An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)*†

STATEMENT ON SMALLPOX VACCINATION

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The National Advisory Committee on Immunization (NACI) provides Health Canada with ongoing and timely medical, scientific, and public-health advice relating to immunization. Health Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge, and is disseminating this document for information purposes. Persons administering or using the vaccine(s) should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian licensed manufacturer(s) of the vaccine(s). Manufacturer(s) have only sought approval of the vaccine(s) and provided evidence as to its safety and efficacy when used in accordance with the product monographs.

INTRODUCTION

Prior to the introduction of vaccination in 1796 and disease eradication in 1980, smallpox, caused by variola virus, was one of the most devastating diseases known to humanity. It repeatedly swept through continents and killed up to 50% of the affected populations⁽¹⁾.

In 1958, the World Health Organization (WHO) launched a global program to eradicate smallpox. Eradication efforts were intensified in 1967 and the last case of wild smallpox was reported in Somalia in 1977⁽²⁾. In 1978, two laboratory-associated cases occurred in the United Kingdom⁽³⁾. Since then, no cases have occurred anywhere in the world. In 1980, the 33^rd World Health Assembly declared the official global eradication of smallpox⁽⁴⁾. Remaining variola virus stocks are kept in two WHO reference laboratories in the United States and in Russia. There are  concerns, however, that other countries may have access to the virus⁽¹⁾. In light of recent terrorist and bioterrorist events in North America, Health Canada has requested NACI to make recommendations regarding the current need for smallpox immunization.

EPIDEMIOLOGY AND CLINICAL DISEASE

Smallpox is believed to have originated > 3,000 years ago. It was a devastating disease with serious complications, including encephalitis and blindness, and a high mortality rate. Smallpox led to > 300 million deaths in the 20^th century alone⁽⁵⁾. In 1796, Edward Jenner demonstrated that inoculation with cowpox (vaccinia virus) could protect against smallpox, thereby developing a vaccine that led to a significant decrease in the threat of the disease⁽¹⁾.

In the period from 1924 to 1929, in Canada, between 1,100 and 3,300 cases of smallpox were reported every year, with an average of 2,263 per year (Dr. P. Varughese, Health Canada, Ottawa: personal communication, 2001). Due to disease control efforts, rates dropped during the 1930s and the last endemic cases occurred in 1946. The last imported case occurred in 1962.

In 1972, NACI recommended that routine immunization of infants be stopped. Immunization of healthcare workers was stopped in 1977⁽⁶⁾. The Canadian Forces discontinued smallpox immunization in 1988 (Dr. R. St. John, Health Canada, Ottawa: personal communication, 2001). Today, very few Canadians born in or after 1972 have ever been immunized against smallpox and it is believed that few of those immunized prior to or in 1972 have adequate residual immunity.

Smallpox is caused by variola virus, a member of the orthopoxvirus genus, which also includes cowpox (vaccinia) and monkeypox viruses. Variola virus can only infect humans and has no animal reservoir. It is transmitted from person-to-person, mainly through respiratory droplets. It can also be transmitted through aerosols and contact with clothing or bedding. Cases are most infectious during the first week of illness, but the period of infectiousness extends from the development of fever (when the first bucco-pharyngeal lesions appear) until all skin lesions have scabbed over^(7,8). Until the disease was eradicated, each case infected approximately five other people. In view of current general susceptibility of the population, this number may now be much higher⁽²⁾.

The incubation period is usually 12 to 14 days (range 7 to 17 days), during which time transmission does not occur. This period is followed by the sudden onset of fever, malaise, headache, backache and prostration. Two to 3 days later, the fever drops and a maculopapular rash with deeply embedded lesions appears on the mucosa of the mouth and on the face, hands, and forearms, eventually progressing to the trunk, legs, and feet. The lesions appear in crops and progress to vesicular and pustular stages. On a given area of the body, all lesions are at the same stage of maturation. Eight to 14 days after the onset of rash, scabs form, which can eventually lead to depressed, depigmented, pitted scars^(1,8).

The centrifugal distribution of the smallpox rash (more prominent on face and extremities) helps distinguish it from chickenpox, in which the rash is centripetal (more prominent on the trunk). In addition, chickenpox lesions are more superficial, are rarely, if ever, seen on the palms and soles, and lesions at different stages of maturation can be seen on the same area of the body⁽⁸⁾.

There are two main forms of smallpox: variola minor and variola major. Variola minor cases experience less severe symptoms and  have a case fatality rate of 1%. Variola major has a case fatality rate of 30%. Two more severe, but rarer, forms are hemorrhagic smallpox and malignant or flat-type smallpox. Hemorrhagic disease is characterised by severe prodromal symptoms, toxemia, and a hemorrhagic rash. It is fatal in all cases and its clinical presentation can be confused with meningococcemia⁽¹⁾. Malignant disease has a 96% case fatality rate and is characterised by severe toxemia and flat confluent lesions that do not progress to the pustular stage⁽¹⁾. It is now thought that rare immune deficiencies may explain some of these atypical presentations. Pictures of smallpox cases can be found at the following URL: <http://www.who.int/emc/diseases/smallpox/slideset/index.htm>.

PREPARATIONS LICENSED FOR IMMUNIZATION

1. Smallpox vaccine

There is currently one licensed smallpox vaccine in Canada, which was produced between 1968 and 1980. There are approximately 365,000 doses of vaccine potentially available. The potency of the vaccine has been tested annually by the manufacturer with satisfactory results (Dr. R. St. John, Health Canada, Ottawa: personal communication, 2001). The possibility of diluting this vaccine is currently being studied in order to generate additional doses.

Currently available smallpox vaccines contain live unattenuated vaccinia virus, an orthopoxvirus closely related to variola virus that confers immunity against smallpox virus through cross-reactivity. North American manufacturers used a vaccinia seed virus derived from the New York City Board of Health strain. Vaccine was manufactured by infecting calf skin with vaccinia virus. The pulp was scraped from the ensuing infection and enough phenol was added to kill contaminating bacteria but not to inactivate the vaccinia virus⁽²⁾. The vaccine was then freeze-dried, sealed in 10 dose ampoules and stored at -20° C. The vaccine is reconstituted by adding sterile diluent to the powder and administered into the dermis using a puncture technique⁽⁹⁾.

The United States (U.S.) has a supply of 12 to 15 million doses of smallpox vaccine (Dr. R. St. John, Health Canada, Ottawa: personal communication, 2001). Vaccine stocks have also been retained by a number of other countries, but none has reserves large enough to meet more than their own potential emergency needs. The WHO has approximately 500,000 doses⁽¹⁾. It is believed that 50 to 90 million doses are available worldwide, but the quality of this stock is not known⁽²⁾.

There are no manufacturers currently equipped to produce smallpox vaccine in large quantities. The establishment of a new vaccine production facility and the development and licensure of a new smallpox vaccine are estimated to require 12 to 36 months (Dr. R. St. John, Health Canada, Ottawa, personal communication, 2001). Several countries are negotiating with pharmaceutical companies to produce additional stocks of vaccine using traditional methods (Dr. R. St. John, Health Canada, Ottawa: personal communication, 2001). New vaccines produced using chicken embryo or other cell culture techniques are currently under development (Dr. L. Palkonyay, Health Canada, Ottawa: personal communication, 2001).

2. Vaccinia immune globulin (VIG)

VIG is a 16.5% solution of gamma globulin from the serum of individuals recently immunized with smallpox vaccine. It also contains glycine, thimerosal and sodium chloride^(10,11). VIG can be given concurrently with smallpox vaccine to help prevent the development of adverse events in high risk individuals. There is limited evidence that if VIG is given shortly after exposure, concurrently with smallpox vaccine, it may be more effective than smallpox vaccine alone in decreasing morbidity and mortality due to smallpox disease^(7,12).

Since it is derived from human plasma, VIG is associated with an increased risk of bloodborne infections and serum sickness. Relative contraindications to VIG include a history of systemic allergic reactions to human immune globulin products and selective immunoglobulin A deficiency⁽¹⁰⁾. Currently, there is no VIG available in Canada (Dr. L. Palkonyay, Health Canada, Ottawa: personal communication, 2001). The U.S. Centers for Disease Control and Prevention (CDC) will provide limited quantities of VIG to Canada, if necessary (Dr. M. Tepper, Health Canada, Ottawa: personal communications, 2001). This VIG should be reserved for the treatment of severe vaccine-associated adverse events.

EFFICACY AND IMMUNOGENICITY

Although vaccine efficacy has never been measured in a controlled trial, the eradication of smallpox is the best evidence available that the vaccine is effective.

Indicators of adequate vaccine response include:

1) Vaccine “take” (Jennerian pustule): If a progressive reaction consisting of a papule, vesicle, pustule, scab and, eventually, a characteristic scar develops at the site of immunization, the vaccinee is considered to have developed smallpox immunity^(1,9). This will occur in both first-time vaccinees and revaccinated individuals who have lost all or part of their original immunity. This reaction is best observed 6 to 8 days post-immunization. A positive “take” indicates successful immunization. Clinical experience has shown that vaccine “take” is close to 100%⁽¹²⁾.

2) Measurement of antibody titres: The level of antibody necessary to protect against smallpox infection is unknown. However, over 95% of primary vaccinees experience a rise of antibody titre > 1/10⁽¹³⁾.

RECOMMENDED USAGE

1. Pre-exposure prophylaxis

1.1 General population

On 26 October, 2001, the WHO reaffirmed its recommendation against immunization of the general population⁽¹⁴⁾. The main reason for this recommendation is the number and severity of adverse reactions that would result from mass immunization.

NACI also believes that there is currently no evidence to support routine smallpox immunization of the general Canadian population. The reasons for this recommendation include:

• The current risk of smallpox disease, although unknown, is believed to be very small.
• The risk of smallpox vaccine-associated adverse events (VAAEs) is high as compared to the possible benefits
  • The overall rate of severe smallpox VAAEs is estimated at 0.13%⁽¹³⁾.
  • The risk of death from a smallpox VAAE is one per million in primary vaccinees and one in four million in re-vaccinees⁽¹³⁾.
• Currently, there is no VIG available in Canada to treat severe VAAEs. It is estimated that <= 250 vaccinees per million would require VIG⁽¹⁾.
• The number and proportion of individuals with contraindications to smallpox immunization have increased since eradication of the disease, due to the emergence of HIV/AIDS and the increased use of immunosuppressive therapies.
• Other methods of outbreak control (isolation of cases and immunization and surveillance of contacts) are available to prevent transmission.

1.2 Groups at potential risk

Groups at potential risk of exposure include:

• laboratory workers who handle or who may handle smallpox virus or other orthopoxvirus specimens
• public health first responders to the scene of a potential smallpox case or outbreak
• other first responders (including police, firefighters, ambulance attendants, military personnel, emergency room personnel, and other healthcare workers).

1.2.1 Laboratory workers

Smallpox immunization is recommended for personnel who work in a laboratory in which live smallpox virus or other orthopoxviruses (including vaccinia virus, monkeypox virus, and recombinant, non-attenuated, vaccinia virus) may be stored, cultured or manipulated. Although workers in high containment (BSL 4) laboratories are normally well protected by the barriers inherent in their work environment, they may be required to work with clinical specimens contaminated with viable smallpox virus. As a result, smallpox vaccine should be made available for these workers and immunization can be considered. Screening to identify and exclude individuals with contraindications to smallpox immunization must be conducted. HIV testing should be considered. Adequate doses of VIG must be available prior to immunization in order to treat severe adverse events in case they arise.

Smallpox immunization of other laboratory workers is not recommended at the present time.

1.2.2 Public health first responders to the scene of a suspected smallpox case or outbreak

A team of public health first responders that can be called upon to investigate and manage a suspected smallpox case or outbreak in Canada should be assembled. The people selected for this team should have the necessary skills, knowledge, and experience in epidemiological field investigation and case management and be available to respond when needed. Priority should be given to selecting people who have received at least one dose of smallpox vaccine in the past and have evidence of vaccine “take” (i.e., a scar). The higher the number of smallpox vaccine doses received in the past, the more likely individuals are to have residual immunity and the less likely they are of experiencing a vaccine-associated adverse event. The people selected on this team should be trained to respond to potential smallpox cases and outbreaks. Smallpox immunization or reimmunization is recommended for this group of people, regardless of their previous immunization status. Screening to identify and exclude individuals with contraindications to smallpox immunization must be conducted. HIV testing should be considered. Adequate doses of VIG must be available prior to immunization in order to treat severe adverse events in case they arise.

1.2.3 Other first responders

Community first responders, including emergency room workers, police officers, firefighters, ambulance attendants, the military, and others, do not require smallpox immunization at this time, prior to the occurrence of a case. The current risk of exposure to smallpox is too small to warrant the risks associated with smallpox immunization. In addition, smallpox vaccine given immediately post-exposure to a case is highly effective at decreasing the risk of disease.

2. Post-exposure prophylaxis

2.1 Smallpox vaccine

Immunization immediately after exposure and <= 4 days post-exposure to an infectious case of smallpox can prevent or decrease the severity of disease and the risk of mortality because antibodies appear more quickly after immunization than the disease pattern occurs after natural exposure^(1,7,15). Smallpox immunization or reimmunization is recommended for contacts as listed in the Outbreak Control section.

2.2 Vaccinia immune globulin (VIG)

VIG, at 0.3mL/kg IM (dosage for prophylactic use), can be given as soon as possible after exposure in conjunction with smallpox vaccine to decrease the risk of severe adverse events in people at risk (see section on Contraindications)^(10,11). There is some evidence that VIG given in conjunction with smallpox vaccine as post-exposure prophylaxis may be more effective than smallpox vaccine alone^(7,12). As there is no VIG currently available in Canada, any VIG that will be obtained at this time should be reserved for use in the treatment of severe adverse events secondary to smallpox immunization.

2.3 Antivirals

In vitro and animal studies have shown that high doses of cidofovir, a nucleoside analog DNA polymerase inhibitor, may decrease the risk of developing smallpox infection if given within 1 to 2 days post-exposure. This drug must be given intravenously and can lead to severe renal toxicity⁽¹⁾. There is no evidence that cidofovir is more effective than immunization⁽¹⁾.

OUTBREAK CONTROL

The Canadian Smallpox Contingency Plan is currently being updated. The plan includes actions to be taken if a case of smallpox occurs in Canada or elsewhere. In general terms:

• Cases should be isolated immediately, preferably at home. In order to decrease the risk of transmission to others, if hospitalisation is required, patients should be admitted to rooms under negative pressure equipped with high efficiency particulate air-filtration (HEPA) filters.
• Contacts should be immunized immediately and placed under observation. Contacts and other groups to be immunized include⁽¹⁶⁾:
  • Face-to-face contacts (< 6.5 feet or 2 meters)
  • Household contacts
  • Personnel involved in the medical care, public health evaluation or transportation of confirmed or suspected smallpox patients or persons who have died of smallpox
  • Laboratory personnel involved in the collection or processing of clinical specimens from confirmed or suspected smallpox patients
  • Persons who have a high likelihood of exposure to infectious materials (e.g., personnel responsible for medical waste disposal, linen disposal or disinfection)
  • Household members of contacts to smallpox cases (to protect household members should smallpox case contacts develop disease while under fever surveillance at home).

SCHEDULE AND DOSAGE

In the current, non-emergency situation (i.e., prior to the occurrence of a case of smallpox anywhere in the world), one dose of smallpox vaccine is administered to recommended recipients > 18 years of age.

ROUTE OF ADMINISTRATION

• The vaccine is applied to the dermis on the outer aspect of the upper arm over the distal insertion of the deltoid muscle.
• Ensure the skin is clean. Disinfectant or alcohol can be used, but the skin must be dry prior to immunization because these products can kill the vaccine virus.
• Place a drop of vaccine onto the skin using the needle provided*.
  • Puncture method: Holding the needle almost parallel to the skin, push the needlepoint through the drop into the skin.
  • Multiple pressure method: With the side of the needle held tangentially to the skin, make a series of strokes through the drop of vaccine within an area no > 3 mm in diameter, using a rapid up-and-down motion, perpendicular to the skin. The pressure is applied with the side of the needle, not the point. For primary immunization, make three to five strokes and, for revaccination, make 10 to 20 strokes⁽⁹⁾.
  • Any remaining vaccine should be wiped off and the gauze, along with the equipment used to immunize and remaining vaccine, should be disposed of in a biohazardous waste container.
  • The site can be left uncovered or a sterile piece of gauze can be used to loosely cover the injection site in order to deter the vaccinee from touching it.

BOOSTER DOSES AND REIMMUNIZATION

Most Canadians born in or since 1972 were never immunized against smallpox. In 2001, approximately 12.2 million persons, or 39% of the Canadian population, are <= 29 years of age⁽¹⁷⁾. These people are considered to be susceptible to smallpox.

The immune status of those who were vaccinated prior to 1972 is not known. Although the duration of clinical protection has never been measured, epidemiological studies have demonstrated that protection can persist for up to, and perhaps beyond, 10 years^(2,12). If smallpox develops > 10 years after immunization, symptoms are usually milder and mortality rates are lower^(15,18,19). Previously immunized persons who develop smallpox are also less likely to transmit the disease^(15,18). Neutralizing antibodies may reflect levels of protection; these antibodies have been shown to decline substantially during the 5- to 10-year period following primary immunization⁽¹⁾. Moreover, several studies have documented an increase in the number of people exhibiting vaccine “take” after reimmunization beginning 3 to 5 years post-immunization, suggesting that vaccine-induced immunity may start to wane as early as 3 years post-immunization⁽¹⁸⁾. Thus, the actual level of protection among Canadians who received the recommended single-dose immunization as children cannot be determined with certainty.

Booster doses prolong the duration of immunity. In subjects immunized with three doses, at birth, 8 years, and 18 years, in the context of a study, neutralizing antibodies remained detectable over a 30-year period⁽²⁰⁾. Because few persons today have been immunized on more than one occasion, it can be assumed that Canadians are probably no longer adequately protected against smallpox.

During the years of endemic smallpox, it was recommended that groups who were at continuous risk of smallpox virus exposure be reimmunized every 3 years^(9,13). For the groups at risk for whom smallpox immunization is recommended in this document, immunization every 10 years is adequate. If smallpox cases do occur and these individuals are at continuous risk, they should be reimmunized every 3 years.

SEROLOGIC TESTING

There is no indication for routine pre- or post-immunization serologic testing. Vaccinees must be examined 6 to 8 days post-immunization to interpret the injection site response. WHO has defined two types of responses:

• A major reaction or vaccine “take” indicates that viral replication has taken place and immunization has been successful (see section on Efficacy and Immunogenicity). The WHO defines this reaction as a “ pustular lesion or an area of definite induration or congestion surrounding a central lesion (scab or ulcer)”⁽¹²⁾. In people being reimmunized, the reaction may be less pronounced and/or accelerated, with a vesicule appearing in 1 to 2 days^(7,12).
• An equivocal reaction is any skin change that is not indicative of a vaccine “take” or major reaction. An equivocal reaction may indicate that the vaccinee has adequate immunity to suppress viral multiplication or it may represent an allergic reaction, the use of an insufficiently potent vaccine or an administration technique failure. An equivocal reaction requires reimmunization with vaccine from a different lot on the opposite arm⁽¹³⁾.

STORAGE REQUIREMENTS

Smallpox vaccine that has not yet been reconstituted (dried format) should be stored < 5° C. Reconstituted vaccine should be stored between 2° C to 8° C while in use. Remaining reconstituted vaccine should be discarded in a biohazardous waste container at the end of each working day.

VIG should be stored between 2° C to 8° C.

SIMULTANEOUS ADMINISTRATION WITH OTHER VACCINES

Smallpox vaccine can be administered simultaneously with other vaccines (live or inactivated) at a different injection site without affecting its safety or efficacy⁽¹⁸⁾. A live vaccine should be administered either on the same day or be separated by an interval of at least 1 month^(21,22).

ADVERSE REACTIONS

Adverse reactions to smallpox vaccine include non-specific reactions (local reaction, bacterial superinfection of a local reaction, urticarial rash, anaphylaxis, erythema multiforme, and Stevens-Johnson Syndrome) and specific smallpox vaccine reactions (see descriptions below). The rates of VAAE are derived from a 1968 study conducted in the U.S. involving > 14 million vaccinees⁽¹³⁾. Overall, nine deaths associated with smallpox vaccine occurred in this population (one death per million primary immunizations and one death per four million reimmunizations). The reactions described below occur > 10 times more frequently among first time vaccinees than revaccinees, and more frequently among infants than older children and adults.

• Inadvertent inoculation is the transfer of the virus from the site of immunization to other body sites (eye, mouth, nose, face, genitalia) resulting in vaccinia lesions. This is the most common adverse reaction, with rates approaching 600 cases per million doses administered. Most ensuing lesions heal spontaneously, but ocular implantation may require treatment with VIG⁽¹³⁾.

• Generalized vaccinia is a vesicular rash developing 6 to 9 days post-immunization in healthy vaccinees, occurring in approximately 250 cases per million. In healthy individuals, the rash is self-limited. Individuals with underlying and unsuspected immunosuppressive illnesses may develop a serious reaction.

• 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. This reaction occurs in 42 vaccinees per million. Usually the illness is mild and self-limited, but it can be severe and fatal.

• Progressive vaccinia (vaccinia necrosum) is a severe, potentially fatal reaction characterised by progressive necrosis at the site of immunization and occasional secondary lesions elsewhere. This reaction occurs in 4.5 per million vaccinees and is fatal in a third of cases⁽¹⁸⁾. It has occurred almost exclusively in persons with cellular immunodeficiency.

• Postvaccinial encephalitis, the most serious complication, most frequently affects primary vaccinees (12 cases/million in primary vaccinees and two cases/million in revaccinees). Approximately 25% of cases with encephalitis develop permanent sequelae and 15% to 25% die.

VIG must be available to treat severe smallpox vaccine-associated adverse events. It may be used to treat all of the above-mentioned adverse events except postvaccinial encephalitis and inadvertent inoculation keratitis, where it may cause corneal scarring^(11,13). It can also be given concurrently with smallpox vaccine to persons who are considered at high risk of adverse events⁽¹¹⁾. Currently, VIG is not available in Canada. Prior to the immunization of recommended recipients, VIG should be secured from external sources.

VIG used for the treatment of smallpox vaccine-associated adverse events is given at a dose of 0.6 mL/kg IM in the buttock for adults and anterolateral aspect of the thigh in children⁽¹¹⁾. If > 10 mL are required, VIG can be given in divided doses over 24 to 36 hours^(11,13). Additional doses of VIG can be given as necessary every 2 to 3 days until recovery⁽¹¹⁾.

CONTRAINDICATIONS

In the non-emergency situation (prior to the occurrence of a case of smallpox), the following groups should not receive smallpox vaccine unless it is felt that the benefits of immunization greatly outweigh the risks and sufficient VIG and appropriate emergency drugs (e.g., epinephrine) are available to treat complications should they arise:

• Persons with a history of anaphylaxis to any of the vaccine components (the vaccine contains traces of tissue of bovine origin, phenol, streptomycin sulfate, and neomycin sulfate);
• Persons < 18 years of age. They are more likely to suffer from adverse reactions and cause inadvertent inoculation in themselves and others⁽¹³⁾;
• Persons with active eczema, a history of eczema or other significant exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, varicella zoster);
• Persons who are immunosuppressed such as
  • persons with leukemia, lymphoma, or a generalized malignancy,
  • persons on immunosuppressive therapies,
  • persons with hereditary immune deficiency disorders,
  • persons with HIV/AIDS;
• Pregnant women. Smallpox vaccine is not known to cause congenital malformations, but can very rarely lead to foetal vaccinia after primary immunization during pregnancy, resulting in stillbirth or neonatal death⁽¹³⁾;
• Persons who have household contacts with active, or a history of, eczema or other exfoliative skin conditions or who have household contacts who are immunosuppressed or pregnant. The risk of transmission of vaccinia virus to contacts is 27 infections per million vaccinees⁽¹³⁾. If immunization of these individuals is required, they can be isolated from their household contacts until the vaccine scab falls off.

In an emergency situation, if smallpox cases occurred and a real risk of infection existed, there would be no absolute contraindications to immunization⁽¹³⁾. In an emergency situation, having sufficient VIG available to treat complications is desirable, but not necessary.

PRECAUTIONS

Smallpox vaccine contains live unattenuated vaccinia virus and should be handled and disposed of in the same way as other live viral vaccines⁽²¹⁾.

OTHER CONSIDERATIONS

All recommended recipients for smallpox immunization, as delineated in this document, should be immunized in a central location, and if possible, on the same day, by trained, (and if possible, experienced) staff. This will help ensure that appropriate storage measures are taken, vaccine wastage is minimized, all vaccine can be accounted for, and appropriate disposal occurs. Plans to collect serum from immunized individuals should be made in order to manufacture VIG.

REFERENCES

1. Henderson DA, Inglesby TV, Bartlett JG et al. Smallpox as a biological weapon: medical and public health management. JAMA 1999;281:2127-37.

2. World Health Organization. Factsheet on smallpox. URL: <www.who.int/emc/diseases/smallpox/factsheet.html>. Date of access: November 2001.

3. World Health Organization. Statement on smallpox vaccination, February 14, 1979. Wkly Epidemiol Rec 1979;54(1):1-6.

4. World Health Organization. Declaration of global eradication of smallpox. Wkly Epidemiol Rec 1980;55(20):148.

5. Oldstone MBA. Viruses, plagues and history. New York: Oxford University Press, 1998:27.

6. National Advisory Committee on Immunizing Agents. Statement on vaccination against smallpox for health care personnel, November 4, 1977. CDWR 1977;3:197.

7. Fenner F, Henderson DA, Arite I et al. Smallpox and its eradication. World Health Organization, 1988. URL: <www.who.int/emc/diseases/smallpox/smallpoxeradication.html>. Date of access: December 2001.

8. Chin J. Control of communicable disease manual. 17^th ed. Washington: American Public Health Association, 2000.

9. Connaught Laboratories Limited. Smallpox vaccine (dried) [product monograph].

10. Grabenstein JD. ImmunoFacts: Vaccines and immunologic drugs. St. Louis: Facts and Comparisons, 2001.

11. Canadian Pharmaceutical Association. Compendium of pharmaceuticals and specialties. 23^rd ed. Ottawa: Canadian Pharmaceutical Association, 1988: 975.

12. Neff JM. Vaccinia virus (cowpox). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. Philadelphia: Churchill Livingstone, 2000:1553-55.

13. Advisory Committee on Immunization Practices. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR 2001;50(RR-10):1-25.

14. World Health Organization. World Health Organization announces updated guidance on smallpox vaccination. URL:  <www.who.int/inf-pr-2001/en/state2001-16.html>. Date of access: November 2001.

15. Dixon CW. Smallpox in Tripolitania, 1946: an epidemiological and clinical study of 500 cases, including trials of penicillin treatment. J Hyg 1948;46(4):351-77.

16. Centers for Disease Control and Prevention. Executive summary for CDC interim smallpox response plan and guidelines. URL: <http://www.cdc.gov/nip/diseases/smallpox/default.htm>.
    Date of access: November 2001.

17. Statistics Canada. Population by age and sex. URL: <http://www.statcan.ca/english/Pgdb/People/Population/demo10a.htm>. Date of access: November 2001.

18. Henderson DA, Moss B. Smallpox and vaccinia. In: Plotkin SA, Orenstein WA, eds. Vaccines. 3^rd ed. Philadelphia: WB Saunders, 1999:74-97.

19. Cohen J. Smallpox vaccination: how much protection remains? Science 2001;294:985.

20. El-Ad R, Roth Y, Winder A. The persistence of neutralizing antibody after revaccination against smallpox. J Infect Dis 1990;161:446-48.

21. National Advisory Committee on Immunization. Canadian immunization guide. 5^th ed. Ottawa, Ont.: Health Canada 1998;103-10:140-43. (Minister of Public Works and Government Services Canada, Cat. No. H49-8/1998E.)

* Members: Dr. V. Marchessault (Chairperson), Dr. A. King (Executive Secretary), J. Rendall (Administrative Secretary), Dr. I. Bowmer, Dr. G. De Serres, Dr. S. Dobson, Dr. J. Embree, Dr. I. Gemmill, Dr. J. Langley, Dr. M. Naus, Dr. P. Orr, Dr. B. Ward, A. Zierler.

Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. V. Lentini (DND),Dr. M. Douville-Fradet (ACE), Dr. T. Freeman (CFPC), Dr. R. Massé (CCMOH), K. Pielak (CNCI), Dr. J Salzman (CATMAT), Dr. L. Samson, (CPS), Dr. D. Scheifele (CAIRE), Dr. M. Wharton (CDC), Dr. A. McCarthy (CIDS).

Ex-Officio Representatives: Dr. L. Palkonyay (BGTD), Dr. P. Riben (FNIHB).

† This statement was prepared by Dr. Eleni Galanis and approved by NACI.

[Canada Communicable Disease Report]