Rotavirus Vaccine Effectiveness Research Articles

The case test-negative design for studies of the effectiveness of influenza vaccine

BackgroundA modification to the case–control study design has become popular to assess vaccine effectiveness (VE) against viral infections. Subjects with symptomatic illness seeking medical care are tested by a highly specific polymerase chain reaction (PCR) assay for the detection of the infection of interest. Cases are subjects testing positive for the virus; those testing negative represent the comparison group. Influenza and rotavirus VE studies using this design are often termed “test-negative case-control” studies, but this design has not been formally described or evaluated. We explicitly state several assumptions of the design and examine the conditions under which VE estimates derived with it are valid and unbiased. MethodsWe derived mathematical expressions for VE estimators obtained using this design and examined their statistical properties. We used simulation methods to test the validity of the estimators and illustrate their performance using an influenza VE study as an example. ResultsBecause the marginal ratio of cases to non-cases is unknown during enrollment, this design is not a traditional case-control study; we suggest the name “case test-negative” design. Under sets of increasingly general assumptions, we found that the case test-negative design can provide unbiased VE estimates. However, differences in health care-seeking behavior among cases and non-cases by vaccine status, strong viral interference, or modification of the probability of symptomatic illness by vaccine status can bias VE estimates. ConclusionsVaccine effectiveness estimates derived from case test-negative studies are valid and unbiased under a wide range of assumptions. However, if vaccinated cases are less severely ill and seek care less frequently than unvaccinated cases, then an appropriate adjustment for illness severity is required to avoid bias in effectiveness estimates. Viral interference will lead to a non-trivial bias in the vaccine effectiveness estimate from case test-negative studies only when incidence of influenza is extremely high and duration of transient non-specific immunity is long.

Determining the effectiveness of the pentavalent rotavirus vaccine against rotavirus hospitalizations and emergency department visits using two study designs

The objective of this study is to determine the vaccine effectiveness (VE) of the pentavalent rotavirus vaccine (RV5) for preventing rotavirus-related hospitalizations and emergency department (ED) visits during the 2006–07 and 2007–08 rotavirus seasons using two study designs. Active, prospective population-based surveillance was conducted to identify cases of laboratory-confirmed rotavirus-related hospitalizations and ED visits to be used in case-cohort and case-control designs. VE was calculated using one comparison group for the case-cohort method and two comparison groups for the case-control method. The VE estimates produced by the three analyses were similar. Three doses of RV5 were effective for preventing rotavirus-related hospitalizations and ED visits in each analysis, with VE estimated as 92% in all three analyses. Two doses of RV5 were also effective, with VE ranging from 79% to 83%. A single dose was effective in the case-cohort analysis, but was not significant in either of the case-control analyses. The case-cohort and the case-control study designs produced the same VE point estimates for completion of the three dose series. Two and three doses of RV5 were effective in preventing rotavirus-related hospitalizations and ED visits.

Effect of Rotavirus Vaccine on Diarrhea Mortality in Different Socioeconomic Regions of Mexico

In Mexico, declines in childhood diarrhea deaths have been documented during 2008-2010 after rotavirus vaccine introduction in 2007. Because of concerns about variation in rotavirus vaccine efficacy by socioeconomic status, we compared reductions in diarrhea mortality in the lesser developed southern region versus the more developed northern and central regions of Mexico. We obtained data from national vital statistics on diarrhea deaths among children aged <5 years from 2002 through 2011. We compared region-specific diarrhea mortality before (2003-2006) and after (2009-2011) vaccine introduction. Regional vaccine coverage was estimated from administrative data, and socioeconomic status was assessed by using the Human Development Index. In northern, central, and southern Mexico, the 2007 Human Development Index was 0.84, 0.82, and 0.77, respectively, and by 2010 an estimated 99%, 84%, and 89% of children aged <12 months had completed rotavirus vaccination. Diarrhea mortality among children <5 years old declined from 8.3, 17.9, and 28.5 deaths per 100,000 children during 2003-2006 to 4.5, 8.1, and 16.2 in 2009-2011 in northern, central, and southern Mexico, respectively, corresponding to rate reductions of 45%, 55%, and 43%. No significant differences were observed in rate reductions between regions (P > .8). After introduction of rotavirus vaccination, marked and sustained declines in diarrhea deaths were seen among children in all regions of Mexico, including in the least developed southern region with the highest baseline diarrhea mortality. This finding indicates equitable vaccine delivery to children with varying risk of mortality and reaffirms the beneficial effects of rotavirus vaccination against fatal diarrheal disease.

Global Seasonality of Rotavirus Disease

A substantial number of surveillance studies have documented rotavirus prevalence among children admitted for dehydrating diarrhea. We sought to establish global seasonal patterns of rotavirus disease before the introduction of widespread vaccination. We reviewed studies of rotavirus detection in children with diarrhea published since 1995. We assessed potential relationships between seasonal prevalence and locality by plotting the average monthly proportion of diarrhea cases positive for rotavirus according to geography, country development and latitude. We used linear regression to identify variables that were potentially associated with the seasonal intensity of rotavirus. Among a total of 99 studies representing all 6 geographic regions of the world, patterns of year-round disease were more evident in low- and low-middle income countries compared with upper-middle and high-income countries where disease was more likely to be seasonal. The level of country development was a stronger predictor of strength of seasonality (P = 0.001) than geographic location or climate. However, the observation of distinctly different seasonal patterns of rotavirus disease in some countries with similar geographic location, climate and level of development indicate that a single unifying explanation for variation in seasonality of rotavirus disease is unlikely. While no unifying explanation emerged for varying rotavirus seasonality globally, the country income level was somewhat more predictive of the likelihood of having seasonal disease than other factors. Future evaluation of the effect of rotavirus vaccination on seasonal patterns of disease in different settings may help understand factors that drive the global seasonality of rotavirus disease.

Treatment and Prevention of Rotavirus Infection in Children

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. No antiviral therapy is available. Treatment of rotavirus gastroenteritis is limited to rehydration therapy. Recently, therapies, such as probiotics, have been developed as adjuncts to rehydration therapy. Two effective rotavirus vaccines are available and recommended for routine immunization of all infants. These vaccines have been introduced in both developed and developing countries. As rotavirus vaccines are implemented, studies that assess health impact, indirect benefits, and strain changes after the introduction of rotavirus vaccine have been reported. In the United States, rotavirus vaccination has led to dramatic drops in severe rotavirus-related hospitalizations and has reduced emergency room visits. Herd immunity has also been noted after routine rotavirus immunization. There have been no significant strain shifts or escape mutants noted since the introduction of rotavirus vaccines.

Effect of Rotavirus Vaccine on Diarrhea Mortality in Different Socioeconomic Regions of Mexico

Effect of Rotavirus Vaccine on Diarrhea Mortality in Different Socioeconomic Regions of Mexico

Effectiveness of an Incomplete RotaTeq (RV5) Vaccination Regimen in Preventing Rotavirus Gastroenteritis in the United States

Effectiveness of the pentavalent rotavirus vaccine (RV5) after administration of the complete (3 dose) regimen has been demonstrated in a real-world setting. This study assessed the effectiveness of RV5 following partial completion of the 3-dose regimen. Using a large national health insurance claims database, 2 cohorts of infants (those who received RV5 and a concurrent group who received diphtheria-tetanus-acellular pertussis, but not RV5) were followed through the 2007 and 2008 rotavirus seasons (January 1 to May 31) to identify cases of rotavirus gastroenteritis and all-cause gastroenteritis resulting in medical care encounters. Vaccine effectiveness following the first and the second RV5 doses was estimated by quantifying reductions in hospitalizations, emergency department (ED) and physician office visits. A first RV5 dose was received by 42,306 infants whereas 28,417 infants in the concurrent comparison group received a first diphtheria-tetanus-acellular pertussis dose; 43,704 infants received a second RV5 dose, and 31,810 infants received a second diphtheria-tetanus-acellular pertussis dose. One dose of RV5 was associated with 88% effectiveness against rotavirus gastroenteritis hospitalizations and ED visits and 44% effectiveness against all-cause gastroenteritis hospitalizations and ED visits. A 2-dose regimen of RV5 was associated with 94% effectiveness against rotavirus gastroenteritis hospitalizations and ED visits and 40% effectiveness against all-cause gastroenteritis hospitalizations and ED visits. The RV5 vaccine exhibits effectiveness against rotavirus gastroenteritis even before completing the full 3-dose regimen. These results are of particular relevance when considering the benefits of a partially completed rotavirus vaccine series.

­­Adherence to rotavirus vaccination quality measures in a commercially insured population

Background: This retrospective study determined the level of compliance to rotavirus vaccination guidelines within a large, commercially insured US population, as well as compliance with PI, ACIP and HEDIS measures for rotavirus vaccination.Methods: Medical and pharmacy claims were obtained from the HealthCore Integrated Research Database. Enrolled children were stratified into PI, ACIP and HEDIS cohorts. The PI cohort was subdivided into RV5 and RV1 cohorts due to the differences in dosing schedules and patients with mixed dosing were excluded from the these two cohorts. Patients identified in the HEDIS cohort were linked to the administering physicians.Results: Of 162,614 patients in PI cohort, 27% did not receive rotavirus vaccinations, 24% (RV5) and 15% (RV1) had incomplete doses (p < 0.0001; RV1 vs. RV5). A total of 76% of patients completed RV5 series but not on schedule, 54% completed on schedule. A total of 85% of patients completed the RV1 series at any time, 69% completed on schedule. Among health plans, 53% of patients completed the series, 22% (RV5) and 15% (RV1) had incomplete doses (p < 0.0001). Of 2,086 physicians who treated ≥ 10 patients within the plan (regardless of vaccination status), 78% had > 50% of patients complete, 22% had > 90% of patients completed.Conclusion: Despite both two effective rotavirus vaccines and national immunization recommendations, rotavirus vaccination remains underutilized for infants.

Rotavirus Vaccine Effectiveness and Case-control Study on Risk Factors for Breakthrough Infections in Germany, 2010–2011

In the German federal state Mecklenburg-Western Pomerania, routine rotavirus (RV) vaccination in infants has been recommended since 2009. The effectiveness of RV vaccination was investigated after an unexpectedly high number of RV infections in fully vaccinated children occurred. Intensified RV surveillance was performed in Mecklenburg-Western Pomerania between 2010 and 2011. The screening method was applied to assess vaccine effectiveness (VE) in children up to 24 months after vaccination. To identify risk factors for breakthrough infections, a case-control study and genotyping were conducted in vaccinated and unvaccinated RV-infected children. VE for the prevention of RV infection requiring medical attention or hospitalization was 68% (95% confidence interval [CI]: 61-71) and 80% (95% CI: 77-83), respectively. VE for preventing hospitalization but not medical attention remained stable over 2 years. Vaccinated were less often hospitalized (23%) than unvaccinated RV-infected children (61%; P < 0.001). Breastfeeding (odds ratio, 3.99; 95% CI: 1.92-8.27) and attending daycare (odds ratio, 3.42; 95% CI: 1.64-7.12) were independently associated with breakthrough infections. Genotype G1P[8] was detected more frequently in RotaTeq-vaccinated (44% versus 11%; P < 0.03) and G2P[4] in Rotarix-vaccinated children (42% versus 6%; P < 0.02). RV vaccination protects young children effectively from RV disease and can reduce disease severity. Breastfeeding might impair VE, but further research is needed to identify the critical time window for this interference and to develop appropriate recommendations.

Neurological Manifestaions in Acute Onset of Viral Gastroentritis

Back ground: AGE is one of the most common causes of morbidity and mortality in infants and children in developing countries with near 11,000 deaths per day in the world. Objective: To evaluate the prevalence of neurological manifestations in acute onset of viral gastrointestinal. Methods: A cross sectional /descriptive study performed upon 50 children admitted due to acute viral gastrointestinal infections in Department of pediatric Infectious Disease, Rasul Hospital, Tehran, Iran, 2010- 2011. Initially, a questionnaire was completed by an authorized physician for each cases (eg: age, gender, clinical signs, vomiting, diarrhea (type, time of onset, frequency) attending time from onset ,type of neurologic symptoms ,analysis of lab test (stool direct exams, biochemical parameters, stool culture, direct viral test in stool). All cases with bacterial or other known causes (except viral causes) for gastroenteritis, chronic diarrhea excluded from study. The studied cases were evaluated for existence of neurologic signs .Stool samples were searched for viral antigens (Rota & Adeno virus) by Rapid immune chromatographic test. P-values less than 0.05 were considered statistically significant. Results: Neurological manifestations observed in 16% of cases included seizure 12% aseptic meningitis 4%, 20% of adenoviral, 13.5% of rota virus and 33.3% of bi-infection had neurologic signs, with no differences (P=0.619). Mean age of cases had not significant difference between cases with and without neurologic manifestation. There was no significant association between neurological symptoms with age (P=0.755), sex, virus type and attending time (P>0.05). Conclusions: This study indicated that viral agents, especially rota virus can be obtained from near 60% of studied cases. Adenovirus (20%); Human Boca virus (8%) and other (undiagnosed) viral infection were less common causes. Neurological symptoms including seizure or aseptic meningitis might observe in 16% of children especially in cases with co-infection rota and adenoviral infection (33.3%) which is not related to age, sex and attending time. Rotavirus-associated encephalopathy described by some authors. Due to presence a safe and effective rotavirus vaccination, we prefer to routine usage of it as a public health priority in Iran. Further study is required to determine the role of rotavirus and other viral infection in diarrhea associated encephalopathy.

Dose sparing and enhanced immunogenicity of inactivated rotavirus vaccine administered by skin vaccination using a microneedle patch

Skin immunization is effective against a number of infectious diseases, including smallpox and tuberculosis, but is difficult to administer. Here, we assessed the use of an easy-to-administer microneedle (MN) patch for skin vaccination using an inactivated rotavirus vaccine (IRV) in mice. Female inbred BALB/c mice in groups of six were immunized once in the skin using MN coated with 5μg or 0.5μg of inactivated rotavirus antigen or by intramuscular (IM) injection with 5μg or 0.5μg of the same antigen, bled at 0 and 10 days, and exsanguinated at 28 days. Rotavirus-specific IgG titers increased over time in sera of mice immunized with IRV using MN or IM injection. However, titers of IgG and neutralizing activity were generally higher in MN immunized mice than in IM immunized mice; the titers in mice that received 0.5μg of antigen with MN were comparable or higher than those that received 5μg of antigen IM, indicating dose sparing. None of the mice receiving negative-control, antigen-free MN had any IgG titers. In addition, MN immunization was at least as effective as IM administration in inducing a memory response of dendritic cells in the spleen. Our findings demonstrate that MN delivery can reduce the IRV dose needed to mount a robust immune response compared to IM injection and holds promise as a strategy for developing a safer and more effective rotavirus vaccine for use among children throughout the world.

Effectiveness of the Lanzhou lamb rotavirus vaccine against gastroenteritis among children

The Lanzhou lamb rotavirus (LLR) vaccine has been in use in China since 2000. This study evaluated this vaccine's effectiveness using a case–control design in Guangzhou. In the study area, there were 3130 laboratory-confirmed rotavirus gastroenteritis cases in children between 2 and 35 months old from 2009 to 2011. A total of 3607 controls were also enrolled in this study. Of the subjects, 970 (14.4%) had received 1 dose of the LLR vaccine. Because of the low vaccination rate, we only obtained an effectiveness of 44.3% (95% CI, 28.4–56.7%) for children 9–11 months old, 52.8% (40.8–62.3%) for children 12–17 months old, and 51.8% (11.6–73.8%) for children 18–35 months old for one dose. This post-marketing study found that one dose of the LLR vaccine confers partial protection when given to children between 9 and 35 months old. Therefore, earlier immunization and the administration of the full immunization regimen should be encouraged.

Effectiveness and cost-effectiveness of pediatric rotavirus vaccination in British Columbia: A model-based evaluation

BackgroundRotavirus gastroenteritis (RVGE) is associated with widespread morbidity and mortality in children worldwide. In high-income countries, including Canada, the burden of RVGE relates largely to morbidity and healthcare utilization. Two live rotavirus vaccines (RotaTeq® (Merck Frosst Canada Ltd.) and Rotarix™ (GlaxoSmithKline Inc.)), are now approved for use in Canada, but their economic attractiveness has not been evaluated in the Canadian context. MethodsWe performed a model-based economic analysis using a Markov chain Monte Carlo simulation of RVGE in populations of British Columbia children. Models were parameterized based on best available data on disease natural history and epidemiology, vaccine effectiveness and cost, and healthcare costs, and calibrated such that projections of healthcare utilization and vaccine coverage closely matched empirical estimates. Robustness of projections was evaluated in deterministic and probabilistic sensitivity analyses. ResultsBased on the best available data, childhood immunization against RVGE was projected to prevent 63–81 infections per 100 children vaccinated, and to prevent substantial numbers of outpatient medical visits. It was projected that either vaccine would prevent 1–2 hospitalizations per 100 children immunized. Vaccination was projected to increase healthcare costs: immunization with Rotarix™ would prevent incident infections at a cost of approximately $10 per infection prevented or $2400 per quality-adjusted life-year gained. Vaccination with RotaTeq™ would be more costly and less effective and would not be preferred. Projections were robust in the face of wide-ranging sensitivity analyses. InterpretationThe use of currently available vaccines against RVGE in British Columbia children is projected to result in a substantial reduction in the burden of illness and healthcare utilization associated with RVGE, with a modest increase in healthcare costs. RVGE vaccination should be considered “highly cost-effective” relative to other commonly available health interventions.

Direct and Indirect Effects of Rotavirus Vaccination: Comparing Predictions from Transmission Dynamic Models

Early observations from countries that have introduced rotavirus vaccination suggest that there may be indirect protection for unvaccinated individuals, but it is unclear whether these benefits will extend to the long term. Transmission dynamic models have attempted to quantify the indirect protection that might be expected from rotavirus vaccination in developed countries, but results have varied. To better understand the magnitude and sources of variability in model projections, we undertook a comparative analysis of transmission dynamic models for rotavirus. We fit five models to reported rotavirus gastroenteritis (RVGE) data from England and Wales, and evaluated outcomes for short- and long-term vaccination effects. All of our models reproduced the important features of rotavirus epidemics in England and Wales. Models predicted that during the initial year after vaccine introduction, incidence of severe RVGE would be reduced 1.8–2.9 times more than expected from the direct effects of the vaccine alone (28–50% at 90% coverage), but over a 5-year period following vaccine introduction severe RVGE would be reduced only by 1.1–1.7 times more than expected from the direct effects (54–90% at 90% coverage). Projections for the long-term reduction of severe RVGE ranged from a 55% reduction at full coverage to elimination with at least 80% coverage. Our models predicted short-term reductions in the incidence of RVGE that exceeded estimates of the direct effects, consistent with observations from the United States and other countries. Some of the models predicted that the short-term indirect benefits may be offset by a partial shifting of the burden of RVGE to older unvaccinated individuals. Nonetheless, even when such a shift occurs, the overall reduction in severe RVGE is considerable. Discrepancies among model predictions reflect uncertainties about age variation in the risk and reporting of RVGE, and the duration of natural and vaccine-induced immunity, highlighting important questions for future research.

Effectiveness of rotavirus vaccination in prevention of hospital admissions for rotavirus gastroenteritis among young children in Belgium: case-control study

Objective To evaluate the effectiveness of rotavirus vaccination among young children in Belgium.Design Prospective case-control study.Setting Random sample of 39 Belgian hospitals, February 2008 to June 2010.Participants 215 children admitted...

Evaluating the health impact of a public-private partnership

The purpose of this article is to describe the RotaTeq® Nicaragua Partnership and the evaluation of the public health impact of the vaccine conducted by the partners, including the creation of a rotavirus surveillance program and a vaccine effectiveness assessment. The three main objectives of the partnership were to demonstrate that a new rotavirus vaccine could (1) be introduced rapidly in a developing country, (2) be successfully integrated into the existing vaccine delivery infrastructure, and (3) have a significant and measurable public health impact at the end of the 3-y program. The vaccine impact assessment required collaboration among partners with different areas of expertise, including the Nicaraguan Ministry of Health, Merck, local hospitals, government health clinics, laboratories, and a Technical Advisory Group. Through the partnership, RotaTeq® became available in a GAVI-eligible developing country, Nicaragua, in the same year it was approved in the United States. Vaccine coverage rapidly reached over > 90% of eligible Nicaraguan children. The impact assessment evaluated over 10,000 subjects and leveraged and enhanced the existing diarrheal surveillance infrastructure, ultimately providing the scientific community with some of the first real-world rotavirus vaccine effectiveness data from a developing country. The successful public-private partnership (PPP) was internationally recognized as a model for the rapid adoption of a new vaccine in a developing world setting. The model could be adapted to benefit other PPPs interested in demonstrating the impact of their own programs.

Trends of Rotavirus in Nepal

Rotavirus gastroenteritis is the major cause of morbidity and mortality in infants and young children worldwide. Safe and effective rotavirus vaccine is needed to have significant impact on severe rotavirus gastroenteritis. Currently, two live oral rotavirus vaccines have been licensed in many countries. Knowledge on distribution of human rotavirus of G and P types are essential before rotavirus vaccines are introduced in the target populations. To observe the trends of rotavirus strains in children below five years of age, during the years, 2003-2005 in Nepal. Stool specimen collected from children with acute diarrhea who were referred to observation unit or hospitalized in Kanti Children Hospital between 2003 and 2005 were examined. Meteorological data was obtained from Ministry of Environment, Nepal to examine the possibility on the impact of weather on rotavirus infection. Of 1250 stool specimens, 271(22%) were positive for rotavirus by Rotaclone ELISA. G1 was the most common serotype in the first year of study, and G2 in the following year. G12 serotype emerged and remained predominant in two consecutive years. In addition, G9 and G3 emerged in the second year of the study. Children less than three years of age were commonly affected. The records reveal that rotavirus infection is related to the climate, and is commonly seen in the dry season, peaking in January. Continued surveillance of different regions is needed to monitor the trend of rotavirus strains and to establish rotavirus disease burden, which will help policy makers to make a decision in introducing rotavirus vaccine in Nepal.

Malnutrition levels among vaccinated and unvaccinated children between 2 and 3 years of age following enrollment in a randomized clinical trial with the pentavalent rotavirus vaccine (PRV) in Bangladesh

A double-masked, individually randomized Phase 3 clinical trial to assess the efficacy, safety and immunogenicity of the pentavalent rotavirus vaccine (PRV), RotaTeq™, was conducted in rural Matlab, Bangladesh (NCT00362648). A total of 1136 infants were enrolled and randomized to receive either vaccine or placebo in a 1:1 ratio administered with the standard EPI vaccines at a mean age of approximately 8, 12, and 16 weeks. Weight was collected at four time points (study vaccine doses 1, 2, and 3, and a close-out visit in March 2009 at 15-26 months of age), and birth weight was retrospectively collected from information contained on the mother's health card when available. Approximately one year following trial completion a separate study was conducted to collect anthropometry measurements, including weight and height. These measurements were linked with Phase 3 trial data and a post hoc analysis was conducted to assess the effects of rotavirus vaccination on malnutrition among enrolled children who could be located when they were between 27 and 38 months old. Among the 1033 (91%) children located, and measured, for this analysis height-for-age and weight-for-height Z scores were calculated and compared between vaccine and placebo recipients at the anthropometry follow-up 1-year post-trial, and weight-for-age Z scores were calculated at four trial time points in addition to the anthropometry follow-up. The data indicated that there was no effect of rotavirus vaccination on malnutrition in this population at any of the measured time points. PRV, estimated to have about 43% efficacy against severe rotavirus gastroenteritis in this population, may not reduce the overall burden of diarrheal illness sufficiently among all vaccinees to appreciably measure impact on growth compared with non-vaccinees. Regardless of the impact on malnutrition indicators, rotavirus vaccines are an important intervention for reducing morbidity and mortality in children in developing countries.

Distributional impact of rotavirus vaccination in 25 GAVI countries: Estimating disparities in benefits and cost-effectiveness

Other studies have demonstrated that the impact and cost effectiveness of rotavirus vaccination differs among countries, with greater mortality reduction benefits and lower cost-effectiveness ratios in low-income and high-mortality countries. This analysis combines the results of a country level model of rotavirus vaccination published elsewhere with data from Demographic and Health Surveys on within-country patterns of vaccine coverage and diarrhea mortality risk factors to estimate within-country distributional effects of rotavirus vaccination. The study examined 25 countries eligible for funding through the GAVI Alliance. For each country we estimate the benefits and cost-effectiveness of vaccination for each wealth quintile assuming current vaccination patterns and for a scenario where vaccine coverage is equalized to the highest quintile's coverage. In the case of India, variations in coverage and risk proxies by state were modeled to estimate geographic distributional effects. In all countries, rates of vaccination were highest and risks of mortality were lowest in the top two wealth quintiles. However countries differ greatly in the relative inequities in these two underlying variables. Similarly, in all countries examined, the cost-effectiveness ratio for vaccination ($/Disability-Adjusted Life Year averted, DALY) is substantially greater in the higher quintiles (ranging from 2-10 times higher). In all countries, the greatest potential benefit of vaccination was in the poorest quintiles. However, due to reduced vaccination coverage, projected benefits for these quintiles were often lower. Equitable coverage was estimated to result in an 89% increase in mortality reduction for the poorest quintile and a 38% increase overall. Rotavirus vaccination is most cost-effective in low-income groups and regions. However in many countries, simply adding new vaccines to existing systems targets investments to higher income children, due to disparities in vaccination coverage. Maximizing health benefits for the poorest children and value for money require increased attention to these distributional effects.

Comparison of two clinical severity scoring systems in two multi-center, developing country rotavirus vaccine trials in Africa and Asia

Clinical severity scoring systems are used in rotavirus vaccine efficacy and effectiveness studies to define the primary endpoint, severe rotavirus gastroenteritis (RVGE). Understanding how scoring systems perform in diverse settings is critical for proper design and interpretation. This investigation aims to understand how the Vesikari scoring system (VSS) and Clark scoring system (CSS) categorize severe disease among children under 2 years of age using data from two Phase III efficacy trials conducted in five developing countries in Africa and Asia. Signs and symptoms were collected on trial participants who presented to a medical facility with study-defined gastroenteritis. Severity scores were calculated using pre-established VSS and CSS criteria and compared to identify differences in the proportions of severe RVGE within regions and sites, and by gender and age. In Africa and Asia, 40.6% and 56.0% of rotavirus-positive episodes were severe according to the VSS, while 9.5% and 6.3% of episodes were severe according to the CSS (Fisher's Exact, p ≤ 0.001). Using the mean scores in these trials (VSS: ≥ 10 Africa, ≥ 11 Asia; CSS: Africa and Asia ≥ 10) as the severity thresholds, agreement between scoring system severity classifications improved substantially within each region (Africa: kappa = 0.67; Asia: kappa = 0.78) as compared to the original severity classification (Africa: kappa = 0.27; Asia: kappa = 0.10). Using the mean score, 17.1% and 9.5% of severe VSS cases in Africa and Asia, respectively, were classified as not severe according to the CSS and 14.7% and 9.5% of severe CSS cases in Africa and Asia were classified as not severe according to the VSS. The two scoring systems performed differently among developing country populations in Africa and Asia, with the VSS classifying more cases as severe in both regions. One accurate and reliable scoring system should be developed and implemented for all trials so that results may be more comparable.