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PubMed2006

An update on smallpox vaccine candidates and their role in bioterrorism related vaccination strategies.

The threat of using variola virus in a bioterrorist attack urged different countries to renew the production of traditional vaccines and develop new generations of smallpox vaccines. Manufacturers try to combine smallpox vaccine past experience with technological advances in vaccine development to achieve protection similar to that of the traditional vaccines with a higher level of safety and fewer contraindications. In light of the reported immunogenicity and reactogenicity of the stockpiled smallpox vaccines employed in the last immunization campaigns of "first responders", we review recently accumulated data on the assessment of new smallpox vaccine candidates and discuss their role in possible vaccination policies.

Bioterrorism↗
PubMed2005

The nonreplicating smallpox candidate vaccines defective vaccinia Lister (dVV-L) and modified vaccinia Ankara (MVA) elicit robust long-term protection.

Current smallpox vaccines are live vaccinia viruses that replicate in the vaccinee inducing immunity against the deadly disease smallpox. Replication resulting in virus spread within the host, however, is the major cause of severe postvaccinal adverse events. Therefore, attenuated strains such as modified vaccinia Ankara (MVA) or LC16m8 are candidates as next generation vaccines. These strains are usually grown in primary cells in which mass production is difficult and have an unknown protective potential in humans. Proven vaccine strains of defined origin and modern production techniques are therefore desirable. In this study, defective vaccinia virus (dVV) lacking a gene essential for replication (derived from the Lister vaccine in a complementing cell line) was compared with the Wyeth smallpox vaccine strain and with MVA in mouse animal models using cowpox and ectromelia virus challenge. Similar to MVA, prime-boost immunizations with defective vaccinia induced robust long-term immunity, suggesting it as a promising next generation smallpox vaccine.

Animals↗
PubMed2003

Smallpox and bioterrorism: public-health responses.

There is great concern that smallpox could be used for bioterrorism. The disease has a high mortality rate and can be spread by aerosols, and immunity in the population is low. Although an initial release of smallpox could infect a large number of people, secondary spread would likely be slow because of the long incubation period and the close contact required for transmission. Hospital personnel and household contacts are at the greatest risk of becoming infected. An outbreak of smallpox will be controlled through surveillance, containment, vaccination, and isolation of cases-the strategy used to eradicate the disease globally in 1978. Pre-exposure vaccination is recommended for hospital personnel likely to be exposed to smallpox while caring for patients during an outbreak.

Bioterrorism↗
PubMed2003

Rates and risks of transmission of smallpox and mechanisms of prevention.

In 1980, the World Health Organization declared smallpox eradicated from the world; the last known natural case had occurred in Somalia in 1977, and the United States had stopped routinely vaccinating its citizens in 1972. However, with increasing concerns regarding domestic and international terrorism, smallpox has resurfaced as a potential threat to global health. We review the direct and indirect modes of smallpox transmission and how patterns of transmission vary substantially, depending on the severity of circulating disease, vaccination status, environmental and socioeconomic factors, and the setting of an outbreak. We examine mechanisms for controlling outbreaks of disease and preventing further transmission in the event of an outbreak, with an emphasis on smallpox vaccination.

Containment of Biohazards↗
PubMed2003

Smallpox vaccine: problems and prospects.

Smallpox justifiably is feared because of its morbidity and mortality. Wide-spread population-level susceptibility to smallpox exists, and the only effective tool against the virus is a live, attenuated vaccine that is highly reactogenic and controversial. A significant minority of the population has contraindications that prevent preexposure use of this vaccine. Newer, safer, and equally immunogenic vaccines must be developed and licensed. Several live, attenuated vaccines are in clinical trials. Although these vaccines may prove to be less reactogenic, they still may not be administered safely to a significant portion of the population because they contain live, attenuated viruses. Newer vaccines will be needed if routine preexposure vaccination is to be instituted universally. The idea of a subunit or peptide-based vaccine is appealing, because it obviates potential safety concerns. It may be possible to use a more-attenuated, live vaccine strain for a large segment of the population on a preexposure basis and accept the morbidity and mortality that would result from its use on a postexposure basis, if necessary. The need for widespread population-level protection against variola infection is apparent. The use of the new biology tools to predict or define who might experience serious reactions to the smallpox vaccine and why these reactions occur is an area ripe for additional research. The reason why an individual develops postvaccinal encephalitis remains unknown, and the development is unpredictable and untreatable. In the future, if the mechanism behind such adverse events is defined, it may be possible to screen persons who are likely to experience such events. Although the authors remain proponents for use of the vaccine in alignment with the CDC vaccination program and recommendations, the previous concerns indicate that new knowledge must be gained and shared. Further research on attenuated vaccines and nonliving or peptide vaccines with equal efficacy should remain the goal, as it is apparent that smallpox vaccine once again will become part of the vaccinologist's and public health official's armamentarium in the decades to come.

Bioterrorism↗
PubMed2002

The smallpox vaccine and postvaccinal encephalitis.

Smallpox is one of the deadliest infectious diseases in history. The discovery by Edward Jenner that inoculation with a droplet of pus from a cow with cowpox protected a person from smallpox resulted in the successful vaccination of millions of people. There were, however, complications associated with smallpox vaccination; the most serious complication was postvaccinal encephalitis, which was reported to occur with an incidence of 1 in 110,000 vaccinations and a case-fatality rate of 50%. Before we become complacent with the idea that we will respond to a bioterrorism attack with a mass immunization program for smallpox, it is important to be reminded of the risk and clinical manifestations of postvaccinal encephalitis and the efficacy of antivaccinia gamma-globulin in preventing this complication. The first case of postvaccinal encephalitis as a complication of the Jennerian cowpox inoculation was observed in 1905. A century later, there is no effective therapy.

Animals↗
PubMed2002

A model for a smallpox-vaccination policy.

BACKGROUND: The new reality of biologic terrorism and warfare has ignited a debate about whether to reintroduce smallpox vaccination. METHODS: We developed scenarios of smallpox attacks and built a stochastic model of outcomes under various control policies. We conducted a systematic literature review and estimated model parameters on the basis of European and North American outbreaks since World War II. We assessed the trade-offs between vaccine-related harms and benefits. RESULTS: Nations or terrorists possessing a smallpox weapon could feasibly mount attacks that vary with respect to tactical complexity and target size, and patterns of spread can be expected to vary according to whether index patients are hospitalized early. For acceptable results, vaccination of contacts must be accompanied by effective isolation. Vaccination of contacts plus isolation is expected to result in 7 deaths (from vaccine or smallpox) in a scenario involving the release of variola virus from a laboratory, 19 deaths in a human-vector scenario, 300 deaths in a building-attack scenario, 2735 deaths in a scenario involving a low-impact airport attack, and 54,729 deaths in a scenario involving a high-impact airport attack. Immediate vaccination of the public in an attacked region would provide little additional benefit. Prior vaccination of health care workers, who would be disproportionately affected, would save lives in large local or national attacks but would cause 25 deaths nationally. Prior vaccination of health care workers and the public would save lives in a national attack but would cause 482 deaths nationally. The expected net benefits of vaccination depend on the assessed probability of an attack. Prior vaccination of health care workers would be expected to save lives if the probability of a building attack exceeded 0.22 or if the probability of a high-impact airport attack exceeded 0.002. The probability would have to be much higher to make vaccination of the public life-saving. CONCLUSIONS: The analysis favors prior vaccination of health care workers unless the likelihood of any attack is very low, but it favors vaccination of the public only if the likelihood of a national attack or of multiple attacks is high.

Bioterrorism↗
PubMed2001

Recent events and observations pertaining to smallpox virus destruction in 2002.

To destroy all remaining stocks of variola virus on or before 31 December 2002 seems an even more compelling goal today than it did in 1999, when the 52d World Health Assembly authorized temporary retention of remaining stocks to facilitate the possible development of (1) a more attenuated, less reactogenic smallpox vaccine and (2) an antiviral drug that could be used in treatment of patients with smallpox. We believe the deadline established in 1999 should be adhered to, given the potential outcomes of present research. Although verification that every country will have destroyed its stock of virus is impossible, it is reasonable to assume that the risk of a smallpox virus release would be diminished were the World Health Assembly to call on each country to destroy its stocks of smallpox virus and to state that any person, laboratory, or country found to have virus after date x would be guilty of a crime against humanity.

Antiviral Agents↗
PubMed2004

Modified vaccinia Ankara: potential as an alternative smallpox vaccine.

Despite the declaration of smallpox eradication in 1980, the existence of variola stockpiles and the threat of bioterrorism demand that immunity to smallpox through vaccination be maintained. Although the currently available vaccine was used for the most successful medical intervention ever accomplished, it also is associated with side effects that are difficult to accept in a vaccine for a disease that has not been present for >25 years. Herein, we review alternative approaches to maintaining immunity to smallpox through vaccination with attenuated poxviruses, and we suggest modified vaccinia Ankara (MVA) as a leading candidate for an alternative smallpox vaccine.

Humans↗
PubMed1975

Evaluation of a measles-smallpox vaccination campaign by a sero-epidemiologic method.

An assessment technique has been devised whereby children from 30 randomly chosen sampling sites are visited within three days of measles-smallpox vaccination and one month later. Vaccination coverage is measured at house visits and immunologic status is determined by collection of early and late blood samples on filter papers from substratified children in priority age-groups, and by looking at vaccination scars. The methodology was employed in a rural area of the Ivory Coast during the maintenance phase of a measles-smallpox vaccination program; 1762 children from 0--72 months old were inspected. Children in the target age groups, 6--24 months, had a vaccination coverage of 53.6% whereas children outside of the target group had a 10.5% coverage. Of 571 target age children, 94.6% had a measles hemagglutination-inhibition antibody titer of less than 1:10 dilution at the first visit, and were presumed susceptible to measles or vaccine. Of 247 substratified children 6--8 months, 98.3% were susceptible to measles before vaccination; 84.3% of 127 vaccinated children in this age-group sero-converted when re-tested. Of 324 children 9--24 months, 91.7% were susceptible before the campaign; 94.7% of 170 vaccinated children in this age-group converted. A positive history of prior measles or prior measles-vaccination was not a good indicator of measles serologic status. The smallpox vaccination major reaction rate was 93.2%; 91.4% of children with a recent vaccination scar sero-converted to measles vaccine. Thus, the smallpox scar read at the second visit proved the best clinical marker for determining both coverage and immunologic effectiveness of the campaign.

Age Factors↗
PubMed2006

Absence of detectable viremia in plasma and peripheral blood mononuclear cells from smallpox vaccinees: implications for blood safety.

BACKGROUND: Mass smallpox vaccination with live vaccinia virus has been considered as a preventive measure to counter bioterrorism involving smallpox. This has raised concerns about the possibility of vaccinia virus being transmitted from vaccinated blood donors to recipients. The results of this study could be used to define an appropriate deferral period for blood donors (vaccinated against smallpox) to ensure safety of the blood supply. STUDY DESIGN AND METHODS: A procedure was developed to culture vaccinia virus from plasma and peripheral blood mononuclear cells (PBMNCs) of vaccinees enrolled in three smallpox vaccine clinical trials. A total of 665 plasma and PBMNC samples were obtained from 95 vaccinated subjects. RESULTS: Vaccinia viremia was not detected by virus culture from plasma and PBMNC samples of healthy vaccinees 3 to 56 days after vaccination under our assay conditions. Plasma viremia assay had a sensitivity of approximately 66 plaque-forming units per mL with a Vero cell culture assay. CONCLUSION: The results of this study present evidence that in the case of mass vaccination, the risk of transmission of vaccinia virus by blood transfusion would likely be low.

Animals↗
PubMed2002

Containing bioterrorist smallpox.

The need for a planned response to a deliberate introduction of smallpox has recently become urgent. We constructed a stochastic simulator of the spread of smallpox in structured communities to compare the effectiveness of mass vaccination versus targeted vaccination of close contacts of cases. Mass vaccination before smallpox introduction or immediately after the first cases was more effective than targeted vaccination in preventing and containing epidemics if there was no prior herd immunity (that is, no prior immunologic protection within the population). The effectiveness of postrelease targeted and mass vaccinations increased if we assumed that there was residual immunity in adults vaccinated before 1972, but the effectiveness of targeted vaccination increased more than that of mass vaccination. Under all scenarios, targeted vaccination prevented more cases per dose of vaccine than did mass vaccination. Although further research with larger-scale structured models is needed, our results suggest that increasing herd immunity, perhaps with a combination of preemptive voluntary vaccination and vaccination of first responders, could enhance the effectiveness of postattack intervention. It could also help targeted vaccination be more competitive with mass vaccination at both preventing and containing a deliberate introduction of smallpox.

Adolescent↗
PubMedDate not supplied

Developing new smallpox vaccines.

New stockpiles of smallpox vaccine are required as a contingency for protecting civilian and military personnel against deliberate dissemination of smallpox virus by terrorists or unfriendly governments. The smallpox vaccine in the current stockpile consists of a live animal poxvirus (Vaccinia virus [VACV]) that was grown on the skin of calves. Because of potential issues with controlling this earlier manufacturing process, which included scraping VACV lesions from calfskin, new vaccines are being developed and manufactured by using viral propagation on well-characterized cell substrates. We describe, from a regulatory perspective, the various strains of VACV, the adverse events associated with calf lymph-propagated smallpox vaccine, the issues regarding selection and use of cell substrates for vaccine production, and the issues involved in demonstrating evidence of safety and efficacy.

Animals↗
PubMed2003

Risks and benefits of preexposure and postexposure smallpox vaccination.

This article presents a model and decision criteria for evaluating a person's risk of pre- or postexposure smallpox vaccination in light of serious vaccine-related adverse events (death, postvaccine encephalitis and progressive vaccinia). Even at a 1-in-10 risk of 1,000 initial smallpox cases, a person in a population of 280 million has a greater risk for serious vaccine-related adverse events than a risk for smallpox. For a healthcare worker to accept preexposure vaccination, the risk for contact with an infectious smallpox case-patient must be >1 in 100, and the probability of 1,000 initial cases must be >1 in 1,000. A member of an investigation team would accept preexposure vaccination if his or her anticipated risk of contact is 1 in 2.5 and the risk of attack is assumed to be >1 in 16,000. The only circumstances in which postexposure vaccination would not be accepted are the following: if vaccine efficacy were <1%, the risk of transmission were <1%, and (simultaneously) the risk for serious vaccine-related adverse events were >1 in 5,000.

Attitude to Health↗
PubMed2004

Implementing a smallpox vaccination program aboard an aircraft carrier.

OBJECTIVE: To determine the feasibility of implementing a smallpox vaccination program aboard an aircraft carrier in conjunction with anthrax vaccination. METHODS: Retrospective review of smallpox vaccination program conducted from January 17, 2003 to February 19, 2003. Morbidity and loss of manpower were the major endpoints. RESULTS: There were 5,204 sailors available for vaccination. There were 243 (4.7%) medical exemptions and 24 administrative exemptions. During the program, 4,931 sailors were vaccinated. There were five reportable complications. Three sailors had autoinoculation, one sailor had localized cellulitis, and one patient had a positive beta human chorionic gonadotropin during vaccination. None of the complications required medical evacuation. Only two sailors required time off from duty. CONCLUSIONS: Smallpox vaccination can be accomplished rapidly and safely aboard an aircraft carrier. There was not an increase in adverse events compared to historical data despite the close-quarter conditions. Smallpox and anthrax vaccinations can be completed simultaneously with minimal morbidity.

Bioterrorism↗
PubMed1997

Smallpox: the triumph over the most terrible of the ministers of death.

More than 200 years ago, Edward Jenner performed an experiment that laid the foundation for the eradication of smallpox and transformed humankind's fight against disease. Smallpox afflicted humankind as no other disease had don; its persistence and diffusion were without parallel. The disease brought down at least three empires. Generations watched helplessly as their children succumbed to the disease or were disfigured or blinded by it. Attempts were made to contain smallpox by isolating its sufferers and, later, by using variolation with varying degrees of success. However, the definitive solution was not found until Jenner's work was done at the end of the 18th century. Milkmaids who had developed cowpox from contact with cow udders informed Jenner that they were protected from the human form of the disease; he listened to their folk wisdom and raised it to the status of scientific fact. Jenner did not discover vaccination, but he was the first to demonstrate that this technique offered a reliable defense against smallpox. It was also a reliable defense against other illnesses, such as poliomyelitis, measles, and neonatal tetanus, although this was not known in Jenner's lifetime.

Disease Outbreaks↗
PubMed1999

Smallpox and its control in Canada.

Edward Jenner's first treatise in 1798 described how he used cowpox material to provide immunity to the related smallpox virus. He sent this treatise and some cowpox material to his classmate John Clinch in Trinity, Nfld., who gave the first smallpox vaccinations in North America. Dissemination of the new technique, despite violent criticism, was rapid throughout Europe and the United States. Within a few years of its discovery, vaccination was instrumental in controlling smallpox epidemics among aboriginal people at remote trading posts of the Hudson's Bay Company. Arm-to-arm transfer at 8-day intervals was common through most of the 19th century. Vaccination and quarantine eliminated endemic smallpox throughout Canada by 1946. The last case, in Toronto in 1962, came from Brazil.

Canada↗
PubMedDate not supplied

Smallpox vaccination in Senta County in the early 19th century.

The objective of this paper was to report data on vaccination against smallpox in the first decades of the 19th century in the documentation of the historical archives of Senta. The most important documents regulating smallpox vaccination, its control and way of conducting it are presented in complete. One of the most important documents is a poster proclamation from 1814 by which vaccination of children against smallpox was requested. Another document from 1817 was found and it certifies, with great certainty that at that time (or since that time) vaccination against smallpox was present at the territory of Senta. Authors consider that these documents are of utmost importance and that they represent documents enriching history of medicine in our regions.

History, 19th Century↗