Compans, Richard W.

Glass, Roger I.

Ivanoff, Bernard N.

Lang, Dennis R.

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SlIntroduction: Rotavirus-from Basic Research to a VaccineRoger I. Glass, Dennis R. Lang, Bernard N. Ivanoff,and Richard W. CompansIn 1976, Jon Rohde, highlighting the importance of diarrheaas a prime killer of children in the developing world, beckonedthe scientific community to "take science where the diarrheais!" [1]. While researchers were discovering many new etio-logic agents that cause diarrhea, progress in preventing diar-rheal deaths-then estimated at about 5 million per year-was slow. Twenty years later, despite massive efforts to preventdiarrheal mortality with programs of oral rehydration therapy,diarrhea still ranks as the first or second most common causeof death and disability-adjusted life years lost among childrenin developing countries [2, 3]. An estimated 3-3.2 millionchildren still die each year from diarrhea (23 deaths/1000 livebirths), making diarrheal disease a major contributor to infantmortality in the developing world. The need for simple, effec-tive7 ~nci inexpensive interventions, not only to treat diarrheabut to prevent its occurrence, is urgent and abundantly clear.The discovery of rotavirus by Bishop and colleagues in 1973initiated a line of research that has progressed rapidly towardthe goal of prevention of rotavirus diarrhea by vaccination [4].First was the development of simple, sensitive, and inexpensivediagnostic tests that allowed epidemiologists to search for ro-tavirus in fecal specimens of children with diarrhea [5]. Rotavi-rus proved to be the most common cause of severe diarrhea,responsible for 20%-70% of hospitalizations for diarrheaamong children worldwide [6,7]. Moreover, diarrhea was tradi-tionally considered to be a disease spread by fecally contami-nated food and water or by poor hygiene and, thus, concentratedamong children in the developing countries; however, rotavirusis a "democratic" virus that infects nearly all children in theworld, rich or poor, by the age of 3-5 years. Clearly, improve-ments in food, water, or hygiene would have little impact onthe control of rotavirus infection. Although early studies docu-mented the tremendous disease burden of rotavirus, little couldbe done to prevent disease.The prospect that vaccines might prevent rotavirus in chil-dren was appreciated early. Natural immunity was suggestedby the concentration of disease among children in the first 2years of life and the decreased incidence of disease with in-creasing age [8-11]. Follow-up of infants neonatally infectedwith rotavirus confirmed that subsequent rotavirus infectionsThe Journal of Infectious Diseases 1996; 174(Suppl 1):S1-2© 1996 by The University of Chicago. All rights reserved.0022-1899/96/7481-0001 $0 1.00Viral Gastroenteritis Section, National Center for Infectious Diseases,Centers for Disease Control and Prevention, and Department ofImmunology and Microbiology, Emory University School ofMedicine,Atlanta, Georgia; Division ofMicrobiology and Infectious Diseases,National Institute ofAllergy and Infectious Diseases, National Institutesof Health, Bethesda, Maryland; Vaccine Research and Development,Global Programme on Vaccines, World Health Organization,Geneva, Switzerlandwere associated with less severe diarrhea. The discovery ofmethods to propagate rotavirus provided a simple technique toprepare vaccine seed lots by using traditional methods of tissueculture and allowed work with the virus to proceed in thelaboratory .The first rotavirus vaccine was tested by Vesikari et al. [12]in 1983, and the success of these trials laid the groundworkfor the current strategy for vaccine development. A single oraldose of a live vaccine prepared from a bovine rotavirus waseffective (> 80%) in preventing clinically significant rotavirusdiarrhea in Finnish infants. This led to a flurry of studies toidentify immune proxies for protection, animal models of dis-ease, and ways to increase the efficacy ofvaccines among otherpopulations by using the technique of gene segment reassert-ment. These studies, methods, and results are all well describedin this supplement. The outcome h3S been the successful fieldtesting of several candidate reassortant live rotavirus vaccines.While reassortant rotavirus vaccines are being prepared forlicensure in the United States, many research questions remain.None of these live oral vaccines, like natural immunity itself,is fully protective against rotavirus diarrhea. Hence, the dooris open for the development of an improved vaccine that mightimmunize by a principle different from that of natural infectionwith a live strain of rotavirus. Many approaches, such as theuse ofbaculovirus-expressed virus-like particles or naked DNAvaccines, are discussed in this volume. Even though much hasbeen learned about immunity to rotavirus, current measures ofimmunity are not reliable in predicting protection by vaccines,and better measures are urgently needed. Animal models haveprovided many insights into the pathogenicity and immunemechanisms of rotavirus disease, but their relevance to humandisease is uncertain. While much is known about the gene-coding assignments and structure-function relations of the vi-rus, key principles, such as genes encoding virulence, attenua-tion, or host range, are still being explored [13].Despite these shortcomings in our understanding of manyrotavirus vaccine research issues, progress with live oral "Jen-nerian" reassortant vaccines may soon lead to the first licensedvaccine. Two field trials of the rhesus reassortant vaccine havebeen completed, and a trial with a bovine reassortant candidatevaccine has demonstrated similar efficacy [14- 16]. The consid-erations for licensure by the US Food and Drug Administrationare reviewed in this supplement, as are the many hurdles thatremain to take these vaccines from licensure to widespread usein the United States with the goal of disease reduction.S2 Glass et al. JID 1996;174 (Suppl I)The major presentations of the Fifth International RotavirusVaccine Workshop are being published with the hope thatpediatricians, public health practitioners, and scientists in theUnited States and abroad will be stimulated to consider howthis first vaccine can be used to specifically prevent the diseaseburden of rotavirus diarrhea. Initial efforts to license and intro-duce these vaccines have been targeted at children in the UnitedStates and other industrialized countries where the disease bur-den is measured in terms of doctor visits, hospitalizations, par-ent work time lost, and overall cost [17]. Additional, moredramatic, benefits lie in the prevention of rotavirus deathsamong children in developing countries, where more than 2000deaths occur each day [18]. The ultimate goal of a rotavirusvaccine should be its incorporation into the schedule of routinechildhood immunizations promoted by the World Health Orga-nization's Expanded Programme for Immunization. The wide-spread use of a rotavirus vaccine could go a long way towardachieving the goals of world leaders who declared at the WorldSummit for Children (New York City, 1990) their desire toeffect a "halving of child deaths caused by diarrhea and a one-quarter reduction in the incidence of diarrheal disease by theyear 2000" [2]. Our next target must be the prevention ofrotavirus diarrhea among children in the developing world.ReferencesI. Rohde JE, Northrup RS. Taking science where the diarrhoea is. In: CibaFoundation Symposium. Acute diarrhoea in children. Amsterdam: Else-vier, 1976:339-65.2. World Bank. World Bank development report 1993: investing in health.New York: Oxford University Press, 1993.3. Bern C, Martines J, de Zoysa I, Glass RI. The magnitude of the globalproblem of diarrhoeal disease: a ten year update. Bull World HealthOrgan 1992; 70:705-14.4. Bishop RF, Davidson GP, Holmes IH, Ruck BJ. Virus particles in epithelialcells ofduodenal mucosa from children with viral gastroenteritis. Lancet1973; 1:1281-3.5. Yolken RH, Kim HW, Clem T, et al. Enzyme-linked immunosorbentassay (ELISA) for detection of human reovirus-like agent of infantilegastroenteritis. Lancet 1977; 2:263-7.6. Cook SM, Glass RI, LeBaron CW, Ho MS. Global seasonality of rotavirusinfections. Bull World Health Organ 1990; 68: 171-7.7. Kapikian AZ, Chanock RM. Rotaviruses. In: Fields BN, Knipe DM, How-ley PM, et al., eds. Fields virology. 3rd ed. Vol 2. Philadelphia: Lippin-cott-Raven Press, 1996: 1657-708.8. Bishop RF, Barnes GL, Cipriani E, Lund JS. Clinical immunity afterneonatal rotavirus infection: a prospective longitudinal study in youngchildren. N Engl J Med 1983; 309:72-6.9. Bhan MK, Lew JF, Sazawal S, Das BK, Gentsch JR, Glass RI. Protectionconferred by neonatal rotavirus infection against subsequent diarrhea.J Infect Dis 1993; 168:282-7.10. Velazquez FR, Matson DO, Calva JJ, et al. Natural protection conferredby rotavirus infection: implications for vaccine strategies. N Engl J Med1996 (in press).II. Bernstein DI, Sander DS, Smith VE, Schiff GM, Ward RL. Protectionfrom rotavirus reinfection: 2-year prospective study. J Infect Dis 1991;164:277-83.12. Vesikari T, Isolauri E, D'Hondt E. Protection of infants against rotavirusdiarrhea by RIT 4237 attenuated bovine rotavirus strain vaccine. Lancet1984; 1:977-81.13. Estes M. Rotaviruses and their replication. In: Fields BN, Knipe DM,Howley PM, eds. Fields virology. 3rd ed. Vol 2. Philadelphia: Lippin-cott-Raven Press, 1996: 1625-55.14. Bernstein DI, Glass RI, Rodgers G, Davidson BL, Sack DA. Evaluationof rhesus rotavirus monovalent and tetravalent reassortant vaccines inUS children. JAMA 1995;273:1191-6.15. Clark HF, Offit PA, Ellis RW, et al. The development of multivalentbovine rotavirus (strain WC3) reassortant vaccine for infants. J InfectDis 1996; I74(suppl 1):S73-80.16. Rennels MB, Glass RI, Bernstein DI, Pichichero ME, Dennehy PH. Safetyand efficacy ofhigh dose rhesus human reassortant rotavirus vaccines-report of the national multicenter trial. Pediatrics 1996;97:7-13.17. Smith J, Haddix A, Teutsch S, Glass RI. Cost effectiveness analysis of arotavirus immunization program for the United States. Pediatrics 1995;96:609-15.18. De Zoysa I, Feachem RV. Interventions for the control of diarrhoealdiseases among young children: rotavirus and cholera immunization.Bull WHO 1985;63:569-83.

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