Connaught Laboratories Research Articles

Oliver Smithies. 23 June 1925—10 January 2017

Oliver Smithies was born in Copley, near Halifax in Yorkshire, UK. He received his doctorate from Oxford in 1951, then began working at the Connaught Laboratories in Toronto, where he developed starch gel electrophoresis. This technology allowed identification of genetic variants in human serum proteins and revolutionized protein analysis. After moving to the University of Wisconsin, he studied the genetics of antibody variability, then turned to nucleic acid methods, developing safe cloning vectors, driving production of software for genetic analysis, sequencing several human genes and finally creating genetically engineered animals, for which he later received the Nobel Prize. He then moved to the University of North Carolina, where he developed methods for altering gene dosage in mice, which he used to develop ways to attack complex physiological questions, including blood pressure regulation. Finally, he formulated a new hypothesis to explain kidney glomerular filtration, then devised methods that confirmed the hypothesis. Oliver collaborated with his wife, Nobuyo Maeda, during a long and happy marriage. While maintaining separate laboratories, they stimulated each other's scientific understanding and frequently published together. During a 70-year life in science, he mentored many students, postdoctoral fellows and collaborators, nearly all remaining his friends for life.

“It Works! Now What?” Insulin Development, Production, and Distribution at Connaught Laboratories, University of Toronto, 1922–24

The first successful human use of a pancreatic extract on Leonard Thompson, a 13-year-old severe diabetic at Toronto General Hospital, on 23 January 1922, is generally seen as the climax of the discovery-of-insulin story. However, this seminal event in the history of medicine begs the question: “It works! Now what?” The story may well have ended abruptly if not for the foresight and leadership of Dr. John G. FitzGerald, director of the University of Toronto’s Connaught Antitoxin Laboratories, based in the basement of the same Medical Building where F.G. Banting and C.H. Best, under the direction of J.J.R. Macleod, conducted the research that led to the first tests on Thompson. Significantly, it was the addition to the team of biochemist J.B. Collip and his purification of the extract that enabled the successful 23 January test. Within a day, however, tensions within the group, especially between Banting and Collip, and Collip’s threat to leave and take out his own patent, prompted FitzGerald to act. On 25 January, FitzGerald finalized a seminal agreement between Connaught and Banting, Best, Collip, and Macleod that secured the further development of methods to prepare the extract on a larger scale to enable further clinical testing. From this point, Connaught would play a fundamental role in the insulin story, although its historical significance has been minimized and often misunderstood, overshadowed by the weight of the primary discovery, as well as by the critical contributions of Eli Lilly and Co. This article focuses on Connaught’s intimate involvement in the history of insulin from January 1922 through the summer of 1924, tracing the challenges and innovations of developing larger-scale production methods, the establishment and expansion of Canadian insulin production capacity, and the key role the labs played in spearheading the global distribution of insulin.

The Tyranny of Distance: The Treatment and Prevention of Diphtheria in Middle Canada, 1894-1920.

Before 1900, diphtheria was a deadly infection in Canadian children. Clinical trials in Europe demonstrated that "antitoxin" decreased mortality of the disease. Canadian physicians first utilized the new medication in 1894 and found it most efficacious when administered early in the illness. Two factors hindered the widespread application of the new medication. Imported antitoxin was expensive, and physicians frequently purchased it themselves rather than let their patients expire. In 1916, Connaught Laboratories in Toronto began domestic production of antitoxin, and provincial governments eventually provided access to the life-saving medication for all citizens. The vast distances between families and physicians in rural districts also made it impossible to access the antitoxin before sick children were beyond hope. During the 1920s, a public health program began to actually prevent diphtheria. Ten years of experience in many regions demonstrated the efficacy of immunization as mortality from diphtheria declined to almost zero.

Immunity and Control Analysis of H. Influenzae Type b Polysaccharide-protein Conjugate Vaccine

Haemophilus influenzae type b (HIb) is the widest known cause of bacterial meningitis and a leading cause of bacterial diseases in the United States and many areas of the world. It causes epiglotitis, pneumonia, septic arthritis, osteomylitis and penricarditis. Many sunvivors of meningitis experience in permanent mild hearing loss and mental retardation. The capsular polysaccharide of polyribosylribitol phosphate (PRP) is a major virulence facor of the organism. Antibody to PRP is the primary contributor to induce serum bactericidal activity. Three types of HIb-protein conjugate vaccines were prepared by different methods, using a different protein carrier, PS size, nature of linkage, and ratio of protein and PS: (1) The Connaught Laboratories combined diphtheria toxoid (DT)to HIb PS by cyanogen bromide activation of PS and conjugation of PS and DT by carbodiimide; (2)In the praxis Biologics, HIb oligosaccharides were conjugated to a mutant diphtheria toxin, CRM197, by the reductive amination; (3)The Merck, Sharp & Dohme conjugate vaccine utilized a 40 KD meningococcal outer membrane protein(OMP)and a mutiple synthetic procedure. HIb PS-protein oonjugate vaccine produced high antibody levels in infants 2-6 months of age and young children with no major adverse reactions. Control tests of HIb conjugate vaccine were carried out in two stages : (A) Each lot of PS shall be examined for(l) the chemical content, such as ribose and phosphorus;(2) contamination of cell components, such as protein, LPS and nucleic acids. The carrier protein was then examined for its purity. The conjugate bulk concentrate was next examined for free ribose content, ratio of PS and protein, molecular size, contamination of LPS and pyrogenicity. (B) The final conjugate vaccine contains 10-25 ug PRP per dose. The vaccine was tested for identity and amount of HIb PS, contents of free ribose, free protein, LPS, as well as sterility, general safety and pyrogenicity. Immunization of HIb PS-protein conjugate vaccine holds great promise for the prevention of HIb diseases in young children. An approach using similar technology can be applied to the prevention in the future of diseases caused by other encapsulated bacteria.

Experiences of First Insulin-Treated Patients (1922-1923).

Historical description of first insulin trials just after its discovery. The review includes first initiatives of insulin treatment. The probability of other trials, not reported to the Insulin Committee of the University of Toronto and conducted in the years 1922 and 1923, is quite low. (1) Archival Collections, University of Toronto: Insulin Discovery and Early Developments of Insulin (University of Toronto Libraries digital special collection, with a particular section entitled "From a Patient's Point of View" containing letters, patient charts, newspaper clippings, and photographs). (2) Thomas Fisher Rare Book Library: Academy of Medicine Collection, F. G. Banting Papers, C. H. Best Papers, J. B.Collip Papers, W. R. Feasby Papers, E. Hugues Papers, J. J. R. Macleod Papers. (3) National Library of Medicine: PubMed search for the topic of history of insulin, History of Medicine-on syllabus archive. (4) Selected Journals for History of Medicine: Bulletin of the History of Medicine, Journal of the History of Medicine and Allied Sciences, Medical History. (5) Selected books: The Discovery of Insulin (M. Bliss); Diabetes, Its Medical and Cultural History (D. von Engelhardt); H. C. Hagedorn and Danish Insulin (T.Deckert), Continuing Quest (W. A. Tomkins). This historical review shows the quick progress from impure pancreatic extract to the selective isoelectric precipitation of the hormone, which made possible the introduction of insulin in the clinic. The coordination between the Departments of Physiology (Connaught Laboratories) and Medicine (Toronto General Hospital) was essential for the discovery and implementation of insulin therapy. The Insulin Committee was decisive for the negotiation with the pharmaceutical industry, the purification, grand-scale production, patents' achievement, and provision of licenses to expert clinicians and prestigious health centers. At the end of the year 1923, insulin treatment was already extended to Europe (mainly Scandinavia, Great Britain, and Spain). Insulin discovery and treatment changed the clinical spectrum of diabetes.

What Disturbs Our Blood: A Son’s Quest to Redeem the Past (review)

Reviewed by: What Disturbs Our Blood: A Son’s Quest to Redeem the Past J.T.H. Connor What Disturbs Our Blood: A Son’s Quest to Redeem the Past. James Fitzgerald. Toronto: Random House Canada, 2010. Pp. 497, $34.95 When classifying What Disturbs Our Blood, one needs to address at least the following keywords: autobiography; biography; pathography; mental institutions, mental health and therapies; medical innovation and discovery; medical education; along with insecurity; infidelity; sex, drugs, rock ’n’ roll, and jazz! Prestigious medical and educational institutions such as Johns Hopkins, Cambridge, Queen’s, the Rockefeller Foundation, Connaught Laboratories, and the University of Toronto figure prominently in FitzGerald’s personal story; so too, such luminaries as Fred Banting, Charlie Best, and Clarence ‘C.B.’ Farrar. Duke Ellington makes an appearance too, as he knew the author’s father and, after his Toronto shows, would visit the FitzGerald home to tickle the ivories while filling the air with the pungent smoke of reefers – who knew such bohemianism existed in upscale Toronto during the 1950s? But FitzGerald’s main goal in writing this book is to see through this purple haze and uncover the many secrets that shrouded his and his family’s rollercoaster history. In attempting to redeem this past, FitzGerald had to delve deep into his own, his father’s, and his grandfather’s lives to reveal their painful struggles with mental illness that too often resulted in attempted or fulfilled suicide. On this journey, [End Page 732] the author discovers that his grandfather, Dr John Gerald ‘Gerry’ Fitz-Gerald, was a truly significant figure in the history of Canadian medicine. Gerry FitzGerald graduated in medicine from the University of Toronto in 1903 and would embark on a career of neurology and psychiatry in an effort to understand the links between body and mind. After postgraduate training with the eminent Dr Adolf Meyer at the Buffalo State Asylum for the Insane (the man who ‘invented’ the term depression), Gerry travelled to Baltimore’s Johns Hopkins Medical School, where he met C.B. Farrar, who appointed him a clinical assistant in the Sheppard and Enoch Pratt Hospital, a private institution for the treatment of nervous diseases. In 1906 he returned to Toronto as pathologist at the asylum at 999 Queen Street West. FitzGerald continued to take extensive trips to the United States as well as key medical centres in Europe, where he was to learn from different research institutes and their functioning. Inspired by these models, FitzGerald created a medical farm ‘factory’ following a rabies outbreak in 1913; this initially modest enterprise would evolve into the University of Toronto Connaught Laboratories, which produced millions of doses of vaccine and antitoxins (against rabies, smallpox, typhoid, diphtheria, tetanus, and meningitis) for Ontario. In the following decade, Connaught would be pivotal in the early production, purification, and standardization of insulin. By 1927, FitzGerald was also heading up the university’s pioneering public health unit known as the School of Hygiene; five years later, he was appointed dean of medicine in the University of Toronto. Then, in 1938, suddenly, FitzGerald ‘went off the deep end’ when he suffered a complete mental breakdown. Two years later, he committed suicide in the Toronto General Hospital, following a previously unsuccessful attempt and after incarceration in a tony American mental hospital where he endured insulin shock therapy – excruciating details of which were preserved in a series of letters between him and C.B. Farrar, who had since become a Toronto colleague and physician-confidante to FitzGerald. Such archival documents well illustrate the author’s research skills. The biography of Gerry’s son, ‘Jack,’ is disturbingly similar to that of his father. Educated first at McGill and Cambridge, Jack FitzGerald then graduated in medicine from the University of Toronto in 1942; he would also undertake postgraduate study at Johns Hopkins. A successful allergist at Toronto Western Hospital who also had a medical entrepreneurial bent, his life was plagued by strained marriages along with his own personal mental health issues. During his life he was a patient at 999 Queen, Clarke Institute of Psychiatry, Donwoods Institute, and Homewood; he was also subjected to insulin sub coma treatment, [End Page 733] electroconvulsive...

A Canada-Brazil network in the global eradication of smallpox.

th anniversary of the global eradication of smallpox, the only public health effort in history to eradicate a disease from the human species. The Smallpox Eradication Program (SEP) of the World Health Organization (WHO) was an assemblage of state, bilateral and multilateral agencies and resources, deftly brought together and coordinated by Donald A. Henderson, SEP director from 1966 to 1977. Less visible but equally crucial to the success of the SEP, especially at the level of vaccine research and production, were informal networks of public health scientists. These “epistemic communities” were made up of knowledgebased experts with authoritative claim to policy-relevant knowledge within their field of expertise. 1 Circulating among and transecting different levels of international cooperation, their members shared similar academic backgrounds and scientific values, frequented the same seminars and specialist committee meetings, and understood the challenges involved in the production of vaccines. Often rooted in well-established research and production facilities, these networks could operate without official nation-state sanction or involvement by working through organizations with authority in international health like WHO and the Pan-American Health Organization (PAHO). One such epistemic community linked Canada’s Connaught Laboratories to the SEP and to Latin American – and particularly Brazilian – vaccine production. Its principal members were Henderson, Jose Fonseca da Cunha (1914-2005), who was responsible for vaccine and serum production at Brazil’s Oswaldo Cruz Institute, and Connaught scientists Robert J. Wilson (1915-1989) and Paul Fenje. Officially, Canada played only an indirect part in the SEP through its role as a WHO member state, and at the outset of the global eradication initiative had no bilateral ventures of any kind in Latin America. The Canada-Brazil network linking Henderson, Wilson, Fenje, Fonseca da Cunha and others, however, allowed Connaught and Canadian scientists to become significant players in the global eradication effort 2 while simultaneously pressing the Canadian government to be less of a “reluctant partner” in health cooperation in the hemisphere. 3

A Canada-Brazil Network in the Global Eradication of Smallpox

th anniversary of the global eradication of smallpox, the only public health effort in history to eradicate a disease from the human species. The Smallpox Eradication Program (SEP) of the World Health Organization (WHO) was an assemblage of state, bilateral and multilateral agencies and resources, deftly brought together and coordinated by Donald A. Henderson, SEP director from 1966 to 1977. Less visible but equally crucial to the success of the SEP, especially at the level of vaccine research and production, were informal networks of public health scientists. These “epistemic communities” were made up of knowledgebased experts with authoritative claim to policy-relevant knowledge within their field of expertise. 1 Circulating among and transecting different levels of international cooperation, their members shared similar academic backgrounds and scientific values, frequented the same seminars and specialist committee meetings, and understood the challenges involved in the production of vaccines. Often rooted in well-established research and production facilities, these networks could operate without official nation-state sanction or involvement by working through organizations with authority in international health like WHO and the Pan-American Health Organization (PAHO). One such epistemic community linked Canada’s Connaught Laboratories to the SEP and to Latin American – and particularly Brazilian – vaccine production. Its principal members were Henderson, Jose Fonseca da Cunha (1914-2005), who was responsible for vaccine and serum production at Brazil’s Oswaldo Cruz Institute, and Connaught scientists Robert J. Wilson (1915-1989) and Paul Fenje. Officially, Canada played only an indirect part in the SEP through its role as a WHO member state, and at the outset of the global eradication initiative had no bilateral ventures of any kind in Latin America. The Canada-Brazil network linking Henderson, Wilson, Fenje, Fonseca da Cunha and others, however, allowed Connaught and Canadian scientists to become significant players in the global eradication effort 2 while simultaneously pressing the Canadian government to be less of a “reluctant partner” in health cooperation in the hemisphere. 3

Smallpox eradication and Brazil: an interview with Donald A. Henderson

Interview with Donald A. Henderson, the U.S. physician and epidemiologist who headed the World Health Organization's Smallpox Eradication Program from 1966 to 1977. The interviewer talks about the endemic nature of smallpox in Brazil; relations between WHO, the Pan American Health Organization, and the Brazilian government; the role of Connaught Laboratories in the quality of the Brazilian smallpox vaccine; the process that brought certification of smallpox eradication in Brazil; international cooperation in eradicating smallpox and the various strategies applied; the role played by Brazilians in eradicating smallpox in India, Bangladesh, and Africa; and the future of the notion of disease eradication

“Couldn’t Live Without It”: Diabetes, the Costs of Innovation and the Price of Insulin in Canada, 1922-1984

This article traces insulin prices in Canada from 1922, just after its discovery at the University of Toronto, to 1984 when production fell out of Canadian control. Connaught Laboratories (part of the University of Toronto from 1914 to 1972) was the first to manufacture insulin and remained the sole Canadian producer. As a public trust, Connaught remained committed to providing insulin at the lowest possible price despite increasing economic pressures. This article analyzes the context surrounding the price of insulin preparations and how they fell from 1922 to 1942, remained unchanged until 1967, and rose during the 1970s.

Basic Fibroblast Growth Factor (bFGF, FGF-2) Potentiates Leukocyte Recruitment to Inflammation by Enhancing Endothelial Adhesion Molecule Expression

Basic fibroblast growth factor (bFGF, FGF-2) is a potent angiogenic factor and endothelial cell mitogen. Although bFGF levels are increased in chronically inflamed tissue, its role in inflammation is unclear. We investigated the effect of bFGF on acute dermal inflammation and the recruitment of monocytes, T cells, and neutrophils. Leukocyte recruitment to inflamed sites was quantified with radiolabeled leukocytes. Intradermal injection of bFGF in rats did not induce leukocyte recruitment or inflammation. However, the recruitment of leukocytes to inflammation induced by tumor necrosis factor-alpha, interferon-gamma, C5a, or a delayed hypersensitivity reaction was enhanced by bFGF by 55 to 132% (P < 0.05). Either acute or prolonged bFGF treatment of dermal sites had this effect. The potentiating effect of bFGF on leukocyte recruitment was also seen in joints. There was no associated modulation of vascular permeability, blood flow, or angiogenesis in the sites by bFGF. However, the expression of the endothelial cell adhesion molecules (CAMs) for leukocytes, P-selectin, E-selectin, and ICAM-1, was significantly up-regulated in the inflamed tissue by bFGF, as quantified by radiolabeled anti-CAM antibody binding in vivo. Thus, although not directly proinflammatory, bFGF synergistically potentiates inflammatory mediator-induced leukocyte recruitment, at least in part, by enhancing CAM up-regulation on endothelium.

Surgical Limits: The Life of Gordon Murray (review)

Reviewed by: Surgical Limits: The Life of Gordon Murray Christopher J. Rutty Surgical Limits: The Life of Gordon Murray. Shelley McKellar. Toronto: University of Toronto Press, 2003. Pp. x, 270, illus. $45.00 Concise, though richly detailed, Shelly McKellar's reluctant biography of Dr Gordon Murray (1894-1976) carefully captures the brilliant, though often restless, lonely, and ultimately tragic life of a Canadian surgical pioneer, forever testing his own surgical limits and those of the Toronto medical establishment. It is a reluctant biography because McKellar was not particularly interested in writing about medical lives, much less about 'great doctors, and shivered at the thought of doing "dead white guy history"' (vii). Her biography of Murray grew out of an interest in the history of medical technology, innovation and change, medical knowledge [End Page 860] diffusion, and the concept of cure. Specifically, her interest in Murray developed from his building of the first North American artificial kidney machine in Toronto in the 1940s. In the process of analysing this new piece of homemade medical technology, McKellar soon found herself 'drawn into this surgeon's extraordinary and controversial career' (vii). Fortunately, McKellar's reluctant approach to tackling a biography of a 'great doctor' like Murray turned out to be quite successful, well written, illuminating, and effective. Surgical Limits began as a PhD thesis McKellar wrote at the University of Toronto under the supervision of Michael Bliss, a Canadian historian well experienced in the art of biography writing, including biographies of such great Canadian doctors as Frederick Banting and William Osler. Interestingly, in her preface that outlines her apprehensions about writing a medical biography, McKellar does not mention Bliss's Banting or Osler biographies, but pointed to Judith Leavitt's Typhoid Mary: Captive to the Public's Health and Jacalyn Duffin's Langstaff: A Nineteenth-Century Medical Life. While both biographies are noteworthy, it would seem that Bliss's Banting: A Biography, in particular, would be a more relevant model for a study of Murray's life as a Canadian surgeon and a celebrated, though tragic, medical hero. There are many similarities between Murray and Banting beyond their shared surgical passions, high public profile, and frustrations at Toronto General Hospital. They were contemporaries - Banting born in 1891 and Murray in 1894 - and both spent most of their lives in Toronto, often the focus of newspapers looking for their next great life-saving discovery. If Banting had not died in a plane crash in 1941, the remainder of his life may well have played out along lines similar to Murray's: working in isolation, driven to repeat and surpass past triumphs, and pushing surgical limits beyond the breaking point, despite the risks to patients and professional reputation. McKellar's life of Gordon Murray follows this path. She takes the reader from the celebrated triumphs of Murray's pioneering clinical use of heparin (a blood anticoagulant prepared and purified by Connaught Laboratories) in the late 1930s under the leadership of insulin co-discoverer Charles H. Best, followed by his 'blue baby' surgical successes, and the building, and clinical use, of his artificial kidney on patients in the 1940s. The tone of the story, however, shifts sharply in the 1950s after Murray abruptly left Toronto General Hospital and the University of Toronto to set up his own private research laboratory, the W.P. Caven Memorial Research Foundation (later the Gardiner Medical Research Foundation), in a small house in Toronto to independently pursue surgical and other medical problems that interested him. Murray's first such [End Page 861] research problem was not surgical, but rather the surprising development, production, application, and public championing of a dubious anti-cancer serum. This was followed by a questionable and sensational method of mending severed spinal cords and curing paraplegia in the 1960s that forced a controversial end to his surgical career. McKellar's Gordon Murray was a brilliant surgeon, though ultimately a flawed character. He was driven by the dichotomy of looking forward, pushing his surgical limits to solve the next great medical problems, while remaining locked in a fiercely individualistic approach to surgery and research that had served him well in the 1930s and early 1940s, but left him...

Identification and characterization of avian retroviruses in chicken embryo-derived yellow fever vaccines: investigation of transmission to vaccine recipients.

All currently licensed yellow fever (YF) vaccines are propagated in chicken embryos. Recent studies of chick cell-derived measles and mumps vaccines show evidence of two types of retrovirus particles, the endogenous avian retrovirus (EAV) and the endogenous avian leukosis virus (ALV-E), which originate from the chicken embryonic fibroblast substrates. In this study, we investigated substrate-derived avian retrovirus contamination in YF vaccines currently produced by three manufacturers (YF-vax [Connaught Laboratories], Stamaril [Aventis], and YF-FIOCRUZ [FIOCRUZ-Bio-Manguinhos]). Testing for reverse transcriptase (RT) activity was not possible because of assay inhibition. However, Western blot analysis of virus pellets with anti-ALV RT antiserum detected three distinct RT proteins in all vaccines, indicating that more than one source is responsible for the RTs present in the vaccines. PCR analysis of both chicken substrate DNA and particle-associated RNA from the YF vaccines showed no evidence of the long terminal repeat sequences of exogenous ALV subgroups A to D in any of the vaccines. In contrast, both ALV-E and EAV particle-associated RNA were detected at equivalent titers in each vaccine by RT-PCR. Quantitative real-time RT-PCR revealed 61,600, 348,000, and 1,665,000 ALV-E RNA copies per dose of Stamaril, YF-FIOCRUZ, and YF-vax vaccines, respectively. ev locus-specific PCR testing of the vaccine-associated chicken substrate DNA was positive both for the nondefective ev-12 locus in two vaccines and for the defective ev-1 locus in all three vaccines. Both intact and ev-1 pol sequences were also identified in the particle-associated RNA. To investigate the risks of transmission, serum samples from 43 YF vaccine recipients were studied. None of the samples were seropositive by an ALV-E-based Western blot assay or had detectable EAV or ALV-E RNA sequences by RT-PCR. YF vaccines produced by the three manufacturers all have particles containing EAV genomes and various levels of defective or nondefective ALV-E sequences. The absence of evidence of infection with ALV-E or EAV in 43 YF vaccine recipients suggests low risks for transmission of these viruses, further supporting the safety of these vaccines.

The Discovery of Insulin

Until 1920, having diabetes meant wasting away to almost certain death, but this started to change in the early 1920s. A few weeks after receiving an honours baccalaureate in physiology and chemistry from the University of Toronto in 1921, Charles Herbert Best jumped at the chance for summer work with Dr Frederick Banting. Over that summer, Banting used a surgical technique that he had developed to isolate an unpurified extract of insulin from the pancreas of beagles. It was Best’s responsibility to complete the chemical assays related to this “antidiabetic component” of the pancreas. When the initial dog experiments proved successful, Professor John James Richard MacLeod, who provided laboratory space and general scientific direction for Banting and Best, put his entire research team to work on the production and purification of insulin. James Bertram Collip, who had graduated from the University of Toronto at 15 years of age, joined the team and developed the process by which insulin was purified in sufficient amounts for clinical trials and use in diabetic patients. The first tests were conducted on Leonard Thompson early in 1922, with spectacular success. For this work, Banting was knighted in 1934 and shared the 1923 Nobel Prize in Physiology or Medicine with MacLeod. Best was accepted into medical school and, after completing doctorates in both medicine and physiology, was appointed professor of physiology at the University of Toronto in 1929. He served as Associate Director of the Connaught Laboratories from 1932 to 1941. Years later, Best was involved in isolating heparin. The complete amino acid sequence of the insulin molecule was described in the early 1950s; in fact, insulin was the first protein to be sequenced in its entirety. This pioneering work was confirmed over the period 1963 to 1966, when several groups reported laboratory synthesis The focus for the front cover of CJHP in 2003 is important Canadian medical institutions and discoveries.

Efficacy of a two-component acellular pertussis vaccine in infants.

This case-control study investigated the protective efficacy against pertussis of three doses of a two-component acellular pertussis vaccine (manufactured by Biken in Japan) combined with diphtheria and tetanus toxoids (manufactured by Connaught Laboratories in the US) in infants. A case-control study was performed in 63 pediatric practices in Germany. Prospective recruitment of 16,780 infants ages 6 to 17 weeks took place between February, 1993, and July, 1994. According to parental choice infants received either Biken acellular pertussis vaccine combined with diphtheria and tetanus toxoids (DTacP) (74.6%) at approximately 2, 4 and 6 months of age, or a licensed German diphtheria-tetanus toxoids-whole cell pertussis vaccine (10.9%), diphtheria-tetanus toxoids vaccine (12.5%) or no vaccine (2.0%). Prospective surveillance of pertussis cases between February, 1993, and May, 1995, was accomplished by culturing all infants < or =2 years of age presenting with cough > or = 7 days. A pertussis case was defined as any cough of 21 days or longer plus a positive Bordetella pertussis culture or household contact exposure. We identified 241 pertussis cases prospectively by 11,017 B. pertussis cultures and 949 controls matched for age were selected from the same pediatric practices. Medical history and demographic and vaccine status data were collected from each case and for four controls. Data were analyzed through conditional logistic regression taking into account individual matching and adjusting for potential confounding variables. DTacP combined with diphtheria and tetanus toxoids vaccine was 82% protective (95% confidence interval, 68 to 90), diphtheria-tetanus toxoids-whole cell pertussis vaccine was 96% protective (95% confidence interval, 78 to 99). Protection against typical B. pertussis infection characterized by paroxysmal cough lasting > or =21 days was 96% (95% confidence interval, 87 to 99) for DTacP and was 97% (95% confidence interval, 79 to 100) for diphtheria-tetanus toxoids-whole cell pertussis vaccine. Adjustment for potentially confounding variables did not change the results significantly. Three doses of the two-component acellular pertussis vaccine protected infants against pertussis disease during the period before the recommended booster vaccination. For typical pertussis disease as defined by the WHO efficacy was high and similar to that of a licensed German diphtheria-tetanus toxoids-whole cell pertussis vaccine.

5604108 Test for determining the dose response of a conjugated vaccine : Becker Robert; Biscardi Karen; McVerry Patric; Ryall Robert Henryville, PA, United States assigned to Connaught Laboratories Inc

5604108 Test for determining the dose response of a conjugated vaccine : Becker Robert; Biscardi Karen; McVerry Patric; Ryall Robert Henryville, PA, United States assigned to Connaught Laboratories Inc

IMMUNOGENICITY OF TWO PNEUMOCOCCAL CONJUGATE VACCINES • 766

To assess the immunogenicity of octavalent pneumococcal vaccines that contained either 3 μg of each serotype conjugated to diphtheria toxoid(PncD) or 1 μg of each serotype conjugated to tetanus toxoid (PncT), 80 infants (20 at each of 4 sites) were enrolled to receive one of these vaccines(a total of 40 infants for each vaccine) given separately but at the same time as other routine immunizations (PRP-T, DTP and OPV) at 2, 4 and 6 months of age. Antibody concentrations before each dose and one month after the third dose were determined by ELISA (after adsorption of serum to C-polysaccharide) by Connaught Laboratories. Adverse side effects were minimal. The geometric mean concentrations (GMT) of IgG antibody (μg/ml) against each serotype and against PRP are shown below. Both vaccines induced significant (P<0.05, and in most instances <0.001) increases in concentrations of antibody against each serotype of pneumococcus (except for PncT against type 9V); GMTs of IgG at 7 months against serotypes 4, 6B and 9V were significantly higher in infants who had received PncT than in those who had received PncD (P<0.003). We conclude that both PncD and PncT induce significant increases in concentrations of serotype-specific anti-pneumococcal antibodies. Concentrations of type-specific antibodies at 7 months of age among children who received PncT were similar to or greater than those of children who received PncD. Table

Acellular Pertussis Vaccine is Licensed for Infants

AFTER 15 YEARS of development and extensive field trials in Europe and the United States, the Food and Drug Administration (FDA) has licensed an acellular pertussis vaccine for use in the primary diphtheria-tetanus-pertussis (DTP) immunization series at age 2, 4, and 6 months, when most serious complications of the disease occur. The new licensure does not require a new product to be manufactured. The acellular version has been licensed since 1992 for use in the fourth and fifth doses of DTP given to children up to 6 years of age. The vaccine, manufactured by Connaught Laboratories, Inc, Swiftwater, Pa, is available now to physicians for use in their pediatric practices. Marketed under the trade name Tripedia, the vaccine contains 2 antigens: pertussis toxin and filamentous hemagglutinin. Acellular vaccines were originally developed in Japan. The principle was further developed by several US manufacturers, including Connaught, in response to concerns over adverse

Adverse reactions and antibody response to four doses of acellular or whole cell pertussis vaccine combined with diphtheria and tetanus toxoids in the first 19 months of life

To assess the safety, immunogenicity, and lot consistency of a five-component acellular pertussis vaccine combined with diphtheria and tetanus toxoid (Connaught Laboratories Limited), we randomly allocated 432 infants to receive one of three lots of an acellular pertussis vaccine or a single lot of whole cell pertussis vaccine. Infants were immunized at 2, 4 and 6 months of age and between 17 and 19 months of age. Local and systemic adverse reactions were reported significantly more frequently by recipients of the whole cell than acellular vaccine after each dose. The antibody response against pertussis toxin, filamentous hemagglutinin, and 69 kDa protein was of greater magnitude in acellular pertussis vaccine recipients than whole cell pertussis vaccine recipients. Small differences were detected amongst the vaccine lots tested. We conclude that the acellular pertussis vaccine is safe and immunogenic for the first four doses in children under 2 years of age.

Acellular pertussis vaccine approaches federal approval

The article, Acellular pertussis vaccine approaches federal approval (March 1996 AAP News ), incorrectly states that Tripedia, manufactured by Connaught Laboratories Inc., is the only available acellular pertussis vaccine in the United States. The acellular vaccine Acel-Imune, manufactured by Wyeth-Lederle Vaccines and Pediatrics, also is currently on the U.S. market.