Vaccines and Emergent Infections

by Frederick C. Robbins, M.D.

University Professor and Dean Emeritus, School of Medicine, Case Western Reserve University, and

Barry R. Bloom, Ph.D.

Investigator, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Yeshiva University

In 1974, fewer that 5 percent of the world's children were immunized against the major vaccine-preventable diseases. In the United States between 1950 and 1970, 58,000 cases of rubella, 700,000 cases of measles, 150,000 cases of mumps, 5,800 cases of diphtheria, 121,000 cases of pertussis, and 57,000 cases of paralytic poliomyelitis were reported in peak years. In 1993, however, thanks to the increased prevalence of immunization, only approximately 9,000 cases of all of those diseases combined were reported in the United States. The most dramatic example of the value of vaccines is the global eradication of smallpox. This monumental achievement was accomplished in the short space of 10 years (the last case of naturally acquired smallpox was reported in 1977) and was entirely dependent upon immunization with the vaccinia virus. Since the declaration in 1980 that smallpox had been eradicated, smallpox vaccination has ceased throughout the world, thus preventing a certain amount of vaccine-induced morbidity and yielding savings of many millions of dollars (the United States itself saves $32 million every 20 days). Although eradication is the ultimate in disease control, unfortunately, not all reported diseases are amenable to eradication even when there is an effective vaccine available.

Poliovirus is the next agent slated for eradication. This has already been achieved in the Americas, and by the year 2000 it is hoped that global



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For the Public Good: Highlights from the Institute of Medicine, 1970–1995 Vaccines and Emergent Infections by Frederick C. Robbins, M.D. University Professor and Dean Emeritus, School of Medicine, Case Western Reserve University, and Barry R. Bloom, Ph.D. Investigator, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Yeshiva University In 1974, fewer that 5 percent of the world's children were immunized against the major vaccine-preventable diseases. In the United States between 1950 and 1970, 58,000 cases of rubella, 700,000 cases of measles, 150,000 cases of mumps, 5,800 cases of diphtheria, 121,000 cases of pertussis, and 57,000 cases of paralytic poliomyelitis were reported in peak years. In 1993, however, thanks to the increased prevalence of immunization, only approximately 9,000 cases of all of those diseases combined were reported in the United States. The most dramatic example of the value of vaccines is the global eradication of smallpox. This monumental achievement was accomplished in the short space of 10 years (the last case of naturally acquired smallpox was reported in 1977) and was entirely dependent upon immunization with the vaccinia virus. Since the declaration in 1980 that smallpox had been eradicated, smallpox vaccination has ceased throughout the world, thus preventing a certain amount of vaccine-induced morbidity and yielding savings of many millions of dollars (the United States itself saves $32 million every 20 days). Although eradication is the ultimate in disease control, unfortunately, not all reported diseases are amenable to eradication even when there is an effective vaccine available. Poliovirus is the next agent slated for eradication. This has already been achieved in the Americas, and by the year 2000 it is hoped that global

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For the Public Good: Highlights from the Institute of Medicine, 1970–1995 eradication will have been accomplished. Here too, the campaign is dependent upon having an effective, readily administered vaccine. The Institute of Medicine (IOM) has been very much involved in assessing U.S. polio vaccine policy. In fact, the first study done by the IOM dealing with vaccines—or, indeed, preventive medicine—was the 1977 report Evaluation of Poliomyelitis Vaccines. In this report the relative merits of the two polio vaccines, IPV (inactivated polio, or Salk, vaccine) and OPV (oral polio vaccine —live attenuated, or Sabin vaccine), were analyzed and recommendations for national policy made. The Institute recommended that OPV continue to be the vaccine of choice, but that IPV be made more available for special cases such as immunodeficient persons or those with whom they have contact, as well as those who for one reason or another would prefer IPV. In addition, suggestions were made about simplifying and developing more informative consent forms and about developing a compensation program for children injured by vaccines. A second report on polio vaccine policy was issued in 1988. By this time, circulation in the United States of wild polio virus had almost certainly been interrupted and, although few in number, cases of paralysis due to the poliovirus were almost all attributable to the vaccine virus itself. The recommendations of this report were that the policy continue unchanged except that the standard IPV be replaced by the more potent “enhanced inactivated vaccine” (eIPV). It was also recommended that when a quadrivalent DTP (diphtheria–tetanus–pertussis)-eIPV was licensed in the United States (such a product was already available in some other countries), a schedule of primary immunizations with the quadrivalent product should be considered, to be followed by one or more doses of OPV. Although at the time it was estimated that DTPeIPV would be available within a few years, it is still not licensed in the United States, and no change has been made in U.S. policy. A third consideration of this topic was conducted in June 1995. This was a workshop to review the situation in the context of the recent declaration that polio has been eradicated from the Americas. No recommendations were made as a result of the workshop, but a summary of the discussion will be made available to the Advisory Committee on Immunization Practices, the body that will recommend changes to U.S. policy. Thus, the IOM has played an important role in determining polio immunization policies in the United States. In view of the great benefits of vaccines and their cost-effectiveness, one might have expected industry to follow up with tremendous innovation and expanded vaccine development. In the United States, the contrary was true. In the early 1980s there were 14 vaccine manufacturers in the United States. In 1994 there were 4 major vaccine manufacturers and 2 state laboratories

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For the Public Good: Highlights from the Institute of Medicine, 1970–1995 that produced vaccines. In the early 1980s there was concern that the major manufacturers would find that the profitability of vaccines was too low and the liability risk too high to continue developing and producing vaccines. It is in this context that the IOM produced three major reports. The first, Vaccine Supply and Innovation (1985), reviewed for the first time the development, supply, research and distribution of vaccines in the United States and the financial and legal constraints placed on the industry. The study committee concluded that the main barrier to innovative vaccine development was liability and suggested a number of models of “no-fault” compensation that, if adopted, might alleviate the threat to the industry in the United States. It further recognized that research, clinical testing, safety considerations, and regulatory concerns were complex and expensive, and suggested that public and private efforts in vaccine development and supply would best be coordinated through a National Vaccine Commission. In 1986, Title XXI of the Public Health Service Act, in accord with some of the visionary innovations suggested in the IOM report, created the National Vaccine Injury Compensation Act and Program—in essence a novel no-fault compensation program for vaccine-related injuries. This program enables families of children with vaccine-related injuries to receive compensation for medical expenses, lifetime lost earnings, and pain and suffering. Compensation can be obtained by filing a valid claim with a special master-of-the-court, without the need for expensive and protracted litigation. The program is financed by Congress and by a trust fund created by an excise tax on each dose of vaccine; the trust fund currently has a surplus. The consequences of this act have been profound. Although any family has a right to reject the decision of the representative of the court and initiate a civil suit, this has rarely occurred. In fact, since the program was established, there has been a dramatic reduction in the number of major suits brought against vaccine manufacturers since 1987. Finally, vaccine prices, as a consequence of the far greater predictability of liability compensation, have remained more stable over the past 10 years, although higher in part because of the excise tax used to finance the trust fund. The National Vaccine Injury Compensation Act is both visionary and in some senses radical, representing a rare example of no-fault health insurance in the United States. Its success depended on the credibility of establishing, to the best that scientific and objective knowledge could do, the causal relations between the administration of a vaccine and subsequent clinical symptoms and adverse events. In an important effort by experts convened by the IOM, all published studies related to adverse events associated with vaccines were examined, and national, scientifically based guidelines were developed and incorporated into the National Vaccine Injury Tables used by the compensation program as the basis for ascertaining, in any individual

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For the Public Good: Highlights from the Institute of Medicine, 1970–1995 case, whether or not a claim is compensable or deemed not to fall within a clear-cut designation as a vaccine adverse event. The fact that the program has continued and has received wide acceptance and appreciation by the families of children who have made such claims, by the medical profession, and by the vaccine companies, in what could otherwise be a highly volatile and controversial circumstance, indicates the power of the IOM to bring together the best representatives of scientific knowledge and judgment on specific and selective health issues. The National Vaccine Act also created a National Vaccine Program with an advisory committee that were intended to foster dialog between the public and private sectors and to serve as a forum for resolving issues relating to vaccine supply, delivery, and access; vaccine adverse effects; and vaccine innovation, all as recommended in the IOM's reports. The advisory committee was to have coordinated the activities of the 27 government agencies that have statutory responsibility for one or more aspects of vaccines. However, despite the additional recommendation in the 1993 IOM report The Childrens' Vaccine Initiative: Achieving the Vision for the creation of a national vaccine authority, the National Vaccine Advisory Committee and program staff have essentially been cut and crippled. In about 1980, the NIAID initiated its program to accelerate the development of vaccines. In 1982, the IOM was asked to develop an approach for setting priorities for vaccine development. In fact, two reports were commissioned, one dealing with vaccines for use in this country and the other with vaccines to be used in developing countries. One of the challenges in priority-setting is how to evaluate the gains achieved by preventing chronic disease and disability in adults relative to the benefits that accrue from preventing death in children. A creative metric was developed, the Infant Mortality Index, in which the effects of chronic diseases were weighted in comparison to the death of a child. The two volumes of New Vaccine Development: Establishing Priorities issued in 1985 (Diseases of Importance in the United States) and 1986 (Diseases of Importance in Developing Countries) have been well received, and the model used in them is adaptable to other situations. In the opinion of some, after 10 years of rapid advances in research and development, a reconsideration of the priorities outlined in these volumes is currently being undertaken by another IOM committee. In September 1990, 77 heads of state met at the United Nations for the International Summit for Children and committed themselves to putting the health and welfare of children at the top of the international agenda. A major outcome of that meeting has become known as the Children 's Vaccine Initiative (CVI). The CVI is a global focus for providing support, both within national research institutions and internationally, to develop new and

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For the Public Good: Highlights from the Institute of Medicine, 1970–1995 improved vaccines against the major infectious killers, including acute respiratory diseases, which take the lives of 6 million children annually; diarrheal diseases, which claim another 4 million lives; and AIDS, which may claim as many as 40 million lives by the end of this decade. The IOM reports on vaccines helped to initiate that process. In that context, the continuing direction of the CVI was the subject of The Children's Vaccine Initiative. As mentioned previously, this report also proposed the creation of a National Vaccine Authority to coordinate the disparate efforts of the multiple agencies of the U.S. government and to focus and organize activities relating to vaccines. Ironically, by 1993, more than 80 percent of the world's children were receiving their recommended childhood vaccines by the age of 2. In the United States, the precise numbers of children who have been vaccinated or who have failed to be vaccinated by the age of 2 are really not known. However, in a 1992 survey of 11 major cities by the Centers for Disease Control and Prevention, vaccine coverage rates for the recommended childhood vaccines by the age of 2 varied from 10 percent to 55 percent—a shockingly low figure. While the Clinton administration has received its greatest notoriety in the area of health, perhaps for failing to achieve a comprehensive health care reform program, it is not widely appreciated that the one major thrust of this administration in the area of health that has been successful, although controversial, is the passage of the Childhood Immunization Initiative, which brought over $630 million in new funding to protect U.S. children from vaccine-preventable illnesses and to develop new and improved vaccines. Since 1974, many millions of lives that would otherwise have been lost to childhood infectious diseases have been saved by immunization. Vaccines have changed the world, and IOM studies and forums on vaccines have contributed significantly to that change. It has become widely appreciated, as most recently documented in the World Bank's World Development Report Investing in Health (1993), that vaccines are one of the most cost-effective medical interventions available globally to prevent death and disease. Finally, with a remarkable prescience, in 1991 the IOM published a report on Emerging Infections: Microbial Threats to Health in the United States. The report's findings emphasized that the dynamic of emerging infections is a continuous evolutionary process, which society deals with only discontinuously when faced with epidemics or immediate threats. The reasons for emergence are varied, including changes in human behavior and demography; changing technology, economic development, and land use; international travel and commerce; microbial change; and the breakdown of the public health system. Even before the recent outbreaks of hantavirus in the U.S. Southwest, a new strain of cholera in Asia, Ebola virus in Africa, and

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For the Public Good: Highlights from the Institute of Medicine, 1970–1995 cryptosporidium in Milwaukee, the report indicated how vulnerable we are to many known pathogens and how unprepared we are for future threats. It made important suggestions for global surveillance, monitoring of emerging drug resistance, research, training, vaccine and drug development, and public education about potential threats before they are upon us. It has captured the interest of the media and been one of the most widely sought IOM publications, perhaps because one of its messages is that, from the point of view of infectious diseases, there is nowhere from which we are remote, no one from whom we are disconnected.