Institute of Medicine Report: "Vaccines for the 21st Century"
Analysis and Action Plan for the National Vaccine Advisory Committee
Prepared by: Stanley Plotkin, Stephen Sepe, and Martin Myers On Behalf of the NVAC Subcommittee on Future Vaccines
The new report by an Institute of Medicine (IOM) committee on vaccine development was anticipated by many to be an update of the two-volume report issued in 1985 which developed a quantitative model for use by decision makers to prioritize vaccine development. In fact, it was an attempt to develop an economic model for societal investment in vaccine development in developed countries.
Because of the varying expectations concerning this report, stating at the outset what it is not is necessary. First, it is not a complete analysis of all possible vaccine targets. The Committee eliminated those diseases for which the members believe vaccine cannot be developed in 20 years, citing syphilis as an example. They were asked not to consider HIV, already a Department of Health and Human Services priority. However, to evaluate the impact of chronic illness on the model, they included an analysis for some diseases for which a vaccine is unlikely to be available in the near future, for example, a vaccine for multiple sclerosis. They were instructed not to attempt an economic analysis of diseases indigenous to poor tropical countries, such as malaria or helminthic diseases, because of the differences in data sets and complexities of evaluating differing societal needs. While quite understandable from the perspective of model development, unfortunately the model they developed is unlikely to be adaptable to cultures and circumstances other than those in developed countries. In addition, the World Health Organization (WHO) and World Bank models (which used disability-adjusted life years as a measure of health outcome) will not be comparable to the one described in the Report because of its use of the Quality Adjusted Life Year (QALY) as the measure of health outcome. (The use of QALYs as a standard measure of health outcomes in cost-effectiveness analyses was recommended by an expert panel convened by the Department of Health and Human Services). Finally, the Committee also specifically excluded water-borne diseases, vector-borne diseases, nosocomial infections and infections of immunocompromised hosts. Thus, many infections, such as HIV, syphilis, malaria, dengue, staphylococcus and pneumocystis, were eliminated from consideration at the outset of the Committee’s review.
The model determines cost effectiveness only from a societal perspective. While reasons to have done so are many, this approach has some unfortunate consequences. For example, priorities are often based upon cost effectiveness from the particular perspective of the organization making the investment, rather than for society as a whole. Further, the needs of specific components of society may be overlooked in such an analysis (e.g. the military and the need for a traveler’s diarrhea vaccine).
The committee identified 26 diverse diseases that occur in normal persons in the United States to test their cost-effectiveness model as a means of comparing very different circumstances. The Report describes the model, its application to these diseases, but it does not presume to set priorities. Annexes and supporting documents are available on the IOM Website - http://www.iom.edu/vaccinepriorities.
The mathematics of the model become fairly complicated, but the basic formula is easy to understand:
Cost Effectiveness = [Cd + Ci - Cc] / Q
Where Cd is the cost of vaccine development, Ci is the cost of immunization, Cc is the cost of medical care for the illness, and Q equals the annual health benefit.
In applying the formula to specific diseases, the annual health benefit becomes the most important number. This benefit was derived by a complex calculation of QALYs- Quality Adjusted Life Years - which is more or less the summation of the acute and chronic problems caused by the illness. The Report justifies extensively why the Committee selected QALYs as the measure of outcome. The model is sufficiently flexible that disability-adjusted life years (DALYs) could be substituted; the analyses would have yielded similar results.
The more severe and/or permanent the sequelae, the larger will be Q. Cost of care is also important, with chronic care being expensive. The Report indicates that adjustments for vaccine efficacy and utilization had a more substantial impact on a vaccine’s cost effectiveness than time required for development.
The results of this analysis were summarized in the Report as follows:
Saves money and QALYs
Cost < $10,000 per QALY saved
Cost > $10,000 and < $100,000 per QALY saved
Cost > $100,000 per QALY saved
Seven of the 26 candidate "vaccines" are in the economically most favorable (I) category for development, i.e., those for which a vaccination development strategy would save society money. The Level I candidate vaccines are as follows (in alphabetical order):
- cytomegalovirus (CMV) vaccine administered to 12 year olds for the prevention of perinatal disease,
- Influenza virus vaccine administered to the general population (once per person every 5 years or one-fifth of the population per year),
- insulin-dependent diabetes mellitus therapeutic vaccine,
- multiple sclerosis therapeutic vaccine,
- rheumatoid arthritis therapeutic vaccine,
- Group B streptococcus vaccine to be well-incorporated into routine prenatal care and administered to women during first pregnancy and to high-risk adults (at age 65 years and to people less than age 65 years with serious, chronic health conditions), and
- Streptococcus pneumoniae vaccine to be given to infants and to 65 year olds.
Nine of the 26 candidate "vaccines" are in the more economically favorable (II) category, i.e., those with which a vaccination strategy would incur small costs (less than $10,000) for each QALY gained. The Level II vaccine candidates are as follows (in alphabetical order):
- chlamydia vaccine to be administered to 12 year olds.
- Helicobacter pylori vaccine to be administered to infants,
- hepatitis C virus vaccine to be administered to infants,
- herpes simplex virus vaccine to be administered to 12 year olds,
- human papillomavirus vaccine to be administered to 12 year olds,
- melanoma therapeutic vaccine,
- Mycobacterium tuberculosis vaccine to be administered to high-risk populations,
- Neisseria gonorrhea vaccine to be administered to 12 year olds, and
- respiratory syncytial virus vaccine to be administered to infants and 12-year-old females.
Four of the 26 candidate "vaccines" are in the economically favorable (III) category, i.e., those with which a vaccination strategy would incur moderate costs (more than $10,000 but less than $100,000) per QALY gained. The Level III vaccine candidates are as follows (in alphabetical order):
- parainfluenza virus vaccine to be given to infants and to women in their first pregnancy,
- rotavirus vaccine to be given to infants,
- Group A streptococcus vaccine to be given to infants, and
- Group B streptococcus vaccine to be given to high-risk adults and to either 12-year-old females or to women during first pregnancy (low utilization).
Seven of the 26 candidate "vaccines" are in the less economically favorable (IV) category, i.e., those with which a vaccination strategy would incur significant costs (more than $100,000 and up to well more than $1 million) per QALY gained. The Level IV vaccine candidates are as follows (in alphabetical order).
- Borrelia burgdorferi vaccine to be given to resident infants born in and immigrants of any age to geographically defined high-risk areas,
- Coccidioides immitis vaccine to be given to resident infants born in and immigrants of any age to geographically defined high-risk areas,
- enterotoxigenic Escherichia coli vaccine to be given to infants and travelers,
- Epstein Barr virus vaccine to be given to 12 year olds,
- Histoplasma capsulatum vaccine to be given to resident infants born in and immigrants of any age into geographically defined high-risk areas,
- Neissria meningitidis type b vaccine to be given to infants, and
- Shigella vaccine to be given to infants and travelers or to travelers only.
Thus, the model gives precise answers, perhaps too precise, to the question "how much money will society save (or have to spend) to develop a particular vaccine," within the constraints mentioned previously that led to the consideration of a limited number of potential vaccine candidates.
The following are the positive features of the IOM Report:
- A method has been developed to estimate the burden of disease produced by disparate infections and chronic conditions. Thus, one can compare very different diseases with respect to how much they damage the quality of life in the United States population.
- The report introduces the concept of preventing chronic diseases with an autoimmune etiology through a process of "tolerization" in which antigens are used to reduce the cellular immune responses to an autoantigen in the host’s tissues.
- The importance of chronic sequelae of disease as an economic burden to society is stressed, such as with congenital cytomegalovirus infection.
- The report suggests a method to help evaluate the priority for society of a given vaccine. This analysis must be supplemented with other measures.
The negative features of the IOM Report are as follows:
- The report is not a comprehensive analysis of all potential target diseases
- The specific charge to the IOM was for a United States-based analysis; therefore, the model is not adaptable to other societies or regions of the world. Thus, the global impact of a disease is not taken into account and does not pertain to the American traveler or residents in developing countries.
- The public health interest for a disease is not evaluated. A relatively uncommon disease might be important because its effect on public health is devastating.
- Diseases that are acute and severe but have no sequelae are underrated.
- The analyses do not take into consideration that the cost of vaccine development, the cost of immunization, and the cost of medical care are borne by different segments of society; respectively, industry, private payers and the federal government, states, and health maintenance organizations and families. Analyses from multiple perspectives is needed.
- Feasibility of vaccine development (i.e., targets of opportunity) is not considered.
- The needs of specialized segments of society, such as the military, are not considered.
- Potential vaccine adverse reactions are not considered in the costs.
National Vaccine Advisory Committee: Actions
The following are action items for NVAC:
- The prevention and treatment of HIV infection should be examined using this model as it is an established societal priority and the data are easily available.
- Evaluation of the disease burden of other infections or chronic conditions maybe desired.
- Consideration needs to be given as to how to compare the benefits of improvements in existing vaccines with the development of vaccines against diseases for which no vaccines are licensed.
- Vaccines that are to be administered at puberty, to adolescents, or to pregnant women will require new approaches to encourage their use as well as the infrastructure to ensure delivery at appropriate times.
- The impact of liability on vaccine development and use for these populations needs to be addressed. For example, the principal obstacle to group B streptococcus vaccine development is that the target population to immunize would be pregnant women, for which liability issues are formidable. NVAC alone cannot effectively address these issues, although a joint task force with the Advisory Commission on Childhood Vaccines and the Vaccine Injury Compensation Program (VICP) could develop options with the Department of Health and Human Services, the Department of Justice, industry, and insurance carriers.
- Concerning development of a cytomegalovirus (CMV) vaccine to prevent perinatal infection, a priority in the IOM Report, the following three problems have impeded development: a paucity of data to convince decision-makers of the need for a vaccine, the perceived difficulty of performing efficacy trials, and the lack of industry interest. In order to address these problems, the National Vaccine Program Office (NVPO) and NVAC should organize a scientific workshop to consider barriers to the development of such a vaccine. This could address the prevalence of intrauterine infection, the pathogenesis of fetal infection, the development of animal and human challenge models, and the rapid diagnosis of infection in the fetus and newborn. The likely steps needed to define vaccine efficacy and safety also should be considered as well as the issues of delivering vaccine to adolescents and during pregnancy.
- Vaccine strategies for insulin dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, and other chronic autoimmune diseases likely will be very different than those for vaccines developed against infectious diseases in the 20th century. In addition, those leading their development may have little experience in conducting efficacy trials and with the regulatory process. NVPO and NVAC should consider sponsoring a multidisciplinary scientific workshop on vaccines targeted for prevention and treatment of autoimmune diseases.
- NVAC should consider the global policy issues concerning vaccines against sexually transmitted diseases other than HIV such as Chlamydia trachomatis, Herpes simplex, and Neisseria gonorrhea. Major technical problems exist in the development of vaccines for these sexually transmitted diseases. However, the range of possible approaches is far from exhausted. Marketing concerns also exist and include questions of vaccine use. Who will use these vaccines once developed and will normal individuals be willing to label themselves as high-risk by accepting the vaccines?
- The NVAC should continue to assess the impact of the Report and methodology for assessing disease burden on vaccine development, decisions to initiate programs in industry, and funding of research in academic and government laboratories.