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Oral Poliomyelitis Vaccine
LEADING ARTICLES
647
after the use of Cox Lederle vaccine in Berlin. KOCH ó decided on epidemiological grounds that the vaccine was safe and effective, despite 16 cases that arose within thirty days of vaccination and the 5 more cases in contacts. The reason for this conclusion was that poliomyelitis had appeared before LONDON 29 SEPTEMBER 1962 vaccination started. MELNICK,6 on the other hand, found that strains of type 1 and type 3 isolated from paralysed patients were antigenically related to the vaccine strains, whereas other naturally occurring strains isolated before feeding and elsewhere in Germany were antigenically different. (The tests used depend upon Oral Poliomyelitis Vaccine minor antigenic variations within the three main types UNFORTUNATELY the recent news from North America of virus of poliovirus.) But the accuracy of identification " has deepened some doubts1 about the safety of from the be a because natural " insecure, gut may attenuated poliomyelitis vaccines, especially for adults alimentary infection (which, once established, may taking Sabin type-3 component. In the United States the inevitably lead to viraemia and paralysis) may be overSurgeon-General’s advisory committee on oral polio- whelmed and masked by a large following dose of a myelitis vaccination met three times on Sept. 15 to different vaccine virus. The precision of these tests is discuss the 16 reported cases of poliomyelitis associated vital in unravelling the vaccine-associated with oral vaccine given in non-epidemic areas. They clearly concluded that there was sufficient epidemiological episodes. Cox strains (not now used) are more virulent for monevidence to indicate that at least some of the 11 cases than Sabin strains, but it is well known that Sabin associated with type-3 vaccine were caused by the keys 3 is not entirely satisfactoryand that the licensing vaccine. All 11cases were in adults, of whom only 2 type of the type-3 strains has been delayed in the U.S.A. had had inactivated vaccine.2 The committee recombecause of their neurovirulence for monkeys. If Sabin mended that the use of type-3 vaccine in mass campaigns 3 is still suspect after further examination of what be limited to children of school age and under. Plans type has happened in the United States and Canada, it may for mass programmes to give types 1 and 2 in monovalent well have to give way to another type-3 strain; and the vaccines to all ages are to continue; and type 3 will still WM III is one possibility. be available for adults in high-risk groups, including Koprowski In view of the very low incidence of cases possibly tourists to hyperendemic areas and those living in associated with vaccine administration and the absence epidemic areas. Meanwhile, 4 type-3 vaccine-associated of antigenic or other marker tests, the U.S. advisory cases of poliomyelitis, developing within thirty days of committee at first thought there was no reason to modify giving the vaccine, were reported in Canada, where 4 Sabin-vaccine programmes.9 Later developments have million people have had trivalent oral vaccine; and we led to the withholding of type-3 vaccine from adults in understand there are 3 contact cases. Serological the U.S.A., though if immunisation is continued in evidence points to the vaccine virus as the cause. Reschildren, as now recommended, they may excrete viruses trictions have been placed on the continued use of oral of enhanced virulence which could spread to adults. vaccine in Canada until the situation has been further is if there a in Conceivably, danger type 3, the children investigated. have not been affected by it because so many of them It is plainly going to take some time to establish what have had killed vaccine. has happened in Canada and the U.S.A. to make their In assessing the cases that have followed vaccination health authorities modify their vaccination programmes. in the U.S.A., the Surgeon-General’s committee ignored In this country most people have shared the view of those arising in epidemic areas, because clearly they WILSONthat, while there was a theoretical risk of might well be due to natural epidemic virus.lO The reversion to virulence after oral vaccination, this could Berlin experience indicates that virus studies might, in be discounted because so many millions had been such a natural from situation, help in vaccinated without incident. This argument is less vaccine-induced infections.distinguishing In Syracuse, New York, forceful than it seems because the vast majority of those there was a higher proportion of adult cases after the vaccinated were not susceptible, having earlier acquired use of type-1 virus in the face of an epidemic than there antibodies either naturally or from Salk vaccine. As was before the vaccine was used Unfortunately, no BURNETwas the first to point out, it is the vulnerable more virus studies of the Syracuse episode have been susceptible adults who are the real test of vaccine safety. reported, and the Surgeon-General’s committee refer When poliomyelitis does appear after a large vaccinato the poliomyelitis surveillance report of January tion campaign, as it may well do occasionally from only this year. MELNICKhas shown in Israel and Yugoslavia chance, it is exceedingly hard to determine what has 5. Koch, H. Amer. J. publ. Hlth, 1962, 52, 611. happened: this is illustrated by two recent reports about 6. Melnick, J. L. ibid. p. 472. cases
arising
West
THE LANCET
1. See Lancet,1961,ii,1021. 2. Surgeon General’s News Release, Sept.15, 1962. 3. Wilson, G. S. Publ.Hlth, 1962, 76, 229. 4. Burnet, F. M. 2nd International Conference
Vaccine; p. 460. Washington,
1961.
7. Tech. Rep. Wld Hlth Org. 1960, no. 205, p. 40. 8. Bodian, D. Science, 1961, 134, 819. 9. Communicable Disease Center, Poliomyelitis Surveillance
on
Live Poliovirus
no. 266. 10. ibid. no. 267. 11. ibid. no. 249.
Report, 1962,
648
that it is possible by antigenic analysis to demonstrate that some cases which follow the feeding of oral vaccine are vaccine failures rather than the result of infection by
should reasonably be expected to show a clear advantage over other therapeutic measures if it is to be generally
attenuated strains. The possible dangers of Sabin vaccine strains must not be exaggerated. The incidence, even if all the
The need.to reach a firm conclusion about this matter has touched off an acute controversy, not only about the value of long-term anticoagulant therapy but about whether anticoagulant treatment is worth starting at all. Exponents of both views were heard earlier this summer at the B.M.A. meeting at Belfast.15 R. B. HUNTER pointed to the value of the treatment in reducing thromboembolism after myocardial infarction; P. A. OWREN supported this and stressed the value of such treatment in patients with angina before they had any myocardial infarction; he suggested that the incidence of infarction and of reinfarction was reduced by treatment. TAGE HILDEN presented evidence for the opposite viewthat it was doubtful whether anticoagulant treatment did in fact reduce the incidence of thromboembolic complications, and that prognosis in acute myocardial infarction seemed to be determined largely by factors uninfluenced by anticoagulants. He was strongly supported by JOHN McMiCHAEL, who concluded that the value of long-term treatment was very problematical and that the use of anticoagulants for angina seemed hardly justified since survival was hardly any better in the treated than in the untreated; there were also the dangers of anticoagulant treatment to be taken into account, and these were not negligible. The report of negative results that aroused so much interest was that of HILDEN et a1.l6 which recorded the results of a trial carried out in Copenhagen over a period of four years and involving 800 patients; 371 were treated with anticoagulants and 429 were not. They stated that the mortality-rate and the incidence of thromboembolic episodes were substantially the same in the treated and untreated groups, except that, among patients who died, thromboembolic lesions were significantly less common in the treated than in the untreated group. Bleeding was only a rare cause of death, but haemorrhagic fluid in the pericardium was found on postmortem examination much more often in the treated
adopted.
’
reported
cases are
accepted
as
being vaccine-associated,
is less than 1 per million vaccinated. The vaccine has proved very effective in preventing poliomyelitis. If poliomyelitis was not being brought increasingly under control, largely as a result of the use of Salk-type vaccine, there would be every justification for the continued use of attenuated vaccine. We have previously argued, however, that, given the possibility of improving the potency of killed vaccine,12 it would probably be wiser to continue with inactivated vaccine in countries where there are substantial numbers of non-immune adults. In other areas, where adults are immune but where poliomyelitis is becoming more important as living and hygiene standards rise, the attenuated vaccine is still probably the best method of controlling the disease. No data derived from the increased use of attenuated vaccine in Britain have yet been published. The incidence of poliomyelitis this summer has been low, and nothing has been made known to suggest that oral vaccination was suspected of being responsible for any of the cases: but in view of the reports from North America a mass campaign for oral vaccination in Bristol, planned to begin last week, was postponed.
Arguments
about
Anticoagulant
Treatment
IT is about twenty years since oral anticoagulant drugs were first used for the treatment of myocardial infarction and other thromboembolic conditions. Many papers have been published about the results of this treatment; most have dealt with dicoumarol or phenindione. The favourable reports have greatly outnumbered the unfavourable or cautious; and nearly all have shown that the main benefit to be expected from the treatment of acute myocardial infarction is the prevention of further thromboembolic episodes, especially venous thrombosis and subsequent pulmonary embolism. Last year we remarked that " this form of treatment is now so widely accepted that most doctors consider it for patients with atherosclerotic diseases, and the patients and their relatives expect them to consider it ".13 Once the treatment with anticoagulants was begun, the next question was: When should it be stopped ? At first the drugs were given for only a few weeks after the acute episode, but the period lengthened until OWREN 14 proposed that treatment should be lifelong. The prospect of providing an anticoagulant service for an increasing population of patients caused physicians and pathologists to look very carefully at the real value of this form of therapy. A treatment so expensive in pathologists’ and technicians’ time, patients’ convenience, staff, and money Dane, D. S., Dick, G. W. A., Simpson, D. I. H., Briggs, E. M., McAlister, J., Nelson, R. Lancet, 1962, i, 939. 13. ibid., 1961, ii, 139. 14. Owren, P. A. Thrombosis and Anticoagulant Therapy (edited by W. Walker); p. 35. Edinburgh, 1961. 12.
patients. In this issue we have two more papers on this subject. Dr. HARVALD, Dr. HILDEN, and Dr. LUND (p. 626) discuss the effects of long-term anticoagulant therapy after myocardial infarction. The series comprised 315 patients randomly divided by date of birth into treated and untreated groups, the untreated group being given placebo tablets; there were 145 in the treated and 170 in the untreated group. The outcome, gauged by reinfarctions and by death from cardiac causes per 100 treatment months and by the survival-rate at the end of a four-year follow-up, showed no difference between the anticoagulant-treated and the placebo-treated groups. These workers conclude that long-term anticoagulant treatment is of only doubtful benefit, and, weighed against the risk of haemorrhage, is hardly justifiable. On p. 654 Dr. IRVING WRIGHT presents an opposite view by criticising severely the conclusions drawn by HILDEN et al. from 15. Brit. med. J., Aug. 18, 1962, p. 467. 16. Hilden, T., Iversen, K., Raaschou, F., ii, 327.
Schwartz,
M.
Lancet, 1961,
647
after the use of Cox Lederle vaccine in Berlin. KOCH ó decided on epidemiological grounds that the vaccine was safe and effective, despite 16 cases that arose within thirty days of vaccination and the 5 more cases in contacts. The reason for this conclusion was that poliomyelitis had appeared before LONDON 29 SEPTEMBER 1962 vaccination started. MELNICK,6 on the other hand, found that strains of type 1 and type 3 isolated from paralysed patients were antigenically related to the vaccine strains, whereas other naturally occurring strains isolated before feeding and elsewhere in Germany were antigenically different. (The tests used depend upon Oral Poliomyelitis Vaccine minor antigenic variations within the three main types UNFORTUNATELY the recent news from North America of virus of poliovirus.) But the accuracy of identification " has deepened some doubts1 about the safety of from the be a because natural " insecure, gut may attenuated poliomyelitis vaccines, especially for adults alimentary infection (which, once established, may taking Sabin type-3 component. In the United States the inevitably lead to viraemia and paralysis) may be overSurgeon-General’s advisory committee on oral polio- whelmed and masked by a large following dose of a myelitis vaccination met three times on Sept. 15 to different vaccine virus. The precision of these tests is discuss the 16 reported cases of poliomyelitis associated vital in unravelling the vaccine-associated with oral vaccine given in non-epidemic areas. They clearly concluded that there was sufficient epidemiological episodes. Cox strains (not now used) are more virulent for monevidence to indicate that at least some of the 11 cases than Sabin strains, but it is well known that Sabin associated with type-3 vaccine were caused by the keys 3 is not entirely satisfactoryand that the licensing vaccine. All 11cases were in adults, of whom only 2 type of the type-3 strains has been delayed in the U.S.A. had had inactivated vaccine.2 The committee recombecause of their neurovirulence for monkeys. If Sabin mended that the use of type-3 vaccine in mass campaigns 3 is still suspect after further examination of what be limited to children of school age and under. Plans type has happened in the United States and Canada, it may for mass programmes to give types 1 and 2 in monovalent well have to give way to another type-3 strain; and the vaccines to all ages are to continue; and type 3 will still WM III is one possibility. be available for adults in high-risk groups, including Koprowski In view of the very low incidence of cases possibly tourists to hyperendemic areas and those living in associated with vaccine administration and the absence epidemic areas. Meanwhile, 4 type-3 vaccine-associated of antigenic or other marker tests, the U.S. advisory cases of poliomyelitis, developing within thirty days of committee at first thought there was no reason to modify giving the vaccine, were reported in Canada, where 4 Sabin-vaccine programmes.9 Later developments have million people have had trivalent oral vaccine; and we led to the withholding of type-3 vaccine from adults in understand there are 3 contact cases. Serological the U.S.A., though if immunisation is continued in evidence points to the vaccine virus as the cause. Reschildren, as now recommended, they may excrete viruses trictions have been placed on the continued use of oral of enhanced virulence which could spread to adults. vaccine in Canada until the situation has been further is if there a in Conceivably, danger type 3, the children investigated. have not been affected by it because so many of them It is plainly going to take some time to establish what have had killed vaccine. has happened in Canada and the U.S.A. to make their In assessing the cases that have followed vaccination health authorities modify their vaccination programmes. in the U.S.A., the Surgeon-General’s committee ignored In this country most people have shared the view of those arising in epidemic areas, because clearly they WILSONthat, while there was a theoretical risk of might well be due to natural epidemic virus.lO The reversion to virulence after oral vaccination, this could Berlin experience indicates that virus studies might, in be discounted because so many millions had been such a natural from situation, help in vaccinated without incident. This argument is less vaccine-induced infections.distinguishing In Syracuse, New York, forceful than it seems because the vast majority of those there was a higher proportion of adult cases after the vaccinated were not susceptible, having earlier acquired use of type-1 virus in the face of an epidemic than there antibodies either naturally or from Salk vaccine. As was before the vaccine was used Unfortunately, no BURNETwas the first to point out, it is the vulnerable more virus studies of the Syracuse episode have been susceptible adults who are the real test of vaccine safety. reported, and the Surgeon-General’s committee refer When poliomyelitis does appear after a large vaccinato the poliomyelitis surveillance report of January tion campaign, as it may well do occasionally from only this year. MELNICKhas shown in Israel and Yugoslavia chance, it is exceedingly hard to determine what has 5. Koch, H. Amer. J. publ. Hlth, 1962, 52, 611. happened: this is illustrated by two recent reports about 6. Melnick, J. L. ibid. p. 472. cases
arising
West
THE LANCET
1. See Lancet,1961,ii,1021. 2. Surgeon General’s News Release, Sept.15, 1962. 3. Wilson, G. S. Publ.Hlth, 1962, 76, 229. 4. Burnet, F. M. 2nd International Conference
Vaccine; p. 460. Washington,
1961.
7. Tech. Rep. Wld Hlth Org. 1960, no. 205, p. 40. 8. Bodian, D. Science, 1961, 134, 819. 9. Communicable Disease Center, Poliomyelitis Surveillance
on
Live Poliovirus
no. 266. 10. ibid. no. 267. 11. ibid. no. 249.
Report, 1962,
648
that it is possible by antigenic analysis to demonstrate that some cases which follow the feeding of oral vaccine are vaccine failures rather than the result of infection by
should reasonably be expected to show a clear advantage over other therapeutic measures if it is to be generally
attenuated strains. The possible dangers of Sabin vaccine strains must not be exaggerated. The incidence, even if all the
The need.to reach a firm conclusion about this matter has touched off an acute controversy, not only about the value of long-term anticoagulant therapy but about whether anticoagulant treatment is worth starting at all. Exponents of both views were heard earlier this summer at the B.M.A. meeting at Belfast.15 R. B. HUNTER pointed to the value of the treatment in reducing thromboembolism after myocardial infarction; P. A. OWREN supported this and stressed the value of such treatment in patients with angina before they had any myocardial infarction; he suggested that the incidence of infarction and of reinfarction was reduced by treatment. TAGE HILDEN presented evidence for the opposite viewthat it was doubtful whether anticoagulant treatment did in fact reduce the incidence of thromboembolic complications, and that prognosis in acute myocardial infarction seemed to be determined largely by factors uninfluenced by anticoagulants. He was strongly supported by JOHN McMiCHAEL, who concluded that the value of long-term treatment was very problematical and that the use of anticoagulants for angina seemed hardly justified since survival was hardly any better in the treated than in the untreated; there were also the dangers of anticoagulant treatment to be taken into account, and these were not negligible. The report of negative results that aroused so much interest was that of HILDEN et a1.l6 which recorded the results of a trial carried out in Copenhagen over a period of four years and involving 800 patients; 371 were treated with anticoagulants and 429 were not. They stated that the mortality-rate and the incidence of thromboembolic episodes were substantially the same in the treated and untreated groups, except that, among patients who died, thromboembolic lesions were significantly less common in the treated than in the untreated group. Bleeding was only a rare cause of death, but haemorrhagic fluid in the pericardium was found on postmortem examination much more often in the treated
adopted.
’
reported
cases are
accepted
as
being vaccine-associated,
is less than 1 per million vaccinated. The vaccine has proved very effective in preventing poliomyelitis. If poliomyelitis was not being brought increasingly under control, largely as a result of the use of Salk-type vaccine, there would be every justification for the continued use of attenuated vaccine. We have previously argued, however, that, given the possibility of improving the potency of killed vaccine,12 it would probably be wiser to continue with inactivated vaccine in countries where there are substantial numbers of non-immune adults. In other areas, where adults are immune but where poliomyelitis is becoming more important as living and hygiene standards rise, the attenuated vaccine is still probably the best method of controlling the disease. No data derived from the increased use of attenuated vaccine in Britain have yet been published. The incidence of poliomyelitis this summer has been low, and nothing has been made known to suggest that oral vaccination was suspected of being responsible for any of the cases: but in view of the reports from North America a mass campaign for oral vaccination in Bristol, planned to begin last week, was postponed.
Arguments
about
Anticoagulant
Treatment
IT is about twenty years since oral anticoagulant drugs were first used for the treatment of myocardial infarction and other thromboembolic conditions. Many papers have been published about the results of this treatment; most have dealt with dicoumarol or phenindione. The favourable reports have greatly outnumbered the unfavourable or cautious; and nearly all have shown that the main benefit to be expected from the treatment of acute myocardial infarction is the prevention of further thromboembolic episodes, especially venous thrombosis and subsequent pulmonary embolism. Last year we remarked that " this form of treatment is now so widely accepted that most doctors consider it for patients with atherosclerotic diseases, and the patients and their relatives expect them to consider it ".13 Once the treatment with anticoagulants was begun, the next question was: When should it be stopped ? At first the drugs were given for only a few weeks after the acute episode, but the period lengthened until OWREN 14 proposed that treatment should be lifelong. The prospect of providing an anticoagulant service for an increasing population of patients caused physicians and pathologists to look very carefully at the real value of this form of therapy. A treatment so expensive in pathologists’ and technicians’ time, patients’ convenience, staff, and money Dane, D. S., Dick, G. W. A., Simpson, D. I. H., Briggs, E. M., McAlister, J., Nelson, R. Lancet, 1962, i, 939. 13. ibid., 1961, ii, 139. 14. Owren, P. A. Thrombosis and Anticoagulant Therapy (edited by W. Walker); p. 35. Edinburgh, 1961. 12.
patients. In this issue we have two more papers on this subject. Dr. HARVALD, Dr. HILDEN, and Dr. LUND (p. 626) discuss the effects of long-term anticoagulant therapy after myocardial infarction. The series comprised 315 patients randomly divided by date of birth into treated and untreated groups, the untreated group being given placebo tablets; there were 145 in the treated and 170 in the untreated group. The outcome, gauged by reinfarctions and by death from cardiac causes per 100 treatment months and by the survival-rate at the end of a four-year follow-up, showed no difference between the anticoagulant-treated and the placebo-treated groups. These workers conclude that long-term anticoagulant treatment is of only doubtful benefit, and, weighed against the risk of haemorrhage, is hardly justifiable. On p. 654 Dr. IRVING WRIGHT presents an opposite view by criticising severely the conclusions drawn by HILDEN et al. from 15. Brit. med. J., Aug. 18, 1962, p. 467. 16. Hilden, T., Iversen, K., Raaschou, F., ii, 327.
Schwartz,
M.
Lancet, 1961,