1.) Edward Jenner and the Discovery of Vaccination

2.) Vaccines in historic evolution and perspective: a narrative of vaccine discoveries.

2.) Montagu's variolation.

3.) [Pharmaceutical development concerning diseases predominating in tropical regions: the concept of indigent drugs].

4.) Smalllpox and its control in Canada.

5.) Vaccines in historic evolution and perspective: a narrative of vaccine discoveries.

6.) Production of recombinant subunit vaccines: protein immunogens, live delivery systems and nucleic acid vaccines.

7.) [Two hundred years ago: the first smallpox vaccinations in Vienna].

8.) Edward Jenner's Inquiry; a bicentenary analysis.

9.) The myth of the medical breakthrough: smallpox, vaccination, and Jenner reconsidered.

10.) Smallpox: gone but not forgotten.

11.) Edward Jenner and the eradication of smallpox.

12.) Cowpox: a re-evaluation of the risks of human cowpox based on new epidemiological information.

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

14.) [Smallpox: an historical review].

15.) Academic surgeons, take heart: the story of a student, his mentor, and the discovery of the etiology of angina pectoris.

16.) The Jenner bicentenary: the introduction and early distribution of smallpox vaccine.

17.) The smallpox saga and the origin(s) of vaccination.

18.) Measuring success in clinical gene therapy research.

19.) [Jenner's cowpox vaccine in light of current vaccinology].

20.) Controlling orthopoxvirus infections--200 years after Jenner's revolutionary immunization.

21.) Traditional methods used for controlling animal diseases in Iran.

22.) Smallpox: emergence, global spread, and eradication.

23.)Gordon memorial lecture. Vaccines and vaccination--past, present and future.

24.) New approaches in viral vaccine development.

25.) The global eradication of smallpox.

26.) [The world is free of pox - Implementation and success of a grandiose program].

27.) Farewell to smallpox vaccination.

28.) [Smallpox vaccine, then and now. From the "cow lymphe" to the cell-culture vaccine].

29.) Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infections.

30.) Global health strategies versus local primary health care priorities--a case study of national immunisation days in Southern Africa.

31.) Are Saudi Arabian hospitals prepared for the threat of biological weapons?

32.) [Smallpox in Telemark in the last part of the 19th century].

33.) Monkeypoxvirus infections.

34.) [Bioterrorism--a public and health threat].

35.) Ensuring vaccine safety in immunization programmes--a WHO perspective.

36.) The threat of smallpox and bioterrorism.

37.) Inmmune response to vaccinia virus is significantly reduced after scarification with TK- recombinants as compared to wild-type virus.

38.) Aeromedical evacuation of biological warfare casualties: a treatise on infectious diseases on aircraft.

39.) An emergent poxvirus from humans and cattle in Rio de Janeiro State: Cantagalo virus may derive from Brazilian smallpox vaccine.

40.) [20 years without smallpox].

Epidemiol Mikrobiol Imunol 2000 Aug;49(3):95-102 Related 

41.) [Circulation of virus and interspecies contamination in wild animals].

============================================================= 

============================================================= 

1.) Edward Jenner and the Discovery of Vaccination

============================================================= 

originally exhibited spring 1996

Thomas Cooper Library, University of South Carolina 

text by Patrick Scott

hypertext by Jason A. Pierce

Edward Jenner

Introduction 

-------------

The year 1996 marked the two hundredth anniversary of Edward Jenner's first experimental vaccination--that is, inoculation with the related cow-pox virus to build immunity against the deadly scourge of smallpox. 

Edward Jenner (1749-1823), after training in London and a period as an army surgeon, spent his whole career as a country doctor in his native county of Gloucestershire in the West of England. His research was based on careful case-studies and clinical observation more than a hundred years before scientists could explain the viruses themselves. So successful did his innovation prove that by 1840 the British government had banned alternative preventive treatments against smallpox. "Vaccination," the word Jenner invented for his treatment (from the Latin vacca, a cow), was adopted by Pasteur for immunization against any disease. 

In the eighteenth century, before Jenner, smallpox was a killer disease, as widespread as cancer or heart disease in the twentieth century but with the difference that the majority of its victims were infants and young children. In 1980, as a result of Jenner's discovery, the World Health Assembly officially declared "the world and its peoples" free from endemic smallpox. 

Note the background view of Berkeley, in Gloucestershire, where Jenner carried out his original vaccinations, with milkmaid and cow on show. Mezzotint by John Raphael Smith, from his pastel portrait exhibited at the Royal Academy in 1800, reproduced from W. R. Le Fanu, A bio-bibliography of Edward Jenner 1749-1823, London: Harvey and Blythe, 1951. 

Edward Jenner, M.D., F.R.S.

An inquiry into the causes and effects of the Variolae Vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire, and known by the name of the cow-pox

Third edition. London: printed for the author by D. N. Shury, 1801. 

Jenner's Inquiry, first published in 1798, reported how, over a period of years, he had noticed the immunity provided by cow-pox, and how he decided deliberately to introduce the disease into a patient to see if the effect could be artificially produced. Soon afterwards, he would again inoculate his patients, this time with live smallpox virus ("variolation"), to see if the cow-pox had worked. The "healthy boy" whom Jenner, on May 14 1796, first vaccinated with virus from the dairymaid Sarah Nelmes was James Phipps, who proved Jenner's point by surviving repeated unsuccessful attempts to infect him with smallpox. 

Case XI: William Stinchcomb 

Part of Jenner's argument in the Inquiry was built up from cases like this one, recording Jenner's failure to inoculate or infect with small-pox itself ("variolate") a farmworker who some years before has caught a bad case of the cow-pox. 

William Woodville, M.D., 1752-1805

Reports of a series of inoculations for the variolae vaccinae, or cow-pox; with remarks and observations on this disease, considered as a substitute for the small-pox

London: James Philips, 1799. 

Soon after the publication of Jenner's case-studies, William Woodville carried out much more extensive trials of vaccination among patients in London. Woodville was Director of London Smallpox and Inoculation Hospital, and he kept detailed records on several thousand patients. Woodville, like Jenner himself, had close ties to Sir Joseph Banks, the influential long-time president of the Royal Society, and his support for vaccination was of great importance to its acceptance. As the cases shown here indicate, however, many of Woodville's inoculees developed the characteristic pustules across the body of genuine smallpox, and the "vaccine" used for his trials may in fact have been contaminated. 

Samuel L. Mitchill, 1764-1831, ed.

The Medical Repository of original essays and intelligence relative to physic, surgery, chemistry and natural history.

New series, volume 1. New York: John Forbes, 1813. 

An early American report on the inroads that vaccination rapidly made on disease rates in London, even with poorly-controlled vaccine sources. 

Christian Charles Schieferdecker, M.D.

Dr. C. G. G. Nittinger's Evils of Vaccination.

Philadelphia: the editor, 1856. 

Because of the lack of clear scientific explanation of its effects, the frequent side-effects, and contaminated vaccines, vaccination itself remained controversial throughout the nineteenth century. It certainly carried risks for the infants being vaccinated, and this volume, playing on parental fears, argued, inter alia, that vaccination was nonsensical, unscientific, criminal, and even sinful. Shown here is a satiric vignette of a protective mother's discussion with the family doctor. 

============================================================= 

2.) Vaccines in historic evolution and perspective: a narrative of vaccine discoveries.

============================================================= 

J Hum Virol 2000 Mar-Apr;3(2):63-76 

Hilleman MR.

Merck Institute for Therapeutic Research, Merck Research Laboratories, West Point, PA 19486, USA.

The sciences of vaccinology and immunology were created only two centuries ago by Jenner's scientific studies of prevention of smallpox through inoculation with cowpox virus. This rudimentary beginning was expanded greatly by the giants of late 19th- and early 20th-century biomedical sciences. The period from 1930 to 1950 was a transitional era, with the introduction of chick embryos and minced tissues for propagating viruses and rickettsiae in vitro for vaccines. Modern vaccinology began about 1950 as a continuum following notable advances made during the 1940s and World War II. Its pursuit has been based largely on breakthroughs in cell culture, bacterial polysaccharide chemistry, molecular biology, and immunology which have yielded many live and killed viral and bacterial vaccines plus the recombinant-expressed hepatitis B vaccine. The present paper was presented as a lecture given at a Meeting of the Institute of Human Virology entitled A Symposium on HIV-AIDS and Cancer Biology, Baltimore, Maryland, on August 30, 1999 and recounts, by invitation, more than 55 years of vaccine research from the venue of personal experience and attainment by the author. The paper is intentionally brief and truncated with focus only on highlights and limited referencing. Detailed recounting and referencing are given elsewhere in text references 1 and 2. This narration will have achieved its purpose if it provides a background of understanding and guidelines that will assist others who seek to engage in creation of new vaccines.

============================================================= 

2.) Montagu's variolation.

============================================================= 

Endeavour 2000;24(1):4-7 

Grundy I.

Arts Faculty, University of Alberta, Canada.

Lady Mary Wortley Montagu is sometimes mentioned by both medical and literary historians as the introducer to England of smallpox inoculation. Usually, the story is garbled by confusion with Edward Jenner's later invention, vaccination. Some historians have rejected her claim, arguing that the credit belongs to the medical establishment of the day. So just how much importance has this gifted amateur in the story of medical science?

============================================================= 

3.) [Pharmaceutical development concerning diseases predominating in tropical regions: the concept of indigent drugs].

============================================================= 

Ann Pharm Fr 2000 Jan;58(1):43-6 

[Article in French]

Trouiller P, Rey JL, Bouscharain P.

Centre Hospitalier Universitaire de Grenoble, BP 217, F38043 Grenoble Cedex 9.

When the WHO certified the eradication of smallpox in 1981, there was a general impression that the fight against infectious diseases which began with Jenner and Pasteur was entering a phase of achievement: poliomyelitis, dracunculasis, leprosy, Chagas' disease and neonatal tetanus were also responding to eradication campaigns. However, in 1995, infectious diseases are still an important cause of mortality and morbidity and the rising incidence of emerging or re-emerging diseases remains a matter of great concern. Although this situation can be explained, at least partly, by the deterioration of health care systems and diverse socio-economic and ecological disorders, important changes occurring in the drug industry since 1980 have also played a role due to changes in pharmaco-epidemiology and new policies of drug development. Among the 1061 new drugs developed from 1975 to 1994, less than 2.7% concern tropical diseases. Since praziquantel, novel drugs have issued from veterinary medicine (ivermectin), military research (halofantrine, mefloquine) or fortuitous analysis of pharmacopoeia (artesunate). The cost of investments and the lack of market potential and market security in developing countries have dampened interest in developing drugs for tropical diseases. Observing the combined effect of deficient pharmaceutical development, drug wear due to chemoresistance (chloroquine, sulfadoxine-pyrimethamine, aminopenicillins), the cost barrier (second generation molecules) and the potential abandon of major drugs (eflornithine, melarsoprol) has led us to establish a classification of these "indigent" drugs (in opposition to "orphan" drugs) into five classes: true indigent drugs (eflornithine), indigent drugs by indication (pentamidine), indigent drugs by function (ceftriaxone), indigent drugs by formulation (melarsoprol) and indigent drugs by default (suramin). This analysis can serve as a basis for a search for solutions (regulatory, administrative and financial incentives) favoring a reactivation of drug development for diseases predominating in intertropical regions.

============================================================= 

4.) Smalllpox and its control in Canada.

============================================================= 

CMAJ 1999 Dec 14;161(12):1543-7 

McIntyre JW, Houston CS.

University of Alberta, Edmonton, Alta.

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.

============================================================= 

5.) Vaccines in historic evolution and perspective: a narrative of vaccine discoveries.

============================================================= 

Vaccine 2000 Feb 14;18(15):1436-47 

Hilleman MR.

Merck Institute for Therapeutic Research, Merck Research Laboratories, West Point, PA 19486, USA.

The sciences of vaccinology and of immunology were created just two centuries ago by Jenner's scientific studies of prevention of smallpox through inoculation with cowpox virus. This rudimentary beginning was expanded greatly by the giants of late 19th and early twentieth centuries biomedical sciences. The period from 1930 to 1950 was a transitional era with the introduction of chick embryos and minced tissues for propagating viruses and Rickettsiae in vitro for vaccines. Modern era vaccinology began about 1950 as a continuum following notable advances made during the 1940s and World War II. Its pursuit has been based largely on breakthroughs in cell culture, bacterial polysaccharide chemistry, molecular biology and immunology, which have yielded many live and killed viral and bacterial vaccines plus the recombinant-expressed hepatitis B vaccine.The present paper was presented as a lecture given(1) on August 30, 1999 and recounts, by invitation, more than five-and-half decades of vaccine research from the venue of personal experience and attainment by the author. The paper is intentionally brief and truncated with focus only on highlights and limited referencing. Detailed recounting and referencing are given elsewhere in text references [Hilleman MR. Six decades of vaccine development - a personal history. Nat. Med. 1998;4 (Vaccine Suppl.): 507-14] and [Hilleman MR. Personal historical chronicle of six decades of basic and applied research in virology, immunology and vaccinology. Immunol. Rev. (in press)]. This narration will have achieved its purpose if it provides a background of understanding and guidelines that will assist others who seek to engage in creation of new vaccines.

============================================================= 

6.) Production of recombinant subunit vaccines: protein immunogens, live delivery systems and nucleic acid vaccines.

============================================================= 

J Biotechnol 1999 Jul 30;73(1):1-33 

Liljeqvist S, Stahl S.

Department of Biotechnology, Royal Institute of Technology (KTH), Stockholm, Sweden.

The first scientific attempts to control an infectious disease can be attributed to Edward Jenner, who, in 1796 inoculated an 8-year-old boy with cowpox (vaccinia), giving the boy protection against subsequent challenge with virulent smallpox. Thanks to the successful development of vaccines, many major diseases, such as diphtheria, poliomyelitis and measles, are nowadays kept under control, and in the case of smallpox, the dream of eradication has been fulfilled. Yet, there is a growing need for improvements of existing vaccines in terms of increased efficacy and improved safety, besides the development of completely new vaccines. Better technological possibilities, combined with increased knowledge in related fields, such as immunology and molecular biology, allow for new vaccination strategies. Besides the classical whole-cell vaccines, consisting of killed or attenuated pathogens, new vaccines based on the subunit principle, have been developed, e.g. the Hepatitis B surface protein vaccine and the Haemophilus influenzae type b vaccine. Recombinant techniques are now dominating in the strive for an ideal vaccine, being safe and cheap, heat-stable and easy to administer, preferably single-dose, and capable of inducing broad immune response with life-long memory both in adults and in infants. This review will describe different recombinant approaches used in the development of novel subunit vaccines, including design and production of protein immunogens, the development of live delivery systems and the state-of-the-art for nucleic acids vaccines.

============================================================= 

7.) [Two hundred years ago: the first smallpox vaccinations in Vienna].

============================================================= 

Wien Klin Wochenschr 1999 Apr 23;111(8):299-306 

[Article in German]

Katscher F.

The first successful smallpox vaccination with cowpox lymph outside of England was carried out in Vienna--only ten months after the publication of Edward Jenner's book "An Inquiry into the Causes and Effects of the Variolae Vaccinae, a Disease ... known by the Name of the Cow Pox", and only a little more than three months after the first vaccinations in London: Two hundred years ago, on 30 April 1799, the medical service chief of Lower Austria, Dr. Paskal Joseph Ferro, born in Bonn, vaccinated his three children with vaccine which had come in a letter from London. Subsequently the vaccination was introduced in Austria. Before 1800 effective prophylactic immunizations against smallpox were carried out, apart from England, only in Vienna and environs. The first efficient vaccine to reach India also came from Vienna.

============================================================= 

8.) Edward Jenner's Inquiry; a bicentenary analysis.

============================================================= 

Vaccine 1999 Jan 28;17(4):301-7 

Department of Medical Microbiology and Genitourinary Medicine, University of Liverpool, UK.

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.

============================================================= 

9.) The myth of the medical breakthrough: smallpox, vaccination, and Jenner reconsidered.

============================================================= 

Int J Infect Dis 1998 Jul-Sep;3(1):54-60 Related Articles, Books, LinkOut 

Gross CP, Sepkowitz KA.

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

A discussion of the particulars leading to the eradication of smallpox is pertinent to both investigators and the public as the clamor for more "breakthroughs" intensifies. The rational allocation of biomedical research funds is increasingly threatened by disease-advocacy groups and congressional earmarking. An overly simplistic view of how advances truly occur promises only to stunt the growth of researchers and research areas not capable of immediate great breakthroughs. The authors review the contributions of Jenner and his countless predecessors to give a more accurate account of how "overnight medical breakthroughs" truly occur-through years of work conducted by many people, often across several continents. In the public eye, few achievements are regarded with such excitement and awe as the medical breakthrough. Developments such as the discovery of penicillin and the eradication of polio and smallpox have each become a great story built around a singular hero. Edward Jenner, for example, is credited with discovering a means of safely conferring immunity to smallpox. The success of vaccination and subsequent eradication of this disease elevated Jenner to a status in medical history that is rivaled by few. However, the story of the eradication of smallpox does not start or end with the work of Jenner. Men such as Benjamin Jesty and Reverend Cotton Mather as well as unnamed physicians from tenth century China to eighteenth century Turkey also made critical contributions to the crowning achievement. Inoculation to prevent smallpox was commonplace in Europe for generations prior to Jenner's work. Jenner himself was inoculated as a child. In fact, vaccination with cowpox matter was documented in England over 20 years prior to Jenner's work. The authors' review of primary and secondary sources indicates that although Jenner's contribution was significant, it was only one of many. It is extremely rare that a single individual or experiment generates a quantum leap in understanding; this "lone genius" paradigm is potentially injurious to the research process. Wildly unrealistic expectations can only yield unsuccessful scientific investigation, but small steps by investigators supported by an informed public can build toward a giant leap, as the story of smallpox eradication clearly demonstrates.

============================================================= 

10.) Smallpox: gone but not forgotten.

============================================================= 

Infection 1998 Sep-Oct;26(5):263-9 Related Articles, Books 

Ellner PD.

Dept. of Microbiology, Columbia University, College of Physicians and Surgeons, New York, NY, USA.

Smallpox represents both the acme of man's efforts to combat infectious diseases and one of his greatest fears. The disease emerged in prehistoric times to spread throughout the world causing blindness and death in millions of people. An acute infection caused by variola virus, one of the Orthopoxviruses, with skin eruption and marked toxemia had an average case fatality rate of 30%. Variola minor, a milder form of the disease, had a case fatality of one percent. Humans are the sole host, and survival confers lifelong immunity. Immunization was practiced since ancient times by inoculation with the variola virus until Jenner's demonstration of the efficacy and safety of vaccination with vaccinia virus. Following an intensive eradication effort by the World Health Organization, the world was declared to be free of smallpox in 1979. The decision to destroy all remaining stocks of variola virus in 1999 has met with some controversy.

============================================================= 

11.) Edward Jenner and the eradication of smallpox.

============================================================= 

Scott Med J 1997 Aug;42(4):118-21 Related Articles, Books 

Willis NJ.

Ninewells Hospital and Medical School University of Dundee.

Edward Jenner's careful investigations into the usefulness of cowpox vaccination for the prevention of smallpox during the late 1790s, and his enthusiastic and continued advocation of vaccination despite the scepticism of critics, laid the foundations for the growth of understanding about the nature of infectious disease and the development of immunity during the 19th century. He began the long process which resulted in the successful eradication of the smallpox virus in 1980. His life story remains an inspiration to physicians facing an uncertain future as viruses and bacteria not yet eradicated adapt to the antibiotic age.

============================================================= 

12.) Cowpox: a re-evaluation of the risks of human cowpox based on new epidemiological information.

============================================================= 

Arch Virol Suppl 1997;13:1-12 

Baxby D, Bennett M.

Alder Hey Childrens' Hospital, Liverpool, U.K.

Human cowpox is a rare but relatively severe infection of interest because of its links with Edward Jenner and the introduction of smallpox vaccine and, more recently, because of re-evaluation of the epidemiology of the infection. This indicates that cowpox is not enzootic in cattle, relegates the cow to a minor role, and emphasizes the importance of feline cowpox as a source of human infection and of wildlife as virus reservoirs. The evidence available suggests that the virus is of low infectivity for humans and should not become an increasing problem despite the cessation of smallpox vaccination and increasing numbers of immunocompromised individuals.

============================================================= 

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

============================================================= 

Ann Intern Med 1997 Oct 15;127(8 Pt 1):635-42 

Erratum in: 

Ann Intern Med 1998 May 1;128(9):787 

Comment in: 

Ann Intern Med. 1998 May 1;128(9):784-5 

Ann Intern Med. 1998 May 1;128(9):784; discussion 785 

Barquet N, Domingo P.

Centre d'Assistencia Primaria Gracia, Institut Catala de la Salut, Barcelona, Spain.

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.

============================================================= 

14.) [Smallpox: an historical review].

============================================================= 

Bull Soc Sci Med Grand Duche Luxemb 1997;134(1):31-51 

[Article in German]

Theves G.

Administration des Services Veterinaires, Luxembourg.

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.

============================================================= 

15.) Academic surgeons, take heart: the story of a student, his mentor, and the discovery of the etiology of angina pectoris.

============================================================= 

Am Surg 1996 Dec;62(12):1076-9 

Manders EC, Manders EK.

Division of Plastic Surgery, The Pennsylvania State University and The Milton S. Hershey Medical Center, Hershey 17033, USA.

Edward Jenner is renowned for developing a vaccination for smallpox. He trained as a surgeon and was an ardent anatomist and naturalist. Part of his formal training was directed by John Hunter, the father of scientific surgery. Jenner diagnosed Hunter as suffering from angina pectoris and correctly identified the cause of angina pectoris from a series of autopsies he conducted. After Hunter died during an altercation in committee, his postmortem examination proved Jenner correct. Jenner can be recognized as the first to correctly ascribe the etiology of angina pectoris to coronary atherosclerosis.

============================================================= 

16.) The Jenner bicentenary: the introduction and early distribution of smallpox vaccine.

============================================================= 

FEMS Immunol Med Microbiol 1996 Nov;16(1):1-10 Related Articles, Books 

Baxby D.

Department of Medical Microbiology, Liverpool University, UK.

This review describes the background to Jenner's first vaccination, his later work, and the dissemination of information about vaccination and the vaccine itself. Although based on relatively slender evidence, Jenner's theories were basically sound and he merits the credit given him. Given the circumstances, particularly the slow speed of travel and the lack of information about the duration of immunity, vaccination became established very quickly in many countries.

============================================================= 

17.) The smallpox saga and the origin(s) of vaccination.

============================================================= 

J R Soc Health 1996 Aug;116(4):253-5 Related Articles, Books 

Cook GC.

Hospital for Tropical Diseases, London.

Two hundred years ago--in May 1796--Edward Jenner carried out a pioneering feat in the history of "clinical investigation' which not only paved the way for the eventual elimination of one of the world's most terrifying infections (variola), but also heralded widespread vaccination campaigns and the foundation of the discipline of clinical immunology. Vaccination superseded the formerly used technique of variolation which had been introduced into England by Lady Mary Wortley Montague. Under-recognised is the fact that the first clinical trial(s) of this new development were carried out under the supervision of William Woodville at the St Pancras Smallpox Hospital (situated at Battle Bridge--now King's Cross); this work was crucially important in the 'vaccination saga' and deserves far greater acceptance than is currently the case.

============================================================= 

18.) Measuring success in clinical gene therapy research.

============================================================= 

Mol Med Today 1996 Jun;2(6):234-6 

Culver KW.

Oncor Pharm, Inc., Gaithersburg, MD 20877, USA. kculver@oncorpharm.com

Medical science is a compelling career choice, filled with the thrill of discovery, joy of learning and a meaningful purpose to lessen human suffering. These benefits and rewards of laboratory and clinical research accumulate in an asynchronous, irregular, and incremental mechanism, euphemistically known as the scientific method. Ultimate success in clinical research is the elusive 'cure'. But in progress towards that goal, success is also measured first as the 'absence of doing harm', and then by various stages of efficacy. Perhaps only in the case of smallpox has medicine achieved total 'victory'; it is now exactly 200 years since Jenner's first clinical trial.

============================================================= 

19.) [Jenner's cowpox vaccine in light of current vaccinology].

============================================================= 

Verh K Acad Geneeskd Belg 1996;58(5):479-536; discussion 537-8 

[Article in Dutch]

Huygelen C.

Two hundred years ago Edward Jenner inoculated James Phipps with vaccinia and 181 years later smallpox had disappeared from the surface of the earth as a result of generalized vaccination. Compared to the requirements of modern vaccinology, the procedures used by Jenner and his successors, were extremely primitive because of an almost total lack of knowledge in the field of microbiology and immunology. The active principle of smallpox vaccine is vaccinia virus, which in many respects, differs from that of natural cowpox; the term "cowpox" has been used for more than a century and a half to designate the vaccine; it appears itself to be a misnomer, because it is most probably by a virus of rodents, which only occasionally infects bovines or other species, especially cats. The origin of vaccinia remains doubtful, but a plausible explanation is that it is derived from horse-pox. Jenner was convinced that he was working with a virus of equine origin, which was occasionally transmitted from the horse to the cow by the personnel on the farms. Horse pox has now completely disappeared. Especially during the first years after Jenner's discovery, great confusion was caused by other lesions on the cow's udder, which were called "spurious cowpox". We know today that these lesions could be caused by the viruses of papular stomatitis, pseudo-cowpox or para-vaccinia (milker's nodules), herpes mammilitis and papillomatosis; they could not be differentiated from those of cowpox or vaccinia, in addition lesions due to bacteria or other causes also led to confusion. During the first eighty years the vaccine was being transferred almost exclusively from arm to arm with the risks inherent in this procedure; one of the reasons for applying this method was the fear of "bestialization" thought to be linked with the use of material of animal origin. Several contaminations have been observed as a result of the use of the arm-to-arm procedure: smallpox was transmitted, especially in the beginning, because vaccinations were carried out in a contaminated environment. Syphilis was diagnosed in several countries after the use of vaccine taken from syphilis patients. At least two foci of hepatitis were reported after the use of contaminated human lymph. Transmission of tuberculosis or what was then designated as scrofulosis was unlikely, but was used as one of the main arguments against vaccination by the antivaccinists. Varicella and measles were transmitted from time to time with the vaccine and also bacterial infections, such as staphylococci, streptococci e.a. From the global point of view, however, the number of contaminations remained limited in comparison with the large numbers of vaccinations that were performed. Another problem the early vaccinators were facing, was that of the decline and disappearance of the immunity after a certain number of years. Jenner and his successors believed that the immunity post vaccination would be lifelong as it was after variolation. When in the early part of the 19th century more and more immunity breakdowns occurred, this observation led to total confusion and it took dozens of years of debate and controversy before the only logical and efficacious measure, i.e. revaccination, was generally accepted and implemented. In the last third of the 19th century "human lymph", obtained by arm-to-arm vaccination, was gradually replaced everywhere by animal lymph i.e. vaccine produced on the skin of animals, mainly calves. The determining factor in the switch was the risk of vaccination syphilis. Everywhere vaccine institutes were created, where the vaccinia virus was propagated on the skin of calves. The harvested virus served each time for the inoculation of fresh calves; this resulted in a gradual increase of the number of passages leading to the possible risk of overattenuation. To avoid this risk, passages in man, donkeys, rabbits or other species were performed from time to time.

============================================================= 

20.) Controlling orthopoxvirus infections--200 years after Jenner's revolutionary immunization.

============================================================= 

Arch Immunol Ther Exp (Warsz) 1996;44(5-6):373-8 

Niemialtowski MG, Toka FN, Malicka E, Gierynska, Spohr de Faundez I, Schollenberger A.

Department of Microbiology and Immunology, Faculty of Veterinary Medicine, Warsaw Agricultural University, Poland.

An 11-year global WHO campaign for eradication of smallpox finished in October 1977 as the result of Edward Jenner's primary success in 1796, who for the first time applied human vaccination against variola virus (VARV). The 200th anniversary of this happening is a good occasion to summarize the current status of the knowledge about the role of B and T lymphocytes in the control of orthopoxvirus infections. This short review concentrates on general characteristics of orthopoxviruses and the immune response to infection, mainly by vaccinia virus (VV) and ectromelia virus (EV).

============================================================= 

21.) Traditional methods used for controlling animal diseases in Iran.

============================================================= 

Rev Sci Tech 1994 Jun;13(2):599-614 Related Articles, Books 

Tadjbakhsh H.

Tehran University, Iran.

In ancient times in Iran, infectious diseases of animals and human beings were referred to as choleraic diseases. Rhazes (9th century), followed by Avicenna (10th century), Jorjani (11th century) and others, had specific opinions on the cause and effect relationship in these diseases, which recall the fermentation theory of Louis Pasteur. In ancient Iran, the methods adopted for veterinary procedures were those of general theoretical and practical medicine, including the humoral theory, accurate diagnosis, signs and symptoms, and the prescription of herbal and mineral medicines or substances of animal origin. If herbal treatment failed, cauterisation and surgery were used. When refractory and contagious infectious diseases occurred, animals were evacuated from the infected region, in order to preserve their health, with resort to the mercy of Allah (God) as a final remedy. Iranian scientists of ancient times had interesting views on rabies. A kind of serotherapy was used for treating persons bitten by rabid dogs. Vaccination was performed many centuries ago by using dried smallpox lesions. In Baluchistan (Iran), infants were encouraged to play with and touch the teats of cows affected with cowpox, in order to immunise the children against smallpox, and this was centuries before the discovery of smallpox vaccine by Edward Jenner. Camelpox was also used for human immunisation. In the case of caprine pleuropneumonia, an extract or juice was obtained from the lungs of affected animals and was inactivated by treatment with certain herbal medicines which had a disinfectant effect. A thread coated with this extract was passed through the ear of healthy goats to render them immune. The author lists various diseases and their treatment. This work forms part of detailed research by the author with reference to some 2,200 books and many ancient manuscripts on the history of veterinary science in Iran.

============================================================= 

22.) Smallpox: emergence, global spread, and eradication.

============================================================= 

Pubbl Stn Zool Napoli II 1993;15(3):397-420 

Fenner F.

John Curtin School of Medical Research, Australian National University, Canberra.

Speculatively, it is suggested that variola virus, the cause of smallpox, evolved from an orthopoxvirus of animals of the central African rain forests (possibly now represented by Tatera poxvirus), some thousands of years ago, and first became established as a virus specific for human beings in the dense populations of the Nile valley perhaps five thousand years ago. By the end of the first millennium of the Christian era, it had spread to all the densely populated parts of the Eurasian continent and along the Mediterranean fringe of north Africa. It became established in Europe during the times of the Crusades. The great voyages of European colonization carried smallpox to the Americas and to Africa south of the Sahara. Transported across the Atlantic by Europeans and their African slaves, it played a major role in the conquest of Mexico and Peru and the European settlement of north America. Variolation, an effective preventive inoculation, was devised as early as the tenth century. In 1798 this practice was supplanted by Jenner's cowpox vaccine. In 1967, when the disease was still endemic in 31 countries and caused ten to fifteen million cases and about two million deaths annually, the World Health Organization embarked on a programme that was to see the disease eradicated globally just over ten years later, and the world was formally declared to be free of smallpox in May 1980. Smallpox is unique--a specifically human disease that emerged from some animal reservoir, spread to become a worldwide, severe and almost universal affliction, and finally underwent the reverse process to emergence, namely global eradication.

============================================================= 

23.)Gordon memorial lecture. Vaccines and vaccination--past, present and future.

============================================================= 

Br Poult Sci 1990 Mar;31(1):3-22 

Biggs PM.

Willows, Huntingdon, Cambridgeshire, England.

1. Immunisation was first practised as early as the 10th century when small doses of smallpox material administered by unusual routes were used to immunise against smallpox. The procedure was introduced into England in the early part of the 18th century. 2. The next major development was the use by Jenner of cowpox to vaccinate against smallpox in the late 18th century. 3. Some eighty years later came the classic studies of Pasteur developing vaccines for fowl cholera, anthrax and rabies. 4. The studies of Jenner and Pasteur established the major principles of vaccination which are in use to this day. 5. The major viral diseases of the domestic fowl were recognised during the 1920s and 1930s and in most cases vaccines were developed within 5 years of the discovery of the viral nature of the cause of each disease. 6. The desirable properties of poultry vaccines required by the user and producer are not completely fulfilled by currently available vaccines. 7. There is a need to use the opportunities provided by modern biotechnology and immunology to search for and develop vaccines that better fulfil the desirable properties of poultry vaccines. 8. There are a number of strategies available for the development of novel vaccines, some of which are appropriate for the needs of poultry vaccines.

============================================================= 

24.) New approaches in viral vaccine development.

============================================================= 

Scand J Infect Dis Suppl 1990;76:39-46 

Brown F.

Department of Virology, Wellcome Biotechnology Ltd, Beckenham, Kent, U.K.

With the exception of the vaccine against hepatitis B the principles involved in the production of the viral vaccines in use today have not changed since Jenner (1) first developed the vaccine which was so important in the control and eventual eradication of smallpox in 1977. All have relied on the presentation of the live attenuated or inactivated virus to the host, either orally or by injection, so that it elicited the formation of antibody and primed memory cells for a rapid response to the subsequent invasion of the virus. With the discovery that protective immunity could be obtained with isolated individual proteins from virus particles and the development of methods for the expression of these proteins, both in vivo and in vitro, there is now considerable promise that immunity can be induced without the need to use the disease agent itself. Moreover, the molecular basis of the immune response is now beginning to be understood, thus allowing a more rational approach to the design of vaccines for individual diseases.

============================================================= 

25.) The global eradication of smallpox.

============================================================= 

Am J Infect Control 1982 May;10(2):53-9 

Strassburg MA.

On May 8, 1980, the 33rd World Health Assembly declared the world free of smallpox. This followed approximately 2 1/2 years after the last documented naturally occurring case of smallpox was diagnosed in a hospital worker in Merca, Somalia. A major breakthrough for the eventual control of this disease was the discovery of an effective vaccine by Edward Jenner in 1796. In 1966 the World Health Assembly voted a special budget to eliminate smallpox from the world. At that time, smallpox was endemic in more than 30 countries. Mass vaccination programs were successful in many Western countries; however, a different approach was taken in developing countries. This approach was known as surveillance and containment. Surveillance was aided by extensive house-to-house searches and rewards offered for persons reporting smallpox cases. Containment measures included ring vaccination and isolation of cases and contacts. Hospitals played a major role in transmission in a number of smallpox outbreaks. The World Health Organization is currently supporting several control programs and has not singled out another disease for eradication. The lessons learned from the smallpox campaign can be readily applied to other public health programs.

============================================================= 

26.) [The world is free of pox - Implementation and success of a grandiose program].

============================================================= 

Z Gesamte Inn Med 1980 Dec 15;35(24):858-63 Related Articles, Books 

[Article in German]

Dittmann S.

At the beginning of this century the compulsory vaccination and revaccination which was legally founded after the introduction of the vaccination by Jenner (1796) led to the removal of the smallpox in Europe and Northern America. However, up to the sixties in the developing countries of Asia, Africa as well as of Southern America and Middle America still fell ill and died of small-pox millions of people. Between 1953 and 1973 importations into countries of Europe and Northern America took place in 51 cases. In 1959 on the motion of the USSR the WHO decided performance of a world-wide eradication programme of small-pox which could be led to success with comprehensive personal, material and financial support of many countries. Flanking scientific, technological and methodical measures were of essential importance. In May 1980 the World Health Assembly in Geneva announced in solemn form the world-wide eradication of the small-pox and gave recommendations to the member countries for concluding measures concerning the small-pox vaccination, the foundation of vaccine reserves and the control of the epidemiological situation in the world. Also in the GDR the small-pox vaccination in childhood could be abolished.

============================================================= 

27.) Farewell to smallpox vaccination.

============================================================= 

Dev Biol Stand 1979;43:283-96 Related Articles, Books, LinkOut 

Arita I.

Man's first attempt to immunize susceptibles against smallpox infection was by variolation, a practice which could be traced back several thousand years. The attempt obviously failed to control the disease until Jenner discovered the effectiveness of cowpox vaccine during the late 18th century. However, it took an additional 180 years until the current smallpox vaccine--a modification of Jenner's vaccine--became fully effective, in terms of quality and usage during the global smallpox eradication campaign. The campaign appears to be on the threshold of success, which could well mean extinction of one of the most dangerous pathogens from the natural environment. If this is verified, we may say farewell to routine smallpox vaccination. The paper discusses different measures taken to ensure the quality and the use of smallpox vaccine in the best possible manner during the eradication campaign and, on its completion, the fate of smallpox vaccination.

============================================================= 

28.) [Smallpox vaccine, then and now. From the "cow lymphe" to the cell-culture vaccine].

============================================================= 

Fortschr Med 1977 Jan 13;95(2):79-84 Related Articles, Books 

[Article in German]

Hochstein-Mintzel V.

There have been few changes in the preparation of smallpox vaccine since Eduard Jenner described his method of preventive inoculation in 1798. Jenner's vaccine, "the matter", was maintained in man by arm to arm passage. The only major achievement in production methods was the introduction of an animal host for virus propagation. The skin of living calves or sheep was inoculated with seed virus and the "pulp" harvested three to four days later. The disadvantages of this procedure are evident: massive bacterial contamination in spite of rigorous cleanliness and excessive amounts of undesired tissue debris in the crude material to be used for vaccine production. In spite of these obvious disadvantages the method is still in use all over the world. Advances in tissue culture techniques have led to the production of all modern vaccines for use in animals and in the human from this substrate with low initial content of foreign protein and of primary sterility. The only exception today is conventional smallpox vaccine. Sporadic attempts to produce smallpox vaccine in tissue culture have been recently and successfully made in England, Holland and Yugoslavia. The Bavarian State Institute of Vaccination has adopted Vaccinia strain Elstree to primary cultures of chick embryo fibroblasts. The virus propagation in roller bottles permits the economical production of a high titered vaccine with a stability equal to that of calf origin. The cell culture harvest is bacteriologically steril and has a minimal content of foreign protein. Within the past two years this cell culture vaccine has totally replaced the old "calf lymph". Vaccination takes are equal, complications have so far not come to our attention.

============================================================= 

29.) Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infections.

============================================================= 

Clin Microbiol Rev 2001 Apr;14(2):382-97 

De Clercq E.

Division of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, K.U. Leuven, B-3000 Leuven, Belgium.

Poxviruses continue to pose a major threat to human health. Monkeypox is endemic in central Africa, and the discontinuation of the vaccination (with vaccinia virus) has rendered most humans vulnerable to variola virus, the etiologic agent of smallpox, should this virus be used in biological warfare or terrorism. However, a large variety of compounds have been described that are potent inhibitors of vaccinia virus replication and could be expected to be active against other poxviruses as well. These compounds could be grouped in different classes: (i) IMP dehydrogenase inhibitors (e.g., EICAR); (ii) SAH hydrolase inhibitors (e.g., 5'-noraristeromycin, 3-deazaneplanocin A, and various neplanocin A derivatives); (iii) OMP decarboxylase inhibitors (e.g., pyrazofurin) and CTP synthetase inhibitors (e.g., cyclopentenyl cytosine); (iv) thymidylate synthase inhibitors (e.g., 5-substituted 2'-deoxyuridines); (v) nucleoside analogues that are targeted at viral DNA synthesis (e.g., Ara-A); (vi) acyclic nucleoside phosphonates [e.g., (S)-HPMPA and (S)-HPMPC (cidofovir)]; and (vii) polyanionic substances (e.g., polyacrylic acid). All these compounds could be considered potential candidate drugs for the therapy and prophylaxis of poxvirus infections at large. Some of these compounds, in particular polyacrylic acid and cidofovir, were found to generate, on single-dose administration, a long-lasting protective efficacy against vaccinia virus infection in vivo. Cidofovir, which has been approved for the treatment of cytomegalovirus retinitis in immunocompromised patients, was also found to protect mice, again when given as a single dose, against a lethal aerosolized or intranasal cowpox virus challenge. In a biological warfare scenario, it would be advantageous to be able to use a single treatment for an individual exposed to an aerosolized poxvirus. Cidofovir thus holds great promise for treating human smallpox, monkeypox, and other poxvirus infections. Anecdotal experience points to the efficacy of cidofovir in the treatment of the poxvirus infections molluscum contagiosum and orf (ecthyma contagiosum) in immunosuppressed patients.

============================================================= 

30.) Global health strategies versus local primary health care priorities--a case study of national immunisation days in Southern Africa.

============================================================= 

S Afr Med J 2001 Mar;91(3):249-54 

Schreuder B, Kostermans C.

Royal Tropical Institute, Amsterdam.

Building on the successful eradication of smallpox, the World Health Organisation, together with other agencies, is now moving quickly to the eradication of poliomyelitis, originally aimed for the year 2000. Plans for the subsequent global eradication of measles are in an advanced stage. Eradication of both polio and measles incorporate as a fundamental strategy high routine coverage, surveillance and special national immunisation days (NIDs), which are supplementary to routine vaccination services. There has been a lively debate on whether poor countries, with many health problems that could be controlled, should divert their limited resources for a global goal of eradication that may have low priority for their children. From a cost-effectiveness perspective, NIDs are fully justifiable. However, field observations in sub-saharan Africa show that NIDs divert resources and, to a certain extent, attention from the development of comprehensive primary health care (PHC). The routine immunisation coverage rates dropped on average since the introduction of NIDs in 1996, which is contrary to what was observed in the western Pacific and other regions. The additional investment to be made when moving from disease control to eradication may exceed the financial capacity of an individual country. Since the industrialised countries benefit most from eradication, they should take responsibility for covering the needs of those countries that cannot afford the investment. The WHO's frequent argument that NIDs are promotive to PHC is not confirmed in the southern African region. The authors think that the WHO should, therefore, focus its attention on diminishing the negative side-effects of NIDs and on getting the positive side-effects incorporated in the integrated health services in a sustainable way.

============================================================= 

31.) Are Saudi Arabian hospitals prepared for the threat of biological weapons?

============================================================= 

Saudi Med J 2001 Jan;22(1):6-9 Related Articles, Books 

Mah MW, Memish ZA.

Department of Infection Prevention and Control, King Fahad National Guard Hospital, PO Box 22490, Riyadh 11426, Kingdom of Saudi Arabia. Tel. +966 (1) 252 0088 Ext. 3720. Fax. +966 (1) 252 0437. Email: memish@NGHA.Med.Sa

The use of biological weapons has been recorded repeatedly in history. Until recently, biological terrorism had been little discussed or written about. However, events over the past 12 to 18 months have made it clear that likely perpetrators already envisage every possible scenario. Nations and dissident groups exist that have both the motivation and access to utilize biological weapons. In April 1994, a Russian biological weapons expert presented the conclusions of the Russian experts as to the agents most likely to be used: smallpox, anthrax, and plague. Health care workers in the Kingdom of Saudi Arabia (physicians, nurses, and emergency medical technicians) need to be aware of the seriousness of the threat of biological weapons, and to have an approach for the early identification, triage, and management of biological weapons victims. Clues to the occurrence of a bioterrorism attack include the abrupt onset of a large number of cases of a similar disease or syndrome, the occurrence of diseases with unusual geographic or seasonal distribution, and epidemics of non-endemic diseases. Health care workers must maintain a high index of suspicion, involve the hospital epidemiologist or infectious diseases specialist, identify a clear administrative chain-of-command to minimize confusion, and rely on existing networks such as the hospital disaster-and-safety committee to ensure a multidisciplinary response. Maximum readiness can be achieved by periodic readiness drills.

============================================================= 

32.) [Smallpox in Telemark in the last part of the 19th century].

============================================================ 

Tidsskr Nor Laegeforen 2000 Dec 10;120(30):3694-8 \

[Article in Norwegian]

Storesund A.

Institutt for allmenn- og samfunnsmedisin, Universitetet i Oslo, Postboks 1130 Blindern, 0317 Oslo. Asbjorn.Storesund@hit.no

Was vaccination the only cause of the decline of smallpox in Norway during the 19th century? This regional study focuses on the history of the disease in Telemark county with special emphasis on the last, extensive epidemic in 1868. In addition to vaccination, other possible causal relations are discussed. In Telemark, smallpox seems to have been relatively mild in the 19th century with the exception of the epidemics at the end of the 1830s and in 1868. In 1868 the disease spread along the main transportation routes northward through the western part and eastward through the more densely populated districts along the coast. The importance of vaccination is apparent from the fact that the municipalities with the lowest annual percentage of newborns vaccinated were most heavily struck by the epidemic. Despite vaccination procedures, both adults and unvaccinated children were groups at risk. Local initiatives--especially isolation and revaccination--largely prevented or restricted outbreaks of smallpox. It seems that the efforts of the district medical officers and local health administrators after 1860 were of decisive importance for the decline in smallpox cases in the period in question.

============================================================= 

33.) Monkeypoxvirus infections.

============================================================= 

Rev Sci Tech 2000 Apr;19(1):92-7 Related Articles, Books 

Pattyn SR.

Institute of Tropical Medicine and University Hospital Antwerpen, Nationalestraat 155, 2000 Antwerp, Belgium.

During and after the smallpox eradication campaign, human cases of monkeypox appeared in West and Central Africa, as isolated cases or as small epidemics. Since inter-human transmission has never or only very exceptionally been documented, monkeypox does not represent a serious threat to humans. The virus reservoir is among tree squirrels living in the tropical rain forests of Africa and humans are infected by hunting, killing and skinning these animals. However, the modernization of society lessens human contact with the virus reservoir. Since the eradication of smallpox, stocks of variola virus have been maintained; whether these stocks should now be destroyed is a political question, which is seriously compromised by mistrust between countries.

============================================================= 

34.) [Bioterrorism--a public and health threat].

============================================================= 

Epidemiol Mikrobiol Imunol 2000 Nov;49(4):165-73 

[Article in Czech]

Jezek Z.

zdenek.jezek@post.cz

In recent years the fear of bioterrorism, of secret modernization and dissemination of biological weapons is increasing. Facts detected recently in Iran, Japan and the former Soviet Union provide evidence that there are countries and dissident groups which have access to modern technology of cultivation of dangerous pathogens as well as motivation for their use in acts of terrorism or war. The menace of biological terrorism is nowadays, as compared with the past, much greater. The most feared candidates as regards production of biological weapons are the pathogens of smallpox, anthrax and plague. The author discusses the serious character of possible events associated with terrorist dissemination of these pathogens. It is much esier to produce and use biological weapons than to create effective systems of defence against them. The menace of bioterrorism and bioweapons must not be exaggerated nor underestimated. The possible terrorist use of bioweapons is real. At present even the most advanced industrial countries cannot quarantee effective protection of their populations. Fortunately they are however aware of their present vulnerability. Our society is not equipped to cope with bioterrorism. Preparation and reinforcement of the health services, in particular of sections specialized in the control of infectious diseases is an effective step to divert the sequelae and suffering associated with terrorist use of biological agents. It is essential to be prepared. This calls for time and funds which unfortunately are not plentiful.

============================================================= 

35.) Ensuring vaccine safety in immunization programmes--a WHO perspective.

============================================================= 

Vaccine 2001 Feb 8;19(13-14):1594-605 

Jodar L, Duclos P, Milstien JB, Griffiths E, Aguado MT, Clements CJ.

Vaccines & Biologicals, Health Technology and Pharmaceuticals, World Health Organization, 20 Avenue Appia, 1211 27, Geneva, Switzerland. jodarl@who.int

Ever since vaccines were firstly used against smallpox, adverse events following immunization have been reported. As immunization programmes expand to reach even the most remote communities in the poorest countries, it is likely that many more events will be temporally linked with vaccine administration. Furthermore, the profound shift in the general public and media interest in adverse events may lead to undue concerns and allegations which may ultimately jeopardize immunization programmes world-wide. While the health professional has understood this issue for some time, the public and the media have now also become all too aware of the significance of vaccine-related adverse events. The familiar vaccines, well-tested over decades, have not changed--but the perception regarding their safety has shifted. Claims outrageous or reasonable are being made against both the old and the newly-introduced vaccines. At the same time, the immunological and genetic revolution of the last decade may well bring to our notice some hypothetical risks that need to be addressed at pre-clinical level. WHO has been at the leading edge to guarantee vaccine safety for the last 30 years and will continue to do so. The Organization's plans for the next decade and beyond include the Safe Injection Global Network (SIGN), the development and introduction of safer technologies, and the prevention, early detection and management of AEFIs. The new technologies include needle-containing injection devices such as the autodisable syringe, as well as mucosal and transcutaneous immunization. Training will continue to be at the centre of WHO's efforts, limiting human error to a minimum. Mechanisms have been set in place to detect and respond to new and unforeseen events occurring. Above all, there is a willingness to respond to new climates and new technologies so that the Organization is in the best position to ensure safe immunization for all the world's children.

============================================================= 

36.) The threat of smallpox and bioterrorism.

============================================================= 

Trends Microbiol 2001 Jan;9(1):15-8 

Berche P.

INSERM U411, Faculte de Medecine Necker-Enfants Malades, 156 Rue de Vaugirard, 75015 Paris, France.

Smallpox (variola) was a devastating disease with a high case-fatality rate. Although the disease was eradicated in 1977, the remaining stocks of smallpox virus constitute one of the most dangerous threats to humanity. The smallpox virus is highly specific for humans and non-pathogenic in animals. There is no antiviral treatment and a vaccine is active only if administered in the first four days post-exposure. Smallpox virus represents a potential biological weapon that could be used by terrorists, and the destruction of stocks raises political, social, scientific and ethical issues.

============================================================= 

37.) Inmmune response to vaccinia virus is significantly reduced after scarification with TK- recombinants as compared to wild-type virus.

============================================================= 

Acta Virol 2000 Jun-Aug;44(3):151-6 Related Articles, Books 

Phillpotts RJ, Lescott T, Gates AJ, Jones L.

DERA, Biological Sciences Department, Chemical and Biological Defense Sector, Porton Down, Wiltshire, SP4 0JQ, U.K. BJPHILLPOTTS@dcra.gov.uk

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.

============================================================= 

38.) Aeromedical evacuation of biological warfare casualties: a treatise on infectious diseases on aircraft.

============================================================= 

Mil Med 2000 Nov;165(11 Suppl):1-21 Related Articles, Books 

Withers MR, Christopher GW.

U.S. Air Force School of Aerospace Medicine, 2602 West Gate Road, Brooks Air Force Base, TX 78235, USA.

A basic understanding of the transmission and isolation of infections would be essential to the safe and effective aeromedical evacuation (AE) of biological warfare (BW) casualties. First, the airframe as microbial environment is considered, and relevant preventive and disinfecting measures are discussed. A survey of past infectious disease transmission on civilian aircraft (including tuberculosis, influenza, measles, smallpox, and viral hemorrhagic fevers) is presented, and the communicability and stability of likely BW agents is described. A brief history of U.S. military aeromedical evacuation (as it relates to contagious diseases and U.S. Air Force BW doctrine) is also outlined. Special containment procedures (especially as used by the U.S. Army Aeromedical Isolation Team) are described. Finally, international legal and regulatory aspects of the AE of BW casualties are considered, and some unanswered questions and suggestions for future research are offered. It is concluded that, given adequate foresight, expertise, and resources, the AE of even contagious BW casualties could be safely and effectively accomplished.

============================================================= 

39.) An emergent poxvirus from humans and cattle in Rio de Janeiro State: Cantagalo virus may derive from Brazilian smallpox vaccine.

============================================================= 

Virology 2000 Nov 25;277(2):439-49 

Damaso CR, Esposito JJ, Condit RC, Moussatche N.

Laboratorio de Biologia Molecular de Virus, Instituto de Biofisica Carlos Chagas Filho, CCS, Rio de Janeiro, RJ 21941-900, Brazil.

The biological properties of poxvirus isolates from skin lesions on dairy cows and milkers during recent exanthem episodes in Cantagalo County, Rio de Janeiro State, Brazil, were more like vaccinia virus (VV) than cowpox virus. PCR amplification of the hemagglutinin (HA) gene substantiated the isolate classification as an Old World orthopoxvirus, and alignment of the HA sequences with those of other orthopoxviruses indicated that all the isolates represented a single strain of VV, which we have designated Cantagalo virus (CTGV). HA sequences of the Brazilian smallpox vaccine strain (VV-IOC), used over 20 years ago, and CTGV showed 98.2% identity; phylogeny inference of CTGV, VV-IOC, and 12 VV strains placed VV-IOC and CTGV together in a distinct clade. Viral DNA restriction patterns and protein profiles showed a few differences between VV-IOC and CTGV. Together, the data suggested that CTGV may have derived from VV-IOC by persisting in an indigenous animal(s), accumulating polymorphisms, and now emerging in cattle and milkers as CTGV. CTGV may represent the first case of long-term persistence of vaccinia in the New World. Copyright 2000 Academic Press.

============================================================= 

40.) [20 years without smallpox].

 ============================================================= 

Epidemiol Mikrobiol Imunol 2000 Aug;49(3):95-102 Related Articles, Books 

[Article in Czech]

Jezek Z.

zdenek.jezek@post.cz

It is 20 years since the 33rd World Health Assembly (WHA) declared that "worldwide eradication of smallpox" was achieved. This was the outcome of many years intensive work of the World Health Organization (WHO) and its member countries. In 1958 the WHA adopted the recommendation that WHO should initiate the eradication of smallpox on a worldwide scale. In 1967 the eradication activities in hitherto endemic countries became more intense. Smallpox affected 31 countries and 15 countries recorded from occasional cases. Every year more than 10 million people contracted the disease and two million of them died. A ten-year limit for the eradication was set. Gradually smallpox were eradicated in South America, then in Asia and last in Africa where the last case of endemic smallpox was recorded in 1977 in Somalia. WHO ensured international collaboration, close coordination of activities and mobilization of financial, personal and material resources. It ensured also that tested methods were fully applied in the affected countries regardless of their political, religious and cultural differences. In the eradication activities participated hundreds of thousands of local and 700 health professionals from abroad, incl. 20 Czechoslovak epidemiologists. The worldwide costs of eradication amounted to some 300 million dollars, i.e. some 23 million per year. The most important contribution of the eradication of smallpox was in addition to the termination of human suffering, worldwide financial savings estimated to 1-2 billion US dollars per year. These saved personal and financial resources could be used for other important health projects. The eradication of variola was defined as eradication of clinical forms of smallpox not as the final eradication of the variola virus. The importance of laboratories keeping the variola virus increased steeply at the time when clinical cases of smallpox were eradicated. From the beginning of the eighties WHO made an effort to reduce their number to a minimum. Since 1984 strains of variola are officially kept only in two centres collaborating with WHO. The Organization suggested destruction of the kept viruses in 1987, i.e. ten years after the eradication of smallpox. Unfortunately some political and scientific circles did not agree with this intention. Even recommendations to destroy the virus in 1993 and again in 1999 were not accepted. In the nineties fear of bio-terrorism and secret modernization of biological weapons influenced some member countries to change their opinion on the intended destruction of the virus. Despite this in May 1999 the WHA adopted a resolution that the final destruction of all variola strains is the objective of all member countries of WHO and recommended to postpone the destruction of the virus to the year 2002. The reason for postponement is current research of new antiviral preparations and better vaccines. There is again hope that all that will be left of the variola virus will be magnetic signals on computer diskettes.

============================================================= 

41.) [Circulation of virus and interspecies contamination in wild animals].

============================================================= 

Bull Soc Pathol Exot 2000 Jul;93(3):156 Related Articles, Books, LinkOut 

[Article in French]

Osterhaus A.

Universite de Rotterdam, Pays-Bas.

Paradoxically, just when we have succeeded in eradicating and/or bringing under control the major viral infections (smallpox, poliomyelitis, measles) numerous viral infections are emerging in man and in animals. Changes in our social environment, technological and ecological equilibrium have facilitated this phenomenon. Furthermore, certain of these viruses have demonstrated an almost unlimited capacity to adapt genetically to environmental change. HIV has already infected 40 million individuals, but monkeypox, Ebola, simian herpes can cause epidemics with serious if not fatal outcomes. Haemorrhagic fever epidemics have resulted from human contact with Flavivirus infected rodents and insects. Paramyxoviruses and morbiliviruses can cause fatal outcomes in man and animals. And the three influenza epidemics having occurred in the 20th century all came from the type A avian reservoir. The often complex combinations of predisposing factors having facilitated the emergence of several epidemics merit further consideration.