1) THE EPIDEMIC OF THE 20^th CENTURY

a) What is Polio?

Poliomyelitis is a unique, fearsome and politically potent disease that has demanded, and continues to demand, a distinctive response and a significant financial investment to control its spread, manage its physical effects and ensure its final eradication from the planet. <pubhl09.jpg>

Polio is a highly infectious disease caused by a virus, of which humans are the only natural host. <Acc0983A.jpg> While almost all poliovirus infections are mild, invisible and immunizing, spread from person-to-person primarily via fecal-oral contact, if the poliovirus invades the nervous system, specifically damaging the anterior horn of the spinal cord, muscle paralysis can result, usually affecting voluntary muscles in the arms and/or legs. However, five to ten percent of cases die because of paralysis of breathing and/or swallowing muscles. <IMG0004.jpg>

From the1880s and before the introduction of the Salk inactivated, injected polio vaccine (IPV) in 1955, and then the Sabin live, oral polio vaccine (OPV) in 1961-62, worsening polio epidemics struck the industrialized world. After centuries as an invisible, harmless and endemic virus, with only rare, isolated cases of "infantile paralysis" reported, polio epidemics emerged when natural, immunizing poliovirus infections among infants declined due to improving public health standards. Small towns, suburban and rural areas were harder hit than cities. <OMD-ironlung2.jpg>

Indeed, as parents tried to keep their infants and toddlers cleaner and isolated from the "dirt" and other young children, polio became more of a threat. This ironic situation left growing numbers of children (and older siblings and parents) susceptible to nervous system infection when they were inevitably exposed to the poliovirus at a later age -- particularly when they first entered school -- when their immune systems were less likely to respond as effectively. <NAC-a116675.jpg>

Rapidly growing in numbers and increasingly obsessed with personal hygiene, middle class families in northern Europe, Australia and particularly in the new suburban areas of North America, were most vulnerable to polio, especially during the post World War II "baby boom."

1 b) An Emerging Epidemic, 1880s to 1910s

Isolated cases of "infantile paralysis" had occurred for centuries, even as far back as ancient Egypt. However, doctors did not describe its distinctive damage to the spinal cord until about 1860, or give the disease its scientific name, "poliomyelitis" -- which means inflammation of the grey matter of the spinal cord -- until 1874. However, there was little direct evidence that the disease was contagious. <EgyptianPolio-Paul-HoP-cov.jpg>

While the earliest modern clinical descriptions were made in England in 1795, Italy in 1813, and India in 1823, the first documented polio outbreaks occurred in northern Europe, specifically in Norway in 1868 and especially Sweden in the 1880s. <ScandPolioincidence1921-53.jpg> Early Studies suggested that the disease might be contagious, with an initial, infectious pre-paralytic phase with general 'flu like symptoms. <Macleans1912-11-2.jpg>

Polio outbreaks in North America were first reported in the 1890s, most notably in the United States, specifically the city of Boston in 1893 and across the state of Vermont in 1894, the latter involving 132 cases. The Vermont outbreak was the subject of an extensive study that could not, however, link the paralytic cases and thus confirm that the disease was contagious. <Macleans1912-11-3.jpg> Larger studies, particularly during the 1905 Swedish epidemic when more than 1,000 cases occurred, followed by the isolation of the poliovirus in laboratory monkeys in 1908 by Karl Landsteiner in Vienna, finally confirmed that the disease was infectious. <Landsteiner2.jpg>

By 1909-10, the main focus of polio research had shifted to the Rockefeller Institute for Medical Research in New York City, lead by Dr. Simon Flexner. <Flexner.jpg> Around the same time, incidence levels in North America reached a new threshold, particularly in 1910, when polio broke out in many parts of Canada and the United States, as well as elsewhere in the world. Indeed, 1910 was a landmark year for polio; the Congress of American Physicians and Surgeons devoted more attention to polio that year than to any other subject. <Macleans1912-11-1.jpg>

It was also increasingly apparent that the victims of polio were not among the poor or delicate. However, this recognition was difficult to reconcile with the dominant "dirt and disease" model of infectious diseases at the time, rendering polio effectively immune to traditional public health measures such as isolation, quarantine and disinfection. Indeed, it was soon clear that the lower the infant mortality rate -- which was the gold standard of modern industrial societies -- the higher the incidence of paralytic polio. <TS1910-10-03-NewDisease.jpg>

2) THE DISEASE OF MIDDLE-CLASS

a) Epidemics in the Industrialized world, 1916-1953

After serious "paralysis" epidemics in many parts of the world in 1910, 1911 and 1912, polio reached a new level of severity in 1916. That year the United States, particularly in the northeastern region around New York City, was struck by one of the worst polio epidemics ever, resulting in some 27,000 cases and 6,000 deaths. <RogersPBFDF-1916NYC-p12.jpg> Global polio incidence remained quite low during World War I and into the early 1920s, although Iceland experienced an extensive epidemic in 1924 with almost 500 cases reported on the small island. The next year, New Zealand was also hit very hard by polio.

During the late 1920s and into the early 1930s polio seemed to march across Canada from west to east, province by province. A more severe second epidemic wave began in 1936 and grew more serious in 1937 in several provinces, especially Ontario. <CAN-PolioCases.jpg> <IronLungTorontoGM370903.jpg> In the US, polio outbreaks struck in 1927 and 1931, and then again on the east and west coasts in 1934-35. <USPolioIncidence1910-52.jpg> Significant polio epidemics also struck in Denmark in 1934 and in Australia in 1937-38. <AustrNZOPolioinc1921-53.jpg>

During World War II global polio incidence remained quite low, although there were several localized epidemics. During the mid-1940s polio incidence was significant in Switzerland, Holland, France and especially South Africa in 1943-44, while in the US several western and eastern states were also affected. <BelgFrNethPolioinc1921-53.jpg> <ItalySpPortPolioinc1921-53.jpg> <AfricaPolioinc1931-53.jpg>

The post-war years between 1946 and 1953 saw polio epidemics occur more often, strike more severely and in more parts of the world than ever before. Central Europe, the United Kingdom, parts of South and Central America, the Middle East, the Soviet Union and Asia, and even the Canadian Arctic during the winter, were severely stricken by polio for the first time during this period. <UKPolioincidence1921-53.jpg> <AuGerSwitzPolioInc1924-1953.jpg> Among other factors, this increased incidence was due to improved hygienic standards, more rapid international travel, a sharply higher birth rate in many parts of the world during this period, especially in North America, and a better recognition of the disease among doctors and the public. <OMD-ironlung-nurse.jpg>

Between 1946 and 1952, polio epidemics struck every year somewhere in the United States, primarily in the west in 1946 and 1948 and coast to coast in 1948-49, and especially 1952, which was America's worst polio year. <USCanadaPolioinc1921-53.jpg> In Canada, post-war polio epidemics were even more severe, especially in 1952 and 1953. <Manitoba1953incidence.jpg> Western provinces were hit particularly hard during both summers and much of the country, from coast to coast to coast, was affected in 1953, the city of Winnipeg, Manitoba, at the geographic centre of North America, was effectively the epicentre. <BranSun531128-WorldsWorst.jpg>

2 b) The First Prevention Strategies

When outbreaks of infantile paralysis first emerged in the 1880s and 1890s, few believed that the disease was contagious. Some polio researchers, however, argued that, not only was it contagious, it spread via healthy carriers. By the time the poliovirus was first isolated in 1908, most agreed polio was contagious, but public health attention was focused on those with paralytic symptoms as the source of spread, not healthy carriers. With the poliovirus now identified and subject to study, confidence grew that like many other infectious diseases, infantile paralysis would soon be controlled through science and strict public health measures. <NLM-142.jpg>

Despite growing evidence to the contrary, during the 1910s, public health authorities treated polio like other infectious diseases they were familiar with, associating this new epidemic disease with poor hygiene, poor sanitation, pollution, flies and poverty. Amidst the panic of the great 1916 polio epidemic in the northeastern US, health authorities promoted fly-capturing contests, pressured slum-dwelling immigrants to clean up, closed all places where children gathered, and imposed strict travel restrictions across the region. Parents had to show special certificates proving that their children were free of polio before they could enter or leave affected areas. <RogersPBFDR-1916clean-p51.jpg> <RogersPBFDR-1916Flies-p65.jpg> <RogersPBFDR-1916travel-p37.jpg>

However, by the 1920s, it was increasingly apparent that middle class suburbs were more vulnerable to polio than immigrant slums; imposing travel restrictions also proved impractical, and flies, while still a target of suspicion, were not the major polio threat once thought. <Macleans480801-DontPanic.jpg> Through the 1930s and into the 1940s, public health authorities shifted their focus on keeping children from crowds, and particularly out of school -- although this strategy was often hotly debated -- and maintaining strict quarantine of polio cases. However, by the 1950s, based on experience, and a better understanding of healthy carriers (the general carrier to case ratio was 100:1), strict public health measures were maintained more to control public fears of polio than to control the disease. <ALBschools490107.jpg>

During the 1920s and 1930s, medical, public and government attention shifted more to science, particularly a convalescent immune serum touted to prevent, or at least minimize, paralysis. For example, in Canada, provincial governments freely supplied convalescent serum to all diagnosed polio cases; however, obtaining a positive polio diagnosis before paralysis appeared, when the serum might be effective, was problematic. <Horizon3710-serum.jpg> By the early 1940s the serum was abandoned, although in the early 1950s a more concentrated immune serum, known as gamma globulin, was introduced to provide some passive protection against polio.

2 c) Early Polio Paralysis Treatments

The history of polio treatment has been driven as much by a physician's desperate need to do something about its tragic effects, as by wisdom, or scientific understanding of its nature. Indeed, polio was a disease that paralyzed more than just muscles.

The earliest medical approaches to the treatment of acute polio, spanning about a century between the 1780s to the early 1890s, was based primarily on brisk purges, cathartics, blisters and other counter-irritants, such as red-hot irons and hitting the spine with wet towels to promote blood flow. Warm baths and electrical treatments were also used to stimulate the muscles. In 1892, world-famous physician, Dr. William Osler, argued against such medieval methods, which did little against "paralysis" and were only cruel to the child. Osler suggested that until there were new treatments that addressed the specific neuropathology of polio, it was best to do nothing and leave the patient to rest in bed with the affected limb(s) wrapped in cotton. Little could be done until after the convalescent stage when orthopaedic surgery was often used to restore as much function as possible. <McKenzieCJMS1911-01-p9.jpg>

Through the late 1920s and 1930s the emphasis of doctors was on preventing or minimizing paralysis through the early use of convalescent serum, and increasingly, enforcing strict immobilization during the acute and convalescent phases of the disease. <Horizon3712-cover.jpg> This approach peaked in the late 1930s with the use of standardized splints <HSCgs981.19.1.105.jpg> and "Bradford Frames" to which children were strapped on boards, often for months at a time, and would have to be carried around by their parents. <HSCgs-981.19.1.100.jpg> <BradfordFrame-HSC-AR1937.jpg>

During the 1930s, Australian nurse, Sister Elizabeth Kenny, reacted against the immobilization orthodoxy. She advocated treating muscle spasms with "hot packs" and employing passive physiotherapy to re-educate affected muscles as soon as possible after the acute stage. In 1940-41 Sister Kenny brought her revolutionary message to North America, travelling across the US and Canada to train nurses in her methods. <SisterKenny1942Montreal.jpg> <HSC-973.39.1.jpg>

For those stricken with paralysis of the muscles that control breathing and/or swallowing -- known as "bulbar" polio because the virus damaged the bulbar region of the upper spinal cord -- there was nothing to prevent death until the development of the iron lung in the late 1920s. <HSC-981.19.8b.jpg> By the 1930s, the iron lung symbolized both the worst aspects of polio and the best that medical technology had to offer to save lives. <HSCgs-981.19.5.jpg> <HSC-973.33.1c.jpg> However, iron lungs were often scarce, leaving doctors with difficult decisions about who would benefit the most with one. By the 1940s and early 1950s, hospital wards were increasingly filled with iron lungs, most breathing for adults, including pregnant women, some of whom gave birth while inside one. <HSC-973.34.1b.jpg>

2 d) Social Supports for Polio Victims

The history of polio can be divided into two distinct periods: before and after 1921. That August, Franklin D. Roosevelt (FDR), later to become President of the United States of America, was stricken with polio on an island near the Canadian-US border. Roosevelt was not a child and certainly not poor, two features popularly associated with victims of infantile paralysis that still persisted. Roosevelt was then a healthy and wealthy 39-year-old man, who, in spite of, and perhaps because of his polio, which paralyzed his legs, would serve as US President from March 1933 to April 1945. <09-1598a.jpg> <Fdrwhchr.jpg>

During his Presidency, FDR also presided over the National Foundation of Infantile Paralysis (NFIP). Founded in 1938, the NFIP was one of the most successful voluntary health organizations ever. The NFIP was created not only to raise money, "a dime at a time" through its annual March of Dimes campaign to fund polio research, but to also provide protection against polio’s increasing financial threat among middle class families. <p_infpar2.jpg> <mod_pin.jpg> The Foundation directly, and unconditionally, paid the medical, hospitalization and rehabilitation costs on behalf of polio victims. <USNA-03-0063a.jpg>

To the north in Canada, provincial governments assumed responsibility for protecting families from the physical and financial effects of polio, primarily through specific polio hospitalization and after-care policies. <LFP370922-poliopolicy.jpg> In addition to supplying convalescent serum, iron lungs and standardized splints and frames were provided at no cost. <HSCgs-981.19.1.103.jpg> <HSCgs-981.19.1.102.jpg> Beginning in the late 1940s, as epidemics worsened, the Canadian government provided epidemiological services, and supported provincial polio hospitalization policies and funded polio research through federal health grants. <GM481229federalgrant.jpg>

Established in 1948, the Canadian Foundation for Poliomyelitis struggled as a national organization, but in 1951 was restructured into provincially-based groups, such as the Ontario March of Dimes, with a broader mandate of support for the physically handicapped, no matter the cause. <CFPpamphlet5001.jpg>

Elsewhere, the establishment of polio foundations and government polio programs varied with the incidence of the disease. Most organizations, particularly in Europe, started after WWII when epidemics struck there more seriously. However, in 1938, a special Swedish fund in the name of King Gustav V soon evolved into the Swedish National Association against Polio. Other countries with strong polio support services include Australia, Great Britain and South Africa.

3) POLIO SCIENCE, 1908-1951

a) Discovering the Natural History of Polio

By the first decade of the 20^th century, there were hopes that a bacteria would be discovered as the cause of polio since a ‘filterable virus’ would be more difficult to isolate. Viruses needed living cells in which to multiply and as tissue culture methods were unknown, a living host was required to study the virus. But Dr. Karl Landsteiner of Vienna would discover in 1908, when he inoculated monkeys with spinal cord tissue from a fatal human polio case, that polio was a viral disease. He then identified the characteristic polio lesions in spinal cord tissues. <LANDSTEINER_7CM.jpg>

As monkeys were required for the study of polio, the number of institutions able to conduct polio research was limited. One of the most important was the Rockefeller Institute for Medical Research in New York City, where Dr. Simon Flexner rapidly became the dominant authority on the disease from the 1910s through 1930s. <Flexner-20_29p.jpg>

In Flexner's lab the poliovirus seemed to only infect the nervous system, but was also present in a small number of non-neural sites, particularly the upper nasal area after direct inoculation. Polio thus seemed to be a respiratory infection with the virus spread by infected droplets followed by direct nervous system invasion via the nerves in the nose. This nasal-nervous system model dominated how polio was approached until the late 1930s, although it offered little of practical value to physicians facing worsening polio epidemics, which reached a new peak in North America during the mid-1930s.

The first great hope emerged in 1934-35 in two rival and independently developed US polio vaccines, an "inactivated" type by Dr. Maurice Brodie and an "attenuated" version by Dr. John Kolmer. Their hasty use in parts of the US, however, proved ineffective and in several cases, deadly. This experience left polio researchers hesitant to attempt another polio vaccine for 20 years. <VanProv340112-BrodieKolmer.jpg>

Another approach to prevent polio involved applying a special nasal spray designed to block the poliovirus from reaching the upper nasal nerves. The spray was used with little control in 1936 during major epidemics in the US south and western Canada. After a controlled trial in Toronto, Canada, in 1937, it was clear that the spray was not only ineffective, it also caused permanent damage to the sense of smell in some cases. <NasalSprayformCJPH3711-p543.jpg> The Toronto nasal spray experience severely undermined the strict nervous system model of polio. <Vaccine-Spray380407.jpg> At about the same time polio researchers were finally able to isolate the poliovirus from the human gastrointestinal tract, and then from sewage water, thus refocusing attention on the natural epidemiology of polio.

3 b) Epidemiological Enigmas, 1945-51

During World War II and into the early post-war years, the polio enigma deepened as epidemics occurred in unexpected parts of the globe, from the tropics to the Arctic. In particular, polio proved surprisingly common in British, American, and other soldiers serving in the Middle East, India, the Philippines, China and Japan. Polio cases among these troops drew attention to the unexpected presence of poliovirus in communities where the paralytic disease did not appear to be prevalent.

At the same time, discovering the poliovirus in the gastrointestinal tract and in sewage water dramatically changed the direction of polio research and drew researchers away from the lab and into the field. Moreover, identifying several distinct strains of poliovirus and then adapting one of the most common (the Lansing strain) to laboratory mice, allowed for detailed serological surveys of poliovirus immunity status among larger groups.

The military experience with polio provided an opportunity to compare immunity levels among different age groups in different countries and living under varying environmental conditions. It soon became clear that in countries with poor hygiene standards, after being given passive immunity from their mothers that lasted for about six months, young children rapidly acquired natural immunity through inapparent poliovirus infection during their first few years. In countries with better sanitation standards, the timing of acquiring natural immunity was delayed until school age or later, when paralytic complications were more likely. <USNA-20-2553a.jpg>

The wartime polio experience revealed that the natural home of the poliovirus was in the tropics, but the virus would occasionally stray into temperate zones during the summer months. However, an unusually severe polio outbreak in the Canadian Arctic, in the middle of the winter of 1948-49, raised many new questions. The sharp epidemic struck a small village near Hudson Bay. Out of a population of 275 native Inuit, 51 were stricken with paralytic polio, with 14 dying. <CMAJ4910-ArcticPoliomap.jpg> The disease appeared in all ages, but was most severe and deadly among people over 40. It was clear that the whole population lacked immunity, suggesting that surveys of other isolated Arctic communities could identify other vulnerable populations and better track how far the poliovirus could spread.

Meanwhile, polio researchers also measured the immunity status in North American rural and urban communities and tracked the poliovirus, particularly in sewage waters during and between outbreaks, demonstrating the year round circulation of the virus. The priority of researchers was to develop more precise laboratory methods of diagnosing polio and the specific strains responsible for paralytic outbreaks.

3 c) Solving the Enigmas of Polio, 1949-1951

Coinciding with the Canadian Arctic epidemic of 1948-49, an important new era in the history of polio began when a short paper was published in the journal Science. This Nobel Prize winning report was by J.F. Enders, T.H. Weller and F.C. Robbins, of Boston Children’s Hospital and Harvard Medical School, who described how they solved the long-standing problem of culturing the poliovirus in test tubes using non-nervous tissues. This discovery finally provided a method to demonstrate the presence of the poliovirus free from the expensive process of inoculating monkeys, or even mice, finally unlocking and cracking open the door to the development of a polio vaccine. <Enders-nobel.jpg>

There were several outstanding problems to solve before the door could be opened wide enough to produce a vaccine. Also, with worsening post-war polio epidemics striking the US and Canada, as well as a growing list of countries around the world, particularly in Europe, parts of South and Central America, the Middle East, the Soviet Union and across Asia, pressures built for some kind of protection. <GM520718-HSC.jpg>

In 1951 a method of providing passive immunity to polio that was similar to convalescent serum, but much more potent, was first tried in North America. It was called gamma globulin and its development into a temporary polio weapon followed the discovery that there was a period after infection when the poliovirus circulated in the blood. Moreover, it was discovered that the small amounts of virus that entered the bloodstream could be overcome by a small amount of poliovirus antibodies. Poliovirus antibodies contained in gamma globulin could thus be used to neutralize poliovirus infection over a limited period of time. <GM520718-HSCultracentrifuge.jpg>

This method also offered an efficient means of concentrating specific types of poliovirus antibodies against which the multiplicity of virus strains could be studied. Spearheaded by Dr. Jonas Salk of the University of Pittsburgh, these methods expedited a major effort to sort out 196 known strains of poliovirus into three immunologically distinct types: I (161 strains), II (20 strains) and III (15 strains). <Salk-SylvaHistory071901.jpg>

By 1951, based on his earlier work developing an inactivated influenza vaccine, Salk's experience with the poliovirus typing project, coupled with the work of others studying poliovirus immunity in monkeys, suggested that an inactivated polio vaccine might stimulate active immunity in humans. While much progress had been made, several practical problems remained before such a vaccine could be tried on children. Memories of the ill-fated vaccines of the mid-1930s still haunted the polio research community.

4) THE SALK VACCINE STORY

a) Developing the First Polio Vaccine, 1951-1953

In 1947, Dr. Andrew J. Rhodes, a leading virologist from England with a special interest in polio, arrived at the University of Toronto's Connaught Medical Research Laboratories -- now Sanofi Pasteur Limited (Connaught Campus) -- and began a comprehensive polio research program. After making significant contributions to unraveling the enigma of polio's epidemiology, particularly through his Arctic polio studies, Rhodes' team played an essential role in the practical development and supply of Salk's inactivated polio vaccine. <FFY-RhodesAJ.jpg>

Since its start as a backyard stable in 1913 producing diphtheria antitoxin, Connaught had acquired considerable research and production experience with a variety of biologicals, such as antitoxins, immune serums and vaccines, as well as insulin. <Acc0096.jpg> The Laboratories had produced convalescent serum during the 1920s and 1930s and began poliovirus studies in the early 1940s. The lab’s growing involvement in the polio problem was reinforced by its unique self-supporting, non-profit, university-based structure, and by its intimate links with national and international public health authorities. <GM520718-HSCresearch.jpg>

By 1951, Rhodes' research team was able to grow all three types of poliovirus in a variety of tissues. Not enough virus was being produced to be practical for a vaccine until one of Rhodes’ research team, Dr. A.E. Franklin, tried a new method using the synthetic nutrient base known as "Medium 199."<Acc0908A.jpg> This medium was a complex and chemically pure mixture of over 60 substances that was the first of its kind, originally developed at Connaught in 1949 as part of a cancer cell nutrition project. <Acc0798.jpg> <PSEBM73-1950-199ingredients.jpg>

In late 1952, using Medium 199 supplied by Connaught and after first injecting himself and his family, Salk proceeded to administer the vaccine to residents of an institution for disabled children near Pittsburgh. The encouraging results of the trial were published in March 1953. <JAMA530328-SalkIPVpaper.jpg> In the meantime, Connaught focused on the problem of cultivating the poliovirus on an ever-larger scale. The breakthrough came in 1952-53, when Dr. Leone Farrell developed the "Toronto technique" to produce bulk quantities of poliovirus fluids in large bottles that were gently rocked in specially designed rocking machines. <Acc0438.jpg>

Encouraged by Salk's and Connaught's results, in July 1953, the National Foundation for Infantile Paralysis asked Connaught to provide all the poliovirus fluids required for an unprecedented, double-blind polio vaccine field trial in the US set to begin in the spring of 1954. <Acc0541A.jpg>

4 b) The First Human Polio Vaccine Trials, 1954-55

Through the fall and winter of 1953-54, some 3,000 litres of bulk poliovirus fluids produced by Connaught Medical Research Laboratories (now Sanofi Pasteur Limited (Connaught Campus)) were shipped to Parke Davis and Eli Lilly in the US to be inactivated and processed into a finished vaccine. <Acc0807.jpg> Before being released for the field trial, each batch of vaccine had to pass a battery of tests, first by Connaught, then each company, Salk's lab and the US government. <Acc0436.jpg>

In Canada, the first news of a possible polio vaccine emerged during the summer of 1953, in the middle of the country’s worst polio season. <GM540405-p21a.jpg> The prospect of a vaccine generated intense publicity, plus challenging political problems for Canadian governments, complicated by the substantial Canadian involvement in the vaccine’s development at Connaught. Other countries could only watch nervously, particularly Sweden, Denmark, France and South Africa, where plans were being developed to produce their own supply of inactivated polio vaccine should the US field trial prove successful.

Amidst intense publicity, that included a few alarmists spreading unfounded fears about the vaccine's safety, the first children were given the new vaccine on April 26, 1954. <FilmScan5404-187.jpg> The field trial was one of the largest medical experiments in history and involved the elaborate tracking of some 1,800,000 children from grades 1, 2 and 3 (about 5-8 years of age). They were either given the vaccine, "Medium 199" as a placebo, or were simply observed to see if they contracted polio or not. <FieldTrial55SummRepmap.jpg>

To broaden its scope and make up for difficulties starting the trial in some southern states, in May 1954 the Canadian government was invited to participate, as was Finland. The lateness of the offer, however, limited Canadian involvement to two western provinces (Alberta and Manitoba) and one eastern city (Halifax, Nova Scotia). <GM540505-Headline.jpg> Connaught, meanwhile, focused on preparing a finished vaccine, and in concert with Canadian public health authorities, set their sights on a national vaccine trial for the spring of 1955. <Acc0763A.jpg>

All anyone could do now was wait and hope for the best. It was not long after the US trial had started, however, that those closely involved with it knew that at least the vaccine was safe and that there would be no repeat of the 1934-35 polio vaccine disaster. However, whether or not Salk's vaccine really worked would remain unclear until April 12, 1955.

4 c) Triumph to Tragedy to Triumph with the First Polio Vaccine

On April 12, 1955, the highly anticipated clinical trial results turned into a major media event, perhaps the biggest in medical history. "SALK'S VACCINE WORKS!" screamed the headlines. <OMD-poliovaccinepaper.jpg> Dr. Thomas Francis, director of the trial, reported that the vaccine was 60 to 80 per cent effective against paralytic polio. <FieldTrial55SummReptcv.jpg> He and Salk stressed that the vaccine was good, but it was not perfect. However, high public expectations and the unprecedented media attention generated the popular perception that the vaccine was completely successful and that the long war against polio was finally over.

After licensing by regulators in Washington, and with 9,000,000 doses paid for by the National Foundation for Infantile Paralysis, US vaccine producers rush-released their vaccine to meet the pent up demand. However, the US government could not test each batch of vaccine produced by the several companies that recently began production of the vaccine. In the meantime, the Canadian trial began with the federal and provincial governments sharing the full cost of the vaccine and distributing it free to children in grades 1 to 3. <550412-CanadaVaccine-hl.jpg>

Suddenly, on April 25, 1955, the Salk vaccine euphoria was shattered when the first of a total of 205 cases of polio associated with vaccine made by Cutter Laboratories in California were reported; 79 were vaccinated children and the others were contacts. Three-quarters of the cases were paralytic and 11 died. On April 27, the US Surgeon General ordered all of Cutter’s vaccine off the market, and by May 8, after launching a massive investigation, the entire American vaccination program was stopped. The problem was confined to Cutter Laboratories and later found to be caused by incomplete inactivation of the virus in selected batches. Not unlike a child stricken by polio, the US government and the public were left paralyzed, scared and confused. What should be done now?

In Canada, the Minister of National Health and Welfare, Paul Martin, faced his most difficult political decision. <Acc1838.jpg> Should he follow the US lead and suspend the Canadian vaccine trials that had just started? Despite pressure from the Prime Minister, based on the experience of Connaught Medical Research Laboratories (now Sanofi Pasteur Limited (Connaught Campus)) with the development of the vaccine, and strict testing by the Canadian government, coupled with his personal experience with polio, Martin maintained his confidence in the Canadian-produced vaccine. The Connaught vaccine was not known to have induced disease in any Canadian children, and so the immunization trial continued uninterrupted. <550507-Martin-headline.jpg>

5) SALK TO SABIN, 1956-1962

a) Meeting Vaccine Demands

The well-publicized success of the Canadian Salk vaccine trials, for Jonas Salk, represented a rare source of great pleasure during a time of serious personal stress and scientific uncertainty. <IMG0005.jpg> Although US vaccinations resumed in June 1955, any hint of trouble with Connaught Medical Research Laboratories (now Sanofi Pasteur Limited (Connaught Campus)) vaccine was used as an excuse by many to question the Salk vaccine’s safety, long-term effectiveness and continued American use. <CLL-Filmscan57-173.jpg>

New minimum standards instituted after the "Cutter crisis" created production difficulties for US vaccine producers, and for Connaught (now Sanofi Pasteur Limited, Connaught Campus). <Acc0988.jpg> Even stricter standards established in November 1955 did not ease the situation. News of these troubles generated further anxiety among Salk vaccine critics, many of whom wondered whether it could ever be safe.

Canada clearly experienced success with the introduction of the Salk vaccine in 1955. <550907-VanRiperCanada-hl.jpg> Denmark was the most successful country in Europe with uninterrupted use, while France maintained a small-scale program based on a variation of Salk's vaccine (developed by Dr. Pierre Lepine of the Pasteur Institute that used different poliovirus strains and an additional inactivation step). <BWHO1955-15-LepineIPV.jpg> Great Britain, Sweden, West Germany and South Africa soon prepared an inactivated vaccine. Connaught's success also attracted the attention of the Soviet Union, which had yet to prepare a vaccine. In 1956, a Soviet delegation visited Connaught for a week of inspections. <560308-USSR-Canada.jpg>

The Salk vaccine clearly struck a crippling blow to paralytic polio, but it was not the final answer. <Acc0282A.jpg> In Canada, for example, a new wave of outbreaks hit several provinces between 1958 and 1960, prompting renewed vaccination campaigns, especially among adults. <HLCan-DefeatofPolio-5710.jpg> <59-ODH-Salkforadults.jpg>

As part of a strategy to boost polio and general immunization levels in Canada, in 1956, Connaught focused on adding Salk polio vaccine to its standard DPT (diphtheria toxoid, pertussis vaccine, tetanus toxoid) product. In 1958-59, DPT-Polio vaccine and related combinations (including Td-Polio and T-Polio) were licensed in Canada and formed the foundation of provincial immunization schedules. <Acc0987.jpg> DPT-Polio was later used elsewhere.

Meanwhile, beginning in 1957, the Salk vaccine was exported by Connaught to Czechoslovakia and also Great Britain, and soon to some 44 other countries that had no, or a limited, local supply and were otherwise without protection against polio's growing global threat. <Acc0455.jpg>

5 b) Developing a Live Oral Polio Vaccine, 1959-61

The history of the live oral polio vaccine (OPV) was considerably quieter than the inactivated type (IPV). A live vaccine had theoretical advantages because it multiplied in the digestive tract in the same way as the wild poliovirus and spread like the natural infection. Thus, mass vaccinations could slow down an epidemic by spreading the attenuated virus through the community to displace the wild virus. With an oral vaccine, administration was also cheap and easy because it could be administered simply, only one dose was necessary, and immunity developed quickly and was expected to last a lifetime.

During the 1950s, several US polio researchers cultivated poliovirus strains for an attenuated vaccine. They included Hilary Koprowski, Herald Cox and Albert Sabin. <102006-1.jpg> In 1953, Sabin announced the he had isolated avirulent strains of each poliovirus type, and by 1955 had fed them to 80 volunteers. Koprowski and Cox also conducted increasingly large human trials in various countries, but with little standardization until 1959 when the World Health Organization assumed a coordinating role.

Pressured by an alarming wave of epidemic polio in parts of Canada during the summer of 1959, and by shortages of Salk vaccine, Connaught Medical Research Laboratories (now Sanofi Pasteur Limited (Connaught Campus)), began production of a trivalent OPV using "seed pools" provided by Sabin. <600611FP-PolioScore1959.jpg> At the same time, Sabin, Cox and Koprowski pushed ahead with increasingly large OPV trials. However, they took place primarily in countries where children, unlike in the US, normally came into contact with the disease at an early age. <Acc1295.jpg >

Overseen by a National Technical Advisory Committee for Live Polio Vaccines, headed by Dr. A.J. Rhodes, Connaught's trivalent OPV was subjected to a well-coordinated series of focused field "demonstrations" in several parts of Canada during 1960-61. <600611FP-ConnaughtOPV-hl.jpg> <CanHW-OPVexperiment6205.jpg>

5 c) Polio Vaccines During the Cold War, 1961-63

During this period the supply and evaluation of the live polio vaccine became increasingly caught up in international politics and "cold war" rivalries. A variety of countries hosted live vaccine field trials based on competing vaccine strains, although Sabin’s seemed the safest. In 1959, Sabin attracted the most attention when the Soviet Union vaccinated its entire population, especially 10 million children under 15, with his vaccine and then offered to give it away to any country willing to accept it.

By June 1960, Sabin’s vaccine had been given to over 50 million people in the Soviet Union, China, Czechoslovakia, the US, Canada and Mexico, Singapore, Africa, the United Kingdom and various other European countries. Rival live vaccines developed by Koprowski and Cox had also been used widely. Some 7 million people had received Koprowski’s vaccine in Africa, Poland and the US, while 2 million had been fed the Cox type in Latin America, Europe and the US.

This situation was further politicized since no US-produced vaccine could be exported without a federal license. While the World Health Organization had established OPV standards, in the US the vaccine had to first meet domestic standards, which were not established until 1960. In Canada, an export license was not required at the time and while meeting the WHO standards, Connaught Medical Research Laboratories (now Sanofi Pasteuer Limited (Connaught Campus)) only had to satisfy the requirements of the importing country. <Acc1296.jpg>

Connaught was able to export its OPV to countries desperate for any kind of protection from polio, as was the case in 1961 when a 3 million-dose supply of OPV was rushed to Japan to bring an epidemic under control. <Acc1304.jpg > This episode led to a further order of 17 million doses from the Japanese government. By 1961-62, Connaught had become a global supplier of OPV. <Acc1802.jpg> <Acc1317.jpg>

In 1962, Connaught was the first company to license a trivalent OPV product and followed the licensing of monovalent versions of OPV in the US and the UK in 1961. Several American and European manufacturers also produced OPV in 1962, including Instiut Merieux in France, which like Connaught, also produced IPV.

6) EPIDEMICS TO ERADICATION

a) Salk and Sabin

By 1962, to have not one, but two highly effective vaccines available against such a dreaded disease as polio, was unique in medical history. For some, it was clear that both vaccines could work well together, utilizing their relative strengths to prevent the disease and limit the risks of inadvertently causing polio. For others, for a variety of scientific, practical, political or personal reasons, choosing one vaccine over the other seemed preferable. In the US, there was an almost complete shift away from Salk's to Sabin's vaccine by the mid-1960s. <NFIP-PolioandSalkVac5704.jpg>

In the US, three companies initially supplied OPV, while five others produced IPV. However, by 1968, they had all abandoned IPV, leaving only Lederle Laboratories to supply the Americans with OPV since 1975. Connaught Medical Research Laboratories (now Sanofi Pasteur Limited (Connaught Campus)) became the sole North American producer of IPV since 1968, and also the sole Canadian supplier of both IPV and OPV. <CLL-IPV-Slide121.jpg> <CLL-slide147.jpg>

In Canada, vaccine policies are set provincially. Since 1955, all polio vaccines have been distributed free across Canada through a special federal-provincial shared program. Since 1962, there has been considerable variation in IPV/OPV use across Canada. <CLL-OPVsqueezetube7908.jpg> Ontario and Nova Scotia have relied almost exclusively on IPV, while, until recently, most other provinces used OPV, or a sequential IPV-OPV program. Between 1994 and 1997, all provinces and territories shifted to the exclusive use of IPV, routinely delivered in combination with DTP and Hib (PentaÔ ), <Acc1009.jpg> and since 1998, in combination with DTaP and Hib vaccine (PentacelÔ ), built around acellular pertussis vaccine. <Pentacel-package.jpg>

By the 1970s most of the world was using OPV, with the WHO basing its Expanded Programme of Immunization (EPI) on its use in developing countries. However, in addition to parts of Canada, Sweden, Iceland, Finland, and the Netherlands have always used IPV. In recent years, because of changing epidemiology and in light of greater risk of OPV-associated polio than of wild polio itself, Norway, France, and the US, after intense debate in the mid-1990s, have switched from OPV to IPV. In 1997 the US used a mixed IPV-OPV schedule, and in 2000 moved to the exclusive use of IPV. The global polio eradication program, however, is based on the wide use of OPV. The ease of use and lower cost, coupled with its ability to control outbreaks and provide protection even among children who don't receive it directly, make OPV a practical and effective tool in countries where wild polio remains a threat.

6 b) Target: Polio Eradication

<droguet02.jpg> Not unlike the shift from endemic to epidemic polio in industrialized nations near the turn of the 20^th century, improving environmental and personal hygiene standards in many developing countries through the last half of the 20^th century created epidemiological conditions that were ripe for escalating polio epidemics. <WHO-nid9.jpg>

TheWorld Health Organization's (WHO) global smallpox initiative, launched in 1967, provided an opportunity to see first hand that several basic pediatric vaccines were being little used in the developing world, including vaccines against diphtheria, measles, pertussis, tetanus, tuberculosis, and in particular, polio. Building on the momentum gained with smallpox vaccination, in 1974 the WHO launched the Expanded Programme on Immunization (EPI), to bring basic vaccines to all of the world's children. <WorldHealth8005.jpg>

Through the late 1970s and 80s, the rising toll of paralytic polio in the developing world, coupled with the threat of wild poliovirus exported from areas of high incidence to where the disease had all but disappeared, reinforced the importance of boosting and maintaining global polio immunization levels. For example, a significant polio outbreak occurred in 1992-93 in the Netherlands that only affected a particular religious group that objected to vaccination. As had also occurred in 1978-79 among the same Dutch group, polio cases appeared among its members living in other parts of the world. While 11 cases occurred in Canada in 1978-79 among this group, none were reported in 1992-93 in Canada. Fortunately, due to high polio immunization rates in Canada, as well as the Netherlands, the disease did not spread outside this group during both episodes. <WorldHealth8912cover.jpg> <WorldHealth9501-02cov.jpg>

These outbreaks underscored the fact that, not unlike had been the case with smallpox vaccine, maintaining polio immunization programs in the polio-free world would have to continue until the disease was eradicated globally. <WHO-slide68.jpg>

The first step towards a global polio eradication initiative was made in 1985, when the Pan American Health Organization aimed to eliminate wild polio from the Americas by 1990; they reached their goal in 1994. <WorldHealth9501-02-p12.jpg> With major funding from Rotary International and backed with substantial support from many governments and reinforced by large OPV donations, particularly from Connaught Laboratories (now Sanofi Pasteur Limited (Connaught Campus)), in May 1988 the World Health Assembly resolved to eradicated polio from the globe by 2000. <Acc1982.jpg> <philpolioeradicatepartners.jpg>

While smallpox was eradicated within the 10-year target that was set, eradicating polio has proven a more complex and daunting challenge. <WorldHealth9501-02-p16.jpg> With some 1000 polio cases occurring per day worldwide in 1988, remarkable progress has been made reducing incidence to less than 1000 polio cases per year, confined to just 10 countries in Asia and Africa. <global11.jpg>

6 c) Modern Polio Vaccine Production Methods

Both IPV and OPV have changed considerably in how they are produced and in their effectiveness since they were first introduced. In 1955, the Cutter incident prompted a number of modifications in how IPV was produced, as well as several variations in the production process utilized outside North America, most notably in France. Introduced in 1956, the Lépine IPV was developed by the Pasteur Institute and used a different poliovirus strain combination, as well as an additional inactivation procedure to doubly ensure safety. <lepine.jpg>

In Canada, Connaught Medical Research Laboratories (now Sanofi Pasteuer Limited (Connaught Campus)) licensed a purified IPV in 1965. By 1976, a new method, called the Multi-Surface-Cell-Propagator, replaced the large racks of rocking bottles. "Medium 199" was also modified during this period. In 1988, Connaught introduced an enhanced potency eIPV, produced by the cultivation of poliovirus using a microcarrier culture fermented in large 1,000 litre tanks. One small vial of this poliovirus culture fluid produced some 700,000 doses of eIPV some 15 to 18 months later. <20732D-1.jpg>

<Acc1840.jpg> In Europe, beginning in the 1980s at RIVM in the Netherlands, and then at Sanofi Pasteur in France (formerly Institut Mérieux, then Pasteur Mérieux Connaught until 1999), high potency IPV was produced on microcarrier cultures in large 1,500 litre fermentors. <Acc1203.jpg> <200103-4.jpg>

The production of OPV is a much simpler process than IPV, based on the cultivation of precisely selected attenuated, or weakened, strains of each type of poliovirus; potent enough to stimulate an immune reaction in the body, but weak enough not to cause paralytic disease. The delicate inactivation process was not necessary. The main challenge for OPV production is maintaining precise control of each vaccine batch through rigorous testing, both for virulent polioviruses, and ensuring the complete absence of other viruses. <OMH-OPVbooklet9002-fig2.jpg>

Since the start of the WHO polio eradication initiative in 1988, Pasteur Merieux Serums and Vaccines (known since 1999 as Aventis Pasteur and Sanofi Pasteur since 2004) has been one of the world's largest suppliers of OPV, upon which the eradication program is based. <IMG0003.jpg> <Acc2025.jpg>

7) LIVING IN A POST POLIO WORLD

a) Ensuring Eradication

When the WHO polio eradication initiative was launched in 1988, in addition to eliminating the wild poliovirus and thus eliminating the high costs of new polio cases, a secondary goal was to ultimately eliminate the cost of polio immunization programs. Today, such polio treatment and prevention costs total about US$1.5 billion per year globally. <WorldHealth9501-02-p20.jpg> While the first goal remains well in sight, albeit slower than first planned, the second goal has recently become the subject of reconsideration due to several unexpected scientific, practical, political and security reasons.

Among the challenges of meeting the first goal include delivering the vaccine in countries affected by conflict and other political and/or economic instabilities. There have been some remarkable successes, however, where "days of tranquility" were agreed to among warring factions to allow all children 5 and under to be immunized. National Immunization Days (NIDs) have also proven effective, but are an enormous challenge to conduct. <WorldHealth9501-02-p7.jpg> In the 10 remaining polio endemic countries -- Afganistan, Angola, Egypt, Ethiopia, India, Niger, Nigeria, Pakistan, Somalia and Sudan -- there are several persistent obstacles to not only delivering and administering the vaccine, but also in maintaining polio surveillance efforts.

The second original goal of the polio eradication effort, that is ending global polio immunization programs, has become more complicated. <WHO-nid17.jpg> While it is possible to eliminate the wild poliovirus with OPV, the very weapon for doing so seems to be the source of an unexpected problem. There have been cases of polio reported where vaccine-derived poliovirus strains have genetically reverted to virulence after circulating among a population for extended periods of time. Thus, if polio vaccination ends after eradication is certified and immunity levels are allowed to decline, then vulnerability to virulent vaccine strains will increase. Complicating the situation, it is not clear how long vaccine-derived strains can persist in the immunocompromised body and circulate among populations. <droguet01.jpg>

The use of IPV does not result in circulation of vaccine-derived poliovirus strains, since the virus is inactivated or killed; it cannot reproduce. But IPV requires stocks of virulent polioviruses during its initial production stages -- such stocks represent a potential risk, the danger of which would increase if vaccination programs ended. Moreover, it has recently been demonstrated that the poliovirus can be synthetically assembled in the laboratory. In the wrong hands, such natural, or artificial polioviruses would become an increasingly potent weapon as global polio immunity levels declined.

Thus, its seems unlikely that polio immunization programs will end immediately after global polio eradication is declared. Ensuring polio eradication will thus likely depend upon maintaining high global levels of poliovirus immunity with OPV, IPV, or both. Thus government investment in, and public support of polio immunization programs, must be reinforced during the last stages of eradication and continue for many years beyond its final certification. <WorldHealth9501-02-p22.jpg>

7 b) Post-Polio Syndrome: A Living Legacy

While eradicating polio will stop the development of new polio cases, this disease will persist as a significant personal, medical, financial and political challenge for many years to come. There remains a living legacy of this disease among those it struck over the past century, especially among a large proportion of whom that have struggled, or will struggle, with its late effects, which are known as Post-Polio Syndrome. <CDC-77-2122_lores.jpg>

Post-polio syndrome first emerged as a particular problem in the late 1970s and early 1980s, although it likely occurred earlier, but was unrecognized until the large numbers of polio victims from the pre-vaccine epidemic era magnified the problem. PPS is a major chronic illness which poses unique problems to polio survivors and their physicians. Like the original illness, there is no specific PPS diagnostic test; diagnosis depends on particular clinical symptoms that must be differentiated from other ailments. Moreover, doctors today, especially younger ones, with little to no knowledge of, or experience with, polio generally, have difficulty understanding and properly managing PPS. <pics.jpg>

PPS is defined by an otherwise unexplained constellation of symptoms, which may include weakness, fatigue, heat or cold intolerance, and swallowing, breathing, or sleep disturbances developing in a patient who had paralytic polio. Post Polio Muscle Atrophy is a label used to describe these symptoms if they include progressive muscle atrophy.

It is estimated that approximately half of all polio survivors will develop PPS. The syndrome has also developed among those who either had a mild polio case, or were unaware of being affected at all. As the poliovirus can affect a wide variety of motor neuron cells and other parts of the brain and central nervous system, its effects can remain sub-clinical over time and only emerge with aging and muscle overuse.

The main cause of PPS is overuse, or over-compensation, of polio-damaged motor neurons by healthy ones. During the original recovery period, to varying degrees, new nerve connections are made to compensate for the damaged connections to voluntary muscle groups. Over time, and under the unusual physical and mental pressures to recover and maintain a normal lifestyle, the healthy nerve cells bear an extra burden and essentially burn out faster than otherwise, thus generating the associated symptoms of weakness, paralysis and pain, much like the original polio infection. More mental effort is required to perform a fixed amount of muscle contraction, which as many PPS patients describe it, feels like hitting "a post polio wall." <PolioParadox-cov.jpg>

As difficult as it has been for polio survivors in the industrialized world to manage post-polio syndrome, even if the poliovirus was eradicated today, the PPS problem will grow into a more serious global challenge in the wake of polio epidemics in the developing world in recent decades. Certainly the legacy of a polio-free world must also include ensuring the ultimate eradication of post-polio syndrome. <WHO-slide20.jpg>