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1.  Removing the Age Restrictions for Rotavirus Vaccination: A Benefit-Risk Modeling Analysis 
PLoS Medicine  2012;9(10):e1001330.
A modeling analysis conducted by Manish Patel and colleagues predicts the possible number of rotavirus deaths prevented, and number of intussusception deaths caused, by use of an unrestricted rotavirus schedule in low- and middle-income countries.
Background
To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur.
Methods and Findings
We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th–95th percentile, to provide an indication of the uncertainty in the estimates.
We estimated that in low and low-middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th–95th centiles, 83,300–217,700) while causing potentially 253 intussusception deaths (76–689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000–281,500) while potentially causing 547 intussusception deaths (237–1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700–63,700) and cause an additional 294 (161–471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%–25% children, beyond the 63%–73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non-fatal outcomes.
Conclusions
Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Rotavirus causes severe diarrhea and vomiting. It is responsible for a large number of hospitalizations among young children in developed countries (an estimated 60,000 hospitalizations per year in the US in 2005, for example). In poor countries, rotavirus is a major cause of death in children under five. In 1998, the first rotavirus vaccine, called RotaShield, was approved in the US by the Food and Drug Administration. Shortly after the vaccine became widely used, doctors noticed a small increase in a problem called intussusception among the vaccinated infants. Intussusception is a rare type of bowel obstruction that occurs when the bowel telescopes in on itself. Prompt treatment of intussusception normally leads to full recovery, but some children with the condition need surgery, and when the disease is left untreated it can be fatal. Because intussusception is a serious condition and because very few children die from rotavirus infection in the United States, the US authorities stopped recommending vaccination with RotaShield in 1999. The manufacturer withdrew the vaccine from the market shortly thereafter.
Since then, two new vaccines (named Rotarix and RotaTeq) have been developed. Before they were approved in the US and elsewhere, they were extensively tested for any adverse side effects, especially intussusception. No increase in the risk for intussusception was found in these studies, and both are now approved and recommended for vaccination of infants around the world.
Why Was This Study Done?
Since 2006, hundreds of thousands of infants have been vaccinated with Rotarix or RotaTeq, with safety being closely monitored. Some countries have reported a small increase in intussusception (one to four additional cases per 100,000 vaccinated infants, compared with one per 2,000 of cases that occur in unvaccinated children). This increase is much lower than the one seen previously with RotaShield. In response to these findings, authorities in the US and other developed countries as well as the World Health Organization declared that the benefits of the vaccine outweigh the risks of the small number of additional intussusception cases in both developed and poor countries. However, because older infants have a higher risk of naturally occurring intussusception, they decided that the course of vaccination (three oral doses for Rotarix and two for RotaTeq) should be initiated before 15 weeks of age and completed before the age of 32 weeks. This is usually not a problem in countries with easy access to health facilities. However, in many poor countries where delays in infant vaccination are common, giving the vaccine only to very young children means that many others who could benefit from its protection will be excluded. In this study, the researchers examined the risks and benefits of rotavirus vaccination in poor countries where most of the rotavirus deaths occur. Specifically, they looked at the benefits and risks if the age restrictions were removed, with a particular emphasis on allowing infants to initiate rotavirus immunization even if they arrive after 15 weeks of age.
What Did the Researchers Do and Find?
The researchers used the most recent estimates for how well the vaccines protect children in Africa and Asia from becoming infected with rotavirus, how many deaths from rotavirus infection can be avoided by vaccination, how many additional cases of intussusception will likely occur in vaccinated children, and what proportion of children would be excluded from rotavirus vaccination because they are too old when they come to a health facility for their infant vaccination. They then estimated the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination in two scenarios. The first one (the restricted scenario) corresponds to previous guidelines from WHO and others, in which rotavirus vaccination needs to be initiated before 15 weeks and the full series completed before 32 weeks. The second one (called the unrestricted scenario) allows rotavirus vaccination of children alongside current routinely administered vaccines up to three years of age, recognizing that most children receive their vaccination by 1 year of life.
The researchers estimated that removing the age restriction would prevent an additional 154 rotavirus deaths for each intussusception death caused by the vaccine. Under the unrestricted scenario, roughly a third more children would get vaccinated, which would prevent an additional approximately 47,000 death from rotavirus while causing approximately 300 additional intussusception deaths.
They also calculated some best- and worst-case scenarios. The worst-case scenario assumed a much higher risk of intussusception for children receiving their first dose after 15 weeks of life than what has been seen anywhere, and also that an additional 20% of children with intussusception would die from it than what was already assumed in their routine scenario (again, a higher number than seen in reality). In addition, it assumes a lower protection from rotavirus death for the vaccine than has been observed in children vaccinated so far. In this pessimistic case, the number of rotavirus deaths prevented was 24 for each intussusception death caused by the vaccine.
What Do These Findings Mean?
If one accepts that deaths caused by a vaccine are not fundamentally different from deaths caused by a failure to vaccinate, then these results show that the benefits of lifting the age restriction for rotavirus vaccine clearly outweigh the risks, at least when only examining mortality outcomes. The calculations are valid only for low-income countries in Africa and Asia where both vaccination delays and deaths from rotavirus are common. The risk-benefit ratio will be different elsewhere. There are also additional risks and benefits that are not included in the study's estimates. For example, early vaccination might be seen as less of an urgent priority when this vaccine can be had at a later date, leaving very young children more vulnerable. On the other hand, when many children in the community are vaccinated, even the unvaccinated children are less likely to get infected (what is known as “herd immunity”), something that has not been taken into account in the benefits here. The results of this study (and its limitations) were reviewed in April 2012 by WHO's Strategic Advisory Group of Experts. The group then recommended that, while early vaccination is still strongly encouraged, the age restriction on rotavirus vaccination should be removed in countries where delays in vaccination and rotavirus mortality are common so that more vulnerable children can be vaccinated and deaths from rotavirus averted.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001330.
The World Health Organization provides information on rotavirus
Wikipedia has information on rotavirus vaccine and intussusception (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US Centers for Disease Control and Prevention rotavirus vaccination page includes a link to frequently asked questions
PATH Rotavirus Vaccine Access and Delivery has timely, useful updates on status of rotavirus vaccines globally
doi:10.1371/journal.pmed.1001330
PMCID: PMC3479108  PMID: 23109915
2.  Cost effectiveness of infant vaccination for rotavirus in Canada 
INTRODUCTION:
Rotavirus is the main cause of gastroenteritis in Canadian children younger than five years of age, resulting in significant morbidity and cost. The present study provides evidence on the cost effectiveness of two alternative rotavirus vaccinations (RotaTeq [Merck Frosst Canada Ltd, Canada] and Rotarix [GlaxoSmithKline, Canada]) available in Canada.
METHODS:
Analysis was conducted through a Markov model that followed a cohort of children from birth to five years of age. Analysis used pertinent data on the natural history of rotavirus and the effects of vaccination. Estimates of heath care costs for children requiring hospitalizations and emergency department visits were derived from the Canadian Immunization Monitoring Program, Active (IMPACT) surveillance, emergency department studies, as well as other Canadian studies. The model estimated the effect of vaccination on costs and quality-adjusted life years (QALYs).
RESULTS:
The incremental cost per QALY gained from the health care system perspective was $122,000 for RotaTeq and $108,000 for Rotarix. From the societal perspective, both vaccination strategies were dominant – both cost saving and more effective. The cost-effectiveness of vaccination is dependent on the mode of administration, the perspective adopted and the cost of the vaccine.
CONCLUSIONS:
From a societal perspective, a universal vaccination program against rotavirus will be both cost saving and more effective than no vaccination. Becasue the majority of rotavirus infections do not require emergency department visits or hospital admission, from a health care system perspective, a program would not be considered cost effective.
PMCID: PMC3403662  PMID: 23730312
Cost effectiveness; Rotavirus; Vaccination
3.  Rotarix in Japan: Expectations and Concerns 
Biologics in Therapy  2011;1(1):4.
A live-attenuated, orally-administered, monovalent, human rotavirus vaccine, Rotarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium), was licensed and launched in 2011 as the first rotavirus vaccine in Japan. The rotavirus causes a substantial disease burden with an estimated 790,000 outpatient visits, 27,000–78,000 hospitalizations, and approximately 10 deaths each year in Japan. Since a recent clinical trial showed that Rotarix was as efficacious in Japan as in other industrialized countries, it is expected that the annual number of rotavirus hospitalizations will be reduced to between 1000–3000, and that outpatient visits will be reduced to 200,000. The universal rotavirus immunization program with Rotarix was calculated to be at the threshold of being cost-effective, even from the healthcare perspective, and it was highly cost-effective from the societal perspective, assuming that Rotarix is co-administered with other childhood vaccines. While Rotarix contains only a single G1P[8] human rotavirus, the postlicensure studies in Brazil showed that Rotarix provided a 75%–85% protective efficacy against severe dehydrating diarrhea or hospitalizations due to fully-heterotypic G2P[4] strains. While postlicensure studies detected a small and finite risk of intussusception associated with the administration of Rotarix, the authors conclude that Rotarix is safe to administer to infants between 6-12 weeks of age for the first dose and by 24 weeks of age for the second dose. However, the authors strongly discourage the delayed administration of the first dose between 13-20 weeks of age, which is allowed without any warning. Given the high incidence of naturally-occurring intussusception in Japan (185 cases per 100,000 children/year among children less than 1 year of age), this should prevent pediatricians and parents from having ill-perceptions of Rotarix being associated with an increased number of temporally-associated intussusception, and fully appreciate the benefit of the rotavirus vaccine.
doi:10.1007/s13554-011-0007-5
PMCID: PMC3873079  PMID: 24392294
diarrhea; heterotypic immunity; immunization; intussusception; Japan; Rotarix; rotavirus
4.  Rotarix in Japan: Expectations and Concerns 
Biologics in Therapy  2011;1(1):4.
A live-attenuated, orally-administered, monovalent, human rotavirus vaccine, Rotarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium), was licensed and launched in 2011 as the first rotavirus vaccine in Japan. The rotavirus causes a substantial disease burden with an estimated 790,000 outpatient visits, 27,000–78,000 hospitalizations, and approximately 10 deaths each year in Japan. Since a recent clinical trial showed that Rotarix was as efficacious in Japan as in other industrialized countries, it is expected that the annual number of rotavirus hospitalizations will be reduced to between 1000–3000, and that outpatient visits will be reduced to 200,000. The universal rotavirus immunization program with Rotarix was calculated to be at the threshold of being cost-effective, even from the healthcare perspective, and it was highly cost-effective from the societal perspective, assuming that Rotarix is co-administered with other childhood vaccines. While Rotarix contains only a single G1P[8] human rotavirus, the postlicensure studies in Brazil showed that Rotarix provided a 75%–85% protective efficacy against severe dehydrating diarrhea or hospitalizations due to fully-heterotypic G2P[4] strains. While postlicensure studies detected a small and finite risk of intussusception associated with the administration of Rotarix, the authors conclude that Rotarix is safe to administer to infants between 6-12 weeks of age for the first dose and by 24 weeks of age for the second dose. However, the authors strongly discourage the delayed administration of the first dose between 13-20 weeks of age, which is allowed without any warning. Given the high incidence of naturally-occurring intussusception in Japan (185 cases per 100,000 children/year among children less than 1 year of age), this should prevent pediatricians and parents from having ill-perceptions of Rotarix being associated with an increased number of temporally-associated intussusception, and fully appreciate the benefit of the rotavirus vaccine.
doi:10.1007/s13554-011-0007-5
PMCID: PMC3873079  PMID: 24392294
diarrhea; heterotypic immunity; immunization; intussusception; Japan; Rotarix; rotavirus
5.  Results from a Randomized Clinical Trial of Coadministration of RotaTeq, a Pentavalent Rotavirus Vaccine, and NeisVac-C, a Meningococcal Serogroup C Conjugate Vaccine ▿ † 
RotaTeq (Merck & Co. Inc./Sanofi Pasteur MSD) is a three-dose, oral pentavalent rotavirus vaccine for the immunization of infants from 6 weeks of age for the prevention of rotavirus gastroenteritis. The primary objective of the present trial was to demonstrate that RotaTeq can be coadministered with meningococcal serogroup C conjugate vaccine (MenCC; NeisVac-C; Baxter Healthcare) to healthy infants without impairing the protective immune responses to MenCC. This was an open-label, randomized, comparative study conducted in Finland. The study was designed to assess concomitant versus sequential administration of RotaTeq and MenCC on the immune response to both vaccines. Healthy infants (n = 247), aged 6 to 7 weeks, were recruited. Coadministration of MenCC with RotaTeq was noninferior to sequential administration for the seroprotection rate against meningococcal serogroup C (the proportion of infants with a serum bactericidal antibody titer using baby rabbit complement of ≥8 was 100% in both groups). The other responses to MenCC (titer of ≥1:128, ≥4-fold increase in titer, and geometric mean titers [GMTs]) and the responses to RotaTeq (IgA and SNA response to G1 to G4 and P1A[8], GMTs, and ≥3-fold increase in titer) were comparable between groups, including a ≥3-fold IgA increase in >96% of the infants in both groups. Concomitant administration of the first doses of MenCC, diphtheria and tetanus toxoids and acellular pertussis vaccine, inactivated poliovirus vaccine, and Haemophilus influenzae type b conjugate vaccine (DTaP-IPV-Hib), and RotaTeq was associated with a higher rate of vomiting and diarrhea than concomitant administration of MenCC and DTaP-IPV-Hib, but that was not observed after the second concomitant administration. The convenience of concomitant administration of RotaTeq and MenCC may, however, outweigh the additive effect of mostly mild adverse events reported after the individual administration of each vaccine. These results support the coadministration of RotaTeq and MenCC.
doi:10.1128/CVI.00437-10
PMCID: PMC3122533  PMID: 21389149
6.  Burden of paediatric Rotavirus Gastroenteritis (RVGE) and potential benefits of a universal Rotavirus vaccination programme with a pentavalent vaccine in Spain 
BMC Public Health  2010;10:469.
Background
Rotavirus is the most common cause of gastroenteritis in young children worldwide. The aim of the study was to assess the health outcomes and the economic impact of a universal rotavirus vaccination programme with RotaTeq, the pentavalent rotavirus vaccine, versus no vaccination programme in Spain.
Methods
A birth cohort was followed up to the age of 5 using a cohort model. Epidemiological parameters were taken from the REVEAL study (a prospective epidemiological study conducted in Spain, 2004-2005) and from the literature. Direct and indirect costs were assessed from the national healthcare payer and societal perspectives by combining health care resource utilisation collected in REVEAL study and unit costs from official sources. RotaTeq per protocol efficacy data was taken from a large worldwide rotavirus clinical trial (70,000 children). Health outcomes included home care cases, General Practioner (GP)/Paediatrician, emergency department visits, hospitalisations and nosocomial infections.
Results
The model estimates that the introduction of a universal rotavirus vaccination programme with RotaTeq (90% coverage rate) would reduce the rotavirus gastroenteritis (RVGE) burden by 75% in Spain; 53,692 home care cases, 35,187 GP/Paediatrician visits, 34,287 emergency department visits, 10,987 hospitalisations and 2,053 nosocomial infections would be avoided. The introduction of RotaTeq would avoid about 76% of RVGE-related costs from both perspectives: €22 million from the national health system perspective and €38 million from the societal perspective.
Conclusions
A rotavirus vaccination programme with RotaTeq would reduce significantly the important medical and economic burden of RVGE in Spain.
doi:10.1186/1471-2458-10-469
PMCID: PMC2927540  PMID: 20698958
7.  Cost-effectiveness of Rotavirus vaccination in Vietnam 
BMC Public Health  2009;9:29.
Background
Rotavirus is the most common cause of severe diarrhea leading to hospitalization or disease-specific death among young children. New rotavirus vaccines have recently been approved. Some previous studies have provided broad qualitative insights into the health and economic consequences of introducing the vaccines into low-income countries, representing several features of rotavirus infection, such as varying degrees of severity and age-dependency of clinical manifestation, in their model-based analyses. We extend this work to reflect additional features of rotavirus (e.g., the possibility of reinfection and varying degrees of partial immunity conferred by natural infection), and assess the influence of the features on the cost-effectiveness of rotavirus vaccination.
Methods
We developed a Markov model that reflects key features of rotavirus infection, using the most recent data available. We applied the model to the 2004 Vietnamese birth cohort and re-evaluated the cost-effectiveness (2004 US dollars per disability-adjusted life year [DALY]) of rotavirus vaccination (Rotarix®) compared to no vaccination, from both societal and health care system perspectives. We conducted univariate sensitivity analyses and also performed a probabilistic sensitivity analysis, based on Monte Carlo simulations drawing parameter values from the distributions assigned to key uncertain parameters.
Results
Rotavirus vaccination would not completely protect young children against rotavirus infection due to the partial nature of vaccine immunity, but would effectively reduce severe cases of rotavirus gastroenteritis (outpatient visits, hospitalizations, or deaths) by about 67% over the first 5 years of life. Under base-case assumptions (94% coverage and $5 per dose), the incremental cost per DALY averted from vaccination compared to no vaccination would be $540 from the societal perspective and $550 from the health care system perspective.
Conclusion
Introducing rotavirus vaccines would be a cost-effective public health intervention in Vietnam. However, given the uncertainty about vaccine efficacy and potential changes in rotavirus epidemiology in local settings, further clinical research and re-evaluation of rotavirus vaccination programs may be necessary as new information emerges.
doi:10.1186/1471-2458-9-29
PMCID: PMC2663769  PMID: 19159483
8.  Rotavirus Vaccines and Pathogenesis: 2008 
Purpose of Review
Rotaviruses cause life-threatening gastroenteritis in children throughout the world. The burden of disease has resulted in the development of two live, attenuated vaccines that are now licensed in many countries. This review summarizes new data on these vaccines, their effectiveness, and remaining challenges including new data on the rotavirus enterotoxin, a potential antiviral target.
Recent findings
Live attenuated rotavirus vaccines are used to protect infants against severe rotavirus-induced gastroenteritis and, RotaTeq®, a pentavalent bovine based vaccine, and, Rotarix®, a monovalent human rotavirus, are now currently licensed in many countries. Initial results of the licensed RotaTeq® vaccine have been promising in the United States and results of immunogenicity and efficacy in developing countries are expected soon. However universal vaccine implementation is challenging due to age limitations on administration of these vaccines. Chronic rotavirus infections in immunocompromised children may remain a problem and require the development of new treatments including antiviral drugs. Increasing data on the mechanisms of action of the rotavirus enterotoxin highlight this pleiotropic protein as a good target as well as unique calcium agonist.
Summary
Rotavirus is now a commonly occurring vaccine-preventable disease among children in developed countries and hopefully this also will soon be true for developing countries. Future studies will determine if other methods of prevention, such as nonreplicating vaccines and antiviral drugs, will be needed to treat disease in immunocompromised children.
doi:10.1097/MOG.0b013e328317c897
PMCID: PMC2673536  PMID: 19114772
Live; attenuated vaccines; enterotoxin; antivirals; rotavirus
9.  Vaccine-Derived NSP2 Segment in Rotaviruses from Vaccinated Children with Gastroenteritis in Nicaragua 
Infection, Genetics and Evolution  2012;12(6):1282-1294.
Rotavirus (RV) vaccination programs have been established in several countries using the human-attenuated G1P[8] monovalent vaccine Rotarix™ (GlaxoSmithKline) and/or the human-bovine reassortant G1, G2, G3, G4, P[8] pentavalent vaccine RotaTeq™ (Merck). The efficacy of both vaccines is high (~90%) in developed countries, but can be remarkably lower in developing countries. For example, a vaccine efficacy against severe diarrhea of only 58% was observed in a 2007–2009 Nicaraguan study using RotaTeq. To gain insight into the significant level of vaccine failure in this country, we sequenced the genomes of RVs recovered from vaccinated Nicaraguan children with gastroenteritis. The results revealed that all had genotype specificities typical for human RVs (11 G1P[8], 1 G3P[8]) and that the sequences and antigenic epitopes of the outer capsid proteins (VP4 and VP7) of these viruses were similar to those reported for RVs isolated elsewhere in the world. As expected, nine of the G1P[8] viruses and the single G3P[8] virus had genome constellations typical of human G1P[8] and G3P[8] RVs: G1/3-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. However, two of the G1P[8] viruses had atypical constellations, G1-P[8]-I1-R1-C1-M1-A1-N2-T1-E1-H1, due to the presence of a genotype-2 NSP2 (N2) gene. The sequence of the N2 NSP2 gene was identical to the bovine N2 NSP2 gene of RotaTeq, indicating that the two atypical viruses originated via reassortment of human G1P[8] RVs with RotaTeq viruses. Together, our data suggest that the high level of vaccine failure in Nicaraguan is probably not due to antigenic drift of commonly circulating virus strains nor the emergence of new antigenetically distinct virus strains. Furthermore, our data suggests that the widespread use of the RotaTeq vaccine has led to the introduction of vaccine genes into circulating human RVs.
doi:10.1016/j.meegid.2012.03.007
PMCID: PMC3372771  PMID: 22487061
rotavirus; genomics; vaccine; RotaTeq
10.  Performance of rotavirus vaccines in developed and developing countries 
Human Vaccines  2010;6(7):532-542.
The World Health Organization estimates that rotavirus diarrhea results in approximately half a million deaths and approximately 2.4 million hospitalizations in developing countries each year. Two live oral rotavirus vaccines, RotaTeq® (RV 5; Merck) and Rotarix® (RV 1; GlaxoSmithKline) with good efficacy against severe rotavirus disease and a reassuring safety profile could substantially impact the burden of rotavirus disease. In April 2009, WHO provided a recommendation for global introduction of these vaccines in national immunization programs of developing countries worldwide. In this article, we review published data on previous candidate rotavirus vaccines and vaccines in current use, with emphasis on their performance in developed versus developing countries. In developed countries, both first and second generation rotavirus vaccines have demonstrated high efficacy against severe rotavirus disease (pooled efficacy = 73% and 85%, respectively). In developing countries, small early trials for the first generation vaccines failed to provide protection against rotavirus disease (pooled efficacy = 20%), however, trials of the second generation vaccines yielded substantial improvements in efficacy in developing countries (pooled efficacy of 51%), leading to a global recommendation for rotavirus vaccine introduction by WHO. Future efforts for these vaccines should focus on optimizing the efficacy and delivery of these vaccines in challenging target populations of Asia and Africa with the greatest burden of severe rotavirus disease.
doi:10.4161/hv.6.7.11278
PMCID: PMC3322519  PMID: 20622508
rotavirus; vaccines; immunization; vaccination; diarrhea; gastroenteritis
11.  Genetic Analyses Reveal Differences in the VP7 and VP4 Antigenic Epitopes between Human Rotaviruses Circulating in Belgium and Rotaviruses in Rotarix and RotaTeq 
Journal of Clinical Microbiology  2012;50(3):966-976.
Two live-attenuated rotavirus group A (RVA) vaccines, Rotarix (G1P[8]) and RotaTeq (G1-G4, P[8]), have been successfully introduced in many countries worldwide, including Belgium. The parental RVA strains used to generate the vaccines were isolated more than 20 years ago in France (G4 parental strain in RotaTeq) and the United States (all other parental strains). At present, little is known about the relationship between currently circulating human RVAs and the vaccine strains. In this study, we determined sequences for the VP7 and VP4 outer capsid proteins of representative G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and G12P[8] RVAs circulating in Belgium during 2007 to 2009. The analyses showed that multiple amino acid differences existed between the VP7 and VP4 antigenic epitopes of the vaccine viruses and the Belgian isolates, regardless of their G and P genotypes. However, the highest variability was observed among the circulating G1P[8] RVA strains and the G1 and P[8] components of both RVA vaccines. In particular, RVA strains of the P[8] lineage 4 (OP354-like) showed a significant number of amino acid differences with the P[8] VP4 of both vaccines. In addition, the circulating Belgian G3 RVA strains were found to possibly possess an extra N-linked glycosylation site compared to the G3 RVA vaccine strain of RotaTeq. These results indicate that the antigenic epitopes of RVA strains contained in the vaccines differ substantially from those of the currently circulating RVA strains in Belgium. Over time, these differences might result in selection for strains that escape the RVA neutralizing-antibody pressure induced by vaccines.
doi:10.1128/JCM.05590-11
PMCID: PMC3295124  PMID: 22189107
12.  The Cost-Effectiveness of Rotavirus Vaccination in Malawi 
The Journal of Infectious Diseases  2010;202(Suppl 1):S108-S115.
Background. Rotarix (GlaxoSmithKline), a newly licensed rotavirus vaccine requiring 2 doses, may have the potential to save hundreds of thousands of lives in Africa. Nations such as Malawi, where Rotarix is currently under phase III investigation, may nevertheless face difficult economic choices in considering vaccine adoption.
Methods. The cost-effectiveness of implementing a Rotarix vaccine program in Malawi was estimated using published estimates of rotavirus burden, vaccine efficacy, and health care utilization and costs.
Results. With 49.5% vaccine efficacy, a Rotarix program could avert 2582 deaths annually. With GAVI Alliance cofinancing, adoption of Rotarix would be associated with a cost of $5.07 per disability-adjusted life-year averted. With market pricing, Rotarix would be associated with a base case cost of $74.73 per disability-adjusted life-year averted. Key variables influencing results were vaccine efficacy, under-2 rotavirus mortality, and program cost of administering each dose.
Conclusions. Adopting Rotarix would likely be highly cost-effective for Malawi, particularly with GAVI support. This finding holds true across uncertainty ranges for key variables, including efficacy, for which data are becoming available.
doi:10.1086/653578
PMCID: PMC3962285  PMID: 20684689
13.  Rotavirus Infection: A Perspective on Epidemiology, Genomic Diversity and Vaccine Strategies 
For centuries, acute diarrhea has been a major cause of death in young children worldwide, and until 1973, before rotavirus was discovered; no infectious agents could be identified in about 80% of patients admitted to hospital with severe dehydrating diarrhea. Rotaviruses have now been shown to cause 40–50% of severe acute diarrhea in young children worldwide in both developing and developed countries. More than 600,000 young children die and approximately 2.4 million hospitalize annually from rotavirus disease, especially in South-East Asia and sub-Saharan Africa. Two safe and effective vaccines are now licensed in 100 countries but used in 17 countries. Rotarix (GSK) vaccine is derived from single attenuated human rotavirus G1P[8], representative of the most common serotype identified worldwide. RotaTeq (Merck) is a pentavalent mixture of naturally attenuated bovine/human rotavirus reassortants representing G1, G2, G3, G4, and P[8] serotypes. Though these vaccines have already dramatically decreased the morbidity associated with rotavirus in countries where they are widely used, the third generation of vaccines, based on inactivated viruses or recombinant virus like particle are already in pipeline. Continuous surveillance and the genetic and antigenic analysis of the various strains of rotavirus circulating worldwide will aid significantly in assessing the effectiveness of these vaccines and monitor emergence of new strains. Introduction of rotavirus vaccines in national vaccine policy along with other childhood vaccines may result in significant reduction in mortality in children in poor socioeconomic countries.
doi:10.1007/s13337-011-0039-y
PMCID: PMC3550723  PMID: 23637497
Rotavirus; Vaccine; 23 G genotypes; 32 P genotypes
14.  Will vaccination against rotavirus infection with RIX4414 be cost-saving in Germany? 
Background
Rotavirus gastroenteritis (RVGE) is a frequent disease in young children. The recommended German paediatric immunisation schedule does not currently include rotavirus vaccination. A lack of economic data on the impact of routine vaccination is stated as one of the reasons. As a result, the current coverage rate is low, around 26%. This study investigated whether rotavirus vaccination using the two-dose rotavirus vaccine RIX4414 (Rotarix®, GlaxoSmithKline Vaccines) would be a cost-saving intervention from the perspective of the statutory health insurance (SHI) in Germany.
Objective
The objective of the study was to analyse health outcomes (number of RVGE cases and hospitalisations prevented) and the associated cost to the SHI when comparing 100% rotavirus vaccination with no vaccination in Germany.
Methods
A Markov cohort model simulated the number of RVGE events and related costs in a German birth cohort over the first 60 months of life with current disease management. The model compared an unvaccinated cohort with a fully vaccinated cohort. Vaccine efficacy data from international clinical trials were combined with German-specific epidemiological and cost data. Results were tested using extensive sensitivity analyses.
Results
Full vaccination of a birth cohort against rotavirus disease would be expected to prevent 82% of RVGE cases, reducing RVGE frequency from 28 to 5 events per 100 children in the birth cohort up to age 5 years. The estimated cost reduction with vaccination for that period is predicted to be €9.2 million with 100% coverage (€6.9 million with 75% coverage), mainly due to reductions in SHI reimbursement for productivity losses, hospital stays and visits to office-based physicians due to the vaccine’s efficacy against severe disease.
Conclusions
Routine rotavirus vaccination in Germany would reduce the number of hospitalised and outpatient cases. The associated investment could be fully offset by costs avoided in hospital stays, physician visits and SHI reimbursement of productivity losses. Sensitivity analysis indicated that vaccination would be cost-saving in 95% of simulations. Incremental cost was observed only under extreme conditions, especially when the time spent at home due to rotavirus disease was low or when vaccine efficacy against severe disease was heavily decreased.
doi:10.1186/2191-1991-3-27
PMCID: PMC3831585  PMID: 24246029
Cost savings; Economic evaluation; Germany; Paediatric; RIX4414; Rotavirus; Vaccination
15.  Human rotavirus vaccine Rotarix™ provides protection against diverse circulating rotavirus strains in African infants: a randomized controlled trial 
BMC Infectious Diseases  2012;12:213.
Background
Rotaviruses are the most important cause of severe acute gastroenteritis worldwide in children <5 years of age. The human, G1P[8] rotavirus vaccine Rotarix™ significantly reduced severe rotavirus gastroenteritis episodes in a Phase III clinical trial conducted in infants in South Africa and Malawi. This paper examines rotavirus vaccine efficacy in preventing severe rotavirus gastroenteritis, during infancy, caused by the various G and P rotavirus types encountered during the first rotavirus-season.
Methods
Healthy infants aged 5–10 weeks were enrolled and randomized into three groups to receive either two (10 and 14 weeks) or three doses of Rotarix™ (together forming the pooled Rotarix™ group) or three doses of placebo at a 6,10,14-week schedule. Weekly home visits were conducted to identify gastroenteritis episodes. Rotaviruses were detected by ELISA and genotyped by RT-PCR and nucleotide sequencing. The percentage of infants with severe rotavirus gastroenteritis caused by the circulating G and P types from 2 weeks post-last dose until one year of age and the corresponding vaccine efficacy was calculated with 95% CI.
Results
Overall, 4939 infants were vaccinated and 4417 (pooled Rotarix™ = 2974; placebo = 1443) were included in the per protocol efficacy cohort. G1 wild-type was detected in 23 (1.6%) severe rotavirus gastroenteritis episodes from the placebo group. This was followed in order of detection by G12 (15 [1%] in placebo) and G8 types (15 [1%] in placebo). Vaccine efficacy against G1 wild-type, G12 and G8 types were 64.1% (95% CI: 29.9%; 82%), 51.5% (95% CI:-6.5%; 77.9%) and 64.4% (95% CI: 17.1%; 85.2%), respectively. Genotype P[8] was the predominant circulating P type and was detected in 38 (2.6%) severe rotavirus gastroenteritis cases in placebo group. The remaining circulating P types comprised of P[4] (20 [1.4%] in placebo) and P[6] (13 [0.9%] in placebo). Vaccine efficacy against P[8] was 59.1% (95% CI: 32.8%; 75.3%), P[4] was 70.9% (95% CI: 37.5%; 87.0%) and P[6] was 55.2% (95% CI: -6.5%; 81.3%)
Conclusions
Rotarix™ vaccine demonstrated efficacy against severe gastroenteritis caused by diverse circulating rotavirus types. These data add to a growing body of evidence supporting heterotypic protection provided by Rotarix™.
Trial registration number
NCT00241644
doi:10.1186/1471-2334-12-213
PMCID: PMC3462149  PMID: 22974466
16.  Incidence and Clinical Characteristics of Group A Rotavirus Infections among Children Admitted to Hospital in Kilifi, Kenya  
PLoS Medicine  2008;5(7):e153.
Background
Rotavirus, predominantly of group A, is a major cause of severe diarrhoea worldwide, with the greatest burden falling on young children living in less-developed countries. Vaccines directed against this virus have shown promise in recent trials, and are undergoing effectiveness evaluation in sub-Saharan Africa. In this region limited childhood data are available on the incidence and clinical characteristics of severe group A rotavirus disease. Advocacy for vaccine intervention and interpretation of effectiveness following implementation will benefit from accurate base-line estimates of the incidence and severity of rotavirus paediatric admissions in relevant populations. The study objective was to accurately define the incidence and severity of group A rotavirus disease in a resource-poor setting necessary to make informed decisions on the need for vaccine prevention.
Methods and Findings
Between 2002 and 2004 we conducted prospective surveillance for group A rotavirus infection at Kilifi District Hospital in coastal Kenya. Children < 13 y of age were eligible as “cases” if admitted with diarrhoea, and “controls” if admitted without diarrhoea. We calculated the incidence of hospital admission with group A rotavirus using data from a demographic surveillance study of 220,000 people in Kilifi District. Of 15,347 childhood admissions 3,296 (22%) had diarrhoea, 2,039 were tested for group A rotavirus antigen and, of these, 588 (29%) were positive. 372 (63%) rotavirus-positive cases were infants. Of 620 controls 19 (3.1%, 95% confidence interval [CI] 1.9–4.7) were rotavirus positive. The annual incidence (per 100,000 children) of rotavirus-positive admissions was 1,431 (95% CI 1,275–1,600) in infants and 478 (437–521) in under-5-y-olds, and highest proximal to the hospital. Compared to children with rotavirus-negative diarrhoea, rotavirus-positive cases were less likely to have coexisting illnesses and more likely to have acidosis (46% versus 17%) and severe electrolyte imbalance except hyponatraemia. In-hospital case fatality was 2% among rotavirus-positive and 9% among rotavirus-negative children.
Conclusions
In Kilifi > 2% of children are admitted to hospital with group A rotavirus diarrhoea in the first 5 y of life. This translates into over 28,000 vaccine-preventable hospitalisations per year across Kenya, and is likely to be a considerable underestimate. Group A rotavirus diarrhoea is associated with acute life-threatening metabolic derangement in otherwise healthy children. Although mortality is low in this clinical research setting this may not be generally true in African hospitals lacking rapid and appropriate management.
Combining prospective hospital-based surveillance with demographic data in Kilifi, Kenya, James Nokes and colleagues assess the burden of rotavirus diarrhea in young children.
Editors' Summary
Background.
Rotavirus is a leading global cause of diarrhea in babies and young children. Indeed, most children become infected at least once with this virus before their fifth birthday. Rotavirus is usually spread by children or their caregivers failing to wash their hands properly after going to the toilet and then contaminating food or drink. The symptoms of rotavirus infection—diarrhea, vomiting, and fever—are usually mild, but if the diarrhea is severe it can quickly lead to dehydration. Mild to moderate dehydration can be treated at home by providing the patient with plenty of fluids or with a special rehydration drink that replaces lost water and salts. However, for infants or toddlers who become severely dehydrated, rehydration with intravenous fluids (fluids injected directly into a vein) in hospital may be essential. Unfortunately, in developing countries in sub-Saharan Africa and elsewhere, this treatment is not widely available and every year more than half a million young children die from rotavirus infections.
Why Was This Study Done?
Two rotavirus vaccines that could reduce this burden of disease are currently undergoing clinical trials to determine their effectiveness in sub-Saharan Africa. However, very little is known about the incidence of severe rotavirus infections among children living in this region (that is, how many children develop severe disease every year) or about the clinical characteristics of the disease here. Public-health officials need this baseline information before they can make informed decisions about the mass introduction of rotavirus vaccination and to help them judge whether the intervention has been successful if it is introduced. In this study, the researchers examine the incidence and clinical characteristics of rotavirus infections (specifically, group A rotavirus [GARV] infections; there are several different rotaviruses but GARV causes most human infections) among children admitted to the district hospital in Kilifi, Kenya.
What Did the Researchers Do and Find?
During the 3-year study, more than 15,000 children under the age of 13 years were admitted to Kilifi District Hospital, a little under a quarter of whom had severe diarrhea. Nearly a third of the patients admitted with diarrhea who were tested had a GARV-specific protein in their stools (faeces); by contrast, only three in 100 children admitted without diarrhea showed any evidence of GARV infection. Two-thirds of the GARV-positive children were infants (under 1 year old). Using these figures and health surveillance data (records of births, deaths, and causes of death) collected in the area around the hospital, the researchers calculated that the annual incidence (per 100,000 children) of GARV-positive hospital admissions in the region was 1,431 for infants and 478 for children under age 5 years. Children with GARV-positive diarrhea were less likely to have other illnesses (for example, malnutrition) than those admitted with GARV-negative diarrhea, the researchers report, but were more likely to have life-threatening complications such as severe dehydration and salt imbalances in their blood. However, despite being more ill on admission, only 1 in 50 children with GARV-positive diarrhea died, compared to nearly 1 in 10 of the children with GARV-negative diarrhea; the GARV-positive children also left hospital quicker than those who were GARV-negative.
What Do These Findings Mean?
These findings indicate that severe GARV-positive diarrhea is a major cause of hospital admission among otherwise healthy young children in the Kilifi region of Kenya. By the time they are 5 years old, the researchers estimate that 1 in 50 of the children living in this region will have been admitted to hospital with severe GARV-positive diarrhea. Because rotavirus vaccines prevent virtually all severe rotavirus-associated disease (at least in developed countries where their effectiveness has been extensively tested), the researchers estimate that vaccination might prevent more than 28,000 hospitalizations annually across Kenya; however, this prediction assumes that it is valid to extrapolate from the data obtained from this one district hospital to the entire country.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050153.
The US Centers for Disease Control and Prevention provides information about rotavirus infections, surveillance, and vaccination (in English and Spanish)
The UK National Health Service Direct health encyclopedia provides information on rotavirus infections
MedlinePlus also provides links to information on rotavirus (in English and Spanish)
The African Rotavirus Surveillance Network is working to improve knowledge about rotavirus infections in Africa
The Rotavirus Vaccine Program aims to reduce child illness and death from diarrhea by increasing the availability of rotavirus vaccines in developing countries (in English and Spanish)
PATH, a nonprofit international organization that aims to create sustainable, culturally relevant solutions to global health problems, also provides detailed information on rotavirus surveillance and disease burden
doi:10.1371/journal.pmed.0050153
PMCID: PMC2488191  PMID: 18651787
17.  Rotavirus Vaccines: an Overview 
Clinical Microbiology Reviews  2008;21(1):198-208.
Rotavirus infection is the most common cause of severe diarrhea disease in infants and young children worldwide and continues to have a major global impact on childhood morbidity and mortality. Vaccination is the only control measure likely to have a significant impact on the incidence of severe dehydrating rotavirus disease. In 1999, a highly efficacious rotavirus vaccine licensed in the United States, RotaShield, was withdrawn from the market after 14 months because of its association with intussusception. Two new live, oral, attenuated rotavirus vaccines were licensed in 2006: the pentavalent bovine-human reassortant vaccine (RotaTeq) and the monovalent human rotavirus vaccine (Rotarix). Both vaccines have demonstrated very good safety and efficacy profiles in large clinical trials in western industrialized countries and in Latin America. Careful surveillance has not revealed any increased risk of intussusception in the vaccinated groups with either vaccine. The new rotavirus vaccines are now introduced for routine use in a number of industrialized and developing countries. These new safe and effective rotavirus vaccines offer the best hope of reducing the toll of acute rotavirus gastroenteritis in both developed and developing countries.
doi:10.1128/CMR.00029-07
PMCID: PMC2223838  PMID: 18202442
18.  Decline in Diarrhea Mortality and Admissions after Routine Childhood Rotavirus Immunization in Brazil: A Time-Series Analysis 
PLoS Medicine  2011;8(4):e1001024.
A time series analysis by Manish Patel and colleagues shows that the introduction of rotavirus vaccination in Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children under 5 years of age.
Background
In 2006, Brazil began routine immunization of infants <15 wk of age with a single-strain rotavirus vaccine. We evaluated whether the rotavirus vaccination program was associated with declines in childhood diarrhea deaths and hospital admissions by monitoring disease trends before and after vaccine introduction in all five regions of Brazil with varying disease burden and distinct socioeconomic and health indicators.
Methods and Findings
National data were analyzed with an interrupted time-series analysis that used diarrhea-related mortality or hospitalization rates as the main outcomes. Monthly mortality and admission rates estimated for the years after rotavirus vaccination (2007–2009) were compared with expected rates calculated from pre-vaccine years (2002–2005), adjusting for secular and seasonal trends. During the three years following rotavirus vaccination in Brazil, rates for diarrhea-related mortality and admissions among children <5 y of age were 22% (95% confidence interval 6%–44%) and 17% (95% confidence interval 5%–27%) lower than expected, respectively. A cumulative total of ∼1,500 fewer diarrhea deaths and 130,000 fewer admissions were observed among children <5 y during the three years after rotavirus vaccination. The largest reductions in deaths (22%–28%) and admissions (21%–25%) were among children younger than 2 y, who had the highest rates of vaccination. In contrast, lower reductions in deaths (4%) and admissions (7%) were noted among children two years of age and older, who were not age-eligible for vaccination during the study period.
Conclusions
After the introduction of rotavirus vaccination for infants, significant declines for three full years were observed in under-5-y diarrhea-related mortality and hospital admissions for diarrhea in Brazil. The largest reductions in diarrhea-related mortality and hospital admissions for diarrhea were among children younger than 2 y, who were eligible for vaccination as infants, which suggests that the reduced diarrhea burden in this age group was associated with introduction of the rotavirus vaccine. These real-world data are consistent with evidence obtained from clinical trials and strengthen the evidence base for the introduction of rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Diarrheal disease, usually caused by infectious agents, is the second major cause of death in children aged under five years. As highlighted in a recent PLoS Medicine series, access to clean water and improved sanitation is the key to the primary prevention of diarrheal illnesses. Yet despite the targets of Millennium Development Goal 7 to half the number of people without access to clean water or improved sanitation by 2015, over one billion people worldwide do not currently have access to clean water and over two billion do not currently have access to improved sanitation.
Since enteric viruses are primarily transmitted directly from one person to another, they cannot be controlled completely by improvements in sanitation. Therefore, although not replacing the urgent need to provide access to clean water and improved sanitation for all, vaccination programs that protect young children against some infections that cause diarrhea, such as rotavirus, which accounts for one-third of all child deaths caused by diarrhea, are a pragmatic way forward. As large clinical trials have shown the safety and efficacy of rotavirus vaccines in population settings, in July 2009, the World Health Organization recommended including rotavirus vaccines into every country's national immunization programs.
Why Was This Study Done?
Although the protective effect of rotavirus vaccines has been assessed in various high-, middle-, and low-income settings, for reasons that remain unclear, the efficacy of live, oral rotavirus vaccines appears to be dependent on geographical location and correlated to the socioeconomic status of the population. Because of these concerns, evaluating the health impact of large-scale rotavirus vaccine programs and ensuring their equity in a real-world setting (rather than in clinical trial conditions) is important.
Therefore, the researchers addressed this issue by conducting this study to evaluate the effect of rotavirus vaccination on mortality and hospital admissions for diarrhea due to all causes among young children in the five regions of Brazil. The researchers chose to do this study in Brazil because of the high incidence of diarrhea-related deaths and hospital admissions and because five years ago, in July 2006, the Brazilian Ministry of Health introduced the single-strain rotavirus vaccine simultaneously in all 27 states through its national immunization program—allowing for “before” and “after” intervention analysis.
What Did the Researchers Do and Find?
The researchers obtained data on diarrheal deaths and hospital admissions in children aged under five years for the period 2002–2005 and 2007–2009 and data on rotavirus vaccination rates. The researchers got the data on diarrhea deaths from the Brazilian Mortality Information System—the national database of information collected from death certificates that covers 90% of all deaths in Brazil. The data on hospital admissions came from the electronic Hospital Information System of Brazil's Unified Health System (Sistema Unico de Saúde, SUS)—the publicly funded health-care system that covers roughly 70% of the hospitalizations and includes information on all admissions (from public hospitals and some private hospitals) authorized for payment by the Unified Health System. The researchers got regional rotavirus vaccination coverage estimates for 2007–2009 from the information department of the Ministry of Health, and estimated coverage of the two doses of oral rotavirus vaccine by taking the annual number of second doses administered divided by the number of infants in the region.
In 2007, an estimated 80% of infants received two doses of rotavirus vaccine, and by 2009, this proportion rose to 84% of children younger than one year of age. The researchers found that in the three years following the introduction of rotavirus vaccination, diarrhea-related mortality rates and admissions among children aged under five years were respectively 22% and 17% lower than expected, with a cumulative total of 1,500 fewer diarrhea deaths and 130,000 fewer admissions. Furthermore, the largest reductions in deaths and admissions were among children who had the highest rates of vaccination (less than two years of age), and the lowest reductions were among children who were not eligible for vaccination during the study period (aged 2–4 years).
What Do These Findings Mean?
These findings suggest that the introduction of rotavirus vaccination in all areas of Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children aged under five years. These real-world impact data are consistent with the clinical trials and strengthen the evidence base for rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea.
These findings have important global policy implications. In middle-income countries, such as Brazil, that are not eligible for financial support from donors, the potential reductions in admissions and other health-care costs will be important for cost-effectiveness considerations to justify the purchase of these still relatively expensive vaccines.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001024
PLoS Medicine has published a series on water and sanitation
More information is available from the World Health Organization on diarrheal illness in children
More information is available about rotavirus vaccines from the World Health Organization, the US Centers for Disease Control and Prevention, and the Rotavirus Vaccine Program
doi:10.1371/journal.pmed.1001024
PMCID: PMC3079643  PMID: 21526228
19.  Health and economic impact of rotavirus vaccination in GAVI-eligible countries 
BMC Public Health  2010;10:253.
Background
Rotavirus infection is responsible for about 500,000 deaths annually, and the disease burden is disproportionately borne by children in low-income countries. Recently the World Health Organization (WHO) has released a global recommendation that all countries include infant rotavirus vaccination in their national immunization programs. Our objective was to provide information on the expected health, economic and financial consequences of rotavirus vaccines in the 72 GAVI support-eligible countries.
Methods
We synthesized population-level data from various sources (primarily from global-level databases) for the 72 countries eligible for the support by the GAVI Alliance (GAVI-eligible countries) in order to estimate the health and economic impact associated with rotavirus vaccination programs. The primary outcome measure was incremental cost (in 2005 international dollars [I$]) per disability-adjusted life year (DALY) averted. We also projected the expected reduction in rotavirus disease burden and financial resources required associated with a variety of scale-up scenarios.
Results
Under the base-case assumptions (70% coverage), vaccinating one single birth cohort would prevent about 55% of rotavirus associated deaths in the 72 GAVI-eligible countries. Assuming I$25 per vaccinated child (~$5 per dose), the number of countries with the incremental cost per DALY averted less than I$200 was 47. Using the WHO's cost-effectiveness threshold based on per capita GDP, the vaccines were considered cost-effective in 68 of the 72 countries (~94%). A 10-year routine rotavirus vaccination would prevent 0.9-2.8 million rotavirus associated deaths among children under age 5 in the poorest parts of the world, depending on vaccine scale-up scenarios. Over the same intervention period, rotavirus vaccination programs would also prevent 4.5-13.3 million estimated cases of hospitalization and 41-107 million cases of outpatient clinic visits in the same population.
Conclusions
Our findings suggest that rotavirus vaccination would be considered a worthwhile investment for improving general development as well as childhood health level in most low-income countries, with a favorable cost-effectiveness profile even under a vaccine price ($1.5-$5.0 per dose) higher than those of traditional childhood vaccines.
doi:10.1186/1471-2458-10-253
PMCID: PMC2893091  PMID: 20470426
20.  A qualitative assessment of factors influencing acceptance of a new rotavirus vaccine among health care providers and consumers 
BMC Pediatrics  2007;7:32.
Background
In 2006, a new rotavirus vaccine (RotaTeq) was licensed in the US and recommended for routine immunization of all US infants. Because a previously licensed vaccine (Rotashield) was withdrawn from the US for safety concerns, identifying barriers to uptake of RotaTeq will help develop strategies to broaden vaccine coverage.
Methods
We explored beliefs and attitudes of parents (n = 57) and providers (n = 10) towards rotavirus disease and vaccines through a qualitative assessment using focus groups and in-depth interviews.
Results
All physicians were familiar with safety concerns about rotavirus vaccines, but felt reassured by RotaTeq's safety profile. When asked about likelihood of using RotaTeq on a scale of one to seven (1 = "absolutely not;" 7 = "absolutely yes") the mean score was 5 (range = 3–6). Physicians expressed a high likelihood of adopting RotaTeq, particularly if recommended by their professional organizations and expressed specific interest in post-marketing safety data. Similarly, consumers found the RotaTeq safety profile to be favorable and would rely on their physician's recommendation for vaccination. However, when asked to rank likelihood of having their child vaccinated against rotavirus (1 = "definitely not get;" 7 = "definitely get"), 29% ranked 1 or 2, 36% 3 or 4, and 35% 5 to 7.
Conclusion
Our qualitative assessment provides complementary data to recent quantitative surveys and suggests that physicians and parents are likely to adopt the newly licensed rotavirus vaccine. Increasing parental awareness of the rotavirus disease burden and providing physicians with timely post-marketing surveillance data will be integral to a successful vaccination program.
doi:10.1186/1471-2431-7-32
PMCID: PMC2203981  PMID: 17945010
21.  Epidemiology and Genetic Diversity of Rotavirus Strains in Children with Acute Gastroenteritis in Lahore, Pakistan 
PLoS ONE  2013;8(6):e67998.
Pakistan harbors high disease burden of gastro-enteric infections with majority of these caused by rotavirus. Unfortunately, lack of proper surveillance programs and laboratory facilities have resulted in scarcity of available data on rotavirus associated disease burden and epidemiological information in the country. We investigated 1306 stool samples collected over two years (2008–2009) from hospitalized children under 5 years of age for the presence of rotavirus strains and its genotypic diversity in Lahore. The prevalence rate during 2008 and 2009 was found to be 34% (n = 447 out of 1306). No significant difference was found between different age groups positive for rotavirus (p>0.05). A subset of EIA positive samples was further screened for rotavirus RNA through RT-PCR and 44 (49.43%) samples, out of total 89 EIA positive samples, were found positive. G and P type prevalence was found as follows: G1P [4] = 3(6.81%); G1P [6] = 9(20.45%); G1P [8] = 1(2.27%); G2P [4] = 21(47.72%); G2P [8] = 1(2.27%); G9P [4] = 1(2.27%); G9P [6] = 1(2.27%) and G9P [8] = 7(15.90%). Phylogenetic analysis revealed that the VP7 and VP4 sequences clustered closely with the previously detected strains in the country as well as Belgian rotaviruses. Antigenic characterization was performed by analyzing major epitopes in the immunodominant VP7 and VP4 gene segments. Although the neutralization conferring motifs were found variable between the Pakistani strains and the two recommended vaccines strains (Rotarix™ and RotaTeq™), we validate the use of rotavirus vaccine in Pakistan based on the proven and recognized vaccine efficacy across the globe. Our findings constitute the first report on rotavirus’ genotype diversity, their phylogenetic relatedness and epidemiology during the pre-vaccination era in Lahore, Pakistan and support the immediate introduction of rotavirus vaccine in the routine immunization program of the country.
doi:10.1371/journal.pone.0067998
PMCID: PMC3692488  PMID: 23825693
22.  Evaluating the safety of a rotavirus vaccine: the REST of the story 
The Rotavirus Efficacy and Safety Trial (REST) was a blinded, placebo-controlled study of the live pentavalent human-bovine vaccine, RotaTeq® (Merck & Co. Inc., West Point, PA). REST was noteworthy because its primary objective was to evaluate the safety of RotaTeq® with regard to intussusception, a rare intestinal illness that occurs with a background incidence of approximately 50 cases per 100 000 infant years. The study involved approximately 70 000 infants at over 500 study sites in 11 countries. The study demonstrated that the risk of intussusception was similar in vaccine and placebo recipients and that the vaccine prevented rotavirus gastroenteritis, ameliorated the severity of disease in those who had any disease, and substantially reduced rotavirus-associated hospitalizations and other health care contacts. This report provides an in-depth review of the background, statistical and regulatory considerations, and execution of REST. We describe the rationale and methods used for sample size, continuous safety monitoring, group sequential design, and detailed study execution. The results of the study have been reported elsewhere. The design and conduct of this study may serve as a useful model for planning other future large-scale clinical trials, especially those evaluating uncommon adverse events.
doi:10.1177/1740774508090507
PMCID: PMC2602609  PMID: 18375651
23.  The temporal relationship between RotaTeq immunization and intussusception adverse events in the Vaccine Adverse Event Reporting System (VAERS) 
Summary
Background
In August of 2006, the Advisory Committee on Immunization Practices (ACIP) recommended RotaTeq for routine vaccination of US infants. The hypothesis tested in the present study is that rotavirus vaccines are associated with an increased risk of intussusception adverse events (AEs) characterized by an onset in a biologically plausible a priori identified temporal period post-vaccination (days 3 to 7).
Material/Methods
The Vaccine Adverse Event Reporting System (VAERS) updated as of December 28, 2010 was analyzed.
Results
Following RotaTeq vaccination, a significantly (p<0.001) higher percentage of AEs were classified as serious, permanently disabling, resulted in hospitalizations, or were life-threatening among intussusception AEs in comparison to the total AE reports (removing intussusception AE reports) submitted to VAERS. A significantly greater portion of intussusception AEs in comparison to the portion of total AE reports (removing intussusception AE reports) were reported to VAERS in the onset interval from 3 to 7 days post-RotaTeq vaccination than within the onset interval from 1 to 2 days post-RotaTeq vaccination (78.7% vs. 29.1%, risk ratio=2.7, 95% CI=2.4–3.0, p<0.0001). It was assumed in our onset time-trend analyses of the distribution of AEs following Rota-Teq vaccination that the AE’s should be equally likely to be reported with an onset time for each day, from 1 to 9 days post-vaccination or, alternatively, should follow similar daily proportions as observed for total AEs reports (removing intussusception AE reports). Results of this onset time-trend analyses of the distribution of intussusception AEs reported to VAERS following Rota-Teq vaccination revealed significant differences (p<0.001) from our expectations. Consistent and similarly remarkable trends were observed for intussusception AE reports associated with RotaShield vaccine.
Conclusions
The present study significantly associates RotaTeq vaccination with intussusception AEs.
doi:10.12659/MSM.882470
PMCID: PMC3560585  PMID: 22293889
intussusception; post-marketing surveillance; rotavirus; timing; vaccine
24.  Construction and Characterization of Human Rotavirus Recombinant VP8* Subunit Parenteral Vaccine Candidates 
Vaccine  2012;30(43):6121-6126.
Two currently licensed live oral rotavirus vaccines (Rotarix® and RotaTeq®) are highly efficacious against severe rotavirus diarrhea. However, the efficacy of such vaccines in selected low-income African and Asian countries is much lower than that in middle or high-income countries. Additionally, these two vaccines have recently been associated with rare case of intussusception in vaccinated infants. We developed a novel recombinant subunit parenteral rotavirus vaccine which may be more effective in low-income countries and also avert the potential problem of intussusception. Truncated recombinant VP8* (ΔVP8*) protein of human rotavirus strain Wa P[8], DS-1 P[4] or 1076 P[6] expressed in E. coli was highly soluble and was generated in high yield. Guinea pigs hyperimmunized intramuscularly with each of the ΔVP8* proteins (i.e., (P[8], P[4] or P[6]) developed high levels of homotypic as well as variable levels of heterotypic neutralizing antibodies. Moreover, the selected ΔVP8* proteins when administered to mice at a clinically relevant dosage, route and schedule, elicited high levels of serum anti-VP8* IgG and/or neutralizing antibodies. Our data indicated that the ΔVP8* proteins may be a plausible additional candidate as new parenteral rotavirus vaccines.
doi:10.1016/j.vaccine.2012.07.078
PMCID: PMC3434302  PMID: 22885016
Rotavirus; Vaccine; Subunit vaccine; VP8* protein; P type
25.  Economic Impact of a Rotavirus Vaccine in Brazil 
The study was done to evaluate the cost-effectiveness of a national rotavirus vaccination programme in Brazilian children from the healthcare system perspective. A hypothetical annual birth-cohort was followed for a five-year period. Published and national administrative data were incorporated into a model to quantify the consequences of vaccination versus no vaccination. Main outcome measures included the reduction in disease burden, lives saved, and disability-adjusted life-years (DALYs) averted. A rotavirus vaccination programme in Brazil would prevent an estimated 1,804 deaths associated with gastroenteritis due to rotavirus, 91,127 hospitalizations, and 550,198 outpatient visits. Vaccination is likely to reduce 76% of the overall healthcare burden of rotavirus-associated gastroenteritis in Brazil. At a vaccine price of US$ 7-8 per dose, the cost-effectiveness ratio would be US$ 643 per DALY averted. Rotavirus vaccination can reduce the burden of gastroenteritis due to rotavirus at a reasonable cost-effectiveness ratio.
PMCID: PMC2740695  PMID: 19069617
Costs and cost analysis; Diarrhoea, Infantile; Gastroenteritis; Morbidity; Rotavirus; Rotavirus vaccines; Vaccination; Brazil

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