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PubMed2003

Rapid diagnosis of smallpox infection and differentiation from its mimics.

The potential for a bioterrorism-induced smallpox outbreak has been much discussed of late. The literature of the late 1960s stressed that the distinction between smallpox and the other viral-induced vesicle-forming diseases, namely varicella zoster and disseminated herpes simplex, was difficult to make. Given that the cutaneous manifestations of smallpox would be among the initial symptoms, we reviewed 2 cases of smallpox diagnosed in South America in the 1970s in conjunction with 9 cases of multiple skin vesicles diagnosed as either disseminated herpes simplex or varicella-zoster. These were examined by routine hematoxylin and eosin stain (H&E) as well as by in situ hybridization. A blind review of the cases demonstrated that each showed striking intraepithelial vesicles containing multinucleated squamous cells exhibiting a ground glass appearance of the nuclear chromatin. Thus, as expected, routine H&E examination could not differentiate the 2 smallpox cases from the other 9 samples. In situ hybridization easily distinguished the 2 cases of smallpox from the other 9 samples, 5 of which contained varicella-zoster (two had been misdiagnosed as herpes) and the other 4 were disseminated herpes simplex. The in situ test, readily accomplished in any histology-based molecular laboratory in 4 hours, allows for the rapid and specific identification of smallpox infection and, importantly, its distinction from its mimics. Formalin fixation, which is optimal for in situ hybridization, guarantees the inactivation of the smallpox virus.

Bioterrorism↗
PubMed2006

Public health surveillance for smallpox - United States, 2003-2005.

In June 1987, nearly 10 years after the World Health Organization (WHO) declared smallpox eradicated, the Council of State and Territorial Epidemiologists (CSTE) recommended removal of smallpox, a highly contagious viral disease, from the National Notifiable Diseases Surveillance System (NNDSS). However, the attacks of September 11, 2001, raised concern that smallpox (variola) virus, might exist in laboratories other than two WHO-designated repositories and could be used as an agent of biologic terrorism. In response to this concern, CSTE and CDC recommended in June 2003 that smallpox again be made reportable through NNDSS and that all states, territories, and cities add smallpox to their lists of reportable diseases. In 2005, CSTE conducted a cross-sectional survey in the United States and its territories to assess key components for surveillance of suspected smallpox disease, including legal reporting requirements, laboratory testing, and training and education (e.g., oral presentations and guides). This report summarizes the results of that survey, which indicated that 100% had the capacity to receive and investigate reports, 94% of states had legal requirements to report suspected smallpox disease, 70% had mandatory laboratory reporting of results indicative of smallpox disease, and 68% were providing ongoing training and education of health-care providers and public health staff.

Humans↗
PubMed1979

Evaluation of smallpox vaccination policy.

During 1978 and 1979 the Global Commission for the Certification of Smallpox Eradication will proceed with verification of smallpox eradication in 31 countries. If current surveillance activities do not discover any further cases before the end of 1979, the world will be declared smallpox free. However, the recent occurrence of two laboratory associated smallpox cases in Birmingham, England, revealed that the stocks of variola virus held in at least 12 laboratories in the world pose a real danger to the achievement of smallpox eradication and efforts are being made to reduce the number of laboratories retaining the virus to not more than 4-all WHO collaborating centres-by 1980. Scientific data indicate the unlikelihood of smallpox recurring once it has been eradicated from the human population, although further confirmatory studies are continuing. If the Global Commission verifies the eradication of smallpox, continuation of smallpox vaccination will be unjustifiable in view of its severe complications, however infrequent, and the expected global savings that would result from the termination of vaccination programmes.

Animals↗
PubMed1965

A study of the effect of simultaneous vaccination with BCG and smallpox vaccine in newborn infants.

In order to determine whether the BCG and smallpox vaccinations of newborn infants could be combined, thus saving staff, time and money, particularly in the developing countries, 696 newborn infants in Taiwan were divided into three groups and vaccinated by one of the following three methods: simultaneous vaccination with BCG and smallpox vaccine, vaccination with BCG only, and vaccination with smallpox vaccine only. On follow-up, no difference was observed between the "simultaneous" group and the "smallpox only" group in respect of either no-take rate and frequency distribution by size of vaccination lesions or reactions to smallpox revaccination at 12 weeks. Tuberculin tests at 12 weeks revealed a normal distribution in the size of tuberculin reactions with a mean of 11.94 mm and 12.19 mm respectively in the "simultaneous" group and the "BCG only" group; in the "smallpox only" group all the reactions were below 9 mm, the great majority being 0-3 mm. The author concludes that there is no interaction between primary BCG and smallpox vaccination when both vaccines are administered simultaneously, and that, despite the reported complications, simultaneous administration of BCG and smallpox vaccine in newborn infants is a safe procedure.

BCG Vaccine↗
PubMed2004

Real-time PCR system for detection of orthopoxviruses and simultaneous identification of smallpox virus.

A screening assay for real-time LightCycler (Roche Applied Science, Mannheim, Germany) PCR identification of smallpox virus DNA was developed and compiled in a kit system under good manufacturing practice conditions with standardized reagents. In search of a sequence region unique to smallpox virus, the nucleotide sequence of the 14-kDa fusion protein gene of each of 14 variola virus isolates of the Russian World Health Organization smallpox virus repository was determined and compared to published sequences. PCR primers were designed to detect all Eurasian-African species of the genus ORTHOPOXVIRUS: A single nucleotide mismatch resulting in a unique amino acid substitution in smallpox virus was used to design a hybridization probe pair with a specific sensor probe that allows reliable differentiation of smallpox virus from other orthopoxviruses by melting-curve analysis. The applicability was demonstrated by successful amplification of 120 strains belonging to the orthopoxvirus species variola, vaccinia, camelpox, mousepox, cowpox, and monkeypox virus. The melting temperatures (T(m)s) determined for 46 strains of variola virus (T(m)s, 55.9 to 57.8 degrees C) differed significantly (P = 0.005) from those obtained for 11 strains of vaccinia virus (T(m)s, 61.7 to 62.7 degrees C), 15 strains of monkeypox virus (T(m)s, 61.9 to 62.2 degrees C), 40 strains of cowpox virus (T(m)s, 61.3 to 63.7 degrees C), 8 strains of mousepox virus (T(m), 61.9 degrees C), and 8 strains of camelpox virus (T(m)s, 64.0 to 65.0 degrees C). As most of the smallpox virus samples were derived from infected cell cultures and tissues, smallpox virus DNA could be detected in a background of human DNA. By applying probit regression analysis, the analytical sensitivity was determined to be 4 copies of smallpox virus target DNA per sample. The DNAs of several human herpesviruses as well as poxviruses other than orthopoxviruses were not detected by this method. The assay proved to be a reliable technique for the detection of orthopoxviruses, with the advantage that it can simultaneously identify variola virus.

Animals↗
PubMed1982

The global eradication of smallpox.

On May 8, 1980, the 33rd World Health Assembly declared the world free of smallpox. This followed approximately 2 1/2 years after the last documented naturally occurring case of smallpox was diagnosed in a hospital worker in Merca, Somalia. A major breakthrough for the eventual control of this disease was the discovery of an effective vaccine by Edward Jenner in 1796. In 1966 the World Health Assembly voted a special budget to eliminate smallpox from the world. At that time, smallpox was endemic in more than 30 countries. Mass vaccination programs were successful in many Western countries; however, a different approach was taken in developing countries. This approach was known as surveillance and containment. Surveillance was aided by extensive house-to-house searches and rewards offered for persons reporting smallpox cases. Containment measures included ring vaccination and isolation of cases and contacts. Hospitals played a major role in transmission in a number of smallpox outbreaks. The World Health Organization is currently supporting several control programs and has not singled out another disease for eradication. The lessons learned from the smallpox campaign can be readily applied to other public health programs.

Cross Infection↗
PubMed2004

Smallpox: the basics.

Variola major is the causative agent of smallpox, a severe disease that was arguably one of the most serious human pathogens in recorded history. Humans are the only known reservoir of variola major; no known animal or insect reservoirs have been identified. Thus, after eradication of smallpox through a global immunization effort, this incredibly lethal scourge was eliminated from all corners of the globe. Despite the total eradication of naturally occurring smallpox, there are still stockpiles of smallpox virus maintained in the United States and the former Soviet Union. Unfortunately, it is impossible to know if all smallpox stocks have been accounted for or whether unknown or unreported stocks of smallpox may still exist. In the age of genetic engineering, these viruses could theoretically be modified to increase their virulence to the levels associated with smallpox itself.

Biological Warfare↗
PubMed2006

Smallpox.

The WHO declared smallpox eradicated in 1980. However, concern over its potential use by terrorists or in biowarfare has led to striking growth in research related to this much-feared disease. Modern molecular techniques and new animal models are advancing our understanding of smallpox and its interaction with the host immune system. Rapid progress is likewise being made in smallpox laboratory diagnostics, smallpox vaccines, and antiviral medications. WHO and several nations are developing stockpiles of smallpox vaccine for use in the event the disease is reintroduced. National and international public-health agencies have also drawn up plans to help with early detection of and response to a smallpox outbreak. These plans hinge on physicians' ability to recognise the clinical features of smallpox and to distinguish it from other illnesses characterised by rashes.

Contraindications↗
PubMed2003

Smallpox vaccination and bioterrorism with pox viruses.

Bioterrorist attacks occupy a special place amongst the innumerable potential types of terrorist attack, with the intentional release of pox viruses being especially feared in this connection. Apart from the variola virus, the agent responsible for smallpox in humans, the monkeypox virus and numerous other animal pox viruses pose potential risks for humans and animals. This risk scenario also includes recombinations between the various pox viruses, changes in hosts and genetically engineered manipulations of pox viruses. For over 200 years, the method of choice for combatting smallpox was via vaccination with a reproductive, original vaccinia virus. Worldwide eradication of smallpox at the end of the 1970s and the discontinuation of routine smallpox vaccination in 1980 can be credited to such vaccination. Unfortunately, these vaccinations were associated with a large number of postvaccinal impairments, sometimes resulting in death (e.g. postvaccinal encephalitis). The only way to restrict such postvaccinal complications was to carry out initial vaccination within the first 2 postnatal years. Initial vaccination at a later age led to such a sharp increase in the number of vaccines with complications that vaccination had to be discouraged. The dilemma of the smallpox vaccine stocks stems from the fact that a large portion of these stocks are produced with the same vaccinia strains as before. This is irresponsible, especially as the percentage of immune-suppressed persons in the population, for whom vaccination-related complications pose an especial threat, is increasing. One solution to the dilemma of the smallpox vaccine stocks is the MVA strain. It is harmless, protects humans and animals equally well against smallpox and can be applied parenterally.

Animals↗
PubMedDate not supplied

Smallpox: a disease of the past? Consideration for midwives.

Smallpox infection was often more severe in pregnant women than in non-pregnant women or in men, regardless of vaccination status. Women with smallpox infection during pregnancy have higher rates of abortions, stillbirths, and preterm deliveries than women without the disease. Pregnant women have high incidences of hemorrhagic-type and flat-type smallpox, which are associated with extremely high fatality rates. Although smallpox was eradicated in the late 1970s, current international concern exists regarding the potential use of smallpox virus as an agent for bioterrorism. This manuscript reviews clinical aspects of smallpox, smallpox immunization, and outcomes in pregnant women.

Abortion, Spontaneous↗
PubMed2003

Separate worlds set to collide: smallpox, vaccinia virus vaccination, and human immunodeficiency virus and acquired immunodeficiency syndrome.

Concerns about the possible release of smallpox by bioterrorists has led to policies that recommend smallpox vaccination of some health care providers, and, in the near future, the vaccine may become available to the general population on a voluntary basis. Both smallpox virus (variola virus) and the smallpox vaccine (vaccinia virus) will have a significant impact on people infected with human immunodeficiency virus (HIV). Given that populations with acquired immunodeficiency syndrome and populations with immunosuppressed conditions due to solid organ and bone marrow transplantation were not present in the days when smallpox was prevalent, we will speculate on how smallpox might present in immunodeficient patients, and we will review the adverse events expected from the smallpox vaccine in hosts with HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

A successful eradication campaign. Global eradication of smallpox.

Smallpox was the first important disease to be eradicated; it was the success of the Smallpox Eradication Programme that inspired this conference. Several biological reasons favored the eradication of smallpox, the most important of which were probably that recurrent infectivity did not occur, that there was no animal reservoir, and that an effective stable vaccine was available. The importance of smallpox as a disease that travelers might import into countries free of smallpox provided a powerful stimulus for its global eradication. This paper highlights some of the problems associated with the eradication of smallpox in two countries where eradication was difficult, India and Ethiopia, and the measures adopted to overcome the problems. The paper also stresses the importance of the development of methods for the certification of smallpox eradication from countries, from regions, and finally from the whole world. It is noted that close links between field work and research were important throughout the eradication campaign.

Epidemiologic Methods↗
PubMed2004

Logistics of community smallpox control through contact tracing and ring vaccination: a stochastic network model.

BACKGROUND: Previous smallpox ring vaccination models based on contact tracing over a network suggest that ring vaccination would be effective, but have not explicitly included response logistics and limited numbers of vaccinators. METHODS: We developed a continuous-time stochastic simulation of smallpox transmission, including network structure, post-exposure vaccination, vaccination of contacts of contacts, limited response capacity, heterogeneity in symptoms and infectiousness, vaccination prior to the discontinuation of routine vaccination, more rapid diagnosis due to public awareness, surveillance of asymptomatic contacts, and isolation of cases. RESULTS: We found that even in cases of very rapidly spreading smallpox, ring vaccination (when coupled with surveillance) is sufficient in most cases to eliminate smallpox quickly, assuming that 95% of household contacts are traced, 80% of workplace or social contacts are traced, and no casual contacts are traced, and that in most cases the ability to trace 1-5 individuals per day per index case is sufficient. If smallpox is assumed to be transmitted very quickly to contacts, it may at times escape containment by ring vaccination, but could be controlled in these circumstances by mass vaccination. CONCLUSIONS: Small introductions of smallpox are likely to be easily contained by ring vaccination, provided contact tracing is feasible. Uncertainties in the nature of bioterrorist smallpox (infectiousness, vaccine efficacy) support continued planning for ring vaccination as well as mass vaccination. If initiated, ring vaccination should be conducted without delays in vaccination, should include contacts of contacts (whenever there is sufficient capacity) and should be accompanied by increased public awareness and surveillance.

Computer Simulation↗
PubMed2006

The smallpox vaccine: An update for oral health care professionals.

BACKGROUND: A heightened awareness of the potential for bioterrorist attacks in the United States has led to the expansion of the nation's supply of smallpox vaccine and the institution of procedures to distribute this vaccine in the unlikely event of a release of this potentially deadly agent. METHODS: The authors conducted a review of the relevant smallpox literature through a MEDLINE search. They also reviewed the Web site of the Centers for Disease Control and Prevention and numerous other Web sites. RESULTS: The authors considered for inclusion more than 100 articles discussing smallpox, the smallpox vaccine and the role of the dental professional in a bioterrorist attack. CONCLUSIONS: Dentists may detect the initial signs of a smallpox infection, provide information concerning the disease to the public and potentially assist in the administration of smallpox vaccine. CLINICAL IMPLICATIONS: Should an intentional release of smallpox occur, the dental professional may play an important role in its treatment and prevention.

Encephalomyelitis, Acute Disseminated↗
PubMed2002

Smallpox vaccine.

After an extensive worldwide eradication program, the last nonlaboratory case of smallpox occurred in 1977 in Somalia. In 1972, routine smallpox immunization was discontinued in the United States, and since 1983, vaccine production has been halted. Stockpiled vaccine has been used only for laboratory researchers working on orthopoxviruses. In recent years, there has been concern that smallpox virus stocks may be in the hands of bioterrorists, and this concern has been heightened by the terrorist attack on the World Trade Center and the Pentagon on September 11, 2001. Because most of the population is considered to be nonimmune, there is debate as to whether smallpox immunization should be resumed. This statement reviews the current status of smallpox vaccine, the adverse effects that were associated with smallpox vaccine in the past, and the major proposals for vaccine use. The statement provides the rationale for a policy based on the so-called ring vaccination strategy recommended by the Centers for Disease Control and Prevention, in which cases of smallpox are rapidly identified, infected individuals are isolated, and contacts of the infected individuals as well as their contacts are immunized immediately.

Bioterrorism↗
PubMed2005

[The last case of smallpox in Denmark--the organizing conditions in 1970].

Smallpox contributed to many deaths in Denmark up to the introduction of the vaccination in the beginning of the 19th. Century. The last minor smallpox epidemic in Denmark was in 1924, and subsequently no doctors had special experience in smallpox. In September 1970 a Norwegian medical student died from smallpox in Copenhagen after returning from a journey to Afghanistan, where he has been hospitalized for enteritis. During the 5 days in Copenhagen before hospitalization he had had extensive contacts with many people. He was hospitalized at Blegdamshospital and was isolated, and the diagnosis of smallpox was verified on day 5. He was then totally isolated in a pavilion with 2 nurses and one doctor. The initial diarrhoea (Salmonella typhimurium), and later septicaemia with salmonella, the copious expectoration up to 1 1/2 l pr day (Streptococcus pneumoniae, Klebsiella pneumoniae, E. coli, 9-streptococci), the enormous exudation from the desquamated skin caused large problems concerning water, electrolytes and protein balance, requiring an input up to 13 1 per day. It was necessary to perform tracheotomy and artificial ventilation. He was treated as a patient with extensive burns with metal sheets and when his body temperature fell to 30 degrees C with electrical heat. He died after 25 days of smallpox with complicating extensive skin ulavs corresponding to a pathological picture of toxic epidermal necrolysis (TEN). The containment was successful in cooperation with the Danish National Board on Health, the Medical Officer of Health from Copenhagen and the county (where the patient lived), police, State Serum Institute, and Ministries of the Interior and Foreign Affairs. Vaccination of the exposed persons and the hospital staff, isolation in small groups (maximum 20 persons) of 589 primary contacts in the hospital pavilion-wards and 12 military tents were performed. No secondary cases occurred. The outbreak of smallpox in Copenhagen ended, and the city was not declared "local infected area", and we avoided a panic mass vaccination of large group of people. The article describes these activities, which are effectuated within a few days and headed by a capable and unanimous leadership, in a serious and complicated situation and with an engaged cooperation from the whole staff.

Denmark↗
PubMed2005

Adverse events associated with smallpox vaccination in the United States, January-October 2003.

CONTEXT: On January 24, 2003, the US Department of Health and Human Services (DHHS) implemented a preparedness program in which smallpox (vaccinia) vaccine was administered to federal, state, and local volunteers who might be first responders during a bioterrorism event. OBJECTIVE: To describe results from the comprehensive DHHS smallpox vaccine safety monitoring and response system. DESIGN, SETTING, AND PARTICIPANTS: Descriptive study of adverse event reports from the DHHS smallpox vaccine safety monitoring and response system received between January 24 and October 31, 2003, through the Vaccine Adverse Event Reporting System (VAERS) and the Centers for Disease Control and Prevention. A total of 37,901 volunteers in 55 jurisdictions received at least 1 dose of smallpox vaccine. MAIN OUTCOME MEASURES: Number of vaccinations administered and description of adverse events and reporting rates. RESULTS: A total of 38,885 smallpox vaccinations were administered, with a take rate of 92%. VAERS received 822 reports of adverse events following smallpox vaccination (overall reporting rate, 217 per 10,000 vaccinees). A total of 590 adverse events (72%) were reported within 14 days of vaccination. Nonserious adverse events (n = 722) included multiple signs and symptoms of mild and self-limited local reactions. One hundred adverse events (12%) were designated as serious, resulting in 85 hospitalizations, 2 permanent disabilities, 10 life-threatening illnesses, and 3 deaths. Among the serious adverse events, 21 cases were classified as myocarditis and/or pericarditis and 10 as ischemic cardiac events that were not anticipated based on historical data. Two cases of generalized vaccinia and 1 case of postvaccinial encephalitis were detected. No preventable life-threatening adverse reactions, contact transmissions, or adverse reactions that required treatment with vaccinia immune globulin were identified. Serious adverse events were more common among older revaccinees than younger first-time vaccinees. CONCLUSIONS: Rigorous smallpox vaccine safety screening, educational programs, and older vaccinees may have contributed to low rates of preventable life-threatening adverse reactions. Other rare, clinically significant, or unexpected cardiac adverse events were detected by timely review of VAERS data and intensive clinical case investigation.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Enhanced immunogenicity and protective effect conferred by vaccination with combinations of modified vaccinia virus Ankara and licensed smallpox vaccine Dryvax in a mouse model.

Significant adverse events are associated with vaccination with the currently licensed smallpox vaccine. Candidate new-generation smallpox vaccines such as the replication-defective modified vaccinia virus Ankara (MVA) produce very few adverse events in experimental animals and in limited human clinical trials conducted near the end of the smallpox eradication campaign. Efficacy evaluation of such new-generation vaccines will be extraordinarily complex, however, since the eradication of smallpox precludes a clinical efficacy trial and the correlates of protection against smallpox are unknown. A combination of relevant animal efficacy studies along with thorough comparative immunogenicity studies between traditional and new-generation smallpox vaccines will be necessary for vaccine licensure. In the present study, a variety of immune responses elicited by MVA and the licensed smallpox vaccine Dryvax in a murine model were compared, with a focus on mimicking conditions and strategies likely to be employed in human vaccine trials. Immunization of mice with MVA, using several relevant vaccination routes including needle-free delivery, elicited humoral and cellular immune responses qualitatively similar to those elicited by vaccination with Dryvax. Similar levels of vaccinia-specific IgG and neutralizing antibody were elicited by Dryvax and MVA when higher doses (approximately 1 log) of MVA were used for immunization. Antibody levels peaked at about 6 weeks post-immunization and remained stable for at least 15 weeks. A booster immunization of either MVA or Dryvax following an initial priming immunization with MVA resulted in an enhanced IgG titer and neutralizing antibody response. In addition, both Dryvax and various MVA vaccination protocols elicited antibody responses to the extracellular enveloped form of the virus and afforded protection against a lethal intranasal challenge with vaccinia virus WR.

Animals↗