Immunization is the induction of immunity against an infectious disease by a means other than experiencing the natural infection. The term is usually used interchangeably with vaccination. Active immunization involves administration of an antigenic substance that then induces development of protective antibodies by the person immunized. This protection usually lasts for years, even for life. Passive immunization refers to temporary immunity resulting from antibodies developed by someone else, either through administration of immune globulin (e.g., gamma globulin, rabies immune globulin) or through the natural transfer across the placenta of antibodies developed by the mother, which provide protection to the newborn infant. Passive immunity usually lasts only a few weeks to a few months.
Substances used for active immunization include vaccines and toxoids. Vaccines may contain living, weakened (attenuated) organisms (measles), killed whole organisms (whole cell pertussis, influenza), portions of organisms (subunit influenza), purified components of organisms (acellular pertussis, pneumococcal polysaccharide), or they may be manufactured artificially (hepatitis B produced by recombinant DNA technology). For some diseases, vaccines may be available in more than one form (live attenuated and inactivated [killed] poliovirus vaccines, whole cell and acellular pertussis vaccines). Toxoids are made by preparing the toxins excreted by microorganisms and inactivating them physically or chemically. Diphtheria and tetanus are the most commonly used toxoids. Vaccines and toxoids may also contain adjuvants, substances that enhance the immune response, as well as preservatives.
Some vaccines (particularly live, attenuated vaccines) provide long-term, even lifelong protection following administration of only a single dose. Others (particularly inactivated vaccines and toxoids) may require administration of more than one dose in order to induce long-lasting immunity. Some vaccines (diphtheria, tetanus) require periodic booster doses in order to maintain immunity. Many vaccines may be inactivated by changes in temperature, particularly heat, and must be kept refrigerated or frozen from the time of manufacture until just before being administered. The need for this "cold chain" makes it difficult to carry out immunization programs in developing countries where refrigerators and freezers are not commonplace.
The rate of development of new vaccines has been accelerating as a result of improved knowledge of immunity and improvements in biotechnology. It was nearly one hundred years between Edward Jenner's first use of smallpox vaccine in 1796 and Louis Pasteur's development of the second vaccine (against rabies) in 1885. In the last twenty years of the twentieth century, many new or improved vaccines were developed and introduced, including vaccines directed against Haemophilus influenzae type b (Hib), hepatitis A, hepatitis B, Japanese encephalitis, meningococcal meningitis, pertussis, typhoid, and varicella (chicken pox). Dozens of other vaccines are under development.
Repeated economic analyses have shown that vaccines are among the most cost-effective health interventions available. For most of the vaccines used in infants and young children, the economic benefits of vaccination (avoidance of costs of medical care, hospitals, etc.) far outweigh the costs of vaccination, and the vaccines are truly cost saving. For others, the cost to prevent an illness or death is quite small and is substantially smaller than the cost to treat or cure the condition.
VACCINE RECOMMENDATIONS
In the United States, recommendations for vaccine use are made by the Public Health Service Advisory Committee on Immunization Practices, in conjunction with the American Academy of Pediatrics, American Academy of Family Practice, American College of Physicians (representing adult medicine specialists), and other professional organizations. Some vaccines are recommended for use in all persons (typically infants and young children, since most communicable diseases primarily strike them) and others are recommended for specific persons or groups who are at increased risk of contracting the particular disease. Vaccines currently recommended for use in all infants and children in the United States are DTP/DTaP (diphtheria and tetanus toxoids and pertussis [or acellular pertussis] vaccine), IPV (inactivated poliovirus vaccine), MMR (measles, mumps, and rubella vaccine), Hib vaccine (Haemophilus influenzae type b vaccine), hepatitis B vaccine, and varicella (chicken pox) vaccine. Several of these vaccines require more than one dose. The recommended schedule of immunizations in the year 2000 for infants and young children is shown in Figure 1.
Adolescents and adults also need vaccines, including MMR and hepatitis B if they have not already received them, as well as periodic boosters of tetanus and diphtheria toxoids. In addition, in the United States it is recommended that all persons sixty-five years of age or older receive a single dose of pneumococcal polysaccharide vaccine and annual doses of influenza vaccine because of the increased risk of complication or death if infected. Individuals younger than sixty-five who have chronic illnesses should also receive pneumococcal and influenza vaccines. Some vaccines recommended for persons at increased risk include yellow fever, hepatitis A, typhoid, meningococcal, and Japanese encephalitis vaccines for travelers to certain developing countries; rabies vaccine for veterinarians and persons working with potentially rabid animals; and hepatitis B vaccine for health care workers and others who might come in contact with body fluids.
VACCINE SAFETY
Although modern vaccines are safe and effective, they are neither perfectly effective nor perfectly safe. Some persons who have been vaccinated may still be susceptible to the disease, and some persons who receive the vaccine may suffer an adverse event caused by the vaccine. In developing a vaccine, major efforts are made to maximize effectiveness and minimize the risk of adverse events.
In determining whether to use a vaccine, it is necessary to balance the benefits of the vaccine against the risk of the disease and the risks from the vaccine. This balance may change over time.
Figure 1
For example, oral polio vaccine (OPV, Sabin vaccine) is made from live, attenuated polioviruses. Rarely, the person who receives the vaccine or someone who is in close contact with him or her may develop paralysis. Vaccine-associated paralysis occurs with a frequency of approximately one case for every million doses of OPV administered. By contrast, the inactivated polio vaccine (IPV, Salk vaccine) has no such risk of paralysis. However, OPV has advantages over IPV because it may be spread from the person who receives the vaccine to family members or other persons in contact with the vaccinee, thereby protecting them. Because it provides greater intestinal immunity than IPV, it protects against the spread of wild poliovirus if the vaccinated individual is exposed to wild poliovirus. The relative advantages of OPV have resulted in its being the vaccine chosen by virtually all countries of the world to control and eradicate polio. However, as the risk of wild poliovirus becomes smaller, the rare complications associated with OPV assume greater prominence. In the United States, the marked decline in risk of exposure to wild poliovirus as a result of global polio eradication efforts led in 1999 to a change in policy to favor use of IPV rather than OPV.
Assessment of adverse events associated with vaccines can be quite difficult. Pre-licensure trials typically involve a few thousand individuals and cannot be expected to detect reactions that occur with a frequency as low as (or lower than) one in 100,000. Consequently, it is important to maintain surveillance for adverse events after vaccines are licensed and introduced for widespread use. It may be very difficult to determine whether an event that occurs after vaccination was caused by the vaccine rather than occurring by chance, particularly if the event is known to occur in that age group. For example, sudden infant death syndrome (SIDS) is the leading cause of death in children two to four months of age. Since children typically receive DTP vaccine at two and four months, it is inevitable that on occasion a child will die of SIDS in the twenty-four hours following vaccination (or in the twenty-four hours preceding planned vaccination). The question is whether there is an increased incidence of SIDS following vaccination. Several studies have demonstrated that the incidence of SIDS is not increased following DTP vaccination.
IMPACT OF VACCINES IN THE UNITED STATES
Immunization provides protection both to the individuals immunized and to the community because immunized individuals do not transmit disease. If a high proportion of the population is immunized, the risk of exposure is reduced both for those who have not been immunized and those who have received vaccine but have not been protected. This "herd immunity" has led to the disappearance of disease in defined geographic areas, even though not everyone has received vaccine.
Introduction and widespread use of vaccines has had a dramatic effect on the occurrence of many diseases in the United States. Table 1 demonstrates the maximum number of cases of specified diseases ever reported in the United States, the number of cases reported in 1998, and the proportion reduction in incidence. Declines of greater than 95 percent are the rule. Similar dramatic reductions have been seen from deaths due to these diseases. Smallpox is not shown on this table as smallpox has been eradicated from the world. Most industrialized countries have seen comparable declines in illnesses and deaths due to vaccine-preventable diseases. Most developing countries have not yet experienced the same level of decline because they have not achieved the same level of immunization coverage.
In the United States, immunization levels in young children are at record highs and reported incidence of vaccine-preventable diseases are at record lows. Nonetheless, several factors threaten this continued success, including the birth every day of eleven thousand infants who will all need to be immunized, the changing immunization schedule, the movement of children between health care providers (25% of U.S. 2-year-olds have received vaccines from two or more providers), continued overestimation of coverage by parents and providers, and the absence of disease as a continuing reminder of the need for immunization (even though the causative organisms are still in circulation).
Because of the continuing birth of susceptible infants, unless communicable diseases are eradicated it will be necessary to continue immunizing
Table 1
Maximum Reported Morbidity and 1998 Provisional Morbidity
against them indefinitely. Several examples exist in industrialized countries (including England and Japan) where epidemic resurgence of pertussis (whooping cough) has occurred as a consequence of declining use of pertussis vaccine. In the United States, a resurgence of measles resulted from the diversion of effort from measles vaccination to rubella vaccination following introduction of rubella vaccine in 1969 (at that time it was not combined with measles vaccine).
Several techniques have been demonstrated to be highly effective in improving and maintaining immunization coverage, including improving access to immunization, developing reminder and recall systems to notify parents and providers about needed or overdue immunizations, assessing immunization coverage in individual facilities, and linking immunization services with other services. By providing accurate, up-to-date information to health care providers, immunization registries (confidential, computerized information systems that contain information about immunizations and children) can make it easier to carry out the demonstrably effective immunization strategies. All states are currently in the process of establishing population-based immunization registries containing information on all children within their borders.
In the United States, infants and children may receive immunizations from private providers (typically in conjunction with other well-child services) or from public sector sites such as local health departments (in which case immunizations might be the only services provided) or community health centers. Traditionally, vaccines provided in the public sector have been free, whereas private providers have charged for the vaccines. Consequently, lower-income families typically went to public sector facilities to receive vaccine, even though they might have been using a private physician for other care. Until the middle of the 1990s, it was estimated that approximately one-half of all U.S. children received immunizations from private providers and one-half from the public sector. Enactment of the Vaccines For Children (VFC) program in 1994 made free vaccine available to private providers for use in uninsured or under-insured children and led to a major shift in immunization provision. In 1998, approximately 70 percent of all childhood vaccines were administered in the private sector and 30 percent in the public sector, meaning that more children were receiving immunizations in their "medical home" than had been the case previously.
IMMUNIZATIONS WORLDWIDE
Since 1979, the World Health Organization (WHO) has coordinated an Expanded Program on Immunization (EPI), which seeks to bring vaccines against six diseases—diphtheria, measles, pertussis (whooping cough), poliomyelitis, tetanus, and tuberculosis—to all children in the world. An abbreviated immunization schedule has been developed that calls for a dose of BCG (Bacille Calmette-Guerin) at birth; three doses of DTP (combined diphtheria and tetanus toxoids and pertussis vaccine) and OPV (oral polio vaccine) given at six, ten, and fourteen weeks of age; and a single dose of measles vaccine at nine months of age. BCG protects infants against severe forms of tuberculosis (such as tuberculous meningitis) but does not alter the overall transmission of tuberculosis.
The EPI succeeded in reaching immunization coverage levels of approximately 80 percent in the world's children by 1990 (the year of the Children's Summit), but levels have been relatively stagnant since that time, even decreasing in some areas. Coverage varied markedly among (and within) countries. Some of the reasons for the lack of further progress include: the overall economic situation in many countries, the fragile nature of the countries' health services, lack of political support, and problems in management of immunization programs. In 1991 a recommendation was made to administer hepatitis B vaccine to all children (three doses: at birth, six weeks, and fourteen weeks; or along with the DTP vaccine) but this has not been widely implemented in most developing countries. Introduction of other (newer) vaccines such as Hib is problematic. These vaccines are considerably more expensive than traditional vaccines, there are few manufacturers (sometimes only one, as a result of innovation and patent protection), and purchase of vaccines may require hard currency, which may be difficult for some developing countries to obtain. The development of the Global Alliance for Vaccines and Immunization and the Global Children's Vaccine Fund in early 2000 give hope that mechanisms may be developed to facilitate introduction of important new vaccines in developing countries.
ERADICATION OF VACCINE- PREVENTABLE DISEASES
Global eradication of smallpox in the late 1970s is probably the greatest single achievement in health to date. Although both William Jenner and Thomas Jefferson predicted eventual eradication at the end of the eighteenth century, it took nearly two hundred years to accomplish. The intensive global effort for eradication began in 1967 with the result that the last naturally occurring case of smallpox occurred in 1977. The World Health Assembly certified eradication in 1980. The initial strategy to achieve eradication was mass vaccination of the population, but over time this was refined to a strategy of search and containment— search for cases of smallpox and containment of transmission through vaccinating all persons who might have been exposed in a geographic area.
An effort is currently underway to eradicate polio from the world by the end of 2000. The strategy for eradication involves attaining high levels of coverage with routine vaccination with OPV, special immunization campaigns, and vigorous surveillance to detect and investigate possible cases of polio. The special immunization campaigns typically occur as National Immunization Days, semiannual events in which all children in the country less than five years old are given OPV on a single day, regardless of their previous vaccination status. Significant progress is being made: no locally arising cases of polio have occurred in the Americas since 1991, none in the Western Pacific Region of the World Health Organization (including China) since 1997, and none in the European Region since 1998. At the beginning of 2000, the major problems remaining were in South Asia and sub-Saharan Africa. Whether the target will be met on schedule is not clear. It is clear that eradication is technically feasible—the uncertainties relate to political will and financial support.
Other diseases that are potential candidates for eradication through appropriate use of vaccines include measles, mumps, and rubella. Measles is the most serious of these, still accounting for nearly 900,000 deaths a year (half of them in sub-Saharan Africa), and there is substantial support for consideration for elimination or eradication. The public health impact of rubella and mumps is not as widely recognized and there is not the same degree of enthusiasm for their eradication, although it is estimated that more than 100,000 cases of congenital rubella syndrome occur each year around the world. Although all three conditions could be attacked simultaneously by using MMR (combined measles-mumps-rubella) vaccine, the additional vaccine costs would be substantial.
FUTURE VACCINES
Recent advances in biotechnology and understanding of the immune process make it likely that the pace of vaccine development and introduction will accelerate. Although this will mean that there is greater opportunity for prevention of disease and death, it will have additional consequences, such as increasing complexity of the immunization schedule and the need for additional injections. Development of combination vaccines can help alleviate this problem but, since there is at least a theoretical issue of incompatibility and interference between different vaccines, each combination must be tested thoroughly before it can be approved. Additionally, the prospective availability of combined vaccines from different manufacturers with slightly different components may add further complexity to the schedule and to decision making about what a given individual needs.
The biotechnology revolution has made it possible to explore novel approaches to immunization, such as incorporating into other microorganisms the antigens that elicit protective antibodies (another way of making combination vaccines) or even incorporating antigens into foodstuffs such as potatoes or bananas. Additionally, the prospect of administering vaccines by aerosol or using transdermal patches is being investigated, as is the possibility of using purified DNA from the causative organism as the means to induce immunity. Because of the potential for transmission of infectious diseases (e.g., hepatitis B, HIV/AIDS) through reuse of needles or inadvertent needle-sticks, disposal of needles has become a significant problem and has led to the development of "auto-destruct" syringes and needles that cannot be used more than once. Most designs to date do not prevent inadvertent needlesticks, however. Consequently, needleless approaches to administration are being pursued, including pressure injection of liquid or powder vaccine, aerosol/inhalation, and use of transdermal absorption.
CONCLUSION
Immunizations have been among the most successful public health interventions to date. Through appropriate use of vaccines, smallpox has been eradicated from the earth, poliomyelitis is on the verge of eradication, and there have been dramatic reductions in morbidity and mortality due to with many other diseases. Recent scientific advances give promise that even more diseases can be brought under effective control. A remaining challenge is to ensure that all people of the world benefit from immunizations.
Centers for Disease Control and Prevention (1999). "Achievements in Public Health, 1900–2000: Impact of Vaccines Universally Recommended for Children; United States, 1900–1998." Morbidity and Mortality Weekly Report 48(12):243–248.
Offit, P. A., and Bell, L. M. (1998). What Every Parent Should Know About Vaccines. New York: MacMillan.
Plotkin, S. A., and Orenstein, W. A., eds. (1999). Vaccines, 3rd edition. Philadelphia, PA: W. B. Saunders.
World Health Organization/UNICEF (1996). State of the World's Vaccines and Immunization. Geneva: WHO/UNICEF. Available online at www.who.int/vaccinesdocuments/DocsPDF/www9532.pdf.
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