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PubMed2004

ACAM2000 clonal Vero cell culture vaccinia virus (New York City Board of Health strain)--a second-generation smallpox vaccine for biological defense.

The threat of smallpox as a biological weapon has spurred efforts to create stockpiles of vaccine for emergency preparedness. In lieu of preparing vaccine in animal skin (the original method), we cloned vaccinia virus (New York City Board of Health strain, Dryvax by plaque purification and amplified the clone in cell culture. The overarching goal was to produce a modern vaccine that was equivalent to the currently licensed Dryvax in its preclinical and clinical properties, and could thus reliably protect humans against smallpox. A variety of clones were evaluated, and many were unacceptably virulent in animal models. One clonal virus (ACAM1000) was selected and produced at clinical grade in MRC-5 human diploid cells. ACAM1000 was comparable to Dryvax in immunogenicity and protective activity but was less neurovirulent for mice and nonhuman primates. To meet requirements for large quantities of vaccine after the events of September 11th 2001, the ACAM1000 master virus seed was used to prepare vaccine (designated ACAM2000) at large scale in Vero cells under serum-free conditions. The genomes of ACAM1000 and ACAM2000 had identical nucleotide sequences, and the vaccines had comparable biological phenotypes. ACAM1000 and ACAM2000 were evaluated in three Phase 1 clinical trials. The vaccines produced major cutaneous reactions and evoked neutralizing antibody and cell-mediated immune responses in the vast majority of subjects and had a reactogenicity profile similar to that of Dryvax.

Animals↗
PubMed2004

Incidence and follow-up of inflammatory cardiac complications after smallpox vaccination.

OBJECTIVES: The purpose of this study was to assess the follow-up of patients with vaccinia-associated myocarditis. BACKGROUND: With the threat of biological warfare, the U.S. Department of Defense resumed a program for widespread smallpox vaccinations on December 13, 2002. One-year afterwards, there has been a significant increase in the occurrence of myocarditis and pericarditis among those vaccinated. METHODS: Cases were identified through sentinel reporting to military headquarters, systematic surveillance, and spontaneous reports. RESULTS: A total of 540,824 military personnel were vaccinated with a New York City Board of Health strain of vaccinia from December 2002 through December 2003. Of these, 67 developed myopericarditis at 10.4 +/- 3.6 days after vaccination. The ST-segment elevation was noted in 57%, mean troponin on admission was 11.3+/- 22.7 ng/dl, and peak cardiac enzymes were noted within 8 h of presentation. On follow-up of 64 patients (96%) at a mean of 32 +/- 16 weeks, all patients had objective normalization of echocardiography, electrocardiography, laboratory testing, graded exercise testing, and functional status; 8 (13%) reported atypical, non-limiting persistent chest discomfort. CONCLUSIONS: Post-vaccinial myopericarditis should be considered in patients with chest pain within 30 days after smallpox vaccination. Normalization of echocardiography, electrocardiography, and treadmill testing is expected, and nearly all patients have resolution of chest pain on follow-up.

Biomarkers↗
PubMed2005

Activity of vaccinia virus-neutralizing antibody in the sera of smallpox vaccinees.

Individuals vaccinated against smallpox maintain substantial antiviral antibody responses for many years after vaccination. In this study, we examined the ability of antiviral antibodies from 104 unique serum samples to neutralize the two infectious forms of vaccinia virus, intracellular mature virus (IMV) and extracellular enveloped virus (EEV). While we found direct correlations between antiviral antibody titers and the ability to neutralize IMV and EEV, correlation with EEV neutralization was weaker. To determine factors that may influence more varied EEV neutralization within a vaccinated population, we asked the following questions. (1) Does vaccinia virus-neutralizing ability remain constant over time? (2) Do multiple vaccinations boost IMV and EEV neutralization activity? We found that serum from vaccinated individuals retained ability to neutralize EEV for a relatively long time, but there was a significant drop in EEV neutralization ability in the third decade after vaccination. While all vaccinees maintained some ability to neutralize IMV, a number of individuals lost the capacity to neutralize EEV. Interestingly, the ability to neutralize either virus form was not altered by the number of vaccinations received. Since it is likely that neutralizing antibodies against both IMV and EEV are required for maximal protective immunity, a loss of anti-EEV-neutralizing ability may warrant the revaccination of individuals who have been vaccinated >20 years ago, should widespread pre-event smallpox vaccination be instituted.

Antibodies, Viral↗
PubMed2006

Comparative efficacy of modified vaccinia Ankara (MVA) as a potential replacement smallpox vaccine.

International concern over the potential consequences of a Bioterrorist or Biowarfare associated release of variola virus have prompted renewed interest in the vaccines for smallpox. The traditional live, replicating vaccine strains are subject to novel safety concerns associated with historical production methods in domesticated ruminants and the additional hazards that vaccinia virus poses for people with immune system abnormalities or a history of eczematous skin conditions. In this study we have examined the longevity and efficacy of immunity induced by a non-replicating smallpox vaccine candidate, modified vaccinia Ankara (MVA) in a murine model using intranasal and aerosol routes of infection. Two-step vaccinations of MVA followed by traditional Lister vaccine are compared with either Lister alone or MVA alone, and the longevity of the protection induced by MVA is assessed. MVA is found to be broadly similar to Lister. Although protection is shown to decay with time, when administered at a standard human dose the longevity of protection induced by MVA is comparable to that induced by Lister.

Administration, Intranasal↗
PubMed2005

[Risk of smallpox, vaccination, bioterrorism].

The use of the smallpox virus as a biological weapon is very old. Confronted with a high probability of a current bioterrorist menace, counteracting strategies have been developed. One of the principle aims relies on the vaccination of teams dedicated to the management of persons infected and the stocking of vaccine for the whole population of a country. Following worldwide eradication of the disease, preventive vaccination was topped in 1978 in France for the primo-vaccination, and in 1984 for repeat vaccinations. The various strains used in the first generation vaccinations are weakened living vaccine, the natural host and origin of which is unknown. Second and third generations vaccines are under study; the principle objective is to obtain efficacy with a minimum of side effects. There are two types of adverse events, generally observed with the first generation vaccines: the first, extremely rare, can be life-threatening; the others, more frequent (10 to 15% of patients) are benign. In emergency situations, in the presence of smallpox, there should be no absolute contraindications to vaccination. In the bioterrorist context, massive vaccination campaigns of the population are unadvisable (because of the considerable risk of death and severe adverse events) in the absence of any real permit, in each case, definition of the vaccinal strategy to be adopted.

Bioterrorism↗
PubMed2002

Smallpox: anything to declare?

Smallpox was eradicated in 1977, but it remains a concern owing to the potential use of the causative agent variola virus in bioterrorism. This article provides an overview of the World Health Organization's spectacular success in achieving the eradication of smallpox. It discusses how variola virus could potentially re-emerge and how prepared we are to counter such a re-emergence. Finally, the potential threat from other orthopoxviruses that exist naturally or that have been genetically engineered is considered. In the words of Rep. Christopher Shay, 'Better to be scared by the improbable possibility than to be unprepared for the catastrophic reality'.

Bioterrorism↗
PubMed2002

Smallpox--eradicated, but a growing terror threat.

Smallpox is a disease that followed humanity for thousands of years up until 30 years ago. It was possible to eradicate, because an effective live vaccine from crossreacting vaccinia could be developed. Twenty years have passed since vaccinations stopped and very few people are protected against the disease today. Variola today has become an object of discussion due to the possibility that it can be used as a bioweapon. Due to the number of complications that can be expected a general vaccination is probably not possible. Research is ongoing to develop new vaccines. Many countries are improving their capabilities to respond to a renewed threat of a smallpox epidemic.

Antiviral Agents↗
PubMed2002

Smallpox vaccination: Risk considerations for patients with atopic dermatitis.

As the threat of bioterrorism with pathogenic microbes such as smallpox virus (Variola major) increases, the question of widespread voluntary vaccination with smallpox (vaccinia) vaccines is being carefully considered. A major challenge lies in the ability to protect the population from the disease while minimizing the considerable side effects from the vaccine. Individuals with active or quiescent atopic dermatitis are at increased risk for vaccinia complications. The nature of these complications and other considerations are summarized in this rostrum.

Child↗
PubMed2003

Smallpox vaccination: a review, part II. Adverse events.

Smallpox vaccination of health care workers, military personnel, and some first responders has begun in the United States in 2002-2003 as one aspect of biopreparedness. Full understanding of the spectrum of adverse events and of their cause, frequency, identification, prevention, and treatment is imperative. This article describes known and suspected adverse events occurring after smallpox vaccination.

Bacterial Infections↗
PubMed2003

Effectiveness of postexposure vaccination for the prevention of smallpox: results of a delphi analysis.

We estimated the effectiveness of postexposure smallpox vaccination in preventing or modifying disease in naive and previously vaccinated adults, using the formal Delphi technique. For persons not previously vaccinated, the median effectiveness in preventing disease with vaccination at 0-6 h, 6-24 h, and 1-3 days after exposure was estimated as 93%, 90%, and 80%, respectively, and effectiveness in modifying disease among those who develop illness was estimated as 80%, 80%, and 75%, respectively. Effectiveness was greater for those vaccinated previously. High postexposure vaccination effectiveness for preventing or modifying smallpox is consistent with the limited data available, is biologically plausible, and is similar to that seen for other viral vaccine-preventable diseases. These estimates support the Advisory Committee on Immunization Practices recommendations and provide a key parameter for mathematical models on which policy decisions may be based.

Delphi Technique↗
PubMed2004

Looking back at smallpox.

Smallpox apparently arose through transfer of variola virus to humans from another animal species. By causing a brief infection that required close contact for transmission and engendered solid immunity, the agent was always vulnerable to simple isolation measures. The high replicative fidelity of the viral DNA polymerase limited variola's ability to adapt to humans and preserved orthopoxviral antigenic cross-reactivity, so that vaccinia vaccination protected against smallpox. Host-derived genes encoding immunomodulatory proteins helped shelter viral replication from innate immune responses. Examination of clinical variants suggests that severity of illness was usually determined by host responses during the incubation period. Control of viral replication was aided by early postexposure vaccination and might be strengthened by additional immunological interventions. Massive inflammatory responses were responsible for major features of illness. Some patients with high levels of circulating virus developed hemorrhagic disease resembling septic shock. Continued study of virus-host interactions is needed to defend against genetically modified agents.

Bioterrorism↗
PubMed2005

Validation of a screening instrument to identify persons for exclusion from smallpox vaccination.

Adults must be screened for atopic dermatitis and other contraindications before smallpox vaccination. We validated the sensitivity of a self-administered Centers for Disease Control and Prevention (Atlanta, GA) screening questionnaire completed by 174 hospital workers, with the workers' medical records as the reference standard. The questionnaire failed to identify one-third of the subjects who had a contraindication, although the incidence of serious adverse events has been low among vaccinees. Further assessment of screening procedures is needed if the administration of smallpox vaccine becomes more widespread in the future.

Adult↗
PubMed2006

Cellular immune responses to diluted and undiluted aventis pasteur smallpox vaccine.

BACKGROUND: Recent primary vaccine trials of diluted Aventis Pasteur smallpox vaccine (APSV) demonstrated that immunization "take" rates, defined by the presence of a vesicle or pustule ("take") at the inoculation site 6-11 days after immunization, did not differ between the dilution groups. To our knowledge, there have been no studies that examine the cellular immune response or that distinguish CD4(+) T cell responses from CD8(+) T cell responses after primary immunization with varying dilutions of APSV. METHODS: In the present study, we examined the cellular immune response in vaccinia-naive healthy adults (n=91) receiving inoculations with an undiluted or diluted (1:5 and 1:10) suspension of the APSV, using an intracellular cytokine staining assay. RESULTS: The diluted vaccine induced vaccinia virus (VV)-specific CD4(+) and CD8(+) T cell responses 1 month after primary immunization that were comparable to those induced by undiluted vaccine. The cellular immune responses were correlated with the reactogenicity profile of subjects and did not differ between dilution groups. Furthermore, expression of the interleukin-7 receptor alpha chain, which has been proposed to distinguish antigen-specific T cells that differentiate into long-lived memory T cells, did not differ among groups, suggesting that dilution of the vaccine does not affect the quantity of VV-specific memory T cells. CONCLUSIONS: APSV is an effective smallpox vaccine inducing strong humoral and cellular immune responses after a primary immunization even at diluted doses.

CD4-Positive T-Lymphocytes↗
PubMed2006

Optimal bandaging of smallpox vaccination sites to decrease the potential for secondary vaccinia transmission without impairing lesion healing.

OBJECTIVE: To assess the optimal method for covering smallpox vaccination sites to prevent transmission of vaccinia. DESIGN: Randomized, nonblinded clinical trial. SETTING: Tertiary care medical center. PARTICIPANTS: Vaccinia-naive and vaccinia-experienced volunteers. INTERVENTIONS: After vaccination, study participants were randomized to receive 1 of 3 types of bandage: gauze, occlusive with gauze lining, or foam. Vaccination sites were assessed every 3 to 5 days until the lesion healed. During each visit, specimens were obtained from the vaccination site, the bandage surface before removal, and the index finger contralateral to the vaccination site and were cultured for vaccinia. Time to lesion healing was assessed. RESULTS: All 48 vaccinia-naive and 47 (87%) of 54 vaccinia-experienced participants developed a vesicle or pustule at the injection site 6-11 days after vaccination. Fourteen (14%) of 102 participants had bandage cultures positive for vaccinia. All but 1 of these vaccinia-positive cultures were of a bandage from participants randomized to the gauze bandage group, and all but 3 were of bandages from vaccinia-naive participants. No finger-specimen cultures were positive for vaccinia. One episode of neck autoinoculation occurred in a vaccinia-naive individual who had vaccinia recovered from his gauze bandage on multiple visits. The foam bandage was associated with more local adverse effects (skin irritation and induration). The time to healing did not differ among the bandage groups. CONCLUSIONS: The potential for transmission of vaccinia from a vaccination site is greater if the site is covered by gauze than if it is covered by occlusive or foam bandages. Use of an occlusive bandage with a gauze lining is the best choice for coverage of smallpox vaccination sites because of a reduced potential for vaccinia transmission and a lower reactogenicity rate. Bandage choice did not affect vaccination lesion healing.

Adult↗
PubMed2006

Programmatic factors related to smallpox vaccine uptake by healthcare workers and others.

We surveyed program coordinators at 106 hospitals and health departments that participated in the National Smallpox Vaccination Program to ascertain how program-level factors affected the rate of smallpox vaccine uptake by staff. In a fully adjusted multivariate model, health departments achieved significantly higher vaccination rates than did hospitals, as did facilities that invited fewer employees to be vaccinated.

Attitude of Health Personnel↗
PubMed2003

Analysis of historical data suggests long-lasting protective effects of smallpox vaccination.

More than half of the US population has received the smallpox vaccine, but it is unknown what fraction is still protected against infection and disease. Residual protection and age-dependent case-fatality ratios have therefore been widely neglected in the current bioterrorism debate. The author analyzed 1902-1903 data from Liverpool, United Kingdom, and from reintroductions of the disease to Europe in 1950-1971 to estimate to what degree vaccinated cases were protected against developing severe or fatal disease and how quickly this protection waned over time. Protection against severe and fatal disease was lost at the rate of 1.41% per year, corresponding to a half-life of 49.2 years (95% confidence interval: 42.0, 57.3), and protection against fatal disease alone declined 0.363% per year. Thus, even 70 years after primary vaccination, 77.6% of cases were still protected (95% confidence interval: 66.6, 85.4). Protection against severe disease should therefore extend for many decades after a single vaccination, and protection against death from smallpox may even be lifelong for the majority of vaccinees. This protection should greatly reduce the number of severe and fatal cases of disease expected in a bioterrorist attack, but residual protection may also increase the risk that some previously vaccinated cases who develop mild disease may remain unrecognized longer, while moving around freely and disseminating the infection.

Adolescent↗
PubMed1976

Surveillance of smallpox.

An intensified global smallpox eradication programme was started by the World Health Organization in 1967. This paper describes the basic techniques employed and the experiences involved in implementing the procedures. Surveillance schemes have varied considerably in detail from country to country according to different health structures, and the emphasis is therefore placed on the more generally used approaches. Finally, important principles in the implementation of the smallpox surveillance programme are considered in relation to the development of such programmes for other communicable diseases.

Communicable Disease Control↗
PubMed2004

Antiviral prophylaxis of smallpox.

Proof-of-concept studies suggest that current defences against smallpox could be strengthened by supplementing vaccination with antiviral drug prophylaxis, based on aerosolized or orally available forms of the long-acting medication cidofovir. Delivery of aerosolized cidofovir to mice results in its prolonged retention in respiratory tissues and protection against lethal intranasal or aerosol poxviral challenge. Although cidofovir itself is not orally available, the addition of an alkoxyalkanol ether side-chain allows it to be absorbed from the gastrointestinal tract. This also markedly increases its antiviral activity and lengthens its intracellular half-life from roughly 3 to 8-10 days. Oral treatment also protected mice against lethal poxviral challenge. These results suggest that a single aerosol dose of cidofovir (or an alkoxyalkanol-ether derivative) could provide prolonged protection against initiation of smallpox infection, whereas oral treatment could prevent both initiation of infection and internal dissemination of virus. Both approaches may avoid the nephrotoxicity that occasionally results from intravenous cidofovir therapy.

Antiviral Agents↗