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PubMed2003

Smallpox: a potential agent of bioterrorism.

The events of 11 September 2001, in New York City, and subsequent identification of anthrax in the United States Postal System, have generated a new sense of awareness for the potential of biological terrorism, if not warfare. Among those agents identified by the Centers for Disease Control and Prevention as 'Class A Bioterrorist Threats', smallpox is among the most dangerous. The ease of transmission of this agent, the lack of immunity in the population at large to this agent, and rapidity of its spread, if released, all generate significant concern for its deployment. A vaccine directed against smallpox is available but it is also associated with significant adverse events-some of which are life-threatening. Further, no antiviral drug has proven efficacious for therapy of human disease, although one licensed drug, cidofovir, does have in vitro activity. Regardless, heightened awareness should lead to the development of a vaccine without significant adverse events and safe and efficacious antiviral drugs. The availability of a vaccine and antiviral drugs that are safe would significantly remove any major threat of smallpox deployment by a terrorist.

Biological Warfare↗
PubMed2006

Preparedness for a smallpox outbreak: comparing metrics for assessing levels of vaccination among health-care workers by state.

By mid-2005, less than 17% of smallpox vaccine doses distributed to American states for health-care workers (HCWs) during the CDC campaign had been used. To understand how states responded, vaccination patterns were studied. Metrics were calculated to compare the level of preparedness for a smallpox outbreak in terms of absolute numbers of HCWs vaccinated compared to the percentage of doses distributed to each state, the rate of vaccination per capita population, and the percentage of HCWs vaccinated compared to the number the CDC recommended. States were then ranked. Results showed that rankings for all four metrics were statistically different (P<0.0001). In addition, when ranks were assigned to quartiles, the states directly affected on 9/11/01 ranked lowest and states widely perceived to be at lower terror risk ranked in the top. These results underscore the need to critically examine how to define an appropriate level of preparedness for a smallpox outbreak.

Bioterrorism↗
PubMed2007

Comparison of smallpox outbreak control strategies using a spatial metapopulation model.

To determine the potential benefits of regionally targeted mass vaccination as an adjunct to other smallpox control strategies we employed a spatial metapopulation patch model based on the administrative districts of Great Britain. We counted deaths due to smallpox and to vaccination to identify strategies that minimized total deaths. Results confirm that case isolation, and the tracing, vaccination and observation of case contacts can be optimal for control but only for optimistic assumptions concerning, for example, the basic reproduction number for smallpox (R0=3) and smaller numbers of index cases ( approximately 10). For a wider range of scenarios, including larger numbers of index cases and higher reproduction numbers, the addition of mass vaccination targeted only to infected districts provided an appreciable benefit (5-80% fewer deaths depending on where the outbreak started with a trigger value of 1-10 isolated symptomatic individuals within a district).

Disease Outbreaks↗
PubMed2001

Transmission potential of smallpox in contemporary populations.

Despite eradication, smallpox still presents a risk to public health whilst laboratory stocks of virus remain. One factor crucial to any assessment of this risk is R0, the average number of secondary cases infected by each primary case. However, recently applied estimates have varied too widely (R0 from 1.5 to >20) to be of practical use, and often appear to disregard contingent factors such as socio-economic conditions and herd immunity. Here we use epidemic modelling to show a more consistent derivation of R0. In isolated pre-twentieth century populations with negligible herd immunity, the numbers of cases initially rose exponentially, with an R0 between 3.5 and 6. Before outbreak controls were applied, smallpox also demonstrated similar levels of transmission in 30 sporadic outbreaks in twentieth century Europe, taking into account pre-existing vaccination levels (about 50%) and the role of hospitals in doubling early transmission. Should smallpox recur, such estimates of transmission potential (R0 from 3.5 to 6) predict a reasonably rapid epidemic rise before the implementation of public health interventions, because little residual herd immunity exists now that vaccination has ceased.

Disease Outbreaks↗
PubMed2003

Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses.

The concern about bioterrorism with smallpox has raised the possibility of widespread vaccination, but the greater prevalence of immunocompromised individuals today requires a safer vaccine, and the mechanisms of protection are not well understood. Here we show that, at sufficient doses, the protection provided by both modified vaccinia Ankara and NYVAC replication-deficient vaccinia viruses, safe in immunocompromised animals, was equivalent to that of the licensed Wyeth vaccine strain against a pathogenic vaccinia virus intranasal challenge of mice. A similar variety and pattern of immune responses were involved in protection induced by modified vaccinia Ankara and Wyeth viruses. For both, antibody was essential to protect against disease, whereas neither effector CD4+ nor CD8+ T cells were necessary or sufficient. However, in the absence of antibody, T cells were necessary and sufficient for survival and recovery. Also, T cells played a greater role in control of sublethal infection in unimmunized animals. These properties, shared with the existing smallpox vaccine, provide a basis for further evaluation of these replication-deficient vaccinia viruses as safer vaccines against smallpox or against complications from vaccinia virus.

Animals↗
PubMed2003

Smallpox vaccination: a review, part I. Background, vaccination technique, normal vaccination and revaccination, and expected normal reactions.

Because smallpox could be a factor in bioterrorism, the United States has provided guidelines for smallpox vaccination of certain members of the population, including health care workers and first responders, as well as military personnel. A plan for more extensive vaccination, if it is needed in the event of a bioterrorist attack, is being developed under the aegis of the Centers for Disease Control and Prevention. The characteristics of smallpox vaccine, the technique of administration, and the expected reactions to primary vaccination and revaccination are outlined in this article.

Bioterrorism↗
PubMed2003

Modeling a safer smallpox vaccination regimen, for human immunodeficiency virus type 1-infected patients, in immunocompromised macaques.

We have modeled smallpox vaccination with Dryvax (Wyeth) in rhesus macaques that had depletion of CD4(+) T cells induced by infection with simian immunodeficiency virus or simian/human immunodeficiency virus. Smallpox vaccination induced significantly larger skin lesions in immunocompromised macaques than in healthy macaques. Unexpectedly, "progressive vaccinia" was infrequent. Vaccination of immunocompromised macaques with the genetically-engineered, replication-deficient poxvirus NYVAC, before or after retrovirus infection, was safe and lessened the severity of Dryvax-induced skin lesions. Neutralizing antibodies to vaccinia were induced by NYVAC, even in macaques with severe CD4(+) T cell depletion, and their titers inversely correlated with the time to complete resolution of the skin lesions. Together, these results provide the proof of concept, in macaque models that mirror human immunodeficiency virus type 1 infection, that a prime-boost approach with a highly attenuated poxvirus followed by Dryvax increases the safety of smallpox vaccination, and they highlight the importance of neutralizing antibodies in protection against virulent poxvirus.

Animals↗
PubMed2004

Risk of vaccinia transfer to the hands of vaccinated persons after smallpox immunization.

Transmission of vaccinia virus after smallpox vaccination is a concern. We conducted a prospective examination of the protection afforded by vaccination-site bandages in recently vaccinated individuals. After smallpox vaccination, inoculation sites were covered with 2 occlusive dressings. Site assessment and bandage changes occurred every 3-5 days until the site was healed. At each visit, specimens from the vaccination site, outer dressing surface, and contralateral hand were obtained for vaccinia culture. For 148 vaccinated subjects, vaccinia was detected from vaccination lesions of every subject on several occasions. Only 6 (0.65%) of 918 dressing (95% CI, 0.24%-1.4%) and 2 (0.22%) of 926 hand (95% CI, 0.03%-0.78%) specimens tested positive for vaccinia. The mean number of bandage changes was 9.6 (95% CI, 9.17-10.0). Vaccinia autoinoculation did not occur. The rate of vaccinia recovery outside occlusive bandages covering smallpox vaccination sites was remarkably low, suggesting excellent protection against inadvertent transmission.

Adult↗
PubMed2004

Adverse events after smallpox immunizations are associated with alterations in systemic cytokine levels.

The immunization of healthy adults with vaccinia virus (VV) induces a protective response against smallpox in most individuals but is also reactogenic in a significant number of vaccinees. The immunological mechanisms underlying the protective response or adverse events in humans are not well defined. Although cytokines contribute to antiviral immunity and, in some cases, cause systemic adverse effects, their role in the human response to VV is unknown. We investigated the effect of smallpox immunization on systemic cytokine concentrations in a cohort of VV-naive individuals. We found that smallpox immunization induces an interferon (IFN)- gamma -dominant response in the systemic compartment 1 week after immunization, with concentrations returning to baseline during convalescence. The level of IFN- gamma induced was not affected by the dilution of vaccine used. We also found that particular adverse events correlated with systemic cytokine patterns, which suggests a role for these molecules in the pathogenesis of adverse events.

Adolescent↗
PubMed2004

Rethinking smallpox.

The potential consequences of a competently executed smallpox attack have not been adequately considered by policy makers. The possibility of release of an aerosolized and/or bioengineered virus must be anticipated and planned for. The transmission and infectivity of variola virus are examined. Arguments for and against pre-event vaccination are offered. The likely morbidity and mortality that would ensue from implementation of a mass pre-event vaccination program, within reasonable boundaries, are known. The extent of contagion that could result from an aerosolized release of virus is unknown and may have been underestimated. Pre-event vaccination of first responders is urged, and voluntary vaccination programs should be offered to the public. Two defenses against a vaccine-resistant, engineered variola virus are proposed for consideration. Methisazone, an overlooked drug, is reported to be effective for prophylaxis only. The extent of reduction in the incidence of smallpox with use of this agent is uncertain. It is useless for treatment of clinical smallpox. N-100 respirators (face masks) worn by uninfected members of the public may prevent transmission of the virus.

Biological Warfare↗
PubMed2006

Clinical and immunological comparison of smallpox vaccine administered to the outer versus the inner upper arms of vaccinia-naive adults.

BACKGROUND: Current recommendations direct health care providers to administer smallpox vaccine to the upper outer arm. However, concerns about cosmetically bothersome scarring, accidental contact transmission, interference by body tattoos, and even malignant transformation suggest evaluation of alternate vaccination sites is warranted. METHODS: We randomized 20 vaccinia-naive adults to undergo smallpox vaccination on the outer (n = 10) or inner (n = 10) upper arm. Evaluations included major reaction ("take") rates and vaccination site cultures on postvaccination day 7, determination of serum vaccinia-specific neutralizing antibody titers on days 0 (prevaccination) and 21, and determination of adverse events. RESULTS: On postvaccination day 7, a total of 18 participants (9 per group) had major reactions, 17 of whom had culture evidence of viable vaccinia. The inner and outer arm groups had similar major reaction mean sizes (P = .17), but the amount of erythema (in square centimeters) was smaller in the inner arm group (P = .05). At day 21, all participants had higher titers of vaccinia-specific neutralizing antibodies, compared with at day 0, and the geometric mean titer values of the 2 vaccine groups were similar (P = .45). Adverse event rates were similar. CONCLUSION: The comparable clinical, immunological, and tolerability outcomes between smallpox vaccine applied to the conventional upper outer arm site versus the upper inner arm, coupled with modestly less vaccine-site erythema on the inner arm, indicate that the inner arm may be a suitable alternate vaccination site.

Adult↗
PubMed1975

Smallpox epidemic in a Brazilian community.

The most severe outbreak of smallpox in Brazil in 1969 took place in the municipio of Utinga, Bahia. Of 507 cases, 246 occurred in residents of the urban area of the municipio. This paper describes the findings of the detailed study of the urban area outbreak. An inverse relationship between age and susceptibility was evident; fully 91% of the children less than 5 years of age as well as 75% of the school-age children had no history of smallpox and had never been vaccinated. The overall attack rate was 11% with nearly three-fourths of the cases in children under 15 years of age. Only 4 of the 246 patients had a vaccination scar, and the estimate of vaccine efficacy was 94%. The continued occurrence of cases after the initial vaccination containment measures prompted detailed studies during 2 follow-up visits to the community which demonstrated that 1) transmission of smallpox may continue in a pocket of susceptibles although the overall immune status of a community is high following containment measures, and 2) clinical illness may have been aborted in those affected individuals who were only in their second to fourth day of incubation at the time of vaccination.

Adolescent↗
PubMed2005

Bioterrorism and smallpox: policies, practices, and implications for social work.

Terrorist acts and the fear of terrorism have become a part of everyday life in the early 21st century. Among the threats most feared is bioterrorism, including the intentional release of smallpox. With the invasion of Iraq and toppling of the Saddam Hussein regime, acute bioterrorism fears have abated; however, an ongoing threat remains.This article addresses the need for knowledge and rational policies in dealing with potential bioterrorism attacks. It presents information on four of the most likely bioterrorism agents: smallpox, anthrax, botulism, and plague. It illustrates the importance of accurate knowledge and rational decision making in addressing the threat of terrorism through the intentional release of biological weapons such as smallpox. Finally, it provides information essential for social workers to make informed practice decisions, to educate clients and the public, and to advocate for sound public policy.

Anthrax↗
PubMedDate not supplied

Smallpox as a biological weapon: implications for the critical care clinician.

Once believed eradicated, smallpox has returned as a potential threat. Healthcare providers, as the first line of defense, must be proactive in maintaining current resources and offering input into the preparation for, diagnosis, and management of smallpox should an outbreak occur. The critical care nurse is integral in all aspects regarding smallpox and bioterrorism.

Bioterrorism↗
PubMed2004

Preventing second-generation infections in a smallpox bioterror attack.

This article presents a new probabilistic model for the prevention of second-generation infections by different vaccination strategies in the event of a smallpox bioterror attack. The main results are independent of the reproductive number R0 (the number of secondary infections transmitted per index infected individual) and population mixing patterns. General expressions are derived for the fraction of second-generation infections that can be prevented through vaccination, whereas specific results are obtained for traced and mass vaccination, respectively. Expressions for total outbreak size in controlled epidemics are also presented. The analysis highlights the importance of vaccination logistics in addition to beliefs and assumptions regarding smallpox epidemiology in evaluating alternative responses to a smallpox bioterror attack.

Bioterrorism↗
PubMedDate not supplied

Smallpox: what the dermatologist should know.

Despite the eradication of naturally occurring smallpox in 1977, stores of the virus have been maintained in laboratories in the United States and Russia. It is feared that certain rogue states and terrorist organizations may have illicitly acquired the virus with the intent of unleashing it as an agent of bioterrorism. The United States and other nations have begun vaccinating individuals in the military and health care workers who might become exposed. Primary care providers and dermatologists will be called upon to evaluate potential index cases and vaccination reactions. In this report, the authors review the essential clinical aspects of smallpox and potential reactions to smallpox vaccination. Special attention is given to eczema vaccinatum, which can occur in vaccinees and their family contacts with active or quiescent atopic dermatitis or a personal history of eczema.

Dermatology↗
PubMed2005

An attenuated LC16m8 smallpox vaccine: analysis of full-genome sequence and induction of immune protection.

The potential threat of smallpox bioterrorism has made urgent the development of lower-virulence vaccinia virus vaccines. An attenuated LC16m8 (m8) vaccine was developed in 1975 from the Lister strain used in the World Health Organization smallpox eradication program but was not used against endemic smallpox. Today, no vaccines can be tested with variola virus for efficacy in humans, and the mechanisms of immune protection against the major intracellular mature virion (IMV) and minor extracellular enveloped virion (EEV) populations of poxviruses are poorly understood. Here, we determined the full-genome sequences of the m8, parental LC16mO (mO), and grandparental Lister (LO) strains and analyzed their evolutionary relationships. Sequence data and PCR analysis indicated that m8 was a progeny of LO and that m8 preserved almost all of the open reading frames of vaccinia virus except for the disrupted EEV envelope gene B5R. In accordance with this genomic background, m8 induced 100% protection against a highly pathogenic vaccinia WR virus in mice by a single vaccination, despite the lack of anti-B5R and anti-EEV antibodies. The immunogenicity and priming efficacy with the m8 vaccine consisting mainly of IMV were as high as those with the intact-EEV parental mO and grandparental LO vaccines. Thus, mice vaccinated with 10(7) PFU of m8 produced low levels of anti-B5R antibodies after WR challenge, probably because of quick clearance of B5R-expressing WR EEV by strong immunity induced by the vaccination. These results suggest that priming with m8 IMV provides efficient protection despite undetectable levels of immunity against EEV.

Amino Acid Sequence↗
PubMed2003

Risks of serious complications and death from smallpox vaccination: a systematic review of the United States experience, 1963-1968.

BACKGROUND: The United States (US) has re-instituted smallpox vaccinations to prepare for an intentional release of the smallpox virus into the civilian population. In an outbreak, people of all ages will be vaccinated. To prepare for the impact of large-scale ring and mass vaccinations, we conducted a systematic review of the complication and mortality risks of smallpox vaccination. We summarized these risks for post-vaccinial encephalitis, vaccinia necrosum (progressive vaccinia), eczema vaccinatum, generalized vaccinia, and accidental infection (inadvertant autoinoculation). METHODS: Using a MEDLINE search strategy, we identified 348 articles, of which seven studies met our inclusion criteria (the number of primary vaccinations and re-vaccinations were reported, sufficient data were provided to calculate complication or case-fatality risks, and comparable case definitions were used). For each complication, we estimated of the complication, death, and case-fatality risks. RESULTS: The life-threatening complications of post-vaccinial encephalitis and vaccinia necrosum were at least 3 and 1 per million primary vaccinations, respectively. Twenty-nine percent of vaccinees with post-vaccinial encephalitis died and 15% with vaccinia necrosum died. There were no deaths among vaccinees that developed eczema vaccinatum; however, 2.3% of non-vaccinated contacts with eczema vaccinatum died. Among re-vaccinees, the risk of post-vaccinial encephalitis was reduced 26-fold, the risk of generalized vaccinia was reduced 29-fold, and the risk of eczema vaccinatum was reduced 12-fold. However, the risk reductions of accidental infection and vaccinia necrosum were modest (3.8 and 1.5 fold respectively).

Bioterrorism↗