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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.

The success of global smallpox eradication in 1980 led all the nations of the world to discontinue smallpox vaccination. To date, however, the threat of deliberate release of smallpox virus has led health authorities to reconsider smallpox vaccination and at the same time, to urge to evaluate duration of the immunity of the population vaccinated before 1980. Although available data is scarce and incomplete, the study suggests that protective immunity lasts longer in a good percentage of vaccinees, although the real percentage and duration are not known. Accordingly, how to establish a national vaccination policy for preparedness in Japan and elsewhere was discussed. The study is intended to cause interest and debate among the medical and public health community.

Background: We conducted a double-blind, randomized trial of three dilutions of vaccinia virus vaccine in previously unimmunized adults in order to assess the clinical success rates, humoral responses, and virus-specific activity of cytotoxic T cells and interferon-gamma-producing T cells., Methods: Sixty healthy adults were inoculated intradermally by bifurcated needle with undiluted vaccine (dose, 10(7.8) plaque-forming units [pfu] per milliliter), a 1:10 dilution (dose, 10(6.5) pfu per milliliter), or a 1:100 dilution (dose, 10(5.0) pfu per milliliter); there were 20 subjects in each group. The subjects were monitored with respect to vesicle formation (an indicator of successful vaccination), the viral titer at the time of peak lesion formation, antiviral antibodies, and cellular immune responses., Results: A vaccinia vesicle developed in 19 of the 20 subjects who received undiluted vaccine (95 percent), 14 of the 20 who received the 1:10 dilution (70 percent), and 3 of the 20 who received the 1:100 dilution (15 percent). One month after vaccination, 34 of 36 subjects with vesicles had antibody responses, as compared with only 1 of 24 subjects without clinical evidence of vaccinia virus replication. Vigorous cytotoxic T-cell and interferon-gamma responses occurred in 94 percent of subjects with vesicles, and a cytotoxic T-cell response occurred in only one subject without a vesicle., Conclusions: The vaccinia virus vaccine (which was produced in 1982 or earlier) still has substantial potency when administered by a bifurcated needle to previously unvaccinated adults. Diluting the vaccine reduces the rate of successful vaccination. The development of vesicular skin lesions after vaccination correlates with the induction of the antibody and T-cell responses that are considered essential for clearing vaccinia virus infections.

The results of fundamental and applied investigations on the development and trial of the oral administration of smallpox vaccine and live recombinant smallpox-hepatitis vaccine (Revax VT) in tablets are summarized. In comparative experiments on animals (rabbits, monkeys and guinea pigs) and human immunization the oral smallpox vaccine in tablets was shown to ensure equal effectiveness and greater safety in comparison with traditional smallpox vaccine for skin application. The study confirmed the natural and physiological character of oral immunization as a result of direct contact of immunogen with the mucous membrane of the digestive tract--an essential immunocompetent organ of the lymphoid system. The conclusion was made that oral immunization was the safe and most promising method of immunization against smallpox under modern conditions.

September 11, 2001, brought the possibility of biologic acts of terrorism against the United States into the national consciousness. As the American people brace themselves for this new threat to the national well-being, clinicians must understand how to prevent, recognize, and treat the biologic agents that could be used in terrorist attacks. This article discusses the most likely biologic agents, including diagnostic laboratory procedures, treatment options, psychological effects, special populations, and reporting requirements.

We constructed a mathematical model to describe the spread of smallpox after a deliberate release of the virus. Assuming 100 persons initially infected and 3 persons infected per infectious person, quarantine alone could stop disease transmission but would require a minimum daily removal rate of 50% of those with overt symptoms. Vaccination would stop the outbreak within 365 days after release only if disease transmission were reduced to <0.85 persons infected per infectious person. A combined vaccination and quarantine campaign could stop an outbreak if a daily quarantine rate of 25% were achieved and vaccination reduced smallpox transmission by > or = 33%. In such a scenario, approximately 4,200 cases would occur and 365 days would be needed to stop the outbreak. Historical data indicate that a median of 2,155 smallpox vaccine doses per case were given to stop outbreaks, implying that a stockpile of 40 million doses should be adequate.

In the context of its plan to fight against bioterrorism, the Ministry of Health asked the Institut de Veille Sanitaire to evaluate the epidemic risk from a release of the small pox virus, and to make recommendations on potential vaccination strategies to be implemented. A benefit/risk assessment of various vaccination scenarios, including vaccination of the whole French population, was carried out to evaluate the severity of a terrorist action threat. This analysis concludes that at this stage, vaccination action does not seem to be justified. Even in the case of a real threat, the vaccination of frontline healthcare personnel, and in particular of contacts of cases, must be given priority.

Although it is unlikely that large-scale vaccination against smallpox will ever be required again, it is conceivable that the need may arise to vaccinate against a human orthopoxvirus infection. A possible example could be the emergence of monkey poxvirus (MPV) as a significant human disease in Africa. Vaccinia virus (VV) recombinants, genetically modified to carry the immunogenic proteins of other pathogenic organisms, have potential use as vaccines against other diseases present in this region. The immune response to parental wild-type (wt) or recombinant VV was examined by binding and functional assays, relevant to protection: total IgG, IgG subclass profile, B5R gene product (gp42)-specific IgG, neutralizing antibodies and class 1-mediated cytotoxic lymphocyte activity. There was a substantial reduction in the immune response to VV after scarification with about 10(8) PFU of recombinant as compared to wt virus. These data suggest that to achieve the levels of immunity associated with protection against human orthopoxvirus infection, and to control a possible future outbreak of orthopoxvirus disease, the use of wt VV would be necessary.

Vaccinia virus MVA is harmless for humans and animals both locally and parenterally. It offers paraspecific activities similar to those of comparable attenuated viruses of other pox genera, e.g. avipox or parapox. At the systemic level, MVA protects baby mice against lethal challenge with vesicular stomatitis virus (dose-response curve). MVA raises phagocytosis and NK-cell activity in humans and animals, whilst encouraging the induction of interferon alpha, interleukin-2 and -12 and colony-stimulating activity at the same time. The paramunity-inducing properties of MVA make it an ideal vector for the insertion of foreign genes. It is superior to other virus vectors because of its complex function. Inactivated MVA is also suitable as an inducer of paramunity.

Edward Jenner's famous Inquiry was published 200 years ago. Probably few now know on what evidence he based his claims but most will be aware that they initiated controversy which to some extent still continues. This paper briefly reviews the Inquiry, analysing its merits and faults. Jenner's claims were based on slender experimental evidence and some of the information presented was incomplete and misleading. However Jenner's role in the introduction of vaccination was seminal and others could only test and extend his ideas. His reputation as the initial promoter of vaccination is justified.

The first protection against smallpox, a disease known already in old China and India, consisted in rubbing infectious material from smallpox patients into the scratched skin of children. Lady Montagu brought this method from Turkey to England in 1721. This "variolation", however dangerous, was adopted in Europe during the eighteenth century mainly by the aristocracy. But it was Edward Jenner (1749-1823) who in 1796 used cowpox to protect against smallpox without the risk of acquiring the disease. During more than 60 years the "vaccination" was carried out from "arm to arm" with a certain risk of transmission of syphilis. From 1864 on the vaccine was mainly produced on cows to avoid this risk. The WHO managed in 1978 to eliminate smallpox from the planet by vaccination. The smallpox outbreaks, the inoculation, the vaccination and the production of cowpox vaccine in Luxembourg are described.

Vaccinia virus, no longer required for immunization against smallpox, now serves as a unique vector for expressing genes within the cytoplasm of mammalian cells. As a research tool, recombinant vaccinia viruses are used to synthesize and analyze the structure-function relationships of proteins, determine the targets of humoral and cell-mediated immunity, and investigate the types of immune response needed for protection against specific infectious diseases and cancer. The vaccine potential of recombinant vaccinia virus has been realized in the form of an effective oral wild-life rabies vaccine, although no product for humans has been licensed. A genetically altered vaccinia virus that is unable to replicate in mammalian cells and produces diminished cytopathic effects retains the capacity for high-level gene expression and immunogenicity while promising exceptional safety for laboratory workers and potential vaccine recipients.

This paper provides serologic investigation of HBV in 302 persons who had a history of smallpox in Zhumadian County. The results showed that the HBsAg positivity rate (1.3%) was significantly lower than those of the control group 1 (8.3%) and 2 (8.6%) (P less than 0.001). The HBsAg positivity rate between the two control groups had no significant difference (P greater than 0.05). The HBV infection rate (19.2%) was also lower than those of control group 1 (47.7%) and 2 (51.3%) (P less than 0.001). There was not much difference between the two control groups. The determination of cellular immunity showed that the rosette positivity rate (75.93%) and lymphocyte conversion rate (70.39%) of the patients' group were higher than those of control group 1 (62.3% and 52.9%) and 2 (60.93% and 55.3%). It may suggested that patients having had smallpox might have enhanced cellular immunity which might interfere with HBV infection.

Persistence of neutralizing antibodies after revaccination against smallpox was studied. Single serum samples from 140 revaccinated donors were tested for neutralizing antibodies using the plaque reduction assay. The donors, aged 21-49 years at sampling, had been vaccinated in infancy and revaccinated at 8 and 18 years; they formed seven groups of 20 men each, revaccinated about 3, 5, 10, 15, 20, 25, and 30 years before sampling. The differences in mean titer among groups were insignificant (P greater than .01). The titer significantly decreased during the first 3 years after the revaccination but remained stable for at least 30 years thereafter (geometric mean titer, 10.5; 95% confidence interval, 6.8-16.4). The results suggest that there is probably no need for routine revaccinations beyond the primary and two revaccinations; nevertheless, persons at high risk should be revaccinated regardless of their vaccination status.

The results of application of the fluorescent antibodies method (MFA) with the diagnostic purpose of detecting pox antigen in specimens from smallpox patients are presented. The method was found highly effective for the examination of material taken directly from the patients (smears) in the early stages of disease (maculo-papular and vesicular). The results of examination of smears from pustular fluid and scabs were not reliable in 44% of cases due to the presence of nonspecific fluorescence of tissue fragments and leukocytes. The technique of preliminary accumulation of the virus in a sensitive cell culture made the MFA suitable for the examination of material taken at any stage of disease. Results of the assessment of sensitivity of MFA in comparison with other methods of rapid diagnosis of smallpox are presented.

Experimentally, by stimulation of the activity of serum DNase and RNase direct evidence of their nonspecific protective role in herpes and influenza infections, respectively was obtained. Potentiation of the protective effect upon interaction of endogenous and exogenous nucleases with specific antibodies was demonstrated. Experiments in mice and observations in humans established a marked inhibition of serum RNase activity due to binding with the inhibitor, in mild and severe forms of influenza in nonimmune hosts and host immunized with live and inactivated vaccines. This is assumed to be one of the causes of insufficient effectiveness of artificial immunity against influenza.

A study was carried out on the humoral response and vaccinal reaction after repeated administration of the smallpox vaccine (1 to 3 times), at ten days interval, to 97 subjects with a past history of repeated vaccination failures. Revaccination ended in 52.6% failures. After revaccination the antibody titer increased in 97.8% of the cases of successful vaccination and in 43.5% of the negative cases. In 29.5% of the latter cases a decrease in the antibody titer by 1--3 binary dilutions was found. The results suggest that the repeated application at short intervals of an antigenic stimulus perturbs the immune response.

Its proof, significance, and the cellular cross reactivity to basic encephalitogenic protein of vaccinia-stimulated T-cells. Vaccination against smallpox induces both, a cellular allergy and immunity, and the production of humoral antibodies. Of greater importance for the defense of the organism against infections by orthopox viruses is the cellular immunity. New methods for the proof of cellular immunity and an in vitro-technique for its examination by challange with variola vera virus are described. In close connection with induction of cellular allergy by vaccination an immunological cell-bound reactivity of isolated lymphocytes develops against the basic encephalitogenic protein. In this antigen-stimulated resp.-irritated stage isolated lymphocytes show an enhanced rate of chromosomal aberrations and a high rate of spontaneous transformations. Lymphocytes of patients with Multiple Sclerosis demonstrate a high stimulation rate (3H- resp. 14C-Thymidine-inlay) after challenge with antigen of vaccinia virus. The T cell-mediated cross reactivity between vaccinia and myelin extracts is discussed as an hypothetic pathogenic factor of CNS complications after primary smallpox vaccination.

The selective survey of the population of the Republic of Congo for the presence of antibodies to orthopoxviruses has been carried out with the use of the neutralization test, the hemagglutination inhibition (HAI) test and the ELISA. Despite a prolonged period (15 years) elapsed since the transmission of natural smallpox stopped in this country and despite the almost complete cessation of immunization against this infection since 1977, antibodies to orthopoxviruses can be detected in a considerable proportion of the population: 29%. This percentage grows as older age groups are examined, reaching 90.6% in the age groups of 16 years and over. Antibodies to orthopoxviruses have also been detected in children under 5 years of age, born after the eradication of smallpox and having no vaccination scars. The possible causes of this phenomenon are discussed. The comparison of the results obtained with the use of different tests has confirmed high sensitivity of ELISA. The HAI test is less sensitive, but this is compensated by its simplicity and its easy use for screening procedures. Besides, the positive results of this test indicate that the corresponding sera contain sufficiently high titers of virus-neutralizing antibodies detected by means of ELISA, which is of importance for their subsequent interspecific differentiation.

The authors present the results of studying the PHAT sensitivity in comparison with the neutralization test and the hemagglutination inhibition test in examination of 254 sera of revaccinated and 95 sera of primarily vaccinated children. It appeared that PHAT was characterized by a sufficiently high sensitivity, and reproducibility, in case the same batch of erythrocytic diagnostic agent was used; at the same time the test was simple, accessible, economic, and gave rapid results. This test can be used for assessment of the immunological efficacy of smallpox revaccination.

In an attempt to prepare highly specific antiserum to variola virus, a chimpanzee was inoculated with a virulent human strain of this virus. Three uninoculated chimpanzees were housed in the same room; two of these developed clinical disease with seroconversion, while the third developed no evidence of infection and no antibody. The three animals that became ill also developed antibody to vaccinia and monkeypox viruses. Human contacts during the study and following a break in containment showed no evidence of infection as determined by serological tests and lack of clinical disease.

Craniopagus twins are described. At the age of 24 years, the twins appeared to have adapted well to their disability. The site of union, their relatively advanced age, and the high risk of operation were the reasons for not proposing surgical separation. Perceptive upbringing and adaptation to the disability may be alternatives to the neurosurgical management of this birth defect.

It has long been assumed that the devastation caused by European epidemic diseases on aboriginal populations was due to their lack of immunity to these diseases. It is argued here, from data on modern Third-World aboriginal people, that this has not been proven, thus it is likely that smallpox epidemics played only a minor role in the disappearance of the Khoikhoi at the Cape in the early 18th century. Increasing usurpation of their pasture land by the colony and loss of livelihood through livestock epidemics and drought, resulting in their subjugation and a downward spiral of anomie, had a much greater effect.

A 21-year-old Indian who worked as a vaccinator in the smallpox programme developed an atypical case of variola major despite several previous, successful vaccinations. The clinical course of the disease was unusual, as there were two distinctly separate "crops" of smallpox. The disease began less than one month after a successful vaccination, which therefore gave the briefest period of protection recorded for this reliable immunization. The patient was found to have a virtually complete IgM deficiency with normal levels of circulating antibody against orthopox virus.

A number of 154 young adults were given a smallpox vaccine inactivated by UV (103 subjects) or by 4degrees/00 formol (51 subjects). Inoculation induced an early cutaneous reaction in 75.4% of the revaccinated subjects. The incidence of positive HAI reactions in this group increased from 30.2% before vaccination to 63.8% after inoculation, while the geometric mean titer increased from 2.88 to 10.73. This would prove the early reactions to be allergic responses of organisms sensitized against smallpox vaccine, capable of stimulating antibody formation. No cutaneous reaction was recorded in the 7 persons vaccinated for the first time (without pre-existent cutaneous scars). These subjects developed neither cutaneous nor humoral response to the killed virus, as there was no previous sensitization to the respective antigen.

The correlation between the reactogenicity and immunogenicity characteristics of different smallpox vaccines, determined under the conditions of a strictly controlled field trial, has been studied by a number of laboratory tests. The most informative and reproducible laboratory methods for evaluating the provisory antigenic and immunogenic potency of smallpox vaccines are the evaluation of the character of lesions developing in rabbits as a result of the intradermal injection of the virus and the determination of the capacity of the virus for multiplication in the skin of a rabbit (reproduction). The most informative and reproducible method for evaluating the provisory reactogenicity of smallpox vaccines for humans is the determination of the capacity of the virus for multiplication at elevated temperature.

Antibodies to surface antigens of intracellular naked vaccinia virus (INV) and in limited studies extracellular enveloped virus (EEV) were determined by single radial immunodiffusion tests (SRDT) with immobilized virions in agarose gels. Antibodies to INV were demonstrable in rabbit hyperimmune sera (one to four visible zones), smallpox convalescent sera and sera from re-vaccinated individuals. A difference in specificity of antibodies reacting with INV and EEV was detectable by SRDT. The SRDT provides a simple, reproducible and specific test for detection of antibodies against vaccinia or variola virus, but the technique requires large quantities of virions.