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Single rotavirus infections have been reported to protect humans against subsequent illnesses caused by both homotypic and heterotypic rotaviruses. On the basis of these observations, a G1P[8] strain of human rotavirus named 89-12 was attenuated by multiple passages in cell culture and was developed into a vaccine candidate (herein referred to as the RIX4414 vaccine). This vaccine is currently licensed in >100 countries worldwide, many of which have a universal recommendation for all infants. The US Food and Drug Administration approved the RIX4414 vaccine for use in the United States in April 2008. This vaccine has been found to provide a reduction in the incidence of severe rotavirus disease of >80% in all trials including a developing country. No increased risk of intussusception has been associated with this vaccine, nor has the vaccine been found to interfere with responses to other routine immunizations. This article describes the history of the development of the RIX4414 vaccine.

Several nonliving rotavirus vaccine candidates have been evaluated in animal models. Among them is the VP6 protein that comprises the intermediate layer of the rotavirus particle. This protein was expressed as a chimera with maltose binding protein (MBP::VP6) and was administered intranasally to mice. When later challenged with rotavirus, vaccinated mice were nearly 100% protected from fecal shedding of rotavirus, a result strictly dependent on coadministration of an effective adjuvant. Protection was stimulated by only 1 dose of MBP::VP6, remained fully intact for at least 1 year, was effective in all strains of mice tested, and could also be effectively delivered orally or intrarectally. When VP6 was derived from a human rotavirus, it stimulated protection comparable to that found when derived from the challenge murine EDIM strain. In contrast to live rotavirus vaccines, CD4+ T cells were found to be the only lymphocytes required for protection. If VP6 elicits comparable protection in humans, it would represent a potential second-generation vaccine candidate.

Rotaviruses cause extensive morbidity and mortality worldwide, thus corroborating the need for a vaccine that is effective in all socioeconomic environments. Vaccines evaluated in clinical trials have all been live attenuated rotaviruses that are delivered orally to mimic the excellent protection observed after natural infection. The mechanisms by which these vaccine candidates or wild-type rotaviruses elicit protection are not fully understood. During the 1980s, several candidate vaccines provided little protection, particularly in developing countries, and were discontinued. Two, however, are in the process of being licensed worldwide, and several others are undergoing clinical trials. Development of live rotavirus vaccines has been highly influenced by views regarding the importance of serotype-specific neutralizing antibody. Development of several candidate vaccines is based on the concept that neutralizing antibody is the primary determinant of protection. These candidates, including 1 of the 2 being licensed worldwide (RotaTeq), are composed of multiple rotavirus strains representative of the major human rotavirus serotypes. The other group of candidates has been developed based on the theory that protection is not solely dependent on neutralizing antibody. These candidates are composed of single rotavirus strains and include the other vaccine being licensed worldwide (Rotarix). Studies that provide the basis for each approach will be presented and discussed.

The G1P1A[8] rotavirus vaccine candidate 89‐12, the precursor to Rotarix, stimulated high titers of neutralizing antibodies to non‐G1/P1A[8] serotypes of human rotavirus in naturally infected subjects before attenuation by cell‐culture passages. These responses were greatly diminished in young infants (median age, 11 weeks) administered the attenuated vaccine. Because of the possibility of improved responses in older infants, the immunogenicity of the 89‐12 vaccine candidate was evaluated after administration of 2 doses beginning at either 4 or 6 months of age. As was found in young infants, neutralizing antibody responses to non‐G1/P1A[8] rotaviruses were considerably lower than those observed after natural infection. The reasons identified were overall (P<.0001) lower neutralizing antibody responses stimulated by the attenuated 89‐12 strain, compared with those stimulated by its virulent precursor, and 5 mutations selected in the gene encoding the immunodominant VP4 (P) neutralization protein. Even so, the Rotarix vaccine developed from attenuated 89‐12 was found to elicit excellent protection against non‐G1 rotaviruses.

The need for a rotavirus vaccine in India is based on the enormous burden associated with the >100,000 deaths due to rotavirus diarrhea that occur annually among Indian children. Two rotavirus strains identified during nosocomial outbreaks of rotavirus infection in New Delhi and Bangalore, India, more than a decade ago are being developed as live oral vaccines. Infected newborns had no symptoms, shed virus for up to 2 weeks after infection, mounted a robust immune response, and demonstrated protection against severe rotavirus diarrhea after reinfection. The 2 strains are naturally occurring bovine-human reassortants. The New Delhi strain, 116E, is characterized as having a P[11],G9 genotype, and the Bangalore strain, I321, is characterized as having a P[11],G10 genotype. The strains have been prepared as pilot lots for clinical trials to be conducted in New Delhi. This unique project, which is developing a new rotavirus vaccine in India with the use of Indian strains, an Indian manufacturer, and an Indian clinical development program, aims to expedite introduction of rotavirus vaccines in India.

Rotavirus vaccine development is a high priority. The association between the tetravalent rhesus-human reassortant rotavirus vaccine and intussusception has increased the need to develop new vaccines. In a small efficacy trial, the human rotavirus vaccine 89-12 recently has been shown to be safe and effective; 184 of the 215 healthy infants initially enrolled in this trial were followed for a second year. Vaccine efficacy during the second year was 59% (P=.047). For the 2 years of observation, vaccine efficacy was 76% against rotavirus gastroenteritis, 83% against severe rotavirus gastroenteritis, and 100% against rotavirus illnesses requiring medical intervention (P<.001 for each). These encouraging results have led to continued evaluation, in several countries, of a vaccine candidate derived from strain 89-12

Type I and type II interferons (IFNs) play a critical role in control of a number of viral infections. To study whether altered and reduced functional capacities of type I and type II IFNs would affect rotavirus-induced diarrhea and viral replication, we obtained signal transducers and activators of transcription 1 (Stat1) knock-out mice (Stat1-/-) that lack many IFN-induced responses. We found that suckling Stat1-/- and immunocompetent mice orally infected with rotavirus experienced diarrhea and shed rotavirus with similar intensity. However, adult Stat1-/- mice shed up to 100-fold more homologous murine rotavirus and heterologous rhesus rotavirus antigen in their stools than did immunocompetent mice 2-6 days after infection. Clearance of rotavirus in stools from adult Stat1-/- mice occurred at the same time as in wild-type (WT) control mice. Clearance in Stat1-/- mice correlated with a potent antibody response and a mixed Th1 and Th2 response, whereas in WT control mice, clearance correlated with a weaker antibody response and a polarized Th1 response. Stat1-/- mice were fully protected against subsequent challenge. Moreover, vaccination of adult Stat1-/- mice with a rotavirus VP6 protein and the mucosal adjuvant Escherichia coli heat-labile toxin LT (R192G) elicited 94% protection, as measured by the total reduction in viral shedding for the group in comparison to unimmunized controls. Thus, modulating IFN function through the loss of Stat1 caused a defective innate immune response in adult mice but had no effect on rotavirus-induced diarrhea and replication in suckling mice. Furthermore, adult Stat1-/-, IFN-γ, and IFN-α/β receptor-/- (IFNAR-2-/-) mice infected with rotavirus or vaccinated with VP6 vaccine and adjuvant were fully protected against rotavirus shedding following a subsequent challenge with rotavirus.

A quadrivalent precursor to the pentavalent rotavirus vaccine candidate RotaTeq was evaluated in a 3-dose, 439-subject study. To determine immunogenicity, the quantity of rotavirus immunoglobulin A (IgA) in stool specimens obtained, at 1 of 10 study sites, from 37 placebo and 37 vaccine recipients was measured. None of the placebo recipients showed a clinically important (⩾3-fold) increase in stool rotavirus IgA, whereas 31 vaccine recipients showed an increase after at least 1 dose of vaccine. In total, 16, 19, and 15 vaccine recipients had increases after 1, 2, and 3 doses, respectively, indicating that a 3-dose regimen increased the immune response elicited by this vaccine.

A \"Meeting on Upstream Rotavirus Vaccines and Emerging Vaccine Producers\" was held at the World Health Organization in Geneva, Switzerland on March 28-30, 2006. The purpose was to discuss, evaluate, and weigh the importance of additional rotavirus vaccine candidates following the successful international licensure of rotavirus vaccines by two major pharmaceutical companies (GlaxoSmithKline and Merck) that had been in development for many years. Both licensed vaccines are composed of live rotaviruses that are delivered orally as have been all candidate rotavirus vaccines evaluated in humans. Each is built on the experience gained with previous candidates whose development had either been discontinued or, in the case of the previously licensed rhesus rotavirus reassortant vaccine (Rotashield), was withdrawn by its manufacturer after the discovery of a rare association with intussusception. Although which alternative candidate vaccines should be supported for development and where this should be done are controversial topics, there was general agreement expressed at the Geneva meeting that further development of alternative candidates is a high priority. This development will help insure that the most safe, effective and economic vaccines are available to children in Third World nations where the vast majority of the >600,000 deaths due to rotavirus occur each year. This review is intended to provide the history and present status of rotavirus vaccines as well as a perspective on the future development of candidate vaccines as a means of promulgating plans suggested at the Geneva meeting.

The etiology and pathogenesis of bile duct obstruction in children with biliary atresia are largely unknown. We have previously reported that, despite phenotypic heterogeneity, genomic signatures of livers from patients display a proinflammatory phenotype. Here, we address the hypothesis that production of IFN-gamma is a key pathogenic mechanism of disease using a mouse model of rotavirus-induced biliary atresia. We found that rotavirus infection of neonatal mice has a unique tropism to bile duct cells, and it triggers a hepatobiliary inflammation by IFN-gamma-producing CD4(+) and CD8(+) lymphocytes. The inflammation is tissue specific, resulting in progressive jaundice, growth failure, and greater than 90% mortality due to obstruction of extrahepatic bile ducts. In this model, the genetic loss of IFN-gamma did not alter the onset of jaundice, but it remarkably suppressed the tissue-specific targeting of T lymphocytes and completely prevented the inflammatory and fibrosing obstruction of extrahepatic bile ducts. As a consequence, jaundice resolved, and long-term survival improved to greater than 80%. Notably, administration of recombinant IFN-gamma led to recurrence of bile duct obstruction following rotavirus infection of IFN-gamma-deficient mice. Thus, IFN-gamma-driven obstruction of bile ducts is a key pathogenic mechanism of disease and may constitute a therapeutic target to block disease progression in patients with biliary atresia.