Gastroenterology

Gastroenterology

Volume 136, Issue 6, May 2009, Pages 1939-1951
Gastroenterology

Rotaviruses: From Pathogenesis to Vaccination

https://doi.org/10.1053/j.gastro.2009.02.076Get rights and content

Rotaviruses cause life-threatening gastroenteritis in children worldwide; the enormous disease burden has focused efforts to develop vaccines and led to the discovery of novel mechanisms of gastrointestinal virus pathogenesis and host responses to infection. Two live-attenuated vaccines for gastroenteritis (Rotateq [Merck] and Rotarix) have been licensed in many countries. This review summarizes the latest data on these vaccines, their effectiveness, and challenges to global vaccination. Recent insights into rotavirus pathogenesis also are discussed, including information on extraintestinal infection, viral antagonists of the interferon response, and the first described viral enterotoxin. Rotavirus-induced diarrhea now is considered to be a disease that can be prevented through vaccination, although there are many challenges to achieving global effectiveness. Molecular biology studies of rotavirus replication and pathogenesis have identified unique viral targets that might be useful in developing therapies for immunocompromised children with chronic infections.

Section snippets

Virology

Rotaviruses are members of the Rotavirus genus of the Reoviridae family, which contains viruses with segmented, double-stranded RNA genomes. Rotavirus particles are large (1000 Å) and complex, with 3 concentric protein layers that surround the viral genome of 11 segments of double-stranded RNA (Figure 1).1 The rotavirus genome segments encode 6 structural proteins that make up virus particles (viral proteins [VPs]) and 6 nonstructural proteins (NSPs). The NSPs are synthesized in infected cells

Epidemiology and Transmission

Human rotaviruses were discovered 36 years ago—a decade after the first animal rotaviruses were visualized.12, 13, 14 Because large amounts of human rotaviruses are shed in the stool, the development of specific and sensitive solid-phase immunoassay systems for detection was straightforward; within 10 years of discovery, it was clear that rotaviruses were ubiquitous and associated with approximately 20%–30% of severe diarrheal diseases that required hospitalization in children younger than the

Intestinal Infection

Rotavirus infection can result in asymptomatic or symptomatic infection. The outcome of infection is affected by both viral and host factors. The most prominent host factor that affects the clinical outcome of infection is age. Thus, neonates infected with rotavirus rarely have symptomatic disease; this protection is thought to be mediated primarily by transplacental transfer of maternal antibodies.39 Reductions in these antibodies coincide with the age of maximum susceptibility of infants to

Immunity

Studies of natural rotavirus infection in human beings and animals were the first to show the existence of acquired immunity both to recurrent disease, and, to a lesser extent, re-infection after primary infection.47 These observations were followed by a large number of experimental studies in a variety of small- and large-animal models, all of which showed the presence of acquired immunity. Each of the animal models has advantages and disadvantages. The 2 most widely studied models are the

Vaccines

Attempts to develop a vaccine against human rotavirus began in the early 1980s. Initial efforts used a Jennerian approach (in reference to Edward Jenner's cowpox vaccine against smallpox) to vaccinate children against rotaviruses, which normally infect animals. It has been observed that injection of an attenuated bovine rotavirus strain protected gnotobiotic calves against subsequent challenge with human rotavirus.66, 67, 68, 69 Several important findings emerged from the first vaccine studies.

Conclusions

Rotavirus diarrhea is considered to be a vaccine-preventable disease based on recent successful outcomes in children in developed countries. Almost 50 years of basic and clinical research on rotavirus have culminated in this breakthrough and also have led to new knowledge about these fascinating pathogens and how they interact with the GI tract. Despite this impressive progress, much remains to be learned about rotavirus infection. We still do not know the mechanism by which current vaccines

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    Note from Editors Rustgi and Hecht: Mary K. Estes, PhD, is a Professor of Molecular Virology and Microbiology and of Medicine-Gastroenterology at Baylor College of Medicine. She obtained her PhD from the University of North Carolina, and joined the faculty at Baylor in 1975. She also is the founding Director of the Texas Gulf Coast Digestive Diseases Center and has held a variety of leadership positions including Chair of the Medical Sciences section of the American Association for the Advancement of Science (AAAS) (2003), President of the American Society for Virology (1996–1997), Editor of Journal of Virology, Member of FDA Vaccines and Related Biological Products Advisory Committee and Chair of the Vertebrate Virus Subcommittee of the International Committee on Virus Taxonomy. Dr. Estes has served on local, state, national and global committees devoted to research development including the National Institutes of Health's Virology Study Section, The Research Advisory Committee to the Texas State Coordinating Board, the United Nations Development Programme for Vaccine Development, the Diarrheal Diseases Vaccine Steering Committee of the World Health Organization, and the US–Japan Cooperative Medical Sciences Program. She is an elected Fellow of the American Academy of Microbiology and the AAAS and a member of the Institute of Medicine, the National Academy of Science and the Academy of Medicine, Engineering and Science of Texas. Her laboratory uses viruses that infect distinct cells in the gastrointestinal tract to learn about the biology of these cells. She studies 2 viruses: rotaviruses, the major cause of diarrhea in children and animals worldwide, and noroviruses, a prototype virus responsible for almost all (>96%) outbreaks of nonbacterial gastroenteritis and important causes of disease in infants and young children. Her laboratory focuses on evaluating viral and host factors that affect pathogenesis, and how to induce a mucosal immune response and protection from virus infection by preclinical and volunteer studies using recombinant virus-like particle vaccines for both viruses.

    Conflicts of interest The authors disclose no conflicts.

    Funding This work was supported in part by Public Health Service grants RO1 AI 021362 (H.B.G.), P30 DK 56339 (H.B.G.), RO1 DK 30144 (M.K.E.), and P30 DK56338 (M.K.E.) from the National Institutes of Health, and a VA Merit Review Research Award (H.B.G.).

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