Anthrax vaccines

Vaccines against the livestock and human disease anthrax—caused by the bacterium Bacillus anthracis—have had a prominent place in the history of medicine, from Pasteur’s pioneering 19th-century work with cattle (the first effective bacterial vaccine and the second effective vaccine ever) to the controversial late 20th century use of a modern product to protect American troops against the use of anthrax in biological warfare. Human anthrax vaccines were developed by the Soviet Union in the late 1930s and in the US and UK in the 1950s. The current vaccine approved by the U.S. Food and Drug Administration (FDA) was formulated in the 1960s. Vaccines against the livestock and human disease anthrax—caused by the bacterium Bacillus anthracis—have had a prominent place in the history of medicine, from Pasteur’s pioneering 19th-century work with cattle (the first effective bacterial vaccine and the second effective vaccine ever) to the controversial late 20th century use of a modern product to protect American troops against the use of anthrax in biological warfare. Human anthrax vaccines were developed by the Soviet Union in the late 1930s and in the US and UK in the 1950s. The current vaccine approved by the U.S. Food and Drug Administration (FDA) was formulated in the 1960s. Currently administered human anthrax vaccines include acellular (USA, UK) and live spore (Russia) varieties. All currently used anthrax vaccines show considerable local and general reactogenicity (erythema, induration, soreness, fever) and serious adverse reactions occur in about 1% of recipients. New third-generation vaccines being researched include recombinant live vaccines and recombinant sub-unit vaccines. In the 1870s, the French chemist Louis Pasteur (1822–1895) applied his previous method of immunizing chickens against chicken cholera to anthrax, which affected cattle, and thereby aroused widespread interest in combating other diseases with the same approach. In May 1881, Pasteur performed a famous public experiment at Pouilly-le-Fort to demonstrate his concept of vaccination. He prepared two groups of 25 sheep, one goat and several cows. The animals of one group were twice injected, with an interval of 15 days, with an anthrax vaccine prepared by Pasteur; a control group was left unvaccinated. Thirty days after the first injection, both groups were injected with a culture of live anthrax bacteria. All the animals in the non-vaccinated group died, while all of the animals in the vaccinated group survived. The public reception was sensational. Pasteur publicly claimed he had made the anthrax vaccine by exposing the bacilli to oxygen. His laboratory notebooks, now in the Bibliothèque Nationale in Paris, in fact show Pasteur used the method of rival Jean-Joseph-Henri Toussaint (1847–1890), a Toulouse veterinary surgeon, to create the anthrax vaccine. This method used the oxidizing agent potassium dichromate. Pasteur's oxygen method did eventually produce a vaccine but only after he had been awarded a patent on the production of an anthrax vaccine. The notion of a weak form of a disease causing immunity to the virulent version was not new; this had been known for a long time for smallpox. Inoculation with smallpox (variolation) was known to result in far less scarring, and greatly reduced mortality, in comparison with the naturally acquired disease. The English physician Edward Jenner (1749–1823) had also discovered (1796) the process of vaccination by using cowpox to give cross-immunity to smallpox and by Pasteur's time this had generally replaced the use of actual smallpox material in inoculation. The difference between smallpox vaccination and anthrax or chicken cholera vaccination was that the weakened form of the latter two disease organisms had been 'generated artificially', so a naturally weak form of the disease organism did not need to be found. This discovery revolutionized work in infectious diseases and Pasteur gave these artificially weakened diseases the generic name 'vaccines', in honor of Jenner's groundbreaking discovery. In 1885, Pasteur produced his celebrated first vaccine for rabies by growing the virus in rabbits and then weakening it by drying the affected nerve tissue. In 1995, the centennial of Pasteur's death, The New York Times ran an article titled 'Pasteur's Deception'. After having thoroughly read Pasteur's lab notes, the science historian Gerald L. Geison declared Pasteur had given a misleading account of the preparation of the anthrax vaccine used in the experiment at Pouilly-le-Fort. The same year, Max Perutz published a vigorous defense of Pasteur in the New York Review of Books. The Austrian-South African immunologist Max Sterne (1905–1997) developed an attenuated live animal vaccine in 1935 that is still employed and derivatives of his strain account for almost all veterinary anthrax vaccines used in the world today. Beginning in 1934 at the Onderstepoort Veterinary Research Institute, north of Pretoria, he prepared an attenuated anthrax vaccine, using the method developed by Pasteur. A persistent problem with Pasteur's vaccine was achieving the correct balance between virulence and immunogenicity during preparation. This notoriously difficult procedure regularly produced casualties among vaccinated animals. With little help from colleagues, Sterne performed small-scale experiments which isolated the 'Sterne strain' (34F2) of anthrax which became, and remains today, the basis of most of the improved livestock anthrax vaccines throughout the world. Anthrax vaccines were developed in the Soviet Union in the 1930s and available for use in humans by 1940. A live attenuated, unencapsulated spore vaccine became widely used for humans. It was given either by scarification or subcutaneously and its developers claimed that it was reasonably well tolerated and showed some degree of protective efficacy against cutaneous anthrax in clinical field trials. The efficacy of the live Russian vaccine was reported to have been greater than that of either of the killed British or US anthrax vaccines (AVP and AVA, respectively) during the 1970s and '80s. Today both Russia and China use live attenuated strains for their human vaccines. These vaccines may be given by aerosol, scarification, or subcutaneous injection. A Georgian/Russian live anthrax spore vaccine (called STI) was based on spores from the Sterne strain of B. anthracis. It was given in a two-dose schedule, but serious side-effects restricted its use to healthy adults. It was reportedly manufactured at the George Eliava Institute of Bacteriophage, Microbiology and Virology in Tbilisi, Georgia, until 1991. British biochemist Harry Smith (1921–2011), working for the UK bio-weapons program at Porton Down, discovered the three anthrax toxins in 1948. This discovery was the basis of the next generation of antigenic anthrax vaccines and for modern antitoxins to anthrax. The widely used British anthrax vaccine—sometimes called Anthrax Vaccine Precipitated (AVP) to distinguish it from the similar AVA (see below)—became available for human use in 1954. This was a cell-free vaccine in distinction to the live-cell Pasteur-style vaccine previously used for veterinary purposes. It is now manufactured by Porton Biopharma Ltd, a Company owned by the UK Department of Health.