SynopsisTetravalent human- rhesus reassortant rotavirus vaccine (RRV- TV) contains the rhesus rotavirus (RRV) strain MMU 18006, which has serotype G3 specificity, and reassortant rotavirus strains with human serotype G1, G2 and G4 specificity. Rotavirus gastroenteritis in humans is predominantly caused by these 4 serotypes.RRV- TV 4 × 104, 4 × 105 or 4 × 106 plaque- forming units (PFU) per dose induces seroresponse rates (generally defined as a ≥ 4- fold increase in antibody titre) of 48 to 93% for IgA against RRV and 49 to 90% for neutralising antibodies to RRV after 1 to 3 doses in infants aged ≥ 4 weeks. Seroresponse rates for neutralising antibodies to human serotypes G1, G2, G3 and G4 are generally lower (2 to 68%). The rates generally increase with sequential doses, but not necessarily with increased vaccine titre. Seroresponse rates appear to be better in older infants than in neonates or infants aged ≤ 12 weeks.RRV- TV is more immunogenic against human G2, G3 and G4 serotypes than the monovalent serotype G1 human- rhesus reassortant rotavirus vaccine (RRV- S1) and tends to be more immunogenic against G1, G2 and G3 serotypes than the human serotype G1 strain vaccine M37.In most settings, RRV- TV has at least moderate efficacy in reducing the incidence of rotavirus gastroenteritis. Importantly, it protects against severe disease, with efficacy rates of 69 to 100% against very severe rotavirus gastroenteritis in large scale studies in the US, Finland and Venezuela. RRV- TV has similar overall efficacy to RRV- S1, but provides greater protection against gastroenteritis caused by rotavirus strains of serotypes other than G1. The efficacy of RRV- TV is not significantly affected by breast feeding or concurrent use of oral poliovirus vaccine.The only adverse effect with which RRV- TV has been associated is a mild, transient febrile reaction.Limited data from the US and Finland suggest that vaccination with RRV- TV could be cost saving.In conclusion, the incidence of paediatric rotavirus gastroenteritis, particularly severe cases, would be reduced in most settings by the incorporation of RRV- TV into routine childhood immunisation schedules. Further refinements to RRV- TV (and/or development of additional candidate vaccines) may eventually produce even greater protective efficacy. In the meantime, RRV- TV is a significant advance in the prevention of paediatric rotavirus gastroenteritis worldwide.Overview of Rotavirus InfectionRotavirus is a double-stranded RNA virus. Human rotavirus gastroenteritis is most commonly caused by group A rotaviruses. Worldwide, the most prevalent glycoprotein antigen-determined (G) serotypes are G1, G2, G3 and G4.The virus is highly infectious, with transmission occurring primarily via the faecal-oral route. Infection is largely limited to the small intestine. Almost all children are infected with rotavirus by the age of 3 to 5 years, and it is the most common causal agent of severe life-threatening diarrhoea in children and infants worldwide. Dehydration and electrolyte imbalance associated with rotavirus gastroenteritis cause significant mortality in developing countries (more than 800 000 children die each year) and the disease is responsible for a large number of hospitalisations in developed countries. Symptomatic illness occurs most commonly in infants aged ≈3 months to 2 years.ImmunogenicityTetravalent human-rhesus reassortant rotavirus vaccine (RRV-TV) is composed of the rhesus rotavirus (RRV) strain MMU 18006, which shares neutralisation specificity with human rotavirus serotype G3, and 3 reassortant strains with human serotype G1, G2 or G4 specificity.In immunogenicity trials in healthy infants aged ≥4 weeks, the seroresponse rate (generally defined as a ≥4-fold increase in antibody titre) for IgA against RRV was 48 to 93% (median 74%) after 1 to 3 doses of RRV-TV 4 × 104, 4 × 105 or 4 × 10 plaque-forming units (PFU) per dose. The seroresponse rate was significantly higher than after placebo (0 to 33%; median 11%). For neutralising antibody assays, the greatest seroresponse rates in RRV-TV recipients were to RRV (49 to 90%), whereas those to human serotypes Gl, G2, G3 and G4 were lower (2 to 68%). Seroresponse rates to RRV-TV were generally higher after 3 doses than after 1 dose. However, increasing the titre of vaccine dose (rather than the number of doses) was not consistently shown to increase seroresponse rates. RRV-TV 4×10 or 4×105 PFU was only moderately immunogenic in neonates, and the seroresponse rate was significantly greater in infants aged 16 to 24 weeks than in those aged 6 to 12 weeks in one study in which infants received a single dose of RRV-TV 4 × 105 or 4 × 106 PFU.Breast feeding did not significantly reduce the immunogenicity of the vaccine in infants aged ≥4 weeks. RRV-TV does not significantly interfere with the immunogenicity of oral poliovirus vaccine (OPV), although a slight reduction in the response to poliovirus serotype 1 has been reported. The IgA seroresponse to RRV is reduced by concurrent use of OPV but the effect does not appear to be clinically significant when 3 doses of RRV-TV are given. Administration of a buffer to prevent inactivation of the acid-labile vaccine is required for the immunogenicity of RRV-TV to be optimal.RRV-TV (3 doses of 4 × 104 or 4 × 105 PFU/dose) induced similar seroresponse rates for IgA against RRV to those induced by monovalent serotype Gl human-rhesus reassortant rotavirus vaccine (RRV-S1; 3 doses of 4 × 104 or 4 × 10 PFU/dose). However, RRV-TV generally had greater immunogenicity than RRV-S1 against serotype G2, G3 and G4 human rotavirus strains, whereas RRV-S1 had greater immunogenicity against serotype G1. Compared with the human serotype Gl strain vaccine M37 (1 dose of 1 × 104 PFU/dose or 2 doses of 1 × 105 PFU/dose), RRV-TV (1 or 2 doses of 4 × 104 or 4 × 105 PFU/dose) tended to induce higher seroresponse rates for IgA against RRV and for neutralising antibodies to human serotypes G1, G2 and G3.Protective EfficacyData on the efficacy of RRV-TV in preventing paediatric rotavirus gastroenteritis are available from 7 trials involving 8720 infants aged 1 to 6 months from 5 countries. A 3-dose schedule of RRV-TV 4 × 104 PFU/dose in the US and 4 × 105 PFU/dose in the US, Finland and Venezuela reduced the incidence of rotavirus gastroenteritis by 48 to 68% compared with placebo. However, when used at the lower dosage (4 × 10 PFU/dose) the vaccine had a relative efficacy of only 35% in Brazil, and was not significantly protective in Peru. Efficacy was most evident in the first year after vaccination in all studies in which this was analysed.The vaccine has greater efficacy against more severe disease. In large US, Finnish and Venezuelan studies, the relative efficacy rate of RRV-TV compared with placebo was 69 to 100% for the most severe rotavirus gastroenteritis. Vaccination provided 100% protection against rotavirus gastroenteritis-associated hospitalisation in Finland, and 70% protection in Venezuela. RRV-TV was associated with a reduction in health service use. Some studies showed a marked reduction in dehydrating rotavirus illness. The efficacy of RRV-TV was not significantly reduced by breast feeding or concurrent administration of OPV.RRV-TV had similar overall efficacy to RRV-S1. However, RRV-TV was more effective than RRV-S 1 against rotavirus gastroenteritis caused by serotypes other than G1.Pharmacoeconomic ConsiderationsDepending on the cost of the vaccine and its administration, the introduction of RRV-TV into routine childhood immunisation schedules could be cost saving, according to US and Finnish data. One US cost-effectiveness analysis calculated that the introduction of RRV-TV at $US30 (1993 US dollars) per dose would produce an annual saving of $US79 million ($US78 per case prevented) for the healthcare system and a saving of $US466 million ($US459 per case prevented) for society. Another analysis calculated that RRV-TV reduces the median expected societal cost of rotavirus gastroenteritis by $US11 (1992 US dollars) per infant, and would thus be cost saving provided that the vaccine cost less than this amount. A similar Finnish analysis calculated that RRV-TV reduces costs associated with rotavirus gastroenteritis by 109 Finnish marks (currency year not stated) per infant.TolerabilityRRV-TV is generally well tolerated at doses of 4 × 10, 4 × 105 or 4 × 106 PFU/dose, but causes a higher incidence of fever (rectal or axillary temperature >38°C) than placebo. The febrile reaction is normally mild (≤39°C) and transient, occurring 3 to 5 days after vaccination and lasting 1 to 2 days. The incidence of fever is not dose related. However, it appears to occur more commonly after the first dose than after subsequent doses, and in older (age 16 to 24 weeks) rather than younger (age 6 to 12 weeks) infants. RRV-TV tended to be associated with a higher incidence of fever than RRV-S 1 or M37.Dosage and AdministrationClinical trial data suggest that ideally a 3-dose schedule of RRV-TV 4 × 105 PFU/dose should be administered to infants between 2 and 7 months of age. RRV-TV can be administered concurrently with other injectable vaccines, but confirmation that there is no clinically significant interference between RRV-TV and OPV is required. Buffering is required to prevent inactivation of the vaccine.