Introduction: rotavirus--from basic research to a vaccine.

In 1976, Jon Rohde, highlighting the importance of diarrhea as a prime killer of children in the developing world, beckoned the scientific community to "take science where the diarrhea is!" [1]. While researchers were discovering many new etiologic agents that cause diarrhea, progress in preventing diarrheal deaths-then estimated at about 5 million per yearwas slow. Twenty years later, despite massive efforts to prevent diarrheal mortality with programs of oral rehydration therapy, diarrhea still ranks as the first or second most common cause of death and disability-adjusted life years lost among children in developing countries [2, 3]. An estimated 3-3.2 million children still die each year from diarrhea (23 deaths/1000 live births), making diarrheal disease a major contributor to infant mortality in the developing world. The need for simple, effective7 ~nci inexpensive interventions, not only to treat diarrhea but to prevent its occurrence, is urgent and abundantly clear. The discovery of rotavirus by Bishop and colleagues in 1973 initiated a line of research that has progressed rapidly toward the goal of prevention of rotavirus diarrhea by vaccination [4]. First was the development of simple, sensitive, and inexpensive diagnostic tests that allowed epidemiologists to search for rotavirus in fecal specimens of children with diarrhea [5]. Rotavirus proved to be the most common cause of severe diarrhea, responsible for 20%-70% of hospitalizations for diarrhea among children worldwide [6,7]. Moreover, diarrhea was traditionally considered to be a disease spread by fecally contaminated food and water or by poor hygiene and, thus, concentrated among children in the developing countries; however, rotavirus is a "democratic" virus that infects nearly all children in the world, rich or poor, by the age of 3-5 years. Clearly, improvements in food, water, or hygiene would have little impact on the control of rotavirus infection. Although early studies documented the tremendous disease burden of rotavirus, little could be done to prevent disease. The prospect that vaccines might prevent rotavirus in children was appreciated early. Natural immunity was suggested by the concentration of disease among children in the first 2 years of life and the decreased incidence of disease with increasing age [8-11]. Follow-up of infants neonatally infected with rotavirus confirmed that subsequent rotavirus infections