Duncan Steele

Global Mortality Associated with Rotavirus Disease among Children in 2004

BACKGROUND As new rotavirus vaccines are being introduced in immunization programs, global and national estimates of disease burden, especially rotavirus-associated mortality, are needed to assess the potential health benefits of vaccination and to monitor vaccine impact. METHODS We identified 76 studies that were initiated after 1990, lasted at least 1 full year, and examined rotavirus among >100 children hospitalized with diarrhea. The studies were assigned to 5 groups (A-E) with use of World Health Organization classification of countries by child mortality and geography. For each group, the mean rotavirus detection rate was multiplied by diarrhea-related mortality figures from 2004 for countries in that group to yield estimates of rotavirus-associated mortality. RESULTS Overall, rotavirus accounted for 527,000 deaths (95% confidence interval, 475,000-580,000 deaths) annually or 29% of all deaths due to diarrhea among children <5 years of age. Twenty-three percent of deaths due to rotavirus disease occurred in India, and 6 countries (India, Nigeria, Congo, Ethiopia, China, and Pakistan) accounted for more than one-half of deaths due to rotavirus disease. CONCLUSIONS The high mortality associated with rotavirus disease underscores the need for targeted interventions, such as vaccines. To realize the full life-saving potential of vaccines, it will be vital to ensure that they reach children in countries with high mortality. These baseline figures will allow future assessment of vaccine impact on rotavirus-associated mortality.

Real-world impact of rotavirus vaccination.

Summary of Studies in the Current Supplement That Assess Health Impact, Indirect Benefits, or StrainChanges After Rotavirus Vaccination Location (Ref) Vaccine Key Findings InterpretationHealth impactEl Salvador(15)RV1 35%–48% decline in all cause diarrhea events(outpatient and inpatient) and 69%–81%decline in rotavirus hospitalizations amongchildren 5 yearsThe consistency of the findings across regions, predominantlyduring seasons when rotavirus predominates, withincreasing effect among children in ages with the highestvaccination rates strongly supports vaccination as theMexico (17) RV1 11%–40% reduction in all cause diarrhea primary cause of the observed declines in diarrheahospitalizations among children 5Panama (18) RV1 22%–37% reduction in all cause diarrheahospitalizations among children 5The sustained declines in disease for 2–3 year aftervaccination indicates that duration of protection in thesesettings was sufficient to impact the youngest childrenwho bear the greatest burden of severe rotavirus diarrheBelgium (20) RV1 65%–83% reduction in rotavirushospitalizationsAustralia (21) RV1 & RV5 89%–94% vaccine efficacy against rotavirushospitalizations among children 5; 68%–93% reduction in under-1 rotavirus admitsLarge declines in all-cause diarrhea hospitalizations indicatethat rotavirus may be a more important cause of childhooddiarrhea than previously estimatedUnited States(19)RV5* No rotavirus epidemic occurred in January–June 2010, the first time in 19 years of USsurveillance within this systemIndirect benefitsEl Salvador(15)RV1 41%–68% decline during 2008 in childrenolder than 2 yr who were unvaccinatedIndirect benefits of vaccination in the early (1–2) years aftervaccination suggests that young infants may be theprimary drivers of epidemic spread (at least in middle andhigh income settings)United States(23)RV5* 42%–45% reduction among children tooyoung or old to be vaccinatedAustralia (21) RV1 & RV5 50% reduction in rotavirus hospitalizationsamong children older than 2 years who wereunvaccinatedIn poorer countries such as El Salvador, the total protectionat a population level as a result of indirect benefits ofvaccination has the potential to offset the lower efficacydirectly afforded to the vaccineStrain monitoringBrazil (45) RV1 Increase in G2P 4 for 2 year after vaccination Epidemiologic assessments, such as case-control vaccineeffectiveness, and robust longitudinal surveillance areneeded to best assess interaction between rotavirusvaccination and strain ecologyAustralia (47) RV1 & RV5 G1P 8 was the predominant strain nationally,however, some transient increase in G2P 4and G3P 8 prevalence occurred in Rotarixand RotaTeq states, respectivelyExisting strain surveillance data, vaccine effectivenessresults, and the dramatic declines in disease burden incountries with rotavirus vaccination support naturalvariation in strain ecology as the likely explanation for thereported observations in short-term changes in strainsafter vaccinationUnited States(46)RV5* Higher prevalence of G3P 8 in some US citiesafter rotavirus vaccinationOngoing disease and strain surveillance is needed to assesslonger term evolution in stain ecology and potential impacton disease burden

Diagnostic Microbiologic Methods in the GEMS-1 Case/Control Study

To understand the etiology of moderate-to-severe diarrhea among children in high mortality areas of sub-Saharan Africa and South Asia, we performed a comprehensive case/control study of children aged <5 years at 7 sites. Each site employed an identical case/control study design and each utilized a uniform comprehensive set of microbiological assays to identify the likely bacterial, viral and protozoal etiologies. The selected assays effected a balanced consideration of cost, robustness and performance, and all assays were performed at the study sites. Identification of bacterial pathogens employed streamlined conventional bacteriologic biochemical and serological algorithms. Diarrheagenic Escherichia coli were identified by application of a multiplex polymerase chain reaction assay for enterotoxigenic, enteroaggregative, and enteropathogenic E. coli. Rotavirus, adenovirus, Entamoeba histolytica, Giardia enterica, and Cryptosporidium species were detected by commercially available enzyme immunoassays on stool samples. Samples positive for adenovirus were further evaluated for adenovirus serotypes 40 and 41. We developed a novel multiplex assay to detect norovirus (types 1 and 2), astrovirus, and sapovirus. The portfolio of diagnostic assays used in the GEMS study can be broadly applied in developing countries seeking robust cost-effective methods for enteric pathogen detection.

Characterisation of rotavirus G9 strains isolated in the UK between 1995 and 1998.

G9P[6] and G9P[8] rotavirus strains were identified during 1995/96 through the molecular epidemiological surveillance of rotavirus strains circulating in the UK between 1995 and 1998. An increase in the incidence and spread of sporadic infections with rotavirus genotype G9P[8] across the UK was detected in the two following seasons. Partial sequencing of the VP7 gene showed that all the UK strains shared a high degree of homology and were related very closely to G9 strains from the US and from symptomatic infections in India (≥96% homology). The UK strains were related more distantly to the apathogenic Indian strain 116E (85–87.8% homology). Phylogenetic analysis revealed clustering of the UK strains into 3 different lineages (I to III) and into two sub‐lineages within lineage I. There were correlations between VP7 sequence clustering, the P type and the geographical origin of the G9 strains. Partial sequencing of the VP4 gene showed high degree of homology (>98%) among all the P[6] strains, and the sequences obtained from the P[8] strains clustered into 2 of the 3 global lineages described for P[8] strains associated with other G types. These data suggest that G9 strains may be a recent importation into the UK, and that G9P[8] strains may have emerged through reassortment in humans between G9P[6] strains introduced recently and the more prevalent cocirculating G1, G3 and G4 strains that normally carry VP4 genes of P[8] type. J. Med. Virol. 61:510–517, 2000.

Prevalence of unusual human rotavirus strains in Ghanaian children

Sixty‐seven rotavirus‐positive fecal samples, collected between January and April 1999, from children with diarrhea in the Upper East Region of Ghana were examined for rotavirus VP7 and VP4 types. Sufficient viral RNA could be obtained from 46 (68.7%) of the samples and all the isolates had short electrophoretic pattern and typed as subgroup I rotaviruses by subgroup ELISA. Three rotavirus strains with G8 specificity were identified for the first time in Ghana. G and P typing by PCR identified two distinct strains, P[6]G2 (50%) and P[6]G8 (4.3%). Eighty‐two percent of the isolates (n = 38) were of the “putative” neonatal P[6] genotype. Two of these G8 isolates carried the VP4 P[6] genotype whereas the third could not be assigned a P type. Mixed infections of G1, G2, G3 and G8 were detected amongst the stool samples. The presence of these unusual strains, especially the high incidence of G2 rotavirus strains in Ghana, reinforces the need to put in place a surveillance system for the detection of new and exotic rotavirus strains, that will provide information on the spread of these strains in West Africa as well as useful data for the formulation of the next generation of rotavirus vaccines. J. Med. Virol. 63:67–71, 2001.

Global Rotavirus Surveillance: Determining the Need and Measuring the Impact of Rotavirus Vaccines

Rotavirus remains the most common cause of severe childhood diarrhea worldwide and of diarrheal mortality in poor countries. In 2003, the GAVI Alliance launched the Rotavirus Vaccine Program and the Accelerated Development and Introduction Plan to close the gap of access to rotavirus vaccines in industrialized and developing countries by generating data on rotavirus disease burden, projected impact, and cost-effectiveness of vaccination and by conducting clinical trials of existing vaccines in impoverished settings. By the end of 2008, rotavirus vaccines were licensed in >100 countries, although only 17 countries have introduced routine rotavirus vaccination. Increased uptake of the vaccine by countries with the highest childhood mortality will depend in part on a solid evidence base of estimated burden and cost of rotavirus illness. Since 2001, regional surveillance networks worldwide have generated burden and strain data from 196 sites in 59 countries. Among children aged <5 years who are hospitalized for severe diarrhea in different regions of the world, a regional median of 39% (range by country, 20%-73%) test positive for rotavirus. Rotavirus vaccines are a cost-effective intervention and may be cost saving with a GAVI Alliance subsidy from the health care perspective. Punctual vaccination and high coverage of populations at highest risk of mortality will maximize the impact of vaccination. Surveillance platforms will allow measurement of the rapid impact of rotavirus vaccine introduction on the heavy burden of rotavirus on child health worldwide.

Novel human rotavirus genotype G5P[7] from child with diarrhea, Cameroon.

We report characterization of a genotype G5P[7] human rotavirus (HRV) from a child in Cameroon who had diarrhea. Sequencing of all 11 gene segments showed similarities to >5 genes each from porcine and human rotaviruses. This G5P[7] strain exemplifies the importance of heterologous animal rotaviruses in generating HRV genetic diversity through reassortment.

Broadening the age restriction for initiating rotavirus vaccination in regions with high rotavirus mortality: benefits of mortality reduction versus risk of fatal intussusception.

INTRODUCTION Recently developed rotavirus vaccines have the potential to reduce diarrhea mortality in children in developing countries. Available data to date do not indicate risk of intussusception with these new vaccines. To avoid a potential unanticipated risk post-licensure, it is recommended that rotavirus immunization be initiated before 12 weeks of age when background intussusception rates are low. This policy could exclude a substantial number of children from vaccination, especially in developing countries where delays in vaccination are common. METHODS We conducted a scenario analysis to assess the potential benefits of mortality reduction from rotavirus versus the risk of fatal intussusception when the first dose of the vaccine is strictly administered by 12 weeks of age compared with a free strategy with vaccine administered before 1 year of age using data on rotavirus disease, vaccine safety and efficacy, and current diphtheria-tetanus-pertussis vaccination rates, and by incorporating hypothetical risks of intussusception. RESULTS In developing countries, assuming vaccine efficacy of 50% and 75% for doses 1 and 2, respectively, and a hypothetical sixfold and threefold increased relative risk of intussusception within 7 days of doses 1 and 2, respectively, initiating rotavirus immunization before 12 weeks of age would prevent 194,564 of the 517,959 annual rotavirus-associated deaths among children <5 years, while potentially resulting in 1106 fatal intussusception events. Administration of the first dose to infants up to 1 year of age would prevent an additional 54,087 rotavirus-associated deaths (total=248,651) while potentially resulting in an additional 1226 intussusception deaths (total=2332). CONCLUSION In developing countries, the additional lives saved by broadening the age restrictions for initiation of rotavirus vaccination would far outnumber the hypothetical excess intussusception deaths that would accompany such an approach.

Identification of viral agents causing diarrhea among children in the Eastern Center of Tunisia

Viral diarrhea remains a major cause of childhood morbidity and mortality worldwide. In Tunisia, no comprehensive studies of all viral agents related to diarrhea in children have yet been conducted. The present study was performed to investigate the role of enteric viruses in acute diarrhea in the country. Six hundred thirty‐eight stool samples were collected from children under 5 years of age seeking medical care for acute diarrhea between October 2003 and September 2005 in hospitals from the Eastern‐Center Tunisia. All samples were tested for rotavirus, astrovirus, and adenovirus using commercial antigen enzyme immunoassays (EIAs). Positive samples for rotavirus and astrovirus were confirmed by an “in‐house” reverse transcriptase‐polymerase chain reaction (RT‐PCR). Samples positive for adenovirus antigen were subjected to further EIA screening for species F enteric adenovirus types 40 and 41. At least one viral agent was found in 30% of the specimens. The frequency of rotavirus, astrovirus, and adenovirus was 20%, 7%, and 6%, respectively. Of the stool samples containing adenovirus, 57% (20/35) were found to be positive for species F adenovirus types 40/41. Dual infections were found in 9% (17/191) of the positive samples. Enteric viruses appear to play an important role in pediatric diarrhea in Tunisia. The introduction of affordable viral diagnosis in pediatric hospitals will improve patient care by reducing the unnecessary use of antibiotics. J. Med. Virol. 78:1198–1203, 2006.

Molecular characterization of unusual human G5P[6] rotaviruses identified in China

BACKGROUND We found an unusual human rotavirus, LL36755 of G5P[6] genotype, in a stool sample collected in Lulong County, Hebei Province, China. This is the first detection of rotavirus serotype G5 in Asia. OBJECTIVES To identify and characterize G5 rotaviruses in 988 stool samples collected from children under 5 years old with acute gastroenteritis. STUDY DESIGN We analyzed 459 rotavirus-positive samples with RT-PCR using G5 genotype-specific primers. The G5 strains were sequenced. RESULTS Two additional G5-positive samples (LL3354 and LL4260) were identified. VP7, VP4, VP6 and NSP4 genes of LL3354, LL4260 and LL36755 strains were sequenced. The VP4 sequences formed a group with porcine P[6] strains. The VP6 sequences of strains LL3354 and LL36755 were phylogenetically close to the major clusters of SGI and SGII rotaviruses, respectively. The deduced VP6 protein of strain LL4260 had characteristics of both SGI and SGII strains, but best fit with a cluster of atypical SGI viruses. In addition, based on NSP4 sequences, the three G5 strains belonged to genogroup B and were closest to human strain Wa. CONCLUSION These results indicate a dynamic interaction of human and porcine rotaviruses and suggest that reassortment could result in the stable introduction and successful spread of porcine gene alleles into human rotaviruses.