Vol. 5, No. 1 Printed in Great Britain
International Journal of Epidemiology © Oxford University Press 1976
Monitoring Communicable Disease: Vaccination Programmes D. L. MILLER1
quences, and faults in production may occur whose effects can be mitigated by early detection. Vaccine failure and vaccine-induced damage can do serious and sometimes irretrievable harm, not only to the recipients but also to those who come after by impairing confidence both in the vaccine in question and, perhaps, in vaccination in general. These are continuing dangers which demand continuing watchfulness.
INTRODUCTION
Vaccination is one of the most effective methods of disease prevention and control available. As such it deserves to be used with discernment and to be protected from the risk of damage to its reputation by either blind trust or ill-founded blame. Vaccine surveillance assists these ends. In current use the term vaccination is applied to immunization by the administration to healthy persons by an appropriate route of live or dead micro-organisms or their products. Preliminary evaluation of the efficacy and hazards of a new vaccine is now accepted as an indispensable condition before its use in routine medical practice is sanctioned. Indeed it was among the first medical procedures to be subjected to the discipline of the randomized control trial, and with good reason. Doctors have a special responsibility to see that procedures which they carry out on healthy people, even for their own protection, are both effective and safe. This responsibility cannot be discharged, however, simply by carrying out trials and granting a seal of once-for-all approval. Potent vaccines and well-planned immunization programmes may in practice fail to control a disease or cease to do so for a variety of reasons not necessarily attributable to the vaccine, particularly if the conditions in which the vaccine is used differ from those under which trials were carried out or if they change with time. Likewise, vaccines that in trials give rise to few reactions may have serious late conse-
AIMS OF VACCINE SURVEILLANCE
The aims of vaccine surveillance are to assemble and assess all data needed to ensure that each product is and continues to be safe in use, and to chart its success or otherwise in controlling the disease in question. The process includes monitoring not only disease incidence and untoward events but also factors that determine effectiveness and safety in order to give responsible authorities early warning of deviations from acceptable standards so that the vaccine or its mode of application can be modified. Where no remedy exists, it may be necessary to reappraise the benefits against the risks and costs of vaccination and to reconsider vaccination policy. VACCINE EFFECTIVENESS
The effectiveness of a vaccine should be measured in terms of its capacity both to protect vaccinated persons against disease and to restrict spread of infection in a community. Several factors which significantly influence vaccine efficacy in practice must be taken into account in the design of any surveillance programme.
1 Professor of Community Medicine, The Middlesex Hospital Medical School, Central Middlesex Hospital, Park Royal, London NW10 7NS, England.
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Downloaded from http://ije.oxfordjournals.org/ at Cornell University Library on July 12, 2015
Miller, D. L (Dept. Community Medicine, The Middlesex Hospital Medical School, Central Middlesex Hospital, Park Royal, London, NW10 7NS, England). Monitoring communicable disease: vaccination programmes. International Journal of Epidemiology 1976. 5 : 45-50. The success of vaccination as a means of disease prevention depends on its appropriate application and its reputation with the profession and the public. Surveillance, by providing accurate information on effectiveness and the frequency and nature of hazards, is essential to this purpose. Several factors that influence the success and safety of vaccination programmes are discussed. The essential elements of a vaccine surveillance scheme are outlined with special reference to experience derived from monitoring vaccines in current use.
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INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Population immunity In infections normally transmitted directly from person to person, and particularly those in which man is the only host, spread is inhibited if a high proportion of the community is resistant to infection. This requires both a uniformly high vaccine acceptance rate and appropriate deployment of vaccines. Uneven acceptance rates or unvaccinated immigrants (3) may create pockets of susceptible individuals where the infection survives and presents a continuing threat to others. The importance of immunization strategy in interrupting transmission has been amply demonstrated in the WHO Smallpox Eradication Programme (4). The agent When the antigenic type of an agent prevalent in an immunized community changes, the immunity possessed by the whole community becomes immunologically inappropriate and, therefore.unlikely to protect. Influenza virus is particularly notorious for its capricious antigenic changes. The antigenic types of other agents may change more insidiously, but equally unpredictably and with equally damaging consequences. For example, the relative frequency of different serotypes of Bordetella pertussis prevalent in the UK changed after the vaccine was introduced for routine use (5, 6). The vaccine and vaccination Inadequate antigenic potency of vaccines in use
may result either from faults in composition or manufacture or from deterioration owing to faulty storage or handling, particularly in the case of live virus vaccines. In these circumstances they may give disappointingly poor protection. The decline in effectiveness of pertussis vaccines in Britain in the early 1960s was perhaps partly attributable to lack of potency which has since been increased (7). Similarly, the effectiveness of smallpox eradication efforts before 1968 were probably limited by the poor quality of vaccine, often compounded by the inadequacy of vaccination techniques. Surveys showed that not more than 10-15 per cent of vaccine then in use in endemic countries met WHO standards and most vaccinations were carried out by the unsatisfactory scratch technique (8). VACCINE SAFETY
Vaccines vary in their safety but probably no vaccine or other product used for active immunization is totally free of the risk of producing adverse reactions or causing accidental harm to the recipient. Sir Graham Wilson (9) classified complications and accidents into those caused by normal toxicity, faulty production, faulty administration, allergy, other direct causes such as abnormal sensitivity of the patient, and indirect causes such as damage to the foetus and provocation disease. Undue frequency of immediate local or general reactions should emerge in the course of preliminary controlled trials. If at this stage more than a small proportion of subjects experience reactions the vaccine is unlikely to be accepted into routine practice unless, as for example in the case of people exposed to rabies, the risks of vaccination are small in comparison with those of contracting the disease. Such trials, however, which are usually on a relatively small scale, may not reveal a risk of reactions in exceptionally susceptible persons, such as progressive vaccinia and encephalitis, or other serious events, such as damage to the foetus or provocation poliomyelitis, that are either extremely rare or long delayed. These will only come to light by careful monitoring after the vaccine has been in use for some time in large populations. It is essential also to maintain a guard against the sometimes disastrous consequences of a contaminated or otherwise faulty batch of vaccine and of other accidents, such as arise from use of nonsterile apparatus. Few will need to be reminded of the notorious and tragic Cutter incident in which 149 cases of poliomyelitis were associated with administration of two pools of inadequately
Downloaded from http://ije.oxfordjournals.org/ at Cornell University Library on July 12, 2015
Individual immunity Individuals vary in the adequacy of their antibody response to vaccination depending on, for instance, genetic factors and, particularly in the very young or malnourished, their immunological competence. Sometimes the immunogenicity of a vaccine is impaired by external factors. In the case of oral poliomyelitis vaccine, for example, other enteroviruses present in the bowel may interfere with colonization by vaccine virus. This is particularly evident in countries where enteroviruses are highly prevalent (1). A separate problem is the waning of immunity with time. Vaccinated persons exposed to smallpox, for instance, are usually fully immune for three years or more, but periodic revaccination is essential to maintain full immunity. The same may be true for other diseases such as measles, particularly where the disease is controlled to the point where reinforcement of immunity by natural exposure to infection is unlikely to occur (2).
MONITORING COMMUNICABLE DISEASE: VACCINATION PROGRAMMES
inactivated Salk vaccine (10), nor of the huge outbreak of serum hepatitis in the American Army in 1942 which resulted from the presence of human serum in early batches of yellow.fever vaccine (11). The very unpredictability of such events demands alert and continuous monitoring both of the process of production and of illnesses following vaccination. THE ELEMENTS OF VACCINE SURVEILLANCE
Case reporting Reporting cases serves two main purposes: to reveal trends in incidence and to detect outbreaks. Complete case identification is difficult to obtain, partly because it relies on routine action by clinicians and partly because some cases do not reach medical attention or are difficult to diagnose. Under-reporting is not necessarily a handicap to measuring trends, provided it is reasonably consistent. But, when monitoring vaccination programmes, it is also important to locate residual reservoirs
of infection and to trace chains of continued transmission so that vaccination strategy can be directed accordingly. It is usual, therefore, to make use of several sources to search for cases including notifications, hospital admission registers and reports from laboratories. Desirable information about each case includes age, place of residence, date of onset, vaccination history, possible sources of infection and evidence for the diagnosis. While incidence rates are high, composite analysis will direct attention to major deficiencies in the cover given by the immunization programme. As the disease is controlled, detailed investigation of each case is required to identify its source and to avert possible spread to contacts. Even a single case of poliomyelitis reported in Britain, for instance, is an indication for urgent action. Unreported paralytic and non-paralytic cases must be found (if necessary by household surveys), neighbourhood or school contacts traced and vaccinated, and specimens for laboratory tests collected. Most important, enquiry must be made into how there came to be a gap in the defences of the community which allowed wild poliovirus to establish itself and spread. This could have arisen from an introduction by an unimmunized returning traveller, perhaps combined with omission of vaccination in a particular group (13, 14) or from mistaken policy or both. For instance, an outbreak of type 3 poliomyelitis was reported in Poland in 1968 after this type had been omitted from the oral vaccine for several years (15). In Blackburn, England, in 1965 there was a type 1 outbreak in a community where only Salk vaccine had been used and acceptance rates were low (16). The potential danger of a particular policy in the first case, and of failure to implement a policy adequately in the second, were apparently not fully appreciated. Antigenic changes Where only one stable antigenic type of an agent exists, like measles or smallpox viruses, or there is a limited number of types, as with poliovirus, there is usually no problem. But if the antigenic type prevalent in the population is liable to change, as with influenza, monitoring is essential. For this reason the World Health Organization has established a world-wide chain of influenza reference laboratories whose task is to identify new variants of the virus and forward them to one of the World Influenza Centres for characterization. The most recent variants can then be supplied to vaccine manufacturers (17). In the case of pertussis, up to 1963 vaccines had incorporated mainly strains
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Every vaccination programme requires to be monitored. The methods will differ according to the nature of the vaccine, whether it includes living organisms or not, how it is administered, and the clinical manifestations and epidemiological behaviour of the disease. The factors that influence the success and safety of a vaccination programme described above point to the essential elements of a surveillance scheme. These include monitoring the number of cases of the disease, changes in the characteristics of the agent, vaccine composition and potency, individual and population immunity and a search for illnesses that may be caused by the vaccine. The system must be sufficiently sensitive to detect early changes in disease frequency and rare untoward events. Surveillance data should be collected on a scale which will do this reliably. This, with the complexity and diversity of the information needed, usually means that it is best organized at national level. Also, data must be sought from all available sources and this requires collaboration between epidemiologists, clinicians, microbiologists, immunologists, statisticians, vaccine manufacturers and local and central administration. Responsibility for the collation, analysis and interpretation of data will usually be in the hands of an epidemiologist who must also see that the results are reported to contributors, administrators and practitioners who use the vaccine (12). (See Surveillance Reports published by the US Public Health Service, Center for Disease Control.)
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The vaccine (a) Batch control Before being approved for trial in humans every new vaccine is extensively tested for safety and potency in animals. Before licensing, its capacity to induce protective antibody and the frequency of reactions are further examined in human volunteers. Stringent standards for production batches are based on the results (19) and monitored by manufacturers and, in many countries, by government laboratories. The distribution of batches of vaccine from different manufacturers are also recorded in case serious reactions occur or there is apparent failure to protect so that the batches concerned can be traced and if necessary withdrawn. In 1969 the measles vaccine produced by one British manufacturer was withdrawn after reports of central nervous system complications within eight days of vaccination, which the measles surveillance programme had brought to light (20). (b) Utilization The number of doses of vaccine issued is a crude measure of utilization, but the number of completed courses of vaccination is more relevant. In England the date, manufacturer and batch number of each dose of vaccine given is normally recorded and often stored on computer. The programme can then be readily monitored and, if there is any serious problem subsequently it is simple to discover whether any particular batch was responsible. For some years the Chief Medical Officer published in his Annual Report a summary of infant immunization rates by Local Health Authority, which may
have stimulated those with below average rates (21). In the United States the success of the programme in reaching target groups is monitored by regular national immunization surveys. Monitoring antibody Vaccines generally induce lower levels of serum antibodies than natural infection, the antibody produced is less durable and protection is less certain. Although antibody titres bear a variable relation to protection in individuals, it is useful to monitor their frequency in order to gauge population susceptibility and to assess the adequacy of the programme in reaching the most susceptible groups and in maintaining immunity (22). This method of evaluation has not been widely implemented on a systematic and regular basis. Its value is illustrated by several surveys of antibody to poliovirus in Britain and the United States which have revealed disturbingly high proportions of apparently vulnerable persons (23, 24). Similar occasional studies have been carried out on antibodies to other agents, including tetanus and diphtheria (25, 26), measles (27) and rubella (28). Detection of complications
With vaccines containing killed microbes or their products, most serious complications arise either from unusual sensitivity in the patient or from the presence of foreign material in the vaccine, including toxic substances, contaminant micro-organisms and incompletely inactivated organisms. The sensitivity reactions that cause greatest concern involve the central nervous system. For example, the risk of neurological sequelae including permanent brain damage after pertussis vaccination (29), allied to doubts about the efficacy of current vaccines, has led some to question the wisdom of continuing its use (30, 31). The second type of incident, represented by the Cutter accident (10), has fortunately been rare. Less serious, but none the less unacceptable, is the type of reaction represented by the cyst formation that may follow administration of influenza vaccines that contain mineral oil adjuvants (32). More nebulous fears about unidentified agents, such as unknown viruses that might survive inactivation, have not so far been realized. Vaccines prepared from living organisms present different problems. Accidents such as the injection of rubella vaccine into a pregnant woman, may occur (33) but the main concern is that the agent may regain some of its virulence and cause illnesses either similar to the natural disease or complications
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of type 1, 2 (6), but it was then shown that the previously unusual serotype 1, 3 had become the predominant type and the vaccine composition was changed accordingly. Specimens from a sample of clinically suspect cases should be examined routinely, both to confirm the species of organism causing illnesses in vaccinated and unvaccinated patients and to establish its antigenic credentials and give early warning of changes. If asymptomatic carriage of an organism is frequent, routine surveys to establish the prevalence of carriers is necessary. For example, routine sampling of the public sewage effluent is useful in monitoring the relative frequency of different serotypes of poliovirus and their origins (18). In Britain collections of strains isolated from patients investigated for clinical reasons have also been used for this purpose (14).
MONITORING COMMUNICABLE DISEASE: VACCINATION PROGRAMMES
49
CONCLUSION
The principles and need for surveillance of vaccines are now widely accepted and generally applied in those countries where routine immunization is practised. There are, however, still questions to be answered and practical problems to be resolved: for instance, the effectiveness and safety both of some new vaccines and those containing multiple antigens; how to establish reliable data collection systems which will record and link details of all vaccinations, the occurrence of diseases against which they are aimed and of accidents and complications with which they may be associated; and the balance of advantage and risk attached to some vaccines.
Incident: Poliomyelitis following formaldehydeinactivated poliovirus vaccination in the United States during the spring of 1955. II. Relationship of poliomyelitis to Cutter vaccine. American Journal of Hygiene 78: 29, 1963. (11) Jaundice following yellow-fever vaccination (Editorial). Journal of the American Medical Association 119: 1110, 1942. (12) Langmuir, A. D.: The surveillance of communicable diseases of national importance. New England Journal of Medicine 268: 182, 1963. (13) Hopkins, C. C , Dismukes, W. E., Glick, T. H. and Warren, R. J.: Surveillance of paralytic poliomyelitis in the United States. Journal of the American Medical Association 210: 694, 1969. (14) Miller, D. L., Reid, D. and Diamond, Judith R.: Poliomyelitis surveillance in England and Wales, 1965-68. Public Health {London) 84: 265, 1970. (15)Pagano, J. S.: Type 3 poliovirus vaccines (Editorial). Journal of Paediatrics 75: 162, 1969.
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Public and professional acceptance of vaccination of that disease in the recipient or his contacts. depends on confidence that it will give safe proWith this in mind, surveillance programmes aim tection. Surveillance, by providing accurate to identify and investigate every case of suspected knowledge of the facts, will show its value as a poliomyelitis after oral vaccine or of encephalitis protective weapon and avoid or minimize the after measles vaccine. The risk of paralytic illness effects of accidents. Sir Graham Wilson's conafter oral polio vaccine is very small, probably between 1 in 2 and 1 in 6 million, depending on the clusion to his Heath Clark Lectures aptly summarizes the responsibility that must be discharged: serotype. There is probably also a small risk of type 'It is for us and for those who come after us, to 2 infection in the unvaccinated contacts of recently see that the sword which vaccines and antisera vaccinated children (13, 14). Acute encephalitis have put into our hands is never allowed to tarnish after measles vaccination is very rare and though through over-confidence, negligence, carelessness, subacute sclerosing panencephalitis is a theoretical or want of foresight on our part.' hazard the latent interval is too long to be certain yet of whether it occurs as a result of measles vaccination (34). In the case of rubella, concern relates to the possible spread of virus to pregnant REFERENCES contacts of vaccinated children, but so far this (1) Cockburn, W. C. and Drozdov, M. D.: Poliomyelitis in seems to be a negligible risk (35, 36). the world. Bulletin of the World Health Organization 42: 405, 1970. The two major difficulties in surveillance of (2) Linnemann, C. C.: Measles vaccine: immunity, reinfecserious complications of vaccination are first the tion and revaccination. American Journal of Epidemdetection of relevant events and second deciding iology 97, 365, 1973. whether they are caused by vaccination or are (3) Scott, H. D.: The elusiveness of measles eradication: coincidental. Detection presupposes a knowledge insights gained from three years of intensive surveillance in Rhode Island. American Journal of of what to expect and when, which only time will Epidemiology 94: 37, 1971. reveal. Surveillance plans must be shaped for each (4) Henderson, D. A.: Epidemiology in the global eradicavaccine based on a list of possible hazards derived tion of smallpox. International Journal ofEpidemiology from consideration of Wilson's six categories. 1:25,1972. These may need to be revised should suspect events (5) Preston, N. W.: Type-specific immunity against whooping cough. British Medical Journal 3: 724,1963. be reported later, which is an important function (6) Preston, N. W.: Effectiveness of pertussis vaccine. of a reporting system such as that of the British British Medical Journal 3: 11, 1965. Committee on Safety of Medicines. The distinction (7) Public Health Laboratory Service: Efficacy of whooping between complications of vaccination and events cough vaccines used in the United Kingdom before of a similar nature due to other causes related in 1968. British Medical Journal 1: 259, 1973. (8) World Health Organization: WHO Expert Committee time to vaccination requires accurate knowledge on Smallpox Eradication, Second Report. WHO of the expected frequency of such events in the Technical Report Series No. 493, 1972. vaccinated population, and controlled population (9) Wilson, Sir Graham S.: The Hazards of Immunisation. studies to measure these risks are an essential University of London, The Athlone Press, 1967. element of a surveillance programme. (10) Nathanson, N. and Langmuir, A. D.: The Cutter
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(26) Millian, S. J., Cherubin, C. E., Sherwin, R. and Fuerst, H. T.: A serologic survey of tetanus and diphtheria immunity in New York City. Archives of Environmental Health 15: 776, 1967. (27) Levitt, L. P., Case, G. E., Neil, J. S., Casey, H. L., Adler, P., Ferreri, S. and Witte, J. J.: Determination of measles immunity after a mass immunisation campaign. Public Health Reports 85: 261, 1970. (28) Zealley, H.: Rubella screening and immunisation of schoolgirls: a long-term evaluation. British Journal of Preventive and Social Medicine 28: 54, 1974. (29) Kulenkampff, M., Schwartzmann, J. S. and Wilson, J.: Neurological complications of pertussis inoculation. Archives of Disease in Childhood 49: 46, 1974. (30) Dick, G.: Immunisation in childhood. Community Medicine 127: 73, 1972. (31) British Medical Journal (Editorial): Vaccination against whooping cough. British Medical Journal 3: 539, 1974. (32) Medical Research Council: Clinical trials of influenza vaccine. British Medical Journal 2, 1, 1957. (33) Larson, H. E., Parkman, P. D., Davis, W. J., Hopps, H. E. and Myer, H. M.: Inadvertent rubella virus vaccination during pregnancy. New England Journal of Medicine 284: 870, 1971. (34) Dick, G.: Register of cases of subacute sclerosing panencephalitis (SSPE). British Medical Journal 3: 238, 1975. (35) Scott, H. D. and Byrne, E. B.: Exposure of susceptible pregnant women to rubella vaccines. Journal of the American Medical Association 215: 609, 1971. (36) Fleet, W. F., Vaughn, W., Lefkowitz, L. B., Schaffner, W., Federspiel, C. F., Thompson, J. and Karzon, D. T.: Gestational exposure to rubella vaccines. A population surveillance study. American Journal of Epidemiology 101: 220, 1975.
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(16) Moss, P. D., Durge, N. D., Robertson, L. and Cowburn, G. R.: The Blackburn poliomyelitis epidemic. Lancet 2: 555, 1968. (17) World Health Organization: Respiratory viruses. Report of a WHO Scientific Group. WHO Technical Report Series No. 408, 1969. (18) Nelson, D. B., Circo, R. and Evans, A. S.: Strategic viral surveillance of sewage during and following an oral poliovirus vaccine campaign. American Journal of Epidemiology 86: 641, 1967. (19) Perkins, F. T.: The quality control of vaccines. Proceedings of an International Conference on the Application of Vaccines against Viral, Rickettsial and Bacterial Diseases of Man. Pan-American Health Organization Scientific Publication No. 226, p. 428, 1971. (20) British Medical Journal (Editorial): A measles vaccine withdrawn. British Medical Journal 1: 791, 1969. (21) Chief Medical Officer's Annual Report: On the State of Public Health. London: HMSO, 1973. (22) Evans, A. S.: Serological surveys. The role of the WHO Reference Serum Banks. WHO Chronicle 21: 185, 1967. (23) Oberhofer, T. R., Brown, G. C. and Monto, A. S.: Seroimmunity to poliomyelitis in an American community. American Journal of Epidemiology 101: 333, 1975. (24) Mortimer, P. P. and Cunningham, P.: Seroimmunity to poliovirus in children and young women: England 1972-4. Journal of Hygiene {Cambridge) 74: 283, 1975. (25) Levine, L. and Wyman, L.: Survey of immunity by serological methods. New England Journal ofMedicine 272: 23, 1965.
International Journal of Epidemiology © Oxford University Press 1976
Monitoring Communicable Disease: Vaccination Programmes D. L. MILLER1
quences, and faults in production may occur whose effects can be mitigated by early detection. Vaccine failure and vaccine-induced damage can do serious and sometimes irretrievable harm, not only to the recipients but also to those who come after by impairing confidence both in the vaccine in question and, perhaps, in vaccination in general. These are continuing dangers which demand continuing watchfulness.
INTRODUCTION
Vaccination is one of the most effective methods of disease prevention and control available. As such it deserves to be used with discernment and to be protected from the risk of damage to its reputation by either blind trust or ill-founded blame. Vaccine surveillance assists these ends. In current use the term vaccination is applied to immunization by the administration to healthy persons by an appropriate route of live or dead micro-organisms or their products. Preliminary evaluation of the efficacy and hazards of a new vaccine is now accepted as an indispensable condition before its use in routine medical practice is sanctioned. Indeed it was among the first medical procedures to be subjected to the discipline of the randomized control trial, and with good reason. Doctors have a special responsibility to see that procedures which they carry out on healthy people, even for their own protection, are both effective and safe. This responsibility cannot be discharged, however, simply by carrying out trials and granting a seal of once-for-all approval. Potent vaccines and well-planned immunization programmes may in practice fail to control a disease or cease to do so for a variety of reasons not necessarily attributable to the vaccine, particularly if the conditions in which the vaccine is used differ from those under which trials were carried out or if they change with time. Likewise, vaccines that in trials give rise to few reactions may have serious late conse-
AIMS OF VACCINE SURVEILLANCE
The aims of vaccine surveillance are to assemble and assess all data needed to ensure that each product is and continues to be safe in use, and to chart its success or otherwise in controlling the disease in question. The process includes monitoring not only disease incidence and untoward events but also factors that determine effectiveness and safety in order to give responsible authorities early warning of deviations from acceptable standards so that the vaccine or its mode of application can be modified. Where no remedy exists, it may be necessary to reappraise the benefits against the risks and costs of vaccination and to reconsider vaccination policy. VACCINE EFFECTIVENESS
The effectiveness of a vaccine should be measured in terms of its capacity both to protect vaccinated persons against disease and to restrict spread of infection in a community. Several factors which significantly influence vaccine efficacy in practice must be taken into account in the design of any surveillance programme.
1 Professor of Community Medicine, The Middlesex Hospital Medical School, Central Middlesex Hospital, Park Royal, London NW10 7NS, England.
45
Downloaded from http://ije.oxfordjournals.org/ at Cornell University Library on July 12, 2015
Miller, D. L (Dept. Community Medicine, The Middlesex Hospital Medical School, Central Middlesex Hospital, Park Royal, London, NW10 7NS, England). Monitoring communicable disease: vaccination programmes. International Journal of Epidemiology 1976. 5 : 45-50. The success of vaccination as a means of disease prevention depends on its appropriate application and its reputation with the profession and the public. Surveillance, by providing accurate information on effectiveness and the frequency and nature of hazards, is essential to this purpose. Several factors that influence the success and safety of vaccination programmes are discussed. The essential elements of a vaccine surveillance scheme are outlined with special reference to experience derived from monitoring vaccines in current use.
46
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Population immunity In infections normally transmitted directly from person to person, and particularly those in which man is the only host, spread is inhibited if a high proportion of the community is resistant to infection. This requires both a uniformly high vaccine acceptance rate and appropriate deployment of vaccines. Uneven acceptance rates or unvaccinated immigrants (3) may create pockets of susceptible individuals where the infection survives and presents a continuing threat to others. The importance of immunization strategy in interrupting transmission has been amply demonstrated in the WHO Smallpox Eradication Programme (4). The agent When the antigenic type of an agent prevalent in an immunized community changes, the immunity possessed by the whole community becomes immunologically inappropriate and, therefore.unlikely to protect. Influenza virus is particularly notorious for its capricious antigenic changes. The antigenic types of other agents may change more insidiously, but equally unpredictably and with equally damaging consequences. For example, the relative frequency of different serotypes of Bordetella pertussis prevalent in the UK changed after the vaccine was introduced for routine use (5, 6). The vaccine and vaccination Inadequate antigenic potency of vaccines in use
may result either from faults in composition or manufacture or from deterioration owing to faulty storage or handling, particularly in the case of live virus vaccines. In these circumstances they may give disappointingly poor protection. The decline in effectiveness of pertussis vaccines in Britain in the early 1960s was perhaps partly attributable to lack of potency which has since been increased (7). Similarly, the effectiveness of smallpox eradication efforts before 1968 were probably limited by the poor quality of vaccine, often compounded by the inadequacy of vaccination techniques. Surveys showed that not more than 10-15 per cent of vaccine then in use in endemic countries met WHO standards and most vaccinations were carried out by the unsatisfactory scratch technique (8). VACCINE SAFETY
Vaccines vary in their safety but probably no vaccine or other product used for active immunization is totally free of the risk of producing adverse reactions or causing accidental harm to the recipient. Sir Graham Wilson (9) classified complications and accidents into those caused by normal toxicity, faulty production, faulty administration, allergy, other direct causes such as abnormal sensitivity of the patient, and indirect causes such as damage to the foetus and provocation disease. Undue frequency of immediate local or general reactions should emerge in the course of preliminary controlled trials. If at this stage more than a small proportion of subjects experience reactions the vaccine is unlikely to be accepted into routine practice unless, as for example in the case of people exposed to rabies, the risks of vaccination are small in comparison with those of contracting the disease. Such trials, however, which are usually on a relatively small scale, may not reveal a risk of reactions in exceptionally susceptible persons, such as progressive vaccinia and encephalitis, or other serious events, such as damage to the foetus or provocation poliomyelitis, that are either extremely rare or long delayed. These will only come to light by careful monitoring after the vaccine has been in use for some time in large populations. It is essential also to maintain a guard against the sometimes disastrous consequences of a contaminated or otherwise faulty batch of vaccine and of other accidents, such as arise from use of nonsterile apparatus. Few will need to be reminded of the notorious and tragic Cutter incident in which 149 cases of poliomyelitis were associated with administration of two pools of inadequately
Downloaded from http://ije.oxfordjournals.org/ at Cornell University Library on July 12, 2015
Individual immunity Individuals vary in the adequacy of their antibody response to vaccination depending on, for instance, genetic factors and, particularly in the very young or malnourished, their immunological competence. Sometimes the immunogenicity of a vaccine is impaired by external factors. In the case of oral poliomyelitis vaccine, for example, other enteroviruses present in the bowel may interfere with colonization by vaccine virus. This is particularly evident in countries where enteroviruses are highly prevalent (1). A separate problem is the waning of immunity with time. Vaccinated persons exposed to smallpox, for instance, are usually fully immune for three years or more, but periodic revaccination is essential to maintain full immunity. The same may be true for other diseases such as measles, particularly where the disease is controlled to the point where reinforcement of immunity by natural exposure to infection is unlikely to occur (2).
MONITORING COMMUNICABLE DISEASE: VACCINATION PROGRAMMES
inactivated Salk vaccine (10), nor of the huge outbreak of serum hepatitis in the American Army in 1942 which resulted from the presence of human serum in early batches of yellow.fever vaccine (11). The very unpredictability of such events demands alert and continuous monitoring both of the process of production and of illnesses following vaccination. THE ELEMENTS OF VACCINE SURVEILLANCE
Case reporting Reporting cases serves two main purposes: to reveal trends in incidence and to detect outbreaks. Complete case identification is difficult to obtain, partly because it relies on routine action by clinicians and partly because some cases do not reach medical attention or are difficult to diagnose. Under-reporting is not necessarily a handicap to measuring trends, provided it is reasonably consistent. But, when monitoring vaccination programmes, it is also important to locate residual reservoirs
of infection and to trace chains of continued transmission so that vaccination strategy can be directed accordingly. It is usual, therefore, to make use of several sources to search for cases including notifications, hospital admission registers and reports from laboratories. Desirable information about each case includes age, place of residence, date of onset, vaccination history, possible sources of infection and evidence for the diagnosis. While incidence rates are high, composite analysis will direct attention to major deficiencies in the cover given by the immunization programme. As the disease is controlled, detailed investigation of each case is required to identify its source and to avert possible spread to contacts. Even a single case of poliomyelitis reported in Britain, for instance, is an indication for urgent action. Unreported paralytic and non-paralytic cases must be found (if necessary by household surveys), neighbourhood or school contacts traced and vaccinated, and specimens for laboratory tests collected. Most important, enquiry must be made into how there came to be a gap in the defences of the community which allowed wild poliovirus to establish itself and spread. This could have arisen from an introduction by an unimmunized returning traveller, perhaps combined with omission of vaccination in a particular group (13, 14) or from mistaken policy or both. For instance, an outbreak of type 3 poliomyelitis was reported in Poland in 1968 after this type had been omitted from the oral vaccine for several years (15). In Blackburn, England, in 1965 there was a type 1 outbreak in a community where only Salk vaccine had been used and acceptance rates were low (16). The potential danger of a particular policy in the first case, and of failure to implement a policy adequately in the second, were apparently not fully appreciated. Antigenic changes Where only one stable antigenic type of an agent exists, like measles or smallpox viruses, or there is a limited number of types, as with poliovirus, there is usually no problem. But if the antigenic type prevalent in the population is liable to change, as with influenza, monitoring is essential. For this reason the World Health Organization has established a world-wide chain of influenza reference laboratories whose task is to identify new variants of the virus and forward them to one of the World Influenza Centres for characterization. The most recent variants can then be supplied to vaccine manufacturers (17). In the case of pertussis, up to 1963 vaccines had incorporated mainly strains
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Every vaccination programme requires to be monitored. The methods will differ according to the nature of the vaccine, whether it includes living organisms or not, how it is administered, and the clinical manifestations and epidemiological behaviour of the disease. The factors that influence the success and safety of a vaccination programme described above point to the essential elements of a surveillance scheme. These include monitoring the number of cases of the disease, changes in the characteristics of the agent, vaccine composition and potency, individual and population immunity and a search for illnesses that may be caused by the vaccine. The system must be sufficiently sensitive to detect early changes in disease frequency and rare untoward events. Surveillance data should be collected on a scale which will do this reliably. This, with the complexity and diversity of the information needed, usually means that it is best organized at national level. Also, data must be sought from all available sources and this requires collaboration between epidemiologists, clinicians, microbiologists, immunologists, statisticians, vaccine manufacturers and local and central administration. Responsibility for the collation, analysis and interpretation of data will usually be in the hands of an epidemiologist who must also see that the results are reported to contributors, administrators and practitioners who use the vaccine (12). (See Surveillance Reports published by the US Public Health Service, Center for Disease Control.)
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The vaccine (a) Batch control Before being approved for trial in humans every new vaccine is extensively tested for safety and potency in animals. Before licensing, its capacity to induce protective antibody and the frequency of reactions are further examined in human volunteers. Stringent standards for production batches are based on the results (19) and monitored by manufacturers and, in many countries, by government laboratories. The distribution of batches of vaccine from different manufacturers are also recorded in case serious reactions occur or there is apparent failure to protect so that the batches concerned can be traced and if necessary withdrawn. In 1969 the measles vaccine produced by one British manufacturer was withdrawn after reports of central nervous system complications within eight days of vaccination, which the measles surveillance programme had brought to light (20). (b) Utilization The number of doses of vaccine issued is a crude measure of utilization, but the number of completed courses of vaccination is more relevant. In England the date, manufacturer and batch number of each dose of vaccine given is normally recorded and often stored on computer. The programme can then be readily monitored and, if there is any serious problem subsequently it is simple to discover whether any particular batch was responsible. For some years the Chief Medical Officer published in his Annual Report a summary of infant immunization rates by Local Health Authority, which may
have stimulated those with below average rates (21). In the United States the success of the programme in reaching target groups is monitored by regular national immunization surveys. Monitoring antibody Vaccines generally induce lower levels of serum antibodies than natural infection, the antibody produced is less durable and protection is less certain. Although antibody titres bear a variable relation to protection in individuals, it is useful to monitor their frequency in order to gauge population susceptibility and to assess the adequacy of the programme in reaching the most susceptible groups and in maintaining immunity (22). This method of evaluation has not been widely implemented on a systematic and regular basis. Its value is illustrated by several surveys of antibody to poliovirus in Britain and the United States which have revealed disturbingly high proportions of apparently vulnerable persons (23, 24). Similar occasional studies have been carried out on antibodies to other agents, including tetanus and diphtheria (25, 26), measles (27) and rubella (28). Detection of complications
With vaccines containing killed microbes or their products, most serious complications arise either from unusual sensitivity in the patient or from the presence of foreign material in the vaccine, including toxic substances, contaminant micro-organisms and incompletely inactivated organisms. The sensitivity reactions that cause greatest concern involve the central nervous system. For example, the risk of neurological sequelae including permanent brain damage after pertussis vaccination (29), allied to doubts about the efficacy of current vaccines, has led some to question the wisdom of continuing its use (30, 31). The second type of incident, represented by the Cutter accident (10), has fortunately been rare. Less serious, but none the less unacceptable, is the type of reaction represented by the cyst formation that may follow administration of influenza vaccines that contain mineral oil adjuvants (32). More nebulous fears about unidentified agents, such as unknown viruses that might survive inactivation, have not so far been realized. Vaccines prepared from living organisms present different problems. Accidents such as the injection of rubella vaccine into a pregnant woman, may occur (33) but the main concern is that the agent may regain some of its virulence and cause illnesses either similar to the natural disease or complications
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of type 1, 2 (6), but it was then shown that the previously unusual serotype 1, 3 had become the predominant type and the vaccine composition was changed accordingly. Specimens from a sample of clinically suspect cases should be examined routinely, both to confirm the species of organism causing illnesses in vaccinated and unvaccinated patients and to establish its antigenic credentials and give early warning of changes. If asymptomatic carriage of an organism is frequent, routine surveys to establish the prevalence of carriers is necessary. For example, routine sampling of the public sewage effluent is useful in monitoring the relative frequency of different serotypes of poliovirus and their origins (18). In Britain collections of strains isolated from patients investigated for clinical reasons have also been used for this purpose (14).
MONITORING COMMUNICABLE DISEASE: VACCINATION PROGRAMMES
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CONCLUSION
The principles and need for surveillance of vaccines are now widely accepted and generally applied in those countries where routine immunization is practised. There are, however, still questions to be answered and practical problems to be resolved: for instance, the effectiveness and safety both of some new vaccines and those containing multiple antigens; how to establish reliable data collection systems which will record and link details of all vaccinations, the occurrence of diseases against which they are aimed and of accidents and complications with which they may be associated; and the balance of advantage and risk attached to some vaccines.
Incident: Poliomyelitis following formaldehydeinactivated poliovirus vaccination in the United States during the spring of 1955. II. Relationship of poliomyelitis to Cutter vaccine. American Journal of Hygiene 78: 29, 1963. (11) Jaundice following yellow-fever vaccination (Editorial). Journal of the American Medical Association 119: 1110, 1942. (12) Langmuir, A. D.: The surveillance of communicable diseases of national importance. New England Journal of Medicine 268: 182, 1963. (13) Hopkins, C. C , Dismukes, W. E., Glick, T. H. and Warren, R. J.: Surveillance of paralytic poliomyelitis in the United States. Journal of the American Medical Association 210: 694, 1969. (14) Miller, D. L., Reid, D. and Diamond, Judith R.: Poliomyelitis surveillance in England and Wales, 1965-68. Public Health {London) 84: 265, 1970. (15)Pagano, J. S.: Type 3 poliovirus vaccines (Editorial). Journal of Paediatrics 75: 162, 1969.
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Public and professional acceptance of vaccination of that disease in the recipient or his contacts. depends on confidence that it will give safe proWith this in mind, surveillance programmes aim tection. Surveillance, by providing accurate to identify and investigate every case of suspected knowledge of the facts, will show its value as a poliomyelitis after oral vaccine or of encephalitis protective weapon and avoid or minimize the after measles vaccine. The risk of paralytic illness effects of accidents. Sir Graham Wilson's conafter oral polio vaccine is very small, probably between 1 in 2 and 1 in 6 million, depending on the clusion to his Heath Clark Lectures aptly summarizes the responsibility that must be discharged: serotype. There is probably also a small risk of type 'It is for us and for those who come after us, to 2 infection in the unvaccinated contacts of recently see that the sword which vaccines and antisera vaccinated children (13, 14). Acute encephalitis have put into our hands is never allowed to tarnish after measles vaccination is very rare and though through over-confidence, negligence, carelessness, subacute sclerosing panencephalitis is a theoretical or want of foresight on our part.' hazard the latent interval is too long to be certain yet of whether it occurs as a result of measles vaccination (34). In the case of rubella, concern relates to the possible spread of virus to pregnant REFERENCES contacts of vaccinated children, but so far this (1) Cockburn, W. C. and Drozdov, M. D.: Poliomyelitis in seems to be a negligible risk (35, 36). the world. Bulletin of the World Health Organization 42: 405, 1970. The two major difficulties in surveillance of (2) Linnemann, C. C.: Measles vaccine: immunity, reinfecserious complications of vaccination are first the tion and revaccination. American Journal of Epidemdetection of relevant events and second deciding iology 97, 365, 1973. whether they are caused by vaccination or are (3) Scott, H. D.: The elusiveness of measles eradication: coincidental. Detection presupposes a knowledge insights gained from three years of intensive surveillance in Rhode Island. American Journal of of what to expect and when, which only time will Epidemiology 94: 37, 1971. reveal. Surveillance plans must be shaped for each (4) Henderson, D. A.: Epidemiology in the global eradicavaccine based on a list of possible hazards derived tion of smallpox. International Journal ofEpidemiology from consideration of Wilson's six categories. 1:25,1972. These may need to be revised should suspect events (5) Preston, N. W.: Type-specific immunity against whooping cough. British Medical Journal 3: 724,1963. be reported later, which is an important function (6) Preston, N. W.: Effectiveness of pertussis vaccine. of a reporting system such as that of the British British Medical Journal 3: 11, 1965. Committee on Safety of Medicines. The distinction (7) Public Health Laboratory Service: Efficacy of whooping between complications of vaccination and events cough vaccines used in the United Kingdom before of a similar nature due to other causes related in 1968. British Medical Journal 1: 259, 1973. (8) World Health Organization: WHO Expert Committee time to vaccination requires accurate knowledge on Smallpox Eradication, Second Report. WHO of the expected frequency of such events in the Technical Report Series No. 493, 1972. vaccinated population, and controlled population (9) Wilson, Sir Graham S.: The Hazards of Immunisation. studies to measure these risks are an essential University of London, The Athlone Press, 1967. element of a surveillance programme. (10) Nathanson, N. and Langmuir, A. D.: The Cutter
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(26) Millian, S. J., Cherubin, C. E., Sherwin, R. and Fuerst, H. T.: A serologic survey of tetanus and diphtheria immunity in New York City. Archives of Environmental Health 15: 776, 1967. (27) Levitt, L. P., Case, G. E., Neil, J. S., Casey, H. L., Adler, P., Ferreri, S. and Witte, J. J.: Determination of measles immunity after a mass immunisation campaign. Public Health Reports 85: 261, 1970. (28) Zealley, H.: Rubella screening and immunisation of schoolgirls: a long-term evaluation. British Journal of Preventive and Social Medicine 28: 54, 1974. (29) Kulenkampff, M., Schwartzmann, J. S. and Wilson, J.: Neurological complications of pertussis inoculation. Archives of Disease in Childhood 49: 46, 1974. (30) Dick, G.: Immunisation in childhood. Community Medicine 127: 73, 1972. (31) British Medical Journal (Editorial): Vaccination against whooping cough. British Medical Journal 3: 539, 1974. (32) Medical Research Council: Clinical trials of influenza vaccine. British Medical Journal 2, 1, 1957. (33) Larson, H. E., Parkman, P. D., Davis, W. J., Hopps, H. E. and Myer, H. M.: Inadvertent rubella virus vaccination during pregnancy. New England Journal of Medicine 284: 870, 1971. (34) Dick, G.: Register of cases of subacute sclerosing panencephalitis (SSPE). British Medical Journal 3: 238, 1975. (35) Scott, H. D. and Byrne, E. B.: Exposure of susceptible pregnant women to rubella vaccines. Journal of the American Medical Association 215: 609, 1971. (36) Fleet, W. F., Vaughn, W., Lefkowitz, L. B., Schaffner, W., Federspiel, C. F., Thompson, J. and Karzon, D. T.: Gestational exposure to rubella vaccines. A population surveillance study. American Journal of Epidemiology 101: 220, 1975.
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(16) Moss, P. D., Durge, N. D., Robertson, L. and Cowburn, G. R.: The Blackburn poliomyelitis epidemic. Lancet 2: 555, 1968. (17) World Health Organization: Respiratory viruses. Report of a WHO Scientific Group. WHO Technical Report Series No. 408, 1969. (18) Nelson, D. B., Circo, R. and Evans, A. S.: Strategic viral surveillance of sewage during and following an oral poliovirus vaccine campaign. American Journal of Epidemiology 86: 641, 1967. (19) Perkins, F. T.: The quality control of vaccines. Proceedings of an International Conference on the Application of Vaccines against Viral, Rickettsial and Bacterial Diseases of Man. Pan-American Health Organization Scientific Publication No. 226, p. 428, 1971. (20) British Medical Journal (Editorial): A measles vaccine withdrawn. British Medical Journal 1: 791, 1969. (21) Chief Medical Officer's Annual Report: On the State of Public Health. London: HMSO, 1973. (22) Evans, A. S.: Serological surveys. The role of the WHO Reference Serum Banks. WHO Chronicle 21: 185, 1967. (23) Oberhofer, T. R., Brown, G. C. and Monto, A. S.: Seroimmunity to poliomyelitis in an American community. American Journal of Epidemiology 101: 333, 1975. (24) Mortimer, P. P. and Cunningham, P.: Seroimmunity to poliovirus in children and young women: England 1972-4. Journal of Hygiene {Cambridge) 74: 283, 1975. (25) Levine, L. and Wyman, L.: Survey of immunity by serological methods. New England Journal ofMedicine 272: 23, 1965.
