Chlortetracycline

In 1796 Edward Jenner showed that vaccination with cowpox protected against smallpox. In 1801 he stated that the final result of vaccination must be the elimination of smallpox.1 In 1958 the Soviet Union proposed the global elimination of smallpox.2 But it was not until 1967 that the World Health Organization (WHO) began its campaign to eradicate smallpox. During 1967 there were an estimated 2 million deaths from smallpox. Ten years later, Ali Maow Maalin was the last person to have naturally occurring smallpox. Alarmingly, in August 1978, Janet Parker, a medical photographer, developed smallpox. Her darkroom was one floor above a laboratory that was conducting research on smallpox. She spread smallpox to her father and mother. Her father died of a myocardial infarct as he began to develop smallpox while her mother recovered. However, Janet Parker, who received the smallpox vaccine 12 years earlier, died of smallpox on September 11, 1978. After no further cases, in 1980 the WHO certified the world as smallpox-free.

The Soviet Union placed improvement of smallpox as a biological weapon on its five-year plan that started in 1981.3 The Soviet's smallpox program had the capacity to produce tons of smallpox annually. When the United States became aware of this capacity, it grew concerned about the use of smallpox as a biological weapon. Because of the aging vaccine kept in storage, the Department of Defense in 1997 contracted with DynPort Vaccine Company to produce 300,000 doses of the smallpox vaccine for use in the military. President Clinton was interested in stockpiling vaccine for the public.4

On September 20, 2000, the Centers for Disease Control and Prevention (CDC) entered into an agreement with OraVax (now Acambis, Inc.) to produce 40 million doses of a new smallpox vaccine for use in civilians.4,5 The projected delivery date for the first production lot was 2004. After the terrorist attacks on September 11, 2001, and the human cases of anthrax in the United States, the Department of Health and Human Services awarded a contract to Acambis/Baxter for 155 million doses of the a smallpox vaccine, to be produced by the end of 2002.

It is possible that terrorists or other groups may have obtained smallpox after the collapse of the Soviet Union.4,6 Because routine vaccination stopped in the United States in 1972 and the vaccine does not provide long-term protection, everybody in the United States (except those who were vaccinated after December 13, 2002, when President Bush announced the availability of the vaccine for medical professionals, emergency personnel and response teams) is susceptible to smallpox. Smallpox is a disease with no available treatment and a 30% mortality rate. Widespread use of the vaccine is not recommended at the present time because of rare but potentially fatal side effects. High-risk groups such as the military are being vaccinated. In the civilian population, high-risk groups including healthcare workers are being offered the vaccine. The risk to healthcare workers is based in part on data from Western Europe.7 From 1950 to 1971 the more severe form of smallpox, variola major, was imported into western Europe 45 times resulting in 680 secondary cases. The majority (53%) of the secondary cases occurred because of spread in hospitals. Twenty-one percent of the secondary cases occurred in healthcare workers; 19% occurred in family members. Twenty-two of the 146 infected healthcare workers died.

SMALLPOX

Smallpox (variola) was previously spread through droplets to close contacts. The first symptoms of smallpox are fever and malaise, followed 2 to 4 days later with a classic rash that starts on the tongue and mouth then spreads to the face, arms and legs, and then to hands and feet. Historically the fatality rate was 30%.

OVERVIEW

Currently Dryvax4 is the only available smallpox vaccine. It was available in the United States for routine use until 1972. The Food and Drug Administration in October 2002 approved a supplement to the original vaccine license.8 The smallpox vaccine contains live vaccinia, a member of the orthopoxvirus family, which helps provide protection against smallpox. The vaccinia virus is genetically distinct from smallpox and cowpox. Because the vaccine contains a live virus, care must be taken not to spread the virus from the vaccination site to other parts of the body, or to other people. A special (bifurcated) needle is required to administer the vaccine into the superficial layers of the skin. The smallpox vaccine is only available through the CDC.

USE OF THE VACCINE

The Advisory Committee on Immunization Practices (ACIP) issued guidelines for use of the smallpox vaccine in the pre-event setting, including voluntary vaccination of healthcare providers.9 Pre-event is defined as the period of time, after the eradication of naturally occurring smallpox, when there is no case of smallpox in the world. The vaccine can also be used after a smallpox exposure. Use of the vaccine within three days, and possibly within four to seven days after an exposure, will prevent or greatly reduce the severity of smallpox symptoms in most people. Additionally, healthcare workers administering the vaccine should be vaccinated.

ADMINISTRATION AND RESPONSE TO VACCINE

A special technique using a unique (bifurcated) needle is used to give the smallpox vaccine.8,10 The vaccine is not given intramuscularly (IM), intravenously (IV), or subcutaneously (SC). The skin over the outer aspect of the upper arm is the preferred site for vaccination. The skin is not prepped with alcohol or other disinfectant (use of a disinfectant can kill the vaccine virus). While wearing protective gloves and using aseptic technique, a sterile bifurcated needle is dipped into the reconstituted vaccine. A small amount is held between the two prongs. The needle, held perpendicular to the skin, is then used to puncture the skin 3 times for primary vaccination and 15 times for revaccination, in a 5-millimeter diameter area. When done correctly, a trace of blood appears after 15-20 seconds. Excess vaccine is wiped from the skin. The site is covered with a dressing.

The inoculated vaccinia virus multiplies in the superficial layers of the skin. The immunity that develops against vaccinia provides protection against smallpox. The vaccination site, with primary vaccination, progresses through a series of changes. Three to four days after vaccination the site becomes reddened, pruritic and a papule appears. Vesicles appear on the fifth or sixth day. The vesicles are surrounded by erythema and induration. The vesicles become umbilicated then pustular (days 7 to 11). Approximately 8 to 12 days following vaccination, the maximal area of erythema is attained. Swelling and erythema subside and a crust forms. By day 21 the crust separates, leaving a permanent scar. Regional adenopathy occurs at the peak of the primary response, fever and malaise may also occur.

Primary vaccination elicits a response in about 95% of those vaccinated. Revaccination elicits a less intense response. Successful vaccination provides full immunity for 3 to 5 years and decreases thereafter. Antibody response after primary vaccination occuts 4 to 8 days earlier than after naturally acquired smallpox infection, explaining why vaccination after exposure may prevent or modify a case of smallpox. Some people can develop an allergy to viral proteins from either live or dead vaccines. When someone with hypersensitivity to the vaccine is revaccinated, they develop skin changes that appear within the first 24 to 48 hours. Individuals with residual immunity from prior vaccination develop skin changes more rapidly than occurs after primary vaccination. Because it is difficult to distinguish a hypersensitivity reaction from a rapid response, due to high-level immunity, the WHO Expert Committee on Smallpox defines such reactions as an equivocal reaction. An equivocal reaction indicates the possibility of immunity or an allergic reaction without protective immunity. An antibody rise occurs in approximately half of those who have an equivocal reaction. Additionally, inadequate technique or impotent vaccine can produce an equivocal reaction.10

The presence of a pustular lesion or an area of definite palpable induration surrounding a central lesion, such as a crust or an ulcer, found 6 to 8 days after vaccination is a major reaction. A major reaction is indicative that virus growth took place and vaccination was successful. Some refer to successful vaccination as a "take".

CONTRAINDICATIONS TO ROUTINE NON-EMERGENCY VACCINE USE

The smallpox vaccine is the best protection against smallpox. Serious complications have occurred as a result of vaccination. Primary vaccination and revaccination with smallpox vaccine are contraindicated for any of the following: 1. individuals who are allergic to polymyxin B sulfate, dihydrostreptomycin sulfate, chlortetracycline hydrochloride, neomycin sulfate, or any other component of the vaccine; 2. individuals with eczema or past history of eczema or exfoliative skin conditions such as burns, wounds, impetigo, or varicella zoster and for those who have household contacts with such conditions; 3. individuals receiving systemic corticosteroids therapy at certain doses (> or =2 mg/kg body weight or > or =20 mg/day of prednisone for > or =2 weeks), or immunosuppressive drugs (e.g., alkylating agents, antimetabolites), or radiation and for those who have household contacts with such conditions; 4. immunosuppressed individuals (leukemia, lymphomas, generalized malignancy, solid organ transplantation, hematopoietic stem cell transplantation, cellular or humoral immunity disorders, agammaglobulinemia) and for those who have household contacts with such conditions; 5. individuals with congenital or acquired deficiencies of the immune system including individuals infected with the human immunodeficiency virus (HIV) and for those who have household contacts with such conditions; 6. pregnant or suspected pregnant women and those who have household contacts who are pregnant or 7. women who are breastfeeding.8 The ACIP advises against non-emergency use of smallpox vaccine in children under 18 years of age.10

CARE OF THE VACCINATION SITE AND PREVENTION OF CONTACT TRANSMISSION OF VACCINIA

The vaccination site should be kept dry. During bathing cover the site with a waterproof dressing. The vaccination site should be kept covered. Vaccinia virus has been cultured from the vaccination site; beginning from the time a papule develops (2 to 5 days after vaccination) until the scab separates from the skin lesion (14 to 21 days after vaccination). Hence, care must be taken to prevent the spread of the virus to other parts of the body, or to others. For example, scratching the site, then touching the eyes can lead to inoculation of the eye. Transmission to others has occurred.

CARE OF THE VACCINATION SITE FOR HEALTHCARE WORKERS

Following smallpox vaccination, the ACIP recommends that health-care workers involved in direct patient care should keep their vaccination sites covered with gauze to absorb any exudate that develops, that in turn is covered with a semipermeable dressing to provide a barrier to vaccinia virus or a dressing that combines both.9 Semi-permeable dressing when used alone can cause maceration of the skin with resultant irritation and pruritus at the site, potentially increasing hand contact with the vaccination site. The vaccination site should be covered during direct patient care until the scab separates.

ADVERSE REACTIONS

Historically, about 1,000 for every 1,000,000 people vaccinated for the first time had a reaction to the vaccine.11 Most reactions were not life-threatening. Approximately 14 to 52 people out of 1 million had potentially life-threatening reactions. Certain adverse events, such as post-vaccinial encephalitis and generalized vaccinia, were more common in infants. (Table 1) In general, adverse events were less common after revaccination than after primary vaccination. Using historical data, it is estimated that 1 or 2 out of every 1 million people who receive the vaccine will die as a complication. Death is most often the result of postvaccinial encephalitis or progressive vaccinia.10,12 Death has also occurred in unvaccinated contacts of recently vaccinated individuals.12 Less serious side effects include fever > or =100°F occurring in up to 70% and >102°F occurring in up to 20% of children after primary vaccination. After revaccination, 35% of children develop temperatures of > or =100°F and 5% have temperatures of >102°F. Fever is less common in adults than children after vaccination or revaccination.10 A recent study of adult vaccine recipients showed that between days 7 to 9; 8.9% had fever > 100°F, 3.0% had fever > or = 101°F, and 0.8% had fever > or =102°F.13 From days 0 to 14; 15.9% to 44.2% of vaccine recipients had headache, 9.3% to 50.4% had muscle aches, 1.8% to 17.7% had chills, 3.8% to 15.8% had nausea, 17.4% to 52.8% had fatigue, 26.6% to 76.7% had pain at the vaccination site. The majority of patients categorized the side effects as mild or moderate, while the minority (3% or less) was severe.13

Cutaneous adverse reactions to the smallpox vaccine include accidental implantation, generalized vaccinia, eczema vaccinatum, and progressive vaccinia. Accidental implantation (inadvertent inoculation) refers to inoculation, usually via the hands, of vaccinia to other body sites. Common sites include the face, eyelid, genitalia, and rectum. Eye involvement may result in blindness. Historically, accidental implantation was the most frequent adverse event. Generalized vaccinia is the occurrence of vesicular lesions beyond the vaccination site. The rash is self-limited in healthy persons and rarely recurs. Eczema vaccinatum is a localized or systemic spread of vaccinia virus in persons who have eczema, or a history of eczema. It occurs independent of the activity of the underlying eczema. It may also occur in individuals with other chronic or exfoliative skin conditions. The severity ranges from a mild self-limited reaction to a severe and sometimes fatal reaction. It occurs more commonly among those receiving primary vaccination compared to those receiving revaccination. (Table 1) Eczema vaccinatum may occur among unvaccinated household contacts of recently vaccinated individuals.

Progressive vaccinia (vaccinia necrosum) is a severe, sometimes fatal adverse event due to the smallpox vaccination. It is characterized by progressive necrosis at the vaccination site. Lesions may appear elsewhere on the body. It usually occurs in individuals with some form of immunodeficiency. Other rare cutaneous adverse events due to smallpox vaccination include generalized rashes (erythematous, urticarial, nonspecific), bullous erythema multiforme (Stevens-Johnson syndrome) and secondary pyogenic infections at the site of vaccination.10

Neurological complications include postvaccinial encephalopathy and postvaccinial encephalitis. The distinction is based on pathologic findings. Studies have included both processes under the category postvaccinial encephalitis. Postvaccinial encephalopathy occurs primarily in children less than 2 years of age. Fevers and convulsions begin within 6 to 10 days of vaccination. The individual is usually left with some permanent sequelae. Postvaccinial encephalopathy can be fatal. Postvaccinial encephalitis usually affects those more than 2 years of age and begins 11 to 15 days after vaccination. The mortality is 10 to 35%. Survivors may have permanent sequelae.2

Vaccinia keratitis is the result of implantation of vaccinia into the conjunctiva and cornea. Initially viral replication and ulceration occur. Corneal cloudiness occurs as a result of antigen-antibody interaction. Use of VIG (vaccinia immune globulin) is contraindicated.

Rare reports of fetal infection have occurred in pregnant women, leading to stillbirth or death of the infants shortly after delivery. This usually occurred after primary vaccination. Vaccinia vaccine is not known to cause congenital malformations.10 Women of childbearing age should be instructed not to become pregnant for at least 4 weeks after vaccination.

The risk of adverse reactions is lower after revaccination, compared to primary vaccination. Adverse reactions can occur in those revaccinated, especially those that have an impaired immune system. It is not known whether individuals who were vaccinated decades ago will respond like primary vaccinees or like those who received revaccination.10

CONTACT VACCINIA

Vaccinia is a live virus that can be spread to others. Hence, unvaccinated contacts such as household contacts can become infected with the vaccinia virus (contact vaccinia) and develop complications. The two most commonly reported complications of contact vaccinia are accidental implantation (inadvertent inoculation) and eczema vaccinatum. For example, in 1963 there were 54 reported cases of contact eczema vaccinatum including two who died.14 During the same year there were 54 reported cases of eczema vaccinatum among 6.2 million primary vaccine recipients. Another complication of contact vaccinia is inadvertent inoculation. In 1963 there were 22 cases of inadvertent inoculation, mostly children age 1 to 4 years of age.

REPORTING ADVERSE REACTIONS

Report adverse reactions to Vaccine Adverse Event Reporting System (VAERS) at (800)-822-7967 or on-line at http://www.vaers.org.

EXPECTED ADVERSE EVENTS TODAY

Adverse event rates may be higher today if used in the general population because there may be more persons at risk from immune suppressive medications, organ transplantation, HIV/AIDS, eczema, etc. Screening for these conditions can decrease the number of adverse events. The use of semipermeable dressing and adherence to hand-hygiene may decrease inadvertent inoculation and contact vaccinia. The outcome associated with adverse events may be less severe than previously reported because of advances in medical care.

TREATMENT OF ADVERSE REACTIONS

Vaccinia immune globulin (VIG) is used to treat specific complications of smallpox vaccination including eczema vaccinatum, inadvertent inoculation of the eye (severe involvement) if keratitis is not present, severe generalized vaccinia if the patient is toxic or has a serious underlying disease, and progressive vaccinia. Vaccinia keratitis is a contraindication to VIG use, as it can make the condition worse. VIG is not indicated for the treatment of postvaccinial encephalitis or erythema multiforme.

Several antiviral compounds are active in vitro against vaccinia virus or other orthopoxviruses. Some are active in animal models. None of these anti-viral compounds are approved by the Food and Drug Administration (FDA) for the treatment of post-vaccination complications or orthopoxvirus infections (including smallpox).10

CONCLUSION

Although the risk of smallpox being used as a biological weapon is extremely small, it is not zero. Terrorist attacks on September 11, 2001, and the cases of human anthrax brought to the public's attention the risk of terrorists' acts occurring inside the United States. The possible use of anthrax, a biological agent, was a major public concern recently. Many biological agents, including smallpox, plague, tularemia, Marburg hemorrhagic fever, and botulinum toxin, may be used as biological weapons. The goal of the current smallpox vaccine program is to minimize the damage of smallpox if it is used as a biological weapon in the United States.

REFERENCES

1. The Jenner Museum. http:// www.jennermuseum.com/resources/ welcome.shtml

2. Henderson DA, Moss B. 1999. Smallpox and vaccinia. In SA Plotkin and WA Orenstein (ed.), Vaccines, 3rd ed. W.B. Saunders Company, Philadelphia, Pennsylvania. http://www.ncbi.nlm.nih.gov/books/ bv.fcgi?call=bv.View.ShowSection&rid= vacc.chapter.d1e2084

3. Alibek K, Handelman S. 1999. Biohazard. Dell Publishing a division of Random House, Inc. New York, New York.

4. Cohen J, Marshall E. Bioterrorism: Vaccines for biodefense: A system in distress. Science 2001; 294:498-501.

5. LeDuc JW, Jahrling PB. Strengthening national preparedness for smallpox: an update. Emerg Infect Dis 2001; 7:155-7.

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

7. Mack TM. Smallpox in Europe, 1950-1971. J Infect Dis 1972; 125:161-9.

8. Dryvax package label. http:// www.fda7.gov/cber/products/ smalwycl02502.htm

9. Summary of October 2002 ACIP Smallpox Vaccination Recommendations (Updated October 21, 2002). http:// www.bt.cdc.gov/agent/smallpox/vaccination/acip-recs-oct2002.asp

10. Vaccinia (Smallpox) Vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR. 2001; 50(RR10).

11. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: results often statewide surveys. J Infect Dis 1970; 122::303-9.

12. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: national surveillance in the United States. NEJM 1969; 281:1201-8.

13. Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. NEJM 2002; 346:1265-74.

14. Neff, JM, Lane JM, Pert JH et al. Complications of smallpox vaccination I. National survey in the United States, 1963. NEJM 1967; 276:125-32.

John R. Lonks, MD

John R. Lonks, MD, is Director, Infectious Diseases Inpatient Consult Service and Hospital Epidemiologist, Miriam Hospital, and Assistant Professor of Medicine, Brown Medical School.

CORRESPONDENCE:

John R. Lonks, MD

Infectious Diseases

Miriam Hospital

164 Summit Avenue

Providence, RI 02906

Phone: (401) 793-4620

Fax: (401) 793-4534

e-mail: John_Lonks@brown.edu

Copyright Rhode Island Medical Society Nov 2003
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