707
THE LANCET
DE, Kunches LM, Kilinsky V, Lichtenberg DA, Make BJ, McCabe WR. Risk factors for pneumonia and fatality in patients receiving continuous mechanical ventilation. Am Rev Resp Dis 1986; 133: 792-96. 6. Donowitz LG, Wenzel RP, Hoyt JW. High risk of hospital acquired infection in the ICU-patient. Crit Care Med 1982; 10: 355-57.
5. Craven
JH, Mevissen-Verhage EAE, et al. Colonization and infection in surgical intensive care patients, a prospective study. Intensive Care Med 1987; 13: 347-51. 8. Kerver AJH, Rommes JH, Mevissen-Verhage EAE, et al. Prevention of colonization and infection in critically ill patients, a prospective randomised study. Crit Care Med 1988; 16: 1087-93.
7. Kerver AJH, Rommes
Hughes JM. Epidemiology and prevention of nosocomical pneumonia. In: Remington JS, Schwartz MM, eds. Current clinical topics in infectious diseases. Vol 9. New York: McGraw-Hill, 1988: 241-59. 10. Gross PA, Neu HC, Aswapokee P, van Antwerpen C, Aswapokee N. Deaths from nosocomial infections: experience in a university hospital and a community hospital. Am J Med 1980; 68: 219-23. 11. Bryant LR, Kent Trinkle J, Mobin-Uddin K, Baker J, Griffen WO. Bacterial colonization profile with tracheal intubation and mechanical 9.
ventilation. Arch Surg 1972; 104: 647-51. HD, Babcock JB. Colonization of intensive care unit patients with gram-negative bacilli. Am J Epidemiol 1975; 101: 495-501. 13. Chow AW, Taylor PhR, Yoshikawa ThT, Guze LB. A nosocomial outbreak of infections due to multiple resistant Proteus mirabilis: role of intestinal colonization as a major reservoir. J Infect Dis 1979; 139: 621-27. 14. Uffelen R van, van Saene HKF, Fidler V, Lowenberg A. Oropharyngeal flora as a source of bacteria colonising the lower airways in patients on artificial ventilation. Intensive Care Med 1984; 10: 233-37. 15. van der Waay D, Berghuis-de Vries JM, Lekkerkerk-van der Wees JEC. Colonization resistance of the digestive tract in conventional and antibiotic treated mice. J Hyg Camb 1971; 69: 405.
12. Rose
der Waay D. The digestive tract in immunocompromised patients; importance of maintaining its resistance to colonisation, especially in hospital in-patients and those taking antibiotics. Antonie Van Leeuwenhoek 1984; 50: 745-61. 17. Sleyfer DT, Mulder NH, Vries-Hospers HG de, et al. Infectionprevention in granulocytopenic patients by selective decontamination of the digestive tract. Eur J Cancer 1980; 16: 859-69. 18. Guiot HFL, van der Meer JW, van Furth R. Selective antimicrobial modulation of human microbial flora; infection prevention in patients with decreased host-defence mechanisms by selective elimination of potentially pathogenic bacteria. J Infect Dis 1981; 143: 644-54. 19. Stoutenbeek ChP, van Saene HKF, Miranda DR, Zandstra DF. The effect of selective decontamination of the digestive tract on colonization and infection rate in multiple trauma patients. Intensive Care Med 1984;
16.
van
20.
Ledingham IMcA, Eastaway AT, McKay IC, Alcock SR, McDonald JC, Ramsey G. Triple regimen of selective decontamination of the digestive tract, systemic cefotaxime and microbiological surveillance for prevention of acquired infection in intensive care. Lancet 1988; i:
21.
Guglielmo BJ, Hohn DC, Koo PJ, Hunt ThK, Sweet RL, Conte JE. Antibiotic prophylaxis in surgical procedures. Arch Surg 1983; 118:
10: 185-92.
785-90.
943-55. 22. Mandelli M, Mosconi P, Langer M, Cigada M. Intensive care unit group of infection-control. Prevention of pneumonia in an intensive care unit. A randomized multicenter clinical trial. Cnt Care Med 1989; 17: 501-05. 23. Donowitz GR, Mandell GL. Beta-lactam antibiotics: second of two parts. N Engl J Med 1988; 318: 490-500. 24. Nord CE, Kager L, Heimdahl A. Impact of antimicrobial agents on the gastrointestinal microflora and the risk of infections. Am J Med 1984; 76 (suppl 5a): 99-106. 25. Turck M, Stamm W. Nosocomial infection of the urinary tract. Am J Med 1981; 70: 651-54.
MODERN VACCINES Immunisation practice in developed countries
Successful immunisation programmes require both effective vaccines and effective systems to deliver them. Developed countries, with their good access to target populations, have often led the way; but even some of these show unacceptably high morbidity from conditions preventable by vaccines. This paper will focus on practice in the thirty-two countries of the European Region of the World Health Organisation (WHO), in North America, in Japan, and in Australia.1 Most countries have their vaccine policies set by central government, often in consultation with the private sector. In the United States, for example, the US Public Health Service has an Immunization Practices Advisory Committee (ACIP) which develops recommendations for vaccine use, primarily aiming at the public sector.7 To ensure coordination with the private sector, the ACIP works closely with the Committee on Infectious Diseases of the
American Academy of Pediatrics8 and the Task Force on Immunization of the American College of Physicians.9 By contrast, in the Federal Republic of Germany there is strong local autonomy, with some physicians using a particular vaccine (eg, pertussis) and others not.10
The vaccines in
use
Almost all the countries under consideration now routinely give DPT (diphtheria and tetanus toxoids and pertussis vaccine), poliomyelitis vaccine (whether oral live attenuated
ADDRESS. Center for Prevention Services, Centers for Disease Control, Atlanta, GA 30333, USA (A. R Hinman, MD, W. A.
Orenstein, MD).
708
[OPV] or injectable inactivated [IPV]), and measles vaccine. About half use rubella vaccines; several use mumps vaccine, typically in combination with measles and rubella as MMR; more than half continue to use bacillus Calmette-Guerin vaccine (BCG); and a few have started giving Haemophilus influenzae type B polysaccharide (either alone or in conjugated form). Of the countries immunising against pertussis, all but one rely on traditional whole-cell vaccines. The exception is Japan, where more than 30 million doses of acellular
vaccines have been administered since 1981.11 Certain countries do not recommend pertussis vaccination at present because of concerns about adverse effects, a feeling that pertussis is no longer an important hazard to health, or a mixture of the two. Only Denmark uses monovalent pertussis vaccine; the other users give it as part of DPT. There is great interest in acellular pertussis vaccines because it is thought that they might be less likely to cause adverse events. However, since the experience in Japan has been almost exclusively in children aged 2 years or more, most authorities are reluctant to recommend their immediate introduction for use in infancy. A large field trial in Sweden evaluated the use of two formulations of acellular pertussis vaccines in infancy. These were not introduced subsequently, because of concerns about the possibility of an increased rate of death from invasive disease caused by encapsulated bacteria in vaccine recipients; efficacy, based on the definitions used to diagnose pertussis during the trial, was also lower than expected.12,13 For immunisation against polio, OPV is much more widely used than IPV, but the oral vaccine will probably lose some ground to the new, enhanced-potency IPVparticularly when it becomes available in combined form with DPT containing acellular pertussis vaccines. At present orily Finland, Iceland, the Netherlands, Norway, Sweden, and some provinces in Canada routinely give IPV. Denmark and Israel offer a combined schedule with both OPV and IPV and France and Italy are content with either. Increasing numbers of countries are now giving MMR vaccine to young children-for many, a switch from the strategy of vaccinating girls just before puberty. The old policy, now abandoned by the UK among others, was to prevent congenital rubella syndrome while allowing rubella virus to circulate freely and induce natural immunity in much of the population. The new policy is interrupt rubella virus transmission completely.
meant to
Immunisation schedules All countries using DPT, except Japan, give three doses during the first year of life. Japan, too, is gradually switching from 2 years to infancy. Most countries give the first dose at 2-6 months, a second about 2 months later, and a third 2-6 months after the second. The USA and Canada, among others, have opted for three doses in the first 6 months of life with the aim of inducing early immunity; a fourth dose then follows at 15-18 months. Several countries also give an additional dose during the second year of life. The United States and Canada administer a fifth dose before school entry (4-6 years), to decrease the likelihood that the child will transmit pertussis, acquired at school, to younger unvaccinated siblings. The different policies seem to affect age distribution for pertussis: for example, in the USA less than 10% of cases reported are in children 5-9 years of age whereas in the UK (third and final dose given at about 9
months) the proportion is over 30%.la°’s A few countries offer regular tetanus and diphtheria toxoid boosters throughout life but none routinely gives pertussis vaccine after age 7. OPV is usually given at the same time as DPT and in the same number of doses in the first year. Countries that see a need for additional doses later in life tend to give them at middle or secondary school. Measles vaccine or MMR is usually given between 12 and 18 months of age, but a few countries give monovalent measles vaccine as early as 6-9 months, if measles in infancy is a problem. One dose is the rule, but Sweden and Finland give a second several years after the first.16,17 Other nations are following suit: the USA has lately adopted a two-dose policy,18 and this strategy was the recommendation of the 1989 meeting of national programme managers to all European member states. The rationale for a two-dose policy is to assure the highest possible level of immunity. Primary vaccine failure occurs in 2-5% of recipients of measles vaccine, and this level of susceptibility may be enough to sustain transmission. It is anticipated that the second dose will protect 95-98% of those who remain susceptible after the first dose.
Approaches and coverage In
most
countries under
consideration, government
provides for immunisation of children as part of a comprehensive health care system. An exception is the United States, where about half of all children receive this service from private physicians, paying for the vaccine and its administration; the others are immunised free of charge in public clinics. Vaccines are typically given as part of ordinary well-child care, but Japan has special immunisation clinics and a few countries hold mass vaccination days. What about compulsory vaccination? How effective are legal requirements for immunisation of children? In each of the 50 states of the USA and in some provinces of Canada, every child is legally required to be immunised before starting school (school attendance is also mandatory). Some authorities extend the requirements to all students from kindergarten to the completion of 12th grade-and even to college entrants-so as to prevent measles and rubella in these populations. Enforcement of these "no shots, no school" laws has resulted in very high levels of immunisation in schoolchildren in the United States and reductions of 90% or more in reported vaccine-preventable diseases. The school laws do not hamper immunisation of preschool children-an estimated 70-80% of children in the US are fully immunised by 2 years of age. Unfortunately there is evidence that in some areas, especially in economically depressed inner-city districts, children may not receive some or all of the recommended doses of vaccine until the time of school entry. This lack of coverage has been reflected in outbreaks of measles in unimmunised preschool children in several cities where as few as 50% of children may receive measles vaccine before their second
birthday. Almost all the countries under consideration achieve 80% better coverage with most vaccines. Rates are hard to compare in the absence of a standard method for collecting and reporting; coverage with polio vaccine and DPT seems rather higher than that with measles vaccine. or
709
In the UK, low coverage has been associated with concern about adverse reactions (pertussis) or with lack of appreciation of the impact of the disease (measles). As a consequence of the drop in coverage with pertussis vaccine there was a major resurgence in the incidence of pertussis, which in turn led to improvements in coverage. Coverage against measles has improved as a result of conscious efforts on the part of the Government and the medical community. The coverage achieved has been sufficient to interrupt transmission of diphtheria and poliomyelitis in most countries but not to interrupt measles transmission in any but a few (eg, Czechoslovakia).
Impact of vaccination
programmes
In each of the developed countries, introduction and widespread use of vaccines have had spectacular effects. Most have essentially eliminated diphtheria, poliomyelitis, and neonatal tetanus; for example, twenty of the thirty-two European countries reported no diphtheria in 1988, twentysix reported no poliomyelitis, and twenty-five reported no neonatal tetanus. The remaining incidence of tetanus is primarily in unvaccinated persons who grew up before tetanus toxoid was widely used. Pertussis and measles have also shown sharp declines in incidence. The impact of vaccines has been so striking that several countries are now working for disease elimination: the target of measles elimination was set by Czechoslovakia19 and the German Democratic Republic in 1976, the United States in 1978,z1 Canada in 1981,2z and Sweden and Finland in 1985. In 1984, the ministers of health of the countries in the European Region of WHO declared that, by the year
2000, poliomyelitis, measles, diphtheria, congenital rubella, and neonatal tetanus should be eliminated from the Region.23 More specific targets and objectives were subsequently established at regional meetings of immunisation programme managers .124 In May, 1988, the World Health Assembly adopted a resolution calling for global eradication of poliomyelitis by the year 2000. If this is to happen, developed countries will need to be generous with technical and financial assistance.
Remaining obstacles and
Too many contraindications and undue fear of adverse In many developed countries vaccination coverage is impeded by excessive concern about adverse events and by an overlong list of contraindications. For example, health care providers commonly decline to immunise a child who has a slight upper respiratory infection. Minor illnesses
be a contraindication to vaccination, and statements to this effect have been issued by the Expanded Programme on Immunisation (endorsed by the International Pediatric Association),26 by the European Regional Advisory Group to the EPI,27 and by advisory bodies in many individual countries. Concern about adverse events typically increases as the incidence of disease decreases. When there are several thousand cases of paralytic poliomyelitis each year, a handful of vaccine-associated cases is much less prominent than when there are no cases of paralysis due to wild poliovirus. Adverse events are very difficult to evaluate, not
are
with elaborate monitoring systems.28 Associations that merely temporal, rather than causal, can easily
undermine public and professional confidence in vaccines. There is no proven approach to forestall the impact of sensationalistic coverage of alleged adverse events but a rapid unified response by official and professional groups may
help.
Deficiences in surveillance in developed countries. Some diseases are not reportable in all vaccine-preventable is an countries-mumps example. Even with reportable one be needs to conditions, sceptical about the completeness of reporting. For poliomyelitis the figures are believed to be fairly reliable, whereas for previously common diseases, especially those that do not always lead to contact with a health worker, they are not-measles is a prime example. In addition, varying definitions may be used for a "case". In countries that rely heavily on laboratory-based surveillance, specificity of reported cases will be high but health impact may be greatly underestimated if laboratory confirmation is seldom requested; some, for example, will not register a case of pertussis unless there has been a positive culture of the bordetella, whereas others accept a clinical diagnosis. Surveillance varies
greatly
Lack of centralised coordination
Many countries lack a central focus to coordinate immunisation activities; and at local level there may be great variations in the effort given to promotion and monitoringand thus vaccine uptake--even within a single country. In the UK, an immunisation coordinator has now been designated for each district health authority, charged with monitoring (and if necessary improving) immunisations within his or her area. A few countries have committees of experts, including key groups such as academic paediatricians and general practitioners, to advise on immunisation policy. Unless, however, their advice is centrally coordinated, local policies will continue to conflict.
unmet needs
events
should
even
Country-to-country variation and lack of commitment to reduction / elimination targets Diseases do not recognise national boundaries, and the different approaches of neighbouring countries can work against each other. An example is rubella: in Europe several countries give rubella vaccine (as MMR) to all young children with the aim of
interrupting transmission and thereby eliminating congenital rubella syndrome. Their immediate neighbours may not use rubella vaccine at all or may vaccinate only susceptible adolescent and adult females, relying on widespread occurrence of rubella in childhood to protect females before they reach childbearing age. Thus, until lately, the Scandinavian countries were vaccinating all children, several Northern European countries were not using rubella vaccine to any appreciable extent, and the UK was giving rubella vaccine only to adolescent and adult females.
Regional target 5---elimination of specified vaccinepreventable diseases-declared by the 34th session of the
710
European Regional Committee, as well as a conference at Karlovy Vary, Czechoslovakia, in 1984, were important first steps in establishment of an Expanded Programme on Immunisation for the European Region. Subsequent annual meetings of the national programme managers have been useful for
promoting commitment and coordination. Adoption of the global poliomyelitis eradication target should help. In North America, the Canadian National Advisory Committee on Immunization and the US ACIP maintain close liaison.
Special groups Some individuals and groups are poorly served by routine medical care; others are vigorously opposed to immunisation. Gypsies and immigrants are examples of the first category and certain religious groups of the second. Outbreaks of poliomyelitis have been reported in gypsies in the UK and in persons religiously opposed to immunisation in the Netherlands .29,30
Prospects The biotechnology revolution offers great promise of new and improved vaccines to prevent yet more of the health burden from infectious diseases. The immunobiological preparations under development that may be considered for universal use in infants or children include Haemophilus influenzae type B vaccines, varicella vaccine, respiratory syncytial virus vaccine, and rotavirus vaccine. In addition, attempts to improve the safety and efficacy of existing vaccines may lead to substitutions of some antigens for others (eg, acellular pertussis vaccines will substitute purified components for the whole-cell vaccine in DPT) or in combined schedules that take advantage of the properties of different vaccines against the same agent (eg, IPV and
OPV). However, each breakthrough is associated with potential barriers to implementation that must be overcome. New vaccines must be integrated into existing schedules. Ideally, they should not require new visits but should be combined with, or given simultaneously with, other vaccines. Thus one must be confident that immunogenicity and efficacy of any of the components are not compromised and that adverse events are not increased. Research on new vaccines will often require two phases-an initial phase examining the safety and efficacy of the new antigen alone and a second phase evaluating safety and efficacy (or immunogenicity) of the antigen when administered simultaneously or in combined form with other vaccines. Apart from the database necessary to integrate new vaccines into the existing schedule, each addition of a vaccine will require a concerted professional and public educational effort to emphasise the benefits and risks of the new vaccine and proper indications, precautions, and contraindications. Without such efforts, vaccine use is likely to be suboptimal and the promise of preventing substantial morbidity with maximum vaccine safety will not be realised. The new attention given to immunisation activities in Europe has already paid handsome dividends, and further improvements are to be expected as the nations adopt common goals and programmes. With smallpox gone and poliomyelitis on the agenda, what diseases should be our next targets for regional elimination or global eradication? The prospects are exciting.
We gratefully acknowledge the assistance of Dr Boris Bytchenko, of the WHO European Regional Office in Copenhagen, in verifying some of the information in this article.
REFERENCES
1. Bytchenko BD, Dittmann S. Elimination of diseases from Europe through use of vaccines. Devel Biol Standard 1986; 65: 3-11. 2. Expanded Programme on Immunization: report of the meeting of national programme managers, Budapest, April 26-29, 1988. Regional Office for Europe (EUR/ICP/EPI 018, 1988). Copenhagen: WHO, 1988. 3. Canadian Immunization Guide. 3rd ed. Ottawa: Health and Welfare Canada, 1989. 4. Hinman AR. Control of communicable diseases. In: Wallace HM, Ryan G, Oglesby AC, eds. Maternal and child health practices. Oakland: Third Party Publishing, 1988. 5. Kimura M, Kuno-Sakai H. Immunization system in Japan: its history and present situation. Acta Paediatr Jap 1988; 30: 109-26. 6. Radford AJ. Immunization in Australia. A continuing national challenge. Med J Austr 1986; 145: 143-45. 7. Centers for Disease Control. Recommendations of the Immunization Practices Advisory Committee (ACIP): general recommendations on immunization. MMWR 1989; 38: 205-27. 8. American Academy of Pediatrics. Report of the Committee on Infectious Diseases. 21st ed. Elk Grove Village, IL: American Academy of Pediatrics, 1988. 9. American College of Physicians. Guide for adult immunization. Philadelphia: American College of Physicians, 1985. 10. Stehr K. Pertussis Schutzimpfung. In: Spilss H, ed. Impfkompendium. Stuttgart: Thieme, 1987. 11. Kimura M, Kuno-Sakai H. Pertussis vaccines in Japan. Acta Paediatr Jap 1988; 30: 143-53. 12. Ad Hoc Group for the Study of Pertussis Vaccines. Placebo-controlled trial of two acellular pertussis vaccines in Sweden-protective efficacy and adverse events. Lancet 1988; i: 955-60. 13. Storsaeter J, Olin P, Renemar B, et al. Mortality and morbidity from invasive bacterial infections during a clinical trial of acellular pertussis vaccines in Sweden. Pediatr Infect Dis J 1988; 7: 637-45. 14. Centers for Disease Control. Pertussis surveillance—United States, 1984 and 1985. MMWR 1987; 36: 168-71. 15. Cherry JD. The epidemiology of pertussis and pertussis immunization in the United Kingdom and the United States: a comparative study. Curr Prob Pediatr 1984; 14: 1-77. 16. Bottiger M, Christenson B, Taranger J, Bergman M. Mass vaccination programme aimed at eradicating measles, mumps and rubella in Sweden: vaccination of schoolchildren. Vaccine 1985; 3: 113-16. 17. Peltola H, Karanko V, Kurki T, et al. Rapid effect on endemic measles, mumps, and rubella of nationwide vaccination programme in Finland. Lancet 1986; i: 137-39. 18. Centers for Disease Control. Measles prevention: recommendations of the Immunization Practices Advisory Committee (ACIP). Recommendations and reports. MMWR 1989; 38(5-9): 1-18. 19. Sejda J. Is eradication or elimination of measles possible? Cesk Pediatrie 1977; 32: 729-31. 20. Dittmann S, Starke G, Ocklitz HW, Grahneis H, Giesecke H. The measles eradication programme in the German Democratic Republic. Bull WHO 1976; 53: 21-24. 21. Hinman AR, Brandling-Bennett AD, Nieburg PI. The opportunity and obligation to eliminate measles from the United States. JAMA 1979; 242: 1157-62. 22. National Advisory Committee on Immunization. Statement on elimination of indigenous measles in Canada. Canada Dis Weekly Rep
1981; 7: 81-82. 23. World Health Organization Regional Office for Europe. Targets for health for all: targets in support of the European regional strategy for health for all. Copenhagen: WHO, 1985. 24. Immunization policies in Europe: report on a WHO Meeting. Karlovy Vary, Czechoslovakia, Dec 10-12, 1984. Regional Office for Europe (ICP/EPI 001 m01, 1984). Copenhagen: WHO, 1984. 25. World Health Assembly. Global eradication of poliomyelitis by the year 2000. Resolution WHA41.28, 41st World Health Assembly, May 13, 1988. 26. Galazka A. Indications and contraindications for vaccines used in the EPI. Bull WHO 1984; 62: 357-66. 27. World Health Organisation. Contraindications for vaccines used in EPI. Weekly Epidem Rec 1988; 37: 279-81. 28. Centers for Disease Control. Adverse Events Following Immunization Report no 3: 1985-86, Atlanta: CDC, February, 1989. 29. Collingham KE, Pollock TM, Roebuck MO. Paralytic poliomyelitis in England and Wales 1976-1977. Lancet 1978; i: 976-77. 30. Bijkerk H. Poliomyelitis epidemic in the Netherlands, 1978. Devel Biol Standard 1979; 43: 195-206.
THE LANCET
DE, Kunches LM, Kilinsky V, Lichtenberg DA, Make BJ, McCabe WR. Risk factors for pneumonia and fatality in patients receiving continuous mechanical ventilation. Am Rev Resp Dis 1986; 133: 792-96. 6. Donowitz LG, Wenzel RP, Hoyt JW. High risk of hospital acquired infection in the ICU-patient. Crit Care Med 1982; 10: 355-57.
5. Craven
JH, Mevissen-Verhage EAE, et al. Colonization and infection in surgical intensive care patients, a prospective study. Intensive Care Med 1987; 13: 347-51. 8. Kerver AJH, Rommes JH, Mevissen-Verhage EAE, et al. Prevention of colonization and infection in critically ill patients, a prospective randomised study. Crit Care Med 1988; 16: 1087-93.
7. Kerver AJH, Rommes
Hughes JM. Epidemiology and prevention of nosocomical pneumonia. In: Remington JS, Schwartz MM, eds. Current clinical topics in infectious diseases. Vol 9. New York: McGraw-Hill, 1988: 241-59. 10. Gross PA, Neu HC, Aswapokee P, van Antwerpen C, Aswapokee N. Deaths from nosocomial infections: experience in a university hospital and a community hospital. Am J Med 1980; 68: 219-23. 11. Bryant LR, Kent Trinkle J, Mobin-Uddin K, Baker J, Griffen WO. Bacterial colonization profile with tracheal intubation and mechanical 9.
ventilation. Arch Surg 1972; 104: 647-51. HD, Babcock JB. Colonization of intensive care unit patients with gram-negative bacilli. Am J Epidemiol 1975; 101: 495-501. 13. Chow AW, Taylor PhR, Yoshikawa ThT, Guze LB. A nosocomial outbreak of infections due to multiple resistant Proteus mirabilis: role of intestinal colonization as a major reservoir. J Infect Dis 1979; 139: 621-27. 14. Uffelen R van, van Saene HKF, Fidler V, Lowenberg A. Oropharyngeal flora as a source of bacteria colonising the lower airways in patients on artificial ventilation. Intensive Care Med 1984; 10: 233-37. 15. van der Waay D, Berghuis-de Vries JM, Lekkerkerk-van der Wees JEC. Colonization resistance of the digestive tract in conventional and antibiotic treated mice. J Hyg Camb 1971; 69: 405.
12. Rose
der Waay D. The digestive tract in immunocompromised patients; importance of maintaining its resistance to colonisation, especially in hospital in-patients and those taking antibiotics. Antonie Van Leeuwenhoek 1984; 50: 745-61. 17. Sleyfer DT, Mulder NH, Vries-Hospers HG de, et al. Infectionprevention in granulocytopenic patients by selective decontamination of the digestive tract. Eur J Cancer 1980; 16: 859-69. 18. Guiot HFL, van der Meer JW, van Furth R. Selective antimicrobial modulation of human microbial flora; infection prevention in patients with decreased host-defence mechanisms by selective elimination of potentially pathogenic bacteria. J Infect Dis 1981; 143: 644-54. 19. Stoutenbeek ChP, van Saene HKF, Miranda DR, Zandstra DF. The effect of selective decontamination of the digestive tract on colonization and infection rate in multiple trauma patients. Intensive Care Med 1984;
16.
van
20.
Ledingham IMcA, Eastaway AT, McKay IC, Alcock SR, McDonald JC, Ramsey G. Triple regimen of selective decontamination of the digestive tract, systemic cefotaxime and microbiological surveillance for prevention of acquired infection in intensive care. Lancet 1988; i:
21.
Guglielmo BJ, Hohn DC, Koo PJ, Hunt ThK, Sweet RL, Conte JE. Antibiotic prophylaxis in surgical procedures. Arch Surg 1983; 118:
10: 185-92.
785-90.
943-55. 22. Mandelli M, Mosconi P, Langer M, Cigada M. Intensive care unit group of infection-control. Prevention of pneumonia in an intensive care unit. A randomized multicenter clinical trial. Cnt Care Med 1989; 17: 501-05. 23. Donowitz GR, Mandell GL. Beta-lactam antibiotics: second of two parts. N Engl J Med 1988; 318: 490-500. 24. Nord CE, Kager L, Heimdahl A. Impact of antimicrobial agents on the gastrointestinal microflora and the risk of infections. Am J Med 1984; 76 (suppl 5a): 99-106. 25. Turck M, Stamm W. Nosocomial infection of the urinary tract. Am J Med 1981; 70: 651-54.
MODERN VACCINES Immunisation practice in developed countries
Successful immunisation programmes require both effective vaccines and effective systems to deliver them. Developed countries, with their good access to target populations, have often led the way; but even some of these show unacceptably high morbidity from conditions preventable by vaccines. This paper will focus on practice in the thirty-two countries of the European Region of the World Health Organisation (WHO), in North America, in Japan, and in Australia.1 Most countries have their vaccine policies set by central government, often in consultation with the private sector. In the United States, for example, the US Public Health Service has an Immunization Practices Advisory Committee (ACIP) which develops recommendations for vaccine use, primarily aiming at the public sector.7 To ensure coordination with the private sector, the ACIP works closely with the Committee on Infectious Diseases of the
American Academy of Pediatrics8 and the Task Force on Immunization of the American College of Physicians.9 By contrast, in the Federal Republic of Germany there is strong local autonomy, with some physicians using a particular vaccine (eg, pertussis) and others not.10
The vaccines in
use
Almost all the countries under consideration now routinely give DPT (diphtheria and tetanus toxoids and pertussis vaccine), poliomyelitis vaccine (whether oral live attenuated
ADDRESS. Center for Prevention Services, Centers for Disease Control, Atlanta, GA 30333, USA (A. R Hinman, MD, W. A.
Orenstein, MD).
708
[OPV] or injectable inactivated [IPV]), and measles vaccine. About half use rubella vaccines; several use mumps vaccine, typically in combination with measles and rubella as MMR; more than half continue to use bacillus Calmette-Guerin vaccine (BCG); and a few have started giving Haemophilus influenzae type B polysaccharide (either alone or in conjugated form). Of the countries immunising against pertussis, all but one rely on traditional whole-cell vaccines. The exception is Japan, where more than 30 million doses of acellular
vaccines have been administered since 1981.11 Certain countries do not recommend pertussis vaccination at present because of concerns about adverse effects, a feeling that pertussis is no longer an important hazard to health, or a mixture of the two. Only Denmark uses monovalent pertussis vaccine; the other users give it as part of DPT. There is great interest in acellular pertussis vaccines because it is thought that they might be less likely to cause adverse events. However, since the experience in Japan has been almost exclusively in children aged 2 years or more, most authorities are reluctant to recommend their immediate introduction for use in infancy. A large field trial in Sweden evaluated the use of two formulations of acellular pertussis vaccines in infancy. These were not introduced subsequently, because of concerns about the possibility of an increased rate of death from invasive disease caused by encapsulated bacteria in vaccine recipients; efficacy, based on the definitions used to diagnose pertussis during the trial, was also lower than expected.12,13 For immunisation against polio, OPV is much more widely used than IPV, but the oral vaccine will probably lose some ground to the new, enhanced-potency IPVparticularly when it becomes available in combined form with DPT containing acellular pertussis vaccines. At present orily Finland, Iceland, the Netherlands, Norway, Sweden, and some provinces in Canada routinely give IPV. Denmark and Israel offer a combined schedule with both OPV and IPV and France and Italy are content with either. Increasing numbers of countries are now giving MMR vaccine to young children-for many, a switch from the strategy of vaccinating girls just before puberty. The old policy, now abandoned by the UK among others, was to prevent congenital rubella syndrome while allowing rubella virus to circulate freely and induce natural immunity in much of the population. The new policy is interrupt rubella virus transmission completely.
meant to
Immunisation schedules All countries using DPT, except Japan, give three doses during the first year of life. Japan, too, is gradually switching from 2 years to infancy. Most countries give the first dose at 2-6 months, a second about 2 months later, and a third 2-6 months after the second. The USA and Canada, among others, have opted for three doses in the first 6 months of life with the aim of inducing early immunity; a fourth dose then follows at 15-18 months. Several countries also give an additional dose during the second year of life. The United States and Canada administer a fifth dose before school entry (4-6 years), to decrease the likelihood that the child will transmit pertussis, acquired at school, to younger unvaccinated siblings. The different policies seem to affect age distribution for pertussis: for example, in the USA less than 10% of cases reported are in children 5-9 years of age whereas in the UK (third and final dose given at about 9
months) the proportion is over 30%.la°’s A few countries offer regular tetanus and diphtheria toxoid boosters throughout life but none routinely gives pertussis vaccine after age 7. OPV is usually given at the same time as DPT and in the same number of doses in the first year. Countries that see a need for additional doses later in life tend to give them at middle or secondary school. Measles vaccine or MMR is usually given between 12 and 18 months of age, but a few countries give monovalent measles vaccine as early as 6-9 months, if measles in infancy is a problem. One dose is the rule, but Sweden and Finland give a second several years after the first.16,17 Other nations are following suit: the USA has lately adopted a two-dose policy,18 and this strategy was the recommendation of the 1989 meeting of national programme managers to all European member states. The rationale for a two-dose policy is to assure the highest possible level of immunity. Primary vaccine failure occurs in 2-5% of recipients of measles vaccine, and this level of susceptibility may be enough to sustain transmission. It is anticipated that the second dose will protect 95-98% of those who remain susceptible after the first dose.
Approaches and coverage In
most
countries under
consideration, government
provides for immunisation of children as part of a comprehensive health care system. An exception is the United States, where about half of all children receive this service from private physicians, paying for the vaccine and its administration; the others are immunised free of charge in public clinics. Vaccines are typically given as part of ordinary well-child care, but Japan has special immunisation clinics and a few countries hold mass vaccination days. What about compulsory vaccination? How effective are legal requirements for immunisation of children? In each of the 50 states of the USA and in some provinces of Canada, every child is legally required to be immunised before starting school (school attendance is also mandatory). Some authorities extend the requirements to all students from kindergarten to the completion of 12th grade-and even to college entrants-so as to prevent measles and rubella in these populations. Enforcement of these "no shots, no school" laws has resulted in very high levels of immunisation in schoolchildren in the United States and reductions of 90% or more in reported vaccine-preventable diseases. The school laws do not hamper immunisation of preschool children-an estimated 70-80% of children in the US are fully immunised by 2 years of age. Unfortunately there is evidence that in some areas, especially in economically depressed inner-city districts, children may not receive some or all of the recommended doses of vaccine until the time of school entry. This lack of coverage has been reflected in outbreaks of measles in unimmunised preschool children in several cities where as few as 50% of children may receive measles vaccine before their second
birthday. Almost all the countries under consideration achieve 80% better coverage with most vaccines. Rates are hard to compare in the absence of a standard method for collecting and reporting; coverage with polio vaccine and DPT seems rather higher than that with measles vaccine. or
709
In the UK, low coverage has been associated with concern about adverse reactions (pertussis) or with lack of appreciation of the impact of the disease (measles). As a consequence of the drop in coverage with pertussis vaccine there was a major resurgence in the incidence of pertussis, which in turn led to improvements in coverage. Coverage against measles has improved as a result of conscious efforts on the part of the Government and the medical community. The coverage achieved has been sufficient to interrupt transmission of diphtheria and poliomyelitis in most countries but not to interrupt measles transmission in any but a few (eg, Czechoslovakia).
Impact of vaccination
programmes
In each of the developed countries, introduction and widespread use of vaccines have had spectacular effects. Most have essentially eliminated diphtheria, poliomyelitis, and neonatal tetanus; for example, twenty of the thirty-two European countries reported no diphtheria in 1988, twentysix reported no poliomyelitis, and twenty-five reported no neonatal tetanus. The remaining incidence of tetanus is primarily in unvaccinated persons who grew up before tetanus toxoid was widely used. Pertussis and measles have also shown sharp declines in incidence. The impact of vaccines has been so striking that several countries are now working for disease elimination: the target of measles elimination was set by Czechoslovakia19 and the German Democratic Republic in 1976, the United States in 1978,z1 Canada in 1981,2z and Sweden and Finland in 1985. In 1984, the ministers of health of the countries in the European Region of WHO declared that, by the year
2000, poliomyelitis, measles, diphtheria, congenital rubella, and neonatal tetanus should be eliminated from the Region.23 More specific targets and objectives were subsequently established at regional meetings of immunisation programme managers .124 In May, 1988, the World Health Assembly adopted a resolution calling for global eradication of poliomyelitis by the year 2000. If this is to happen, developed countries will need to be generous with technical and financial assistance.
Remaining obstacles and
Too many contraindications and undue fear of adverse In many developed countries vaccination coverage is impeded by excessive concern about adverse events and by an overlong list of contraindications. For example, health care providers commonly decline to immunise a child who has a slight upper respiratory infection. Minor illnesses
be a contraindication to vaccination, and statements to this effect have been issued by the Expanded Programme on Immunisation (endorsed by the International Pediatric Association),26 by the European Regional Advisory Group to the EPI,27 and by advisory bodies in many individual countries. Concern about adverse events typically increases as the incidence of disease decreases. When there are several thousand cases of paralytic poliomyelitis each year, a handful of vaccine-associated cases is much less prominent than when there are no cases of paralysis due to wild poliovirus. Adverse events are very difficult to evaluate, not
are
with elaborate monitoring systems.28 Associations that merely temporal, rather than causal, can easily
undermine public and professional confidence in vaccines. There is no proven approach to forestall the impact of sensationalistic coverage of alleged adverse events but a rapid unified response by official and professional groups may
help.
Deficiences in surveillance in developed countries. Some diseases are not reportable in all vaccine-preventable is an countries-mumps example. Even with reportable one be needs to conditions, sceptical about the completeness of reporting. For poliomyelitis the figures are believed to be fairly reliable, whereas for previously common diseases, especially those that do not always lead to contact with a health worker, they are not-measles is a prime example. In addition, varying definitions may be used for a "case". In countries that rely heavily on laboratory-based surveillance, specificity of reported cases will be high but health impact may be greatly underestimated if laboratory confirmation is seldom requested; some, for example, will not register a case of pertussis unless there has been a positive culture of the bordetella, whereas others accept a clinical diagnosis. Surveillance varies
greatly
Lack of centralised coordination
Many countries lack a central focus to coordinate immunisation activities; and at local level there may be great variations in the effort given to promotion and monitoringand thus vaccine uptake--even within a single country. In the UK, an immunisation coordinator has now been designated for each district health authority, charged with monitoring (and if necessary improving) immunisations within his or her area. A few countries have committees of experts, including key groups such as academic paediatricians and general practitioners, to advise on immunisation policy. Unless, however, their advice is centrally coordinated, local policies will continue to conflict.
unmet needs
events
should
even
Country-to-country variation and lack of commitment to reduction / elimination targets Diseases do not recognise national boundaries, and the different approaches of neighbouring countries can work against each other. An example is rubella: in Europe several countries give rubella vaccine (as MMR) to all young children with the aim of
interrupting transmission and thereby eliminating congenital rubella syndrome. Their immediate neighbours may not use rubella vaccine at all or may vaccinate only susceptible adolescent and adult females, relying on widespread occurrence of rubella in childhood to protect females before they reach childbearing age. Thus, until lately, the Scandinavian countries were vaccinating all children, several Northern European countries were not using rubella vaccine to any appreciable extent, and the UK was giving rubella vaccine only to adolescent and adult females.
Regional target 5---elimination of specified vaccinepreventable diseases-declared by the 34th session of the
710
European Regional Committee, as well as a conference at Karlovy Vary, Czechoslovakia, in 1984, were important first steps in establishment of an Expanded Programme on Immunisation for the European Region. Subsequent annual meetings of the national programme managers have been useful for
promoting commitment and coordination. Adoption of the global poliomyelitis eradication target should help. In North America, the Canadian National Advisory Committee on Immunization and the US ACIP maintain close liaison.
Special groups Some individuals and groups are poorly served by routine medical care; others are vigorously opposed to immunisation. Gypsies and immigrants are examples of the first category and certain religious groups of the second. Outbreaks of poliomyelitis have been reported in gypsies in the UK and in persons religiously opposed to immunisation in the Netherlands .29,30
Prospects The biotechnology revolution offers great promise of new and improved vaccines to prevent yet more of the health burden from infectious diseases. The immunobiological preparations under development that may be considered for universal use in infants or children include Haemophilus influenzae type B vaccines, varicella vaccine, respiratory syncytial virus vaccine, and rotavirus vaccine. In addition, attempts to improve the safety and efficacy of existing vaccines may lead to substitutions of some antigens for others (eg, acellular pertussis vaccines will substitute purified components for the whole-cell vaccine in DPT) or in combined schedules that take advantage of the properties of different vaccines against the same agent (eg, IPV and
OPV). However, each breakthrough is associated with potential barriers to implementation that must be overcome. New vaccines must be integrated into existing schedules. Ideally, they should not require new visits but should be combined with, or given simultaneously with, other vaccines. Thus one must be confident that immunogenicity and efficacy of any of the components are not compromised and that adverse events are not increased. Research on new vaccines will often require two phases-an initial phase examining the safety and efficacy of the new antigen alone and a second phase evaluating safety and efficacy (or immunogenicity) of the antigen when administered simultaneously or in combined form with other vaccines. Apart from the database necessary to integrate new vaccines into the existing schedule, each addition of a vaccine will require a concerted professional and public educational effort to emphasise the benefits and risks of the new vaccine and proper indications, precautions, and contraindications. Without such efforts, vaccine use is likely to be suboptimal and the promise of preventing substantial morbidity with maximum vaccine safety will not be realised. The new attention given to immunisation activities in Europe has already paid handsome dividends, and further improvements are to be expected as the nations adopt common goals and programmes. With smallpox gone and poliomyelitis on the agenda, what diseases should be our next targets for regional elimination or global eradication? The prospects are exciting.
We gratefully acknowledge the assistance of Dr Boris Bytchenko, of the WHO European Regional Office in Copenhagen, in verifying some of the information in this article.
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