Smallpox and mpox (monkeypox) vaccine: Canadian Immunization Guide
Key information

# What
- Smallpox is a systemic viral illness with a characteristic rash that can have a 15% to 45% or higher mortality rate in an unimmunized population.
- Naturally occurring smallpox disease was eradicated by 1977 through a worldwide vaccination program.
- Remaining variola virus (causative agent of smallpox) stocks are kept in two World Health Organization (WHO) reference laboratories.
- The monkeypox virus is an orthopoxvirus that is genetically related to the variola virus.
- Since May 2022, cases of mpox (monkeypox) have been reported and transmission has occurred in a number of countries where it was not previously reported, including Canada.
- Smallpox vaccine provides cross-protection against all orthopoxviruses and can be used to protect individuals at risk against these viruses.

# Who
- Routine immunization of the general Canadian population with smallpox (vaccinia virus) vaccine is not recommended.
- Vaccination is recommended for individuals at risk of exposure to vaccinia or other replicative orthopoxviruses (including laboratory workers in research settings).
- In the event of a suspect case of smallpox, vaccination of public health and health care personnel involved in the case investigation and clinical management is indicated.
- Once a case of smallpox is confirmed, vaccination of contacts of cases and those living in the immediate vicinity (ring vaccination) is indicated. Vaccination of public health staff and health care workers, as well as first responders, such as police officers, firefighters, ambulance attendants, the military and others may also be indicated.
- Because of the relatively long incubation period for smallpox, historical data collected during the smallpox eradication program using the first generation vaccine showed that vaccination within 2 to 3 days of exposure may protect against clinical disease, and if given within 4 to 5 days, may decrease the risk of death.
- In the event of an outbreak involving other orthopoxviruses (e.g., monkeypox virus), vaccination of individuals at risk of infection is recommended. Vaccination can be offered as post-exposure prophylaxis as soon as possible, ideally within 4 days (but up to 14 days) after the last exposure, and can also be offered as pre-exposure vaccination for groups at highest risk of mpox.

# How
- Should a smallpox case be suspected, immediate telephone communication with local or provincial/territorial public health officials is required; the Public Health Agency of Canada (PHAC) should then be notified.
- Smallpox vaccine can be obtained by contacting PHAC's Centre for Emergency Preparedness and Response.
- For outbreak management guidance involving immunization against orthropoxviruses, the most recent National Advisory Committee on Immunization (NACI) statement should be consulted.

# Why
- To protect individuals at risk from monkeypox virus infection and other orthopoxvirus infections.
- To prevent the re-emergence and spread of smallpox, a severe and frequently fatal disease that has been eradicated by vaccination.
- A case of smallpox anywhere in the world constitutes a global health emergency.
- Under the International Health Regulations, it is the responsibility of PHAC to notify the WHO if a case of smallpox is suspected.
The Canadian Smallpox Contingency Plan provides recommendations for actions to be taken if smallpox occurs in Canada or elsewhere in the world. For additional information, refer to NACI's  (PDF format).
Epidemiology

# Disease description

## Infectious agent
Smallpox is a systemic viral disease caused by the variola virus, a species of the *Poxviridae- family, belonging to the genus of *Orthopoxvirus*. For additional information about the variola virus, refer to the .
Mpox is a systemic viral disease caused by the monkeypox virus, a species of the *Poxviridae- family, belonging to the genus of *Orthopoxvirus*. For additional information about the monkeypox virus, refer to the .

## Reservoir
The reservoir for variola virus is exclusively humans. There are no animal reservoirs of variola virus and the last human case occurred in 1978. Currently, the virus is maintained in two designated laboratories.
The reservoir for monkeypox virus is not fully understood, but is believed to be rodents. Hosts include humans, squirrels, non-human primates, black-tailed prairie dogs, African brush-tailed porcupines, rats, and shrews. The virus is endemic in West and Central Africa.

## Transmission
Smallpox is spread by droplets from the respiratory tract or by direct or indirect contact with the virus shed from skin lesions. Airborne spread is thought to be less frequent, but transmission over significant distances has been documented, including transmission through a hospital stairwell. In addition, the virus is stable in dried form for months and has been transmitted by fomites such as bed linen.
The incubation period for smallpox is from 7 to 19 days, typically 10 to 14 days to the onset of illness and 2 to 4 more days to the onset of the rash. Infectivity can occur at any time from the development of the rash to the disappearance of all scabs - approximately 3 weeks. Infectivity is highest early in the clinical disease.
Monkeypox virus is spread from infected animals through a bite or scratch via direct contact with the infected animal's blood, body fluids, or lesions, or by preparing or eating meat or using products from an infected animal. It can also be spread from human-to-human, by direct contact with an infected person or their body fluids, including during sexual activity, by direct contact with virus-contaminated objects, and less frequently via respiratory droplets.
Mpox has a typical incubation period of 6-13 days from exposure, but can range from 5-21 days.

## Risk factors
Canadians born in 1972 or later have not been routinely immunized against smallpox and are therefore considered susceptible to orthopoxvirus infections. Discontinuation of vaccination for travel was recommended by the WHO in 1980 and was no longer required by any country by 1982. Individuals who have been vaccinated in the past against smallpox may have partial immunity to other orthopoxviruses.

## Spectrum of clinical illness
Early symptoms of smallpox include the sudden onset of high fever, malaise, headache, fatigue, severe backache, and occasional abdominal pain and vomiting. After 2 to 4 days the fever subsides and there is a characteristic rash consisting of deep-seated lesions first appearing on the face and extremities, including the palms and soles, and subsequently on the trunk. The rash progresses through all the phases of macules, papules, vesicles, pustules and then crusted scabs that fall off 3 to 4 weeks after the appearance of the rash. There are two strains of the smallpox virus, each with a different clinical course. *Variola minor- has a case fatality rate of less than 1%; *Variola major- has a case fatality rate among unvaccinated populations ranging from 15% to 45% or higher. Rates may vary depending up the virulence of the specific variola virus strain that circulates, and the vulnerability of the population it attacks. The case fatality rate is higher in pregnant women and in young children.
Mpox disease is usually self-limiting and resolves within 14 to 28 days. For information on the clinical manifestations of monkeypox virus infection, refer to the . The duration of communicability for monkeypox virus may be up to 2 to 4 weeks, based on limited evidence of polymerase chain reaction (PCR) detection of monkeypox virus in the upper respiratory tract, and people are considered infectious until all the lesions have scabbed, fallen off and been replaced with healed skin.

# Disease distribution

## Incidence/prevalence

### Global
The last known case of naturally occurring smallpox occurred in Somalia in 1977; two cases of smallpox occurred in England in 1978 as a result of a laboratory accident. In December 1979, the WHO officially declared that smallpox had been eradicated globally and in 1980 the World Health Assembly recommended all countries cease routine smallpox immunization programs. Remaining variola virus stocks are kept in two WHO reference laboratories in the United States (US) and Russia for research purposes.
With the breakup of the Soviet Union and the subsequent loss of safety and security controls over their biological weapon stockpiles, there has been a concern that there could be an accidental release of variola virus. In the US, a smallpox vaccination program was initiated in the military in December 2002. Subsequent smallpox vaccination programs were conducted in some health care workers in the US and the United Kingdom.
Due to its current eradication yet potential use as a biological weapon, the occurrence of a single case of smallpox anywhere in the world constitutes a global health emergency.
Mpox is endemic in Central and West Africa, but there have been cases and outbreaks in non-endemic countries due to international travel or the importation of infected animals from affected areas. There are two distinct clades of monkeypox virus: the Congo Basin (Central African) clade (now referred to as Clade I) and the West African clade (now referred to as Clade II). The Congo Basin clade has caused more severe illness. The 2022 multi-country monkeypox outbreak represented the first incidence of broader community transmission in a number of countries outside of certain regions of Africa. The international outbreak has primarily affected men who identify as gay, bisexual men or other men who have sex with men (gbMSM).

### National
Concerted vaccination campaigns were successful in eliminating endemic smallpox from Canada by 1946. Nova Scotia had a suspected case in 1949; with rigid quarantine, the disease did not spread. The final laboratory-confirmed case in Canada in 1962 involved an adolescent who returned to Toronto from Brazil.
Canada has been one of the countries affected by the 2022 multi-country mpox outbreak.
Preparations authorized for use in Canada
PHAC has a stock of three types of smallpox (vaccinia virus) vaccine (Sma):
- lyophilized (freeze-dried) vaccine - Smallpox Vaccine (dried) (Sanofi Pasteur Ltd.)
- frozen liquid formulation vaccine - Smallpox Vaccine (frozen-liquid) (Sanofi Pasteur Ltd).
- Imvamune - Smallpox and Mpox (monkeypox) Vaccine (live-attenuated, non-replicating) (Bavarian Nordic A/S ), (Progress Therapeutics Inc. )
The lyophilized smallpox vaccine is an authorized product to vaccinate laboratory workers working with orthopoxviruses. The frozen liquid smallpox vaccine could be released in emergency situations (e.g., in response to a smallpox case) through Health Canada's Special Access Program. Both vaccines are prepared from live, vaccinia virus. Vaccinia virus is a member of the *Orthopoxvirus- family and confers immunity against variola (smallpox) and other orthopoxviruses through cross-reactivity.
Imvamune , is a non-replicating, third generation smallpox vaccine manufactured by Bavarian Nordic. Imvamune was initially authorized for use in Canada on November 21, 2013 as an Extraordinary Use New Drug Submission (EUNDS) for use by the Government of Canada in an emergency situation for active immunization against smallpox infection and disease in persons 18 years of age and older who have a contraindication to the first or second generation smallpox vaccines. It was subsequently approved under a supplement to the EUNDS on November 5, 2020 for active immunization against smallpox, monkeypox virus and related orthopoxvirus infections and disease in adults 18 years of age and older determined to be at high risk for exposure.
PHAC provides smallpox vaccine to laboratory staff working with vaccinia virus or other orthopoxviruses and would also provide vaccine to provinces/territories in the event of a smallpox case or orthopoxvirus outbreaks. In the context of the ongoing mpox outbreaks, Imvamune is currently being provided to provinces and territories for post-exposure and pre-exposure vaccination to individuals/groups considered at high risk of mpox. Imvamune is not available for general use.
For emergency (suspected or confirmed smallpox cases) or non-emergency situations, contact the Centre of Emergency Preparedness and Response, Health Portfolio Operations Centre, PHAC by telephone: 1-800-545-7661 or 613-952-7940 or e-mail: .

# Vaccinia immune globulin
Vaccinia Immune Globulin Intravenous (Human) (VIG) is a solution of gamma globulin from the serum of individuals recently immunized with smallpox vaccine. It is used to treat severe smallpox vaccine-associated adverse events. The Canadian Smallpox Contingency Plan indicates that VIG would be sent to the provinces/territories at the same time as smallpox vaccine and related supplies if smallpox occurs in Canada.
Immunogenicity, efficacy and effectiveness
In the early 1970s before smallpox was eradicated, a retrospective study conducted in West Pakistan showed a mortality rate of 52% among those who had never been vaccinated, 1.7% among those who had been vaccinated within 10 years, and 11% among those who had been vaccinated 20 or more years earlier.
The specific mechanisms that result in immunity to smallpox following vaccination have not been well characterized. Studies conducted in the 1970s suggest that both antibody and cell-mediated immunity are stimulated by smallpox vaccination. A more recent study showed that more than 95% of primary vaccinees had detectable neutralizing antibody within 1 to 2 weeks after immunization and strong increases in vaccinia-specific CD8+ cytotoxic T lymphocytes and interferon-gamma-producing T cells.
There is very little data indicating the efficacy or effectiveness of Imvamune vaccination against monkeypox virus infection or mpox disease in the context of pre-exposure or post-exposure vaccination, although efforts are underway to determine the effectiveness of the vaccine during the current mpox outbreak. The majority of clinical data for Imvamune pre-exposure vaccination are limited to clinical immunogenicity or indirect protection from vaccinia (the virus used for first or second generation smallpox vaccines). Indirect clinical immunological evidence showed that Imvamune was able to generate immune responses by week two after a first dose, and comparable immune responses to previous generation smallpox vaccines after two doses by week six.
Recommendations for use
Given that naturally occurring smallpox has been eradicated worldwide and smallpox vaccination is associated with the risk of significant morbidity and even mortality, the overall risk benefit analysis supports the recommendation to not routinely immunize the general Canadian population against smallpox. As a result, smallpox vaccination is highly restricted.

# Outbreak control

## Smallpox
The Canadian Smallpox Contingency Plan includes actions to be taken if a case of smallpox occurs in Canada or elsewhere. A single case of smallpox is considered an outbreak. In general terms, cases should be isolated immediately, preferably at home. If hospitalization is required, cases should be admitted to rooms under negative pressure equipped with high efficiency particulate air-filtration (HEPA) filters (airborne infection isolation rooms). Contacts and those living in the immediate vicinity of the identified case should be immunized immediately (ring vaccination) and placed under observation in quarantine. Vaccination is indicated for face-to-face contacts (less than 6 feet or 2 meters), household contacts, personnel involved in the medical care, public health evaluation or transportation of confirmed or suspected smallpox cases, laboratory personnel involved in the collection or processing of clinical specimens from confirmed or suspected smallpox cases, and persons who have a high likelihood of exposure to infectious materials (e.g., those responsible for medical waste disposal, linen disposal or disinfection) of smallpox cases.
Vaccine can be given after exposure with beneficial effect as smallpox has a relatively long incubation period. Historical data collected during the smallpox eradication program using first generation vaccine showed that vaccination within 2 to 3 days of exposure may protect against clinical disease, and if given within 4 to 5 days, may decrease the risk of death.

## Mpox (monkeypox)
In the context of an active mpox outbreak, vaccination using Imvamune should be offered to individuals/groups considered at high-risk of mpox.
Post-exposure vaccination using a single dose of Imvamune may be offered to individuals with high risk exposures to a probable or confirmed case of mpox, or within a setting where transmission is happening. Post-exposure vaccination should be offered as soon as possible, ideally within 4 days (but up to 14 days) of last exposure. A second dose may be offered after 28 days from the first dose if an assessment indicates an ongoing risk of exposure or if the individual is in a high-risk group for whom pre-exposure vaccination is recommended.
During the 2022 outbreak, the following individuals/groups have been considered for pre-exposure vaccination with Imvamune:
- Men who have sex with men (MSM), and individuals who have sex with MSM, and who meet at least one of the following criteria:
	+ Having two or more sexual partners or being in a relationship where at least one of the partners has other sexual partners
	+ Having had a confirmed sexually transmitted infection acquired in the last year
	+ Engaging in sexual contact in sex-on-premises venues
- Individuals who self-identify as sex workers regardless of self- identified sex/gender
- Staff or volunteers in sex-on-premises venues where workers may have contact with fomites potentially contaminated with monkeypox virus without the use of personal protective equipment
Individuals receiving pre-exposure vaccination should be offered Imvamune as a two-dose primary series, with at least 28 days between first and second 0.5 mL sub-cutaneous doses. Individuals considered moderately to severely immunocompromised and eligible for pre-exposure vaccination should be prioritized to receive two doses of Imvamune administered at the authorized interval (28 days between doses).
Neither post-exposure nor pre-exposure vaccination should be offered to individuals with a prior documented history of monkeypox virus infection or those who are symptomatic and meet the definition of suspect, probable or confirmed mpox case.
Immunocompetent individuals recommended for Imvamune pre-exposure or post-exposure vaccination should receive a single dose if they have previously been vaccinated with a live replicating first or second generation smallpox vaccine (i.e., as a booster dose). However, individuals considered moderately to severely immunocompromised should receive two doses, regardless of previous smallpox vaccination.
In situations where there is ongoing mpox outbreak activity and limited vaccine supply, dose sparing strategies should be considered for pre-exposure vaccination of immunocompetent individuals in order to expand coverage to a broader population. These strategies may include extending the interval between doses and intradermal fractional dose administration. Intradermal administration (ID) can be used among immunocompetent adults when given as a second dose following a first dose given subcutaneously, provided dose sparing and safe administration practices are feasible. In situations where individuals received a first dose of Imvamune using an ID route, then the dose should be considered valid. Individuals who are <18 years of age, at risk of keloid scars, or moderately to severely immunocompromised should be offered Imvamune using the subcutaneous route of administration with a full dose only. For additional details, refer to .

# Vaccinia immune globulin
PHAC's Centre for Emergency Preparedness and Response has a supply of VIG based on a requirement of 1 dose of VIG for every 10,000 doses of first and second generation smallpox vaccines. VIG is indicated to treat severe smallpox vaccine-associated adverse events: eczema vaccinatum, progressive vaccinia, severe or recurrent generalized vaccinia, and extensive lesions resulting from accidental implantation (transfer of vaccinia virus from the primary vaccination site to other parts of the body). VIG is ineffective in the treatment of post-vaccinial encephalitis and has no role in the treatment or prevention of smallpox.

# Booster doses and re-immunization
For both first and second generation smallpox vaccines, booster doses should be given every 10 years for laboratory workers with ongoing risk of exposure.
Imvamune may be offered to personnel working with replicating orthopoxviruses that pose a risk to human health (vaccinia or monkeypox virus) in laboratory settings and who are at high risk of occupational exposure. If Imvamune is used, two doses should be given at least 28 days apart. A booster dose may be offered after 2 years if the risk of exposure extends beyond that time.
For immunocompetent individuals who have received a live replicating first or second generation smallpox vaccine in the past and who are at high risk for occupational exposure, a single dose of Imvamune may be offered (i.e., as a booster dose), rather than the two-dose primary vaccine series. This single Imvamune dose should be given at least two years after the latest live replicating smallpox vaccine dose.
Vaccination of Specific Populations

# Workers
Smallpox vaccine, including Imvamune, may be indicated for certain workers at high risk of exposure, such as laboratory workers who handle vaccinia or other replicating orthopoxviruses (including monkeypox virus and recombinant vaccinia vaccine products) in specialized reference or research facilities.
In the event of a suspect case of smallpox, vaccination of public health and health care personnel involved in the case investigation and clinical management is indicated. Once a case is confirmed, vaccination of public health staff and health care workers, as well as first responders such as police officers, firefighters, ambulance attendants, the military and others may also be indicated.
Serologic testing
Serologic testing is not recommended before or after receiving smallpox vaccine.
Administration Practices

# Dose, route of administration and schedule
Both first and second generation smallpox vaccines are administered by scarification into the epidermis, usually in the deltoid area of the non-dominant arm, by using the multiple-puncture technique with a bifurcated needle, packaged with the vaccine and diluent. According to the product labelling, 15 punctures are recommended for vaccination. A trace of blood should appear at the vaccination site after 15 to 20 seconds; if no trace of blood is visible, additional insertions should be made by using the same bifurcated needle without reinserting the needle into the vaccine vial. If alcohol is used to cleanse the skin before immunization, the skin must be allowed to dry thoroughly before the vaccine is administered, to prevent inactivation of the vaccine by alcohol.
Other methods of administration, such as multiple pressure method are possible in case bifurcated needles are not readily available. Refer to the product label for detailed instructions.
When vaccinia virus is inoculated into the epidermis the virus induces an immune reaction that is termed "a take". There is often no visible reaction for the first few days. On day 3 to 4 a papule appears and progresses to a vesicle with surrounding erythema. Typically, one week or so after vaccination, the centre of the vesicle umbilicates and pustulates. After about 2 weeks, the pustule crusts and a dark brown or black scab forms. After 3 weeks, the scab detaches leaving a scar. The vaccination site should be inspected 6 to 8 days after vaccination to ensure that a take has occurred. If there is no evidence of papules or vesicles and erythema, the person should be vaccinated again.
Optimal infection-control practices and appropriate vaccination site care should be used. Gloves should be worn by the vaccine provider when administering smallpox vaccine due to the increased risk of autoinoculation from the use of a bifurcated needle. Each vaccinee and anyone caring for the vaccination site should wash their hands thoroughly after touching the site or handling bandages used to cover the site. Contaminated bandages and scabs should be placed in sealed plastic bags before disposal in the garbage. The vaccinee should avoid rubbing or scratching the site.
A sterile piece of porous bandage (e.g., gauze) should be used to loosely cover the vaccination site until the scab falls off in order to deter the vaccinee from touching the scab, to prevent inadvertent self-inoculation or inoculation of others, and to contain the scab so it is not lost. Preferably, a semi-permeable dressing should be placed over the gauze and not directly on the site; occlusive dressings should not be used. Dressings used to cover the site should be changed frequently to prevent accumulation of exudates and consequent maceration. Frequent dressing changes are particularly important for vaccinees who have close contact with children or people at high risk for vaccinia complications.
Health care workers providing direct patient care should keep their vaccination sites covered with gauze in combination with a semipermeable membrane dressing to absorb exudates and to provide a barrier for containment of vaccinia virus to minimize the risk of transmission; the dressing should also be covered by a layer of clothing. Similar precautions should be used for vaccinated persons in close contact with children or other persons at high risk of serious complications of vaccinia.
Imvamune is administered as 0.5 mL subcutaneously (SC) using a two-dose schedule with a minimum interval of 28 days between doses. In cases of limited vaccine supply, Imvamune can also be administered using a fractional second dose (1/5th of SC dose) administered intradermally.
For information on the management of Imvamune administration errors, refer to the .

# Vaccinia immune globulin
VIG should be given intravenously through a dedicated infusion line at a rate of 2 mL/min; VIG is compatible with sodium chloride 0.9%. Parenteral products should be inspected visually for particulate matter and discoloration prior to administration; it should not be used if the solution is turbid. The vial should not be shaken as it may cause foaming.
VIG should be administered at a dose of 6,000 units/kg as soon as symptoms appear and are judged to be due to a severe vaccinia-related complication. Two exceptions to this are vaccinia keratitis and encephalitis. VIG should not be given for vaccinia keratitis due to the potential of increased corneal scarring, and should not be given for encephalitis due to lack of efficacy. For other VIG-treated complications, consideration may be given to repeat dosing, depending on the severity of the symptoms and response to treatment; however, clinical data on repeat doses are lacking. The administration of an additional dose of 9,000 units/kg may be considered in the event that the person does not respond to the initial 6,000 units/kg dose.

# Concurrent administration with other vaccines
In non-emergency situations (i.e., non-outbreaks), both first and second generation smallpox vaccines can be administered concurrently with any inactivated vaccine. To avoid confusion in ascertaining which vaccine might have caused post-vaccination skin lesions or other adverse events, varicella (chickenpox) vaccine should not be administered concurrently with smallpox vaccine; there must be an interval of at least 4 weeks between administration of varicella vaccine and smallpox vaccine. Smallpox vaccine can be administered simultaneously concurrently with other live parenteral vaccines; if not administered concurrently, there must be an interval of at least 4 weeks between smallpox vaccine and other live parenteral vaccines.
Currently, no data exist on the concurrent administration of Imvamune with other vaccines. If concurrent administration with another vaccine is indicated, immunization should be done in different limbs.
To minimize the potential risk of interactions or erroneous attribution of an adverse event following immunization (AEFI) to a particular vaccine, it is recommended to administer non-live vaccines more than 2 weeks and live vaccines at least 4 weeks before or after administration of Imvamune.
First and second generation orthopoxvirus vaccines and mRNA COVID-19 vaccines both have a potential risk of cardiac adverse events (myocarditis). Risk for myo- or pericarditis with the newer generation non-replicating attenuated virus vaccine Imvamune is still unknown. It would be prudent to wait for a period of at least 4 weeks before or after the administration of mRNA COVID-19 vaccine in order to prevent erroneous attribution of an adverse event following immunization (AEFI) to one particular vaccine or the other. This suggested minimum waiting period between vaccines is precautionary at this time. Protection from monkeypox virus exposure should be prioritized and recent mRNA vaccine receipt should not delay Imvamune pre-exposure vaccination or post-exposure vaccination if protection is urgent.

# Post-vaccination counselling
All vaccine and VIG recipients should be instructed to seek medical care if they develop signs or symptoms of a serious adverse event or an allergic reaction following immunization.
Storage requirements
Lyophilized smallpox vaccine should be stored in a refrigerator at +2C to +8C and reconstituted before use. The frozen liquid smallpox vaccine is frozen for long-term storage and thawed for shipping; the thawed vaccine should be maintained between +2C and +8C. Open vaccine vials should be used within 24 hours.
Imvamune should be stored frozen at -20C  5C or -50C  10C or -80C  10C. After thawing, the vaccine should be used immediately or can be stored at +2C to +8C for up to 2 weeks prior to use. Do not refreeze a vial once it has been thawed. Store in the original package to protect from light.
Safety and adverse events
Common adverse events occur in 1% to less than 10% of vaccinees. Very common adverse events occur in 10% or more of vaccinees.
Uncommon adverse events occur in 0.1% to less than 1% of vaccinees. Rare and very rare adverse events occur, respectively, in 0.01% to less than 0.1% and less than 0.01% of vaccinees.

# First and second generation smallpox vaccines and immunoglobulin safety and adverse events

## Common and local adverse events
In a UK study of 200 health care workers, 142 (71%) of vaccinees reported pain at the injection site, of which 25% considered it to be moderate or severe; 32 vaccinees (16%) recorded a temperature of greater than 37.7C, two of which exceeded 39C. Other, mainly minor, adverse events were common; local itching was reported in 72%, erythema at the injection site in 27%, axillary pain or lymphadenopathy in 38%, malaise or influenza-like symptoms in 40% and headache in 23%. The incidences of minor adverse events were lower in re-vaccinees, compared with primary vaccine recipients. The study used a single dose of the Swiss Serum Institute (SSI) vaccine, containing the Elstree/Lister strain of vaccinia virus.
Bacterial infection of the vaccination site can occur.

## Less common and serious or severe adverse events

### Inadvertent inoculation
Inadvertent inoculation is the transfer of the virus from the site of immunization to other body sites or other persons resulting in vaccinia lesions. The most susceptible areas are the eye, mouth, nose, face and genitalia. Children are most susceptible to inadvertent inoculation. Inadvertent inoculation is the most common (significant) adverse reaction, with rates approaching 600 cases per million doses administered. Most ensuing lesions heal spontaneously. There are case reports of secondary and tertiary vaccinia arising in sexual contacts of a person recently vaccinated; these cases were severe enough to require VIG to manage vaccinia-related complications. When a secondary case of vaccinia is diagnosed, contract tracing is indicated to ascertain whether there are additional secondary or tertiary cases.

### Generalized vaccinia
Generalized vaccinia may occur within a week after vaccination. Lesions appear on unimmunized skin and are thought to arise from viremia. Lesions are similar to those associated with the vaccination site but are usually smaller and evolve to scarring more rapidly, often within a week. In healthy individuals this is a benign complication of primary vaccination that needs to be differentiated from progressive vaccinia. Individuals with underlying and unsuspected immunosuppressive illnesses may develop a serious reaction.

### Progressive vaccinia (Vaccinia Necrosum)
Progressive vaccinia is a severe complication of smallpox vaccination. It often occurs because of an immune defect, especially T cell deficiencies. It is characterized by progressive necrosis at the site of immunization and, in the presence of viremia, leads to implants in distant skin sites and multiple organs. Progression is slow, persistent and resistant to treatment. In those with profound T cell defects, it is nearly always fatal.

### Eczema vaccinatum
Eczema vaccinatum occurs in vaccinees or their unvaccinated contacts with active or healed eczema lesions or other exfoliative skin conditions. Vaccinial skin lesions appear on skin that is currently or was previously affected by eczema. Usually the illness is mild and self-limited, but it can be severe and fatal.

### Vaccinia keratitis
Vaccinia keratitis can threaten eyesight through corneal abrasions, ulcerations and subsequent corneal clouding. If this occurs, consultation with an ophthalmologist is strongly recommended. VIG is contraindicated because of the potential of increased corneal scarring.

### Post-vaccinial encephalitis
Post-vaccinial encephalitis is a rare but serious complication that can develop 7 to 14 days after vaccination. There are no known predictors of susceptibility, but the incidence is somewhat higher among infants less than 1 year of age. Approximately, 25% of cases with encephalitis develop permanent sequelae (both motor and/or intellectual impairment) and up to 35% die. VIG is not recommended due to lack of efficacy.

### Acute myopericarditis
During a smallpox vaccination program for US military personnel which started in 2002, a previously unreported adverse event, acute myopericarditis, was recognized. Most of the affected vaccinees experienced chest pain and returned to normal activities within 7 to 10 days, and all recovered. It is unclear whether these events were adverse outcomes of smallpox vaccination. The smallpox vaccine (Dryvax, Wyeth Laboratories) containing the New York City Board of Health strain of vaccinia was used in this program.
VIG is available to treat certain smallpox vaccine-associated adverse events. Refer to  for additional information.

# Third generation smallpox vaccine safety and adverse events

## Common adverse events
Most adverse events develop within a few days after receiving the vaccine.
The most common local adverse events following Imvamune immunization are pain, erythema, induration and swelling at the site of injection. The most common systemic adverse reactions observed after subcutaneous vaccination with Imvamune are fatigue, headache, myalgia, and nausea. Most of these reactions are mild to moderate intensity and resolve within the first seven days following vaccination.

## Less common and serious or severe adverse events
In clinical trials, cardiac adverse events of special interest (AESI) were reported to occur in 1.4% (91/6,640) of Imvamune recipients, 0.2% (3/1,206) of placebo recipients who were smallpox vaccine-naive and 2.1% (16/762) of Imvamune recipients who were smallpox vaccine-experienced. Among the cardiac AESIs reported, 6 cases were considered to be causally related to Imvamune vaccination. The events reported included tachycardia, electrocardiogram T wave inversion, abnormal electrocardiogram, electrocardiogram ST segment elevation, abnormal electrocardiogram T wave, and palpitations. None of the 6 events considered vaccine-related were considered serious.
No trends have been identified which suggest the occurrence of any particular unexpected adverse reaction or classes of adverse reactions following vaccination. To date, myocarditis has not been determined to be causally associated with Imvamune, but monitoring is ongoing.

# Guidance on reporting Adverse Events Following Immunization (AEFI)
To ensure the ongoing safety of vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical.
Vaccine providers are asked to report, through  officials, any serious or unexpected adverse event thought to be temporally related to smallpox vaccination, including any case of secondary or tertiary vaccinia. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.

# Contraindications and precautions

## First and second generation smallpox vaccines
Contraindications to smallpox vaccines are only applicable if the variola (smallpox) virus has not been introduced into the environment. In an outbreak situation, if smallpox cases are occurring and a risk of infection exists for an individual, there are no absolute contraindications to immunization.
The product leaflet lists the following contraindications in a non-emergency setting. For people at higher risk of vaccinia complications, potential risks and benefits must be weighed, including VIG availability. A third generation smallpox vaccine would be a better choice for these individuals, if available.

### Persons less than 18 years of age
Smallpox vaccination is contraindicated for children and adolescents because they are more likely to suffer from adverse reactions and cause inadvertent self-reinoculation and inoculation of others.

### Hypersensitivity or anaphylaxis
Smallpox vaccines are contraindicated in people with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to  in Part 1 for lists of all vaccines and passive immunizing agents authorized for use in Canada and their contents. For smallpox vaccines, potential allergens include: streptomycin, neomycin and latex in the stopper of vial.

### Immunodeficiency or immunocompromised
Smallpox vaccination is contraindicated for people who are immunocompromised such as those with leukemia, lymphoma, or a systemic malignancy; persons on immunocompromising therapies; persons with some hereditary immune deficiency disorders; and persons with HIV/AIDS. It is generally contraindicated pre/post solid organ transplant and hematopoietic stem cell transplant (HCST). Refer to  in Part 3 for additional information.

### Atopic dermatitis and other widespread skin disorders
Diffuse vaccinia virus infection can occur in the presence of acute atopic dermatitis and other widespread exfoliative skin disorders.

### Pregnancy and breastfeeding
Smallpox vaccine is generally contraindicated in pregnant women in non-emergency situations although it is not known to cause congenital malformations. It can very rarely lead to fetal vaccinia after primary immunization during pregnancy, resulting in stillbirth or neonatal death. Women of childbearing age should be asked before vaccination if they are pregnant or intend to become pregnant during the next 4 weeks. If a woman becomes pregnant within 4 weeks after smallpox vaccination she should be counselled regarding concern for the fetus.
Breastfeeding mothers should not receive the smallpox vaccine in non-emergency situations. The close physical contact that occurs during breastfeeding increases the chance of inadvertent inoculation of the baby. It is not known whether vaccine virus or antibodies are excreted in human milk. A breastfeeding woman should only be immunized if she has been exposed to smallpox and a third generation vaccine is not available; in that case breastfeeding and other close contact should be delayed until after the vaccination scab has separated from the vaccination site.

### Heart disease and cardiac risk factors
Smallpox vaccine is contraindicated in people with known underlying heart disease (with or without symptoms), or who have three or more known major cardiac risk factors (i.e., hypertension, diabetes, hypercholesterolemia, heart disease at age 50 years or younger in a first-degree relative, and smoking). A risk assessment needs to be done in an emergency situation such as exposure to a case of smallpox.
The product monograph lists the following precautions:
Ocular or periorbital disease
Persons with inflammatory eye disease may be at increased risk for inadvertent inoculation as a result of touching or rubbing the eye. Therefore, deferring vaccination is prudent for persons with inflammatory eye diseases requiring steroid treatment until the condition resolves and the course of therapy is complete.
Close contacts
Generally, smallpox vaccine should not be administered to household contacts of an immunocompromised person in a non-emergency situation. If vaccination is required in an outbreak situation, precautions should be taken for unvaccinated household and other close contacts. Vaccinees with household and other close contacts with active eczema or a history of eczema or other exfoliative skin conditions, immunocompromising conditions, or with close contact with infants or pregnant women, should take special precautions in order to prevent viral transfer to these contacts. Such precaution can include isolation of the vaccinee from their higher risk household contacts until the vaccine scab falls off.

## Third generation smallpox vaccine
Contraindications to Imvamune include hypersensitivity to this vaccine. Individuals with suspected severe hypersensitivity reactions (e.g., anaphylaxis) after receiving the first dose of the vaccine should consult an . There is evidence that some individuals with immediate allergic reactions to vaccines in general (although less data are available for Imvamune) can safely receive a subsequent dose of the same vaccine with low risk of a systemic reaction under the supervision of an allergist. Individuals with confirmed or suspected hypersensitivity to the potential allergens contained in the vaccine components (egg, tromethamine, or antibiotics) can receive the vaccine without expert consultation; prolonged observation (30 minutes) may be considered.
Data on Imvamune are limited in people who are pregnant, lactating or <18 years of age, requiring an assessment of the benefits vs. the risks in these populations.

## Vaccinia immune globulin
The most common adverse events related to VIG are headache, nausea, rigors and dizziness.
Relative contraindications to VIG include:
- a history of systemic allergic reactions to human immune globulin products
- isolated vaccinia keratitis due to the potential of increased corneal scarring
- selective immunoglobulin A deficiency with antibodies against IgA and a history of IgA hypersensitivity (because VIG contains trace amounts of IgA)
It is not known whether VIG can cause fetal harm when given to pregnant women. Counselling based on an individual risk benefit assessment is indicated. VIG should not be withheld if a pregnant woman experiences a condition for which VIG is needed.
Other Considerations

# Drug interactions
There is some evidence for tuberculin skin test (TST) suppression following the administration of live, attenuated virus vaccines; a TST can be done on the same day as immunization or delayed until 4 weeks after administering a first or second generation smallpox vaccine.
Chapter revision process
This chapter was updated to reflect guidance based on current evidence and NACI's expert opinion on the use of Imvamune in the context of mpox outbreaks in Canada.