rotavirus gastroenteritis ( rvge ) is the most common cause of severe diarrhea among infants and young children aged < 5 years in developed and developing countries.[24 ] symptoms can range from mild watery diarrhea to severe diarrhea with forceful vomiting , abdominal distress , and fever , which can lead to serious complications including dehydration , electrolyte imbalance , seizures , and death.[3,57 ] although most of the estimated 600 000 childhood deaths associated with rvge each year occur in developing countries , rvge is also responsible for significant morbidity among infants and young children in developed countries , as well as a substantial economic and societal burden on their parents , caregivers , and healthcare providers . infants and young children who are infected with rotavirus develop partial immunity to subsequent infections and protection against subsequent severe rvge , as demonstrated in longitudinal studies.[1012 ] these beneficial effects increase with each natural infection,[1012 ] and antibody responses to natural infection appear to provide protection against multiple serotypes of rotavirus , the most common being g1 , g2 , g3 , and g4 in conjunction with p or p. these serotypes ( g1g4 ) are responsible for > 90% of episodes of rvge in europe and north america , with regional and seasonal variations in the most prevalent types .
data from a large european study conducted in 20045 indicate that serotypes g1 , g2 , g3 , g4 , and g9 accounted for > 98% of cases of rvge .
these data highlight the importance of rotavirus vaccines that mimic natural rotavirus infection and protect against the most common serotypes of rotavirus , as reflected in international guidelines advocating universal vaccination of infants and children against rotavirus.[4,1720 ] despite these guidelines , which recommend either of the orally administered rotavirus vaccines currently available ( a two - dose series of the monovalent vaccine rix4414 [ rotarix ] or a three - dose series of the pentavalent rotavirus vaccine [ rotateq ] ) , vaccination of infants and children against rotavirus is a much - debated topic often entangled in issues of cost effectiveness and health economics .
this article focuses on the rotavirus vaccine rix4414 , which is composed of a monovalent , live , attenuated , human rotavirus strain of g1p type.[2123 ]
data on the protective efficacy of rotavirus vaccine rix4414 against rvge in developed countries are available primarily from a large , randomized , double - blind , phase iii trial conducted in six european countries ( czech republic , finland , france , germany , italy , and spain ) , although supporting data from other relevant studies are also available .
the large european study evaluated the efficacy of the vaccine in terms of its effects on the incidence of rvge ( including severe rvge ) and on healthcare resource use , such as hospitalization due to rvge , among infants during their first 2 years of life .
a total of 3994 healthy infants aged 614 weeks were randomized to receive two oral doses of rotavirus vaccine rix4414 ( n = 2646 ) or placebo ( n = 1348 ) , which were administered at the same time as the first two doses of other , routine childhood vaccinations .
the primary endpoint was vaccine efficacy against rvge of any severity during a follow - up period from 2 weeks after administration of the second dose to the end of the first rotavirus season ( 20045 ) , and all efficacy analyses were conducted in the per - protocol population .
vaccine efficacy was calculated using the following formula : 1  incidence of rvge in the vaccine group / incidence of rvge in the placebo group . for the primary endpoint ,
the protective efficacy of rotavirus vaccine rix4414 against rvge of any severity was 87.1% ( 95% ci 79.6 , 92.1 ; p < 0.0001 ) during the first follow - up period .
similar results were also demonstrated in the second follow - up period ( 20056 ) and when both follow - up periods were combined .
for all follow - up periods , vaccine efficacy was also significant ( p < 0.0001 ) against severe rvge ( defined as a score of 11 on the 20-point vesikari scale ) , rvge requiring hospitalization , and rvge requiring medical attention .
in addition , vaccine efficacy against any and severe rvge caused by each of the rotavirus g types identified ( g1 , g2 , g3 , g4 , and g9 ) was significant ( p  0.02 ) in the combined efficacy follow - up period .
various naturalistic studies conducted in developed countries have demonstrated the  real - world effectiveness of rotavirus vaccination after introduction of the vaccine for routine use in the community setting . typically , these studies compared various outcomes , such as the numbers of rvge cases , rvge - related hospitalizations , and/or emergency department visits , that occurred during the pre - vaccination period with those that occurred during a specific period after widespread or universal introduction of a rotavirus vaccination program .
studies conducted in the australian state of queensland and in european countries[2830 ] involved rotavirus vaccination programs with either the monovalent or pentavalent rotavirus vaccine , whereas studies conducted in the us generally focused only on the pentavalent vaccine ( reviewed elsewhere ) .
rotavirus vaccine rix4414 was generally well tolerated in clinical trials , with an overall tolerability profile similar to that of placebo .
there was no increased risk of intussusception with rotavirus vaccine rix4414 in a large ( n = 63 225 ) , placebo - controlled , pre - licensure safety study conducted in latin america and finland .
however , interim results from a postmarketing active surveillance study conducted in mexico , along with worldwide passive surveillance data , suggest that there may be an increased risk of intussusception during the first 7 days after administration . both the us prescribing information and the eu summary of product characteristics state that rotavirus vaccine rix4414 should not be administered to infants with a previous history of intussusception or to those with uncorrected congenital malformation of the gastrointestinal tract ( e.g. meckel s diverticulum ) that would predispose them to intussusception .
most of the published cost - effectiveness analyses of rotavirus vaccine rix4414 were conducted in european countries and used decision - tree or markov models that incorporated data from various sources , including protective efficacy results from large phase iii trials with rotavirus vaccines and local cost data , to evaluate the cost effectiveness of introducing a universal rotavirus vaccination program compared with no universal vaccination program against rotavirus . in several analyses ,
both the healthcare payer and societal perspectives were used,[3340 ] whereas other studies were conducted from either a societal or a healthcare payer perspective .
limited societal perspective , which excluded indirect costs but included out - of - pocket medical expenses along with other direct medical costs .
some studies focused only on rix4414,[36,37,4244 ] while others also included indirect comparisons with the pentavalent rotavirus vaccine or , in some cases , the universal rotavirus vaccination program being evaluated allowed for the use of either rix4414 or the pentavalent rotavirus vaccine . a wide range of results was reported across the cost - effectiveness analyses , which appears to be related , at least in part , to the substantial heterogeneity among the models used in the studies .
the analyses typically showed that the cost of a universal rotavirus vaccination program was partly offset by reductions in rvge - related healthcare resource use and that the program was associated with quality - adjusted life - year ( qaly ) gains .
however , the universal rotavirus vaccination program was deemed to be cost effective from the perspective of the healthcare payer only in some studies , but not in others,[3335,3840,43 ] when applying commonly reported cost - effectiveness thresholds , such as  20 00050 000 , $ us50 000 , or  20 00030 000 per qaly gained.[4649 ] a consistent finding across studies that were conducted from both a healthcare payer and a societal ( or  limited societal ) perspective was that incremental cost - effectiveness ratios ( icers ) were more favorable from a societal perspective,[3340,43 ] as might be expected because additional costs associated with rvge ( e.g. out - of - pocket medical expenses and/or lost productivity of parents of children who develop rvge ) were included .
another consistent finding of the studies was that , compared with no universal vaccination program , icer values for a two - dose oral series of rotavirus vaccine rix4414 were more favorable than those for a three - dose oral series of pentavalent rotavirus vaccine when cost effectiveness of the two vaccines was evaluated separately in the same study .
however , modelled analyses directly comparing the two vaccines would require head - to - head clinical trial data , which are currently lacking .
in addition , there are inherent uncertainties in comparing icer values of the available rotavirus vaccines because of the tender process that would be used to establish the vaccine price in a universal program .
although results of the cost - effectiveness analyses were sensitive to a number of parameters , which often varied between studies , there were also some common findings in the sensitivity analyses .
variations in the cost of vaccine , qaly losses for a caregiver , and the number of caregivers affected , as well as annual discount rates ( particularly for outcomes ) , were among the most frequently reported parameters having the greatest impact on icer values .
economic models such as those used in the cost - effectiveness analyses with rotavirus vaccine rix4414 have , out of necessity , the inherent limitations of using data from a variety of sources and extrapolating shorter - term clinical trial data to project longer - term costs and outcomes .
moreover , data or assumptions used to populate the models ( e.g. waning of vaccine protection , rate of vaccine uptake , protective efficacy of partial vaccination , time period over which infections could be acquired , incidence of rvge , probability of rvge hospitalization ) often varied between studies , which , together with results of sensitivity analyses , highlights some of the uncertainties in results from these modelled analyses . along with differences in the selection of data sources used in the analyses , other factors contributing to the wide variability in results include differences in the study perspective , year of costing , and discount rates , as well as country- or region - specific differences in estimates of healthcare resource use and associated costs .
the type of model used in vaccine cost - effectiveness analyses can also affect results ; for example , whether the main features of the model change over time ( dynamic model ) or not ( static model).[5054 ] the effects of herd immunity , whereby vaccination of part of a population confers partial indirect protection for the remainder , are not captured in static models ( e.g. decision - tree , markov ) , which results in an underestimation of the cost effectiveness of a vaccination program .
two analyses of rotavirus vaccine rix4414 included the effects of herd immunity , using data from dynamic transmission models in the sensitivity analyses , and in both cases the inclusion of herd immunity effects markedly improved icer values .
 the most common cause of severe diarrhea in infants and young children is rotavirus gastroenteritis ( rvge ) , which is associated with significant morbidity , healthcare resource use , and direct and indirect costs in industrialized nations . 
 the monovalent rotavirus vaccine rix4414 ( rotarix ) is administered as a two - dose oral series in infants and has demonstrated protective efficacy against rvge in clinical trials conducted in developed countries . 
 in addition , various naturalistic studies have demonstrated  real - world effectiveness after the introduction of widespread rotavirus vaccination programs in the community setting.numerous cost - effectiveness analyses have been conducted in developed countries in which a universal rotavirus vaccination program using rix4414 was compared with no universal rotavirus vaccination program . 
 there was a high degree of variability in base - case results across studies even when the studies were conducted in the same country , often reflecting differences in the selection of data sources or assumptions used to populate the models . 
 in addition , results were sensitive to plausible changes in a number of key input parameters . 
 as such , it is not possible to definitively state whether a universal rotavirus vaccination program with rix4414 is cost effective in developed countries , although results of some analyses in some countries suggest this is the case . 
 in addition , international guidelines advocate universal vaccination of infants and children against rotavirus . 
 it is also difficult to draw conclusions regarding the cost effectiveness of rotavirus vaccine rix4414 relative to that of the pentavalent rotavirus vaccine , which is administered as a three - dose oral series . although indirect comparisons in cost - effectiveness analyses indicate that rix4414 provided more favorable incremental cost - effectiveness ratios when each vaccine was compared with no universal rotavirus vaccination program , results were generally sensitive to vaccine costs . 
 actual tender prices of a full vaccination course for each vaccine were not known at the time of the analyses and therefore had to be estimated . 
1. Introduction
2. Clinical Profile of Rotavirus Vaccine RIX4414
3. Pharmacoeconomic Analyses of Monovalent Rotavirus Vaccine RIX4414