Featured Report:
Smallpox: A Scientific Update (I-02) Full Text

This Council on Scientific Affairs report summarizes the numerous reviews on smallpox that have been published, provides an update on recent scientific developments in smallpox and smallpox vaccine, and presents several recommendations.

Data Sources: Literature searches conducted in the MEDLINE database for English-language articles published between 1987 to 2002 using the search terms smallpox or variola yielded a combined total of 822 references. Emphasis was placed on 273 articles published from 1997 to 2002. Fifty-one additional references were culled from the bibliographies of these references. Lexis/Nexis news databases were searched for current developments using the search terms smallpox or variola. The World Wide Web was searched using the Google search engine with the search terms smallpox or variola. Relevant Web references were examined for accuracy and appropriateness.

CLINICAL FEATURES OF SMALLPOX

Since the eradication of smallpox was declared in 1980, many excellent reviews have been published in the medical literature on the clinical features of smallpox.^1-17 It is not the intention of this report to repeat that information but to provide a brief overview of the clinical features of this disease.

The variola virus, the agent of smallpox, belongs to the poxviridae family of viruses. In this family, variola is a member of the orthopoxvirus genus along with the vaccinia virus (which is the virus used for the smallpox vaccine), cowpox, rabbitpox, monkeypox, and others.¹⁸ There are 2 forms of variola¹⁶; Variola major, the most severe form, is the subject of this report. Variola minor is much less severe, with a case fatality rate of about 1%.⁹ As first described by Ramachandra Rao and affirmed by the World Health Organization in 1972,1^6,17,19 there are 5 clinical types of variola major:

Ordinary-type smallpox: This type presents clinically with raised pustular skin lesions; there are 3 subtypes based on the density of the rash/pustules: (a) confluent – confluent rash on the face and forearms; (b) semiconfluent – confluent rash on the face but discrete pustules elsewhere; and (c) discrete – areas of normal skin exist between pustules, even on the face.

Modified-type smallpox: This type is similar to the ordinary type but has an accelerated course.

Variola sine eruptione: This type of smallpox presents clinically with a fever, but without the rash caused by variola virus; it generally occurs in vaccinated contacts of persons with smallpox. Serological confirmation is needed to confirm this type of disease.

Flat-type smallpox: This type presents clinically with flat pustules that are usually confluent or semiconfluent. This type of smallpox has a very high mortality rate.

Hemorrhagic-type smallpox: This type presents clinically with widespread hemorrhages in skin and mucous membranes. There are 2 subtypes: (a) early, with a purpuric rash; this form is always fatal; and (b) late, with hemorrhages into the base of the pustules. This type is usually fatal. Back to Top

Clinical Progression of Smallpox

Smallpox proceeds in 3 distinct stages: the incubation period, the pre-eruptive stage, and the eruptive stage.^8,10,16 The eruptive stage can be subdivided based on the appearance of the rash and the stage of development of the pustules.

Incubation period: This is the period between infection with the variola virus and onset of the first clinical symptoms. During the incubation period, intense viral replication occurs, virus load increases, and virus spreads throughout the body. In the majority of cases this period extends from 10 to 14 days following implantation of the virus. There are no symptoms of infection or disease. The patient is not infectious during this period.

Pre-eruptive stage: The incubation period ends when the patient develops a fever and becomes ill, presumably due to viremia. This pre-eruptive or prodrome stage is characterized by sudden onset of fever and malaise, with the temperature usually rising to between 101^oF and 105^oF. Patients experience an intense headache and extreme backache leading to prostration. Many develop delirium, and more than half develop severe vomiting; 10% develop diarrhea. Some patients also suffer abdominal colic, which can lead to the mistaken diagnosis of appendicitis. The patient is generally very ill, with an appearance of general toxemia. This stage usually lasts for 2 to 3 days prior to the appearance of a rash, and at this time the patient is still not infectious to others. By the second or third day (but rarely the fourth), body temperature falls and the patient feels somewhat better. At about this time, the eruptive stage begins and a macular rash appears.

Eruptive stage (macules): Lesions on the mucous membranes (the enanthem) are the first to appear as visible spots on the tongue and palate, about 24 hours prior to the appearance of rash on the skin. Lesions also may occur in the respiratory tract. Patients who complain of sore throat usually have an enanthem on the pharynx. This enanthem evolves quickly and becomes papular and then vesicular and breaks down by the third day. This is important because when the enanthem breaks down, it releases large amounts of infectious virus into the saliva. The pharyngeal lesions are most significant epidemiologically as they are the primary source of infectious virus. Thus, it is at the macular stage of the disease that the person becomes infectious and can transmit smallpox to his/her contacts.

The ensuing skin rash appears about 2 to 4 days after the onset of fever, typically as a few small flat macules on the face, usually the forehead. Lesions then appear on the proximal extremities, on the trunk, and lastly on the distal extremities. This spread of the macules is rapid and usually occurs within 24 hours of its first appearance. The rash appears on all parts of the body.

Eruptive stage (papules): By the second day of the skin rash, the macules become raised and are now described as papules. While a misnomer, because the reason for the raising is the movement of fluid into the tissue spaces (effectively making them vesicles), the term has remained in use.

Eruptive stage (vesicles): By the fourth or fifth day of the skin rash, all papules are obviously vesicles. The fluid contained in the vesicles initially appears opalescent, but over the course of 24 to 48 hours becomes opaque and turbid.

Eruptive stage (pustules): By the seventh day of the rash, all skin lesions reach one stage of development and have become pustules, which mature and reach their maximum size by the tenth day of the rash. Beginning on the eleventh day of the rash, the pustules begin to heal and the lesions flatten. Fluid within the pustules is slowly absorbed.

Eruptive stage (scabs, scars): By the end of the second week of the skin rash, the fluid in the pustules has been absorbed and the central portion of the lesion is dry and hardened, forming a scab. This scab later separates, leaving behind an area that is depigmented and possibly scarred. Historically, the patient is not discharged until the last scabs have fallen off. While smallpox can survive for up to weeks in these infected scabs, there are no data indicating that scab-borne virus can serve as a source of infection. Historically, smallpox was inevitably followed by death or recovery. There is no persistent, chronic, recurrent, or latent infection with variola, and cases are never infectious following disappearance of the rash.

Distinguishing Smallpox from Chickenpox: Smallpox is most commonly confused with chickenpox, and in the early stages of the skin rash, it may be impossible to distinguish between the two. However, smallpox lesions generally develop simultaneously at the same rate, and on any one part of the body will appear identical. The smallpox rash evolves centripetally and lesions appear on the palms and soles.^8,11,12,16 With chickenpox, vesicles, pustules, and scabs all may appear on adjacent areas of the skin.^11,12 Chickenpox lesions also tend to be most dense in the trunk region, and are much more superficial than smallpox lesions.^11,12 It is highly recommended that the interested reader refer to the publication by Fenner et al for a more detailed description and for color images of the different stages of clinical smallpox.¹⁶ The Centers for Disease Control and Prevention (CDC) provides a tool for evaluating patients for smallpox at http://www.cdc.gov/nip/smallpox/Providers.htm#Poster. Back to Top

EPIDEMIOLOGY OF SMALLPOX

The following discussion summarizes information published in numerous reviews.^7,10,16 However, it focuses primarily on epidemiological issues that are most pertinent to understanding the issues surrounding the use of smallpox as a bioweapon.

Infection and Infectivity

Smallpox can theoretically enter the body by 3 main routes: the respiratory tract, the alimentary tract, and the skin. However, no evidence exists to indicate that infection occurs via the alimentary tract,¹⁶ and natural infection through the skin is unusual. The primary route for infection is via the oropharynx or nasopharynx, and sometimes via the lower respiratory tract.¹⁶ After the virus enters the nose or mouth, usually by inhalation of infectious droplets expelled by an infected person, it moves to the respiratory tract and infects the mucous membranes and passes into the local lymph nodes.^8,16

The infectiveness of the aerosol droplets is determined by size.²⁰ Large droplets are retained in the nose or are trapped in the oropharynx and swallowed. Only particles <1 micron pass into the lungs. Particle size also affects the speed with which they fall to the ground. Small liquid particles dry rapidly and have a better likelihood of floating for a longer time in the air, increasing the opportunity for inhalation.¹⁶ The other factor that determines infectivity of aerosol droplets is the amount of infectious virus in the particles.¹⁶ Obvious difficulties exist in determining the exact dose of variola virus necessary to produce an infection in humans. However, the form in which the infectious virus is presented is more indicative of a successful infection than the dose of virus. Thus, exposure to infectious virus in fresh oropharyngeal droplets from an infected person during enanthem is likely to cause infection while exposure to virus enclosed in scabs is not, even though scabs contain far more virus particles.^8,16

Following entry into the lymph nodes, after a brief viremia, the virus reproduces in the reticuloendothelial system.^8,21 Just before the onset of the pre-eruptive or prodromal phase, there is another spike of viremia leading to infection of the mucous membranes of the mouth and pharynx. At this point, the lesions characteristic of the enanthem begin to appear, rash becomes visible on the body, and the person becomes infectious.¹⁶

Smallpox Transmission from Infected Persons

People infected with smallpox release infectious virus through oropharyngeal secretions and later, into their scabs. However, virus in scabs is trapped in the fiber of the scab and has not been demonstrated to be transmissible.¹⁶ As noted above, smallpox spreads primarily through the droplets of oropharyngeal secretions (direct transmission), but infected clothing or bed linens can also spread disease (indirect transmission).^16,22 Once bedding is wet down, however, it is no longer infectious.^16,22 Very rarely, longer-range indirect transmission of smallpox can occur when contaminated droplets are coughed or sneezed into the air and carried away from the patient by air currents. Smallpox is not transmitted via food or water.

Direct transmission: The maximum period for infectivity is during the first week of the rash, corresponding to the time when the lesions in the oropharyngeal cavities associated with the enanthem are ulcerating and releasing virus into the mouth.^8,10,16 Infectivity declines significantly once the oropharyngeal lesions in the mouth heal, generally during the second week of the disease. Epidemiological evidence strongly indicates that transmission of smallpox rarely occurs before the first day of the rash; that is, during the incubation and the pre-eruptive stages.¹⁶

The overwhelming majority of secondary infections due to direct contact with an infected person have been in close family contacts of overt cases of smallpox, especially those who slept in the same room or the same bed.^{8,10,16,23,24} The next most frequently infected were those living in the same house. People living in other houses within the same immediate community as the infected patient were less likely to be infected. These epidemiological data indicate that successful transmission of smallpox requires prolonged close contact with the infected person.^23,24 Similarly, data from India indicate that long-distance travel by train or bus of smallpox-infected persons with an overt rash rarely resulted in infection of casual fellow travelers in the same train or bus.¹⁶

Indirect transmission: Indirect transmission in the absence of direct patient contact is possible via airborne viral particles or via viral particles on fomites.¹⁶ However, evidence indicates that direct face-to-face contact is primarily responsible for transmission and thus, indirect contact is only considered responsible when all possibilities of direct contact have been eliminated. With respect to bioterrorism, indirect transmission via airborne infection poses the most interest.

There is evidence that indirect airborne transmission of smallpox can occur, but not frequently. For example, over a 10-year period in the Madras Infectious Diseases Hospital, out of more than 130,000 non-smallpox patients housed in wards only a few feet away from the smallpox wards, only 7 cases of smallpox could be presumed to have been acquired in the hospital.¹⁶ The smallpox vaccination status of these 130,000 patients was also known to be poor. However, 2 outbreaks of smallpox in Germany, at Monschau and at Meschede, were almost certainly due to airborne transmission.^16,25 In Meschede,²⁵ an electrician was admitted to the isolation ward of a large general hospital with a fever suspected to be typhoid. He was confined to his room and 3 days later developed a rash. smallpox was confirmed 2 days later and the patient was transferred to the smallpox hospital. Despite rigorous isolation of the patient due to the suspicion of typhoid fever, and vaccination of all patients and nurses in the general hospital, ¹⁹ further cases of smallpox occurred on all 3 floors of the building where the electrician had been housed. Extensive examinations conducted in the hospital included measurement of air currents. Notably, smoke released in the isolation room where the index patient was housed easily spread to many other areas on the same floor and significantly into many areas on the 2 floors above the patient’s room. Following the investigation, 3 unusual factors were identified that facilitated this airborne transmission of smallpox²⁵:(1) the electrician (index case) had an unusual case of smallpox with a densely confluent rash and severe bronchitis and cough facilitating expulsion of infectious aerosol droplets; (2) the relative humidity of the hospital was very low, promoting survival of the virus; and (3) the hospital design was such that when the building’s heat was turned on (and it was as it was winter) strong air currents were generated.

A substantive study on indirect transmission through the contaminated clothing and bed linens of smallpox patients concluded that for laundry workers, the greatest risk of infection was among those who sorted the incoming laundry and could thus inhale contaminated dust.²² Once the bed linens were wet down, they were no longer infectious.²²

Average Transmissibility of Smallpox in the Human Population

An important factor in assessment of the risk from an outbreak of smallpox is R0: the average number of secondary cases infected by each primary case of smallpox. Based on the variables described above, this value for smallpox is estimated to be between 3.5 and 6 for populations with negligible herd immunity.²⁶ This places smallpox at the same level of infectiousness as diphtheria, mumps, polio, and rubella, but far below that of measles, pertussis and influenza.^26-28 This R0 figure is consistent with the data summarized above and reflects the fact that infection almost always involves prolonged face-to-face contact with an infectious person, and that smallpox spreads very slowly.^23,24,29 There generally was an interval of 2 to 3 weeks between each generation of cases, and data indicate that even during the winter transmission season, the R0 value rarely exceeded 5.^16,26

Surveillance and Containment for Controlling Transmission of Smallpox

Data from the campaign to eradicate smallpox showed conclusively that the strategy of surveillance and containment (also known as ring vaccination) was remarkably successful at detecting and containing disease transmission from multiple outbreaks of smallpox. ^16,23 During the eradication campaign, it was shown that despite mass vaccination efforts, smallpox cases continued to occur among unvaccinated persons.²³ Surveillance and containment involves surveillance for cases of smallpox, the provision of immunity around each case via vaccination and quarantine, and then the provision of immunity and quarantine around the contacts. This strategy is facilitated by the slow spread of disease from the primary cases to the secondary contacts.^23,29 Ultimately, the eradication of smallpox was due to the success of the surveillance and containment strategy.

Survivability of the Variola Virus

A study has been performed by Rao on the ability of the variola virus to survive on various inanimate objects.¹⁶ Significantly, even on heavily contaminated objects, the virus was rapidly inactivated. Virus in scabs has a much longer survival time but such virus is not a source of infection.^16,30

Smallpox virus survivability is adversely affected by both high heat and high humidity.^16,31,32 It has been shown that aerosols of infectious droplets can survive for 60 minutes in low relative humidity and that 60-minute survivability drops somewhat at a high relative humidity.³¹ For longer periods, experiments with vaccinia virus indicate that viability of virus within aerosols is greatest at low temperatures (51^oF to 53_oF) and low humidity (less than 50%).³² In these conditions, 59% to 66% of virus can survive for 23 hours. However, when the humidity increases to 82%, even at low temperatures, survivability at 23 hours drops to 27%.³² Significantly, at 71^oF to 73^oF and 50% humidity, only 50% of virus remained viable after 6 hours, and at 23 hours only 12% remained viable.³² This effect seems to be consistent with variola virus as well¹⁰ and explains the epidemiologic observation that smallpox is a winter disease and more common in the colder and drier months.¹⁶ Finally, variola virus does not appear to survive well in direct sunlight.^10,13,33  Back to Top

MANAGEMENT OF SMALLPOX CASES

Should a case of smallpox be suspected, state health officials must be contacted immediately.³⁴ Confirmatory diagnosis would require the use of a Biological Safety Level 4 laboratory where all staff have been vaccinated. Patient isolation should occur as rapidly as possible and interviews performed to identify contacts.³⁴ Contacts should be vaccinated as soon as possible but within 3 days after exposure, as vaccination for up to 4 days following the initial exposure is protective against acquiring infection.^7,10,22 Health care providers caring for the patient should observe universal precautions and also use airborne and contact precautions.³⁴

Treatment

A patient with suspected smallpox must be isolated in a negative pressure treatment room and should be vaccinated, especially if the disease is still in an early stage.⁸ Respiratory and contact isolation must be maintained. There is no approved treatment for smallpox and care is primarily supportive. Experimental models with rabbitpox suggest that death is primarily due to inflammation and its complications.^35,36 Thus, smallpox patients should be treated as for inflammatory shock or burns.³⁷ There is a possibility of bacterial superinfection, in which case a penicillinase-resistant antimicrobial agent is indicated.8,17 Other indications for antibacterial therapy are if the eyes are threatened or if the eruptive phase is very dense and widespread.¹⁷ At all times, dehydration, renal failure, nutritional support, and airway maintenance must be considered.¹⁷

Cidofovir: Cidofovir is a nucleotide analogue that inhibits viral DNA polymerase by competitive inhibition of dCTP.^38,39 It is currently approved for clinical use in the treatment of cytomegalovirus retinitis in AIDS patients. It has broad spectrum activity against virtually all DNA viruses and the poxviruses also have been shown to be sensitive to cidofovir in vitro.^38,39 Recent studies on the efficacy of cidofovir indicate that subcutaneous administration protects mice from a lethal aerosol or intranasal challenge with vaccinia or cowpox virus.⁴⁰ Further studies have demonstrated that cidofovir administered as an aerosol can effectively treat an aerosolized cowpox infection in mice.⁴¹ Additionally, in humans, cidofovir has been shown to be highly effective in treatment of recalcitrant molluscum contagiosum, a cutaneous skin growth caused by the poxvirus (molluscum contagiosum)⁴² and for orf caused by the parapoxvirus.⁴³ At the 15th International Conference on Antiviral Research in March 2002, Hostetler and coworkers reported that hexadecyloxy-propyl-cidofovir (HDP-cidofovir) administered orally to mice that had been lethally inoculated with cowpox virus effectively protected them from death.⁴⁴ HDP-cidofovir has also been shown to have in vitro activity against the variola virus.⁴⁴ These data suggest that cidofovir is likely to be effective in the therapy and short-term prophylaxis of smallpox and other poxvirus infections in humans, and it should be investigated as a promising strategy for treatment of smallpox infections.

Cidofovir, however, does have some serious side effects. Indeed, more than 20% of patients on cidofovir terminate therapy due to a side effect.^45,46 Toxicities include nephrotoxicity, with proteinuria and an increase in creatine levels, and neutropenia.⁴⁵  Back to Top

VACCINIA (SMALLPOX) VACCINATION

The Vaccinia (Smallpox) Vaccine

Vaccination to protect against smallpox is achieved by inoculation with the live vaccinia virus or the cowpox virus.⁷ The latter, of course, harkens back to the days of Edward Jenner’s observation of protection from smallpox in cowpox-infected persons.⁴⁷ In the United States, routine vaccination with vaccinia vaccine was halted in 1972, 8 years before the global eradication of smallpox was declared. It was judged at that time that the risk of adverse events from smallpox vaccination outweighed any benefits, due to the low risk for infection in a population with minimal potential exposure to smallpox. Additionally, this decision was made easier because the US population was already well immunized for smallpox,^48,49 and it was felt that any outbreaks could be immediately dealt with using the strategy of surveillance and containment (ring vaccination).^23,48

The vaccinia vaccine currently under license as an Investigational New Drug (IND) in the United States is a lyophilized, live-virus preparation of infectious vaccinia virus.^37,50 The vaccine is prepared from calf lymph with a seed virus derived from the New York City Board of Health (NYCBOH) strain of vaccinia virus and has a minimum concentration of 108 pock-forming units (PFU)/ml. The vaccine is administered using the multiple-puncture technique with a bifurcated needle.⁵¹ Currently, about 15 million doses of this vaccine are available in the United States.⁵² Additionally, in March 2002, Aventis-Pasteur discovered a stockpile of 75 to 90 million doses of vaccinia vaccine held in storage since routine smallpox vaccination ended in 1972 and early signs indicate that the vaccine is still potent.⁵³ The company has donated these vaccine doses to the US government.⁵⁴

A reformulated vaccinia vaccine, produced using cell-culture techniques, is now being developed.^21,50,51 This new vaccine was contracted for by the US government, and 150 million doses are expected to be ready by March 2003.^37,50 A second contract has also been initiated by the US government to produce an additional 54 million doses of vaccine over the next year.^37,50 This, coupled with the existing supply of original vaccine, would be sufficient to provide vaccinations to the entire population if necessary.

However, all smallpox vaccines are under IND status and it is expected that clinical trials on the new cell-culture vaccines will proceed through the end of 2003.^21,37,50 Thus licensure for the new vaccines from the Food and Drug Administration is not expected until the end of 2003 or in 2004.³⁷ Consequently, until licensure is achieved, vaccine administration can only be performed by federal, state, or local health personnel, and would require a significant informed consent process. The CDC is currently developing a simplified informed consent form that could be used in the event of a smallpox outbreak that demands rapid vaccination of a large population.³⁷

Vaccinia Vaccine Efficacy: Neutralizing antibodies induced by vaccinia vaccine are cross-protective for other Orthopoxviruses (eg, monkeypox and variola viruses).^16,55,56 Although the efficacy of vaccinia vaccine has never been precisely measured in controlled trials, epidemiologic studies demonstrate that an increased level of protection against smallpox persists for <5 years after primary vaccination and substantial but waning immunity can persist for >10 years.^5,57

Greater than 95% of primary vaccinees will experience neutralizing or hemagglutination inhibition antibody at a titer of >1:10. Neutralizing antibody titers of >1:10 persist among 75% of persons for 10 years after receiving second doses of vaccine and <30 years after receiving 3 doses. Generally, less than 10% of persons with neutralizing titers of >1:10 exhibit a primary-type response at revaccination, compared with >30% of persons with titers <1:10, implying that the 1:10 titer level is indicative of protection against infection.⁵¹

Finally, it has been demonstrated that smallpox vaccine can be administered as late as 4 days after the first exposure and provide significant protection against acquiring smallpox infection or mortality should infection occur.^10,16,22

Duration of Immunity: The duration of immunity following a smallpox vaccination is unknown; however, there are reports suggesting that humoral immunity wanes within 10 to 20 years following vaccination.5 Conversely, some data suggest that even after 30 years, enough immunity persists to prevent mortality or severe disease. In a study by Hanna et al, 93% of adults who were vaccinated in infancy and were exposed to smallpox in their 50s survived and did not experience severe disease.^16,57 In contrast, 50% of unvaccinated adults died. Another study⁵⁸ following the importation of cases into Europe and Canada (1950–1971) showed that mortality was 52% in unvaccinated persons, 1.4% in those vaccinated up to 10 years before exposure, and 11% in those vaccinated more than 20 years before exposure. For those aged 10 to 49 years, the mortality rate was 49% in the unvaccinated and 4.3% in those vaccinated 20 years earlier. In a study on Israeli defense forces, it was reported that while antibody levels may drop after the first 3 years following vaccination, the cellular immune response remains active for at least 30 years.⁵⁹ Furthermore, in 1996, Demkowicz and coworkers reported that cellular immunity to smallpox antigens persists as long as 50 years after vaccination.⁶⁰ These data on the long-term persistence of cellular immunity have recently been supported by another report from Frelinger and Garba.⁶¹ These persistent cellular immune responses may explain the data seen in the study by Hanna et al.

Contraindications to Vaccinia (Smallpox) Vaccination: Before administering vaccinia vaccine, a thorough patient history must be performed to document the absence of vaccination contraindications among both vaccinees and their household contacts. Efforts should be made to identify vaccinees and their household contacts who have eczema, a history of eczema or atopic dermatitis, or immunodeficiencies. Vaccinia vaccine should not be administered if these conditions are present among either recipients or their household contacts. Contraindications to vaccination as summarized from the ACIP 2001 recommendations, include:⁵¹

• History or presence of eczema, atopic dermatitis, or other skin conditions.
  Vaccinia vaccine should not be administered to persons with eczema/atopic dermatitis of any degree, those with a past history of eczema/atopic dermatitis, those whose household contacts have active eczema/atopic dermatitis, or whose household contacts have a history of eczema/atopic dermatitis because of the increased risk for eczema vaccinatum. Persons with other acute, chronic, or exfoliative skin conditions (eg, burns, impetigo, or varicella zoster) may also be at higher risk for eczema vaccinatum and should not be vaccinated until the condition resolves.
• Pregnancy.
  Live-viral vaccines are contraindicated during pregnancy; therefore, vaccinia vaccine should not be administered to pregnant women for routine nonemergency indications. Vaccinia virus has been reported to cause fetal infection on rare occasions, almost always after primary vaccination of the mother. When fetal vaccinia does occur, it usually results in stillbirth or death of the infant soon after delivery.
• Altered Immunocompetence.
  Replication of vaccinia virus can be enhanced among persons with immunodeficiency diseases and among those with immunosuppression (eg, as occurs with leukemia, lymphoma, or generalized malignancy; solid organ transplantation; cellular or humoral immunity disorders; or therapy with alkylating agents, antimetabolites, radiation, or high-dose corticosteroids). Persons with immunosuppression also include hematopoietic stem cell transplant recipients who are <24 months post-transplant, and hematopoietic stem cell transplant recipients who are >24 months post-transplant but who have graft-versus-host disease or disease relapse. Persons with such conditions or whose household contacts have such conditions should not be administered vaccinia vaccine.
• Persons infected with HIV and their household contacts.
• Infants and Children.
  While vaccinia vaccine was routinely administered during childhood before the eradication of smallpox, it is no longer indicated for infants and children. With respect to the new reformulated vaccine, clinical trials with a pediatric population should be considered to determine the effects of vaccinia vaccine on this population.
• Persons with Allergies to Vaccine Components.
  The currently available vaccinia vaccine contains trace amounts of polymyxin B sulfate, streptomycin sulfate, chlortetracycline hydrochloride, and neomycin sulfate. Persons who experience anaphylactic reactions to any of these antibiotics should not be vaccinated.
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RISK OF ADVERSE EVENTS FROM VACCINIA (SMALLPOX) VACCINATION

Because the vaccinia vaccine is a live virus vaccine, adverse events associated with its administration differ from those associated with other currently used vaccines.^{1,37,51,62-67} Data from CDC national public forums indicate a widespread belief by physicians and the public that the smallpox vaccine is "as safe as routinely recommended childhood vaccines."³⁷ However, although the vaccine is safe and effective in the presence of smallpox, a careful risk-benefit assessment is necessary given that there are no smallpox cases in the world.^21,48,49,65 When the United States stopped routine vaccination with vaccinia vaccine in 1972, policymakers at the time concluded that the risks of adverse events no longer justified the benefits of vaccination when smallpox was no longer a major threat in the United States.^48,49 These adverse events include:^{1,37,51,62-67}

Noninfectious rashes: Erythema mulitiforme and a variety of others; rarely, Stevens-Johnson syndrome.
Bacterial superinfection: Staphylococcus, Streptococcus, others.
Accidental inoculation: autoinoculation (self) or from a vaccine recipient.
Congenital vaccinia: rare.
Generalized vaccinia: more common; usually benign, but can progress.
Progressive vaccinia: vaccinia necrosum, vaccinia gangrenosa, primarily in immunodeficient individuals and children.
Post-vaccination encephalitis: rare.
Other miscellaneous adverse events: hemolytic anemia, arthritis, osteocarditis, pericarditis, myocarditis.

Rates of Adverse Events Following Smallpox Vaccination

Historically, individuals who were vaccinated for the first time experienced adverse events at a greater than 10-fold higher rate than those being revaccinated, and rates of adverse reactions are higher in infants and young children than in older children and adults.^1,37,66 It is important to realize that beliefs about the incidence of adverse events are based on data obtained when smallpox was extant and vaccination programs were ongoing. Thus, these rates do not reflect the current US population, a large proportion of which would be receiving the vaccine for the first time. Also, the US population includes a large segment of immunodeficient individuals due to HIV infection, cancer chemotherapy, immunosuppressive therapy of organ transplant recipients, and other causes.⁶⁸ Additionally, it is uncertain what the impact of vaccination would be on the large elderly population in the United States.

Inadvertent inoculation at other sites (either via autoinoculation or from secondary inoculation through contact with a vaccine recipient) is the most common vaccine complication.^62,63,66 It accounts for almost 50% of all adverse events associated with primary vaccination. Although most lesions heal without therapy, circumstances exist that predispose an exposed person to serious complications. These include ocular inoculation and eczema vaccinatum.⁶⁹ Eczema vaccinatum may merit vaccinia immune globulin (VIG) therapy (other adverse events that merit VIG therapy include generalized vaccinia and vaccinia necrosum). Eczema vaccinatum is actually more severe in the contacts of vaccine recipients.⁷⁰ In the absence of VIG therapy, mortality in secondary contacts who develop eczema vaccinatum can be as high as 30%.^1,67 Factors that predispose persons to develop more severe problems following an inadvertent inoculation include: (1) burns; (2) surgical or trauma wounds; (3) dermal infection or disease; (4) current or prior history of atopic dermatitis (also a contraindication for vaccination itself); and (5) any mucosal inoculation. Historically, inadvertent inoculation occurred most frequently in young infants and children and their caretakers, and most commonly was due to transfer from the vaccine site to the skin or mucosa, and through eye rubbing.³⁷ Even contact with the site of inoculation during bathing can result in autoinoculation.³⁷ The overall rate of inadvertent inoculation is about 530 cases per million vaccinations.^62,71

Significantly, as many as 20% of all vaccinia vaccine adverse events occur in the secondary contacts of vaccine recipients.^62,63 In the 1960s, about 20% of those receiving VIG due to vaccinia vaccine complications were actually secondary contacts who had developed eczema vaccinatum.

Progressive vaccinia occurs primarily in immunodeficient persons exposed to vaccinia vaccine and is fatal in most cases (a few survivors have been reported). The incidence of progressive vaccinia is reported to be 1.5 cases per million vaccinations.^1,62,72

Post-vaccination encephalitis occurs at a rate of 12.3 cases per million vaccinations.⁶² The encephalitis varies in severity and prognosis, from mild and self-resolving to a progressive and fatal course. Approximately 15% to 25% of vaccine recipients who develop post-vaccination encephalitis die, and approximately 25% have permanent neurological sequelae such as residual paralysis.⁷² Young age appears to be the only known risk factor for this adverse event.⁶⁷

Thus, most deaths caused by vaccinia vaccination are due to progressive vaccinia or post-vaccination encephalitis. This death rate, based on data from 1970, is estimated to be 1 death per million vaccinations.⁷² In today’s society, this rate will likely be higher.⁶⁸

Atopic dermatitis. Atopic dermatitis is the most common disorder that has been associated with severe vaccinatum eczema. In Europe, the incidence of atopic dermatitis is approximately 15.6% in 7-year-olds.⁷³ While data are only just emerging, it is believed that the incidence of atopic dermatitis in the United States is 7% to 17% in 5- to 9-year-olds, depending on the diagnostic criteria used.⁷⁴

A history of this condition predisposes the person to adverse events from the vaccinia vaccine and represents a contraindication for vaccination.^62,70 Significantly, a person living in the same household with a recipient of vaccinia vaccine is at a higher risk of developing eczema vaccinatum, and at higher risk for severe disease.70 However, a universally accepted definition for the condition does not exist, and specific clinical, histological, or immunologic markers are lacking.³⁷ Thus, there is no way to screen those at higher risk for adverse events from smallpox vaccination. Consequently, a screening tool will need to be developed to exclude people with atopic dermatitis or who have a history of this condition.³⁷  Back to Top

TREATMENT OF ADVERSE EVENTS FOLLOWING VACCINIA (SMALLPOX) VACCINATION

The only product available for treatment of adverse events from vaccinia vaccination is vaccinia immune globulin (VIG).51,65 VIG is the immunoglobulin fraction of plasma from persons vaccinated with vaccinia vaccine and is effective for treatment of eczema vaccinatum and certain cases of progressive vaccinia. The use of VIG in the treatment of ocular vaccinia resulting from inadvertent inoculation is controversial.

VIG Availability: It is currently estimated that depending on the potential vaccination scenario, anywhere from 6,000 (selective vaccination, pre-event) to 70,000 (mass vaccination) doses of VIG will be needed for the treatment of adverse reactions.³⁷ Currently, there is enough VIG available to treat about 600 adverse events, far below anticipated needs.⁶⁵ Thirty thousand doses have been contracted for by the US government; vaccination of volunteers has already begun and the doses of VIG will be available by January 2004.³⁷ Hence, there currently is insufficient VIG to cover any extensive vaccination program.³⁷  Back to Top

RECENT STUDIES ON THE USE OF VACCINIA  (SMALLPOX) VACCINE

As a result of concern over the availability of smallpox vaccine in the event of a smallpox outbreak,² recent studies examined: (1) the clinical responses to diluted smallpox vaccine52; and (2) the dose-related effects of smallpox vaccine.⁷⁵ These studies demonstrated that the existing vaccinia vaccine could be diluted as much as 10-fold and still induce local viral replication and vesicle formation in more than 97% of volunteers.⁵² Significantly, a 5-fold dilution yielded a vaccine "take" of greater than 99% of volunteers. Additionally, the development of vesicular skin lesions after vaccination correlates with the induction of antibody and T cell responses required for the clearance of vaccinia virus.⁵² While there is a dose-response effect on cytotoxic T cell and interferon-g responses, the data indicate that regardless of dose, as long as a vesicle forms following vaccination, the resulting immunologic response will be protective.⁷⁵

However, despite extensive screening of the healthy adult volunteers prior to vaccination, considerable morbidity was observed.⁵² Fever (>100^oF) occurred in 9% of volunteers, and headache was common. Severe headache presented in about 5% of the volunteers. Muscle aches and chills were also common: 20% reported severe muscle aches and 6.5% reported severe chills. Moderate or severe fatigue was also reported in almost 20% of the vaccinees. Almost 15% experienced rashes distant from the vaccination site and 25% of these cases were deemed moderate or severe. Pain at the vaccination site was present in more than 33% and of these, more than 36% indicated the pain was severe enough to cause absence from work and difficulty sleeping. Significantly, 12 subjects (out of 680 vaccinated) experienced serious adverse events as defined by the need to visit a clinic or emergency room or be hospitalized, despite the extensive screening process. Of these 12, ³ were probably associated with the vaccination. Back to Top

ADVISORY COMMITTEE ON IMMUNIZATION PRACTICE (ACIP)  RECOMMENDATIONS ON THE USE OF VACCINIA (SMALLPOX)  VACCINE

On June 20, 2002, the Advisory Committee on Immunization Practices (ACIP) released its latest guidance on the use of vaccinia vaccine,⁶⁵ which states that pre-event vaccination of the general population is not recommended, because the potential benefits do not outweigh the risks of complications (the Table provides a listing of the pros and cons of voluntary routine smallpox vaccination).⁶5 However, the ACIP does recommend targeted pre-event vaccination of federal, state, and local "smallpox responders."65 Press reports that followed the release of the guidance speculated that as many as 500,000 persons may receive vaccine,⁷⁶ but the CDC has declared this estimate premature.⁷⁷ Additionally, although the ACIP considers surveillance and containment (ring vaccination) the primary method of containing a potential smallpox outbreak, the guidance allows for expansion of vaccination should that be necessary to contain an outbreak.⁶⁵ Finally, the Committee also stated that its recommendations would be evaluated on an ongoing basis and immediately revised as necessary should evidence become available that the assumptions underlying these recommendations (detailed below) have changed. For example, if credible data emerge suggesting the risk of a smallpox outbreak is higher than currently believed, the ACIP would revisit the recommendations and revise them accordingly. Flexibility has also been built into the current recommendations that would allow state and local bioterrorism planners to construct their own local preparedness plans, as requested by the Association of State and Territorial Health Officials (ASTHO).³⁷

In devising its recommendations, the ACIP made several assumptions to help guide its deliberations:

1. The risk of smallpox occurring as a result of a deliberate release by terrorists is not zero but is considered low, and the population at risk for such an exposure cannot be determined.
2. Vaccinia vaccine will continue to be classified by the Food and Drug Administration as an Investigational New Drug (IND) vaccine until late 2003 or early 2004. Thus, vaccination programs are likely to be administered by federal, state and local public health agencies.
3. In pre-event use of vaccinia vaccine, appropriate pre-vaccination screening for contraindications will be implemented and precautions will be taken to ensure the safety of individual vaccinees, patients, clients, and colleagues.
4. Health care workers will employ appropriate infection control and personal protection measures.
5. Vaccinia vaccines and VIG will be available for use, in sufficient supply, and handled and administered correctly.
   

The AMA was represented at meetings of the ACIP smallpox working group that examined the data on smallpox vaccination, examined the risks and benefits of voluntary smallpox vaccination, and provided the recommendations that were discussed, revised, and accepted by the entire ACIP on June 20, 2002. Other medical organizations represented on, or advising this working group, include the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), the American College of Physicians-American Society of Internal Medicine (ACP-ASIM), the American College of Obstetricians and Gynecologists, the National Medical Association, and the Infectious Diseases Society of America (IDSA). Also advising this working group were many acknowledged individual experts.

Many of these specialty societies and organizations (ie, AAFP, ACP-ASIM, AAP, IDSA) have issued formal statements similar to, or in support of, the June 2002 ACIP guidance. The AMA has also issued a press release in support of the ACIP recommendations.

On October 17, 2002, the ACIP met again to discuss and to provide recommendations as to which health care individuals should be first to be vaccinated as a result of the June 20, 2002, recommendations. While maintaining their original June 20, 2002, recommendations, the ACIP acknowledged that the recruitment of "smallpox responders" in designated "smallpox hospitals" would be impractical and thus the vaccination program should be offered to general acute care hospitals with emergency rooms. If this recommendation becomes final, then the initial target population of health care workers vaccinated would rise from 15,000 to 20,000 to about 500,000.⁷⁸

In crafting its guidance the ACIP considered all major aspects of smallpox disease and vaccination including the natural history; the clinical and diagnostic features of smallpox; medical care and treatment issues; control strategies; adverse events from vaccination; the current status and use of VIG to treat such events; and the current status of the vaccinia vaccine in the United States. The ACIP also considered opinions expressed by physicians and the public at regional forums, models developed to assist smallpox vaccination decision-making, and the level of state and local preparedness. Information pertaining to special populations affected by smallpox vaccination, such as immunodeficient patients, organ transplant recipients, and patients undergoing chemotherapy was also presented to the ACIP. Thus, a comprehensive set of criteria was considered by the ACIP in its deliberations to establish recommendations on the use of vaccinia vaccine in the absence of a smallpox outbreak.^37,78

The Council on Scientific Affairs believes that the ACIP guidance has considered the important aspects pertinent to smallpox disease and vaccination, and represents a comprehensive set of evaluations by accomplished leaders in the field. Back to Top

MODELING SMALLPOX OUTBREAKS AND VACCINATION POLICY

Mathematical models have been published to assist smallpox vaccination decision-making. Results from these models range from suggesting that mass vaccination of the public may not the best option⁷⁹ to recommending mass vaccination of the entire US population to contain an outbreak.80 Specifically, a model published by Kaplan et al suggested that mass vaccination of the entire US population would be more effective at containing an outbreak than traced vaccination, as recommended by the ACIP.⁸⁰ This raises the question of whether this model is accurate, thereby contradicting the scientific evaluation performed by the ACIP, or whether reasons exist to explain why Kaplan’s conclusion differs from the opinion proffered by experts in the field. Advocates for mass vaccination have used the Kaplan study as ammunition against the ACIP recommendations.⁸¹

To simplify the analysis, an assumption will be made that the mathematical engine behind the model is sound. That is, this report will presume the mathematical processes are accurate and that the primary reasons for the discrepancy in conclusions are entirely due to the data that are fed into the model.

Two principal problems can be identified with the Kaplan study. First, has Kaplan provided his model with an accurate natural history of smallpox? Second, has Kaplan fed his model the best data pertaining to the ability of the public health system to vaccinate people after an outbreak of smallpox has occurred; that is, the efficacy of traced vaccination?

Natural History of Smallpox and the Kaplan Model: Following infection with the smallpox virus there is an incubation period of about 10 to 14 days when the virus reproduces in the person.¹⁶ Following the incubation period is the pre-eruptive stage or prodrome phase when the infected person will experience symptoms of extreme exhaustion and fever, together with severe backache. In the eruptive stage following the prodrome phase, the person will begin to develop a rash that first starts in the mouth region and the extremities, but spreads to the entire body within 24 hours.¹⁶ Significantly, the person usually becomes infectious at this point in the disease.16 While one report has suggested the possibility of some infectivity during pre-eruptive stage of the disease, epidemiological studies have failed to confirm this. Thus, transmission of smallpox occurs when the person first begins to display a rash.^8,10,16

However, Kaplan assumes that the entire transmission of smallpox occurs during the pre-eruptive stage of the disease; that is, during the prodrome phase.80 With this assumption, the model has smallpox-infected individuals transmitting the virus much earlier than the natural history indicates. While the natural history of smallpox would have people becoming contagious starting at about 15 to 17 days following infection,^8,16 the Kaplan model has people becoming contagious at the start of the prodrome, at about days 13 to 15 after infection, and completing their transmissibility by day 17 following infection.⁸⁰ This assumption therefore accelerates the mathematical model with respect to what happens in nature. By doing so, the model automatically biases against traced vaccination, which would require more time to trace and vaccinate the contacts of suspected cases of smallpox. The Kaplan model would also automatically bias in favor of mass vaccination, which requires no time for tracing of contacts since the entire population will be vaccinated. A final effect of the assumption is that more contacts will be infected in the model than in reality, thereby stretching out the window during which there are infected people potentially transmitting the disease to others.

Furthermore, smallpox epidemiology indicates that the disease is slow to spread and requires close prolonged contact of less than 6 feet with the infected person.^23,24,29 This fact favors traced vaccination, as public health officials need target only those contacts who report prolonged contact with the infected individual. Kaplan’s model assumes that disease transmission derives from free mixing among available susceptible and asymptomatic infectious individuals in the population, deliberately addressing the worst case scenario, but one not necessarily supported by the natural history of this disease. This works against traced vaccination in the model.

Efficacy of Traced Vaccination and the Kaplan Model: In attempting to derive an input value for the efficacy of traced vaccination, Kaplan relied on data from an actual situation with contact tracing for a sexually transmitted disease.⁸² Using these data, Kaplan deduced that following an outbreak, one vaccinator in a mass vaccination program would be able to effectively immunize 200 persons/day, while one vaccinator in a traced vaccination program would only effectively immunize 50 persons/day. This factor again placed traced vaccination at an automatic disadvantage, despite the fact that with mass vaccination, many of the 200 persons being immunized might not even have been exposed to smallpox.

Moreover, it is probably not appropriate to use the sexually transmitted disease model to obtain the data to extrapolate the efficacy of traced smallpox vaccination. Sexually transmitted diseases are usually associated with some form of stigma, and anonymity is generally preferred by those infected.⁸³ This makes contact tracing much more difficult, as infected persons may not divulge the names of their contacts and a public announcement would be considered a violation of privacy. A more appropriate situation to use for data on the efficacy of contact tracing might be the hepatitis A outbreak in 1992 in Colorado.⁸⁴ In this situation, more than 5000 contacts were very quickly traced to 43 infected cases because there was no stigma associated with the disease. In fact, the author reports that more than 16,000 were in fact vaccinated against hepatitis A. This was probably attributable to the use of the mass media in contact tracing. As a result, many persons requested vaccination, and were vaccinated, despite not being able to demonstrate a direct association with the initial 43 cases. This same effect would occur with any outbreak of smallpox. Thus, it is probable that if the hepatitis A situation were used to provide data on the efficacy of traced vaccination, the results from the Kaplan model would improve dramatically in favor of traced vaccination.

Thus, the greatest problem with the Kaplan model is that the authors should have more thoroughly investigated the science of smallpox prior to input of data into the model. The best step forward from this point would be to reapply Kaplan’s model using parameters that are closer to the natural history of smallpox and that more accurately reflect the efficacy of traced vaccination, perhaps using the hepatitis A situation⁸⁴ to provide input data. The results would then be more useful for making policy decisions on smallpox vaccination in the event of an outbreak due to a bioterrorist attack. Back to Top

SMALLPOX AS A BIOWEAPON

Smallpox is believed to be more difficult to weaponize than anthrax.⁸⁵ The virus is sensitive to high temperatures and humidity.^16,31,32 Data indicate that while variola can be transmitted via aerosol over a short distance, this is the exception (the 2 incidences in Germany where this occurred involved unusual circumstances that facilitated aerosol transmission)^16,25; airborne transmission over a long distance has not been documented.¹⁶ Although smallpox could be transmitted as fomites via bedclothes, linens, pillows, data indicate that this is an uncommon event and once the materials are wet down, the risk disappears.^16,22 While smallpox can survive for up to weeks in infected scabs, there are no data indicating that scab-borne virus can serve as a source of infection.^16,30 Experiments on the persistence of virus on various environmental objects indicate that such virus is rapidly deactivated.¹⁶ Traditionally, smallpox was transmitted from person-to-person via airborne droplets that required prolonged face-to-face (within 6 feet) contact with the infected person.^23,24,29 Therefore, smallpox is less communicable than pertussis, measles, or influenza and is more similar to mumps, rubella, and polio in its transmissibility.^26-28 Finally, smallpox only becomes contagious when the infected person begins to develop a rash (about 17 days following infection).^8,10,16 A prodrome lasting 2 to 3 days occurs just prior to development of the rash.16 The severe illness that accompanies this pre-eruptive stage includes high fever and malaise, intense headache, delirium, severe vomiting, diarrhea, and extreme backache leading to prostration.^8,10,16 Thus, a smallpox-infected person would most likely be bedridden prior to becoming infectious and restricted in his or her ability to transmit smallpox. However, the risk of smallpox being used as a bioterrorist agent exists and the public health implications of outbreaks as a result of such use are immense. Thus, it is appropriate that the United States remain vigilant and prepared for this possibility, as small as it appears at this time. Back to Top

CURRENTLY PROPOSED DHHS PLANS FOR SMALLPOX VACCINATION

The DHHS has indicated that the following phase-in plan for voluntary smallpox vaccination for pre-event smallpox exposure is being considered:

Phase I: States will be asked to work with hospitals to determine which hospitals will be selected to receive smallpox vaccine. It is likely that larger hospitals will be targeted. While the DHHS has said that it has given states the flexibility to work out these issues, it would prefer to have as many hospitals involved as possible. Smallpox vaccine would be offered voluntarily to hospital health care workers who are at greatest risk of exposure, eg, ER staff, ICU teams, and infectious disease teams. The DHHS is relying on the ACIP to develop recommendations as to which specific groups within the hospital should be vaccinated and whether administrative leave is necessary for those health care workers receiving the vaccine. The ACIP will also be asked to provide recommendations pertaining to vaccination site care, screening for contraindications, and simultaneous administration with other vaccines. Additionally, the DHHS wants federal- and state-level public health response teams to be vaccinated during this phase. This first phase is similar in scope to the second recommendation from the ACIP’s June 20, 2002, recommendations. However, it appears that the DHHS is advocating that more hospitals be prepared to receive smallpox cases. The DHHS anticipates that, once initiated, this phase will take about 3 months to complete.

Phase II: In this phase, the DHHS would likely expand smallpox vaccination to ALL health care workers, including physicians in office settings, and ALL first responders, including paramedics, firefighters, and police. This would expand vaccination beyond what the ACIP has recommended.

Phase III: On completion of phase II, the DHHS could propose making the vaccine available to any member of the public who would like to receive vaccination. This contradicts the current ACIP recommendations. The DHHS has stated that while Phase I is close to finalization, Phases II and III are still subject to change.

Licensing of the smallpox vaccine: The DHHS also stated that the undiluted use of the original smallpox vaccine, Dryvaxâ , should be licensed by December 2002, and the use of a 1:5 dilution of the Dryvaxâ vaccine will be licensed by early 2003. Additionally, the DHHS expects that 150 million doses of the newly produced vaccinia vaccine will be available by March 2003 and licensed by the end of 2003. Finally, the recently discovered stock of vaccine from Aventis-Pasteur is currently in trials for licensure. It appears that at 1:3 and 1:5 dilutions, this vaccine works as well as, if not better than, the Dryvaxâ vaccine. Back to Top

RECOMMENDATIONS (Adopted AMA Policy and Directives)

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as AMA policy and directives at the 2002 AMA Interim Meeting (December 2002):

1. The AMA strongly supports the June 20, 2002, Advisory Committee on Immunization Practices (ACIP) recommendations on the use of vaccinia (smallpox) vaccine in light of the available science and data. (Policy)
2. The AMA will remain engaged with the Centers for Disease Control and Prevention (CDC), the ACIP, and the Federation on this issue and support a commitment to monitor the current status of smallpox and smallpox vaccination in the world and in the United States. Data on issues such as medical furlough, vaccination site care, and contraindications to vaccination should be monitored, as Phase I of the 2002-2003 Department of Health and Human Services (DHHS) smallpox vaccination program progresses, with particular attention to adverse effects and inadvertent vaccinia transmission, and appropriate recommendations developed as necessary. (Directive)
3. The AMA will work with the DHHS to ensure that vital federal liablity protections are in place prior to the initiation of any smallpox vaccination programs. (Directive)
4. The AMA will continue to collaborate with the CDC on educational outreach to physicians and the public regarding not only smallpox itself, but also the Investigational New Drug status of the vaccine and the risks and benefits of smallpox vaccination. (Directive)
5. The AMA will work with the appropriate authorities to ensure that as the ACIP recommendations are implemented, appropriate mechanisms to deal with the liability issues associated with the adverse events of smallpox vaccination are developed in the event that a more encompassing vaccination program is required. (Directive)
6. The AMA will work with the DHHS as it implements its phase-in plan for pre-event smallpox vaccination to ensure that physicians and the public are informed and educated on the risks and benefits of vaccinia (smallpox) vaccine and that physicians receive the relevant clinical information on the vaccinia (smallpox) vaccine. (Directive)  Back to Top
   

Advantages

• Individuals may wish to have the choice to receive the vaccine.
• Protection of some of the population could deter the use of smallpox as a terrorist agent. [Note: In several recent CDC public forums, after the risk of adverse events was fully explained, most members of the public indicated they would choose not to be vaccinated.³⁷]
• Voluntary vaccination will result in disease prevention for those vaccinated if a smallpox outbreak occurs.
• If a smallpox case did occur, prior vaccination of some members of the population would decrease the number of people to be vaccinated and simplify a rapid emergency response.
• Groups of health care professionals in each state could be trained to implement smallpox vaccination screening procedures and to administer vaccinations, thereby providing some measure of preparedness if an attack did occur.
• Voluntary vaccination under controlled circumstances would facilitate identification and deferral of persons with contraindications; thus, more care would be taken in vaccine administration, with a subsequent reduction in adverse events.
• Protection against smallpox through vaccination would allay individual concerns about the threat of smallpox.
• Allowing for some vaccination could protect some response personnel and allow them to respond to an attack in a more timely fashion.
  

Disadvantages

• Significant vaccine-induced morbidity and mortality will occur. Some individuals will not fully comprehend the severity and frequency of the adverse events following smallpox vaccination compared to other vaccines. Others will be vaccinated without, or in spite of, proper screening. The amount of time available to physicians to screen potential recipients will depend on the number of people opting for vaccination.
• Some individuals seeking vaccination will not be aware of the presence of contraindications to vaccination (eg, positive HIV serostatus, history of atopic dermatitis). Adverse events would likely vary from place to place due to vaccination of persons with unrecognized contraindications (eg, undiagnosed immunosuppressive disorders such as HIV or AIDS).
• Voluntary vaccinations must rely on individuals to accurately know or recall the contraindications of their household members and close contacts. Because the vaccinia vaccine is a live virus vaccine, there is some likelihood of inadvertent inoculation of contacts of those vaccinated, who will then be at risk for potentially severe complications if they have contraindications to vaccination. The larger the pool of people vaccinated, the greater the incidence of inadvertent inoculations will be.
• Some individuals may not be aware that their activities may be restricted for up to 21 days following vaccination. For example, physicians may be asked not to see patients for 21 days to reduce the risk of secondary inoculation. The impact of activity restrictions will increase as the number of people who opt for vaccination increases.
• Some individuals will not practice proper hygiene of their vaccination site, leading to adverse events. As with the previous point, the impact of this problem will increase as the number of people who opt for vaccination increases.
• Health care providers will be burdened by having to treat or care for individuals experiencing adverse events following the vaccination.
• Voluntary vaccination places the burden of counseling people about risks and benefits on individual health care professionals. However, lack of familiarity with the complications of vaccinia vaccination would likely result in variable screening and counseling techniques.
• Since the vaccine is available only as an IND, indemnification may not apply for "non-emergency" use. As such, vaccine recipients may be liable for the cost of vaccine, treatment of adverse events, and associated hospitalizations, particularly if the vaccine is administered on a "voluntary" or "optional" basis. Additionally, as an IND vaccine, vaccination may have to be performed by federal, state, and local health agencies.
• Voluntary vaccination of individuals may not be cost-effective unless significant numbers of the population opt to be vaccinated (70% required for effective herd immunity).
• Some individuals will feel pressure to be vaccinated if their friends or families have been vaccinated increasing the potential pool of recipients with contraindications.
• Protection against smallpox through vaccination would increase public concern about the threat of smallpox even though there is no evidence of a higher risk of a smallpox outbreak following September 11, 2001.
• The occurrence of serious adverse events would strengthen already-existing anti-vaccine sentiment, threatening more widespread routine vaccination programs.
• The international community may respond negatively to use of the vaccine in the absence of actual disease.
• Issues such as potential cost inflation and difficulty in setting a "fair market price" can potentially create a "black-market" for the vaccinia vaccine. This could lead to perception of stratified access to health care (eg, the unvaccinated poor will remain at the greatest risk in an outbreak).
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References
1. Rosenthal SR, Merchlinsky M, Kleppinger C, Goldenthal KL. Developing new smallpox vaccines. Emerg Infect Dis. 2001;7:920-926.
2. Ridings H, Evans M. Understanding the threat of smallpox. JAAPA. 2002;15:41-4, 46.
3. Robinson-Dunn B. The microbiology laboratory's role in response to bioterrorism. Arch Pathol Lab Med. 2002;126:291-294.
4. Henderson DA. Countering the posteradication threat of smallpox and polio. Clin Infect Dis. 2002;34:79-83.
5. Beeching NJ, Dance DA, Miller AR, Spencer RC. Biological warfare and bioterrorism. BMJ. 2002;324:336-339.
6. Miller JM. Agents of bioterrorism. Preparing for bioterrorism at the community health care level. Infect Dis Clin North Am. 2001;15:1127-1156.
7. Henderson DA, Moss B. smallpox and Vaccinia, in Plotkin SA, Orenstein WA, eds: Vaccines. Philadelphia: W.B. Saunders Company; 1999.
8. Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med. 2002;346:1300-1308.
9. Gordon SM. The threat of bioterrorism: a reason to learn more about anthrax and smallpox. Cleve Clin J Med. 1999;66:592-600.
10. Henderson DA, Inglesby TV, Bartlett JG, et al. smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. 1999;281:2127-2137.
11. Noeller TP. Biological and chemical terrorism: recognition and management. Cleve Clin J Med. 2001;68:1001-9, 1013.
12. Varkey P, Poland GA, Cockerill FR, III, Smith TF, Hagen PT. Confronting bioterrorism: physicians on the front line. Mayo Clin Proc. 2002;77:661-672.
13. World Health Organization. WHO fact sheet on smallpox. Available at: http://www.who.int/emc/diseases/smallpox/factsheet.html. Accessed: 8-29-2002.
14. Henderson DA. smallpox: clinical and epidemiologic features. Emerg Infect Dis. 1999;5:537-539.
15. Whitby M, Street AC, Ruff TA, Fenner F. Biological agents as weapons 1: Smallpox and botulism. Med J Aust. 2002;176:431-433.
16. Fenner F, Henderson DA, Arita I, Jezek Z , Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization; 1988.
17. Koplan JP, Foster SO. Smallpox: clinical types, causes of death, and treatment. J Infect Dis. 1979;140:440-441.
18. Moss B. Poxviridae and their replication, in Fields BN, Knipe DM, Chanock RM, et al , eds: Fundamental Virology. New York: Raven Press; 1991:953-985.
19. Rao AR. smallpox. Bombay: The Kothari Book Depot; 1972.
20. Hers JFPL, Winkler KC. Airborne transmission and airborne infection. New York: Wiley; 1973.
21. Modlin JF. A mass smallpox vaccination campaign: reasonable or irresponsible? Eff Clin Pract. 2002;5:98-99.
22. Dixon CW. Smallpox. London: Churchill; 1962.
23. Foege WH, Millar JD, Henderson DA. smallpox eradication in West and Central Africa. Bull World Health Organ. 1975;52:209-222.
24. Mack TM, Thomas DB, Muzaffar KM. Epidemiology of smallpox in West Pakistan. II. Determinants of intravillage spread other than acquired immunity. Am J Epidemiol. 1972;95:169-177.
25. Wehrle PF, Posch J, Richter KH, Henderson DA. An airborne outbreak of smallpox in a German hospital and its significance with respect to other recent outbreaks in Europe. Bull World Health Organ. 1970;43:669-679.
26. Gani R, Leach S. Transmission potential of smallpox in contemporary populations. Nature. 2001;414:748-751.
27. Fine PE. Herd immunity: history, theory, practice. Epidemiol Rev. 1993;15:265-302.
28. Luman ET, Barker LE, Simpson DM, et al. National, state and urban-area vaccination-coverage levels among children aged 19-35 months, United States, 1999. Am J Prev Med. 2001;20:88-153.
29. Heiner GG, Fatima N, McCrumb FR, Jr. A study of intrafamilial transmission of smallpox. Am J Epidemiol. 1971;94:316-326.
30. MacCallum FO, McDonald JR. Survival of variola virus in raw cotton. Bull World Health Organ. 1957;16:247-254.
31. Huq F. Effect of temperature and relative humidity on variola virus in crusts. Bull World Health Organ. 1976;54:710-712.
32. Harper GJ. Airborne micro-organisms: survival tests with four viruses. J Hygiene. 1961;59:479-486.
33. Graber M. Bioterrorism Update: smallpox. Available at: http://www.emedmag.com/stories/storyReader$331. Accessed: 8-29-2002.
34. Centers for Disease Control and Prevention. Interim smallpox Response Plan & Guidelines: Updated Jan 23, 2002. Available at: http://www.bt.cdc.gov/DocumentsApp/smallpox/RPG/index.asp. Accessed: 8-29-2002.
35. Lancaster MC, Boulter EA, Westwood JC, Randles J. Experimental respiratory infection with poxviruses. II. Pathological studies. Br J Exp Pathol. 1966;47:466-471.
36. Westwood JC, Boulter EA, Bowen ET, Maber HB. Experimental respiratory infection with poxviruses. I. Clinical virological and epidemiological studies. Br J Exp Pathol. 1966;47:453-465.
37. Advisory Committee on Immunization Practices. Advisory Committee on Immunization Practices, June 18-20 meeting materials. June 20, 2002.
38. De Clercq E. Cidofovir in the treatment of poxvirus infections. Antiviral Res. 2002;55:1-13.
39. De Clercq E. Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infections. Clin Microbiol Rev. 2001;14:382-397.
40. Bray M, Martinez M, Smee DF, et al. Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge. J Infect Dis. 2000;181:10-19.
41. Bray M, Martinez M, Kefauver D, West M, Roy C. Treatment of aerosolized cowpox virus infection in mice with aerosolized cidofovir. Antiviral Res. 2002;54:129-142.
42. Meadows KP, Tyring SK, Pavia AT, Rallis TM. Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus-infected patients treated with cidofovir. Arch Dermatol. 1997;133:987-990.
43. Geerinck K, Lukito G, Snoeck R, et al. A case of human orf in an immunocompromised patient treated successfully with cidofovir cream. J Med Virol. 2001;64:543-549.
44. Bradbury J. Orally available cidofovir derivative active against smallpox. Lancet. 2002;359:1041.
45. Lea AP, Bryson HM. Cidofovir. Drugs . 1996;52:225-230.
46. Plosker GL, Noble S. Cidofovir: a review of its use in cytomegalovirus retinitis in patients with AIDS. Drugs. 1999;58:325-345.
47. Barquet N, Domingo P. smallpox: the triumph over the most terrible of the ministers of death. Ann Intern Med. 1997;127:635-642.
48. Neff JM. The case for abolishing routine childhood smallpox vaccination in the United States. Am J Epidemiol. 1971;93:245-247.
49. Lane JM, Millar JD, Neff JM. smallpox and smallpox vaccination policy. Annu Rev Med. 1971;22:251-272.
50. LeDuc JW, Damon I, Relman DA, Huggins J, Jahrling PB. smallpox research activities: US interagency collaboration, 2001. Emerg Infect Dis. 2002;8:743-745.
51. Centers for Disease Control and Prevention. Vaccinia (smallpox) Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR Morb Mortal Wkly Rep. 2001;50:1-25.
52. Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med. 2002;346:1265-1274.
53. Roos R. Trial of Aventis smallpox vaccine getting under way. Available at: http://www1.umn.edu/cidrap/content/bt/smallpox/news/avent.html. Accessed: 8-29-2002.
54. Aventis-Pasteur. Aventis Pasteur donates approximately 75-90 million doses of smallpox vaccine to the U.S. Available at: http://www.us.aventispasteur.com/press_releases/smallpox_o.htm. Accessed: 8-29-2002.
55. Moss B. Genetically engineered poxviruses for recombinant gene expression, vaccination, and safety. Proc Natl Acad Sci U S A. 1996;93:11341-11348.
56. Radetsky M. smallpox: a history of its rise and fall. Pediatr Infect Dis J. 1999;18:85-93.
57. Cohen J. Bioterrorism. smallpox vaccinations: how much protection remains? Science. 2001;294:985.
58. Mack TM. smallpox in Europe, 1950-1971. J Infect Dis. 1972;125:161-169.
59. el Ad B, Roth Y, Winder A, et al. The persistence of neutralizing antibodies after revaccination against smallpox. J Infect Dis. 1990;161:446-448.
60. Demkowicz WE, Jr., Littaua RA, Wang J, Ennis FA. Human cytotoxic T-cell memory: long-lived responses to vaccinia virus. J Virol. 1996;70:2627-2631.
61. Frelinger JA, Garba ML. Responses to smallpox vaccine. N Engl J Med. 2002;347:689-690.
62. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: results of ten statewide surveys. J Infect Dis. 1970;122:303-309.
63. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968. N Engl J Med. 1969;281:1201-1208.
64. Neff JM, Drachman RH. Complications of smallpox vaccination, 1968 surveillance in a Comprehensive Care Clinic. Pediatrics. 1972;50:481-483.
65. Advisory Committee on Immunization Practices. Draft Supplemental Recommendation of the ACIP: Use of smallpox (Vaccinia) Vaccine, June 2002 . Available at: http://www.cdc.gov/nip/smallpox/supp_recs.htm. Accessed: 8-29-2002.
66. Kempe CH. Studies on smallpox and complications of smallpox vaccination. Pediatrics. 1960;23:176-189.
67. Goldstein JA, Neff JM, Lane JM, Koplan JP. smallpox vaccination reactions, prophylaxis, and therapy of complications. Pediatrics. 1975;55:342-347.
68. Kemper AR, Davis MM, Freed GL. Expected adverse events in a mass smallpox vaccination campaign. Eff Clin Pract. 2002;5:84-90.
69. Kempe CH, Fulginiti V, Minamitani M, Shinefield H. smallpox vaccination of eczema patients with a strain of attenuated live vaccinia (CVI-78). Pediatrics. 1968;42:980-985.
70. Copeman PW, Wallace HJ. Eczema vaccinatum. BMJ. 1964;2:906-908.
71. Neff JM, Lane JM, Fulginiti VA, Henderson DA. Contact vaccinia transmission of vaccinia from smallpox vaccination. JAMA. 2002;288:1901-1905.
72. Lane JM, Ruben FL, Abrutyn E, Millar JD. Deaths attributable to smallpox vaccination, 1959 to 1966, and 1968. JAMA. 1970;212:441-444.
73. Schultz LF, Diepgen T, Svensson A. The occurrence of atopic dermatitis in north Europe: an international questionnaire study. J Am Acad Dermatol. 1996;34:760-764.
74. Laughter D, Istvan JA, Tofte SJ, Hanifin JM. The prevalence of atopic dermatitis in Oregon schoolchildren. J Am Acad Dermatol. 2000;43:649-655.
75. Frey SE, Newman FK, Cruz J, et al. Dose-related effects of smallpox vaccine. N Engl J Med. 2002;346:1275-1280.
76. Broad, W. J. U.S. to Vaccinate 500,000 Workers Against smallpox. New York Times: 7-7-2002. Final Edition. Available at: URL: http://www.nytimes.com/. Accessed: 7-7-2002.
77. Centers for Disease Control and Prevention. Smallpox Vaccination Policy Update. Health Alert Network. 2002.
78. Advisory Committee on Immunization Practices. Advisory Committee on Immunization Practices, October 16-17, 2002, meeting materials. October 17, 2002.
79. Meltzer MI, Damon I, LeDuc JW, Millar JD . Modeling potential responses to smallpox as a bioterrorist weapon. Emerg Infect Dis. 2001;7:959-969.
80. Kaplan EH, Craft DL, Wein LM. Emergency response to a smallpox attack: The case for mass vaccination. Proc Natl Acad Sci U S A. 2002,99;10935-10940.
81. Broad, W. J. Study favors different tack on smallpox. New York Times: 7-9-2002. Final Edition. Available at: URL: http://www.nytimes.com/. Accessed: 7-9-2002.
82. Macke BA, Hennessy M, McFarlane MM, Bliss MJ. Partner notification in the real world: A four site time-allocation study. Sex Transm Dis. 1998;25:561-568.
83. Hook EW, III, Richey CM, Leone P, et al. Delayed presentation to clinics for sexually transmitted diseases by symptomatic patients. A potential contributor to continuing STD morbidity. Sex Transm Dis. 1997;24:443-448.
84. Dalton CB, Haddix A, Hoffman RE, Mast EE . The cost of a food-borne outbreak of hepatitis A in Denver, Colo. Arch Intern Med. 1996;156:1013-1016.
85. Enserink M. Bioterrorism. How devastating would a smallpox attack really be? Science. 2002;296:1592-1595.  Back to Top

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