Established and new rotavirus vaccines: a comprehensive review for healthcare professionals.

Robust scientific evidence related to two rotavirus (RV) vaccines available worldwide demonstrates their significant impact on RV disease burden. Improving RV vaccination coverage may result in better RV disease control. To make RV vaccination accessible to all eligible children worldwide and improve vaccine effectiveness in high-mortality settings, research into new RV vaccines continues. Although current and in-development RV vaccines differ in vaccine design, their common goal is the reduction of RV disease risk in children <5 years old for whom disease burden is the most significant. Given the range of RV vaccines available, informed decision-making is essential regarding the choice of vaccine for immunization. This review aims to describe the landscape of current and new RV vaccines, providing context for the assessment of their similarities and differences. As data for new vaccines are limited, future investigations will be required to evaluate their performance/added value in a real-world setting.

PLAIN LANGUAGE SUMMARYThe diseaseRotaviruses are a leading cause of acute diarrhea, also called gastroenterities, among young children. They can lead to servere dehydration, hospitilization, and even death.Several vaccines against rotavirus disease have been developed. Their design is based on:weakened human rotavirus that mimic natural infection without causing disease, such as Rotarix, Rotavin-M1, Rotavac and RV3-BB (not yet marketed)non-infective animal viruses such as RotaTeq, Rotasiil or LLR.new concepts, such as inactivated vaccinesWhat is new?We reviewed the current, recently launched and soon-to-be-launched rotavirus vaccines and found that:Rotarix and RotaTeq have been used globally for more than a decade with demonstrated impact and favourable safety profileLimited data on the impact and safety profile are available to date for:Rotavin-M1 and LLR vaccines, locally marketed in Vietnam and China, respectivelyRotavac and Rotasiil, licensed in indiaNew vaccine concepts have been mainly investigated animal models with encouraging resultsWhat is the impact?Despite their different designs, the current rotavirus vaccines demonstrate effectiveness in protecting against rotairus gastroenterits.Data for most recent vacciness are currently limited, for which additional data are needed to demonstrate how they will perform on a larger scale, their added value in a real setting and ther safety profile.

Incidence of rotavirus gastroenteritis by age in African, Asian and European children: Relevance for timing of rotavirus vaccination.

Variability in rotavirus gastroenteritis (RVGE) epidemiology can influence the optimal vaccination schedule. We evaluated regional trends in the age of RVGE episodes in low- to middle- versus high-income countries in three continents. We undertook a post-hoc analysis based on efficacy trials of a human rotavirus vaccine (HRV; Rotarix™, GSK Vaccines), in which 1348, 1641, and 5250 healthy infants received a placebo in Europe (NCT00140686), Africa (NCT00241644), and Asia (NCT00197210, NCT00329745). Incidence of any/severe RVGE by age at onset was evaluated by active surveillance over the first two years of life. Severity of RVGE episodes was assessed using the Vesikari-scale. The incidence of any RVGE in Africa was higher than in Europe during the first year of life (≤2.78% vs. ≤2.03% per month), but much lower during the second one (≤0.86% versus ≤2.00% per month). The incidence of severe RVGE in Africa was slightly lower than in Europe during the first year of life. Nevertheless, temporal profiles for the incidence of severe RVGE in Africa and Europe during the first (≤1.00% and ≤1.23% per month) and second (≤0.53% and ≤1.13% per month) years of life were similar to those of any RVGE. Any/severe RVGE incidences peaked at younger ages in Africa vs. Europe. In high-income Asian regions, severe RVGE incidence (≤0.31% per month) remained low during the study. The burden of any RVGE was higher earlier in life in children from low- to middle- compared with high-income countries. Differing rotavirus vaccine schedules are likely warranted to maximize protection in different settings.

Early exposure of infants to natural rotavirus infection: a review of studies with human rotavirus vaccine RIX4414.

BACKGROUND: Rotaviruses are the leading cause of severe acute gastroenteritis in children aged <5 years worldwide. A live attenuated human rotavirus vaccine, RIX4414 has been developed to reduce the global disease burden associated with rotavirus gastroenteritis. Serum anti-rotavirus immunoglobulin A (IgA) antibody measured in unvaccinated infants during clinical trials of RIX4414 reflects natural rotavirus exposure, and may inform the optimal timing for rotavirus vaccination. METHODS: We reviewed phase II and III randomized, placebo-controlled clinical trials conducted by GlaxoSmithKline Vaccines, Wavre, Belgium between 2000 and 2008 which used the commercial formulation of RIX4414 lyophilized vaccine. We included trials for which demographic data and pre-dose-1 and post-last-dose anti-rotavirus IgA antibody status were available from placebo recipients. RESULTS: Sixteen clinical trials met the inclusion criteria. The studies were conducted across Africa (N = 3), Asia (N = 4), Latin America (N = 4), Europe (N = 4) and North America (N = 1). Overall, 46,398 infants were enrolled and among these, 20,099 received placebo. The mean age at pre-dose-1 time point ranged from 6.4 - 12.2 weeks while the mean age at post-last-dose time point ranged from 13.5 - 19.6 weeks. The anti-RV IgA seropositivity rates at both time points were higher in less developed countries of Africa, Asia and Latin America (pre-dose-1: 2.1%-26.3%; post-last-dose: 6.3%-34.8%) when compared to more developed countries of Asia, Europe and North America (pre-dose-1: 0%-9.4%; post-last-dose: 0%-21.3%), indicating that rotavirus infections occurred at a younger age in these regions. CONCLUSION: Exposure to rotavirus infection occurred early in life among infants in most geographical settings, especially in developing countries. These data emphasize the importance of timely rotavirus vaccination within the Expanded Program on Immunization schedule to maximize protection.

Investigation of a regulatory agency enquiry into potential porcine circovirus type 1 contamination of the human rotavirus vaccine, Rotarix: approach and outcome.

In January 2010, porcine circovirus type 1 (PCV1) DNA was unexpectedly detected in the oral live-attenuated human rotavirus vaccine, Rotarix (GlaxoSmithKline [GSK] Vaccines) by an academic research team investigating a novel, highly sensitive analysis not routinely used for adventitious agent screening. GSK rapidly initiated an investigation to confirm the source, nature and amount of PCV1 in the vaccine manufacturing process and to assess potential clinical implications of this finding. The investigation also considered the manufacturer's inactivated poliovirus (IPV)-containing vaccines, since poliovirus vaccine strains are propagated using the same cell line as the rotavirus vaccine strain. Results confirmed the presence of PCV1 DNA and low levels of PCV1 viral particles at all stages of the Rotarix manufacturing process. PCV type 2 DNA was not detected at any stage. When tested in human cell lines, productive PCV1 infection was not observed. There was no immunological or clinical evidence of PCV1 infection in infants who had received Rotarix in clinical trials. PCV1 DNA was not detected in the IPV-containing vaccine manufacturing process beyond the purification stage. Retrospective testing confirmed the presence of PCV1 DNA in Rotarix since the initial stages of its development and in vaccine lots used in clinical studies conducted pre- and post-licensure. The acceptable safety profile observed in clinical trials of Rotarix therefore reflects exposure to PCV1 DNA. The investigation into the presence of PCV1 in Rotarix could serve as a model for risk assessment in the event of new technologies identifying adventitious agents in the manufacturing of other vaccines and biological products.

Impact of rotavirus vaccination on hospitalisations in Belgium: comparing model predictions with observed data.

BACKGROUND: Published economic assessments of rotavirus vaccination typically use modelling, mainly static Markov cohort models with birth cohorts followed up to the age of 5 years. Rotavirus vaccination has now been available for several years in some countries, and data have been collected to evaluate the real-world impact of vaccination on rotavirus hospitalisations. This study compared the economic impact of vaccination between model estimates and observed data on disease-specific hospitalisation reductions in a country for which both modelled and observed datasets exist (Belgium). METHODS: A previously published Markov cohort model estimated the impact of rotavirus vaccination on the number of rotavirus hospitalisations in children aged <5 years in Belgium using vaccine efficacy data from clinical development trials. Data on the number of rotavirus-positive gastroenteritis hospitalisations in children aged <5 years between 1 June 2004 and 31 May 2006 (pre-vaccination study period) or 1 June 2007 to 31 May 2010 (post-vaccination study period) were analysed from nine hospitals in Belgium and compared with the modelled estimates. RESULTS: The model predicted a smaller decrease in hospitalisations over time, mainly explained by two factors. First, the observed data indicated indirect vaccine protection in children too old or too young for vaccination. This herd effect is difficult to capture in static Markov cohort models and therefore was not included in the model. Second, the model included a 'waning' effect, i.e. reduced vaccine effectiveness over time. The observed data suggested this waning effect did not occur during that period, and so the model systematically underestimated vaccine effectiveness during the first 4 years after vaccine implementation. CONCLUSIONS: Model predictions underestimated the direct medical economic value of rotavirus vaccination during the first 4 years of vaccination by approximately 10% when assessing hospitalisation rates as compared with observed data in Belgium.

Rotarix in developing countries: paving the way for inclusion in national childhood immunization programs in Africa.

Rotavirus gastroenteritis causes more than half a million deaths annually among children aged <5 years, the great majority of which occur in Africa and Asia. Vaccination is considered to be the most effective public health strategy to prevent rotavirus disease and to reduce the significant global burden of rotavirus gastroenteritis. Rotarix (GlaxoSmithKline Biologicals) is an oral, live attenuated rotavirus vaccine derived from a human G1P[8] rotavirus strain. Results of phase III studies in Europe, Latin America, and Asia have shown that Rotarix offers sustained high protection against severe rotavirus gastroenteritis during the first 2 years of life, when disease burden is highest, with broad protection demonstrated against each of the 5 main rotavirus types that circulate globally (G1, G2, G3, G4, and G9). Coupled with the availability of local burden of disease data and promising interim efficacy data from an ongoing study in Malawi and South Africa, this further reinforces the case for introduction of this rotavirus vaccine in national childhood immunization programs in Africa, where rotavirus-related mortality is significant.

Live attenuated human rotavirus vaccine, RIX4414, provides clinical protection in infants against rotavirus strains with and without shared G and P genotypes: integrated analysis of randomized controlled trials.

BACKGROUND: : The 2-dose, oral live attenuated human G1P[8] rotavirus vaccine (RIX4414) is highly effective against rotavirus gastroenteritis caused by circulating G1 and non-G1 types. An integrated analysis on vaccine efficacy was undertaken to obtain more precise estimates of the overall protective effect of the RIX4414 vaccine against rotavirus gastroenteritis due to common rotavirus types (G1, G3, G4, G9, P[8]) and less commonly encountered strains such as G2P[4] across heterogenous settings. METHODS: : The studies used in the integrated analysis were all previously reported randomized, double-blind, placebo-controlled, phase II and III trials with at least 1 report of rotavirus gastroenteritis in the efficacy follow-up period (up to 1 year of age or end of first RV epidemic season after vaccination). The integrated analysis was performed for all circulating rotavirus strains sharing G and/or P genotype and not sharing G or P genotype with the vaccine strain. Vaccine efficacy was estimated as 1 minus rate of rotavirus gastroenteritis relative to placebo, using exact Poisson rate ratio stratified by study. RESULTS: : The integrated estimates for vaccine efficacy against severe rotavirus gastroenteritis were 87.43% (95% confidence interval [CI]: 78.89-92.86) for G1P[8] strains, 71.42% (95% CI: 20.12-91.11) for G2P[4] strains, 90.19% (95% CI: 55.51-98.94) for G3P[8] strains, 93.37% (95% CI: 51.50-99.85) for G4P[8] strains, and 83.76% (95% CI: 71.18-91.28) for G9P[8] strains. The integrated estimates for vaccine efficacies against rotavirus gastroenteritis of any severity were 82.57% (95% CI: 73.91-88.56) for G1P[8] strains, 81.04% (95% CI: 31.58-95.76) for G2P[4] strains, 87.66% (95% CI: 34.57-98.76) for G3P[8] strains, 84.86% (95% CI: 50.92-96.41) for G4P[8] strains, and 60.64% (95% CI: 38.15-74.96) for G9P[8] strains. CONCLUSIONS: : Two doses of RIX4414 provide overall good clinical protection against all cases of rotavirus gastroenteritis and comparable, high clinical protection against severe rotavirus gastroenteritis caused by circulating rotavirus strains with and without G and P genotypes shared with the vaccine strain, such as G2P[4].