Primary prevention
Vaccination is recommended to prevent infection with mpox. Smallpox vaccines are used for this purpose, although these vaccines are now also approved for the prevention of 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, 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/non-replicating) vaccines
Attenuated live virus (replication-deficient/non-replicating) 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). A third dose has been recommended in immunocompromised people in some countries, but there are no data to support additional doses.[166]
Intradermal administration (fractional dosing at one fifth the usual dose) may be recommended in outbreak situations where there are supply constraints, depending on advice from local public health authorities.[167][168] The lower intradermal dose was found to be immunologically non-inferior to the standard subcutaneous dose. However, there is an increased risk of local reactions after intradermal injection.[169][170] An observational study found that intradermal administration was associated with a high incidence of mild to moderate local injection-site reactions. Systemic adverse reactions were reported in 39% of patients after the first dose (26% after the second dose), but serious adverse events were rare.[171]
Consult your local public health authority for more information.
Third-generation vaccines are licensed for the prevention of mpox, although supply may be limited in some countries. MVA-BN is available under different brand names (e.g., Imvanex®, Imvamune®, Jynneos®).
Imvanex® is approved in the UK and Europe for active immunisation against mpox in children aged ≥12 years. Jynneos® may be available in the UK during periods of limited vaccine supply.[172]
Jynneos® is approved in the US for the prevention of mpox in adults aged ≥18 years. The US Food and Drug Administration (FDA) has also issued an emergency use authorisation to also allow the use of Jynneos® in people aged <18 years who are at high risk of infection.
LC16 (a minimally-replicating vaccine) may be available in some countries (e.g., Japan, Democratic Republic of the Congo).[173][174] It has been granted emergency use listing by the WHO, and is recommended as a single-dose vaccine for people aged ≥1 year. It is not recommended in pregnant women or people who are immunocompromised.[175]
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.[176]
The risk of myocarditis after third-generation 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.[177]
Data from the US Vaccine Adverse Event Reporting System (VAERS) based on vaccination during the 2022 global clade II mpox 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.[178] However, cardiovascular events following two doses were significantly more common compared with placebo.[179]
Symptoms of vaccinia have been reported after vaccination with Jynneos®.[180]
Third-generation vaccines are preferred in certain patient populations.
Non-replicating vaccines are generally preferred in immunocompromised people (including those with HIV), pregnant and breastfeeding women, and children and adolescents (use in children may be off-label).[168]
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. Timing of vaccination should take into account planned or current immunosuppressive therapies.[47][48] However, immunogenicity among people with CD4 counts <100 cells/microlitre or who are not virologically suppressed remains unknown.[181] Vaccine efficacy was reduced in people living with HIV in one study.[182]
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.[145]
Safety data in children are limited. However, one study found that a single dose of MVA-BN was well-tolerated.[183]
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 mpox in people who are at high risk for infection.
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 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, moderately or severely ill on the day of vaccination, and underlying heart disease or cardiac risk factors.[184] Check your local drug information source for a full list of contraindications.
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 vaccination appears to be low. Outcomes of 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 vaccination, it is associated with a high rate of fetal loss.[185]
Inoculation with traditional vaccinia may cause eczema vaccinatum, generalised vaccinia, or potentially fatal progressive vaccinia (see Complications).[186]
There are many other potential adverse 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 8-14 days (up to 6 weeks).[187] However, the true risk may be higher. Fatal cases have been described.[188] For more information see Complications.
Vaccine adverse events may be managed with vaccinia immunoglobulin and antiviral agents.
Mass vaccination is not recommended for mpox outbreaks or for 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 (WHO) recommends pre-exposure vaccination for laboratory personnel working with orthopoxviruses, with periodic revaccination considered every 2-5 years for people who are at high risk of exposure to more virulent orthopoxviruses. In the context of an mpox outbreak, the WHO recommends pre-exposure vaccination for people at high risk of exposure, including:[168]
Members of a geographically defined area or community, including children, with a documented high risk of exposure to people with mpox, based on local epidemiology.
Sex workers, gay, bisexual, or other men who have sex with men with multiple sexual partners, or other individuals with multiple casual sexual partners.
Healthcare workers at risk of repeat exposure.
Clinical laboratory and healthcare personnel performing diagnostic testing for mpox or providing care.
Outbreak response team members as designated by national public health authorities.
The WHO recommends certain vaccines in special populations.
Immunocompetent non-pregnant adults: any appropriate second- or third-generation vaccine (e.g., MVA-BN, LC16, ACAM2000®) is recommended.
Children and adolescents: non-replicating or minimally replicating vaccines are recommended. MVA-BN is not currently licensed for people <18 years; however, it may be used in the context of an outbreak when the benefits of vaccination outweigh the potential risks. LC16 is only approved in Japan for use in children.
Pregnant women: non-replicating vaccines are recommended.
Immunocompromised: non-replicating vaccines are recommended in immunocompromised people for whom replicating or minimally replicating vaccines are contraindicated.
International guidelines on pre-exposure vaccination vary; consult your local guidance for more information.
Limited evidence suggests that vaccines provide protection against mpox.
Data acquired from the final stages of the smallpox eradication programme implied that first- and second-generation vaccines yielded 85% protection upon subsequent exposure to mpox.[110]
One systematic review found that prior immunisation 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.[189]
Antibodies elicited by first-generation vaccines have recently been found to neutralise the clade II monkeypox virus, the virus responsible for the 2022 global clade II mpox outbreak, more than 40 years after administration of the vaccine.[190]
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.[191]
Approval of third-generation vaccines was based on data from animal studies that showed protection against mpox in non-human primates.[192] 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 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.[193]
Limited data are available on the efficacy of third-generation vaccines used since the 2022 global clade II mpox outbreak.
No randomised clinical trials of vaccination against mpox have been conducted.
One systematic review of real-world evidence in outbreak settings found that vaccine efficacy estimates ranged from 35% to 86% for one dose, and 66% to 90% for two doses, for pre-exposure vaccination.[194]
Jynneos® (a third-generation vaccine) resulted in a better humoral response compared with ACAM2000® (a second-generation vaccine) in one study.[195]
There is emerging evidence that natural infection induces a more robust antibody response than vaccination.[196][197]
There is emerging observational evidence of waning immunity by 12 months.[198] In one study, the MVA-BN vaccine did not induce durable antibody immunity in people without prior smallpox vaccination.[199]
Other vaccines are also in development. A fourth-generation vaccine (VACΔ6) is available in the Russian Federation.
Secondary prevention
Post-exposure vaccination may be recommended in specific groups of people to prevent or attenuate infection. For more information on available mpox vaccines, see Primary prevention.
The World Health Organization (WHO) 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).[168]
International guidelines on post-exposure vaccination vary; consult your local guidance for more information.
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 vaccination history). However, data on these regimens are limited.[391]
Intradermal dosing has been used for post-exposure vaccination in healthy adults in certain circumstances (e.g., limited supply during an outbreak).
Post-exposure vaccination of close contacts has successfully limited transmission of mpox in past outbreaks, and can abort infection or significantly attenuate it.[392]
Vaccination with standard first- or second-generation vaccinia virus vaccines was demonstrated through several observational studies to be about 85% effective in preventing mpox.[110] 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 post-exposure is thought to be beneficial.[393] There is a theoretical possibility of attenuating disease if vaccination occurs towards the end of the range of the incubation period.
Real-world data from the 2022 global clade II mpox outbreak indicates that the incidence of mpox among males aged 18-49 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.[394]
Observational studies report vaccine efficacy to be between 36% and 89% after one dose, and between 66% to 86% after two doses. However, these studies have various limitations.[395][396][397][398][399]
Neutralising antibody responses at 6 months have been found to be much lower in vaccinated people compared with those with previous natural infection.[400]
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