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Smallpox: clinical highlights and considerations for vaccination. MC Mahoney, AB Symons, SR KimmelDepartment of Family Medicine, State University of New York at Buffalo, ECMC Clinical Center, 462 Grider Street, Buffalo, New York 14215, USA. , USA Correspondence Address: PMID: 12867690
Smallpox virus has gained considerable attention as a potential bioterrorism agent. Recommendations for smallpox (vaccinia) vaccination presume a low risk for use of smallpox as a terrorist biological agent and vaccination is currently recommended for selected groups of individuals such as health care workers, public health authorities, and emergency/rescue workers, among others. Information about adverse reactions to the smallpox vaccine is based upon studies completed during the 1950s and 1960s. The prevalence of various diseases has changed over the last four decades and new disease entities have been described during this period. The smallpox vaccination may be contra-indicated in many of these conditions. This has made pre-screening of potential vaccines necessary. It is believed that at present, the risks of vaccine-associated complications far outweigh the potential benefits of vaccination in the general population.
The Centers for Disease Control and Prevention (CDC) classifies smallpox as one of several Category A pathogens that could pose a risk to national security as it can be easily transmitted, has the potential to cause significant morbidity and mortality, and has the ability to create social disruption. The last case of (natural) smallpox occurred in Somalia in 1977 and the World Health Organization (WHO) announced the global eradication of smallpox in 1980. The early 1980s saw the end of smallpox vaccination all over the world. The decision to end smallpox vaccination was based upon the eradication of naturally occurring smallpox, resulting in a situation where the risk of adverse reactions from the vaccinia vaccine outweighed the risk of contracting smallpox.
Smallpox is caused by the variola virus, which belongs to the genus orthopoxvirus. Cowpox, vaccinia and monkeypox are the other species belonging to the same genus.[1] During the period of endemic smallpox infection, humans represented the only known viral reservoir. Variola virus is known to exist in two repositories: one in Atlanta (at the Centers for Disease Control & Prevention) and a second in Moscow (at the Institute for Viral Preparations).[2] It is possible that more nations and some groups may possess additional viral stores. The probability of multiple owners has raised concerns regarding a potential bioterrorist threat using this agent. It is transmitted through droplet spread of viral particles onto the mucosal surfaces of the oropharyngeal or respiratory tract among susceptible persons. This transmission occurs through close personal contact (face-to-face within 6 feet or household contact) for extended periods;[3],[4],[5],[6] it has a lower transmission rate as compared to measles, pertussis and influenza.[3],[7],[8] Transmission through casual and limited contact is unlikely. Although rare, airborne (i.e. suspended viral particles) and fomite transmission can occur. Patients with skin rash are infectious and remain so until all the lesions are scabbed. Transmission can also occur during the prodromal phase through aerosolisation of viral particles from oral mucosal lesions. Infection cannot be spread during the incubation period or during the early prodromal phase.[4],[9] Survivors of natural infection have lifelong immunity. Identification of contacts, isolation of cases and contacts, vaccination of susceptible individuals, and surveillance can help interrupt transmission.[3],[4],[7],[8] Most secondary smallpox infections occur among household contacts and hospital personnel.[3] Secondary attack rates among unvaccinated household contacts range between 37% and 88%.[10] Generations of infection typically occur at intervals of 1-3 weeks. Health care providers should use airborne (e.g. use of a NIOSH N-95 mask) and contact precautions (e.g. gloves, gowns, eye shields, and shoe covers) to protect themselves.[4] The incubation period lasts for 10-14 days (range 7-17 days). This is followed by a prodromal period with manifestations such as fever, chills, malaise, headaches, vomiting, and backache. Patients appear severely ill with fever exceeding 40 degrees Celsius. This prodrome is followed by an enanthem involving the tongue and oropharynx, which is followed by a maculopapular rash involving the oral mucosa, face, and upper extremities. The rash spreads to involve the trunk and lower extremities and evolves synchronously into vesicles and then umbilicated pustules. Historically, mortality rates are reported to be generally about 30% among unvaccinated groups.[4] While there are four clinical forms of smallpox, the two forms most commonly observed prior to the eradication of smallpox were variola major and variola minor.[3] Variola major accounted for about 90 percent of cases and demonstrated the classic picture of diffuse pustular skin lesions.[3] Variola minor, resulting from infection with a less virulent form of variola virus, exhibited fewer lesions with a generally mild clinical course. While less common, flat type smallpox and hemorrhagic smallpox were reported to have had fatality rates that approached 100%.[2], [11] Supportive treatment is the mainstay of treatment as there is no proven pharmacotherapy for smallpox infection. Use of vaccinia immune globulin provides no benefit to persons with clinical smallpox.[3] The differential diagnosis for smallpox includes chickenpox, disseminated herpes zoster, impetigo, erythema multiforme, scabies, and enteroviral infections, including Hand, Foot and Mouth disease. Resources comparing the clinical features of chickenpox and smallpox are readily accessed (http://www.bt.cdc.gov/agent/smallpox/smallpox-images).[12] It is unlikely that individuals previously immunized many years ago against smallpox have adequate immunity. For example, given the 30-year interval since widespread smallpox immunization in the United States, coupled with waning immunity over time, the U.S. population is considered susceptible to smallpox infection. Persons under the age of 30 years are particularly susceptible, given the fact that they have never been vaccinated against smallpox.[2] Similar susceptibility exists across Europe, and worldwide, since most vaccination programs ceased 20 or more years ago. Few studies of long-term immunity have been conducted. Protection has been noted to persist up to 30 years after administration of 3 doses of the Lister vaccine strain used in Israel.[13] Fatality rates of 10% have been observed among those vaccinated 20 years previously, compared to fatality rates of up to 50% among unvaccinated persons.[14] The determinants of long-term immunity are unknown.
The smallpox vaccine is a live viral vaccine, containing an attenuated vaccinia virus. Intra-dermal administration of smallpox vaccine (vaccinia virus), using a bifurcated needle, can prevent or lessen infection if administered within five days following smallpox exposure. Five vaccine products are available or planned. Stockpiled vaccine product consists of bovine products produced by Wyeth (Dryvax?) and Aventis-Pasteur (Wetvax?, a liquid preparation, as compared to the lyophilized Dryvax? vaccine product. The Dryvax? formulation includes polymyxin B, dihydrostreptomycin, chlortetracycline and neomycin as antibacterials. There are no plans to license the Wetvax? product due to problems with proper documentation of appropriate storage of the vaccine over the years; it will always be used under an investigational protocol and only in an emergency at a 1:5 dilution. Two new tissue-based vaccine products, ACAM 2000, from the Vero cell line, and ACAM 1000, using the MRC-5 cell line, are being produced by Acambis and will generate an additional 54 million doses. Oravax Inc., a small Massachusetts (United States) biotechnology firm, is poised to enter the market. Biopreparedness plans call for a smallpox vaccine supply sufficient to vaccinate all U.S. citizens, the capacity to deliver millions of doses within 12-24 hours to any state or U.S. territory, and accomplish the distribution of 280 million doses within 5 days; this planning has encouraged other countries to address smallpox preparedness. Presently, only the Dryvax? smallpox vaccine product (Wyeth Laboratories) is licensed by the FDA for use in persons age 18 years and older. Several Investigational New Drug (IND) protocols are underway to evaluate other smallpox vaccine products. Vaccination continues to represent a primary strategy for persons at occupational risk of exposure through culture handling or contact with animals infected with non-highly attenuated vaccinia viruses (e.g. laboratory workers and health care workers) and immediately following exposures.[4],[5],[8]
The modified vaccinia virus Ankara (MVA) vaccine was derived by taking material from a horse’s pox lesion in Ankara, Turkey and passing it in chick embryo fibroblasts.[15] During the 1970s, MVA was given to over 100,000 persons in Germany and Turkey as a primer to establish basic immunity before later administering the traditional smallpox vaccine during the final phases of a smallpox eradication program. MVA is immunogenic in human cells and appears to have limited capacity for replication.[15] However, its efficacy in an outbreak situation has not been evaluated. The defective vaccinia virus Lister (dVV Lister) genetically alters the Lister strain that is used for the smallpox vaccine in the United Kingdom, Europe, and Israel, so that the virus replicates in few permanent mammalian cell lines.[16] However, dVV Lister has been demonstrated to induce humoral and cellular immunity in mice and both the MVA and dVV Lister were tolerated in immunodeficient mice.[16] Further development and study of these attenuated vaccines in humans is required before they can be introduced on a large scale.
Vaccine efficacy is 95% among vaccinees in whom a 1-2 cm loculated and umbilicated pustule (called a Jennerian pustule) is noted 6-8 days after inoculation.[2],[4],[8],[17] The presence of a Jennerian pustule is considered a major reaction and indicates a successful vaccination; lesser reactions require revaccination.[3] Primary vaccination results in immunity for 5-10 years, with revaccination yielding immunity for 10-20 years.[11] Studies examining 1:5 and 1:10 dilutions of the Dryvax? product show no decrease in vaccine efficacy among selected populations.[18],[19] Clinicians should be aware of what constitutes a normal cutaneous vaccination response.[20]
Guidelines for pre-exposure smallpox vaccination are given in [Table - 1]. Recent reports of myopericarditis among U.S. vaccinees have resulted in additional restrictions against vaccination for persons with a history of cardiac disease, stroke or transient ischemic attack or cardiac symptoms, or persons reporting three or more risk factors for cardiac disease. Significant immune dysfunction represents an absolute contra-indication to use of smallpox vaccine.[5] CDC has defined household contacts as persons with whom the vaccinee is likely to have prolonged intimate contact (e.g. sexual contacts) or contact with the vaccination site.[8]
Prior vaccine experience Risk of complications from the smallpox vaccine is higher than for any other routinely used vaccine product. [21] Most of our knowledge about adverse reactions to the smallpox vaccine (vaccinia) is based upon studies completed during the 1950s and 1960s, a period when the general population was vaccinated as part of standard care. Studies from the 1960s document a death rate of 1 per million primary smallpox vaccinations; rates of adverse reactions are highest among children aged less than 5 years. Minor side effects include fever in 70% of children lasting up to 14 days.[4] Complication rates were higher among primary vaccines (125 per 100,000) than in those receiving revaccination (10.8 per 1,000,000) Serious adverse events, based on past experience, included death (1/million primary vaccines) and post-vaccine encephalitis (range 1 to 10 cases /million). These generally occur among infants and the elderly.[4],[17],[22] Other commonly observed adverse reactions included a robust primary reaction (incidence of 4-18%); generalized vaccinia (240 cases/1 million primary vaccinations) with vesicles/pustules distant from vaccine site, and mild systemic illness. Inadvertent inoculation to other places on the body (529 cases/million), eczema vaccinatum (1/25,000) generally occurring among persons with a history of eczema; progressive vaccinia (1/600,000) seen among persons with impaired T-cell function with necrosis at the vaccine site and with severe and potentially fatal systemic illness. In addition, transmission of vaccinia from vaccinees to susceptible contacts occurred at a rate of 27 infections/million vaccinations.[4] Recent vaccine experience Beginning in early 2003, a pre-event smallpox vaccination program was initiated in the U.S. As of May 2003, 36,217 civilians have been vaccinated, in addition to more than 240,000 military vaccinees. Recent experiences have revealed that one-third of 680 persons who received smallpox vaccine reported missing school, modifying recreational activities or disturbed sleep following vaccinia vaccination;[18],[19] 1 in 4 recent vaccinees noted mild systemic reactions (B. Schwartz, CDC, June 2002). Local skin irritation, satellite lesions, headache, myalgia, lymphadenopathy, nausea, chills and fever for 1-2 weeks post-innoculum is common.[18],[19] A robust primary reaction is likely to result in either ambulatory visits or time lost from work or school. Six cases of myopericarditis have been confirmed with an additional 18 suspect cases reported among vaccinees.[23] These events have resulted in three deaths. Following extensive review, these data were judged to be sufficient to establish causality between the development of myocarditis/pericarditis and administration of the smallpox vaccine. However, no causal relationship was found between cardiac ischemic events and smallpox vaccination.[24] It is worthwhile to note that in 1968, only one case of transient pericarditis was reported (<1/million vaccinees).[22] Aside from these cardiac events, no other serious complications have been reported in the current immunization program at the time of this writing.[25] [Table - 2] summarizes selected adverse events following smallpox vaccination from both the 1960s[22] and recent experience.[23] It should be emphasized that current experiences are based upon a limited number of vaccinees and the occurrence rates might be considered somewhat unstable. Nonetheless, several differences are apparent, including the high rate of myopericarditis that was not previously noted in the 1960s. The high rate of overall adverse events and “non-serious adverse events” noted for the 2003 data likely reflects a surveillance bias and tendency to over-report relatively benign conditions and symptoms unrelated to smallpox vaccine. Continued surveillance will be important in further characterizing these experiences. The increased risk for serious adverse events among persons with certain medical conditions has guided the CDC in carefully outlining contra-indications for vaccination in the pre-event immunization program. However, over the last 20-40 years, the prevalence of many of these risk conditions has increased. For example, not only have incidence rates increased for many cancer sites, but also mortality rates have remained stable or even decreased, leading to an increased prevalence of cancer (e.g. including cancer survivors and chemotherapy patients) among the general population. This has resulted in increased numbers of immunocompromised individuals. Also, dramatic enhancements in management of rejection have made organ transplantation much more common today than in the 1960s and increased the numbers of patients on immunosuppressive medications. HIV/AIDS was not a clinical entity prior to the early 1980s. Also, although precise figures are lacking, rates of atopic dermatitis are estimated to have doubled or tripled since the era of universal smallpox vaccination.[26] In addition, Smith et al recently estimated that a considerable proportion of hospitalized patients might be at an increased risk for contacting vaccinia based on a review of discharge diagnoses.[27] Based on experiences in the U.S., it has been estimated that the list of contra-indications (particularly that for atopic dermatitis/chronic exfoliative skin conditions in the patient or a household contact) may result in more than 50% of the population becoming ineligible for smallpox vaccination in the first stage of the pre-event vaccination program.[26] The prevalence of medical contra-indications to smallpox vaccination is summarised in [Table - 3]. Even acknowledging the possibility that individuals might have multiple contra-indications to smallpox vaccine, these data suggest that a considerable number of individuals will fall into one or more of these categories irrespective of cardiac history, cardiac risk factors and contraindications among household contacts of potential vaccinees. Post-vaccination site management Until the vaccination site is scabbed there is a risk of inoculating nonvaccinees with vaccinia virus. Although, no cases of vaccinia transmission from civilian vaccinees have been reported, transmission has occurred in military populations.[25] The CDC does not recommend routine administrative leave for healthcare workers after vaccination, so vaccinees will potentially come into contact with patients who are at increased risk of ‘contact vaccinia.’ Recommendations for inoculation site management include covering the vaccination site with a semi-permeable dressing on top of gauze, with clothing to be worn on top of the dressing. The dressing is to be changed every 3-5 days, particularly if exudate collects on the gauze. Currently most vaccinees are assessed daily and would have daily dressing changes.
The occurrence of adverse events following smallpox vaccination should be immediately reported to health officials. In the U.S., severe events should be reported electronically via the Vaccine Adverse Events Reports System (VAERS) at http://secure.vaers.org/VaersDataEntry.htm or by calling 800-822-7967 for a postage-paid paper report form.
For cases of progressive vaccinia, eczema vaccinatum, severe generalized vaccinia or inadvertent inoculation resulting in extensive lesions and/or ocular involvement, vaccinia immunoglobulin (VIG) and cidofovir can be used. These drugs are available from the CDC under investigational new drug (IND) protocols.[8],[28] The current VIG supply is sufficient to treat about 4,000 adverse events anticipated to result from vaccination of 40 million persons.
Recommendations for smallpox (vaccinia) vaccination are based upon a scenario of low risk for use of smallpox as a terrorist biological agent, disease transmission consistent with prior disease experience, adherence to recommended infection control measures, appropriate screening for contra-indications to vaccination, a procedure for informed consent, surveillance of vaccinated persons, adequate supplies of vaccine and vaccinia immunoglobulin (VIG), and voluntary vaccine administration (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5207a1.htm).[8] Accordingly, smallpox vaccination in the U.S. is currently recommended for persons pre-designated by the appropriate bioterrorism and public health authorities to conduct investigation and follow-up of smallpox cases. Smallpox vaccination is also recommended for selected personnel in facilities pre-designated to serve as referral centers to provide care for the initial cases of smallpox. Personnel within these facilities would be designated for vaccination by the hospital. As outlined in the CDC Interim Smallpox Response Plan and Guidelines (see URL above), state bioterrorism response plans should designate initial smallpox isolation and care facilities. In the event that a smallpox outbreak were to occur, vaccination of primary contacts and persons exposed to these contacts (e.g. a ring vaccination strategy) would be initiated as outlined in the CDC Draft Smallpox Response Plan. In addition, if circumstances warrant, vaccination of communities may be undertaken based upon existing biopreparedness plans. Surveillance and containment, including ring vaccination, represent the primary strategy for the control and containment of a smallpox outbreak. In addition, local, federal, and international public health agencies would be able, if necessary, to expand immunisation to additional groups, up to and including the entire population, in a timely manner. Since prompt identification of a smallpox case is critical to initiating a public health response, the CDC has developed a rash assessment algorithm to assist medical and public health professionals in evaluating the likelihood of smallpox in patients with febrile rash illnesses. Poster copies of this algorithm are available at http://www.bt.cdc.gov/agent/smallpox/diagnosis In the event of a documented outbreak, use of smallpox vaccine for post-exposure prophylaxis warrants clinical judgment since the benefits resulting from use of vaccine would likely exceed risk among most high-risk populations. The CDC and internal health agencies, such as the World Health Organization, would promptly provide recommendations under such a scenario. Vaccination within 3-4 days of viral exposure can afford complete protection.[2],[4] It can be supplemented with administration of vaccinia immunoglobulin (VIG) in the dose of 0.6 ml/kg.[3],[4]
[Table - 1], [Table - 2], [Table - 3]
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