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PubMed1965

ONTOGENESIS OF HUMAN SMALLPOX VIRUS.

THE VEGETATIVE STAGE OF DEVELOPMENT OF THE HUMAN SMALLPOX VIRUS IS DESCRIBED AS BEING COMPRISED OF FOUR SUCCESSIVE PERIODS: "without membrane" period; "open-cavity" period; "single-cavity" period; and "double-cavity" period. This classification is based on the organization of the virus membranes. This paper presents a description of the changes in virus structure during each period. It shows the strict sequence of morphological continuity and succession of differentiation of viral components. The most important stage of the development, the differentiation of virus nucleoid, takes place in the virus cavity morphologically isolated from the cellular milieu and limited originally by the external membrane of the virus and then by the second one, the primary membrane of the nucleoid. Osmiophilic fibrils 20 to 25 A wide, which fill the cavity of a mature nucleoid, become clearly evident after staining with uranyl acetate and are revealed only at the end of the last or double-cavity period. The main features of the developmental cycle of human smallpox virus may probably be characteristic of certain other groups of viruses.

Cell Biology↗
PubMed2004

Distinct time effects of vaccination on long-term proliferative and IFN-gamma-producing T cell memory to smallpox in humans.

Residual immunity to the smallpox virus raises key questions about the persistence of long-term immune memory in the absence of antigen, since vaccination ended in 1980. IFN-gamma-producing effector-memory and proliferative memory T cells were compared in 79 vaccinees 13-25 yr after their last immunization and in unvaccinated individuals. Only 20% of the vaccinees displayed both immediate IFN-gamma-producing effector-memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all. Both responses were mediated by CD4 and CD8 T cells. The vaccinia-specific IFN-gamma-producing cells were composed mainly of CD4Pos CD45RANeg CD11aHi CD27Pos and CCR7Neg T cells. Their frequency was low but could be expanded in vitro within 7 d. Time since first immunization affected their persistence: they vanished 45 yr after priming, but proliferative responses remained detectable. The number of recalls did not affect the persistence of residual effector-memory T cells. Programmed revaccination boosted both IFN-gamma and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector-memory cells. Such long-term maintenance of vaccinia-specific immune memory in the absence of smallpox virus modifies our understanding of the mechanism of persistence of long-term memory to poxviruses and challenges vaccination strategies.

Adult↗
PubMed2004

Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines.

The large size of poxvirus genomes has stymied attempts to identify determinants recognized by CD8+ T cells and greatly impeded development of mouse smallpox vaccination models. Here, we use a vaccinia virus (VACV) expression library containing each of the predicted 258 open reading frames to identify five peptide determinants that account for approximately half of the VACV-specific CD8+ T cell response in C57BL/6 mice. We show that the primary immunodominance hierarchy is greatly affected by the route of VACV infection and the poxvirus strain used. Modified vaccinia virus ankara (MVA), a candidate replacement smallpox vaccine, failed to induce responses to two of the defined determinants. This could not be predicted by genomic comparison of viruses and is not due strictly to limited MVA replication in mice. Several determinants are immunogenic in cowpox and ectromelia (mousepox) virus infections, and immunization with the immunodominant determinant provided significant protection against lethal mousepox. These findings have important implications for understanding poxvirus immunity in animal models and bench-marking immune responses to poxvirus vaccines in humans.

Amino Acid Sequence↗
PubMed2001

Countering the posteradication threat of smallpox and polio.

After eradication, there is a small but finite risk that smallpox and/or poliomyelitis viruses could accidentally escape from a laboratory or be released intentionally. The reintroduction of either virus into a highly susceptible population could develop into a serious catastrophe. To counter such an occurrence will require the use of vaccine, perhaps in substantial quantities. In the United States, new stocks of smallpox vaccine are being procured and arrangements are being made for a standby production facility. Similar provisions need to be considered for polio. To counter an epidemic of polio will require the use of the oral vaccine, which is presently the World Health Organization-recommended vaccine of choice for countries throughout the developing world. In these countries, its continued use is advised because of its ability to induce intestinal immunity, its ability to spread to other susceptible household members and to protect them, its ease of administration, and its low cost.

Bioterrorism↗
PubMed2004

Urticaria, exanthems, and other benign dermatologic reactions to smallpox vaccination in adults.

A phase 1 smallpox vaccine trial involving 350 adult volunteers was conducted. Of these subjects, 250 were naive to vaccinia virus vaccine (i.e., "vaccinia naive"). Volunteers received a new cell-cultured smallpox vaccine or a live vaccinia virus vaccine. Nine self-limiting rashes (3.6%) were observed in the vaccinia-naive group. None of the vaccinia-experienced patients had a rash. Rashes appeared 6-19 days after vaccination and had 5 different clinical presentations. Five volunteers had urticarial rashes that resolved within 4-15 days, 1 had an exanthem that lasted 20 days, and 1 each presented with folliculitis, contact dermatitis, and erythematous papules found only on the hands and fingers. Volunteers reported pruritus, tingling, and occasional headaches. Relief was obtained with antihistamine and acetaminophen therapy. No volunteer experienced fever or significant discomfort.

Adult↗
PubMed2004

Unintended smallpox vaccination of HIV-1-infected individuals in the United States military.

We identified 10 individuals who had undiagnosed human immunodeficiency virus type 1 (HIV-1) infection at the time of smallpox vaccination. Mean CD4 cell count was 483 cells/mm3 (range, 286-751 cells/mm3), and mean log10 plasma HIV-1 RNA load was 4.13 copies/cm3 (range, 2.54-5.16 copies/cm3). All vaccinees (3 primary and 7 repeat) had a normal, robust reaction without complications. Smallpox vaccine was well-tolerated in this small series of HIV-1-infected military personnel.

Adult↗
PubMed2004

Induction of human T cell-mediated immune responses after primary and secondary smallpox vaccination.

BACKGROUND: Postexposure vaccination strategies rely on a rapid induction of poxvirus-specific immune responses. Postvaccination cell-mediated immune (CMI) responses have not been compared by use of controlled trials in previously vaccinated (vaccinia-nonnaive) and nonvaccinated (vaccinia-naive) individuals. METHODS: To assess the time course of vaccinia-specific CMI responses, 20 previously vaccinated and 10 vaccinia-naive individuals were vaccinated with Dryvax, and serial blood samples were drawn. RESULTS: Both groups developed peak levels of vaccinia-specific interferon (IFN)- gamma -producing T cells by day 14 after vaccination. In vaccinia-nonnaive individuals, vaccinia-specific CMI responses were detected by day 7 after vaccination and preceded the increase in antibody titers. IFN- gamma enzyme-linked immunospot responses were significantly different between the 2 groups on days 7 (greater in vaccinia-nonnaive than in vaccinia-naive individuals) and 14 (greater in vaccinia-naive than in vaccinia-nonnaive individuals). Lymphoproliferation responses in vaccinia-nonnaive individuals were significantly higher on days 3 and 7, but cytotoxic T cell lysis activity was not statistically different at any time point. Antibody responses conformed to expected primary and secondary patterns of induction. CONCLUSIONS: This study demonstrates that the kinetics of CMI responses are different after primary vaccination versus after revaccination and indicates that memory can exist in individuals vaccinated >/=30 years ago. These data support the epidemiological observation in smallpox outbreaks that successful revaccination within 4 days of exposure is partially protective. In vaccinia-nonnaive individuals, protection against smallpox during the postexposure revaccination period may require T cell memory as an essential component for the rapid induction of protective cellular and humoral responses.

Adult↗
PubMed2004

Smallpox vaccine: "non-take" responses in previously vaccinated adults.

This small, retrospective study of laboratory workers who received smallpox vaccine showed a strong correlation between "non-take" reactions and the presence of prior vaccination scars. Although we cannot exclude technique and vaccine potency as causes, the association we observed may indicate that these workers are displaying residual immunity to smallpox.

Adult↗
PubMed1990

Correlation between cutaneous reaction in vaccinees immunized against smallpox and antibody titer determined by plaque neutralization test and ELISA.

The correlation between skin reaction, exhibited by vaccinees immunized against smallpox, and antibody titer determined by plaque neutralization and ELISA, was evaluated. Twenty eight out of 35 young adults (vaccinated at infancy and at the age of 8 years), who were injected with vaccinia virus, displayed a major skin reaction a week later. An increase of four-folds and more, in antibody titer against vaccinia virus, is generally considered positive immunization take-up against smallpox. According to this criterion, only 17 of the vaccinees were found positive by plaque neutralization, while 25 by the indirect micro-ELISA. Thus, there were eight vaccinees who were considered immunized by the ELISA, (seven of them also according to the skin reaction), but not by the plaque neutralization test.

Adolescent↗
PubMed2004

Myopericarditis following smallpox vaccination.

Myopericarditis has been a rare or unrecognized event after smallpox vaccinations with the New York City Board of Health strain of vaccinia virus (Dryvax; Wyeth Laboratories, Marietta, Pennsylvania). In this article, the authors report an attributable incidence of at least 140 clinical cases of myopericarditis per million primary smallpox vaccinations with this strain of vaccinia virus. Fifty-eight males and one female aged 21-43 years with confirmed or probable acute myopericarditis were detected following vaccination of 492,730 US Armed Forces personnel from December 15, 2002, through September 30, 2003. The cases were identified through sentinel reporting to military headquarters, active surveillance using the Defense Medical Surveillance System, or reports to the Vaccine Adverse Event Reporting System. The observed incidence (16.11/100,000) of myopericarditis over a 30-day observation window among 347,516 primary vaccinees was nearly 7.5-fold higher than the expected rate of 2.16/100,000 (95% confidence interval: 1.90, 2.34) among nonvaccinated, active-duty military personnel, while the incidence of 2.07/100,000 among 145,155 revaccinees was not statistically different from the expected background rate. The cases were predominantly male (58/59; 98.3%) and White (51/59; 86.4%), both statistically significant associations (p = 0.0147 and p = 0.05, respectively).

Acute Disease↗
PubMed1980

Smallpox surveillance in Bangladesh: I - Development of surveillance containment strategy.

A major epidemic of Variola major with an estimated 90 000 cases and 18 000 deaths occurred in Bangladesh in 1972. During a 3-year period methods of active surveillance (market search, outbreak investigation, and house-to-house search) were developed to supplement the passive reporting system. The percentage of smallpox cases detected increased from 11.8% in 1972 to 83% in 1975. Together with the implementation of improved methods of outbreak control, smallpox transmission was interrupted in October 1975.

Bangladesh↗
PubMedDate not supplied

Legal implications of the Smallpox Vaccination Program.

President George W. Bush's Smallpox Immunization Program will expose health care workers and public health agencies to liability for negligent administration of the vaccine. Section 304 of the Homeland Security Act, supplemented by Secretary Thompson's Emergency Declaration, shifts liability to the federal government. State indemnification laws and workers' compensation laws protect some potential defendants. The Smallpox Personnel Protection Act of 2003 provided a new source of compensation to injured health care workers. This article examines the scope of protection offered by these laws.

Compensation and Redress↗
PubMed1994

Modelling the different smallpox epidemics in England.

Time series analysis has revealed two different patterns of smallpox epidemics in Britain in the seventeenth and eighteenth centuries: in large conurbations (exemplified by London) the disease was endemic whereas medium-sized rural towns (exemplified by Penrith, Cumbria) suffered from 5 year epidemics with no cases of smallpox in the inter-epidemic years. The oscillations (epidemics) persisted for over 150 years and it is suggested that both systems were pumped up by regular fluctuations in susceptibility (delta beta). Modelling suggests that: (i) the natural frequency of oscillations in large cities is two years and the system is pumped up by a 1 year, seasonal input; (ii) it takes five years to build up a pool of susceptibles in medium-sized towns by new births and epidemics are then triggered by a 5 year input. The equations represent a system that has two components, a basic linear element with the remainder of the system being nonlinear; modelling a progressive increase in delta beta in London illustrates theoretically how a predominantly linear response changes to a nonlinear response and ultimately to chaos. A variation in susceptibility is a theoretical condition for inducing chaos; the undriven system cannot become chaotic. Modelling populations of progressively increasing size/density and applying a 1 year or 5 year sinusoidal oscillation in delta beta illustrates the fundamental distinction in the response of medium-sized rural towns and large cities.

Child↗
PubMed1985

Possible changes in the frequency of the human ABO blood groups in Iceland due to smallpox epidemics selection.

The hypothesis is put forward that the low frequency of A and high frequency of O blood group genes in the Icelandic human population is the result of a selective disadvantage of A during severe smallpox epidemics. The hypothesis is supported by data from India in 1965-6, which show a marked selective effect of a smallpox epidemic against the phenotypes A and AB (Vogel & Chakravartti, 1971). The conclusion is drawn that the present-day ABO blood group gene frequencies of the Icelandic population should be used with reservation as markers in the study of the origin of the Icelanders.

ABO Blood-Group System↗
PubMed1973

Consequences of smallpox vaccination in leprosy patients.

This study illustrates the consequences of smallpox revaccination in 45 lepromatous, 28 tuberculoid, and 47 normal individuals. Results obtained with intradermal inoculations indicated that the patients with leprosy were associated with a relative anergy against the vaccinia virus, the anergy being minimal in the tuberculoid leprosy but marked in the cases with lepromatous leprosy. Major vaccinial reactions were observed more often in patients with lepromatous leprosy than in the controls or patients with tuberculoid leprosy. Furthermore in a patient with lepromatous leprosy, vaccinia necrosum also developed. The smallpox vaccination with live virus also appeared as a provocative factor for the precipitation of lepra reaction in the lepromatous leprosy cases. After 3 weeks of vaccination, the frequency of the specific humoral antibody response was the same in the tuberculoid patients and controls while it was higher in the cases with lepromatous leprosy. The prevaccination titer of total hemagglutination inhibition antibody was significantly higher in the lepromatous leprosy cases. However, the postvaccinial, humoral antibody response of the lepromatous patients was of the same magnitude as that observed in the normal individuals, and it was mainly due to a 2-mercaptoethanol-resistant antibody.

Adult↗
PubMed2003

Smallpox: residual antibody after vaccination.

Of all the microorganisms and toxins, poxviruses (Orthopoxvirus) have the greatest potential for use by terrorists. These viruses can spread rapidly through the environment following initial infection. In 1980, the World Health Organization Eradication Program discontinued vaccination for smallpox and declared that the disease had been eliminated. With the threat of smallpox virus as a bioterrorism weapon, questions have been asked about the persistence of protection (as offered by antibodies) following vaccination with vaccinia virus vaccine. To address this, sera from 204 adults vaccinated as children were tested by enzyme immunoassay (EIA) for the presence of vaccinia virus antibody. Of the 204 individuals whose sera were examined for the presence of vaccinia antibody, 165 (80.9%) had been vaccinated once and 39 (19.1%) had been vaccinated at least twice. Of the 165 sera from individuals vaccinated once, 112 (67.9%) were positive. Of the 39 sera from individuals vaccinated more than once, 31 (79.5%) were positive. The presence of a vaccination scar at the time of blood collection was not determined. Fifty-six nonvaccinated individuals, under 30 years of age, were tested by EIA; four of these (7.1%) were positive for vaccinia virus antibody by EIA. Forty-four EIA-positive and 16 EIA-negative sera were also tested by serum neutralization (SN) as a comparison with the EIA test results; one serum (negative by EIA) was SN positive. No attempt was made to ascertain any demographics other than age (date of birth) and "remembered" times of vaccination.

Adult↗
PubMed2004

Smallpox and pan-orthopox virus detection by real-time 3'-minor groove binder TaqMan assays on the roche LightCycler and the Cepheid smart Cycler platforms.

We designed, optimized, and extensively tested several sensitive and specific real-time PCR assays for rapid detection of both smallpox and pan-orthopox virus DNAs. The assays are based on TaqMan 3'-minor groove binder chemistry and were performed on both the rapid-cycling Roche LightCycler and the Cepheid Smart Cycler platforms. The hemagglutinin (HA) J7R, B9R, and B10R genes were used as targets for the variola virus-specific assays, and the HA and DNA polymerase-E9L genes were used as targets for the pan-orthopox virus assays. The five orthopox virus assays were tested against a panel of orthopox virus DNAs (both genomic and cloned) at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). The results indicated that each assay was capable of detecting both the appropriate cloned gene and genomic DNA. The assays showed no cross-reactivity to the 78 DNAs in the USAMRIID bacterial cross-reactivity panel. The limit of detection (LOD) of each assay was determined to be between 12 and 25 copies of target DNA. The assays were also run against a blind panel of DNAs at the Centers for Disease Control and Prevention (CDC) on both the LightCycler and the Smart Cycler. The panel consisted of eight different variola virus isolates, five non-variola virus orthopox virus isolates, two varicella-zoster virus isolates, and one herpes simplex virus isolate. Each sample was tested in triplicate at 2.5 ng, 25 pg, 250 fg, and 2.5 fg, which represent 1.24 x 10(7), 1.24 x 10(5), 1.24 x 10(3), and 1.24 x 10(1) genome equivalents, respectively. The results indicated that each of the five assays was 100% specific (no false positives) when tested against both the USAMRIID panels and the CDC blind panel. With the CDC blind panel, the LightCycler was capable of detecting 96.2% of the orthopox virus DNAs and 93.8% of the variola virus DNAs. The Smart Cycler was capable of detecting 92.3% of the orthopox virus DNAs and between 75 and 93.8% of the variola virus DNAs. However, all five assays had nearly 100% sensitivity on both machines with samples above the LOD (>12 gene copies). These real-time PCR assays represent a battery of tests to screen for and confirm the presence of variola virus DNA. The early detection of a smallpox outbreak is crucial whether the incident is an act of bioterrorism or an accidental occurrence.

Base Sequence↗
PubMed1980

Basal cell carcinoma arising in a smallpox vaccination site.

A case of pigmented basal cell carcinoma developing in a smallpox revaccination site is presented. Any progressive change within a smallpox vaccination scar should be thoroughly evaluated and treated appropriately after tissue diagnosis.

Adult↗