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British Medical Bulletin 62:201-211 (2002)
© 2002 The British Council

Vaccine programmes and policies

D M Salisbury*, P C L Beverley{dagger} and E Miller{ddagger}

*Department of Health, London, UK
{dagger}The Edward Jenner Institute for Vaccine Research, Berkshire, UK
{ddagger}Immunisation Division, Public Health Laboratory Service, Communicable Disease Surveillance Centre, London, UK


   Abstract
Top
 Abstract
Introduction
 Delivery of the UK...
 Strategic planning
 Vaccine safety
 Conclusions
 References
 
Management of an effective national vaccine strategy necessitates careful planning. In the face of budgetary constraints and the likely development of many new vaccines over the next few years, a rational choice of which vaccines to use and how best to use them will depend on first class disease surveillance, economic analysis of cost effectiveness and mathematical modelling to ensure optimal vaccine delivery. Effective immunisation programmes require strategic planning that integrates the outputs of these parameters with available health facilities with the least possible disruption. At the present time, the greatest threat to vaccination is resistance to continuing vaccination in the face of declining prevalence of many infectious diseases and heightened fears over vaccine safety. Re-assurance of the public that vaccines are safe demands effective detection of vaccine-related side-effects and rigorous investigation of any safety concerns.


   Introduction
Top
 Abstract
 Introduction
Delivery of the UK...
 Strategic planning
 Vaccine safety
 Conclusions
 References
 
This review considers the issues that need to be taken into account in formulating a national strategy for the development and implementation of vaccines. It is based on experience in the UK, but many of the issues considered are generic although here they are illustrated by reference to the UK experience.

Vaccination has been demonstrated repeatedly to be cost-effective, indeed even cost saving, a standard rarely expected of other healthcare interventions. Table 1 illustrates the impact of the immunisation programme in the UK in preventing disease and deaths. Most of these vaccines predate the modern era of genomics and recombinant DNA technology and were empirically derived and cheap. Health services in industrialised countries now face a period in which new techniques, that include genetic manipulation of organisms, will bring more vaccines to market in the near future than have ever been produced over a similar time frame.


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  		Table 1. Effect of vaccines on incidence of infectious diseases

 
The diseases against which new vaccines will become available, are either relatively rare but serious (e.g. meningococcal disease), or more common but with lower case fatality and complication rates (e.g. varicella). There will also be vaccines to prevent or treat malignant disease arising from a communicable disease basis (e.g. HPV). There is also the prospect of vaccines against atheroma and gastric ulcer, both of which have recently been shown to have an infective aetiology.

To anticipate the advent of new vaccines requires a national co-ordinated approach. The elements that contribute to such an approach include surveillance, economic analysis, scientific studies to support policy development, strategic planning for implementation, and close collaboration with the international vaccine industry1.


   Delivery of the UK immunisation programme
Top
 Abstract
 Introduction
 Delivery of the UK...
Strategic planning
 Vaccine safety
 Conclusions
 References
 
In the UK, all childhood immunisations and nationally recommended immunisations for adults, such as influenza vaccine, are provided free. No immunisations are compulsory. When a child's birth is reported, the local health authority is alerted and allocates the child to a general practitioner (GP). This process enrols the child onto the local health authority computerised database that will schedule the immunisations, calculate local coverage, identify defaulters and arrange payments for the GPs. By the time that an infant is 10 days old, the health visitor will have visited the parents. The health visitor discusses immunisation arrangements and seeks parental consent for the child to be entered into a computer-based programme. Consent is almost universal2. By the time the child is around 6 weeks old, an invitation for the first immunisation has been issued and the GP or local health clinic informed of the date and time scheduled for the child's immunisations and the antigens needed. Invitations for subsequent immunisations are issued in the same way. After each immunisation, the GP submits a completed form to the local computer unit, triggering the next step in the process.

These arrangements, put in place during the 1980s and 1990s, have contributed to a high coverage rate for immunisation. Several factors are thought to contribute to this3: (i) the payment of GPs only when they reach coverage targets; (ii) improvements in the computerised tracking system has facilitated the identification and follow-up of defaulters; (iii) widespread dissemination of up-to-date guidelines on immunisation theory and practice, sent free to all health care professionals involved in immunisation; (iv) appointment of immunisation co-ordinators in each health district; (v) acceleration of the timing of scheduled immunisations; and (vi) the development of a national immunisation communication strategy. Table 2 shows the current immunisation regimen in the UK.


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  		Table 2. UK schedule of recommended vaccines

 

   Strategic planning
Top
 Abstract
 Introduction
 Delivery of the UK...
 Strategic planning
Vaccine safety
 Conclusions
 References
 
UK immunisation policy is influenced by the policies that are developed through the World Health Organization (WHO) for the European region. The process and outcome targets established by WHO have been used to guide the objectives of the UK programme. These have specified the coverage levels to be attained (e.g. 90% by 1990) and outcomes such as elimination of target diseases (e.g. polio, measles, diphtheria)4.

Ministers take decisions on the most appropriate use of vaccines on the basis of advice from the UK Joint Committee on Vaccination and Immunisation (JCVI). This, in turn, receives advice from many sources. Epidemiological factors are taken into account through the surveillance work of the Public Health Laboratory Service (PHLS) and its Communicable Disease Surveillance Centre (CDSC), and through notifications of disease to the Office for National Statistics (ONS). PHLS/CDSC receive samples and data from hospital laboratories throughout the country. The PHLS also carries out surveillance on the extent of immunity to specific diseases within the population at large, based on coverage rates of existing immunisation programmes5, as well as on surveys of antibody levels in blood or saliva samples6. This allows early detection of new trends in infectious disease and provides the basis for effective decisions on vaccine use.

In addition to safety and efficacy and epidemiology of the diseases, other factors are taken into account in deciding national policy. Public attitudes towards immunisation are monitored through research undertaken on behalf of the Department of Health (DoH). Quality assurance and quality control of vaccines are monitored by the National Institute for Biological Standards and Control (NIBSC) through batch release testing. The National Health Service Supplies (NHSS) advises on vaccine availability and the logistics of cold-chain distribution and storage. DoH/JCVI also seek advice from independent experts and receives valuable feedback on the implementation of current vaccine policy from the regular meetings of the District Immunisation Co-ordinators (DICs).

These activities are co-ordinated by the DoH, and result in advice to Ministers. For example, the decision to undertake a mass immunisation campaign against measles in 1994 was based on information including sero-surveillance, which showed that a significant proportion of school children were not immune, increasing measles notifications throughout the UK during 1993/94, and experience of measles in other countries7. Using such information in mathematical models, it is possible to predict future disease patterns, the impact of different vaccination options and their economic consequences in order to inform policy decisions.

The use of mathematical models in the design of vaccination programmes

A crucial part of the assessment of a potential vaccination programme is an evaluation of its likely effectiveness (and cost-effectiveness). Vaccination can affect transmission, either by protecting vaccinated individuals from infection or by reducing their infectivity if infected. In either case, vaccination of infants leads to a reduction in transmission, an increase in the average age at infection and possibly an absolute increase in the number of cases in older age groups. Depending on the characteristics of the disease in question, particularly the effect of age at infection on severity of disease, the reduction in the risk of infection in the population may have a beneficial or adverse impact. For those infections for which severity of disease is higher in older age groups (e.g. rubella [congenital rubella syndrome]. varicella, hepatitis A) it is even possible that introducing a poorly designed or poorly implemented vaccination programme may increase the burden of disease8.

Sophisticated dynamic mathematical models of disease transmission provide the only effective method of investigating the epidemiological impact of vaccination programmes since many vaccine trials are designed to provide a measure of individual protection, not a measure of effectiveness at the population level. The chapter by Scherer and McLean in this issue describes in further detail the application of mathematical modelling to immunisation strategy.

The role of health services in vaccine development

In an ideal world, the burden from communicable disease would be continuously monitored so that priorities in morbidity, mortality, and health costs could be balanced against priorities in vaccine development. An attempt has been made to do this by the National Institutes of Health in the US with their annual Jordan Report on the Accelerated Development of Vaccines9. However, it remains unclear whether this has influenced the priorities of industry in its plans for bringing new vaccines to market, since these are heavily influenced by profit considerations and feasibility.

There is no formal framework in the UK for assessment of the burden of disease and development of vaccines, but the PHLS does monitor trends in communicable disease epidemiology to prioritise its activities (Overview of Communicable Disease). The leaders in UK immunisation are actively involved at high level in the international vaccine policy environment (e.g. WHO) and the international scientific community, as well as maintaining contacts with industry. Thus key individuals in the DoH and allied agencies are made aware of advances in the field, and may even influence the bringing of products to market by the manufacturers10. The strategy outlined in Getting Ahead of the Curve will provide a base for priority setting across the spectrum of potentially vaccine-preventable diseases.

Obstacles to the development of new vaccines

Despite recent technical advances, there are many hurdles which limit the translation of scientific research into new vaccines. The biggest obstacles are economic – vaccines are used on such a wide scale that there is pressure on manufacturers to keep prices very low, even in industrialised countries, yet vaccines take as long, and cost as much to develop as conventional medicines. Thus, development costs in the 1970s for recombinant hepatitis B vaccine were put at around $200 million. In recent years, attitudes to pricing of vaccines have changed with industry arguing that higher prices will have to be paid to fund high cost research and development, and that vaccine prices should reflect their worth.

These economic ‘facts of life’ do not rule out the commercial development of new vaccines, as witnessed by the introduction of Hib, hepatitis A and B vaccines, conjugate meningococcal and pneumococcal vaccines, and combinations based on acellular pertussis vaccine. Rather, it means that companies will tend to develop only those products for which there is a big demand in the industrialised world, and which are very safe (e.g. sub-units or conjugates rather than live vaccines). Persuading companies to develop vaccines for the non-industrialised world or to protect against rare diseases will require greater co-operation between researchers, industry and the main purchasers of vaccines (governments and international bodies such as UNICEF and the Global Alliance for Vaccines and Immunisation [GAVI]). Currently, new vaccines are often introduced into industrialised country markets at high prices to recoup development costs, and later become available in less developed countries at lower prices, until ultimately they are provided to the poorest countries at cost price. GAVI in particular is trying to break this mould and accelerate the availability of new vaccines for developing countries.

Public perception

Whereas most drugs are given only to people who are already ill, vaccines are given to entire populations of healthy people and thus even the safest vaccines may still incur significant costs from compensation or litigation. Public and media attitudes towards immunisation also affect the willingness of companies to invest in vaccine research and development. There is a perception that the media pay undue attention to stories involving extremely rare problems without fully understanding the issues. The recent furore over MMR provides an example. Publication of a description of a small number of cases, in which development of bowel disorders and autism were temporally associated with MMR vaccination11, led to a public belief that autism can be caused by the vaccine, despite overwhelming epidemiological evidence to the contrary. Nor has molecular, virological or immunological evidence demonstrated a causal association12. The effect of this has been a fall in the uptake of MMR and re-appearance of measles in Ireland and the UK.

New vaccines under consideration for licensure

Notwithstanding the difficulties of vaccine development, there are a number of vaccines that are either already in use elsewhere or are under consideration for use in the UK. Examples are varicella, acellular pertussis and pneumococcal conjugate vaccine. In these cases, the choice of whether to introduce the vaccine is less influenced by questions of vaccine safety and efficacy than by the absolute health gain from their introduction, or the incremental gain, where they reflect an improvement to existing vaccines. The introduction of vaccines such as these depends more on considerations of economic analysis (i.e. cost effectiveness) than the scientific specifics of the vaccines.

While decisions about whether and how to use the first generation of vaccines such as diphtheria, poliomyelitis, pertussis, and measles were relatively easily made, decisions about the use of new vaccines against diseases with a less severe clinical impact, such as rotavirus, or improved versions of existing vaccines, such as acellular pertussis, require more sophisticated decision-making techniques. Similarly, changes in the age-specific recommendations for influenza vaccination may hinge on the economic outcomes. Economic analysis provides a framework for evaluating the value-for-money given by different health interventions, but standardised methodologies must be used to make the results from different economic studies directly comparable13.

Well conducted, randomised, controlled trials provide the best data on effectiveness; but where data from clinical trials are not sufficient for inclusion in economic analyses, mathematical and statistical models have been used to augment their results. This is important because implementation of a universal immunisation programme affects the risk of infection not only in vaccinated individuals but also in unvaccinated individuals, because there are fewer infectious people to infect them (the herd immunity effect). The degree of protection to unvaccinated individuals depends on the vaccine coverage, the vaccine efficacy, the mechanism and duration of vaccine-induced protection, and the epidemiological characteristics of the infection in the population. Predicting these non-linear effects requires the use of sophisticated, dynamic mathematical models of disease transmission. Thus these tools have rarely been used and, as a result, some studies have attempted to include herd immunity effects, whereas others have ignored them completely. (A good example is provided by hepatitis B vaccination in the UK where two studies used the same cost estimates and yet came to opposite conclusions regarding the relative merits of mass versus targeted vaccination because of the inclusion, or not, of herd immunity effects14.)

Responsibility to ensure that available but unused, or emerging vaccines are properly considered lies with the Communicable Disease group at DoH. Work involves bringing together epidemiological data and economic data, along with scientific information available on such candidate vaccines. The difficulty inherent in this decision making is illustrated by the (by no means comprehensive) list of likely candidates shown in Table 3.


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  		Table 3. Future vaccines

 

   Vaccine safety
Top
 Abstract
 Introduction
 Delivery of the UK...
 Strategic planning
 Vaccine safety
Conclusions
 References
 
Public confidence in the safety of vaccines is critical for the maintenance of successful immunisation programmes. Failure to sustain confidence can have disastrous consequences, as shown in the 1970s when pertussis vaccine coverage plummeted following fears about the risk of brain damage from the vaccine15. The cohort and case-control studies that established its safety took many years to complete and in the meantime hundreds of thousands of children suffered unnecessarily from whooping cough. Ideally, post-licensure surveillance of vaccine safety would identify novel or rare adverse events not detected in pre-licensure assessment and provide reliable estimates of their rate of occurrence in a vaccinated cohort (i.e. provide a measure of the absolute risk following vaccination). It would also identify any causal association between vaccination and the adverse event (i.e. measure the attributable risk) and identify any risk factors predisposing to the development of specific adverse events, for example particular clinical conditions in the vaccine recipient or factors associated with the method of administration16.

Advances in molecular biology will lead to the development of new vaccines against infectious and non-infectious diseases, including conditions such as peptic ulceration and atherosclerosis as well as therapeutic vaccines for malignant disease. These new roles for vaccines mean that contentious issues in immunisation will assume increasing importance. These include the surveillance of vaccine safety and the higher profile of public perception of vaccine safety and risk assessment and its communication, the greater utilisation of information systems, and opportunities arising from linking information systems.

Passive surveillance

The basis of most post-licensure surveillance systems is the passive reporting of events suspected by clinicians to be vaccine reactions. One of the simplest passive reporting systems is the UK ‘Yellow Card’ system, established in 1964 in the wake of the thalidomide disaster. Clinicians have a statutory responsibility to report suspected drug or vaccine reactions. After its introduction, an assessment of the safety of the M/R vaccine used in the 1994 campaign, was published by the Medicines Control Agency and provided re-assuring evidence of the absence of novel or severe events associated with its administration to over 7 million children. A similar exercise has been undertaken after the 1999 introduction of conjugate meningococcal C vaccine. The major limitation of the ‘Yellow Card’ system is under-reporting of events and biased reporting of those that occur in close temporal association with vaccination. The US Centers for Disease Control operates a ‘stimulated-passive’ Vaccine Adverse Events Reporting System, but there is little evidence that this is more effective17.

Active surveillance

To try to overcome the deficiencies of passive reporting systems, attempts have been made to monitor vaccine safety using active surveillance methods. In Canada, the Immunisation Monitoring Programme Active (IMPACT) system was established in 1992 in sentinel hospitals covering 80% of paediatric admissions to academic centres. All discharges from these hospitals are scrutinised for conditions conforming to a defined set of vaccine adverse events. The IMPACT system supplements the passive reporting scheme to the Laboratory Centre for Disease Control. The findings of the IMPACT system have to date been re-assuring with no new adverse events identified and only one death attributable to vaccination. This resulted from disseminated BCG infection in a child with severe combined immunodeficiency. The IMPACT system is backed up by a special Advisory Committee on Causality Assessment (ACCA) to review all case reports meeting defined criteria for severity or unexpectedness. The IMPACT and ACCA systems are considered to make a significant contribution to sustaining public confidence in the Canadian immunisation programme.

Record linkage studies

The growing availability of computerised medical records compiled for administrative purposes provides novel opportunities to conduct cohort studies in vaccinated populations. Existing data systems, linking clinical events to the immunisation record, allow adverse events to be identified and their relationship to vaccination studied. Such databases are available in some Canadian provinces, such as Manitoba, and in health maintenance organisations in the US such as Kaiser Permanente, covering a large proportion of the private care population of California. CDSC has established expertise in the application of computerised record linkage for the identification of vaccine attributable risks. Starting with the linking of viral meningitis with Urabe based MMR vaccines in 199218, the technique, which links Hospital Episode Statistics (HES) with the community immunisation registers, has been used to study: (i) the risks for convulsions after DTP and MMR vaccines19; (ii) the attributable burden of convulsions after the introduction of Hib vaccine16; (iii) the risks of ITP after MMR vaccination20; and (iv) the risks of autism after MMR vaccine21.


   Conclusions
Top
 Abstract
 Introduction
 Delivery of the UK...
 Strategic planning
 Vaccine safety
 Conclusions
References
 
In the UK, the immunisation programme functions as a seamless service. There is integration of policy, procurement, promotion, research and strategic planning. PHLS/CDSC, NIBSC, NHSS, and the NHS are the main partners.

Arrangements for the accelerated introduction of new vaccines are well rehearsed. Recent activities to bring forward the availability of group C meningococcal conjugate vaccine have demonstrated the value of identifying critical policy related questions and delivering the research to resolve the issues.

If new vaccines are to be used, then the Department of Health needs to ensure that all relevant questions have been answered in order to assure the population of their safety and efficacy. In some instances, the deciding factors will be economic.

The responsibilities for the earliest stage of the development continuum rest with industry and academia, along with the support of the appropriate research councils.

As a result of the DoH sponsored research, there is already a wealth of knowledge on public attitudes to immunisation, vaccine preventable diseases, and vaccine safety. These data are regularly used in the promotion of immunisation and in responding to vaccine scares over safety. Nevertheless, there is no room for complacency, since it is reasonable to anticipate that the public will remain vulnerable to vaccine scares as long as the target diseases are absent. Despite all the advances in new vaccines, and the improvements in the provision of immunisation services, the greatest threat comes not from new or re-emerging infectious diseases, but from public loss of confidence in vaccine safety.


   Footnotes
 
Correspondence to:Dr P C L Beverley, Scientific Head, The Edward Jenner Institute for Vaccine Research, Compton, Berkshire RG20 7NN, UK


   References
Top
 Abstract
 Introduction
 Delivery of the UK...
 Strategic planning
 Vaccine safety
 Conclusions
 References
 

  1. Department of Health. Getting Ahead of the Curve – A strategy for combating infectious diseases (including other aspects of health prevention). London: Department of Health, 2002 (www.doh.uk/cmo/publications.htm)
  2. Simpson N, Lenton S, Randall R. Parental refusal to have children immunised: extent and reasons. BMJ 1995; 310: 227[Web of Science][Medline]
  3. White JM, Gillam SJ, Begg NT, Farrington CP. Vaccine coverage: recent trends and future prospects. BMJ 1992; 304: 682–4[Abstract/Free Full Text]
  4. Health For All by the Year 2000 (http://www.who.int/aboutwho/en/healthforall.htm)
  5. CDSC. COVER programme: July to September 2001. Commun Dis Rep CDR Wkly [serial online] 2002; 12: immunisation. Available online at http://www.phls.org.uk/publications/CDR%20Weekly/PDF%20files/2002/cdr0402.pdf
  6. Morgan-Capner P, Wright J, Miller CL, Miller E. Surveillance of antibody to measles, mumps and rubella by age. BMJ 1988; 297: 770–772[Abstract/Free Full Text]
  7. Gay N, Hesketh LM, Morgan-Capner P, Miller E. Interpreting serological surveillance data for measles using mathematical models: implications for vaccine strategy. Epidemiol Infect 1995; 115: 1390–406
  8. Miller E. Gay N. Effect of age on outcome and epidemiology of infectious diseases. Biologicals 1997; 25: 137–42[Web of Science][Medline]
  9. The Jordan Report. http://www.vaccinealliance.org/pdf/jordan2000.pdf
  10. Miller E, Salisbury D, Ramsay M. Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story. Vaccine 2002; 20: S58–67[Web of Science]
  11. Wakefield AJ, Murch SH, Anthony A et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children: an early report. Lancet 1998; 351: 637–41[Web of Science][Medline]
  12. Stratton K, Gable A, Shetty P, McCormick M. (eds) Immunization Safety Review. Measles-mumps-rubella vaccine and autism. Washington DC: National Academy Press, 2001; 102
  13. Edmunds WJ, Medley GF, Nokes DJ. Evaluating the cost-effectiveness of vaccination programmes: a dynamic perspective. Stat Med 1999; 18: 3263–82[Web of Science][Medline]
  14. Edmunds WJ. Universal or selective vaccination against hepatitis B virus in the United Kingdom? A review of recent cost-effectiveness studies. Commun Dis Public Health 1998; 1: 221–8
  15. Gangarosa EJ, Galazka AM, Wolfe CR et al. Impact of anti-vaccine movements on pertussis control: the untold story. Lancet 1998; 351: 356–61[Web of Science][Medline]
  16. Miller E. Waight P, Farrington P. Safety Assessment Post-licensure. Developments in Biological Standardization, vol. 95. Basel: Karger, 1998; 235–43
  17. Rosenthal S, Chen R. The reporting sensitivities of two passive surveillance systems for vaccine adverse events. Am J Public Health 1995; 85: 1706–9[Abstract/Free Full Text]
  18. Miller E, Goldacre M, Pugh S et al. Risk of aseptic meningitis after measles, mumps and rubella vaccine in UK children. Lancet 1993; 341: 979–82[Web of Science][Medline]
  19. Farrington P, Pugh S, Colville A et al. A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines. Lancet 1995; 345: 567–9[Web of Science][Medline]
  20. Miller E, Waight P, Farrington P, Andrews N, Stowe J, Taylor B. Idiopathic thrombocytopenic purpura and MMR vaccine (short report]. Arch Dis Child 2001; 84: 227–9[Abstract/Free Full Text]
  21. Taylor B, Miller E, Farrington P et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999; 353: 2026–9[Web of Science][Medline]

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