Primary prevention

Vaccination with the smallpox vaccine can prevent infection.

  • 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.

  • Routine vaccination against smallpox ceased in the 1970s. However, smallpox vaccines are stockpiled in case of an emergency.

  • Vaccine availability varies between countries. Consult your local public health authority for guidance on how to obtain vaccines and their use.

First- and second-generation vaccines used during the smallpox eradication programme provided protection against monkeypox.

  • Data acquired from the final stages of the programme implied that standard vaccinia administration yielded 85% protection upon subsequent exposure to monkeypox.[74] 

  • Non-human primate studies suggest that modified vaccinia Ankara (a third-generation vaccine) also offers protection against monkeypox; however, clinical trial data are limited.[106]

  • No data are available yet on the efficacy of smallpox vaccines in the current ongoing multi-country outbreak. However, there have been case reports of breakthrough infections in people previously vaccinated with a smallpox vaccine.[107] There is limited evidence for a milder disease course in patients with a history of childhood smallpox vaccination, but hospitalisation rates were not lower in vaccinated people.[108]

Attenuated live virus (replication-deficient) vaccines

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

    • These vaccines represent more attenuated vaccine strains specifically developed by further passage in cell culture or animals.[109][110]  

    • 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 some countries with limited vaccine supply, thereby increasing the number of vaccine doses available per vial.[111] The lower intradermal dose was found to be immunologically non-inferior to the standard subcutaneous dose in one study. However, there is an increased risk of local reactions after intradermal injection.[112] Subcutaneous administration is preferred in people with a history of developing keloid scars.[113] Consult your local public health authority for more information.

    • CDC: how to administer a Jynneos® vaccine intradermally Opens in new window

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

    • Imvanex® is approved in Europe for active immunisation against monkeypox, smallpox, and disease caused by vaccinia virus in adults.[114]

    • Imvanex® is currently approved in the UK only for the prevention of smallpox. 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 market.[115] The UK Health Security Agency (UKHSA) and the European Medicines Agency support intradermal dosing of MVA-BN in healthy adults (including pregnant women, but not immunocompromised people) in the current ongoing outbreak during periods of limited vaccine supply.[116][117][118]

    • Jynneos® is approved in the US for the prevention of monkeypox and smallpox in adults ≥18 years of age. The US Food and Drug Administration has issued an emergency use authorisation to also allow the use of Jynneos® in people <18 years of age who are at high risk of infection. The emergency use authorisation also allows for the two doses of Jynneos® to be administered intradermally in adults ≥18 years of age who are at high risk for monkeypox infection.[119]

    • 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 (see below). However, safety and efficacy data are limited, and the duration of immunity is unknown.

    • Approval is based on data from several animal studies that showed protection against monkeypox virus in non-human primates. Safety and efficacy in humans was inferred from these animal studies.

    • 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.[120]

    • A two-dose MVA-BN series was shown to yield relatively low levels of monkeypox virus neutralising antibodies in non-primed individuals in one study. However, the role of these neutralising antibodies as a correlate of protection against transmission and disease is currently unclear.[121]

    • 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 counselled about the theoretical risk for myopericarditis following vaccination with a third-generation vaccine.[122]

    • Safety and efficacy in people with HIV infection has been evaluated. The vaccine can be offered to people with HIV, if indicated, after a discussion of the risks and benefits and using shared decision-making. However, immunogenicity among people with CD4 counts <100 cells/microlitre or who are not virologically suppressed remains unknown.[97][98][123]

    • 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.[92]

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 programme 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 monkeypox in the current outbreak 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.[97][124]

    • 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.[125]

  • Inoculation with traditional vaccinia may cause eczema vaccinatum, generalised vaccinia, or potentially fatal progressive vaccinia (see Complications).[126]

    • 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 ischaemia, encephalitis and other severe neurological 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).[127] However, the true risk may be higher. Fatal cases have been described.[128] For more information see Complications.

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

Mass vaccination is not required or recommended for 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:[129] 

    • 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 monkeypox

    • 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 prioritised in those who are at high risk of exposure.[129]

  • 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 monkeypox) 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.[116]

    • 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 behaviour 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).[130]

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

    • UKHSA: 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:[122]

    • 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.

    • CDC: monkeypox and smallpox vaccine guidance Opens in new window

  • In addition to this, the Centers for Disease Control and Prevention recommends that pre-exposure prophylaxis may be considered for people at increased risk of monkeypox from non-occupational exposure during the current outbreak in some jurisdictions.[113] Consult your local guidelines.

  • 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.[129]

    • Non-replicating, minimally-replicating, or replication-competent vaccines are appropriate for use in healthy adults. Non-replicating 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.[122] 

    • 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.[122]

Consider a 4-week interval between administration of smallpox vaccines and COVID-19 vaccines.

  • Myocarditis has been documented after administration of ACAM2000® and COVID-19 mRNA and protein subunit vaccines. The risk of myocarditis after third-generation smallpox vaccines (e.g., Jynneos®) is currently unknown.

  • The US Centers for Disease Control and Prevention recommends considering waiting 4 weeks after Orthopoxvirus vaccination before administering a COVID-19 mRNA or protein subunit vaccine, particularly in adolescent or young adult males. However, if Orthopoxvirus vaccination is recommended for prophylaxis in the setting of an outbreak, administration should not be delayed because of recent COVID-19 vaccination.[131]

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

Secondary prevention

Post-exposure 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 post-exposure 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).[129] 

    • Children, pregnant women, and immunocompromised people should be prioritised 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 post-exposure vaccination with a single dose of MVA-BN if appropriate as soon as possible and within 4 days after an identified exposure.[116]

    • Post-exposure vaccination may be extended up to 14 days for those at high risk of ongoing exposure (e.g., men who have sex with men in the current ongoing multi-country outbreak, 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).

    • Post-exposure 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).[118]

    • People with HIV infection who are immunosuppressed (i.e., CD4 count <200 cells/microlitre, persistent viraemia, or immunosuppression related to another condition or treatment) should receive two full subcutaneous doses. People with CD4 counts >200 cells/microlitre 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.[123]

    • Although Imvanex® is not licensed in the UK for monkeypox (it is currently only licensed for smallpox), it has been used in previous incidents in the UK. 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 market.[115]

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

  • In the US, the Centers for Disease Control and Prevention (CDC) recommends post-exposure vaccination with two doses of Jynneos® or a single dose of ACAM2000®.[113][190]

    • Post-exposure vaccination is recommended for contacts with higher-risk exposures, and may be considered for contacts with intermediate-risk exposures (see Screening).

    • In addition to this, people with certain risk factors and recent experiences that may make them more likely to have been recently exposed to monkeypox may be considered for expanded post-exposure vaccination. This includes certain men who have sex with men or transgender people who (in the past 14 days): 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 geographical area where transmission is occuring. It may also be considered in people who are aware that a recent sex partner within the last 14 days was diagnosed with monkeypox.[113] Consult your local guidelines.

    • HIV infection: post-exposure vaccination with Jynneos® can be offered to people with HIV infection, if indicated, after a discussion of the risks and benefits and using shared decision-making. ACAM2000® should not be used in people with HIV infection. The antiviral medication tecovirimat and vaccinia immunoglobulin may be considered for post-exposure 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.[97][98]

    • Children and adolescents: post-exposure vaccination with Jynneos® or ACAM2000® may be offered to children and adolescents who are otherwise eligible. Jynneos® is the preferred option, and is authorised under an emergency use authorisation for post-exposure 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 post-exposure vaccination in children and adolescents are limited. Vaccinia immunoglobulin may be considered for post-exposure 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.[90]

    • Pregnant and breastfeeding women: post-exposure 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.[92]

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

    • The recommended dose schedule for post-exposure vaccination with a non-replicating vaccine is generally two doses (given 28 days apart).

    • However, some countries may recommend only one dose for post-exposure 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.[268]

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

Post-exposure vaccination with smallpox vaccination of close contacts has successfully limited transmission of monkeypox in past outbreaks, and can abort infection or significantly attenuate it.[269]

  • 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 monkeypox.[74] However, there is very limited evidence on whether third-generation vaccines prevent or modify disease when given to contacts after exposure. A preprint (not peer reviewed study) has reported breakthrough infections after post-exposure vaccination in the current ongoing outbreak.[270]

  • Vaccination up to 14 days post-exposure is thought to be beneficial.[271] 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 current ongoing outbreak indicates that the incidence of monkeypox among males aged 18 to 49 years who were recommended to receive post-exposure 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.[272] Breakthrough infections have been reported.[273]

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