Connaught Laboratories

Last updated
Connaught Laboratories
The Varsity war supplement 1917 (1917) (14579564429).jpg
The Varsity (newspaper) magazine feature on Connaught Farm and Laboratories, 1917
Founder(s) John G. FitzGerald
Established1914
Formerly calledAntitoxin Laboratory (1914), Connaught Antitoxin Laboratories and University Farm (1917)
Location
Toronto
,
Ontario
,
Canada

The Connaught Medical Research Laboratories was a non-commercial public health entity established by Dr. John G. FitzGerald in 1914 in Toronto to produce the diphtheria antitoxin. Contemporaneously, the institution was likened to the Pasteur Institutes in France and Belgium and the Lister Institute in London. It expanded significantly after the discovery of insulin at the University of Toronto in 1921, manufacturing and distributing insulin at cost in Canada and overseas. Its non-commercial mandate mediated commercial interests and kept the medication accessible. In the 1930s, methodological advances at Connaught updated the international standard for insulin production.[ citation needed ]

Contents

Efforts at Connaught to purify heparin for human clinical trials lay the foundation for various critical surgeries including vascular surgery, organ transplantation and cardiac surgery. During the First and Second World Wars, the Labs produced various antitoxins that became crucial due to increased risks of injury infection and exposure to diseases in other parts of the world, including the typhus vaccine and penicillin. Connaught's production technologies also enabled the mass-scale field trial of Jonas Salk's polio vaccine and its subsequent expansion. The institution played a particularly important role in restoring U.S. public faith in the polio vaccine after a production mishap at California-based Cutter Laboratories.

In 1972, the University of Toronto sold Connaught Laboratories to the Canada Development Corporation (CDC), a federally-controlled corporation charged with developing and maintaining Canadian-controlled companies in the private sector through a mixture of public and private investment. The sale continued to stir controversy in the following years as the Labs increased prices on its products and came under allegations of mismanagement and deteriorated manufacturing standards. In 1986, the Labs were transferred to private ownership as the CDC was dismantled as part of the Mulroney government's program of privatization. Connaught was merged with Institut Mérieux in 1989, and in 1999 it was transformed into the Canadian component of "Pasteur Mérieux Connaught", owned by Rhône-Poulenc. A series of acquisitions since then have transferred ownership of what used to be the Connaught Laboratories to the global vaccine business of Sanofi.

History

Early history

Canadian public health at the turn of the 20th century was defined by increasing local and provincial efforts to control the spread of infectious diseases which worsened with urbanization. In particular, diphtheria (known as "The Strangler" for its infection of the respiratory system) was the leading cause of death among Canadian children under 14 until the mid-1920s. [1] In Ontario alone, 36,000 children died from diphtheria between 1880 and 1929. [1] Research at the end of the 19th century, notably involving Pierre Paul Émile Roux and Alexandre Yersin of the Pasteur Institute as well as Emil von Behring and Kitasato Shibasaburō, had paved the way for diphtheria antitoxin production using horses. [1] [2] [3] The antitoxin could save lives when given early enough in the course of the disease, and in large enough doses. Despite the developments, treatment was often too costly for middle class families since Canadian public health efforts to counter the spread of diphtheria were largely dependent upon expensive imports from commercial U.S. firms.[ citation needed ]

In 1913, John G. FitzGerald took up a new role as part-time Associate Professor of Hygiene at the University of Toronto. After becoming one of the youngest graduates of the University of Toronto Medical School in 1903, he had spent a decade pursuing further study across North America and Europe, learning how to make antitoxins and observing novel approaches to public health education, research, and biological manufacture. Around that time, calls had mounted for a "Pasteur Institute" in Toronto following a rabies outbreak in southwestern Ontario, since the only closest-available source of life-saving treatment was in New York. FitzGerald worked with William Fenton to prepare the rabies vaccine. Following the success, they soon moved to tackle the lack of access to the diphtheria antitoxin with a commitment from Ontario's Chief Medical Officer that the Ontario Board of Health would buy the antitoxin at cost and ultimately distribute it for free. The initial work done with a stable of horses in Fenton's backyard proved successful, and in 1914 FitzGerald presented a plan to the Board of Governors of the University of Toronto which included dedicating any proceeds to the improvement of public health and education. [1]

On May 1, 1914, the Antitoxin Laboratory was formally established in the Department of Hygiene. It was to be self-supporting and received no funds from the University. $500 in donations from Edmund Boyd Osler (Ontario politician), brother of famous Canadian physician William Osler, helped establish the space which contained a general laboratory, a sterilising facility, and a small bacteriological lab. The lab soon began to produce the diphtheria antitoxin and Pasteur rabies treatment that would eventually be made available to all Canadians, regardless of class or income. [1] [4]

World War I: 1914-1918

Canada entered World War I on August 4, 1914, and soon the need for anti-toxins against tetanus became an urgent wartime matter. Robert Defries who joined the Antitoxin Lab in 1915 proposed that its operations be expanded to treat Canadian soldiers fighting trench warfare, for "not a fraction of the necessary amount [of tetanus antitoxin] was available". [5] The proposal was quickly approved by the University of Toronto Board of Governors despite the lack of immediate funds, with University President Robert Falconer making an appeal to Prime Minister Robert Borden and the Ottawa administration. Shortly after, whisky magnate and then-Chairman of the Red Cross Society Colonel Albert Gooderham funded an operation to equip the Lab with the capacity to produce a Canadian supply by August 1915. Gooderham had seen a need for anti-toxins against tetanus, which had become an urgent wartime matter for the Canadian Expeditionary Force. He was impressed by the fledgling laboratory's capacity to produce the tetanus antitoxin in controlled conditions and at a lower price than the American sources than the Red Cross had initially contacted. He turned over a 58-acre farm on Dufferin Street north of Toronto for a new production plant on condition that it be named after the Duke of Connaught, then Governor-General of Canada (1911-1916). [6] In February 1916, the Ontario Board of Health began to distribute the Antitoxin Laboratory's products for free across the province. Other provincial governments soon followed suit, starting in Saskatchewan. [5]

On October 25, 1917, the expanded lab was inaugurated under its new title, Connaught Antitoxin Laboratories and University Farm. John G. FitzGerald, the Director, was given full authority over the Labs' staff and the Connaught Laboratories Research Fund, which remained autonomous of University finances and supported the development of preventive medicine research. An Honorary Advisory Committee was also established so that Connaught would provide a truly national public health service, appointing representatives of each provincial government health department and the federal government to an annual meeting with FitzGerald. [5]

By the end of the war in 1918, the Labs' wounded soldier treatment practices had reduced the rate of tetanus infection to 0.1%, making its anti-tetanus program one of the most successful health campaigns in wartime medicine. [4] That same year, the Spanish flu spread across North America, spread in part through infected soldiers returning from overseas. [7] Connaught swiftly intervened with large quantities of what Robert Defries described as an "experimental" vaccine, freely supplying it to health services and hospitals across the country as well as to several U.S. states and to Great Britain. While no claims for the effectiveness of the vaccine were made, it did no apparent harm and helped cement Connaught as a national public health centre in the minds of Canadian public health authorities. [5]

The Spanish flu crisis revealed the inadequacies of Canadian public health infrastructure at the time. As a direct result, the government of Canada created the Department of Health in 1919. [7] The new department's Dominion Council of Health had FitzGerald as its key member and took over the work of Connaught Labs' Honorary Advisory Committee. In April 1920, Connaught was granted a U.S. license. In July of the same year, it became an independent unit within the University of Toronto governed by a separate "Connaught Committee" of the Board of Governors. [5]

Discovery and early development of insulin: 1921-1936

Peacemaking

In 1921, the Ontario Royal Commission on University Finances reported that "the work of the Connaught Antitoxin Laboratories is analogous to that done in the Pasteur Institutes in France and Belgium and to that of the Lister Institute in London, with this advantage on the side of these Laboratories that the Connaught Antitoxin Laboratories are an organic part of the University, are self-supporting and provide funds and facilities for research in Preventive Medicine and also opportunity for graduate teaching in Public Health." [8] That same year in the physiology laboratory two floors above FitzGerald's Connaught Labs office, Frederick Banting and Charles Best (medical scientist) under the auspices of J.J.R. Macleod successfully extracted insulin from the pancreas of dogs, fetal calves, and adult cows. [9] [10] In particular, Banting's experimental work with calf pancreas tissue took place at Connaught's farm site, where calves were involved in smallpox vaccine production. FitzGerald had arranged access to Connaught's modest facilities, along with $5,000 from the Labs' reserves, to expedite the team's work. [11] In the months that followed, the researchers worked to refine the extracts to a degree safe for human injection with the help of biochemist James Collip. Tensions mounted during this time between the four "co-discovers" of insulin, exacerbated greatly by Collip's suggestion that he could return anytime to Alberta with his purification work and patent it. FitzGerald therefore stepped in as peacemaker to prepare a seminal research and development agreement between the Connaught Laboratories and the researchers. It established two key conditions: 1) that the collaborators would sign a contract agreeing not to take out a patent with a commercial pharmaceutical firm during an initial working period with Connaught; and 2) that no changes in the research policy would be allowed unless first discussed among FitzGerald and the four collaborators. [11] [12]

As clinical trials progressed through 1922, a number of early patients benefitted from the developments, including Leonard Thompson at the Toronto General Hospital, [13] [14] [15] Elizabeth Hughes Gossett (daughter of U.S. Secretary of State Charles Evans Hughes), [16] and future woodcut artist James D. Havens. [17] In 1923, The Nobel Committee credited the practical extraction of insulin to the Toronto team and awarded the Nobel Prize in Physiology or Medicine to Frederick Banting (who shared his prize with Charles Best) and J.J.R. Macleod (who shared his prize with James Collip). [18] [19] [20] [21] [22] [23] [24] The Insulin Committee of the Board of Governors of the University of Toronto was created in the same year to administer the patents (as previously agreed) and undertake licensing arrangements for the manufacture of insulin worldwide. [25] The original committee consisted of John G. FitzGerald of Connaught, three University Governors, and the four co-discoverers. The authors registered the University of Toronto's commitment as a public institution "to ensure that, at the earliest possible date, adequate supplies of potent and non-toxic preparations of Insulin will be constantly and readily available at reasonable prices all over the world." [26]

Improving production and affordability

By the summer of 1922, a number of key advances were made at Connaught to significantly increase insulin production. David Scott, whom FitzGerald had personally recruited for the task, successfully replaced Collip's alcohol-based method with acetone use to allow for consistent results during the three months prior to external collaboration. Peter J. Moloney pioneered an adsorption method using benzoic acid that reduced the amount of necessary alcohol/acetone to a minimal dose and eliminated far more protein material than had been previously possible. Some 250,000 units of insulin using the combination of these methods were produced at Connaught for clinical use in Toronto during the fall of 1922, with "very satisfactory results," according to Best and Scott. By early November, Connaught was producing about 1 litre of insulin per week. [11] Nonetheless, large-scale manufacture of insulin at Connaught reached its limits, prompting the researchers to contract with Eli Lilly and Company to increase production and accept patents in Canada, the United States, and Great Britain. [27] [28] Banting objected initially to the taking out of patents and the charging of royalties for the manufacture of insulin; the Canadian patent was sold to the University of Toronto for a symbolic dollar. [29] Following the discovery of the isoelectric point for insulin, Eli Lilly hoped to win an insulin production patent for itself but could not due to a similar and concurrent discovery by Michael Somogyi, Phillip Shaffer and E. A. Doisy at Washington University in St. Louis, news of which had already reached the researchers in Toronto. [11] [30] To prevent related legal complications, Connaught's Assistant Director and Head of the Insulin Division Robert Defries worked to establish an "innovative patent pooling policy". The policy outlined that "it shall be required of all licenses that any patents taken out by them shall be assigned to the University of Toronto who may then authorize other licensees to use the methods patented, in other words the policy of pooling the patents was decided upon.” [11] Based on a November 1923 Insulin Committee report, patents and trade marks had "been applied for in Egypt, Palestine, etc., Japan, and South Africa". [31] Nobel prize-winning physiologist August Krogh was given permission to manufacture insulin in Denmark while visiting Toronto in 1922, and a Danish patent was granted in February 1924 via Løvens kemiske Fabrik  [ da ] (now LEO Pharma). [31] [32] In the second half of 1923, Connaught's insulin operations were expanded into a sizeable "factory" at a vacant YMCA building that was transformed through a mix of donations and government grants. The main purpose of expansion was to lower the cost of insulin as much as possible. As Defries told the press, Connaught "would now be able to produce enough insulin for all of Canada in the new facility and at a steadily declining price." [11] [33] By November, Connaught was producing 250,000 units of insulin weekly; the average diabetic needed 15-20 units every day. It exported to countries across the globe entirely at cost of materials and production, since Connaught was “not engaged in commercial business.” [11]

During this period, Connaught was the world’s primary driver of research and innovation in insulin production as well as some of its earlier specialisations including the diphtheria antitoxin. The Labs' relevant advances are reflected in scientific publications of the time by Peter Moloney, David Scott, and Charles Best. Rockefeller Foundation noted the surrounding development of public health services and services in Toronto and met with John G. FitzGerald, Director of Connaught Laboratories, in its search to found a third school of public health (the first two being at Johns Hopkins University and Harvard University). Shortly after, it approved the creation of the School of Hygiene at the University of Toronto. The School of Hygiene opened its doors in June 1927. [34] Connaught and the School shared their administration under FitzGerald's directorship, the School serving as the academic research and teaching arm of the Labs and the Hygiene Building also accommodating much of the Labs’ operational facilities. [35]

In 1926, John Jacob Abel at Johns Hopkins University discovered a method to crystallize insulin to a purer form, but only in small quantities with a shorter lifespan. A team at Connaught led by David Scott and assisted by Arthur Charles and Albert Fisher refined this process into 1933 to consistently produce highly pure insulin. [36] Charles and Fisher prepared a new international standard for insulin, the first in crystalline form. In 1936, Fisher and Scott built upon the work of Hans Christian Hagedorn, one of Banting and Best's original Danish collaborators (along with August Krogh), to formulate protamine zinc insulin. This was the first long-acting alternative to regular insulin. [35]

Preventing diphtheria: 1924-1927

Initially established in 1914 to produce the diphtheria antitoxin, the Connaught Laboratories continued to prioritize the eradication of diphtheria. Though the institution's efforts had made the antitoxin freely available to the public, the disease remained one of the leading public health threats to children under 14. [34] The objective was to move from treatment to prevention.

In 1924, John G. FitzGerald visited the Pasteur Institute to meet with Gaston Ramon, who had recently discovered that treating a potent diphtheria toxin with formaldehyde and heat could make it non-toxic (resulting in a toxoid), making it safe for vaccination. Since Ramon could only test the effectiveness of the toxoid on a small scale in his lab, FitzGerald cabled Ramon's methods to Peter Moloney and requested that he "drop everything and immediately begin preparing and improving the toxoid". [34] In 1925, Edith M. Taylor joined Connaught Laboratories and contributed immensely to improving the culturing process. [37]

Trials in Toronto soon proved to be a success, demonstrating immunity in staff members given the toxoid. Field trials were soon launched, beginning in Windsor, Ontario. Between September 1925 and February 1927, some 120,000 individuals in 9 provinces were vaccinated. During the initial uses, allergic reactions were reported among older children already immune to diphtheria. Moloney developed a simple reaction test (which came to be known as the "Moloney Test") to test for potential reactors to avoid the issue. [34] [38]

The results of toxoid use in Hamilton, Ontario were particularly significant and widely recognized. In 1922, there were 747 cases and 32 deaths due to diphtheria in Hamilton. By 1927, the numbers had fallen to 11 cases and 1 death. In 1931, there were only 5 cases and no deaths. A year later, there was a single case and no deaths. [39]

Development of heparin: 1928-1930s

Heparin is a blood thinner (anticoagulant), originally discovered in 1916 by Jay McLean and William Henry Howell at Johns Hopkins University. However, the crude substance was toxic and could only be extracted in small quantities. [40] As co-discoverer of insulin Charles Best returned from his postgraduate studies in Europe to continue as Connaught's Assistant Director, he began a program in 1928 to purify heparin for clinical use. This direction of development benefitted from Connaught's experience with insulin production and ongoing arrangements with Canadian meat processors to obtain research material. [35]

In 1933, Arthur Charles and David Scott published the first papers on increasing the yield of heparin by rotting source tissues. By 1936, Charles and Scott managed to crystallise the heparin extract into a dry form that could be administered in a salt solution. This became Connaught' second product, after insulin, to be recognised as an international standard. Gordon Murray, a prominent surgeon based at Toronto General Hospital, demonstrated that heparin effectively cleared up internal blood clots and that it showed promise in dangerous operations in which blood would otherwise thicken too quickly. [35]

Initial clinical trials, begun in April 1937 or slightly earlier with cruder forms, involved hundreds of complex surgical cases "in which heparin played an essential and often dramatic life-saving role". [35] The advances that made heparin a safe, easily available and effective anticoagulant were welcomed internationally, and lay the foundation for vascular surgery, organ transplants, and open-heart surgery. [40] [41] [42] The developments also allowed Gordon Murray to pioneer the artificial kidney in North America. [35] [43]

World War II: 1939-1945

Canada entered World War II on September 10, 1939. In 1940, Connaught lost its founder and director Dr. John G. FitzGerald to mental health struggles. Robert Defries, who had already been leading much of the Labs' efforts through the 1930s, stepped in to fill the role as director of Connaught Laboratories and of the School of Hygiene. [44]

This period saw the rapid expansion of Connaught's research capacities to accommodate the military demands of protection against tetanus, typhus, and other bacterial infections. The Labs began the war with a staff of 252; peaked at 1,500 staff in 1944; and ended the war with a staff of 800. The period also saw heavy collaboration with other local researchers at Banting Institute (named after Frederick Banting) and the Department of Bacteriology, both at the University of Toronto. [44] In 1943, Connaught acquired more processing space at One Spadina Crescent, a building originally established for Knox College, then during WWI used for Spadina Military Hospital, where Amelia Earhart had worked as a nurse aide. [45]

Tetanus

Connaught's previous efforts during World War I (1914-1918) had led to a highly successful campaign focusing on treatment of affected soldiers. In 1927, Connaught had begun to build on recent advances by Gaston Ramon at Pasteur Institute to develop various toxoids (inactivated toxins used to vaccinate against future infections).

During WWII, Connaught intensified research on the tetanus toxoid to eliminate its negative side-effects and scale production. Edith M. Taylor led these efforts, building on previous successes with the diphtheria toxoid. Her methods for preparing the tetanus toxin (from which the toxoid was prepared) used a culture far more sophisticated than commercially available options, and yielded a more potent toxoid which was free of any negative side-effects. Taylor's work during this time led to her being awarded the Order of the British Empire at the end of the war. [44] [37] [46]

Typhus

Typhus is a group of infectious bacterial diseases often spread through lice, fleas, and mites. Typhus fever, spread by the body louse, had ravaged both the military and civilian populations of Eastern Europe throughout WWI and continued to plague the European populace. [47] While no typhus vaccine was available at the beginning of WWII, there had been promising research by the United States Public Health Service and the Harvard School of Public Health. At Connaught Laboratories, James Craigie launched a federally supported research program in July 1940 seeking to build on these findings. Their efforts culminated in a much richer bacterial culture and an improved ether-based purification method which lay the foundations for a large-scale vaccine production program in August 1942, overseen by Drs. Laurella McClelland and Raymond Parker. The operation proved successful, and the vaccine was soon made available to Canadian as well as British and American troops. At peak, one million doses were produced each month at Connaught. Craigie received the United States of America Typhus Commission Medal after the war for his pioneering work. [44]

Blood processing

As violence mounted across the theatres of war, so did the need for blood transfusion to wounded soldiers. In 1941, Connaught undertook an initiative to dramatically expand capacity for blood processing into freeze-dried serum, which could be transported more effectively than liquid blood. By March 1942, more than 11,000 blood donations were collected monthly through the national Red Cross. By October, over 57,000 donations were received monthly. [44] Over the course of the war, Connaught received more than 2.5 million blood donations which made it possible to furnish 500,000 bottles of dried serum. [47]

To accommodate the increasing need for processing space, some peacetime projects were stopped or crowded together to make room. The former Knox College building on One Spadina Crescent was purchased in August 1943, further expanding capacity for dried serum production. Connaught contributed all space and services without charge. [47]

Penicillin

Penicillin was discovered in 1928 by Alexander Fleming, who noticed airborne moulds (later identified as penicillum) on his Petri dish that seemed to be inhibiting bacterial growths. These initial findings received little attention, however, although Fleming did conduct several experiments on the antibiotic substance to stabilize the compound and prove its safety for human use. [48] [49] [50] Researchers at Connaught Laboratories' neighbouring Banting Institute had also requested a small sample, but had not pursued further development. [51] Then in 1941, a team led by Howard Florey at the University of Oxford completed an initial re-investigation of the properties and preparation methods of penicillin. In recognition of this work, the Nobel Prize was awarded in 1945 to Fleming, Florey, and Chain. [47] [52]

War meant a greater incidence of wound infections, often by staphylococcus ("staph") and streptococcus ("strep") bacteria. Since demand was high and it took weeks to cultivate penicillin, the supply of penicillin ran out. Therefore, Howard Florey and Norman Heatley accepted an invitation by the Rockefeller Foundation to come to North America to round up production capacity. In Toronto, Drs. Phillip Greey and Alice Gray of the University of Toronto Department of Pathology and Bacteriology began this work in collaboration with Drs. C.C. Lucas and S.F. MacDonald of the Banting Institute. [47] [51]

Following initial advances in chemical preparation, the National Research Council of Canada arranged for large-scale production via the Connaught Laboratories in 1943. [47] The work "was carried on twenty-four hours a day, seven days a week", and involved heavy collaboration across Boston, Toronto, New York, and Oxford. [51] It was effectively "a major military operation at the Labs", orchestrated with an eye to the "D-Day" landings in occupied France in June 1944. [44]

Trial and expansion of the polio vaccine: 1946-1960s

Throughout the first half of the 20th century, polio outbreaks grew larger and more severe as the disease struck most provinces from west to east. In 1953, Canada’s worst polio epidemic year, a total of almost 9,000 cases had claimed the lives of 494 people across the country. [53]

In 1946, Robert Defries, Director of Connaught Laboratories, began an initiative to tackle the growing polio problem. To reflect the institution's expanding scope of virology research, Connaught was renamed "Connaught Medical Research Laboratories". The initiative benefitted from a surge in available polio research funding, particularly from the United States where Franklin D. Roosevelt's personal polio experience had led to the establishment of the National Foundation for Infantile Paralysis (NFIP), later renamed March of Dimes. First recruited to the polio initiative were Clennel van Rooyen and Andrew J. Rhodes. Following an especially severe epidemic that struck the Inuit community of igluligaarjuk in the Northwest Territories, the Labs' Arctic investigations revealed that the polio had very little to do with geography or a summer "polio season", factors that had been thought to affect transmissibility of the disease. [53]

In 1949, researchers at Connaught discovered a purely synthetic blend of 60 ingredients that efficiently fed the cells required to cultivate viruses. They named it "Medium 199", having hit upon the mix after 198 attempts and more than two years or experimentation. In November 1951, the Medium 199 team supplied the poliovirus research team with a sample that effectively resolved the roadblocks that poliovirus research had run into in cultivating the poliovirus. News of the success reached Jonas Salk in Pittsburgh, who upon receiving the supply of Medium 199 was able to prepare a small supply of the polio vaccine for its first human use. Meanwhile, Leone N. Farrell, also a researcher at Connaught and one of the few women to earn a Ph.D. in the sciences in the first half of the twentieth century, led progress in large-scale production methods. In early July 1953, National Foundation for Infantile Paralysis sponsored a mass field trial across 44 U.S. States, Canada, and Helsinki, Finland. Connaught became responsible for the field trial supply of bulk poliovirus fluids, and shipped out some 3,000 litres of it. On April 12, 1955, the vaccine was announced to be 60-90% effective against the three antigenic types of poliovirus and was immediately licensed for use in U.S. and Canada. [53]

In the U.S., licenses for vaccine production was granted to five pharmaceutical companies: Eli Lilly, Parke-Davis, Wyeth, Pitman-Moore, and Cutter. Shortly thereafter, in what became known as the Cutter incident, some batches of the vaccine from California's Cutter Laboratories led to an outbreak of polio and was immediately recalled. The Epidemic Intelligence Service of the Communicable Disease Center found that two production pools made by Cutter Labs contained live poliovirus. [54] On May 7, the U.S. Surgeon General suspended the country's entire vaccine program. [53]

In Canada, Connaught's vaccine was the only version in use, and had demonstrated no cases of polio linked with its production. Therefore, Canadian use of the vaccine continued uninterrupted. Political and public health confidence in the vaccine north of the border during the Cutter incident helped pave the way for the U.S. to resume polio immunizations in July 1955. [53]

The Connaught Laboratories continued to improve and expand polio vaccine production during the latter half of the 1950s and into the early 1960s.

Eradicating smallpox: 1960s-early 1970s

Pre-1960s

Smallpox is a highly contagious disease which has been fatal throughout most of recorded human history. Various techniques of variolation (protection against smallpox) have been documented globally, the most prominent records of established practice dating back to the Ming dynasty (present-day China) in the 15th century. [55] [56] In Europe, variolation was taken up in the 18th century via Constantinople. At the turn of the century into the 19th, a number of individuals including Benjamin Jesty and Edward Jenner began to demonstrate considerable success using a vaccine made from cowpox material. [57] Variolation eventually declined as vaccines were shown to be effective and became better appreciated. [55]

In present-day Canada, the history of smallpox stretches back to European contact with indigenous peoples in the 17th century. Since the aboriginal demographic had no natural immunity, smallpox devastated populations that settlers made contact with. It spread first in New France near Tadoussac in 1616 and quickly reached tribes in the Maritimes, James Bay, and Great Lakes area. [58] It reached the west coastal regions of Canada in the 1780s. [59] [60] On numerous occasions, the disease was used with official sanction by British troops as a form of germ warfare to suppress indigenous populations. [61] [62] [63] [64] After the smallpox vaccine was brought to Canada in 1796 by John Clinch, more concerted efforts were made to stem the further spread of smallpox.

Between 1885 and 1907, Dr. Alexander Stewart's Ontario Vaccine Farm in Palmerston, Ontario successfully provided a dependable supply of vaccines to much of Canada. [55] In 1916, the newly-established Connaught Laboratories purchased the equipment of the Ontario Vaccine Farm and took over the production process to bring domestic incidences[ spelling? ] under control by the 1940s. [55] [65] The Institut de microbiologie et d’hygiène (now INRS-Institut Armand-Frappier  [ FR ]) at the Université de Montréal began preparing the smallpox vaccine in 1939, primarily for distribution in Québec. [65]

Collaboration with the World Health Organization

In addition to Canada's routine, domestic immunization needs, demand for Connaught's smallpox vaccine had expanded through the war years given military needs and the growing scale of transnational medical operations. Simultaneously, the pharmaceutical industry was drastically transformed by such interlinked factors as the post-war boom, factory-based mass-production, increased barriers to entry, and heavy consolidation of private industry (in 1951 alone, Pfizer opened subsidiaries in nine new countries). [66] Small domestic producers fell under foreign control as they were unable to compete on the scale demanded by the new technology. [67] Given these developments, by the 1950s the Labs' leadership saw a necessary and advantageous niche in the growing international market for the smallpox vaccine. [65]

To meet demands for transportability and a longer shelf-life, Connaught began its efforts to produce a dried version of the vaccine under Cleeve R. Amies, previously of the Lister Institute. In 1967, the institution entered into formal collaboration with the World Health Organization (WHO) on its smallpox eradication program. [65] Under the leadership of Robert J. Wilson (then Assistant Director of Connaught) and Paul Fenje, Connaught assumed regional responsibility for the smallpox eradication effort in Latin America, especially in Brazil. Their early efforts focused on ensuring the availability of high-quality local vaccine supplies. [68] WHO codified vaccine production standards in its document, Methodology of Freeze-dried Smallpox Vaccine Production, based largely on Connaught's experience and Wilson and Fenje's initiative. [69] By the fall of 1968, five of the major vaccine producers in Latin America were meeting, or almost meeting, the requisite standards of adequate potency, stability and bacteriological sterility. [65] In 1969, Connaught was designated as the WHO Regional Reference Centre for Smallpox Vaccine in the Region of the Americas. [70]

Globally, approximately 50 million cases still occurred each year in the 1950s. Through transnational collaboration, this figure was reduced significantly to 10-15 million cases in 1967. [71] The last naturally occurring case was confirmed in Somalia on October 26, 1977. Smallpox was declared eradicated by the World Health Organization in 1980. [72]

Ownership transfer and privatization

Transfer to the Canada Development Corporation

Beginning in the mid-1960s the University of Toronto began to question its continued ownership of Connaught. As the University's Connaught Fund states in an historical note: "The consolidation of the Labs’ operations at the Steeles Ave. site, especially since the Labs’ 1955 administrative split from the School of Hygiene underscored its geographic distance from the main University campus (20 km), as well as a growing academic separation. There was a clear drift in what had been more common scientific and research enterprises and in the opportunities for teaching and the supervision of graduate studies by cross-appointed members of Connaught’s staff. In addition, sharply rising regulatory demands, a growing export business and intensified international competition , created a challenging situation. New production facilities, built to meet higher standards, were urgently needed. Yet, the self-sufficient Labs’ resources were limited and the University was struggling to meet demands brought on by the post-war baby boom generation coming of age. During 1971-72, this sense of uncertainty sharply intensified, especially after the University received a compelling offer to buy Connaught Laboratories and transform it into a profit-oriented company." [73] The University used proceeds of the sale to establish the Connaught Fund, which supports graduate students, early-career researchers, interdisciplinary teams, and innovators. [74]

In June 1972, the Connaught Medical Research Laboratories was sold to the Canada Development Corporation (CDC) for $25 million (Canadian Dollars) and became known as "Connaught Laboratories Limited". [75] Logistically, it was incorporated as "CDC Life Sciences Inc." under the CDC's healthcare division titled "ConnLab Holdings Ltd." [76] [77] [78] At the time the CDC, charged with developing and maintaining Canadian-controlled companies in the private sector through a mixture of public and private investment, was federally owned. Nonetheless, the sale continued to stir controversy in the following years as the Labs became profit-driven and became subject to governmental investigation under allegations of mismanagement and deteriorated manufacturing standards. [79] By 1974, Connaught had increased prices with one-day notice on most products, including insulin, such that one report noted that "some of its insulin wholesale prices became higher than the top U.S. retail prices found in a check just across the border at Niagara Falls." A more serious faux pas was noted in regard to an unannounced increase in the potency of a smallpox vaccine which caused strong reactions in patients and alarmed health authorities in Saskatchewan. [80] The following February, The Globe and Mail ran a series of articles inquiring into Connaught's activities under the CDC. [81] A separate review in 1989 reiterated that "staff was cut and plans were made to sell land and other assets to raise cash to cover financial mismanagement." [30]

Expansion into the United States

In 1978, Connaught expanded into the United States with the acquisition of a vaccine production facility in Swiftwater, Pennsylvania. [75] [82] The expansion established "Connaught Laboratories Inc.", a U.S. subsidiary of Connaught Laboratories Ltd. The acquired facility was previously operated by Merrell-National Laboratories, the largest producer of swine flu vaccine in the U.S. Government's ill-fated mass immunization program in 1976 and the sole source of the yellow fever vaccine in the United States. [83]

The expansion consisted of a three-way deal between Connaught Laboratories Ltd., Richardson-Merrell Inc., and the Salk Institute for Biological Studies. The Salk Institute would take over the entirety of Richarson-Merrell's research and production plant as the company exited the market. Connaught would acquire the vaccine manufacturing facilities from the Salk Institute. [83]

Privatization and sale to Institut Mérieux

By 1984, government enterprise had become unfashionable under Brian Mulroney and CDC Life Sciences was sold to the private sector. [84] [85] Its holdings, including Connaught, were sold through two public issues in 1984 and in 1987. [30] As the shares were sold off, CDC Life Sciences Inc. was renamed "Connaught Biosciences Inc." on July 4, 1988. [77]

In April 1988, Institut Mérieux of France tried to buy a controlling stake in Connaught, but was blocked by the Ontario and Quebec securities commissions because the acquisition favoured one group of shareholders over others. A year later on 7 March 1989, Institut Mérieux proposed a merger between Connaught and its drug division that would result in Mérieux owning 51% of the combined operations. [86] [87] [88] The move was rejected by shareholders. [89] In September 1989, Swiss-based Ciba-Geigy (now Novartis) and California-based Chiron Corporation made a joint offer of $30-a-share (US$764 million). Institut Mérieux made yet another bid for Connaught, topping the joint offer with a bid of $37-a-share (US$813 million). [90] In October, the Canadian government rejected the initial bid on the ground that the offer could not be judged as being of "net benefit" to Canada. [91] At that time, Connaught was the world's largest manufacturer of influenza vaccines but no longer manufactured insulin, instead "ironically ... selling insulin products made by Novo Nordisk Group of Denmark." [30] [76] [92]

Since the 1972 sale of the laboratories to the CDC stipulated that the drug firm could not be sold to a foreign-owned company, the University of Toronto opposed the merger "on the ground that a foreign takeover would mean a loss of research spending and jobs in Canada." [93] [94] It took Connaught to court seeking an injunction to block the sale, but withdrew its objection following an agreement with Mérieux that medical research support would continue if the company's bid succeeded. [95] [96] The Canadian government approved the bid for Connaught in December 1989. [97] The move was criticized by many, including Liberal MP Jim Peterson, who was critical of Brian Mulroney's industrial policy and voiced that "no other industrialized country ... would permit the takeover of its leading biotechnology firm." [89]

Connaught was sold to Mérieux, and transformed into the North American component of Pasteur Mérieux Connaught (PMC) owned by Mérieux's parent company, Rhône-Poulenc. [89] Since ownership of Connaught had been transferred, "Connaught Biosciences Inc." was formally dissolved in 1990. [77] A decade later in 1999, Rhône-Poulenc merged with Hoechst of Germany to create Aventis. PMC thus became Aventis-Pasteur, a subsidiary of Aventis devoted to vaccines. In 2004, Aventis was acquired by Sanofi. Aventis-Pasteur, the vaccine subsidiary, became Sanofi Pasteur. [98] [75]

Today, the Connaught Laboratories' facilities are known as the "Connaught Campus" of Sanofi Pasteur. [98]

See also

Related Research Articles

<span class="mw-page-title-main">Vaccine</span> Pathogen-derived preparation that provides acquired immunity to an infectious disease

A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and recognize further and destroy any of the microorganisms associated with that agent that it may encounter in the future.

<span class="mw-page-title-main">Diphtheria</span> Bacterial disease

Diphtheria is an infection caused by the bacterium Corynebacterium diphtheriae. Most infections are asymptomatic or have a mild clinical course, but in some outbreaks, the mortality rate approaches 10%. Signs and symptoms may vary from mild to severe, and usually start two to five days after exposure. Symptoms often develop gradually, beginning with a sore throat and fever. In severe cases, a grey or white patch develops in the throat, which can block the airway, and create a barking cough similar to what is observed in croup. The neck may also swell, in part due to the enlargement of the facial lymph nodes. Diphtheria can also involve the skin, eyes, or genitals, and can cause complications, including myocarditis, inflammation of nerves, kidney problems, and bleeding problems due to low levels of platelets.

<span class="mw-page-title-main">Charles Best (medical scientist)</span> Canadian co-discoverer of insulin (1899–1978)

Charles Herbert Best, was an American-Canadian medical scientist and one of the co-discoverers of insulin with Frederick Banting. He served as the chair of the Banting and Best Department of Medical Research at the University of Toronto and was further involved in research concerning choline and heparin.

In biology, immunity is the state of being insusceptible or resistant to a noxious agent or process, especially a pathogen or infectious disease. Immunity may occur naturally or be produced by prior exposure or immunization.

This is a timeline of the development of prophylactic human vaccines. Early vaccines may be listed by the first year of development or testing, but later entries usually show the year the vaccine finished trials and became available on the market. Although vaccines exist for the diseases listed below, only smallpox has been eliminated worldwide. The other vaccine-preventable illnesses continue to cause millions of deaths each year. Currently, polio and measles are the targets of active worldwide eradication campaigns.

<span class="mw-page-title-main">Émile Roux</span> French physician (1853–1933)

Pierre Paul Émile Roux FRS was a French physician, bacteriologist and immunologist. Roux was one of the closest collaborators of Louis Pasteur (1822–1895), a co-founder of the Pasteur Institute, and responsible for the institute's production of the anti-diphtheria serum, the first effective therapy for this disease. Additionally, he investigated cholera, chicken-cholera, rabies, and tuberculosis. Roux is regarded as a founder of the field of immunology.

<span class="mw-page-title-main">Pasteur Institute</span> French disease research organization

The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who invented pasteurization and vaccines for anthrax and rabies. The institute was founded on 4 June 1887 and inaugurated on 14 November 1888.

<span class="mw-page-title-main">DPT vaccine</span> Combination vaccine

The DPT vaccine or DTP vaccine is a class of combination vaccines against three infectious diseases in humans: diphtheria, pertussis, and tetanus (lockjaw). The vaccine components include diphtheria and tetanus toxoids, and either killed whole cells of the bacterium that causes pertussis or pertussis antigens. The term toxoid refers to vaccines which use an inactivated toxin produced by the pathogen which they are targeted against to generate an immune response. In this way, the toxoid vaccine generates an immune response which is targeted against the toxin which is produced by the pathogen and causes disease, rather than a vaccine which is targeted against the pathogen itself. The whole cells or antigens will be depicted as either "DTwP" or "DTaP", where the lower-case "w" indicates whole-cell inactivated pertussis and the lower-case "a" stands for "acellular". In comparison to alternative vaccine types, such as live attenuated vaccines, the DTP vaccine does not contain any live pathogen, but rather uses inactivated toxoid to generate an immune response; therefore, there is not a risk of use in populations that are immune compromised since there is not any known risk of causing the disease itself. As a result, the DTP vaccine is considered a safe vaccine to use in anyone and it generates a much more targeted immune response specific for the pathogen of interest.

<span class="mw-page-title-main">Instituto Butantan</span> Biotech research center in Brazil

The Instituto Butantan is a Brazilian biologic research center located in Butantã, in the western part of the city of São Paulo, Brazil. Instituto Butantan is a public institution affiliated with the São Paulo State Secretariat of Health and considered one of the major scientific centers in the world. Butantan is the largest immunobiologicals and biopharmaceuticals producer in Latin America. It is world-renowned for its collection of venomous snakes, as well as those of venomous lizards, spiders, insects and scorpions. By extracting the reptiles' and insects' venoms, the Institute develops antivenoms and medicines against many diseases, which include tuberculosis, rabies, tetanus and diphtheria.

Sanofi Pasteur is the vaccines division of the French multinational pharmaceutical company Sanofi. Sanofi Pasteur is the largest company in the world devoted entirely to vaccines. It is one of four global producers of the yellow fever vaccine.

<span class="mw-page-title-main">William Hallock Park</span>

William Hallock Park was an American bacteriologist and laboratory director at the New York City Board of Health, Division of Pathology, Bacteriology, and Disinfection from 1893 to 1936.

<span class="mw-page-title-main">Diphtheria vaccine</span> Vaccine against diphtheria

Diphtheria vaccine is a toxoid vaccine against diphtheria, an illness caused by Corynebacterium diphtheriae. Its use has resulted in a more than 90% decrease in number of cases globally between 1980 and 2000. The first dose is recommended at six weeks of age with two additional doses four weeks apart, after which it is about 95% effective during childhood. Three further doses are recommended during childhood. It is unclear if further doses later in life are needed.

<span class="mw-page-title-main">John G. FitzGerald</span>

John Gerald "Gerry" FitzGerald was a Canadian physician and public health specialist who was instrumental in the control of diphtheria, first by producing and freely distributing antitoxin, and then in 1924 by using mass production to enable widespread use of the vaccine devised by Gaston Ramon.

<span class="mw-page-title-main">Dalla Lana School of Public Health</span> School of public health at the University of Toronto

Dalla Lana School of Public Health is the school of public health at the University of Toronto. It was founded in 1927, and was home for 50 years to Connaught Laboratories, a manufacturer of vaccines, insulin, and many other pharmaceutical products. Having grown to be the largest cluster of public health scholars in Canada, the school was revitalized in 2008 with the support of a major gift from the Dalla Lana family.

<span class="mw-page-title-main">Frieda Fraser</span> Canadian physician (1899–1994)

Frieda Fraser was a Canadian physician, scientist and academic who worked in infectious disease, including research on scarlet fever and tuberculosis. After finishing her medical studies at the University of Toronto in 1925, she completed a two-year internship in the United States, studying and working in Manhattan and Philadelphia. Afterward, she conducted research in the Connaught Laboratories concentrating on infectious disease, making important contributions in the pre-penicillin age to isolation of the strains of streptococci likely to lead to disease. From 1928, she lectured in the Department of Hygiene at the University of Toronto on preventive medicine, working her way up from a teaching assistant to a full professor by 1955. In college, around 1917 Fraser met her life partner, Edith Williams, and though their families tried to keep them apart, their relationship spanned until Edith's death in 1979. The correspondence between the two has been preserved and is an important legacy for the lesbian history of Canada.

DTaP-IPV/Hib vaccine is a 5-in-1 combination vaccine that protects against diphtheria, tetanus, whooping cough, polio, and Haemophilus influenzae type B.

Leone Norwood Farrell (1904–1986) was a Canadian biochemist and microbiologist who identified microbial strains of industrial importance and developed innovative techniques for the manufacture of vaccines and antibiotics. Her inventions enabled the mass production of the polio vaccine.

Edith M. Taylor (1899-1993) was a Canadian biochemist known primarily for her work in producing novel techniques in vaccine production, especially her work on the production of diphtheria toxoid, while employed as a researcher by Connaught Laboratories in Toronto, Canada.

<span class="mw-page-title-main">Olga Povitzky</span> American physician

Olga Raissa Povitzky, also seen as Olga Povitsky, was a Russian-born American physician and bacteriologist with the New York Health Department; she also worked at a field hospital in France during World War I.

Peter Joseph Moloney was a Canadian chemist. He is known for his work on developing vaccines against diphtheria and tetanus, purifying insulin preparations for clinical use, demonstrating antibodies against insulin in humans and animals, and developing sulfated insulin preparations for the treatment of diabetics with insulin resistance. He also invented a quick-acting pH electrode and helped to develop an antiserum that was used in WW II for protection against gas gangrene.

References

  1. 1 2 3 4 5 Rutty, Christopher J. "Origins: From the Connaught Fund & Back to Connaught Laboratories". Connaught Fund. Retrieved 12 Apr 2019.
  2. ↑ "Nobel Lectures, Physiology or Medicine 1901-1921: Emil von Behring". NobelPrize.org. Amsterdam: Elsevier Publishing Company. 1967. Retrieved 2019-04-12.
  3. ↑ Markel, Howard (2007-07-10). "Diphtheria - Vaccines - Horses". The New York Times. ISSN   0362-4331 . Retrieved 2019-04-12.
  4. 1 2 "Waging War on Infection". University of Toronto Magazine. 23 September 2014. Retrieved 2019-05-28.
  5. 1 2 3 4 5 Rutty, Christopher J. "Connaught Laboratories & The Crucible of World War I". Connaught Fund. Retrieved 12 April 2019.
  6. ↑ "Biography – GOODERHAM, Sir ALBERT EDWARD – Volume XVI (1931-1940) – Dictionary of Canadian Biography". www.biographi.ca. Retrieved 2019-05-28.
  7. 1 2 "Wartime Tragedies - Influenza, 1918-1919". Canada and the First World War. Retrieved 2019-05-28.
  8. ↑ Report of the Royal Commission on University Finances. Toronto: King's Publisher. 1921. pp.  36–38 – via Toronto Public Library: Research and Reference Libraries.{{cite book}}: |website= ignored (help)
  9. ↑ Bliss, Michael (2007-05-15). The Discovery of Insulin. University of Chicago Press. ISBN   9780226058993.
  10. ↑ Altman, Lawrence K. (1982-09-14). "The Tumultuous Discovery of Insulin: Finally, Hidden Story Is Told". The New York Times. ISSN   0362-4331 . Retrieved 2019-05-29.
  11. 1 2 3 4 5 6 7 Rutty, Christopher J. "Connaught Laboratories & The Making of Insulin". Connaught Fund.
  12. ↑ University of Toronto Board of Governors Insulin Committee (25 Jan 1922). "Memorandum in reference to the co-operation of the Connaught Antitoxin Laboratories in the researches conducted by Dr. Banting, Mr. Best and Dr. Collip under the general direction of Professor J.J.R. Macleod to obtain an extract of pancreas having a specific effect on blood sugar concentration". University of Toronto Libraries.
  13. ↑ "Work on diabetes shows progress against disease". Toronto Star Weekly. University of Toronto Libraries. 14 Jan 1922.
  14. ↑ Fletcher, A. A. (17 Nov 1962). "Early clinical experiences with insulin". Canadian Medical Association Journal. 87 (20): 1052–5. PMC   1849803 . PMID   13945508.
  15. ↑ Banting, Frederick G. (Dec 1921 – Jan 1922). "Patient Records for Leonard Thompson". University of Toronto Libraries.
  16. ↑ Banting, Frederick G. (16 August 1922). "Patient records for Elizabeth Hughes". University of Toronto Libraries.
  17. ↑ Woodbury, David Oakes (February 1963). "Please save my son!". University of Toronto Libraries.
  18. ↑ "Nobel medicine prize awarded to Drs. Banting and Macleod, Toronto discoverers of insulin for treatment of diabetes". University of Toronto Libraries. New York Herald. 26 October 1923.
  19. ↑ "Macleod awards Collip half of his Nobel Prize". Toronto Daily Star. University of Toronto Libraries. 7 Nov 1923.
  20. ↑ Royal Karolinska Institute (1923). "Nobel Prize medal inscribed to F. G. Banting". University of Toronto Libraries. Stockholm.
  21. ↑ Royal Karolinska Institute (1923). "Citation to F. G. Banting and J. J. R. Macleod accompanying the Nobel Prize". University of Toronto Libraries. Stockholm.
  22. ↑ "Dr. Banting's hard work won Nobel Prize". New York Herald. University of Toronto Libraries. 4 Nov 1923.
  23. ↑ "University honours professors Banting and Macleod as winners of the Nobel Prize award for medicine in board of governors' banquet held at Hart House". The Globe. University of Toronto Libraries. 27 Nov 1923.
  24. ↑ "Four men will share in the Nobel Prize". University of Toronto Libraries. Nov 1923.
  25. ↑ "UofT Board of Governors - Insulin Committee". University of Toronto Libraries. Retrieved 10 June 2019.
  26. ↑ Insulin Committee of the University of Toronto (1925). "Memorandum on the course pursued by the University of Toronto in the development of the manufacture of insulin". University of Toronto Libraries.
  27. ↑ Banting, F.G.; Best, C.H.; Collip, J.B. (Nov 1922). "Draft copy of the patent for insulin manufacture in Great Britain". University of Toronto Libraries.
  28. ↑ Banting, F.G.; Best, C.H.; Collip, J.B. (19 Dec 1922). "Documents submitted with application to the Canadian Patent Office for a patent". University of Toronto Libraries.
  29. ↑ Banting, Frederick G. (27 Jan 1923). "Letter to Sir Robert Falconer regarding Banting's views on patents". University of Toronto Libraries.
  30. 1 2 3 4 Enchin, Harvey (30 Sep 1989). "History fuels nationalism-global trade debate". The Globe and Mail. p. B1. ISSN   0319-0714.
  31. 1 2 University of Toronto Insulin Committee (8 Nov 1923). "Report on situation in various foreign countries". University of Toronto Libraries.
  32. ↑ Denmark Patent Office (27 Feb 1924). "Denmark patent No. 34874". University of Toronto Libraries.
  33. ↑ "New laboratory". The Globe. Toronto, ON. 1 Aug 1923. p. 11. ISSN   0839-3680.
  34. 1 2 3 4 Rutty, Christopher J. "A Relentless Pace: Connaught Labs, Insulin Innovation, School Building and Defeating Diphtheria, 1923–29". Connaught Fund.
  35. 1 2 3 4 5 6 Rutty, Christopher J. "From Insulin to Heparin: Innovation at Connaught Labs During the 1930s". Connaught Fund.
  36. ↑ Scott, David Alymer; Fisher, Albert Madden (May 1935). "Crystalline insulin". Biochemical Journal. 29 (5): 1048–1054. doi:10.1042/bj0291048. ISSN   0264-6021. PMC   1266596 . PMID   16745762.
  37. 1 2 "Vaccines and Immunization: Epidemics, Prevention and Canadian Innovation - Profiles". Museum of Healthcare at Kingston. Retrieved 2019-06-07.
  38. ↑ Underwood, E. Ashworth (1935). "The Diphtheria Toxoid-Reaction (Moloney) Test: Its Applications and Significance". The Journal of Hygiene. 35 (4): 449–475. doi:10.1017/s0022172400032496. ISSN   0022-1724. JSTOR   3859776. PMC   2170935 . PMID   20475296.
  39. ↑ DEADMAN, WILLIAM J.; ELLIOTT, F. J. (1933). "The Laboratory History of Diphtheria in Hamilton". Canadian Public Health Journal. 24 (3): 137–141. ISSN   0319-2652. JSTOR   41976815.
  40. 1 2 "Funding the first clinical trials of heparin". Banting and Best Research Foundation. Retrieved 2019-06-03.
  41. ↑ "Heparin use is described". The Globe and Mail. 21 Oct 1941. p. 18. ISSN   0319-0714.
  42. ↑ "Success With Heparin in Toronto Is Welcomed by British Surgeons". The Globe and Mail. 4 June 1939. p. 2. ISSN   0319-0714.
  43. ↑ "Gordon Murray". The Canadian Encyclopedia. Retrieved 2019-06-03.
  44. 1 2 3 4 5 6 Rutty, Christopher J. "Connaught Labs, World War II & Biotech Innovation". Connaught Fund. Retrieved 7 Jun 2019.
  45. ↑ Bradburn, Jamie (2016-11-08). "A Short History of One Spadina Crescent". Torontoist. Retrieved 2019-06-07.
  46. ↑ Blatherwick, John (1 October 2017). "Officer - Order of the British Empire" (PDF). Canadian Orders, Decorations, and Medals. p. 57. Retrieved 7 Jun 2019.
  47. 1 2 3 4 5 6 DEFRIES, R. D. (1948). "The Connaught Medical Research Laboratories 1914-1948". Canadian Journal of Public Health. 39 (8): 330–344. ISSN   0008-4263. JSTOR   41979831. PMID   18878250.
  48. ↑ Lax, Eric (February 2005). The Mold in Dr. Florey's Coat: The Story of the Penicillin Miracle. Macmillan. ISBN   9780805077780.
  49. ↑ Fleming, A. (2001). "On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. 1929". Bulletin of the World Health Organization. 79 (8): 780–790. ISSN   0042-9686. PMC   2566493 . PMID   11545337.
  50. ↑ Wainwright, Milton; Swan, Harold T. (Jan 1986). "C.G. Paine and the earliest surviving clinical records of penicillin therapy". Medical History. 30 (1): 42–56. doi:10.1017/S0025727300045026. ISSN   0025-7273. PMC   1139580 . PMID   3511336.
  51. 1 2 3 MacTaggart, Ken W. (1 Dec 1943). "It's Penicillin". Maclean's Archive. Retrieved 2019-06-10.
  52. ↑ "The Nobel Prize in Physiology or Medicine 1945". NobelPrize.org. Retrieved 2019-06-10.
  53. 1 2 3 4 5 Rutty, Christopher J. "Connaught Labs, Polio Research & Conquering "The Crippler"". Connaught Fund. Retrieved 2019-03-22.
  54. ↑ Offit, Paul A. (2005-04-07). "The Cutter Incident, 50 Years Later". New England Journal of Medicine. 352 (14): 1411–1412. doi:10.1056/NEJMp048180. ISSN   0028-4793. PMID   15814877.
  55. 1 2 3 4 Houston, C. Stuart; McIntyre, John W. R. (1999-12-14). "Smallpox and its control in Canada". CMAJ. 161 (12): 1543–1547. ISSN   0820-3946. PMC   1230874 . PMID   10624414.
  56. ↑ Needham, Joseph (2000-04-13). Science and Civilisation in China: Volume 6, Biology and Biological Technology, Part 6, Medicine. Cambridge University Press. ISBN   9780521632621.
  57. ↑ Pead, Patrick J. (2003-12-20). "Benjamin Jesty: new light in the dawn of vaccination". The Lancet. 362 (9401): 2104–2109. doi:10.1016/S0140-6736(03)15111-2. ISSN   0140-6736. PMID   14697816. S2CID   4254402.
  58. ↑ "Smallpox". The Canadian Encyclopedia. Retrieved 2019-06-10.
  59. ↑ Hopper, Tristin (2017-02-21). "Everyone was dead: When Europeans first came to B.C., they stepped into the aftermath of a holocaust". National Post. Retrieved 2019-06-10.
  60. ↑ Harris, Cole (1994). "Voices of Disaster: Smallpox around the Strait of Georgia in 1782". Ethnohistory. 41 (4): 591–626. doi:10.2307/482767. ISSN   0014-1801. JSTOR   482767.
  61. ↑ Warren, Christopher (2014-01-02). "Smallpox at Sydney Cove – who, when, why?". Journal of Australian Studies. 38 (1): 68–86. doi:10.1080/14443058.2013.849750. ISSN   1444-3058. S2CID   143644513.
  62. ↑ "Chicken pox or smallpox in the colony at Sydney Cove in April, 1789". Radio National. 2010-09-17. Retrieved 2019-06-10.
  63. ↑ Gill, Harold B. Jr. (Spring 2004). "Colonial Germ Warfare". Colonial Williamsburg Journal. Retrieved 2019-06-10.
  64. ↑ Dixon, David (2005). Never Come to Peace Again: Pontiac's Uprising and the Fate of the British Empire in North America. University of Oklahoma Press. ISBN   9780806136561.
  65. 1 2 3 4 5 Rutty, Christopher J. "Connaught Labs, Smallpox & Stopping "The Speckled Monster"". Connaught Fund. Retrieved 11 June 2019.
  66. ↑ Walsh, Robin (1 Oct 2010). "A history of the pharmaceutical industry". PharmaPhorum.
  67. ↑ "Pharmaceutical Industry". The Canadian Encyclopedia. 4 Mar 2015. Retrieved 11 June 2019.
  68. ↑ Steven Palmer; Gilberto Hochman; Danieli Arbex (2010). "Smallpox eradication, laboratory visits, and a touch of tourism: travel notes of a Canadian scientist in Brazil". História, Ciências, Saúde - Manguinhos. 17 (3). ISSN   0104-5970.
  69. ↑ Organization, World Health (1968). "Methodology of freeze-dried smallpox vaccine production". World Health Organization. hdl:10665/67966.
  70. ↑ Fenner, Frank; Ladnyi, Ivan Danilovich; Jezek, Zdenek; Arita, Isao; Henderson, Donald A. (1988). Smallpox and its eradication. World Health Organization. hdl:10665/39485. ISBN   9789241561105.
  71. ↑ "WHO | Smallpox". 2007-09-21. Archived from the original on 2007-09-21. Retrieved 2019-06-10.
  72. ↑ "WHO | The Smallpox Eradication Programme - SEP (1966-1980)". WHO. Archived from the original on May 18, 2010. Retrieved 2019-06-10.
  73. ↑ "Chapter 12: Drifting Apart 1966-1972 | Connaught Fund". connaught.research.utoronto.ca.
  74. ↑ "Research & Innovation | University of Toronto". Archived from the original on 2023-06-29.
  75. 1 2 3 "Sanofi Pasteur - The Legacy Project". thelegacyproject.ca. Retrieved 2019-07-23.
  76. 1 2 "Old contract may prevent merger of drug companies". The Ottawa Citizen. Canadian Newsstream. 11 Apr 1989. p. B7. ISSN   0839-3222.
  77. 1 2 3 "Connaught Biosciences Inc". OpenGovCA. Retrieved 4 Jun 2019.
  78. ↑ Geekie, D.A. (5 Feb 1977). "Why did the CMA set up a committee to investigate Connaught?". Canadian Medical Association Journal. 116 (3): 293–294. PMC   1878940 .
  79. ↑ Gerald, McAuliffe; Hollobon, Joan; Marshall, John (26 Feb 1975). "CONNAUGHT AND THE CDC: Trouble in test tubes, treasury of world-famous Canadian firm". The Globe and Mail. p. 1. ISSN   0319-0714.
  80. ↑ McAuliffe, Gerald; Hollobon, Joan; Marshall, John (26 Feb 1975). "Prices, oversights cloud reputation in Canada: Foreign holdings could hurt Connaught CDC push into world health-care market takes priority over firm's business at home". The Globe and Mail. p. 4. ISSN   0319-0714.
  81. ↑ McAuliffe, Gerald; Hollobon, Joan; Marshall, John (26 Feb 1975). "Connaught and the CDC". The Globe and Mail. ISSN   0319-0714.
  82. ↑ "MEDICAL RESEARCH: A brief history of Connaught". The Ottawa Citizen. 7 Oct 1991. p. A5. ISSN   0839-3222.
  83. 1 2 "Connaught is Making Some Vaccines in the U.S.". The Globe and Mail. 21 Jan 1978. p. 16.
  84. ↑ Goar, Carol (31 Dec 1987). "The 'blueing' of Canada In 1987, this country quietly joined the capitalist revival under Mulroney's deft master plan". Toronto Star. p. A16. ISSN   0319-0781.
  85. ↑ Walkom, Thomas; Kwinter, Monte (12 Oct 1989). "Peterson must save Connaught for Canada". Toronto Star. Canadian Newsstream. p. A17. ISSN   0319-0781.
  86. ↑ Benzing, Karen; McMurdy, Deirdre (7 Mar 1989). "Institut Merieux offers merger with Connaught". Financial Post. Toronto, ON: Canadian Newsstream. p. 52. ISSN   0838-8431.
  87. ↑ Bertin, Oliver (7 Mar 1989). "Merieux targeting Connaught once again". The Globe and Mail. Canadian Newsstream. p. B11. ISSN   0319-0714.
  88. ↑ McCarthy, Shawn (15 Jul 1989). "Connaught to step up research if Merieux deal goes through". Toronto Star. p. C1. ISSN   0319-0781.
  89. 1 2 3 McGee, Suzanne (14 Dec 1989). "Merieux Bid Wins In Canadian Fight For Vaccine Firm". Wall Street Journal. p. B4. ISSN   0099-9660.
  90. ↑ "Rival's Connaught Bid Is Topped by Merieux". New York Times. 26 Sep 1989. p. D5. ISSN   0362-4331.
  91. ↑ "French Concern's Bid For Connaught Stalled". New York Times. 14 Oct 1989. p. 1.35. ISSN   0362-4331.
  92. ↑ "Pasteur Merieux Connaught Canada". The Globe and Mail. 24 July 1997. p. B4. ISSN   0319-0714.
  93. ↑ "Merieux Bid Gains". New York Times. 26 Oct 1989. p. D5. ISSN   0362-4331.
  94. ↑ Roseman, Ellen (29 Jun 1989). "Canadian rights to insulin now shared worldwide". The Globe and Mail. p. B14. ISSN   0319-0714.
  95. ↑ Ferguson, Jonathan (2 Oct 1989). "U of T near agreement on drug lab sale". Toronto Star. Canadian Newsstream. p. D1. ISSN   0319-0781.
  96. ↑ Rusk, James (26 Oct 1989). "Merieux, U of T reach accord on Connaught". The Globe and Mail. p. B1. ISSN   0319-0714.
  97. ↑ "Canada Approves Connaught Offers". New York Times. 14 Dec 1989. p. D5. ISSN   0362-4331.
  98. 1 2 "Sanofi Pasteur Limited (formerly Connaught) | The Discovery and Early Development of Insulin". University of Toronto Libraries. Retrieved 2019-06-11.

Bibliography

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.