Pediatric Annals

Prospects for Childhood Immunization in the Next Decade

Samuel L Katz, MD

Abstract

Programs in vaccine research and development and those in implementation and delivery offer exciting prospects for the next decade. On the research and development level, the vaccine field bursts with activity as new technology permits approaches to the prevention of infectious diseases not previously possible. Instead of only two major pharmaceutical firms engaged in research, development, and production, there are now five operating in the United States. Additionally, several large foreign firms are seeking entry to the American market. There is a large group of smaller American research organizations probing modem molecular biology to pursue innovative vaccines that hopefully will find their way to production by larger companies. On an international level, the Children's Vaccine Initiative (CVI) and the World Health Organization (WHO) are collaborating with many governmental and nongovernmental organizations in an effort to mobilize resources so that new vaccines and new programs will impact children of all nations, especially those in the developing world.

Those vaccines that are either nearing completion or are in promising stages of development include those listed in Table 1. It is obvious that priorities for children in the United States differ from those for children in sub-Saharan Africa, the Indian subcontinent, the Western Pacific rim, and other developing areas. With the multiplicity of vaccines on the horizon, it also is apparent that immunization schedules will become more complex, infants may be subject to far more injections, and parents may need to pay more frequent visits to physicians or clinics to complete these immunizations. In order to ameliorate these complexities, major efforts are devoted to the provision of combination vaccines, thereby reducing the requisite numbers of injections and visits.

Table

How to resolve the large numbers of cases that lawyers filed prior to the deadline for injuries allegedly incurred prior to 1988 remains a problem. However, the results of prospective application of the Act's provisions (Tables 5, 6, and 7) have brought order to a previously tumultuous process that involved the tort system, rewarded attorneys more often and more generously than plaintiffs, and placed in the hands of well-meaning juries decisions that frequently were made on an emotional rather than an intellectual basis. Indeed, in a prospective fashion, the excise tax collections have accumulated a fund of more than $600 million, above and beyond that which has been paid out in claims judged appropriate. Another component of OBRA was the reinstitution of the Vaccine Injury Compensation Program, which had been allowed to lapse on December 31, 1992 due to the veto of a bill that had included its renewal by former President George Bush late in his term of office.

Another forthcoming deliberation will involve the revision of the current table of compensable injuries following vaccination. When these were originally written, they were exceptionally broad and inclusive, covering a number of infant and childhood disorders that are not at all related to vaccines. Studies conducted in 1991 by the Institute of Medicine (IOM) at the request of Congress have reviewed exhaustively the data on vaccine- induced injuries with pertussis vaccine, rubella vaccine,10 and, more recently, (1993) all the other mandated childhood vaccines plus hepatitis B and hemophilus influenza B." With these studies as the basis, the tables of compensable injuries will be rewritten in a more restrictive and justifiable fashion. This, too, should reduce the costs and expenditures of the Vaccine Injury Compensation Program. For example, the IOM study failed to find any convincing evidence that pertussis vaccine ever accounts for permanent brain damage or death. Because this one vaccine was the "culprit" in a very large portion of cases previously filed under the…

Programs in vaccine research and development and those in implementation and delivery offer exciting prospects for the next decade. On the research and development level, the vaccine field bursts with activity as new technology permits approaches to the prevention of infectious diseases not previously possible. Instead of only two major pharmaceutical firms engaged in research, development, and production, there are now five operating in the United States. Additionally, several large foreign firms are seeking entry to the American market. There is a large group of smaller American research organizations probing modem molecular biology to pursue innovative vaccines that hopefully will find their way to production by larger companies. On an international level, the Children's Vaccine Initiative (CVI) and the World Health Organization (WHO) are collaborating with many governmental and nongovernmental organizations in an effort to mobilize resources so that new vaccines and new programs will impact children of all nations, especially those in the developing world.

Those vaccines that are either nearing completion or are in promising stages of development include those listed in Table 1. It is obvious that priorities for children in the United States differ from those for children in sub-Saharan Africa, the Indian subcontinent, the Western Pacific rim, and other developing areas. With the multiplicity of vaccines on the horizon, it also is apparent that immunization schedules will become more complex, infants may be subject to far more injections, and parents may need to pay more frequent visits to physicians or clinics to complete these immunizations. In order to ameliorate these complexities, major efforts are devoted to the provision of combination vaccines, thereby reducing the requisite numbers of injections and visits.

Table

TABLE 1New Vaccines at Various Stages of Research and Development

TABLE 1

New Vaccines at Various Stages of Research and Development

Table

TABLE 2Anticipated Combination Vaccines

TABLE 2

Anticipated Combination Vaccines

More distantly, further exploitation of mucosal routes of immunization (gastrointestinal or respiratory tract) will reduce the number of parenteral administrations and mimic the natural routes of contact and immunizing experiences with most viral and bacterial pathogens. Progress has been more rapid with the combination vaccines, whereas mucosal immunization has proven more difficult to achieve. It is interesting to compare this 1993 perspective with that reviewed 3 years ago in this same journal.1

COMBINATION VACCINES

It is often overlooked that we have long used combination vaccines for the standard antigens (diphtheria and tetanus toxoids with pertussis vaccine [DTP] and measles-mumps-rubella [MMR]). Diphtheria and tetanus toxoids with pertussis vaccine has become the "core" to which to add the newer injectable vaccines. The addition of Hemophilus in/luenzoe, type b conjugate3 has been achieved already with licensure in the spring of 1993 (Tetramune, Lederle-Praxis Biologicals, Wayne, New Jersey). Another product available in Europe and perhaps to be licensed in the United States adds enhanced inactivated polio virus vaccine (IPV) to DTP.3 Table 2 lists some of the other potential additions and combinations using the DTP core.

In addition to the efforts to produce combination vaccines that retain safety, immunogenicity, and efficacy, another goal is the "packaging" of these vaccines in a fashion that would reduce the requirement for repeated injections. These approaches include microencapsulation, antigens incorporated in liposomes, new adjuvants, and other innovations that would provide sustained or pulsed release of antigens from the initial site of deposition, stimulating the immune system in a fashion that is now invoked by three or four injections of DTP, hepatitis B, or hemophilus B conjugates. Tetanus toxoid has been the "trial balloon" for these approaches and work progresses under the aegis of the CVI.

In the area of live virus vaccines, similar combination products already exist (MMR; oral poliovirus vaccine types 1, 2, and 3). Table 2 lists some additional combination products under study. Once again, the challenge to the laboratory workers is how to combine these products successfully so they retain their full infectivity without inhibiting one another's replication. The exploitation of live viruses (poxviruses, adenovirus, and polio virus) or bacteria (salmonella and bacille Calmette-Guérin [BCG] tuberculosis vaccine) as vectors in which to introduce other selected antigens is another imaginative technique for new vaccine developments. Experimental measles vaccine (in canary pox) and human immunodeficiency virus1 (in vaccinia) are under testing.4,5

Table

TABLE 3Goals of the Children's Vaccine Initiative Vaccines

TABLE 3

Goals of the Children's Vaccine Initiative Vaccines

Table

TABLE 5Petitions Filed Under the Vaccine Injury Compensation Program

TABLE 5

Petitions Filed Under the Vaccine Injury Compensation Program

Table

TABLE 4Current World Health Organization's Expanded Program on Immunization Schedule for Vaccines

TABLE 4

Current World Health Organization's Expanded Program on Immunization Schedule for Vaccines

All of these products, inactivated or live attenuated, will require extensive laboratory development, clinical trials to confirm immunogenicity and safety, new !icensure review, and increased costs. Although the health budgets of developed nations may tolerate these added expenditures, it is unlikely that the developing countries can do so. Vaccines have proven to be among the most cost beneficial of quantifiable disease preventive measures. Nevertheless, it will require significant external support and technology transfer to make these new products available to children throughout the world. This is the mission of the CVI.

CHILDREN'S VACCINE INITIATIVE

On September 10, 1990 at the Children's Summit at the United Nations in New York, the "Declaration of New York - The Children's Vaccine Initiative" was created. Some of its goals are listed in Table 3. Since then, there have been three major meetings of the CVI consultative groups and many sessions of smaller task forces considering the necessary research and product development. Currently, the CVI is supported by four major groups: the United Nations Children's Fund (UNICEF), the United Nations Development Program, the World Bank, and the Rockefeller Foundation.

In general, the initiative has supported the WHO's Expanded Program on Immunization (EPI), which arose from the successful global Smallpox Eradication Program that was begun in 1974, 3 years before the last case of endemic smallpox was detected in Somalia. At that time, it was estimated that fewer than 5% of the world's children were immunized fully with the basic vaccines included in the EPI schedule (Table 4). By 1984, the figure had risen to 25%. Remarkably, by 1991, the EPI announced that 80% of the world's children had been immunized fully according to their schedule.6 This has resulted in more than 3 million children's lives saved each year in the less developed nations. Current goals call for the eradication of poliomyelitis by the year 2000 and a 95% reduction of measles deaths by 1995.

In reviewing these achievements and goals, it is sobering to realize that there are many areas in our own country where fewer than 50% of infants in the first 2 years of Hie receive the recommended immunizations.7 Some of our major urban centers have rates of 20% to 60% immunization for children under 2 years of age. The measles outbreaks of 1989-1991 in Los Angeles, Houston, San Diego, Philadelphia, and New York reflected this inadequacy.8 Once more, this emphasized the two major populations that exist in our nation - the privileged and the deprived. National statistics indicated that even in 1993, between 37% and 56% of our nation's 2 year olds, approximately 4 million children, had not received all of the immunizations recommended for the first 15 to 18 months of life.

PROSPECTS FOR THE UNITED STATES

The juxtaposition of the CVI and the comments on our own failures in the United States were deliberate and intended Co highlight the lack of priority assigned to children's health in recent years. Optimism arises, however, from the Clinton administration in Washington, DC, which has stated clearly its commitment to childhood immunization programs and overall improvement of child health. Secretary of Health and Human Services Donna Shalala and Deputy Assistant Secretary of Health D.A. Henderson have firmly articulated the administration's commitment to develop and implement aggressive programs in order to overcome the aforementioned deficits.

Table

TABLE 6Adjudications of Petitions Filed*

TABLE 6

Adjudications of Petitions Filed*

Under the Omnibus Budget Reconciliation Act (OBRA), Public Law 103-66 of August 1993, funds will be made available (as of October 1, 1994) to provide free vaccines to all children who are not covered already by health insurance or Medicaid. Although it failed to be included in the final bill, the Clinton administration intends to develop a National Registry System so that physicians can rapidly determine the immunization status of any child and provide reminders when they fall behind their intended schedules. Immu' nization stations adjacent to or included in other offices commonly visited by parents (eg, Women, Infants, and Children; Aid to Families with Dependent Children; Medicaid) would help to provide "one-stop shopping." Revisions to provide briefer, more appropriate, and multhingual "Important Information Statements" regarding vaccines will be made so that parents will receive a balanced intelligible presentation of the assets, as well as the rare liabilities, of the immunizing agents and procedures. The media will be challenged to develop educational programs to inform parents of the benefits of immunization for their children, rather than the "scare tactics" more often used in sensational presentations.

All of these measures will be mobilized at the same time we anticipate the availability of the new and combined vaccines discussed above. This will require careful attention and further education of physicians, nurses, public health officials, and all health-care workers.

VACCINE LITIGATION

One of the most destructive and inhibiting factors in immunization during the last 12 years has been the proliferation of lawsuits relating to alleged adverse outcomes of immunization procedures. Although the great majority of these have proven frivolous, the judicial awards of exorbitant amounts in those few cases judged to be legitimate served in the mid-1980s to dampen the interest of pharmaceutical firms in further vaccine research and development. Only with the passage of the Vaccine Injury Compensation Program in 1986 and its implementation in 1988 have we begun to recover from these setbacks. The levy of a federal excise tax on all recommended vaccines, the review of cases by medical experts, the provision of a table of compensable injuries, and the use of judiciary masters have all been direct results of this Act. The situation has come into some degree of realistic balance, and those cases filed after the 1988 implementation of the Act demonstrate a far more reasonable approach to the problems.9

Table

TABLE 7Awards Made

TABLE 7

Awards Made

How to resolve the large numbers of cases that lawyers filed prior to the deadline for injuries allegedly incurred prior to 1988 remains a problem. However, the results of prospective application of the Act's provisions (Tables 5, 6, and 7) have brought order to a previously tumultuous process that involved the tort system, rewarded attorneys more often and more generously than plaintiffs, and placed in the hands of well-meaning juries decisions that frequently were made on an emotional rather than an intellectual basis. Indeed, in a prospective fashion, the excise tax collections have accumulated a fund of more than $600 million, above and beyond that which has been paid out in claims judged appropriate. Another component of OBRA was the reinstitution of the Vaccine Injury Compensation Program, which had been allowed to lapse on December 31, 1992 due to the veto of a bill that had included its renewal by former President George Bush late in his term of office.

Another forthcoming deliberation will involve the revision of the current table of compensable injuries following vaccination. When these were originally written, they were exceptionally broad and inclusive, covering a number of infant and childhood disorders that are not at all related to vaccines. Studies conducted in 1991 by the Institute of Medicine (IOM) at the request of Congress have reviewed exhaustively the data on vaccine- induced injuries with pertussis vaccine, rubella vaccine,10 and, more recently, (1993) all the other mandated childhood vaccines plus hepatitis B and hemophilus influenza B." With these studies as the basis, the tables of compensable injuries will be rewritten in a more restrictive and justifiable fashion. This, too, should reduce the costs and expenditures of the Vaccine Injury Compensation Program. For example, the IOM study failed to find any convincing evidence that pertussis vaccine ever accounts for permanent brain damage or death. Because this one vaccine was the "culprit" in a very large portion of cases previously filed under the program, its elimination from the table should further reduce the funds expended.

SUMMARY

Prospects for vaccine research, development, and use over the next decade are extraordinarily optimistic. Innovative investigative programs promise new vaccines with reduced numbers of injections, combinations of multiple antigens, and confinement of administration to the early weeks or months of life. Enhanced attention to the infrastructure and support of immunization programs should rapidly augment coverage to more than 90% of the US infant population in the first 2 years of life with all the recommended vaccines. Programs of the WHO and CVI should extend protection from morbidity and mortality of diseases preventable with vaccine to children of all nations. Adjustments and realignments of the Vaccine Injury Compensation Program should reduce to realistic dimensions the finances of benefits for children who suffer the rare, true adverse responses to required immunizations. In order to maintain familiarity and leadership in childhood immunization, pediatricians will need to maintain careful attention to and familiarity with all these emerging developments.

REFERENCES

1. Pichichero ME, Green JL, Francis AB, et al. New vaccines and vaccination policies. Pediatr Ann. 1990;19:6S6-694.

2. ACIR Recommendations for UH; of Haemophiliis h conjugate vaccines and a combined diphtheria, retanus, pertussis and Hacmophilus tt vaccine. MMWR. 1993;42:1-15 (RR-13).

3. Drucket J. Poliomyelitis in France: epidemiology and vaccination status. Pediatr Infect Dis. J 1991;10:907-969.

4. Taylor J, Weinberg R, Tartaglia J, et al. N on replie at ing viral vectors as potential vaccines; rccombinant canary pox virus expressing measles virus fusion (F) and hemagglutinin (HA) glycoproteins. Virology. 1992;187:321-328.

5. Cooney EL, Collier AC, Grecnberg PD, et al. Safety of and immunological response to a recombinant vaccinia virus raceme expressing HIV envelope glycoprotein. Lancet. 1991;337=567-572.

6. Kim-Farley RJ. Expanded programme on immuni:alion: achievements and challenges. World Health, 1993;Mar- Apr: 14-16.

7. Cutts FT, Zeli ER, Mason D. et al. Monitoring progress toward US preschool immunization goals. JAMA, 1992;267: 1952-1955.

8. Kati SL. Measles in the United States: 1989 and 1990. In: Aronoff SC, ed. Admises in Pediatric Infectious Diseases. Vol 6. St Louis, Mo: Mosby Year Book; 1991:79-90.

9. Office of Communications HRSA. Vaccine injury Compensation Program (Pre-1988 and Post-1988 Programs) Fact Sheet. Rock ville, Md; 1993.

10. Institute of Medicine. Adverse Effect of Pertussis and Rubella Vaccines. Washington, DC: National Academy Pressi 1991.

11. Institute of Medicine. Adivrse Events Associated With Chldhnod Vaccines. Washington, DC: National Academy Press; 1993.

TABLE 1

New Vaccines at Various Stages of Research and Development

TABLE 2

Anticipated Combination Vaccines

TABLE 3

Goals of the Children's Vaccine Initiative Vaccines

TABLE 5

Petitions Filed Under the Vaccine Injury Compensation Program

TABLE 4

Current World Health Organization's Expanded Program on Immunization Schedule for Vaccines

TABLE 6

Adjudications of Petitions Filed*

TABLE 7

Awards Made

10.3928/0090-4481-19931201-11

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