THE STORY OF THE SALK ANTI-POLIOMYELITIS VACCINE BY M. BEDDOW BAYLY, M.R.C.S.,
L.R.C.P.
THE STORY OF THE SALK ANTI-POLIOMYELITIS VACCINE BY M. BEDDOW BAYLY, M.R.C.S., L.R.C.P. THE STORY OF THE SALK ANTI-POLIOMYELITIS VACCINE BY M. BEDDOW BAYLY, M.R.C.S., L.R.C.P. 1956 (WHALE, Nov 2000. Supplied by John Wantling) PREFACE GAMMA-GLOBULIN POLIOMYELITIS VACCINES THE SALK VACCINE HOW THE VACCINE IS MANUFACTURED THE LAUNCHING OF THE SALK VACCINE THE SALK VACCINE DISASTER CUTTER VACCINE NOT SAFE NOT THE FIRST FAULTY VACCINE A SOBER SUMMING UP THE FRANCIS REPORT STATISTICAL ERRORS CLAIMS FOR THE SALK VACCINE SOBERING CRITICISMS DR. SALK’S TECHNIQUE POTENCY OF VACCINES ANTIBODY FORMATION AND IMMUNITY KILLED VIRUS v. ATTENUATED VIRUS WHAT IS AN ATTENUATED VIRUS? THE POSITION IN GREAT BRITAIN THE VACCINE IN OTHER COUNTRIES POLIO RISK IN THE UNITED STATES POLIO RISK IN GREAT BRITAIN PREDISPOSING HOST-FACTORS CONFIRMATORY EXPERIMENTS PRESENT RISKS ATTACHED TO SALK VACCINE IS MASS VACCINATION WORTH WHILE? RESEARCH IN THE IMMEDIATE FUTURE CHICKEN-EMBRYO VIRUS HUMAN-TISSUE VIRUS MANY MONKEYS NEEDED IN VACCINE PRODUCTION BAN ON EXPORT BY INDIAN GOVERNMENT? VALUE OF RESEARCH IN MONKEYS THE COMMERCIAL ELEMENT STOP PRESS! — ANOTHER SALK-TYPE VACCINE PREFACE The author has attempted in the following pages to put before the reader some of the main facts relevant to the recent development and launching of the Salk poliomyelitis vaccine. In order to view these events in their true perspective it is necessary to glance, however briefly, at the story of persistent research and experiment which led up to the present situation In this recital of the historical and scientific facts reliance has been placed upon the statements of leading authorities on the subject to build up a true picture without the intrusion of any undue comment on the part of the author In this way. although the presentation may lose something in interest for those who look for pungent criticism and comment in a pamphlet of this kind, it may be that it will commend itself to the thoughtful reader who prefers to judge for himself and reach his own conclusions without the distraction of the interpolated opinions and beliefs of the author HISTORICAL SURVEY Poliomyelitis was first transmitted to monkeys experimentally in 1908 by Landsteiner and Popper. Soon after this it was observed that monkeys which had survived one attack became resistant to subsequent infection. This suggested the use of serum from human beings who had had poliomyelitis for the treatment of those who had contracted it. A serum derived from convalescent children and adults was introduced for this purpose in 1911 and was extensively used and widely eulogised in the public press for some years. Eventually it was abandoned as useless. In 1917, Pettit advocated the preparation of a serum against poliomyelitis obtained by inoculating a horse with virulent nervous tissue from monkeys that had been experimentally infected with the virus: and in 1932 he obtained another serum by immunising a chimpanzee by the same method. But neither of these serums proved more effective than Netter’s serum from convalescent humans. After twenty years’ trial with these various serums the situation was summed up by the Editor of the British Medical Journal (December 30, 1933, p. 1221) in the statement: "In the light of the most recent investigations it is difficult to refute Dr. Walshe’s contention that serum treatment has proved a broken reed." Even the Editor of the Journal of the American Medical Association (July 28, 1934. p. 262) felt obliged to call attention to "the total failure of statistical presentations to make a case for serum therapy in this disease." A few years ago what is called gamma-globulin was introduced as a prophylactic against poliomyelitis and is still used for this purpose among contacts of actual cases of the disease. It will be recalled that Her Majesty the Queen and the Duke of Edinburgh were given this preparation during their Australian tour, on account of an outbreak of poliomyelitis in that country. It should prove of interest to describe this preparation in a little more detail. GAMMA-GLOBULIN Gamma-Globulin is contained in the blood of a person who has had the disease. It takes about a pint of blood to produce one dose of gamma globulin. This is injected into people who may be liable to come into contact with the disease with the idea of protecting them front infection. Its value in this respect was investigated in America in 1952, 54.772 children being inoculated half of them with globulin, the other half with gelatin. It was found that after the eighth week there was no protective value which could be ascribed to the globulin and that the injection of gelatin in the controls was itself associated with an increase of paralysis in the limb injected. In the following year 235,000 children were inoculated. The National Advisory Committee conducting the inquiry were of the opinion that "it had no apparent effect on the incidence or severity of paralysis developing in subsequent cases." According to Dr. Geffen (Public Health March 1955) "it is expensive, uncertain, unreliable, and at the best the immunity it gives is shortlived." Probably, he says. 5.8 weeks. At any rate it was unsuccessful in protecting a laboratory technician who (in November 1954) accidentally sustained an abrasion of one linger with a hone spicule from the vertebral column of a monkey that had died after repeated intramuscular inoculation with type 2 virus. He was given gamma-globulin intramuscularly on the same day, but developed symptoms of polio eight days later. (Lancet, April 2. l955. p 702). Nor did it prevent the occurrence of 40 cases of poliomyelitis among 6000 inoculated persons during an epidemic in Manitoba in 1953. In 36 cases the disease developed within 7 days of the inoculation. The Times (November 16. 1953) in reporting the incident stated that the Manitoba health authorities, while holding that gamma-globulin is useful, concluded that it is not a final answer in curbing outbreaks of polio. No one could call this an overstatement. The more favourable results which had been reported in the first of the two trials referred to above were due, it was explained, to the fact that in this trial (1952) the controls were injected with gelatin, while in the second (1953) they were given no injections of any kind. Hammon and his colleagues who conducted the former, "appreciated the possibility that inoculation of gelatin, like that of many other substances, might provoke paralytic poliomyehitis in certain cases, and so give gamma—globulin a false reputation for protective action." (Lancet. March 13. 1954. p.558). It may hardly he credited that, in spite of this scientific proof of the ineffectiveness of gamma-globulin the President of the National Foundation for Infantile Paralysis. Inc.. announced that they were making three million doses of the serum available in l954 compared with one million in I953. It is the more extraordinary that in the August 1954 issue of their own bulletin, Poliomyelitis Current Literature (Quoted in Medical Officer Nov 19, 1954, p260) they actually published the information that ‘ Dr. Draber studied the possible effect of gamma-globbulin in a mass inoculation programme in Wisconsin. He comments that there is no evidence that gamma-globulin had any effect in altering the course of the poliomyelitis outbreak or preventing cases of the disease.’ They also admitted that "following the failure of gamma-globulin in household contacts this substance is not being provided in Illinois for use in 1954." It was not, however on account of its failure as a prophylactic that in 1953 the Glasgow Public Health Department declined the offer of a supply of the serum by the trustees of the United States Roosevelt Memmorial Fund. The reason given was interesting and, according to the Weekly Scotsman (January 22, 1953), was that with the comparatively small incidence of poliomyelitis in that city, it would have required the inoculation of 1,250,000 people to prevent an epidemic that might attack, at most, only 250. This alleged prophylactic is one more pitiful example of the unreliability of animal experimentation, for Bodian had found in 1949 that gamma-globulin was highly successful in protecting monkeys against subsequent infection with all three types of virus.’ POLIOMYELITIS VIRUS Flexner and Lewis established a filterable virus as the causal agent in 1909, but more detailed study of this organism was hampered by the fact that monkey’s and chimpanzees were for a long time the only susceptible animals in which the disease could be experimentally induced. Later some strains of the virus were adapted to rodents, but this did not prove very helpful, apparently, and the great advances in our knowledge of poliomyelitis during the past few years began with the discovery by Enders, Weller, and Robbins in 1949 that poliomyelitis virus could readily be grown in tissue-cultures. a discovery which won for them the Nobel prize for physiology and medicine in 1954. A monograph published by the World Health Organisation (No. 26, Geneva 1955) gives a comprehensive description of all the work done in connection with this, and shows how the diagnosis of the various types of virus has been made possible by the examination of the tissue-cultures. It was by these methods, too, that Cox, Sabin and Koprowski were able to segregate low virulence viruses and even what is believed to be an avirulent (non-poisonous) variant. This last has been prepared from all three types of polio virus and is the basis for the manufacture of vaccines. Both Sabin and Koprowski believe that the live but avirulent vaccine will prove best in the end. This is more fully discussed later in this pamphlet. Here it will be sufficient to call attention to the warning uttered by the late Professor James McIntosh, who was Professor of Pathology at London University, when addressing the Royal Society of Medicine on October 19, 1926: "Scientifically it cannot be disputed that from every point of view the injection of a virus capable of multiplying in the body of the individual is bad. When multiplication of the virus occurs, then there is no possibility of estimating the dose to which the patient has been subjected. Thus the effect cannot be controlled, and in susceptible individuals this may lead to unforeseen results." Professor McIntosh emphasised the fact that no one knew how long an attenuated virus could lie dormant and then assume its former virulence. Dr. Albert Sabin himself found that when 26 volunteers between the ages of 26 and 30 were given a minute droplet of a single strain of polio virus in milk " some of the virus changed in the subjects’ bodies to a somewhat virulent form". (Time. May 23, 1955). Further details regarding attenuated and tissue-cultured viruses will be round on pages 18-20. POLIOMYELITIS VACCINES As it became more and more clearly realised that animal and human sera were quite ineffective and that little progress could be expected in this direction, attention was directed towards the production of a vaccine which might prove successful in preventing the disease. The chief difficulty was to find a culture-medium in which the virus would multiply. As is well known, unlike bacteria which will grow on a simple medium such as potato, blood or agar in a test-tube, viruses require a living tissue for their development. After many years of research involving the use of many thousands of monkeys, it was found possible to grow the virus in brain tissue derived from humans, monkeys and certain rodents: but the procedures, according to Lederle Laboratories,’ were most cumbersome and expensive and unsuited to large-scale production. Also, it was realised, a vaccine prepared from such material would hold the frightful danger of causing an allergic inflammation of the brain which might well he even worse than the disease it was designed to present. (Time. March 29, l954). It was in l949 that a team of Harvard research workers headed by Finders reported that they had succeeded in growing polio virus in the kidney tissue of rhesus monkeys. Then Dr. Jonas F. Salk, of Pittsburgh, adopted Finders tissue-culture technique and improved upon it by devising a special broth (No. 199) in which to grow the kidney cells. It was already known that there were three main types of virus: (I) Brunhilde. (2) Lansing, and (3) Leon. but Dr. Salk and his associates isolated and typed 74 strains. By 1952, after he had made experimental vaccines and tested them on monkeys, he was satisfied he had produced one safe enough to be given to human beings. THE SALK VACCINE AN interesting account of how the Salk vaccine is made appeared in Time (March 29, l954). The story begins with the trapping of rhesus monkeys in large numbers in the N Indian State of Uttar Pradesh. They are stuffed into cages and carried on shoulder-poles to Lucknow. A train journey of 260 miles takes them to New Delhi whence a transport plane carries them the 4.000 miles to London Airport. From London another plane transports them another 3,000 miles across the Atlantic to New York, whence they travel in trucks for a final 700 miles to Okatie Farms in South Carolina. There these rhesus monkeys from India are caged with other hordes of ‘Java’ (Cynomolgus) monkeys from the Philippines." "Though Okatie Farms," the reports states, may receive 5,000 monkeys a month, the supply never catches up with the demand. After 21 days for rigorous health checks, they are on their way to laboratories in Toronto, Pittsburgh, Detroit and Berkeley, California." It was at the University of Pittsburgh’s Virus Research Lab’ that the bulk of the work in research was carried out and the vaccine initially produced. Dr Salk, who pursues his investigations here, has behind him 81 million dimes, contributed by the National Foundation for Infantile Paralysis Inc, to spend on this enterprise. This is part of the three billion dimes subscribed by the public to the National Foundation. But in order to vaccinate the million children as proposed in the 1954 tests it was necessary to hand over the manufacture of the Salk vaccine to five pharmaceutical firms, Parke. Davis & Co, in Detroit: Pitman-Moore and Eli Lilly & Co, in Indianapolis: Wyeth Inc, in Philadelphia: and the Cutter Laboratories in Berkeley, California. For all of them, we are told, " the indispensable material is the monkey, and the procedure much the same." HOW THE VACCINE IS MANUFACTURED Let us take, as an example, the University of Toronto Medical Research Laboratories. Some 50 to 65 monkeys will be used in a single morning. Under an anaesthetic a surgeon removes the kidneys, after which the monkey is killed by an overdose of ether. Then the kidneys are cut into tiny pieces and placed in glass bottles with a special nutrient solution (No 199) devised by Dr. Salk. These bottles are then rocked in a mechanical machine for six days in an incubator to stimulate the growth of the kidney cells. At this stage fluid containing live polio virus is introduced and the bottles again rocked. After about four days the virus has multiplied a thousandfold in the kidney cells and is now chilled in 21 gallon bottles ready for transportation from Toronto to Eli Lilly & Co, and Parke, Davis & Co. There the brew is filtered free from the kidney cells (which might cause nephritis if injected into a human being) and diluted with formaldehyde to kill the virus. As we have already seen, there are three main strains of polio virus, against all of which there is need for protection. Consequently three tankfuls each containing one type of virus, cultivated and killed in the above manner, are mixed together. After neutralising the formaldehyde with sodium bisulphite there begins a month-long process of testing to see if the vaccine is safe for injection into human beings. This necessitates inoculations into live monkeys, rabbits, guinea-pigs and mice. These tests are carried out simultaneously, on each batch issued, by Dr. Salk’s laboratories and by the National Institute of Health at Bethesda, Maryland. Having passed the final tests the vaccine is distributed in little glass bottles for inoculation into children. Before this complicated procedure could he devisd, Dr. Salk and his staff engaged in a long investigation to discover which part of the anatomy of the monkey provided the most useful virus-growing cells. Like John H. Enders. of Harvard, they came to the conclusion that this was the kidney: but a leading article in the Lancet (April l8, 1953. p. 777) stated that the testicles as well as the kidneys are used as source of the cells which form the culture-medium. Monkey-tissue is apparently preferred to human tissue because, it has been pointed out, it is more readily available and also because human material might contain the virus of serum-hepatitis and thus prove dangerous and even fatal, as was the case with the earlier types of yellow-fever vaccine. Nevertheless we learn that one country, Sweden, is experimenting with the production of a vaccine derived from virus grown in human foetal material. THE LAUNCHING OF THE SALK VACCINE IT was on April 12th. 1955, the tenth anniversary of President Franklin Roosevelt’s death, that the Foundation for Infantile Paralysis told the world, using every possible means of publicity, that the vaccine devised by Dr. Jonas E. Salk was "safe, potent, and efficient." For it was on this day that the eagerly awaited report on the 1954 tests of the vaccine was issued by Dr. Thomas Francis, of Michigan University. who had been entrusted with the task of evaluating the results. At a meeting of 500 doctors and scientists at Ann Arbor. Michigan, Dr. Salk and Dr. Francis made such sweeping claims for the vaccine that nearly every American newspaper declared that Dr. Salk had abolished poliomyelitis. Already, in the past year, before any report as to the efficiency of the vaccine was available, six manufacturing firms had had orders from the Foundation for Infantile Paralysis to manufacture enough vaccine to inoculate 9 million children and pregnant women. Two hours after the announcement by Drs. Salk and Francis the Government Department responsible licensed the vaccine and released it for distribution to all the States that had agreed to employ it. The British newspapers and more especially the scientific journals were somewhat more guarded in their statements and their cautionary advice was well justified by subsequent events, as was also the attitude first adopted by our own Ministry of Health. THE SALK VACCINE DISASTER Only thirteen days after the vaccine had been acclaimed by the whole of the American Press and Radio as one of the greatest medical discoveries of the century, and two days after the English Minister of Health had announced he would go right ahead with the manufacture of the vaccine, came the first news of disaster. Children inoculated with one brand of vaccine had developed poliomyelitis. In the following days more and more cases were reported, some of then after inoculation with other brands of the vaccine. Then came another, and wholly unlooked-for complication. The Denver Medical Officer, Dr. Florio announced the development of what he called ‘satellite’ polio, that is, cases of the disease in the parents or other close contacts of children who had been inoculated and. alter a few days’ illness in hospital, had returned home: they communicated the disease to others, although not suffering from it themselves. On June 23rd, 1955 the American Public Health Service announced that there had been 149 confirmed cases of poliomyelitis among the vaccinated, with six deaths, and 149 cases among the contacts of children given the Salk vaccine, with six deaths. Nor is this the end of the story; how many vaccinated children will eventually be reported as developing the disease is as yet unknown, but it is at… truncated (75,534 more characters in archive)