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Evaluation of 21st-century risks of smallpox vaccination and policy options.

The United States stopped vaccinating against smallpox in 1972 because the risks were judged to outweigh the benefits. The possibility of a terrorist attack using smallpox has led to renewed interest in a vaccination program. Smallpox vaccination carries considerable risks, which may be of greater concern today than in the late 1960s because of the increased prevalence of immunosuppression and atopy in the population. This paper reviews the clinical presentations of major adverse events after vaccination and the rates of occurrence of these events observed in the 1960s. The normal dynamics of the spread of smallpox is slow, and usually only persons who have had close personal contact with an overtly ill patient are affected. There are several preattack vaccination policy options, but immunization of medical workers, especially those who might have close contact with infected patients, is sufficient in the absence of a known threat of a bioterrorist attack or the identification of a smallpox-infected person.

Bioterrorism↗

[Results of basic and applied investigations on oral immunization against smallpox ].

The results of fundamental and applied investigations on the development and trial of the oral administration of smallpox vaccine and live recombinant smallpox-hepatitis vaccine (Revax VT) in tablets are summarized. In comparative experiments on animals (rabbits, monkeys and guinea pigs) and human immunization the oral smallpox vaccine in tablets was shown to ensure equal effectiveness and greater safety in comparison with traditional smallpox vaccine for skin application. The study confirmed the natural and physiological character of oral immunization as a result of direct contact of immunogen with the mucous membrane of the digestive tract--an essential immunocompetent organ of the lymphoid system. The conclusion was made that oral immunization was the safe and most promising method of immunization against smallpox under modern conditions.

Administration, Oral↗

Preparation for an outbreak of smallpox in Israel.

Because of its high case-fatality rate, its very high transmission potential, and the worldwide shortage of effective vaccine, smallpox tops international lists of over a dozen possible bioterror and biologic warfare agents. In a scenario involving aerosol variola virus release, tens to hundreds of first-generation cases would ensue, as would hundreds to thousands of subsequent cases resulting from person-to-person transmission. A smallpox outbreak in Israel must not be regarded as a doomsday event: the methods of smallpox outbreak control are known and will be implemented. The rapidity with which organized outbreak control measures are competently executed will determine how many generations of cases occur before the outbreak is brought under control. Planning, vaccine stockpiling, laboratory expansion, professional training and public education, all carried out well in advance of an epidemic, will minimize the number of casualties. The reinstitution of routine smallpox vaccination in Israel, as in other countries, must be given serious consideration, since it has the potential for eliminating the threat of smallpox as a bioterror agent.

Bioterrorism↗

[Smallpox--past, present and future].

Smallpox has played a notorious role in human history. It has been the cause of millions of deaths throughout the centuries, yet, it was the first infectious disease that was ever eradicated thanks to a worldwide program. Smallpox vaccine, manufactured from the vaccinia virus, was the first vaccine ever produced. Recent bioterrorism events in the USA have brought smallpox back into the limelight, both medically and politically, because of the fear of the return of this horrific disease through the unscrupulous actions of terrorists who might spread variola virus. This article presents the history of smallpox, emphasizing its clinical variants. We also review the treatment of the disease, especially the vaccine--its efficacy and its disadvantages, and the public health measures that must be taken in order to control the disease. In conclusion, we will discuss the possibility of the resurgence of smallpox and global preparedness for such an outbreak.

Bioterrorism↗

Smallpox in the post-eradication era.

Smallpox is a recently extinct human viral infection for which herd immunity has rapidly waned. The threat of smallpox during a bioterrorist event using caches of virus outside reference repositories would lead to epidemics of great and predictable mortality. The result would be short-term societal chaos. Control of smallpox requires vaccination and quarantine, the same measures that eliminated this disease in the 1970's. Extensive coordination and planning would be needed among the healthcare infrastructure, law enforcement agencies and political leadership for effective responses to this public health threat. Despite this challenge, we must remind ourselves that smallpox transmission and vaccinia effectiveness are well understood. Strategies that successfully eradicated smallpox 25 years ago, if appropriately implemented again, would undoubtedly lead to its elimination once again.

Bioterrorism↗

Smallpox: clinical highlights and considerations for vaccination.

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.

Humans↗

[Smallpox vaccination techniques: considerations and unresolved issues].

The smallpox vaccine is the oldest--and was, for 90 years, the only--vaccine known to man. Many vaccination techniques have been used over time, with no fewer than ten employed during the 20th century alone. In Israel, two main techniques were used prior to smallpox eradication in 1978--multiple punctures using a standard needle, and jet injection--while most other countries adopted the bifurcated needle as the method of choice. Despite the vaccination experience gained over time, doubt remains today as to the preferred vaccination technique. During 2002, when Israel became the first country to conduct large-scale smallpox vaccination in the 21st century, multiple standard needle puncture was adopted as the method of choice, while at the same time the bifurcated needle was readopted in the United States. The article reviews the various smallpox vaccination techniques, the supporting scientific data, and the current lacunae in knowledge related to the subject. Together, these factors will most likely influence the adoption of a preferred vaccination technique during a smallpox emergency.

Humans↗

[Smallpox--historical or real threat].

Presently, there is no real possibility of natural re-emergence of smallpox virus, which was eradicated globally more then 25 years ago. During the last decade the possibility of use of smallpox virus as a biological weapon by a criminal organisation was emphasised. The re-emergence of smallpox virus would lead to unprecedented disaster. Theoretical models indicated that only extremely strict and enforced interventions could stop the spread of epidemic, but the assumptions of these models were unrealistic. Presently, there are limited stocks of the first generation smallpox vaccine left in the world. This vaccine, as well as the second-generation vaccine are associated with multiple adverse events, including fatalities and may not be accepted by society. Much safer vaccines are now being developed. Strategic plan of prophylactic vaccinations requires defining the groups to be immunised in the first place and whether immunisation should start before or after a first smallpox case would occur.

Bioterrorism↗

Smallpox vaccination by intradermal jet injection. I. Introduction, background and results of pilot studies.

Jet injection has met with great success in the rapid and effective mass administration of several immunizing agents. The recent development of a jet injector nozzle specifically designed for intradermal inoculation suggested the possible extension of jet injector methodology to mass smallpox vaccination. A total of 156 volunteer subjects, 16 unvaccinated and 140 vaccinated more than 5 years previously, received either undiluted smallpox vaccine by the multiple-pressure technique, or 0.1 ml of various dilutions of smallpox vaccine by jet injector using the new nozzle. Cutaneous and serological responses in revaccinees revealed that jet injection of diluted vaccine with a titre of 10(7) TCID(50)/ml was as effective as multiple-pressure inoculation of undiluted vaccine. Among the small number of primary vaccinees, jet injection of diluted vaccine with a titre of 10(6) TCID(50)/ml appeared as effective as multiple-pressure inoculation of undiluted vaccine. No complications of vaccination occurred.The findings confirm the utility of the intradermal nozzle for jet injection of smallpox vaccine. In view of the speed of administration and the economy of vaccine, it is suggested that there is a distinct role for jet injection in global smallpox eradication efforts. Further studies on larger numbers of unvaccinated subjects and on persons with significant residual vaccinial immunity are needed to define the optimal concentration of vaccine for mass vaccination by jet injection.

Animals↗

[The last victims of smallpox in Ytre Nordhordland. Experiences of a local physician].

Smallpox caused devastating epidemics in Bergen and surrounding areas down to the early 19th century. A few attempts at variolisation were performed after 1765, and vaccination started in Bergen during a new wave of smallpox in 1803. The more distant rural parish of Manger did not start vaccination until 1829, and was heavily struck by the 1803 epidemic. That year, 208 died out of a total population of 3500. In 1859 Manger again experienced a serious smallpox epidemic. The local doctor ordered mass vaccination, but the peasants were uncooperative, and the campaign was even sabotaged by the assistant vaccinator. Eventually, 27 people died of smallpox that year, the last persons ever to die of smallpox in Manger.

Disease Outbreaks↗

[Smallpox: an historical review].

The first protection against smallpox, a disease known already in old China and India, consisted in rubbing infectious material from smallpox patients into the scratched skin of children. Lady Montagu brought this method from Turkey to England in 1721. This "variolation", however dangerous, was adopted in Europe during the eighteenth century mainly by the aristocracy. But it was Edward Jenner (1749-1823) who in 1796 used cowpox to protect against smallpox without the risk of acquiring the disease. During more than 60 years the "vaccination" was carried out from "arm to arm" with a certain risk of transmission of syphilis. From 1864 on the vaccine was mainly produced on cows to avoid this risk. The WHO managed in 1978 to eliminate smallpox from the planet by vaccination. The smallpox outbreaks, the inoculation, the vaccination and the production of cowpox vaccine in Luxembourg are described.

Animals↗

Smallpox.

Smallpox is a highly infectious disease, which, in 1980, was declared eradicated by the World Health Organization as a result of successful vaccination campaigns. Because of its highly infectious nature and historical 30% mortality rate, the disease has possibly been developed as a biological weapon. Variola, the virus that causes smallpox, is readily transmissible from person to person during the incubation period, before infected individuals show signs of illness. When a victim develops the characteristic rash and viral syndrome associated with smallpox infection, the disease requires complex isolation and possibly quarantine. Diagnosis can be confirmed in a high-containment laboratory. The only effective treatment for smallpox is rapid administration of smallpox vaccine.

Bioterrorism↗

Smallpox vaccination and myopericarditis: a clinical review.

Smallpox is a devastating viral illness that was eradicated after an aggressive, widespread vaccination campaign. Routine U.S. childhood vaccinations ended in 1972, and routine military vaccinations ended in 1990. Recently, the threat of bioterrorist use of smallpox has revived the need for vaccination. Over 450,000 U.S. military personnel received the vaccination between December 2002 and June 2003, with rates of non-cardiac complications at or below historical levels. The rate of cardiac complications, however, has been higher than expected, with two confirmed cases and over 50 probable cases of myopericarditis after vaccination reported to the Department of Defense Smallpox Vaccination Program. The practicing physician should use the history and physical, electrocardiogram, and cardiac biomarkers in the initial evaluation of a post-vaccination patient with chest pain. Echocardiogram, cardiac catheterization, magnetic resonance imaging, nuclear imaging, and cardiac biopsy may be of use in further workup. Treatment is with non-steroidal anti-inflammatory agents, four to six weeks of limited exertion, and conventional heart failure treatment as necessary. Immune suppressant therapy with steroids may be uniquely beneficial in myopericarditis related to smallpox vaccination, compared with other types of myopericarditis. If a widespread vaccination program is undertaken in the future, many more cases of post-vaccinial myopericarditis could be seen. Practicing physicians should be aware that smallpox vaccine-associated myopericarditis is a real entity, and symptoms after vaccination should be appropriately evaluated, treated if necessary, and reported to the Vaccine Adverse Events Reporting System.

Forecasting↗

Mouse neurotoxicity test for vaccinia-based smallpox vaccines.

The only US FDA licensed smallpox vaccine, Dryvax, was associated with rare but serious neurological adverse events. After smallpox was eradicated in the United States, mass vaccination ceased in 1971. As counter-bioterrorism/biowarfare measures, new smallpox vaccines are now being investigated. However, there are no established pre-clinical neurotoxicity assays with which to evaluate these new vaccines prior to licensure. Here we report the development and initial characterization of a small animal neurotoxicity assay for vaccinia-based smallpox vaccines using Dryvax virus as a reference vaccine strain and the neuroadapted Western Reserve (WR) strain as a neurotoxic positive control. In neonatally inoculated mice, the WR strain produced significantly greater and more rapid onset of mortality than the Dryvax vaccine reference. Expression of virus antigen in neural cells and infectious virus replication in the brain was also significantly different between the two strains. In addition, the appearance of high titer virus antibody correlated with the clearance of virus from brain. With further validation, this assay incorporating a licensed vaccine reference standard and positive control strain may provide important pre-clinical neurotoxicity data on new vaccinia-based smallpox vaccine strains.

Animals↗

Absence of oropharyngeal vaccinia virus after vaccinia (smallpox) vaccination.

BACKGROUND: With the resumption of the vaccinia (smallpox) vaccination, questions regarding transmission risk prompted this study to determine whether vaccinia virus could be detected in the oropharynx of adults recently vaccinated with vaccinia (smallpox) vaccine. German, Russian, and American studies on the oropharyngeal presence of vaccinia virus revealed conflicting results in different age groups. OBJECTIVE: To measure vaccinia viral particle or antigen presence in the oropharynx of adult health care workers after vaccination with vaccinia (smallpox) vaccine using viral culture and high-sensitivity assays (polymerase chain reaction [PCR] and electrochemiluminescence) and to determine whether there is an association between the presence of vaccinia virus and adverse reactions. METHODS: A total of 155 adults (primary vaccinees and revaccinees) were enrolled for 1 baseline and 5 subsequent throat swabs. The swabs were evaluated using viral culture, PCR, and electrochemiluminescence. RESULTS: Of the 155 participants, 144 had more than 2 throat swabs in the 2 weeks after vaccination. Of the 801 specimens evaluated, there were no positive results by culture, PCR, or electrochemiluminescence except in the control samples (n = 6), which were positive by all 3 methods. CONCLUSIONS: Based on the absence of detectable vaccinia virus in this study population, one can be 95% certain that the true rate of vaccinia virus in the oropharynx of adults during the 2 weeks after vaccination with vaccinia (smallpox) vaccine is 0% to 3.3%. These data should be reassuring to the medical community and support the Advisory Committee on Immunization Practice guidelines that respiratory precautions are not necessary after vaccinia (smallpox) vaccination in healthy adults.

Adolescent↗

Duration of antiviral immunity after smallpox vaccination.

Although naturally occurring smallpox was eliminated through the efforts of the World Health Organization Global Eradication Program, it remains possible that smallpox could be intentionally released. Here we examine the magnitude and duration of antiviral immunity induced by one or more smallpox vaccinations. We found that more than 90% of volunteers vaccinated 25-75 years ago still maintain substantial humoral or cellular immunity (or both) against vaccinia, the virus used to vaccinate against smallpox. Antiviral antibody responses remained stable between 1-75 years after vaccination, whereas antiviral T-cell responses declined slowly, with a half-life of 8-15 years. If these levels of immunity are considered to be at least partially protective, then the morbidity and mortality associated with an intentional smallpox outbreak would be substantially reduced because of pre-existing immunity in a large number of previously vaccinated individuals.

Adult↗

A chemokine-binding domain in the tumor necrosis factor receptor from variola (smallpox) virus.

Variola virus (VaV) is the causative agent of smallpox, one of the most devastating diseases encountered by man, that was eradicated in 1980. The deliberate release of VaV would have catastrophic consequences on global public health. However, the mechanisms that contribute to smallpox pathogenesis are poorly understood at the molecular level. The ability of viruses to evade the host defense mechanisms is an important determinant of viral pathogenesis. Here we show that the tumor necrosis factor receptor (TNFR) homologue CrmB encoded by VaV functions not only as a soluble decoy TNFR but also as a highly specific binding protein for several chemokines that mediate recruitment of immune cells to mucosal surfaces and the skin, sites of virus entry and viral replication at late stages of smallpox. CrmB binds chemokines through its C-terminal domain, which is unrelated to TNFRs, was named smallpox virus-encoded chemokine receptor (SECRET) domain and uncovers a family of poxvirus chemokine inhibitors. An active SECRET domain was found in another viral TNFR (CrmD) and three secreted proteins encoded by orthopoxviruses. These findings identify a previously undescribed chemokine-binding and inhibitory domain unrelated to host chemokine receptors and a mechanism of immune modulation in VaV that may influence smallpox pathogenesis.

Amino Acid Sequence↗

Smallpox vaccination does not elevate systemic levels of prothrombotic proteins associated with ischemic cardiac events.

BACKGROUND: During the recent smallpox vaccination campaigns, ischemic cardiac complications were observed after vaccination. To examine a possible association between the smallpox vaccine and postvaccination ischemic events, we investigated alterations in levels of prothrombotic proteins (plasminogen activator inhibitor type 1 [PAI-1] and soluble CD40 ligand [sCD40L]) in recently vaccinated individuals. METHODS: Vaccinia-naive (cohort N; aged 18-32 years) and vaccinia-experienced (cohort E; aged 33-49 years) healthy adults were vaccinated with a 1 : 5 dilution of the Aventis Pasteur smallpox vaccine. Plasma levels of PAI-1 and sCD40L were measured in 30 subjects (cohort N, n=15; cohort E, n=15) at baseline and twice after vaccination (between days 7 and 9 and between days 26 and 30). RESULTS: Baseline mean PAI-1 levels significantly differed between cohorts N and E (P=.04). Within each exposure cohort, mean PAI-1 levels did not significantly change after vaccination. Baseline sCD40L levels did not differ between cohorts N and E. In cohort N, sCD40L levels significantly decreased after vaccination but returned to baseline levels within 1 month. Vaccination did not significantly alter levels of sCD40L in cohort E. CONCLUSIONS: Levels of PAI-1 and sCD40L did not significantly increase after smallpox vaccination. Vaccine-induced alterations in levels of these prothrombotic proteins do not appear to play a role in ischemic events observed after smallpox vaccination.

Adolescent↗