or soles.
    - Fever, headache, myalgia, fatigue
    - Lymphadenopathy
    - Respiratory symptoms include dry cough, sore throat and nasal congestion.
- The illness resolves within 4 weeks.
- Mortality ranges from 1 to 10% in reported series from Africa; the 2022 outbreak appears milder, though capable of severe illness, especially in immunocompromised people.
  - Most deaths occur in children or people with HIV.
    - Lessons from the 2022 outbreak showed that more severe disease occurs in people immunocompromised or living with HIV, particularly those with advanced HIV.
  - Risk factors for severe illness appear to be a fever of≥ 38.3 °C and more than 100 skin lesions.
Differential diagnosis: varicella zoster (primary infection, aka chickenpox), other pox infections (cowpox, orf), smallpox.
- Consider herpes zoster (shingles), measles, and STIs, i.e., syphilis, HSV, LGV and chancroid.
- Test for STIs in mpox patients as above, including HIV if not known.
Diagnosis:
- Clinical suspicion is necessary; contact the local or state health department for assistance with diagnosis.
- Real-time PCR of skin lesion material; obtain two specimens for testing.
  - Obtain multiple samples and collect them dry; do not add or store them in viral or universal transport media.
  - CDC guidance for specimen collection
    - Contact the lab for specimen requirements.
    - Wear PPE
    - Skin lesion, pharyngeal and rectal swabs are appropriate.
- Serology may be helpful if specimens are not available.
  - Submitting specimens to the CDC instructions link.
- CDC case definitions:
  - Suspect, probable, and confirmed
  - Confirmed:
    - Confirmation of Orthopoxvirus DNA by PCR or NGS of a clinical specimen or isolation of the virus in culture is required.
  - Probable:
    - No suspicion of other recent Orthopoxvirus exposure (e.g., Vaccinia virus in ACAM2000 vaccination) and shows demonstration of
      - Orthopoxvirus DNA
        PCR from a clinical specimen or
        Immunohistochemical or electron microscopy or
        Detectable anti-orthopoxvirus IgM antibody 4 to 56 days after rash onset
    - Suspect
      - New characteristic rash or
      - Meets one of the epidemiologic criteria and has a high clinical suspicion for mpox
  - Epidemiological criteria: within 21 days of onset
    - Contact with a person or people with a similar appearing rash or who received a diagnosis of confirmed or probable mpox or
    - Close or intimate in-person contact with individuals in a social network experiencing mpox activity, including men who have sex with men (MSM) who meet partners through an online website, digital application ("app"), or social event (e.g., a bar or party) or
    - Traveled outside the U.S. to a country with confirmed cases of mpox or where MPXV is endemic or
    - Had contact with a dead or live wild animal or exotic pet that is an African endemic species or used a product derived from such animals (e.g., game meat, creams, lotions, powders, etc.)
  - Exclusions:
    - Alternate diagnosis achieved
    - The rash doesn’t develop within 5d of illness onset
    - A good quality specimen doesn’t contain Orthopoxvirus DNA or orthopox antibodies.
- Interim CDC definition for clade 1 mpox (June 2024, see link above)
  - Similar to the above definitions, but uses testing to discriminate mpox clade I and II and has epidemiological links such as--
    - Within 21 days of illness onset:
      - Traveled to an area with evidence of sustained human-to-human transmission of clade I mpox or where clade I MPXV is endemic or
      - Reports having contact with a person with confirmed, probable or suspect clade I mpox or
      - Had close or intimate in-person contact with individuals in a social network currently experiencing clade I mpox activity or
      - Had contact with a dead or live wild animal or exotic pet that is a central African endemic species or used a product derived from such animals (e.g., game meat, creams, lotions, powders, etc.)
    - If a travel history is elicited, contact the local or state health department.
- The CDC recommends that clinicians collect two specimens from each patient, each from multiple lesions, preferably from different locations on the body and from lesions with varying appearances.

SITES OF INFECTION

Oral: oral ulceration(s) or pharyngitis.
Ocular: may threaten vision and suggest rapid treatment initiation, though there is limited data on effectiveness in this situation.
Cutaneous: Before crusting, macular or papular lesions evolve into nodules, vesicles, or pustules (pox lesions). Lesions often start on the face, mouth, genitals or anus. It may remain limited in a regional area and spread over the body, including palms and soles.
LN: lymphadenopathy
Pulmonary: pneumonitis, particularly in severe cases
Proctitis: may be severe; a frequent reason for hospital admission
Cardiac: myocarditis, pericarditis, myopericarditis
CNS: encephalitis, myelitis
- Lymphocytic pleocytosis in CSF.
- MRI may have enhancing lesions.

TREATMENT

General

There are no approved treatments for mpox.
- Most patients recover with supportive care, including pain control.
- Patients with severe disease or if immunocompromised may benefit from antiviral medications.
  - Severe disease includes involvement--
    - Ocular
    - Cardiac
    - CNS
    - Complicated mucosal disease (pharyngeal, genital or rectal)
    - Progressive spread, especially if with underlying severe immunosuppression, including advanced HIV
  - Patients with eczema or atopy
CDC recommends approaching it as similar to smallpox, as a consideration for those with severe disease (CNS, hemorrhagic, requiring hospitalization, ocular disease) or those at high risk (immunocompromised, children < 8 yrs, pregnant/breastfeeding women, or experiencing complications).
- State and territorial health authorities can direct their requests for medical countermeasures to treat mpox to the CDC Emergency Operations Center (770-488-7100).
  - CDC Treatment Recommendations (January 2025) for non-severe disease suggest pain control and supportive care, as most patients recover without other interventions.
    - Two trials have not found that the antiviral tecovirimat sped up the resolution of infection faster than a placebo.
      - The PALM and STOMP trials suggest that most patients do not benefit from antivirals.
        PALM007 [7]: showed no faster resolution in patients with clade 1 disease in the Congo with skin lesions in this 600-person trial. Mortality was the same in both arms of this tecovirimat vs. placebo RCT, 1.7%.
        STOMP: examined tecovirimat in clade II patients; NIH ceased the trial early when there was no difference when 75% of enrollment (719 participants) was achieved in terms of speeding lesion resolution or pain.
  - CDC 2023 interim recommendations: consider the use of antivirals if:
    - Severe disease or evidence of organ system involvement or disseminated infection
    - People at high risk and those who may develop the severe disease may be evaluated on a case-by-case basis (e.g., children < 8, based on smallpox and endemic mpox, although glade IIb outbreak disease is rare in children and appears mild).
      - Immunocompromised condition
        Advanced HIV not on ART is a common high-risk group. European reports state that 30-51% of cases have known HIV.
        Specific guidance from the CDC for this group.
        CD4 < 350 may be at risk of not clearing the mpox virus.
      - Hx of atopic dermatitis, exfoliative skin conditions
      - Complicated infection (secondary bacterial infection, gastroenteritis, bronchopneumonia or concurrent disease or comorbidities)
      - Accidental inoculation into the eye, genitals or anus
        Author note: uncertain how this might differ from the customary acquisition in the 2022 outbreak; however, it could represent a lab accident issue, large inoculum, or, ocular, unknown consequence.
- Antivirals (see smallpox module for additional details): It is important to note that there are limited data on the use of these drugs in mpox. Reduce immunosuppression if feasible.
  - The efficacy of treating mpox with tecovirimat is not established for severe disease. It does not appear to be beneficial for mild to moderate disease in immunocompetent individuals.
    - Tecovirimat (TPOXX): oral or IV drug (if absorption is uncertain), FDA-approved for smallpox treatment in adults and children ≥ 13 kg.
      - CDC has an Expanded Access Investigational New Drug (EA-IND) protocol.
      - The oral drug should be taken with a high-fat meal (~600 calories with at least 25 g of fat).
    - Note: The STOMP trial did not reveal any significant safety concerns associated with the drug.
  - Other therapies are infrequently used and may be combined in patients who are severely ill or immunosuppressed. The change in 2023 is to consider combination therapy in the severely immunosuppressed at the outset.
    - Tecovirimat PLUS/MINUS
      - Brincidofovir: oral drug, FDA-approved on June 4, 2021, for smallpox in all ages, including neonates.
        CDC has an E-IND to facilitate the use in mpox.
        It often causes a brisk elevation in LFTs, prompting discontinuance.
        It should be taken on an empty stomach or with a lower-fat meal (~400 calories, with no more than 25% of the calories from fat).
      - Cidofovir: injectable, has in vitro activity but little human data. Has been used as part of a combination therapy for patients with severe disease and those who are immunocompromised.
        It needs to be administered with probenecid.
        Check for drug interactions with probenecid.
      - Vaccinia immune globulin (VIGIV)
        It may have cross-reactivity, but its effectiveness for mpox is unknown.
        Has been used as part of a combination therapy for patients with severe disease and those who are immunocompromised.
      - Licensed for the treatment of complications or aberrant infections due to vaccinia vaccination
      - The CDC holds an Emergency Authorization (EA) for IND that allows the use of VIVIG in an orthopoxvirus outbreak, including mpox.
  - Severely ill and immunocompromised patients with disseminated or persistent infection:
    - The CDC recommends combination therapy for individuals with disease progression or those who have not responded to initial treatment.
    - For example, tecovirimat IV + cidofovir or brincidofovir + VIVIG.
  - Ocular lesions: tecovirimat +/- topical trifluridine.
    - Obtain an ophthalmology consultation.
  - Myopericarditis
    - Antivirals suggested.
    - Cardiology consultation; rule out other causes, e.g., receipt of mRNA SARS-CoV-2 vaccine or COVID.
  - CNS disease:
    - Some clinicians employ immunosuppressive therapy with antivirals. There is little data available to guide a recommendation, which needs to weigh the risks against the benefits.
      - Corticosteroids, IVIG, plasmapheresis, or plasma exchange.
    - Tecovirimat penetrates the CNS well.
  - Supportive care:
    - Analgesia, especially for oropharyngeal or rectal, may also require narcotics or PCA.
    - IV fluids

Prevention

Monitoring: People with suspected or confirmed mpox should be monitored for 21d after the last contact or potential close exposure.
- If symptoms develop, they should self-isolate and contact their PCP and local health department.
- CDC monitoring recommendations.
Prevention of exposure:
- Avoid direct or intimate contact with people with mpox who have active rashes
- WHO has suggested limiting sexual partners.
- Avoid contact with objects used by people with mpox, including bed linens, towels, and clothing.
- Avoid respiratory secretions and close contact without personal protective equipment (PPE) in individuals with mpox.
General measures if suspected or confirmed mpox:
- Isolate infected patients from others.
- Hand hygiene after contact with infected animals or humans.
  - Use soap and water or an alcohol-based sanitizer.
- Avoid contact with animals that could harbor the virus (including animals that are sick or found dead in areas where mpox occurs).
- Avoid direct contact with any potentially contaminated materials.
  - CDC notes that the mpox virus can be killed using a standard washing machine with warm water and detergent.
- Use appropriate personal protective equipment (PPE) for patient care (gown, gloves, respirator, and eye protection).
- CDC Infection Prevention and Control of Monkeypox for healthcare settings; for those sent home, CDC isolation recommendations vary depending on the home situation and if people at high risk are present (young children, immunocompromised).
Vaccines: ACIP 2025[1] for at-risk or people with mpox contacts, formalizes 2023 recommendations; two doses of JYNNEOS, see vaccine module for further details.
- CDC has changed the language of pre-exposure prophylaxis (PrEP) to "vaccination before exposure" in the U.S., offered to at-risk groups, including gay, bisexual, and other MSM, transgender, and nonbinary people who, in the last six months, have had sex in a commercial sex venue currently offered PrEP strategy.
  - People ages ≥ 18 years
    - HIV or other immunosuppression with the potential for exposure to mpox should be vaccinated.
    - Known or suspected exposure to someone with mpox
    - Sex partner in the past 2 weeks who was diagnosed with mpox
    - Gay, bisexual, or other men who have sex with men or a transgender, nonbinary, or gender-diverse person who in the past 6 months has had any of the following:
      - A new diagnosis of one or more sexually transmitted diseases (e.g., chlamydia, gonorrhea, or syphilis)
      - More than one sex partner
  - Any of the following in the past 6 months:
    - Sex at a commercial sex venue (like a sex club or bathhouse)
    - Sex-related to a large commercial event or in a geographic area (city or county, for example) where mpox virus transmission is occurring
    - Sex in exchange for money or other items
  - Sex partner with any of the above risks
  - Anticipation of any of the above scenarios
  - Work in settings where you may be exposed to mpox:
    - Work with orthopoxviruses in a laboratory
- Note: WHO has given prequalification of "off-label" use of JYNNEOS for use in adolescents due to the frequency of infection in this age group of clade 1 infection in the DRC. The European Medicines Agency (EMA) approved the vaccine (known as Imvanex in Europe) for teens based on U.S. NIH data among 315 adolescents in September 2024.
- Travelers to countries experiencing Clade 1 outbreaks:
  - CDC (HAN 2024, document has additional details):
    - As of April 15, 2025, these countries include Burundi, the Central African Republic, the Democratic Republic of the Congo, Kenya, the Republic of the Congo, Rwanda, Tanzania, Uganda, and Zambia.
    - Discuss the patient’s sexual history, travel plans, and if they anticipate intimacy during travel. Advise on mpox risks.
    - Recommend vaccination with the 2-dose JYNNEOS vaccine series to any adult if:
      - They are traveling to a country where clade I MPXV is spreading between people, AND
      - They anticipate experiencing any of the following:
        Sex with a new partner
        Sex at a commercial sex venue, like a sex club or bathhouse
        Sex in exchange for money, goods, drugs, or other trade
        Sex in association with a large public event, such as a rave, party, or festival
        Recommend starting the mpox vaccine series, if possible, at least 6 weeks before travel begins, as two doses should be administered 28 days apart, and it takes an additional 14 days for immunity to peak.
        Emphasize safe sexual practices regardless of whether immunization is elected.
- Post-exposure prophylaxis (PEP): Ideally, it is administered within 4 days of exposure; later (d5-14) use may decrease the severity of infection if it occurs; however, neither concept is evidence-based yet for MPXV.
  - Offer to those with known or presumed exposure.
  - If administered on days 4-14 post-contact, it may not prevent infection, but could lessen the severity if acquired.
  - Routine administration of vaccines to the general public is not recommended.
- The FDA has approved JYNNEOS^TM (MVA-BN), also known as Imvamune or Imvanex in the UK, an attenuated live virus vaccine that is non-replicating for the prevention of mpox. The ACIP recommends pre-exposure prophylaxis (PrEP) for individuals at risk of occupational exposures.
  - FDA-approved for mpox prevention, though efficacy data are limited and observational.
    - Some preliminary data have found that among U.S. males aged 18–49 years eligible for JYNNEOS vaccination, mpox incidence was 14x as high among unvaccinated males compared with those who had received a first vaccine dose ≥14 days earlier.
  - SC injection for ≥ 18 years with risks for mpox or exposure
    - Granted SC immunization for adolescents < 18 years determined to be at high risk for mpox.
  - Two doses, 4 weeks apart, to render sufficient efficacy for protection.
    - Limited data exist on vaccine efficacy (VE). Real-world data from Aug ’22 - Mar ’23 suggests VE was 75% for 1 dose and 86% for 2 doses of the JYNNEOS vaccine,
  - It appears to have fewer side effects than the smallpox vaccine/vaccinia.
  - Intradermal method using 0.1 mL instead of 0.5 mL SC now with FDA EUA (8/9/2022, now with a fact sheet, see link) based on 2015 data suggesting equivalent generation of neutralizing antibody titers in healthy adults compared to the SC method.
    - Only authorized for ≥ 18 years; used when supply is limited.
- Smallpox vaccine
  - ACAM2000 (live attenuated): more adverse reactions than JYNNEOS.
  - 85% vaccine efficacy when used in Africa to prevent mpox.
  - A far larger supply in the U.S. stockpile, but its aging status may mean lower potency.
  - Not currently used for mpox, as a primarily non-lethal disease, ACAM2000 is judged too dangerous a vaccine to use in these circumstances compared to smallpox.

Selected Drug Comments

Drug	Recommendation
Brincidofovir	The FDA-approved oral drug is available in tablet or suspension form for smallpox in neonates and older. Three patients received the drug for mpox in a UK case series, though uncertain if it helped in their good outcome[26]. None of the three in this series completed the course due to rising LFTs. CDC holds e-IND for use in mpox
Cidofovir	The U.S. maintains a Strategic National Stockpile for use in the case of smallpox. The drug has in vitro activity; however, it has not been used in a way that enables an understanding of effectiveness against mpox. Has been part of a combination therapy employed for people with severe disease, especially among the immunocompromised/AIDS.
Tecovirimat	FDA-approved for smallpox. However, recent RCTs (PALM007 clade I and STOMP, clade II) failed to show improvement in lesion resolution or pain compared to the placebo, with mortality being the same in PALM007 in both the antiviral and placebo arms. However, a non-statistically significant subanalysis suggested some benefit in those with severe disease. The trials did not address whether the drug might help those who are severely immunosuppressed or have severe disease, or if the drug was used in combination. Evidence suggests that for individuals with mild to moderate disease, supportive care alone may be an appropriate approach.
VIVIG	The CDC controls vaccine immune globulin (VIG) primarily for the treatment of complications of smallpox vaccination, including eczema, progressive vaccinia, and generalized vaccinia. The effectiveness of its use in mpox is unknown. Has been part of a combination therapy employed for people with severe disease, especially among the immunocompromised/AIDS.

FOLLOW UP

If new lesions are forming ≥ 7d of antiviral therapy, consider:
- Orthopoxvirus PCR testing of new lesions
- Assess for superinfection (bacterial)
- Serology to assess IgM response
- Tecovirimat pharmacokinetic testing
- Tecovirimat resistance testing
Upon crusting of lesions, patients are often considered non-infectious; however, viral kinetics in mpox are not yet fully understood.
Sterile abscesses, bacterial superinfection, and bacteremia are seen.
Isolation practices for confirmed mpox.
- Isolate at home or another location for the duration of the illness.
- Isolation ceases when all symptoms have resolved, including all skin lesions that have healed with a fresh layer of skin (not just crusted).
  - The duration ranges from 2 to 4 weeks.
- While with rash, cover all parts of the skin with clothing, gloves or bandages.
- Wear a tight-fitting mask, even if you have no fever or respiratory symptoms.
- Do not share items with others, avoid close contact, and wash hands with alcohol-based sanitizer or soap and water.

OTHER INFORMATION

The low level of cases continues; we may expect clusters of cases to occur in the U.S. and elsewhere, especially among high-risk individuals who gather for community events.
- Two-dose JYNNEOS vaccination is strongly recommended for all individuals at risk.
- Those who have received only 1 dose are encouraged to get a second dose for enhanced protection against infection.
- Two-dose efficacy studies have reported a range of 66-86%. Lower rates were seen among immunocompromised, advanced HIV or 1 dose (51%).
An increase in mpox cases has been ascribed to the successful eradication of smallpox and the cessation of vaccinia immunization programs.

Basis for recommendation

Rao AK, Minhaj FS, Carter RJ, et al. Use of JYNNEOS (Smallpox and Mpox Vaccine, Live, Nonreplicating) for Persons Aged ≥18 Years at Risk for Mpox During an Mpox Outbreak: Recommendations of the Advisory Committee on Immunization Practices - United States, 2023. MMWR Morb Mortal Wkly Rep. 2025;74(22):385-392. [PMID:40531798]
Comment: ACIP has now issued formal guidance superseding prior interim recommendations. ACIP recommends immunization for adults at risk. New data over the last couple of years have yielded safety information as well as efficacy data. Moreover, immunization is recommended during clade IIb outbreaks for those at risk. Identified risks have remain unchanged since 2022 recommendations and are 1) MSM who, during the past 6 months, have had or anticipate experiencing at least one of the following: a new diagnosis of one or more sexually transmitted infections, more than one sex partner, sex at a commercial sex venue, or sex in association with a large public event in a geographic area where mpox transmission is occurring; 2) sexual partners of persons who have any of these risk factors; and 3) persons who anticipate experiencing any of these risk factors.
Dalton AF, Diallo AO, Chard AN, et al. Estimated Effectiveness of JYNNEOS Vaccine in Preventing Mpox: A Multijurisdictional Case-Control Study - United States, August 19, 2022-March 31, 2023. MMWR Morb Mortal Wkly Rep. 2023;72(20):553-558. [PMID:37200229]
Comment: More complete data is available, and this is from real-world data for vaccine efficacy which found VE was 75% for one dose and 86% for two doses. This was irrespective of the route of administration or immune status. These data have led to the strong recommendation to recommend a two-dose schedule for risk groups.
Rao AK, Schrodt CA, Minhaj FS, et al. Interim Clinical Treatment Considerations for Severe Manifestations of Mpox - United States, February 2023. MMWR Morb Mortal Wkly Rep. 2023;72(9):232-243. [PMID:36862595]
Comment: Updated guidance based on low levels of evidence for the use of tecovirimat, brincidofovir, cidofovir, trifluridine ophthalmic solution, and vaccinia immune globulin intravenous,
O'Shea J, Filardo TD, Morris SB, et al. Interim Guidance for Prevention and Treatment of Monkeypox in Persons with HIV Infection - United States, August 2022. MMWR Morb Mortal Wkly Rep. 2022;71(32):1023-1028. [PMID:35951495]
Comment: The guidance is directed explicitly at people with HIV as they are a substantial portion of the current outbreak. The concern is that they may be at increased risk for severe infection, so using tecovirimat is suggested. The cut-off is not known, but some consider CD4 < 350 as a value. They also note early administration of vaccines (≤4 days after exposure) might prevent monkeypox, and later use (5–14 days after exposure) might decrease the severity of monkeypox if infection occurs---although this is unstudied re: MPVX.
Mpox: Treatment Information for Healthcare Professionals. https://www.cdc.gov/mpox/hcp/clinical-care (last updated 1/30/2025, accessed 7/10/2025)
Comment: Treatment should be considered in sensitive anatomical areas with a risk of scarring and those with severe illness. Also, those at high risk of severe mpox infections. Recent trials showing a lack of efficacy of tecovirimat in mild-moderate disease have not yet been incorporated. Combination therapy is often employed in progressive disease in those with advanced immunosuppression. Advice is also given for brincidofovir, VIVIG, and cidofovir.

References

Rohilla S, Gaidhane S, Balaraman AK, et al. Ophthalmic Manifestations of the Mpox Virus: A Systematic Review and Meta-Analysis. J Infect Dis. 2025. [PMID:39913333]
Comment: In this review of the literature and meta-analysis, conjunctivitis is the most common ophthalmic complication of Mpox, followed by notable rates for keratitis, eye lesions, and visual impairment. Visual impairment ranged considerably in studies. The treatment effect is not addressed.
PALM007 Writing Group, Ali R, Alonga J, et al. Tecovirimat for Clade I MPXV Infection in the Democratic Republic of Congo. N Engl J Med. 2025;392(15):1484-1496. [PMID:40239067]
Comment: A placebo-controlled randomized controlled trial (RCT) for Clade I disease did not find that tecovirimat led to faster disease resolution in these immunocompetent patients. The mortality rate was lower than usual for clade one disease (1.7%). No safety issues were seen in this trial of 597 patients, with 295 receiving the antiviral.
Musuka G, Moyo E, Tungwarara N, et al. A critical review of mpox outbreaks, risk factors, and prevention efforts in Africa: lessons learned and evolving practices. IJID Reg. 2024;12:100402. [PMID:39157420]
Comment: While most in North America focused on Clade II, Clade I and Ib have been wreaking havoc in the DRC for years, with increasing cases in other African countries. This is an informative perspective on the insufficient efforts to stymie the outbreak.
Marcus U, Michel J, Lunchenkov N, et al. A seroprevalence study indicates a high proportion of clinically undiagnosed MPXV infections in men who have sex with men in Berlin, Germany. BMC Infect Dis. 2024;24(1):1153. [PMID:39396951]
Comment: This study was conducted in Berlin, Germany and found among 1119 MSM participants in 2023 that 70 (7.4%) had clinical mpox diagnosis, however 91 had asymptomatic, mild or unrecognized infection!
Berry MT, Khan SR, Schlub TE, et al. Predicting vaccine effectiveness for mpox. Nat Commun. 2024;15(1):3856. [PMID:38719852]
Comment: Authors argue that delaying a second dose provides more durable immunity, and allows for more first doses to be given in an outbreak situation.
Leonard CM, Poortinga K, Nguyen E, et al. Mpox Outbreak - Los Angeles County, California, May 4-August 17, 2023. MMWR Morb Mortal Wkly Rep. 2024;73(2):44-48. [PMID:38236779]
Comment: Mpox has been identified especially in gay, bisexual and other MSM in the LA County region since spring of 2023. The majority of patients were not immunized, particularly among younger Black, African American, Hispanic, and Latino persons with HIV.
Hazra A, Zucker J, Bell E, et al. Mpox in people with past infection or a complete vaccination course: a global case series. Lancet Infect Dis. 2024;24(1):57-64. [PMID:37678309]
Comment: This report comprises the largest series of people who have reinfection or infection after two doses of JYNNEOS. People who experienced infection after natural immunity (7) had shorter and less severe illnesses. This population was mostly young, gay/bisexual, sexually active men. Typically, fewer lesions were seen, including in the mucosa, with less need for hospitalization or teciviromat.
Deputy NP, Deckert J, Chard AN, et al. Vaccine Effectiveness of JYNNEOS against Mpox Disease in the United States. N Engl J Med. 2023;388(26):2434-2443. [PMID:37199451]
Comment: Case-control data using EHRs found that those without 1 or 2 doses of JYNNEOS were more likely to acquire mpox, suggesting effectiveness.
Ogoina D, James HI. Mpox among Linked Heterosexual Casual Partners in Bayelsa, Nigeria. N Engl J Med. 2023;388(22):2101-2104. [PMID:37195934]
Comment: Without a high index of suspicion, mpox appears likely to go underdiagnosed in the heterosexual population, as this letter reflecting some experience in West Africa suggests.
Li P, Li J, Ayada I, et al. Clinical Features, Antiviral Treatment, and Patient Outcomes: A Systematic Review and Comparative Analysis of the Previous and the 2022 Mpox Outbreaks. J Infect Dis. 2023;228(4):391-401. [PMID:36735342]
Comment: This review includes 33 of 73 identified studies for this meta-analysis that compares Clade I and Clade II outbreak data. Insufficient information is available to assess the tecovirimat effect.
Payne AB, Ray LC, Kugeler KJ, et al. Incidence of Monkeypox Among Unvaccinated Persons Compared with Persons Receiving ≥1 JYNNEOS Vaccine Dose - 32 U.S. Jurisdictions, July 31-September 3, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(40):1278-1282. [PMID:36201401]
Comment: Most in the US, as of this writing (Oct 2022), had only received one dose of the vaccine due to supply and administration constraints. It appears that one dose does offer some protection based on this observational sample.
Hagan LM, Beeson A, Hughes S, et al. Monkeypox Case Investigation - Cook County Jail, Chicago, Illinois, July-August 2022. MMWR Morb Mortal Wkly Rep. 2022;71(40):1271-1277. [PMID:36201399]
Comment: Close exposure in jail setting to index patient did NOT cause new cases
Miller MJ, Cash-Goldwasser S, Marx GE, et al. Severe Monkeypox in Hospitalized Patients - United States, August 10-October 10, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(44):1412-1417. [PMID:36327164]
Comment: CDC report wherein they offered consultation to 57 severely ill patients who were predominantly Black with AIDS. Among this group, which is a biased sample, nearly one-third (30%) received ICU-level care, and 21% of patients died. Combination therapy was offered, tecovirimat/cidofovir/VIVIG and suggested for those with severe or progressive disease despite initial therapy. Twelve deaths were reported by CDC, which participated in management. The majority were Black men with advanced HIV and had severe disease ascribed to an immunocompromising state. Not all deaths yet directly attributed to a cause, and one was not thought to be related to MPXV. Combination therapy was often employed, with tecovirimat +/- cidofovir and VVIG. Only four patients were on ART.
Luong Nguyen LB, Ghosn J, Durier C, et al. A prospective national cohort evaluating ring MVA vaccination as post-exposure prophylaxis for monkeypox. Nat Med. 2022. [PMID:35831633]
Comment: The authors note in this letter that recent cases in Nigeria (3552) with only one reported fatality, far less than the 1-10% range reported in earlier years. Modified Vaccinia Ankara–Bavarian Nordic (MVA-BN) is a third-generation live vaccine that is non-replicating and reports predominantly African and European experience with PEP, which appears effective.
Orviz E, Negredo A, Ayerdi O, et al. Monkeypox outbreak in Madrid (Spain): clinical and virological aspects. J Infect. 2022. [PMID:35830908]
Comment: Spain has the most reported cases; this experience from Madrid from May to June 2022 is reported for 48 men. The mean age was 35 years, and 87.5% were MSM; lesions appeared in the area where they had sexual intercourse (genital or anal). Sequencing found the isolates consistent with the western African clade, specifically the Nigerian outbreak of 2017-18 that had low mortality.
Kwok KO, Wei WI, Tang A, et al. Estimation of local transmissibility in the early phase of monkeypox epidemic in 2022. Clin Microbiol Infect. 2022. [PMID:35817231]
Comment: No doubt an imperfect estimate based on early data suggests that in UK, Portugal and Spain, the Ro ranged between 1.3 to 2.1.
Aden TA, Blevins P, York SW, et al. Rapid Diagnostic Testing for Response to the Monkeypox Outbreak - Laboratory Response Network, United States, May 17-June 30, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(28):904-907. [PMID:35834423]
Comment: During the first month and a half of the US monkeypox outbreak, the CDC evaluated 2009 specimens from their external lab network on suspicion of monkeypox. The CDC found that 36% were positive for non-variola Orthopoxvirus. All of those sequenced to date were from the West African clade, similar to findings from patients in Spain and the UK.
Seang S, Burrel S, Todesco E, et al. Evidence of human-to-dog transmission of monkeypox virus. Lancet. 2022. [PMID:35963267]
Comment: In a brief report from Paris, two men with MPXV had subsequent skin lesions in their Italian greyhound PCR positive for MPXV. This canine isolate had 100% homology with one of the patients. The men did sleep with their dog. Worrisome, this is the first report ever in the medical history of viral transmission to a dog. It is not absolutely certain that the dog didn’t harbor the virus first, but it seems unlikely.
Philpott D, Hughes CM, Alroy KA, et al. Epidemiologic and Clinical Characteristics of Monkeypox Cases - United States, May 17-July 22, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(32):1018-1022. [PMID:35951487]
Comment: Early US experience n = 1195. Median age 35, men 98.7%, 94% with MSM in the prior 3 weeks, 41% w/ HIV. Rash in 100% with genitals the most common site (46%). Fever in 63%, lymphadenopathy in 59%.
Du Z, Shao Z, Bai Y, et al. Reproduction number of monkeypox in the early stage of the 2022 multi-country outbreak. J Travel Med. 2022. [PMID:36006837]
Comment:
Using data as of 7/22/22, this group estimates a Ro of 1.29 (95% CI, 1.26-1.33).
Adler H, Gould S, Hine P, et al. Clinical features and management of human monkeypox: a retrospective observational study in the UK. Lancet Infect Dis. 2022;22(8):1153-1162. [PMID:35623380]
Comment: The current state-of-the-art review and clinical experience regarding management. Oral antivirals (brincidofovir and tecovirimat) were used but had an uncertain effect in this small patient series. Patients had a surprisingly long period of PCR detection of viral DNA.
Russo AT, Grosenbach DW, Chinsangaram J, et al. An overview of tecovirimat for smallpox treatment and expanded anti-orthopoxvirus applications. Expert Rev Anti Infect Ther. 2021;19(3):331-344. [PMID:32882158]
Comment: This oral drug has broad activity against many known orthopox viruses.
Hutson CL, Kondas AV, Mauldin MR, et al. Pharmacokinetics and Efficacy of a Potential Smallpox Therapeutic, Brincidofovir, in a Lethal Monkeypox Virus Animal Model. mSphere. 2021;6(1). [PMID:33536322]
Comment: Animal model of monkeypox, however, authors state that dosing selection may have impacted results.
Petersen E, Kantele A, Koopmans M, et al. Human Monkeypox: Epidemiologic and Clinical Characteristics, Diagnosis, and Prevention. Infect Dis Clin North Am. 2019;33(4):1027-1043. [PMID:30981594]
Comment: Authors have organized clinical data and impressions from outbreaks of monkeypox in Africa and the UK. Increase in monkeypox cases has been ascribed to the successful eradication of smallpox and the cessation of vaccinia immunization programs.
Grosenbach DW, Honeychurch K, Rose EA, et al. Oral Tecovirimat for the Treatment of Smallpox. N Engl J Med. 2018;379(1):44-53. [PMID:29972742]
Comment: Animal model data lead to approval of the drug for smallpox since human data is impossible.
Huhn GD, Bauer AM, Yorita K, et al. Clinical characteristics of human monkeypox, and risk factors for severe disease. Clin Infect Dis. 2005;41(12):1742-51. [PMID:16288398]
Comment: Risk factors for severe disease appeared to be two: fever ≥ 38.3°C and > 100 lesions.
Learned LA, Reynolds MG, Wassa DW, et al. Extended interhuman transmission of monkeypox in a hospital community in the Republic of the Congo, 2003. Am J Trop Med Hyg. 2005;73(2):428-34. [PMID:16103616]
Comment: Six cases among those in this pediatric outbreak had an extended chain of transmission among humans. Authors aptly noted the potential for more concerning and widespread transmission among humans in future if cases are not contained early in an outbreak.
Centers for Disease Control and Prevention (CDC). Update: multistate outbreak of monkeypox--Illinois, Indiana, Kansas, Missouri, Ohio, and Wisconsin, 2003. MMWR Morb Mortal Wkly Rep. 2003;52(27):642-6. [PMID:12855947]
Comment: The report describes 71 cases, 35 lab-confirmed and 36 suspected cases, with the majority exposed to prairie dogs. Use of smallpox vaccine included pre-exposure administration to 3 veterinarians, 2 lab workers, and two healthcare workers and post-exposure to 23 individuals. All 35 confirmed cases traced back to prairie dogs housed, at an Illinois animal distributor, with Gambian giant rats and dormice that originated from Ghana.
Rating: Important