Primary prevention

Smallpox vaccines are recommended to prevent infection with mpox. Vaccines are based on the vaccinia virus because it is less harmful than the variola virus, and due to the cross-protection afforded by the immune response to orthopoxviruses. Although routine vaccination against smallpox ceased in the 1970s, smallpox vaccines are stockpiled in most countries in case of an emergency. Vaccine availability varies between countries and you should consult your local public health authority for guidance on how to obtain and use vaccines.

Attenuated live virus (replication-deficient) vaccines

  • Attenuated live virus (replication-deficient) vaccines are third-generation vaccines based on modified vaccinia Ankara (available as modified vaccinia Ankara Bavarian Nordic strain, or MVA-BN).

    • These vaccines represent more attenuated vaccine strains compared with first- and second-generation vaccines (see below), specifically developed by further passage in cell culture or animals.

    • Vaccines are typically administered subcutaneously (two doses given 28 days apart), and protection begins 2 weeks after the second dose (i.e., maximum protection takes 6 weeks).

    • Intradermal administration (fractional dosing at one fifth the usual dose) may be recommended in select people in some countries.[120] The lower intradermal dose was found to be immunologically noninferior to the standard subcutaneous dose in one study. However, there is an increased risk of local reactions after intradermal injection.[121] 

    • Consult your local public health authority for more information.

  • Third-generation vaccines are approved or available off-label in some countries for the prevention of mpox, although supply may be limited. MVA-BN is available under different brand names (e.g., Imvanex®, Imvamune®, and Jynneos®).

    • Imvanex® is approved in the UK and Europe for active immunization against mpox, smallpox, and disease caused by vaccinia virus in adults.

    • Jynneos® is approved in the US for the prevention of mpox and smallpox in adults ≥18 years of age. The Food and Drug Administration has issued an emergency use authorization to also allow the use of Jynneos® in people <18 years of age who are at high risk of infection. The emergency use authorization also allows for the two doses of Jynneos® to be administered intradermally in adults ≥18 years of age who are at high risk for infection.[122]

    • Jynneos® may be available in the UK during periods of limited vaccine supply; however, the conditions of regulatory approval in the UK vary slightly from those in the US.[123] The UK Health Security Agency (UKHSA) and the European Medicines Agency support intradermal dosing in healthy adults (including pregnant women, but not immunocompromised people) during periods of limited vaccine supply.[124][125][126]

    • LC16 (a minimally-replicating vaccine) may be available in some countries (e.g., Japan).

  • Third-generation vaccines are considered to be safer compared with first- and second-generation vaccines. However, safety data are limited.

    • Replication-deficient vaccines have fewer contraindications and cautions, and are associated with fewer serious adverse events compared with replication-competent vaccines.

    • A history of a severe allergic reaction (e.g., anaphylaxis) to a previous dose of the vaccine is a contraindication. Caution is required in people who have a history of a severe allergic reaction to a component of the vaccine (e.g., gentamicin, ciprofloxacin, chicken or egg protein) or an acute illness. There is no risk for inadvertent inoculation and autoinoculation.

    • A phase 3 trial found that immune responses with Jynneos® were not inferior compared with patients who received ACAM2000®, and no safety concerns were identified. Typical severe adverse effects associated with replication-competent vaccinia virus strains were not observed. However, the trial was small (220 participants received at least one dose of Jynneos®) and the follow-up time was limited to 29 days.[127]

    • The risk of myocarditis after third-generation smallpox vaccines (e.g., Jynneos®) is currently unknown. However, people with underlying heart disease or three or more major cardiac risk factors should be counseled about the theoretical risk for myopericarditis following vaccination with a third-generation vaccine.[128]

    • Emerging data from the US Vaccine Adverse Event Reporting System (VAERS) based on vaccination during the 2022-23 global outbreak indicates that the safety profile of Jynneos® is consistent with prelicensure studies, and that serious adverse events (e.g., anaphylaxis, myocarditis) were rare among adults.[129]

  • Third-generation vaccines are recommended in certain patient populations.

    • ​Nonreplicating vaccines are preferred in immunocompromised people (including those with HIV), pregnant and breastfeeding women, and children (use in children may be off-label).[130]

    • Safety and efficacy data in immunocompromised people, including those with HIV infection, are limited. The MVA-BN vaccine can be offered to immunocompromised people and those with HIV, if indicated, after a discussion of the risks and benefits and using shared decision-making.[24][25] However, immunogenicity among people with CD4 counts <100 cells/microliter or who are not virologically suppressed remains unknown.​[131]

    • There are insufficient data to determine the risks of these vaccines in pregnant and breastfeeding women. However, the vaccine can be offered to pregnant and breastfeeding women who are otherwise eligible, after a discussion of the risks and benefits and using shared decision-making.[104]

Live replication-competent vaccines

  • First-generation vaccines (e.g., Dryvax®, Wetvax®/Aventis Pasteur smallpox vaccine) and second-generation vaccines (e.g., ACAM2000®) are not available to the general public. However, they may be stockpiled in case of an emergency.

    • First-generation vaccines from the smallpox eradication program may be held in national reserves but do not meet current safety and manufacturing standards and are not recommended at this time.

    • ACAM2000® is approved in the US for the prevention of smallpox in people ≥1 year of age who are considered to be at high risk for smallpox infection. It has been made available for use against mpox under an expanded access investigational new drug application.

    • These vaccines are administered percutaneously as a single dose using a multiple puncture technique with a bifurcated needle. If inoculation is successful, a lesion develops at the site of vaccination (known as "a take"). Protection occurs within 28 days. Duration of immunity is unknown.

  • Contraindications include history of severe allergic reaction (e.g., anaphylaxis) after a previous dose of the vaccine, atopic dermatitis, other exfoliative skin conditions, immunosuppression (congenital or acquired), history of drugs or treatments that cause immunosuppression, HIV infection (regardless of immune status), transplant recipients, autoimmune disease, eye disease being treated with topical corticosteroids, pregnancy and breastfeeding, age <1 year, allergy to vaccine component, and underlying heart disease or cardiac risk factors.​[132]

    • Although first- and second-generation vaccines are usually contraindicated in pregnant women, a systematic review and meta-analysis found that the overall risk associated with maternal smallpox vaccination appears to be low. Outcomes of smallpox vaccination in 12,201 pregnant women were included. No association with spontaneous abortion, preterm birth, or stillbirth was identified. Vaccination in the first trimester was associated with a small increased risk of congenital defects (based on limited data). While fetal vaccinia appears to be a rare consequence of maternal smallpox vaccination, it is associated with a high rate of fetal loss.[133]

  • Inoculation with traditional vaccinia may cause eczema vaccinatum, generalized vaccinia, or potentially fatal progressive vaccinia (see Complications).[134]

    • There are many other potential side effects including superinfection of the vaccination site or regional lymph nodes, cellulitis, unintentional transfer of vaccinia virus (e.g., accidental autoinoculation of other body parts, ocular vaccinia, inoculation of close household contacts), fetal vaccinia, myopericarditis, dilated cardiomyopathy, cardiac ischemia, encephalitis and other severe neurologic manifestations, and even death.

    • The risk of myopericarditis was 3.6-fold higher in vaccinated military personnel compared with unvaccinated after administration of the ACAM2000® vaccine, and usually occurred within 8 to 14 days (up to 6 weeks).[135] However, the true risk may be higher. Fatal cases have been described.[136] For more information see Complications.

    • Vaccine adverse events may be managed with vaccinia immune globulin and antiviral agents.

Mass vaccination is not required or recommended for mpox outbreaks or the general public. However, pre-exposure vaccination may be recommended in certain groups of people where appropriate vaccines are available, taking into account the possibility of limited supply.

  • The World Health Organization recommends pre-exposure vaccination with an appropriate approved (or off-label) second- or third-generation vaccine (e.g., MVA-BN, ACAM2000®, LC16) for people at high risk of exposure, including:[130]

    • People who self-identify as gay or bisexual or other men who have sex with men with multiple sexual partners

    • People with multiple casual sexual partners

    • Sex workers

    • Health workers at risk of repeated exposure

    • Laboratory personnel working with orthopoxviruses

    • Clinical laboratory and healthcare personnel performing diagnostic testing for mpox

    • Outbreak response team members as designated by national public health authorities.

  • Pre-exposure vaccination for special population groups who are at increased risk of severe disease (e.g., children, pregnant or breastfeeding women, immunocompromised people) is not recommended based on their higher risk of severe disease. However, vaccination may be prioritized in those who are at high risk of exposure.[130]

  • In the UK, the UK Health Security Agency (UKHSA) recommends pre-exposure vaccination with MVA-BN for:

    • Occupational vaccination: smallpox-naive individuals at risk of exposure on the basis of an occupational health assessment (e.g., healthcare workers or designated staff in hospital units due to care for a patient with mpox) or staff working in sexual health services who have been identified as assessing suspected cases, even if they will be wearing full personal protective equipment.[124]

    • Targeted pre-exposure vaccination: men who have sex with men at highest risk due to a large number of contacts (i.e., using markers of high-risk behavior similar to those used to assess eligibility for HIV pre-exposure prophylaxis such as history of multiple partners, participation in group sex, and attending sex-on-premises venues).[137]

    • UKHSA: recommendations for the use of pre and post exposure vaccination during an mpox incident Opens in new window

    • UKHSA: mpox (monkeypox) outbreak - vaccination strategy Opens in new window

  • In the US, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) recommends pre-exposure vaccination with either Jynneos® or ACAM2000® for:[128]

    • People who are at occupational risk for exposure to orthopoxviruses (e.g., research laboratory personnel who work with orthopoxviruses, clinical laboratory personnel who perform diagnostic testing for orthopoxviruses, designated response team members)

    • People who administer live replication-competent smallpox vaccines (e.g., ACAM2000®)

    • People who care for patients with infection with replication-competent orthopoxviruses.

  • In addition to this, the Centers for Disease Control and Prevention recommends that pre-exposure prophylaxis may be offered to people at highest potential for exposure (or who anticipate potential exposure) to mpox.[138] 

    • Eligible populations include: gay, bisexual, or other men who have sex with men, and transgender or nonbinary people (including adolescents), who have had a new diagnosis of one or more sexually-transmitted infections or more than one sex partner in the past 6 months; people who have had sex at a commercial sex venue or sex in association with a large public event in a geographic area where mpox transmission is occuring in the past 6 months; sexual partners of people with these risks; and people with HIV or other causes of immunosuppression who have had recent, or anticipate potential, mpox exposure.

  • Consider the safety and reactogenicity of available vaccines and the risk of vaccine-related adverse events in the need-risk-benefit analysis when choosing a vaccine, as part of a shared clinical decision-making process.[130]

    • Nonreplicating, minimally-replicating, or replication-competent vaccines are appropriate for use in healthy adults. Nonreplicating vaccines are preferred in children, pregnant and breastfeeding women, immunocompromised people (including those with HIV), and anyone with a contraindication or caution to a minimally-replicating or replication-competent vaccine, if vaccination is required (use in children may be off-label). Minimally-replicating vaccines may be used in children.

  • Booster doses may be recommended.

    • In the US, the ACIP recommends a booster dose in people who are at ongoing risk for occupational exposure to orthopoxviruses.[128]

    • The booster dose is recommended every 2 years (Jynneos®) or 3 years (ACAM2000®) for people working with more virulent orthopoxviruses such as variola virus or monkeypox virus, or every 10 years (Jynneos® or ACAM2000®) for those working with less virulent orthopoxviruses such as vaccinia virus.[128]

Limited evidence suggests that smallpox vaccines provide protection against mpox.

  • Data acquired from the final stages of the smallpox eradication program implied that first- and second-generation vaccines yielded 85% protection upon subsequent exposure to mpox.[79]

    • One systematic review found that prior immunization with the smallpox vaccine yielded 81% protection against mpox, and that immunity provided by the vaccine is long lasting. However, the review only included six studies with approximately 2000 participants, and most studies had a high risk of selection bias.[139]

    • Antibodies elicited by first-generation vaccines have recently been found to neutralize the Clade II monkeypox virus, the virus responsible for the 2022-23 global outbreak, more than 40 years after administration of the vaccine.[140]

    • Differences in the appearance of the rash have been noted in vaccinated versus unvaccinated people. Vaccinated people tend to have fewer lesions, smaller lesions, and better representation of the centrifugal distribution.[141]

  • Approval of third-generation vaccines was based on data from animal studies that showed protection against mpox in nonhuman primates.[142] Safety and efficacy in humans was inferred from these animal studies.

    • A two-dose MVA-BN series was shown to yield relatively low levels of neutralizing antibodies in nonprimed individuals in one study. However, the role of these neutralizing antibodies as a correlate of protection against transmission and disease is currently unclear.[143]

  • Limited data are available on the efficacy of third-generation vaccines used during the 2022-23 global outbreak.

    • Real-world data from the US demonstrates a reduced incidence of mpox among vaccinated men ages 18 to 49 years. Protection was higher after two doses compared with one dose.[144] However, one dose may attenuate disease severity and reduce the risk of hospitalization in people who become infected after vaccination compared with unvaccinated people.[145]

    • Vaccine efficacy has been reported to be 69% (full vaccination with 2 doses) and 37% (partial vaccination with one dose) based on unpublished data reported by the Centers for Disease Control and Prevention.[146]

    • There have been reports of breakthrough infections in people previously vaccinated with a smallpox vaccine.[147][148][149]​​​​

    • There is limited evidence for a milder disease course in patients with a history of childhood smallpox vaccination, but hospitalization rates were not lower in vaccinated people.[150]

    • Jynneos® (a third-generation vaccine) resulted in a better humoral response compared with ACAM2000® (a second-generation vaccine) in one study.[151]

A 4-week interval between the administration of smallpox vaccines and COVID-19 vaccines may be considered in some patients.

  • Myocarditis has been documented after administration of ACAM2000® and COVID-19 vaccines. The risk of myocarditis after third-generation smallpox vaccines is currently unknown.

  • The Centers for Disease Control and Prevention recommends considering waiting 4 weeks after Orthopoxvirus vaccination before administering a COVID-19 vaccine, particularly in adolescent or young adult males. People who previously received a COVID-19 vaccine may be given an Orthopoxvirus vaccine without a minimum interval between vaccinations.[152]

Resources on smallpox vaccination are available from public health authorities; check your local guidance.

Other vaccines are also in development.

Secondary prevention

Postexposure vaccination with the smallpox vaccination (off-label use) may be recommended in specific groups of people to prevent or attenuate infection.

  • The World Health Organization recommends postexposure vaccination with an appropriate second- or third-generation vaccine for contacts of cases, ideally within 4 days of first exposure (and up to 14 days in the absence of symptoms).[130]

    • Children, pregnant women, and immunocompromised people should be prioritized for vaccination in case of limited vaccine supply.

    • For more information on vaccines, see Primary prevention.

  • In the UK, the UK Health Security Agency (UKHSA) recommends risk assessing people and offering postexposure vaccination with a single dose of MVA-BN if appropriate as soon as possible and within 4 days after an identified exposure.[124]

    • Postexposure vaccination may be extended up to 14 days for those at high risk of ongoing exposure (e.g., men who have sex with men, healthcare workers where the dose will act as their first pre-exposure dose), and those who are at risk of more severe disease (e.g., immunocompromised people, pregnant women, children ≤5 years of age).

    • Postexposure vaccination may be temporarily restricted to contacts at highest risk of severe illness during periods of limited vaccine supply (e.g., immunocompromised people, pregnant women, children ≤5 years of age).[126]

    • People with HIV infection who are immunosuppressed (i.e., CD4 count <200 cells/microliter, persistent viremia, or immunosuppression related to another condition or treatment) should receive two full subcutaneous doses. People with CD4 counts >200 cells/microliter and viral suppression can receive intradermal fractionated dosing. Slightly lower antibody responses can occur after the first dose, but the difference is less compared with people without HIV after the full vaccine course.[131]

    • UKHSA: recommendations for the use of pre and post exposure vaccination during an mpox incident Opens in new window

  • In the US, the Centers for Disease Control and Prevention (CDC) recommends postexposure vaccination after known or presumed exposure with two doses of Jynneos® or a single dose of ACAM2000®, ideally within 4 days and up to 14 days (use can be considered on a case-by-case basis after 14 days).[138]

    • Postexposure vaccination is recommended for contacts with higher-risk exposures, and may be considered for contacts with intermediate-risk exposures (see Screening).[215]

    • Eligible populations include: people who are known contacts to someone with mpox; people who are aware that a recent sex partner was diagnosed with mpox within the past 14 days; and gay, bisexual, or other men who have sex with men, and transgender or nonbinary people (including adolescents), who have had sex with multiple partners or group sex, sex at a commercial sex venue, or sex in association with an event, venue, or defined geographic area where transmission is occuring, within the past 14 days.[138]

    • Immunocompromised: postexposure vaccination with Jynneos® can be offered to immunocompromised people including those with HIV infection, if indicated, after a discussion of the risks and benefits and using shared decision-making. ACAM2000® should not be used in immunocompromised people. The antiviral medication tecovirimat and vaccinia immune globulin may be considered for postexposure prophylaxis in these patients on an individual case-by-case basis if an alternative option to vaccination is required, but the efficacy of these therapies for this indication is unknown.[24][25]

    • Children and adolescents: postexposure vaccination with Jynneos® or ACAM2000® may be offered to children and adolescents who are otherwise eligible. Jynneos® is the preferred option, and is authorized under an emergency use authorization for postexposure vaccination of children and adolescents <18 years of age (clinicians should contact their local health department before using in children <6 months of age). ACAM2000® should be used with caution in children only after a discussion of the benefits and risks due to an increased risk of adverse events (e.g., myopericarditis) and accidental inoculation/autoinoculation in this age group. ACAM2000® is contraindicated in children <12 months of age and those with certain conditions. Data on the safety and efficacy of postexposure vaccination in children and adolescents are limited. Vaccinia immune globulin may be considered for postexposure prophylaxis, particularly for infants <6 months of age, if an alternative option to vaccination is required. Antivirals (e.g., tecovirimat) may be considered in unusual circumstances (e.g., if vaccination is contraindicated), but the efficacy of these therapies for this indication is unknown.[102]

    • Pregnant and breastfeeding women: postexposure vaccination with Jynneos® can be offered to pregnant and breastfeeding women who are otherwise eligible, after a discussion of the risks and benefits and using shared decision-making. ACAM2000® is contraindicated in pregnant and breastfeeding women.[104]

  • The dose for postexposure vaccination may differ between countries and you should consult your local public health authority.

    • The recommended dose schedule for postexposure vaccination with a nonreplicating vaccine is generally two doses (given 28 days apart).

    • However, some countries may recommend only one dose for postexposure vaccination (two doses may be recommended in certain patients, such as those with HIV infection), and some countries may recommend three doses (e.g., in patients with HIV infection and low CD4 counts depending on smallpox vaccination history). However, data on these regimens are limited.[332]

    • Intradermal dosing may be used for postexposure vaccination in healthy adults (see above).

Postexposure vaccination with smallpox vaccination of close contacts has successfully limited transmission of mpox in past outbreaks, and can abort infection or significantly attenuate it.[333]

  • Vaccination against smallpox with standard first- or second-generation vaccinia virus vaccines was demonstrated through several observational studies to be about 85% effective in preventing mpox.[79] However, there is very limited evidence on whether third-generation vaccines prevent or modify disease when given to contacts after exposure.

  • Vaccination up to 14 days postexposure is thought to be beneficial.[334] There is a theoretical possibility of attenuating disease if vaccination occurs towards the end of the range of the incubation period.

  • Emerging real-world data from the 2022-23 global outbreak indicates that the incidence of mpox among males ages 18 to 49 years who were recommended to receive postexposure vaccination with Jynneos® was 14 times higher among unvaccinated people compared with those who had received their first vaccine dose ≥14 days earlier. However, there are numerous limitations to these data.[335] A retrospective cohort study found vaccine efficacy to be 86% after a single subcutaneous dose. However, the study had noteworthy limitations (e.g., small number of participants, unmeasured differences in lifestyle behaviors between the groups, no screening for mpox was carried out, and cases were limited to those who reported symptoms to physicians).[336]​ Another observational study based on cases in England reported a vaccine efficacy of 78% at least 14 days after a single subcutaneous dose.[337]​ Breakthrough infections have been reported.[338][339][340]​​​

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