Smallpox Vaccination in 2003: Key Information, focus on HIV
Clinical Infectious Diseases 2003;36:883-902
John Bartlett,1,3 Luciana Borio,1,3 Lew Radonovich,1 Julie Samia Mair,2,4 Tara O'Toole,1,2 Michael Mair,1 Neil Halsey,2 Robert Grow,1,3 and Thomas V. Inglesby1,3
1Center for Civilian Biodefense Strategies and Schools of 2Public Health and 3Medicine, Johns Hopkins University, and 4Center for Law and the Public's Health at Johns Hopkins and Georgetown Universities, Baltimore, Maryland
from Jules Levin: The following are excerpts from a much larger article in CID. IÕve selected these excerpts for their particular relevance to HIV and immune deficiency.
The purpose of this article is to provide clinicians with answers to some of the most important and frequently asked questions related to smallpox vaccination. Information that has direct bearing on this issue is broad in scope, complex, and multidisciplinary, and this article is offered as an attempt to distil this information into a single accessible resource.
What instructions should be given to the vaccine recipient? The vaccinee must understand that there is viable vaccinia virus in the lesion from the moment the papule forms (which occurs on days 25 after vaccination) until the scab dislodges (on days 1421) . For revaccination, this time period is accelerated. Thus, the vaccination site should be covered (as described in the previous subsection, "How is the smallpox vaccine administered?"), because vaccinia may be transmitted to an unvaccinated individual after close contact (termed "contact vaccinia") or to other body parts of the vaccinee (termed "accidental vaccinia") after the accidental contamination of the vaccinee's hands by touching the site of the recent vaccination. Accidental autoinoculation may lead to serious complications, such as keratitis. The vaccinee should be instructed not to touch, rub, or scratch the site, even though pruritis is typically experienced. Showering is acceptable, but the dressing should be replaced afterward to keep the site dry. Prolonged exposure to water should be avoided. The vaccinee should avoid contact with persons who have contraindications to vaccination until the scab spontaneously separates. Strict hand hygiene should be maintained after vaccine administration and changes of the dressing, to prevent transmission of vaccinia.
What is the expected (typical) reaction after primary smallpox vaccination? The local reaction after primary vaccination typically begins as a papule that occurs at the vaccination site 34 days after vaccination. Subsequently, a vesicle with surrounding erythema develops, and by days 89, a pustule is well formed. The size of the pustule depends on the size of the area of inoculation; it is usually 712 mm in diameter, but larger reactions occur. This pustule crusts over and forms a scab, which spontaneously detaches, usually on days 1721 after vaccination [7, 20]. The presence of a papule, vesicle, ulcer, or crusted lesion, surrounded by erythema and induration, when the lesion is examined at days 68, is considered to be a major reaction (a take) . The evolution of the normal local reaction or take with primary vaccination is shown in table 2. A major reaction indicates that virus growth has taken place and implies that there is immunity to smallpox, with antibody and cytotoxic T cell response . All other reactions are deemed "equivocal." Since equivocal reactions are not guaranteed to indicate immunity, it is recommended that persons who have equivocal reactions be revaccinated. The take rate for primary vaccination depends largely on the quality of the vaccine and whether proper vaccination technique was used. In a recent trial that compared administration of diluted and undiluted DryVax vaccine to 680 previously unvaccinated, healthy adult volunteers aged 1832 years, the take rate was 97.1%99.1%, which demonstrated that DryVax maintains efficacy at dilutions as high as 1 : 10 . Phase I clinical trials using the Acam1000 and Acam2000 vaccine have resulted in 99%100% take rates.
Common local reactions are to be expected in up to 6.6% of patients who receive primary vaccination (hereafter, "primary vaccinees"); they are less frequent among patients who are revaccinated. These reactions include satellite lesions, lymphangitis in regional axillary nodes, lymphadenopathy, local edema, and intense circumferential erythema (often confused with bacterial cellulitis). Common systemic symptoms include headache, nausea, fever, chills, malaise, and myalgia. At least 1 of these symptoms is noted in most vaccine recipients. The onset of systemic symptoms typically peaks on days 810 after vaccination, and the symptoms generally resolve in 13 days . Fever with a temperature of 38.8¡C is noted in 10%15% of vaccine recipients; fever with a temperature of >38.9¡C or fever after day 16 are seen in 1% of vaccine recipients.
What is contact vaccinia? Contact vaccinia is an inadvertent vaccinia virus infection in a person other than the vaccine recipient; it is the result of the spread of vaccinia from a vaccination site to another person. The incidence of contact vaccinia is reported to be 2060 cases per million vaccinations, although this probably represents substantial underreporting, with bias toward the more serious cases. Most cases occur because of contact with a person who received primary smallpox vaccination, and most involve children with exposure to a family member in the home . A national survey of 139 cases of contact eczema vaccinatum found that 81 cases (58%) occurred in siblings of vaccinees, 16 (12%) occurred in playmates of vaccinees, and 13 (9%) occurred in adult members of the families of vaccinees . Occasional cases occur because of transmission in the hospital; such cases accounted for 4 (2%) of the 223 cases included in data combined from 2 surveys [39, 40]. Sepkowitz  has recently reported 85 cases of nosocomial spread on the basis of 12 reports from 1907 to 1975, but most of these cases occurred in hospital settings very different from those of today. Nearly all fatal cases involve children <1 year of age . Historically, eczema vaccinatum accounted for nearly all of the serious cases of contact vaccinia; 2 national surveys found incidences of 8.7 cases per million vaccinations  and 10.7 cases per million vaccinations .
Is contact vaccinia a greater concern now than it was in the 1960s and 1970s, during the global eradication program? Many of the reports from the 1960s and 1970s were based on very large surveys of results for vaccination with the same vaccinia strain that is to be used in the smallpox vaccination effort, and these studies were performed by well-qualified investigators. However, studies based on surveys often suffer from underreporting, inconsistent reporting, and reporting bias that favors more serious forms of disease. The risk that this disease will develop may have increased substantially, because the prevalence of eczema during the years 19501970 was 3%6%, but it is now believed to be 6%22% . The proportion of patients with immunodeficiency, especially defective CMI, has increased substantially because of the currently large number of persons with HIV infection (550,000900,000); patients who have undergone organ transplantation (184,000); patients with rheumatologic disease who are receiving immunomodulatory therapy (2.1 million); persons with a history of cancer and receipt of chemotherapy (8 million); and asthmatic patients (14 million), many of whom take systemic or aerosolized steroids. Finally, primary vaccination imparts a more significant risk for contact vaccinia than does revaccination, and most Americans <33 years old have not been vaccinated.
What are the risks associated with vaccination for patients with HIV infection? Routine smallpox vaccination of civilians was ended in the United States in 1972. AIDS was first reported in 1981, and serologic testing for HIV was introduced in 1985. The reported experience of adverse reactions to the vaccine is limited to a single case in a 19-year-old military recruit with AIDS, who was not known to have HIV infection until he developed progressive vaccinia following smallpox vaccination in May 1984 . This patient received extensive treatment with 12 weekly doses of VIG. The progressive vaccinia ulcers completely healed. The patient, who also had cryptococcal meningitis, died 18 months later from what appeared to be an HIV-related complication. This case occurred before the institution of routine testing of military recruits for HIV. A more recent analysis by the military estimates that at least 350 other military recruits with HIV infection had received smallpox vaccination without apparent incident. These data, a wealth of clinical experience, and common sense suggest that the risk of progressive vaccinia is low for HIV-infected patients and is presumably CD4 cell countdependent and that receipt of HAART and concomitant immune reconstitution would decrease the likelihood and severity of complications from smallpox vaccination . Nevertheless, the conservative approach, based on the paucity of cases, is to exclude all persons with HIV infection from the current smallpox vaccination program.
Are negative results of HIV serologic tests required as a contingency for vaccination? The CDC recommends that HIV serologic testing be readily available to individuals who volunteer to be vaccinated in the smallpox vaccination program and who wish to be tested . Universal testing is not recommended or mandatory. A quick survey of leading hospitals suggests that most will "recommend" or "strongly recommend" the performance of HIV serologic tests prior to smallpox vaccination (T. Perl, personal communication). There are 25,000 health care workers in the United States with HIV infection .
If screening HIV serologic testing is done, what test should be performed? Standard serologic tests for HIV have sensitivities and specificities approaching 100%. Informed consent is required for performance of these tests. With standard tests, results take 27 days to obtain, but the SUDS test (Murex Diagnostics) and the OraQuick test (OraShure Technologies) can provide results in 20 min. The OraQuick test no longer requires interpretation by a Clinical Laboratory Improvement Amendmentscertified lab technician, which means that the test usually can be read on-site. Negative results of the EIA screening test for routine serologic testing and negative results of the SUDS or OraQuick tests are considered definitive for excluding the diagnosis of HIV infection; positive results require confirmation by a standard serologic test.
What patients with congenital or acquired immunodeficiency are at highest risk for progressive vaccinia? Defective CMI appears to be most important risk factor for progressive vaccinia, as indicated by case reports of progressive vaccinia, including one of a case in a patient who had defective CMI but a normal humoral response . Prior reports also indicate that most cases of progressive vaccinia occur in children with severe defective CMI function [34, 76, 77]. Conditions that are associated with defective CMI and therefore would be associated with high risk of progressive vaccinia after vaccination are as follows: severe combined immune deficiency syndrome (SCID), Wiskott-Aldrich syndrome, ataxia telangiectasia, cartilage hair hypoplasia, and purine nucleoside phosphorylase deficiency. Common variable immunodeficiency is associated with normal or near normal CMI and poses a theoretical risk, but a small one. Hypogammaglobulinemia is a lesser risk, but a case of progressive vaccinia has been reported in a patient with Bruton-type agammaglobulinemia . Conditions that would not appear to pose risk, on the basis of current understanding of CMI and the risk of complications, are complement defects, neutropenia, IgA deficiency, and chronic granulomatous disease. It is anticipated that vaccination would be safe for patients with these conditions, but there is no published experience to confirm this impression.
Should there be screening for congenital or acquired immune deficiencies? Most persons with serious immunodeficiencies manifest serious sequelae of infections before they reach adulthood. The most relevant exception is persons with common variable immunodeficiency, because these individuals are often unaware of the condition until they are >20 years old. It is not clear that this group is at significant risk, because most have normal or near-normal CMI, but lack of risk it not established. Clues in a patient's medical history that would suggest common variable immunodeficiency include serious infections (such as osteomyelitis and pneumonia) involving at least 2 noncontiguous anatomical sites, autoimmunity, and a family history of the disorder. The appropriate screening test for persons suspected of having common variable immunodeficiency is a serum quantitative immunoglobulin assay. Another diagnostic concern relates to children with as yet undetected SCIDs. More than 80% of children with SCID receive the diagnosis in the first year of life, so the greatest concern is the group of children with undiagnosed SCID who are <1 year old. In the current smallpox vaccination program, children are not being vaccinated, so the concern is children with undiagnosed SCID, who could contract contact vaccinia. It should be emphasized that SCID is rare (estimated prevalence, 1 case per 100,000 to 1 case per million children), and contact vaccinia is also rare. If SCID is suspected, the appropriate screening test would be a complete blood cell count with a lymphocyte count. Given the rarity of SCID, routine performance of screening is unrealistic; however, some hospitals are not administering smallpox vaccination to persons with household contacts that include children aged <1 year.
What is the definition of atopic dermatitis? Atopic dermatitis a chronic inflammatory skin condition commonly associated with other atopic disorders (e.g., asthma and allergic rhinitis) that is characterized by defective CMI and acutely pruritic, erythematous patches on the face, scalp, and extremities.
How does atopic dermatitis affect the risk of a serious reaction to smallpox vaccination? Atopic dermatitis poses a risk with smallpox vaccination because of its association with eczema vaccinatum, which was the most common life-threatening complication of smallpox vaccination in the 1960s . Patients with active lesions are at greatest risk, but 3%23% of patients who develop eczema vaccinatum have a history of atopic dermatitis but no active lesions at the time of exposure .
What are the clinical features of atopic dermatitis? In children, the characteristic skin lesions are intensely pruritic, red patches with papules and scaling on the face, scalp, extremities, and/or trunk. In adults, the lesions often show lichenification with a predilection for flexor surfaces (e.g., the antecubital fossa and the popliteal fossa), the face, wrists, and forearms. Other clinical features are onset at an early age (by age 57 years), a family history of atopy, and a chronic recurring course .
How does one make the formal diagnosis of atopic dermatitis? There are no pathognomonic diagnostic tests. The diagnosis is made on the basis of the clinical features, as defined in the previous paragraph and as formalized by diagnostic criteria in 1982 . The formal diagnosis requires that 3 of 4 major criteria be met. They are as follows:
2. Dermatitis involving flexural surfaces, in adults, and involving the face and the extensors, in infants
3. Chronic or relapsing dermatitis
4. Personal or family history of cutaneous or respiratory atopy
The minor criteria are as follows:
1. Features of "atopic facies": face pallor or erythema, hypopigmentated patches, infraorbital darkening, infraorbital folds or wrinkles, cheilitis, recurrent conjunctivitis, and anterior neck folds
2. Triggers of atopic dermatitis: foods, emotional factors, environmental factors, and skin irritants (wool, solvents, and sweat)
3. Complications: susceptibility to cutaneous viral and bacterial infections, impaired CMI, immediate skin test reactivity, elevated IgE level, keratoconus, and anterior subcapsular cataracts
4. Other: early age at onset, dry skin, ichthyosis, hyperlinear palms, keratosis pilaris, hand and foot dermatitis, nipple eczema, white dermatographism, and perifollicular accentuation
As a practical matter, how should the health care provider screen for atopic dermatitis in persons who are considering smallpox vaccination? Most health care providers have not in the past and do not now distinguish between eczema and atopic dermatitis, so smallpox vaccination should not be administered to patients with either current manifestations or a history of either condition. As noted in the previous subsection (above), there are no specific tests for atopic dermatitis; it is diagnosed clinically on the basis of the criteria listed above. The ACIP has suggested 2 screening questions:
1. Have you or a member of your household ever been diagnosed with eczema or atopic dermatitis?
2. Eczema/atopic dermatitis usually is an itchy, red, scaly rash that lasts >2 weeks and often comes and goes. Have you or a member of your household ever had a rash like this?
A positive answer to either question is a contraindication to smallpox vaccination, in the current vaccination program .
What are the pathophysiologic characteristics of atopic dermatitis? The pathogenesis is poorly understood but involves immune deficiency (i.e., reduced CMI) and atopy (elevated IgE levels and positive results of immediate skin tests of foods and inhaled allergens) . There is a family history of respiratory atopy (asthma or allergic rhinitis) for 50% of patients, and genetic studies suggest inheritance on chromosome 11 .
Why is atopic dermatitis so important with regard to smallpox vaccination? Atopic dermatitis predisposes to eczema vaccinatum (see above), and eczema vaccinatum was the most common serious complication of smallpox vaccination in the 1960s. Atopic dermatitis is now expected to be the most common exclusion criterion for smallpox vaccination because of its reported prevalence (6%-22% of the US population), and the prevalence of the condition has been increasing for the past 3 decades. In addition, there will be difficulty in distinguishing it from other chronic inflammatory skin conditions [40, 5457]. The risk applies to the vaccinee with atopic dermatitis and to household contacts with active or inactive atopic dermatitis.
What type of allergy to the vaccine components should be a contraindication to vaccination? This issue could be the source of significant confusion. Many patients report "allergy" to topical neomycin, a common ingredient in antibiotic ointments and lotions. Patch testing for allergy to neomycin and other aminoglycosides reveals reactions indicating hypersensitivity in 4%-13% of healthy adults . Patch testing for neomycin allergy is performed because it is a component of a standard battery of allergy tests or because of concern about reactions to topical antibiotics . However, patients with a topical reaction to neomycin may be treated with parenteral neomycin or other aminoglycosides without consequences, so the relevance of this topical allergy to the safety of smallpox vaccination is not clear. This observation may be analogous to the experience with lidocaine: patch testing commonly detects hypersensitivity to the drug, but it is well tolerated when injected. The individual clinician must use his or her judgment about reported allergies; if a patient has manifested symptoms that suggest a true allergic response to components of the vaccine (streptomycin, neomycin, polymyxin, chlortetracycline, or phenol), vaccination should be avoided, in this voluntary vaccination program.
What groups of persons are now being vaccinated or being offered voluntary vaccination? The 3-phase vaccination plan is summarized in table 1. Smallpox vaccination has been mandated for a portion of the US Armed Forces, and that program has begun. Smallpox vaccination for medical and health care personnel is being administered on a voluntary basis and was initiated in late January 2003. It has been announced that vaccination will be offered to additional groups of citizens later this year, in phase II and Phase III of the planned smallpox vaccination program. Details regarding the plans of phase II and phase III are not yet available.
What is a Smallpox Response Team? The US President's smallpox vaccination plan calls for the creation of voluntary Smallpox Response Teams. These teams are intended to provide health care to patients infected with smallpox during the first 710 days of an outbreak and to assist in epidemiological investigation and vaccination efforts. States have been asked to form these teams according to their own planning needs, but these teams are meant to comprise health care workers and public health officials . State governments have requested specific quantities of vaccine from the Centers for Disease Control and Prevention (CDC; Atlanta, GA). In turn, health care institutions are participating on a voluntary basis and, after consultation with state governments, are determining the number of volunteers to seek.
How are health care institutions identifying volunteers for this program? Individual health care organizations have been asked to identify volunteers in their institutions who could care for patients with smallpox during the first 710 days after a biological attack with smallpox virus. Such volunteers and the members of their households should have no contraindications to vaccination (see the section Contraindications to Smallpox Vaccination, below). The Advisory Committee on Immunization Practices (ACIP) of the CDC has recommended that health care institutions have teams that include the following groups of persons :
1. Emergency department staff, including both physicians and nurses.
2. Intensive care unit staff, including physicians, and nurses. In hospitals that care for infants and children, this encompasses pediatricians, pediatric intensivists, and pediatric emergency department physicians and nurses.
3. General medical unit staff, including internists, pediatricians, obstetricians, and family physicians in institutions where these individuals are the essential providers of primary medical care.
4. Primary-care house staff (i.e., selected medical, pediatric, obstetric, and family physicians).
5. Medical subspecialists, including infectious diseases specialists. This may also involve the creation of regional teams of subspecialists (e.g., local medical consultants with smallpox experience, dermatologists, ophthalmologists, pathologists, surgeons, and anesthesiologists in facilities where intensivists are not trained in anesthesia) to deliver consultative services.
6. Infection-control professionals.
7. Respiratory therapists.
8. Radiology technicians.
9. Security personnel.
10. Housekeeping staff (e.g., those staff involved in maintaining the health care environment and decreasing the risk of fomite transmission).
Some health care organizations have indicated that they will only vaccinate persons who have been previously vaccinated, because of the lower incidence of side effects in that population. This would exclude most persons aged <33 years, a group that includes a large number of interns, residents, and nurses.
Why have some hospitals decided not to participate in the US smallpox vaccination program? A number of hospitals have declined participation. Leaders of those institutions have said that they do not believe that the threat of smallpox attack, as currently articulated, justifies the risks that vaccination would pose to their staff or their patients. Other concerns include liability and workers' compensation issues. A recent survey suggested that at least 80 of the 5000 hospitals in the United States have declined participation. The Emergency Infections Network of the Infectious Diseases Society of America asked participants, "Is your primary hospital currently planning to vaccinate a group of HCWs [health care workers] when the vaccine is released?" Responses from 301 participants indicted that 241 (80%) planned to participate, 23 (8%) planned not to participate, and 37 (12%) were undecided (L. Strausbaugh, personal communication).
Why not designate "smallpox hospitals," as was done in some cities in the early 1900s? In June 2002, the ACIP suggested that states designate hospitals that have isolation facilities as smallpox hospitals, in the event of an outbreak. There was historic precedent for this, including the Boston epidemic of 19011903, in which all patients were hospitalized at 2 publicly administered smallpox hospitals . However, it was later decided by the ACIP that this was not feasible, because patients would most likely to go to hospitals where they are accustomed to receiving care. In addition, it was judged likely that few health care organizations would choose to become one of the few dedicated smallpox hospitals.
What was the origin of the early smallpox vaccine? The original smallpox vaccine used by Edward Jenner in 1796 was an inoculum of cowpox, an orthopox virus that causes a pustular rash on the skin of cattle. Eventually, smallpox vaccinations were performed with vaccinia virus, another orthopoxvirus. It is unclear when vaccinia supplanted cowpox as the commonly used vaccine virus. The global eradication effort in the 1960s and 1970s led to the development of a stable, freeze-dried formulation of vaccinia virus. The product, which was produced by Wyeth Pharmaceuticals in the United States, was called DryVax.
What is the vaccine currently licensed by the US Food and Drug Administration (FDA)? The strain of smallpox virus used to produce DryVax was provided by the New York City Board of Health (NYCBH) in the 1970s for a mass production program. It is grown in the skin of calves. DryVax is freeze-dried and packaged in 100-dose vials that are reconstituted with 50% glycerin and 0.25% phenol. After reconstitution, DryVax has a potency that averages 1.6 ´ 107 pfu/mL . Approximately 14.8 million doses of DryVax exist.
Where is the vaccine stored and how does one acquire it? The CDC controls the repository of smallpox vaccine. The CDC is in the process of distributing vaccine to state health departments in sufficient quantity to vaccinate the 440,000 health care personnel and public health officials identified in phase I of the smallpox vaccination plan (table 1). In the event of a smallpox attack, vaccine would be distributed to the locations where it is needed by way of the National Pharmaceutical Stockpile (NPS). The NPS is a supply of prepacked essential medical equipment and pharmaceuticals that is stored in undisclosed locations around the country in environmentally controlled and secured warehouses, ready for rapid deployment .
Are new smallpox vaccines being developed? In addition to DryVax, there is also a supply of a second vaccine produced years ago by Aventis Pasteur; this vaccine is also in the NPS and would be available for use as an investigational new drug in the event of an emergency. There are 85 million doses of this Aventis vaccine available. It could be diluted 1 : 5, if necessary. Four other vaccines are under study; they are as follows.
Acam1000 vaccine. In 2000, Acambis (Cambridge, UK) was contracted to produce 54 million doses of vaccine from the NYCBH strain by means of a modernized vaccine development process in which vaccinia is grown in MRC-5 cell culture . The ACAM1000 vaccine is in development, but phase I clinical trials that enrolled 100 individuals have been completed and yielded a 100% "take" rate (i.e., the proportion of patients who demonstrated a major reaction to the vaccine, or a "take," which is defined as the presence of a papule, vesicle, ulcer, or crusted lesion, surrounded by erythema and induration, on days 68 after vaccination ). Phase II trials are under way.
Acam2000 vaccine. After 11 September 2001, it was decided that the stockpiles of smallpox vaccine needed to be rapidly augmented. The US government contracted with Acambis-Baxter to produce 155 million doses of vaccine employing the same process developed for Acam1000 but using a Vero cell culture system. Bulk production has been completed, and a considerable amount of vaccine has been delivered to the NPS. Delivery of all 155 million doses is expected by April 2003. Phase I trials have been completed, and phase II trials were initiated in January 2003.
Modified vaccinia Ankara (MVA) vaccine. This vaccine was attenuated by high passage in chick embryo fibroblasts, and it shows reduced replication capacity in mammalian cells. It is administered by needle and syringe. In contrast to DryVax, which induces a skin lesion that permits measurement of the strength of the reaction (the "take") and, thus , the effectiveness of the vaccine, MVA does not produce a skin lesion. The serologic response to MVA in humans will be compared to that noted for DryVax, and the ability of MVA to protect monkeys exposed to monkeypox virus will be evaluated. Because of its inability to replicate, MVA is expected to be safer than DryVax. Studies in mice show tat MVA elicits a cell response comparable to that achieved with replication competent vaccinia in immunocompromised individuals . MVA is undergoing phase I studies at the National Institute for Allergy and Infectious Diseases (National Institutes of Health), and a contract program has been initiated for its industrial development and acquisition .
Japanese strain LC16m8 vaccine. This vaccine is an attenuated, temperature-sensitive vaccine strain produced by repeated passage of Lister strain vaccinia in rabbit kidney cells. It was initially developed in Japan in the 1970s, and vaccination of 50,000 well-studied Japanese children resulted in less-severe reactions than those observed with other vaccines. Currently, it is licensed by Vaxgen from Kaketsuken. Vaxgen is planning to initiate phase I trials in the spring of 2003 .
How large is the smallpox vaccine supply in the United States? The existing DryVax supply consists of 14.8 million doses. There are 85 million doses of the Aventis product. Both of these vaccines could be diluted 1 : 5, if necessary [7, 14, 15]. When the Acam1000 and Acam2000 production is complete, there will be an additional 209 million doses of vaccine available .
EFFICACY AND DURATION OF IMMUNITY FOLLOWING VACCINATION
When administered prior to exposure to smallpox virus, vaccinia vaccine has historically had an efficacy in the range of 90.7%96.7% . Vaccination within the first few days (perhaps as late as 4 days) after exposure to smallpox virus may prevent or significantly ameliorate subsequent illness .
Are individuals who have been previously vaccinated protected against smallpox? In the United States, routine vaccination ceased in 1972. With relatively few exceptions, since global eradication was declared by the World Health Organization in 1980, the only US citizens who have undergone vaccination have been some military personnel in the 1980s and personnel in experimental laboratories who were at risk of exposure to nonhighly attenuated orthopoxviruses. Neutralizing antibodies and evidence of cell-mediated immunity (CMI) may persist for 30 years after primary (first-time) vaccination, but it is not known what serologic markers correlate with protection against infection. Prior to smallpox eradication, immunity to smallpox in countries where it was endemic resulted from the combined effects of vaccination and exposure to variola virus that led only to subclinical disease (variola sine eruptione). Data from countries where smallpox virus was introduced after a prolonged absence does show that having been vaccinated many years before is at least partially protective against a fatal outcome. Among patients who were infected with smallpox after it had been imported into Europe, 52% of those who had never been vaccinated died, whereas only 11.1% of those vaccinated >20 years previously died . Best estimates are that an increased level of protection against smallpox persists for at least 3 years after primary vaccination and that substantial but waning immunity may persist for 10 years .
VACCINE SAFETY AND ADVERSE REACTIONS (excerpts)
What is progressive vaccinia? The term "progressive vaccinia" is synonymous with "vaccinia necrosum" and "vaccinia gangrenosum." Progressive vaccinia has typically been seen in patients with severe impairment of immune defenses, primarily impaired CMI, but a few cases were reported in patients with agammaglobulinemia at a time when immunology studies could not readily define CMI . In progressive vaccinia, the vaccine injection site shows progressive enlargement after postvaccination day 15. This reaction may be restricted to the vaccination site, but most cases are complicated by 1020 large, painless skin ulcers at other sites that evolve over weeks and expand concentrically without inflammation. Biopsy of the lesions confirms the presence of minimal lymphocytic infiltrates; at autopsy, cultures of organ and skin tissue specimens demonstrate viremic dissemination [24, 2832]. Progressive vaccinia may occur after primary vaccination or after revaccination and does so with near equal frequency (13 cases per million persons vaccinated), according to studies from the 1960s, when smallpox vaccine was routinely given and there were far fewer high-risk patients with CMI defects (e.g., due to organ transplantation, immunosuppressive therapy, or AIDS) . The older reports show that most cases were lethal unless the patient was treated with VIG [10, 33]. Treatment includes administration of VIG in cumulative doses up to 10 mL/kg, but results seem less impressive than those obtained for cases of eczema vaccinatum. For example, Fulginiti et al.  reported that 5 of 8 individuals with progressive vaccinia died despite receiving very aggressive therapy that often included VIG, surgical debridement, and exchange transfusions. The role of surgical debridement is unclear.
What is postvaccinial encephalitis? CNS complications of smallpox are rare but serious, and they occur with a frequency that ranges from 1 case per 100,000 to 1 case per 500,000 primary vaccinations [24, 35, 36]. CNS complications are thought to be autoimmune reactions; they typically occur after primary immunization and occur more rarely after revaccination. There are 2 forms: postvaccinial encephalitis and postvaccination encephalomyelitis (PVEM). Postvaccinial encephalitis is most common in children aged <2 years, presents on days 610 after vaccination, and manifests as aseptic meningitis with cerebral vascular inflammation changes. Clinical features are fever, mental status changes, and vomiting, which progress in association with focal neurologic signs and seizures. PVEM is most common in children aged >2 years, presents on days 1115 after vaccination, and has pathologic features similar to those seen in other postinfectious encephalopathies. Clinical features include mental status changes, fever, seizures, and spinal cord signs.
Lumbar puncture may reveal elevated CSF pressure and presence of mononuclear cells and an increased protein concentration in the CSF, or findings may be normal. Treatment is supportive; VIG therapy is not useful for either postvaccinial encephalitis or PVEM. Overall mortality rates are variable but are reported to be as high as 25%, with 25% of the survivors having neurologic deficits . Valid data on the incidence of and the prognosis for postvaccinial encephalitis and PVEM are confounded by the lack of precise diagnostic criteria and the erroneous inclusion of data for other forms of encephalitis. The data summarized in this section are for the experience with DryVax. The European experience has indicated that postvaccinial encephalitis occurred after primary vaccination at a rate of up to 1 case per 4000 adults . There is no clear explanation for the difference in rates, but they likely relate to the different stains of vaccinia used for vaccine.
What is eczema vaccinatum? Eczema vaccinatum occurs when vaccinees that have an active or a past history of atopic dermatitis (or eczema) develop a specific form of cutaneous vaccinia lesions that is characterized by the occurrence of localized or generalized maculopapular rash, vesicles, or pustules in areas predisposed to eczema; this is accompanied by systemic signs such as fever, malaise, and lymphadenopathy. There may be hundreds of lesions, and they evolve rapidly; by contrast, progressive vaccinia generally is characterized by a much smaller number of cutaneous lesions that evolve over weeks or months. Most cases occur in children as a result of primary vaccination or contact with a vaccinee. Pathologic studies of the skin lesions characteristic of eczema vaccinatum reveal neutrophils, macrophages, and large numbers of viral particles . The severity of the disease is highly variable; some patients have mild disease, and others have extensive lesions that result in a substantial loss of the dermal barrier and need to be managed like a large surface burn. In the 1960s, eczema vaccinatum accounted for 20% of smallpox vaccineassociated deaths [30, 39]. Treatment with VIG (at dosages of 0.61 mL/kg) appears to have reduced mortality substantially; this therapy should be given early in the disease course . Most cases of eczema vaccinatum occur in patients with active eczema, but 3%20% of cases may occur in patients who do not have eczema lesions at the time of smallpox exposure .
What is generalized vaccinia? As the name implies, generalized vaccinia is a generalized rash that resembles the skin manifestations seen at the primary vaccination site. The incidence is 200800 cases per million persons who receive primary vaccination, and it typically occurs in children following primary vaccination . The suspected pathophysiologic mechanism is vaccinia viremia rather than autoinoculation. Generalized vaccinia typically presents as multiple, disseminated, maculopapular-vesicular lesions that appear to be at the same stage of development as and are usually smaller than the lesion at the primary vacation site. The onset is generally on days 69 after vaccination, and the lesions usually heal rapidly, possibly because of immunity induced by the primary vaccination. Despite the sometimes striking appearance of the rash, it is typically a benign process. The differential diagnosis of generalized vaccinia includes eczema vaccinatum, progressive vaccinia, erythema multiforme, accidental inoculation vaccinia, smallpox, and chickenpox. Most patients do not appear seriously ill and do not require any treatment, but occasional severe cases have been treated with VIG.
What is accidental inoculation vaccinia? This is the inadvertent transfer of vaccinia virus from the vaccination site to another anatomical site, most commonly to a skin site that has been disrupted by a lesion, and disease severity is often dependent on the extent of the predisposing condition. Mucous membranes may be uniquely susceptible, since many cases involve the eyelids, the mouth, the lips, the nose, and the vulva . These lesions are usually seen on days 7 10 after vaccination, and they evolve like the lesion at the primary site or somewhat more rapidly because of immunity .
What are the ocular complications of vaccinia? These include blepharitis, blepharo-conjunctivitis, and keratitis occurring as complications of autoinoculation or contact vaccinia. Previous ocular inflammation may predispose to these conditions, but most cases occur in previously healthy eyes. The greatest concern is vaccinia keratitis, which is uncommon but serious. This typically begins 10 days after inoculation and progresses with pain, inflammation, and a characteristic central grayish corneal ulcer that is best detected by means of a slit-lamp examination. With progression, there may be deep corneal ulceration and residual vision loss. Ocular vaccinia should be managed by an ophthalmologist. Topical administration of trifluridine or vidarabine is used for treatment of vaccinia keratitis; this should be considered in order to protect the cornea when there is orbital infection or accidental exposure. VIG therapy should not be used for isolated keratitis, because there is no evidence of benefit, and studies involving rabbits indicate increased rates of residual corneal scaring . However, VIG therapy should not be withheld if otherwise indicated, including for treatment of severe ocular disease without keratitis [10, 4649].