When, Where, and How Do Immunizations Fail? Alan R. Hinman, MD, MPH, Walter A. Orenstein, and Edward A. Mortimer, Jr., MD
MD,
There are two main I~USOIISfor failure of immunizations: (I) failure of he mccine delivery system to provide potent vaccines properly to persons in need; and (2) failure of the immune response, whether due to in&+&es of the vaccine or factors inherent in the host. The first category is by far the most important worldwide. The major factor contributing to failure of the delivery system is failure to vaccinate; in the deweloping world this is commonly a result of inadequacy of the vaccine supply. Other important factors include barriers to immunizaarions, improper use of vaccines, vaccine ineffectiveness at the time of use, and factors relating to client attitudes and knowledge. Failure of the immune response may be either primary or secondary (loss of protection after initial effectiweness). The shortcomings of existing vaccines must not deter us from taking maximal advantage of their benefits. Ann Epidemiol 1992;2:805-812. KEY WORDS:
Immunization, vaccination, vaccines.
INTRODUCTION
Vaccines represent one of the most effective prevention tools available. Widespread immunization of children in the United States has led to reductions of 90% or greater in all of the diseases for which children are routinely vaccinated. Nevertheless, the full potential of vaccines has not yet been realized. This article will consider some of the main causes of immunization failure and some possible approaches to remedy the problems, using measles and measles vaccine as primary examples. There are two main reasons for failure of immunizations: (1) failure of the vaccine delivery system to provide potent vaccines properly to persons in need; and (2) failure of the immune response, whether due to inadequacies of the vaccine or factors inherent in the host. The first category is by far the most important worldwide.
FAILURE
OF THE
VACCINE
DELIVERY
SYSTEM
Failure to Vaccinate This is the most common cause of immunization failure. Simply put, vaccines are no good in the bottle. Worldwide the most important reason for nonuse of vaccines is unavailability of the vaccines themselves or of the system to deliver them. The World Health Organization estimates that as of December 1989, one-third or more of all the children in the world had not received appropriate immunization by their first birthday (1). In the United States we estimate that nationwide, approximately 20 to 30% of children do not receive a complete series of immunizations by their second birthday. Even poorer vaccine coverage is seen in some inner cities. A recent survey of public
From the Center for Prevention Services, Centers for Disease Control, Atlanta, GA (A.R.H., W.A.O.) and Case Western Reserve University, School of Medicine, Cleveland, OH (E.A.M., Jr.). Address reprint requests to: Information Services, Center for Prevention Services, Centers for Disease Control, Atlanta, GA 30333. Received February 8, 1991; revised July 8, 1991. 0 1992 Elsevier Science Publishmg Co., Inc.
1047.2797192/$05.00
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Hinman et al. IMMUNIZATION
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schools in eight inner cities (Boston, Bronx, Cleveland, Houston, Jersey City, Phoenix, Pittsburgh, and Seattle) revealed that as many as one-half of first graders had not received a dose of measles vaccine by their second birthday even though the vaccine is recommended at the ages of 12 to 15 months (2). An investigation in Chicago demonstrated that neighborhoods with low coverage were at substantially higher risk for measles than neighborhoods with high coverage (3). Where coverage was 70 to 80%, virtually no measles occurred. In contrast, with coverage of 40 to 60%, substantial numbers of cases were reported. In the United States, the major problem is not inadequacy of vaccine supply-97 to 98% of children receive measles vaccine before school entry. Ours is a problem of inadequate delivery systems to reach the preschool population.
Barriers
to Immunization
Delivery systems may be inadequate because of barriers to immunization (4). Some of these may result from policies designed to permit clinics to run smoothly such as the requirement that immunizations only be given by appointment (rather than on a walkin basis). Others may result from the desire to provide immunization in the setting of comprehensive care when such care is difficult to obtain (e.g., immunization only after a complete well-child appraisal, which may have to be scheduled weeks in advance). The net effect is to discourage parents from seeking immunization. Other barriers relate to insufficient resources for delivery. A recent survey of state health department immunization projects revealed that 50% of projects had barriers to immunization such as insufficient clinic staff, inadequate clinic hours, or deficient clinic facilities (5). Other barriers include excessive interpretation of contraindications to vaccination and failure to administer all indicated vaccines at a single visit. In a recent review of records at a public health department child health clinic in Los Angeles, it was found that only approximately two-thirds of children received measles, mumps, and rubella vaccine (MMR) on their first visit after becoming eligible (6). The missed opportunities occurred because of otitis media (42%), well-child care only (27%), acute respiratory illness (14%)) other mild illness (1 l%), or administration of another vaccine (6%). None of these is considered a valid reason for nonadministration of MMR (7). Many of the barriers can be reduced by training health care providers and reviewing administrative practices, although this can be a difficult and labor-intensive task.
Improper Use of Vaccines Some providers may give reduced doses of vaccine in the mistaken belief that this may reduce side effects without reducing effectiveness. In the United States, this has particularly been true with pertussis vaccine (8). Others may give reduced doses in the hope of protecting two or three children for the same cost. This has been most common with measles vaccine in the developing world (C. DeQuadros. Personal communication, 1989). These problems are addressed through the education of health care providers. With many vaccines, several doses are required to achieve full protection. Failure to complete a series may result from inattention or from the occurrence of reactions associated with earlier doses. This problem, which has been most prominent with diphtheria and tetanus toxoids and pertussis vaccine (DTP), is amenable to education and follow-up. Finally, vaccines must be administered by the proper route in order to ensure effectiveness. A small dose of hepatitis B vaccine may yield an adequate immune response when it is given intradermally but be insufficient to protect if the vaccine is
Hinman et al. IMMUNIZATION FAILURE
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administered subcutaneously (9). Similarly, administration of the standard intramuscular dose of hepatitis B vaccine into the buttock, where it is likely to be deposited into fat, is associated with a lower rate of seroconversion than when the vaccine is administered into the deltoid muscle (10). Here again, training is the answer.
Vaccine
Ineffectiveness
at the Time of Use
One of the most important causes of vaccine ineffectiveness is the thermal instability of many vaccines, which must be kept under refrigeration or frozen from the point of manufacture to the point of administration. This problem has led to the development of an extensive “cold chain” system, with improved management and technology playing major roles (11). Ultimate resolution of this problem could result from the development of heat-stable vaccines. Early measles vaccines were extremely heatsensitive and there were instances of vaccine failure because of improper handling (12). Current vaccines are much more stable before reconstitution (13). Vaccines also have finite “shelf life,” so another cause of impotency can be use of vaccines after their expiration date. Additionally, if the wrong diluent is used in reconstituting a vaccine, particularly a live vaccine, it may inactivate it. These problems can be addressed through training. Sometimes, vaccines may not be effective at the time of use because their constitution is not appropriate to the situation. One example of this is the need to keep changing the constituents of influenza vaccine to match the antigenic variants of influenza virus currently circulating (14). Another example came to light in the face of an epidemic of paralysis due to poliovirus 3 in Brazil in 1986, which was found to result from insufficient quantities of type 3 virus relative to the other two types in the trivalent oral vaccine in use (15). These problems are addressed through changes in the makeup of the vaccine.
Client Factors Vaccines may be available and offered but be refused because of cultural or religious beliefs, ignorance, or misinformation. Cultural and religious beliefs may be difficult to change but ignorance and misinformation can be alleviated. Ignorance and misinformation may affect the provider, as noted above, as well as the recipient. Finally, vaccines may not be offered or accepted because of side effects, real or perceived, and the failure to understand that the benefits of immunization exceed the risks (16). Resolution of this problem involves development of improved vaccines with fewer side effects as well as education. Even when potent vaccines are given, however, the individual may not be protected.
FAILURE
OF THE
IMMUNE
RESPONSE
Primary Vaccine
Failure
Unkrmwn cause. Even when conditions are apparently optimal, some individuals do not respond to a vaccine. This is thought to be random and has led to recommendations for administration of multiple doses of some vaccines. For example, serologic data indicate that 95 to 98% of 15month-olds in the United States respond to a single dose of measles vaccine (7) and clinical measures of vaccine efficacy during outbreaks regularly indicate vaccine efficacy of 90% or greater. Some of the small proportion who were not protected are found to have received vaccine at an age when they
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still might have had circulating, maternally derived antibody. However, no possible explanation is found in many others. If vaccine failure is a random event, most of those who initially did not respond should be protected by a second dose. Observational studies in the United States have found increased measles vaccine efficacy in children who had received more than one dose of vaccine compared to those who had received only one dose (17). Similarly, data provided by Professor P.F. Rykushin of the Leningrad Pasteur Institute indicate a vaccine efficacy of 78% in singledose vaccinees and 98% in those who had received two doses (personal communication, 1990). These findings are consistent with random vaccine failure but are not helpful in determining whether this might have resulted from vaccine factors rather than host factors. Serologic studies are currently underway to address this problem. Knoaun cause. The most obvious situation is a congenital or acquired immune deficiency. In these situations, there is concern not only that the host may not respond adequately to the vaccine but also that he or she may not be able to contain infection with replicating vaccine viruses such as measles or polio. For example, patients with symptomatic human immunodeficiency virus (HIV) infection are substantially less likely to mount an immune response to a variety of vaccines than are normal patients (18). Immaturity of the immune system may also render a host unable to respond to some antigens. The T-cell-independent immune response does not develop fully for 1 or 2 years after birth. In consequence, some polysaccharide antigens such as HaemophiIus influenpae type b or pneumococcal polysaccharides may not be effective in infants. Conjugation of the polysaccharide with a protein carrier converts it to a T-cell-dependent antigen and increases the response induced (19). Immunosuppressive therapy can also alter the safety and effectiveness of vaccines. This can be addressed by administering vaccines before or after persons are given immunosuppressive drugs (20). Another extrinsic factor affecting host response is the presence of passively acquired antibody. This is most commonly seen in the inability of very young infants to respond to measles vaccine because of the persistence of circulating, maternally derived antibody for the first 6 to 9 months of life or longer (21). Several studies in the United States have demonstrated that persons vaccinated at 12 months old with measles vaccine are at significantly higher risk of vaccine failure than persons vaccinated at older ages (22). Other studies have demonstrated that maternal antibody can persist at least into the 13th month of life in some children (23). Resolution of this problem requires studies to determine the age-specific response to vaccines and appropriate adjustment of the recommended age of administration. Similarly, administration of exogenous immune globulin may impede an individual’s ability to respond to a live vaccine such as measles or rubella (24). This interference has not been demonstrated with inactivated vaccines or toxoids. Recent evidence indicates that there may be some genetic influence on the ability of otherwise normal individuals to respond to hepatitis B vaccine (25). It is not known whether there are similar genetic factors affecting responses to other vaccines. There is some evidence that concurrent infection with enteroviruses may reduce the host’s ability to respond to oral poliovirus vaccine (26). Since there is likely to be no practical way to detect such concurrent infections, the remedy is to administer several doses of vaccine. It is theoretically possible that stimulation of the immune system by one live virus could interfere with the host’s ability to respond to a second live virus. Petralli and
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colleagues demonstrated that smallpox vaccine “takes” were significantly decreased when the vaccine was given 9 to 15 days after administration of a measles vaccine, at the peak of interferon production induced by the measles vaccine (27). This possibility has led to recommendations that live virus vaccines be administered simultaneously or with an interval of at least 4 weeks. In general, it is believed that live viral vaccines and inactivated vaccines do not interfere with the immune response to one another. However, such interference has been documented in one circumstance. Antibody titers to yellow fever vaccine were lower when it was administered within 3 weeks after cholera vaccine was given. Consequently, it is recommended that yellow fever and cholera vaccines ideally should be administered at least 3 weeks apart (28). Many of the reasons for a host’s inability to respond cannot be overcome with current vaccines and technology. It is possible that adjuvants or immunostimulants might be developed to increase the likelihood of an adequate immune response.
Secondary Vaccine Failure In this situation, protection is initially conferred but subsequently disappears. Titers of circulating protective antibodies are usually at their peak shortly after vaccination and typically decline over time, sometimes becoming undetectable by currently available techniques. This decline in circulating antibody levels is clinically important in protection against toxin-induced diseases such as tetanus. Declining antibody levels are also apparently important with pertussis (29). In contrast, persons who have lost detectable antibody after initial seroconversion to a viral vaccine such as measles typically demonstrate a rapid “secondary” antibody response if they are challenged by exposure to the wild virus or revaccination (30). Whether this “waning immunity” is clinically significant has been the subject of substantial debate. It has generally been believed that protection following initial immunization was lifelong, even though detectable titers of antibody may disappear. This contention has been supported by epidemiologic data indicating no differential in vaccine efficacy based on time since vaccination, if corrections were made for other confounding factors. More recent data suggest that on occasion, some individuals who were originally protected may actually lose protective immunity (31). Concern about the possible significance of waning immunity contributed to the recent recommendation by the American Academy of Pediatrics that the second dose of measles vaccine should be given to children entering middle or junior high school, in contrast to the Public Health Service recommendation that the second dose should be given at the time of entry to kindergarten or first grade (7, 32). Several other factors entered into these recommendations, including administrative feasibility and the speed with which an impact would occur. Two approaches can be taken to deal with this problem-improvements in vaccines and administration of periodic reinforcing or “booster” doses. The former will take time. The latter is immediately available and is the current approach with tetanus and diphtheria toxoids.
COMMENT In a sense, immunizations may also fail when they are successful. This may occur as a result of changes in the epidemiology of disease brought about by immunization. For example, in recent years the reported incidence of pertussis in the United States has
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FAILURE
increased, with the greatest increase in incidence being seen in persons more than 15 years old (33). In part this may represent a greater awareness of pertussis but such a factor would be expected to affect reporting of pertussis in all age groups more or less equally. Additionally, it may be that newer technology has afforded the opportunity to recognize mild or atypical pertussis in adults (34). However, a third factor is also plausible. Pertussis vaccine-induced immunity is known to wane over time. In the past, this waning immunity might have been of little clinical importance since individuals were repeatedly exposed to the pertussis organism and could thereby have been “boosted” naturally. With the incidence of pertussis dramatically decreased by widespread immunization, the opportunities for such re-exposures have decreased and it may be that adults who have lost immunity may serve as important reservoirs and transmitters of pertussis. In a recent outbreak in Ohio, nearly one-third of cases occurred in adults and it appeared that at least 18 of the total 39 cases were acquired from adults (including seven cases in infants) (35). If this factor is confirmed to be important in the current epidemiology of pertussis, it would raise questions about the potential necessity of providing repeated booster doses of pertussis vaccine throughout life (36). Another example of immunization failure as a result of success results from changing public perceptions of risk of disease and risk of immunization. In the United Kingdom in the mid-1970s, pertussis incidence was low and the public perceived little risk from the disease. When possible adverse effects of pertussis vaccine received substantial media attention, many persons (and many physicians) incorrectly concluded that the risks of vaccine outweighed the risks of disease and pertussis immunization levels fell, with a consequent epidemic of pertussis (37).
CONCLUSION This article has focused primarily on the “negative” aspects of immunization, which in reality are overwhelmingly offset by the positive aspects. Current vaccines provide protection to a high proportion of recipients when handled and administered properly. The shortcomings of existing vaccines must not deter us from taking maximal advantage of their benefits.
This paper was presented at the Angeles, CA, August 2, 1990.
Annual Meeting of the American College of Epidemiology,
Los
REFERENCES 1.
Expanded Programme on Immunization.
Organization, System/90.2; 2.
WHO/Expanded
dren in 8 selected 3. 4.
for Disease Control. cities,
Centers
5.
United
States,
for Disease Control.
Cutts FT, Orenstein Orenstein
1990:1:315-29.
System. Geneva:
World Health
EPI Information
Measles vaccination MMWR. Update:
levels among preschool
aged chil-
1991;40:36-9. Measles outbreak-Chicago,
1989,
MMWR.
325-6.
age in the United immunization:
Information
on Immunization/Computerized
July 1990:1-16.
Centers
1990;39:317-9,
Programme
States. WA,
WA,
Bemier RH. Causes of low preschool
Ann Rev Pub1 Health. Atkinson
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immunization
cover-
1992;13:385-98.
W, Mason D, Bemier RH. The promise and the reality of
delivery in our inner cities, J Health Care Poor Underserved.
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6. Farizo KM, Stehr-Green PA, Markowitz LE, Patriarca PA. Immunization levels and missed opportunities for measles vaccination: A record audit in a public pediatric clinic. Pediatrics. 1992;89:589-92. 7. Centers for Disease Control. Measles prevention: Recommendations of the Immunization Practices Advisory Committee (ACIP), MMWR. 1989; 38(S-9):1-18. 8. Wassilak SGF, Brink EW, Orenstein WA, et al. Reduced dose of DTP vaccine, J Pediatr. 1985;106:693-695. 9. Wahl M, Hermodsson S. Intradermal, subcutaneous, or intramuscular administration of hepatitis B vaccine; Side effects and antibody response, Stand J Infect Dis. 1987;19:617-21. 10. Centers for Disease Control. Suboptimal response to hepatitis B vaccine given by injection into the buttock, MMWR. 1985;34:105-13. 11. World Health Organization. Expanded Programme on Immunization. Manage the Cold Chain System: Training for Mid-Level Managers. Geneva: WHO; February 1985. 12. Hayden GF. Measles vaccine failure. A survey of causes and means of prevention, Clin Pediatr. 1979;18:155-67. 13. McAleer WJ, Markus HZ, McLean AA, Buynak EB, Hilleman MR. Stability on storage at various temperatures of live measles, mumps, and rubella virus vaccines in new stabilizer, J Biol Stand. 1980;8:281-7. 14. Centers for Disease Control. Prevention and control of influenza. Recommendations of the Immunization Practices Advisory Committee (ACIP), MMWR. 1990;39(RR-7):1-15. 15. Patriarca PA, Laender F, Palmeira G, et al. Randomized trial of an alternative formulation of polio vaccine in Brazil, Lancet. 1988;1:429-33. 16. Cherry JD, Brunell PA, Golden OS, K arzon DT. Report of the Task Force on Pertussis and Pertussis Immunization-1988, Pediatrics. 1988;81(supp):939-84. 17. Markowitz LE, Orenstein WA. Measles vaccines, Pediatr Clin North Am. 1990;37:603-25. 18. Onorato IM, Markowitz LE, Oxtoby MJ. Childhood immunization, vaccine-preventable diseases, and infection with human immunodeficiency virus, Pediatr Infect Dis J. 1988;6:588-95. 19. Weinberg GA, Granoff DM. Polysaccharidedprotein conjugate vaccines for the prevention of Haemophilus influenzas type b disease, J Pediatr. 1988;113;621-31. 20. Siber GR, Gorham C, Martin P, Corkery JC, Schiffman G. Antibody response to pretreatment immunization and post-treatment boosting with bacterial polysaccharide vaccines in patients with Hodgkin’s disease, Ann Intern Med. 1986;104:467-75. 21. Wilkins J, Wehrle PF. Additional evidence against measles vaccine administration to infants less than 12 months of age: Altered immune response following active/passive immunization, J Pediatr. 1979;94:865-9. 22. Orenstein WA, Markowitz L, Preblud SR, Hinman AR, Tomasi A, Bart KJ. Appropriate age for measles vaccination in the United States, Dev Biol Stand. 1985;65:13-21. 23. Albrecht P, Ennis FA, Saltzman EJ, et al. Persistence of maternal antibody in infants beyond 12 months: Mechanism of measles vaccine failure, J Pediatr. 1977;91:715-8. 24. Centers for Disease Control. General recommendations on immunization: Recommendations of the Immunization Practices Advisory Committee (ACIP), MMWR. 1989;38:205-14, 219-27. 25. Alper CA, Kruskall MS, Marcus-Bagley D, et al. Genetic prediction of non-response to hepatitis B vaccine, N Engl J Med. 1989;321:708-12. 26. Melnick JL. Live attenuated poliovaccines. In: Plotkin SA, Mortimer EA Jr, eds. Vaccines. Philadelphia: WB Saunders; 1988: 148-9. 27. Petralli JK, Merigan TC, Wilbur JR. Action of endogenous interferon against vaccinia infection in children, Lancet. 1965;2:401-5. 28. Centers for Disease Control. Yellow fever vaccine: Recommendations of the Immunization Practices Advisory Committee (ACIP), MMWR. 1990;39(RR-6):1-6. 29. VanKinson D. Duration of effectiveness of pertussis vaccine: Evidence from a 10 year community study, Br Med J. 1988;296:612-4.
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30. Krugman S. Further attenuated measles vaccine: Characteristics and use, Rev Infect Dis. 1983;5:477-81. 3 1. Mathias RG, Meeklson WG, Arcand TA, et al. The role of secondary vaccine failures in measles outbreaks, Am J Public Health. 1989;79:474-8. 32. American Academy of Pediatrics. Committee on Infectious Diseases. Measles: Reassessment of the current immunization policy, Pediatrics. 1989;84:1110-3. 33. Centers for Disease Control. Pertussis surveillance-United States 1986-1988, MMWR. 1990;39:57-8, 63-6. 34. Steketee RW, Burstyn DG, Wassilak SGF, et al. A comparison of laboratory and clinical methods for diagnosing pertussis in an outbreak in a facility for the developmentally disabled, J Infect Dis. 1988;157:441-9. 35. Ohio Department of Health Immunization Program. Pertussis Outbreak in Northwest Ohio-1987. Ohio Dept. Health, Columbus, OH. April 1988. 36. Mortimer EA Jr. Pespective. Pertussis and its prevention: A family affair, J Infect Dis. 1990;161:473-9. 37. Joint Committee on Vaccination and Immunization. VI. The whooping cough epidemic 1977-1979. In: Whooping Cough. Reports from the Committee on Safety of Medicines and the Joint Committee on Vaccination and Immunization, Department of Health and Social Security. London: Her Majesty’s Stationery Office; 1981: 170-84.
MD,
There are two main I~USOIISfor failure of immunizations: (I) failure of he mccine delivery system to provide potent vaccines properly to persons in need; and (2) failure of the immune response, whether due to in&+&es of the vaccine or factors inherent in the host. The first category is by far the most important worldwide. The major factor contributing to failure of the delivery system is failure to vaccinate; in the deweloping world this is commonly a result of inadequacy of the vaccine supply. Other important factors include barriers to immunizaarions, improper use of vaccines, vaccine ineffectiveness at the time of use, and factors relating to client attitudes and knowledge. Failure of the immune response may be either primary or secondary (loss of protection after initial effectiweness). The shortcomings of existing vaccines must not deter us from taking maximal advantage of their benefits. Ann Epidemiol 1992;2:805-812. KEY WORDS:
Immunization, vaccination, vaccines.
INTRODUCTION
Vaccines represent one of the most effective prevention tools available. Widespread immunization of children in the United States has led to reductions of 90% or greater in all of the diseases for which children are routinely vaccinated. Nevertheless, the full potential of vaccines has not yet been realized. This article will consider some of the main causes of immunization failure and some possible approaches to remedy the problems, using measles and measles vaccine as primary examples. There are two main reasons for failure of immunizations: (1) failure of the vaccine delivery system to provide potent vaccines properly to persons in need; and (2) failure of the immune response, whether due to inadequacies of the vaccine or factors inherent in the host. The first category is by far the most important worldwide.
FAILURE
OF THE
VACCINE
DELIVERY
SYSTEM
Failure to Vaccinate This is the most common cause of immunization failure. Simply put, vaccines are no good in the bottle. Worldwide the most important reason for nonuse of vaccines is unavailability of the vaccines themselves or of the system to deliver them. The World Health Organization estimates that as of December 1989, one-third or more of all the children in the world had not received appropriate immunization by their first birthday (1). In the United States we estimate that nationwide, approximately 20 to 30% of children do not receive a complete series of immunizations by their second birthday. Even poorer vaccine coverage is seen in some inner cities. A recent survey of public
From the Center for Prevention Services, Centers for Disease Control, Atlanta, GA (A.R.H., W.A.O.) and Case Western Reserve University, School of Medicine, Cleveland, OH (E.A.M., Jr.). Address reprint requests to: Information Services, Center for Prevention Services, Centers for Disease Control, Atlanta, GA 30333. Received February 8, 1991; revised July 8, 1991. 0 1992 Elsevier Science Publishmg Co., Inc.
1047.2797192/$05.00
806
Hinman et al. IMMUNIZATION
FAILURE
AEP Vol. 2, No. 6 November 1992: 805-812
schools in eight inner cities (Boston, Bronx, Cleveland, Houston, Jersey City, Phoenix, Pittsburgh, and Seattle) revealed that as many as one-half of first graders had not received a dose of measles vaccine by their second birthday even though the vaccine is recommended at the ages of 12 to 15 months (2). An investigation in Chicago demonstrated that neighborhoods with low coverage were at substantially higher risk for measles than neighborhoods with high coverage (3). Where coverage was 70 to 80%, virtually no measles occurred. In contrast, with coverage of 40 to 60%, substantial numbers of cases were reported. In the United States, the major problem is not inadequacy of vaccine supply-97 to 98% of children receive measles vaccine before school entry. Ours is a problem of inadequate delivery systems to reach the preschool population.
Barriers
to Immunization
Delivery systems may be inadequate because of barriers to immunization (4). Some of these may result from policies designed to permit clinics to run smoothly such as the requirement that immunizations only be given by appointment (rather than on a walkin basis). Others may result from the desire to provide immunization in the setting of comprehensive care when such care is difficult to obtain (e.g., immunization only after a complete well-child appraisal, which may have to be scheduled weeks in advance). The net effect is to discourage parents from seeking immunization. Other barriers relate to insufficient resources for delivery. A recent survey of state health department immunization projects revealed that 50% of projects had barriers to immunization such as insufficient clinic staff, inadequate clinic hours, or deficient clinic facilities (5). Other barriers include excessive interpretation of contraindications to vaccination and failure to administer all indicated vaccines at a single visit. In a recent review of records at a public health department child health clinic in Los Angeles, it was found that only approximately two-thirds of children received measles, mumps, and rubella vaccine (MMR) on their first visit after becoming eligible (6). The missed opportunities occurred because of otitis media (42%), well-child care only (27%), acute respiratory illness (14%)) other mild illness (1 l%), or administration of another vaccine (6%). None of these is considered a valid reason for nonadministration of MMR (7). Many of the barriers can be reduced by training health care providers and reviewing administrative practices, although this can be a difficult and labor-intensive task.
Improper Use of Vaccines Some providers may give reduced doses of vaccine in the mistaken belief that this may reduce side effects without reducing effectiveness. In the United States, this has particularly been true with pertussis vaccine (8). Others may give reduced doses in the hope of protecting two or three children for the same cost. This has been most common with measles vaccine in the developing world (C. DeQuadros. Personal communication, 1989). These problems are addressed through the education of health care providers. With many vaccines, several doses are required to achieve full protection. Failure to complete a series may result from inattention or from the occurrence of reactions associated with earlier doses. This problem, which has been most prominent with diphtheria and tetanus toxoids and pertussis vaccine (DTP), is amenable to education and follow-up. Finally, vaccines must be administered by the proper route in order to ensure effectiveness. A small dose of hepatitis B vaccine may yield an adequate immune response when it is given intradermally but be insufficient to protect if the vaccine is
Hinman et al. IMMUNIZATION FAILURE
AEP Vol. 2, No. 6 November 1992: 805-8 I2
807
administered subcutaneously (9). Similarly, administration of the standard intramuscular dose of hepatitis B vaccine into the buttock, where it is likely to be deposited into fat, is associated with a lower rate of seroconversion than when the vaccine is administered into the deltoid muscle (10). Here again, training is the answer.
Vaccine
Ineffectiveness
at the Time of Use
One of the most important causes of vaccine ineffectiveness is the thermal instability of many vaccines, which must be kept under refrigeration or frozen from the point of manufacture to the point of administration. This problem has led to the development of an extensive “cold chain” system, with improved management and technology playing major roles (11). Ultimate resolution of this problem could result from the development of heat-stable vaccines. Early measles vaccines were extremely heatsensitive and there were instances of vaccine failure because of improper handling (12). Current vaccines are much more stable before reconstitution (13). Vaccines also have finite “shelf life,” so another cause of impotency can be use of vaccines after their expiration date. Additionally, if the wrong diluent is used in reconstituting a vaccine, particularly a live vaccine, it may inactivate it. These problems can be addressed through training. Sometimes, vaccines may not be effective at the time of use because their constitution is not appropriate to the situation. One example of this is the need to keep changing the constituents of influenza vaccine to match the antigenic variants of influenza virus currently circulating (14). Another example came to light in the face of an epidemic of paralysis due to poliovirus 3 in Brazil in 1986, which was found to result from insufficient quantities of type 3 virus relative to the other two types in the trivalent oral vaccine in use (15). These problems are addressed through changes in the makeup of the vaccine.
Client Factors Vaccines may be available and offered but be refused because of cultural or religious beliefs, ignorance, or misinformation. Cultural and religious beliefs may be difficult to change but ignorance and misinformation can be alleviated. Ignorance and misinformation may affect the provider, as noted above, as well as the recipient. Finally, vaccines may not be offered or accepted because of side effects, real or perceived, and the failure to understand that the benefits of immunization exceed the risks (16). Resolution of this problem involves development of improved vaccines with fewer side effects as well as education. Even when potent vaccines are given, however, the individual may not be protected.
FAILURE
OF THE
IMMUNE
RESPONSE
Primary Vaccine
Failure
Unkrmwn cause. Even when conditions are apparently optimal, some individuals do not respond to a vaccine. This is thought to be random and has led to recommendations for administration of multiple doses of some vaccines. For example, serologic data indicate that 95 to 98% of 15month-olds in the United States respond to a single dose of measles vaccine (7) and clinical measures of vaccine efficacy during outbreaks regularly indicate vaccine efficacy of 90% or greater. Some of the small proportion who were not protected are found to have received vaccine at an age when they
808
Hinman er al. IMMUNIZATION
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still might have had circulating, maternally derived antibody. However, no possible explanation is found in many others. If vaccine failure is a random event, most of those who initially did not respond should be protected by a second dose. Observational studies in the United States have found increased measles vaccine efficacy in children who had received more than one dose of vaccine compared to those who had received only one dose (17). Similarly, data provided by Professor P.F. Rykushin of the Leningrad Pasteur Institute indicate a vaccine efficacy of 78% in singledose vaccinees and 98% in those who had received two doses (personal communication, 1990). These findings are consistent with random vaccine failure but are not helpful in determining whether this might have resulted from vaccine factors rather than host factors. Serologic studies are currently underway to address this problem. Knoaun cause. The most obvious situation is a congenital or acquired immune deficiency. In these situations, there is concern not only that the host may not respond adequately to the vaccine but also that he or she may not be able to contain infection with replicating vaccine viruses such as measles or polio. For example, patients with symptomatic human immunodeficiency virus (HIV) infection are substantially less likely to mount an immune response to a variety of vaccines than are normal patients (18). Immaturity of the immune system may also render a host unable to respond to some antigens. The T-cell-independent immune response does not develop fully for 1 or 2 years after birth. In consequence, some polysaccharide antigens such as HaemophiIus influenpae type b or pneumococcal polysaccharides may not be effective in infants. Conjugation of the polysaccharide with a protein carrier converts it to a T-cell-dependent antigen and increases the response induced (19). Immunosuppressive therapy can also alter the safety and effectiveness of vaccines. This can be addressed by administering vaccines before or after persons are given immunosuppressive drugs (20). Another extrinsic factor affecting host response is the presence of passively acquired antibody. This is most commonly seen in the inability of very young infants to respond to measles vaccine because of the persistence of circulating, maternally derived antibody for the first 6 to 9 months of life or longer (21). Several studies in the United States have demonstrated that persons vaccinated at 12 months old with measles vaccine are at significantly higher risk of vaccine failure than persons vaccinated at older ages (22). Other studies have demonstrated that maternal antibody can persist at least into the 13th month of life in some children (23). Resolution of this problem requires studies to determine the age-specific response to vaccines and appropriate adjustment of the recommended age of administration. Similarly, administration of exogenous immune globulin may impede an individual’s ability to respond to a live vaccine such as measles or rubella (24). This interference has not been demonstrated with inactivated vaccines or toxoids. Recent evidence indicates that there may be some genetic influence on the ability of otherwise normal individuals to respond to hepatitis B vaccine (25). It is not known whether there are similar genetic factors affecting responses to other vaccines. There is some evidence that concurrent infection with enteroviruses may reduce the host’s ability to respond to oral poliovirus vaccine (26). Since there is likely to be no practical way to detect such concurrent infections, the remedy is to administer several doses of vaccine. It is theoretically possible that stimulation of the immune system by one live virus could interfere with the host’s ability to respond to a second live virus. Petralli and
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colleagues demonstrated that smallpox vaccine “takes” were significantly decreased when the vaccine was given 9 to 15 days after administration of a measles vaccine, at the peak of interferon production induced by the measles vaccine (27). This possibility has led to recommendations that live virus vaccines be administered simultaneously or with an interval of at least 4 weeks. In general, it is believed that live viral vaccines and inactivated vaccines do not interfere with the immune response to one another. However, such interference has been documented in one circumstance. Antibody titers to yellow fever vaccine were lower when it was administered within 3 weeks after cholera vaccine was given. Consequently, it is recommended that yellow fever and cholera vaccines ideally should be administered at least 3 weeks apart (28). Many of the reasons for a host’s inability to respond cannot be overcome with current vaccines and technology. It is possible that adjuvants or immunostimulants might be developed to increase the likelihood of an adequate immune response.
Secondary Vaccine Failure In this situation, protection is initially conferred but subsequently disappears. Titers of circulating protective antibodies are usually at their peak shortly after vaccination and typically decline over time, sometimes becoming undetectable by currently available techniques. This decline in circulating antibody levels is clinically important in protection against toxin-induced diseases such as tetanus. Declining antibody levels are also apparently important with pertussis (29). In contrast, persons who have lost detectable antibody after initial seroconversion to a viral vaccine such as measles typically demonstrate a rapid “secondary” antibody response if they are challenged by exposure to the wild virus or revaccination (30). Whether this “waning immunity” is clinically significant has been the subject of substantial debate. It has generally been believed that protection following initial immunization was lifelong, even though detectable titers of antibody may disappear. This contention has been supported by epidemiologic data indicating no differential in vaccine efficacy based on time since vaccination, if corrections were made for other confounding factors. More recent data suggest that on occasion, some individuals who were originally protected may actually lose protective immunity (31). Concern about the possible significance of waning immunity contributed to the recent recommendation by the American Academy of Pediatrics that the second dose of measles vaccine should be given to children entering middle or junior high school, in contrast to the Public Health Service recommendation that the second dose should be given at the time of entry to kindergarten or first grade (7, 32). Several other factors entered into these recommendations, including administrative feasibility and the speed with which an impact would occur. Two approaches can be taken to deal with this problem-improvements in vaccines and administration of periodic reinforcing or “booster” doses. The former will take time. The latter is immediately available and is the current approach with tetanus and diphtheria toxoids.
COMMENT In a sense, immunizations may also fail when they are successful. This may occur as a result of changes in the epidemiology of disease brought about by immunization. For example, in recent years the reported incidence of pertussis in the United States has
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increased, with the greatest increase in incidence being seen in persons more than 15 years old (33). In part this may represent a greater awareness of pertussis but such a factor would be expected to affect reporting of pertussis in all age groups more or less equally. Additionally, it may be that newer technology has afforded the opportunity to recognize mild or atypical pertussis in adults (34). However, a third factor is also plausible. Pertussis vaccine-induced immunity is known to wane over time. In the past, this waning immunity might have been of little clinical importance since individuals were repeatedly exposed to the pertussis organism and could thereby have been “boosted” naturally. With the incidence of pertussis dramatically decreased by widespread immunization, the opportunities for such re-exposures have decreased and it may be that adults who have lost immunity may serve as important reservoirs and transmitters of pertussis. In a recent outbreak in Ohio, nearly one-third of cases occurred in adults and it appeared that at least 18 of the total 39 cases were acquired from adults (including seven cases in infants) (35). If this factor is confirmed to be important in the current epidemiology of pertussis, it would raise questions about the potential necessity of providing repeated booster doses of pertussis vaccine throughout life (36). Another example of immunization failure as a result of success results from changing public perceptions of risk of disease and risk of immunization. In the United Kingdom in the mid-1970s, pertussis incidence was low and the public perceived little risk from the disease. When possible adverse effects of pertussis vaccine received substantial media attention, many persons (and many physicians) incorrectly concluded that the risks of vaccine outweighed the risks of disease and pertussis immunization levels fell, with a consequent epidemic of pertussis (37).
CONCLUSION This article has focused primarily on the “negative” aspects of immunization, which in reality are overwhelmingly offset by the positive aspects. Current vaccines provide protection to a high proportion of recipients when handled and administered properly. The shortcomings of existing vaccines must not deter us from taking maximal advantage of their benefits.
This paper was presented at the Angeles, CA, August 2, 1990.
Annual Meeting of the American College of Epidemiology,
Los
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