Designing tomorrow's vaccines.

Copyright © 2013 Massachusetts Medical Society. Vaccines are among the most effective interventions in modern medicine. Ever since Edward Jenner’s first use of a vaccine against smallpox in 1796 (see text box), the use of vaccines has become indispensable to the eradication of disease. In the 20th century alone, smallpox claimed an estimated 375 million lives, but since 1978, after the completion of a successful eradication campaign, not a single person has died from smallpox. Today, more than 70 vaccines have been licensed for use against approximately 30 microbes, sparing countless lives (Fig. 1A and 1B).1,2 Diseases including poliomyelitis, measles, mumps, rubella, and others caused an estimated 39 million infections in the 20th century in the United States, but vaccines have since rendered them uncommon (Table 1).3,4 The success of this public health intervention emanates not only from the identification of effective vaccines but also from a robust infrastructure for vaccine manufacturing, regulatory and safety oversight, and organized approaches to delivery. Vaccines represent the least expensive and most facile way to protect against devastating epidemics. Society derives economic benefits by preventing hospitalization, avoiding long-term disability, and reducing absence from work. In brief, vaccines provide the most cost-effective means to save lives, preserve good health, and maintain a high quality of life. Despite this legacy, infectious diseases still extract an extraordinary toll on humans. Vaccines have yet to realize their full potential for several reasons. First, effective vaccines are often not available in developing countries. The Global Alliance for Vaccines and Immunization (GAVI) estimates that every year more than 1.5 million children (3 per minute) die from vaccine-preventable diseases. Second, effective vaccines have not yet been developed for diseases such as human immunodeficiency virus (HIV) infection, tuberculosis, and malaria, which claim the lives of more than 4 million people worldwide each year.5-7 For nearly all successful licensed vaccines, natural immunity to infection has been shown, and the vaccine mimics the protective immune response. In contrast, for HIV infection, tuberculosis, and malaria, it has been difficult to show preventive immunity. Protection against these pathogens requires a distinct approach to vaccine design, based on an understanding of immunopathogenesis and reliance on animal models. In these cases, the challenge is greater, the development path longer, and the outcome less certain. Finally, many vaccine technologies are old and ill-suited for a rapid response to emerging outbreaks. For example, influenza vaccines rely largely on 50-year-old technology. Current seasonal influenza vaccines are not always well “I have received a copy of the evidence at large respecting the discovery of the vaccine inoculation which you have been pleased to send me, and for which I return you my thanks . . . . I avail myself of this occasion of rendering you a portion of the tribute of gratitude due to you from the whole human family. Medicine has never before produced any single improvement of such utility. Harvey’s discovery of the circulation of the blood was a beautiful addition to our knowledge of the animal economy, but on a review of the practice of medicine before and since that epoch, I do not see any great amelioration which has been derived from that discovery. You have erased from the calendar of human afflictions one of its greatest. Yours is the comfortable reflection that mankind can never forget that you have lived. Future nations will know by history only that the loathsome small-pox has existed and by you has been extirpated.” Letter to Dr. Edward Jenner from Thomas Jefferson, Monticello (May 14, 1805) Interactive graphics showing a vaccine timeline and the molecular structure of pathogens are available at NEJM.org