Evaluation of Intussusception after Monovalent Rotavirus Vaccination in Africa.

BACKGROUND: Postlicensure evaluations have identified an association between rotavirus vaccination and intussusception in several high- and middle-income countries. We assessed the association between monovalent human rotavirus vaccine and intussusception in lower-income sub-Saharan African countries. METHODS: Using active surveillance, we enrolled patients from seven countries (Ethiopia, Ghana, Kenya, Malawi, Tanzania, Zambia, and Zimbabwe) who had intussusception that met international (Brighton Collaboration level 1) criteria. Rotavirus vaccination status was confirmed by review of the vaccine card or clinic records. The risk of intussusception within 1 to 7 days and 8 to 21 days after vaccination among infants 28 to 245 days of age was assessed by means of the self-controlled case-series method. RESULTS: Data on 717 infants who had intussusception and confirmed vaccination status were analyzed. One case occurred in the 1 to 7 days after dose 1, and 6 cases occurred in the 8 to 21 days after dose 1. Five cases and 16 cases occurred in the 1 to 7 days and 8 to 21 days, respectively, after dose 2. The risk of intussusception in the 1 to 7 days after dose 1 was not higher than the background risk of intussusception (relative incidence [i.e., the incidence during the risk window vs. all other times], 0.25; 95% confidence interval [CI], <0.001 to 1.16); findings were similar for the 1 to 7 days after dose 2 (relative incidence, 0.76; 95% CI, 0.16 to 1.87). In addition, the risk of intussusception in the 8 to 21 days or 1 to 21 days after either dose was not found to be higher than the background risk. CONCLUSIONS: The risk of intussusception after administration of monovalent human rotavirus vaccine was not higher than the background risk of intussusception in seven lower-income sub-Saharan African countries. (Funded by the GAVI Alliance through the CDC Foundation.).

Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial.

Importance: Preventive interventions are needed to protect residents and staff of skilled nursing and assisted living facilities from COVID-19 during outbreaks in their facilities. Bamlanivimab, a neutralizing monoclonal antibody against SARS-CoV-2, may confer rapid protection from SARS-CoV-2 infection and COVID-19. Objective: To determine the effect of bamlanivimab on the incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. Design, Setting, and Participants: Randomized, double-blind, single-dose, phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case. A total of 1175 participants enrolled in the study from August 2 to November 20, 2020. Database lock was triggered on January 13, 2021, when all participants reached study day 57. Interventions: Participants were randomized to receive a single intravenous infusion of bamlanivimab, 4200 mg (n = 588), or placebo (n = 587). Main Outcomes and Measures: The primary outcome was incidence of COVID-19, defined as the detection of SARS-CoV-2 by reverse transcriptase-polymerase chain reaction and mild or worse disease severity within 21 days of detection, within 8 weeks of randomization. Key secondary outcomes included incidence of moderate or worse COVID-19 severity and incidence of SARS-CoV-2 infection. Results: The prevention population comprised a total of 966 participants (666 staff and 300 residents) who were negative at baseline for SARS-CoV-2 infection and serology (mean age, 53.0 [range, 18-104] years; 722 [74.7%] women). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5% vs 15.2%; odds ratio, 0.43 [95% CI, 0.28-0.68]; P < .001; absolute risk difference, -6.6 [95% CI, -10.7 to -2.6] percentage points). Five deaths attributed to COVID-19 were reported by day 57; all occurred in the placebo group. Among 1175 participants who received study product (safety population), the rate of participants with adverse events was 20.1% in the bamlanivimab group and 18.9% in the placebo group. The most common adverse events were urinary tract infection (reported by 12 participants [2%] who received bamlanivimab and 14 [2.4%] who received placebo) and hypertension (reported by 7 participants [1.2%] who received bamlanivimab and 10 [1.7%] who received placebo). Conclusions and Relevance: Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT04497987.

Infectious Etiologies of Intussusception Among Children <2 Years Old in 4 Asian Countries.

BACKGROUND: The etiology of intussusception, the leading cause of bowel obstruction in infants, is unknown in most cases. Adenovirus has been associated with intussusception and slightly increased risk of intussusception with rotavirus vaccination has been found. We conducted a case-control study among children <2 years old in Bangladesh, Nepal, Pakistan, and Vietnam to evaluate infectious etiologies of intussusception before rotavirus vaccine introduction. METHODS: From 2015 to 2017, we enrolled 1-to-1 matched intussusception cases and hospital controls; 249 pairs were included. Stool specimens were tested for 37 infectious agents using TaqMan Array technology. We used conditional logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) of each pathogen associated with intussusception in a pooled analysis and quantitative subanalyses. RESULTS: Adenovirus (OR, 2.67; 95% CI, 1.75-4.36) and human herpes virus 6 (OR, 3.50; 95% CI, 1.15-10.63) were detected more frequently in cases than controls. Adenovirus C detection <20 quantification cycles was associated with intussusception (OR, 18.59; 95% CI, 2.45-140.89). Wild-type rotavirus was not associated with intussusception (OR, 1.07; 95% CI, 0.52-2.22). CONCLUSIONS: In this comprehensive evaluation, adenovirus and HHV-6 were associated with intussusception. Future research is needed to better understand mechanisms leading to intussusception, particularly after rotavirus vaccination.

Monovalent Rotavirus Vaccine Effectiveness Against Rotavirus Hospitalizations Among Children in Zimbabwe.

BACKGROUND: Rotavirus is a leading cause of mortality among children <5 years old. We evaluated monovalent rotavirus vaccine effectiveness (VE) under conditions of routine use at 2 surveillance sites in Harare, Zimbabwe, after vaccine introduction in May 2014. METHODS: Children aged <5 years hospitalized or treated in the accident and emergency department (A&E) for acute watery diarrhea were enrolled for routine surveillance. Copies of vaccination cards were collected to document vaccination status. Among children age-eligible to receive rotavirus vaccine, we estimated VE, calculated as 1 - odds ratio, using a test-negative case-control design. RESULTS: We included 903 rotavirus-positive cases and 2685 rotavirus-negative controls in the analysis; 99% had verified vaccination status. Rotavirus-positive children had more severe diarrhea than rotavirus-negative children; 61% of cases and 46% of controls had a Vesikari score ≥11 (P < .01). Among cases and controls, 31% and 37%, respectively, were stunted for their age (P < .01). Among children 6-11 months old, adjusted 2-dose VE against hospitalization or treatment in A&E due to rotavirus of any severity was 61% (95% confidence interval [CI], 21%-81%) and 68% (95% CI, 13%-88%) against severe rotavirus disease. Stratified by nutritional status, adjusted VE was 45% (95% CI, -148% to 88%) among stunted infants and 71% (95% CI, 29%-88%) among infants with a normal height for age. CONCLUSIONS: Monovalent rotavirus vaccine is effective in preventing hospitalizations due to severe rotavirus diarrhea among infants in Zimbabwe, providing additional evidence for countries considering rotavirus vaccine introduction that live, oral rotavirus vaccines are effective in high-child-mortality settings.

Burden of Severe Norovirus Disease in Taiwan, 2003-2013.

Background: Despite the increasingly recognized role of norovirus in global acute gastroenteritis (AGE), specific estimates of the associated disease burden remain sparse, primarily due to limited availability of sensitive norovirus diagnostics in the clinical setting. We sought to estimate the incidence of norovirus-associated hospitalizations by age group in Taiwan using a previously developed indirect regression method. Methods: AGE-related hospitalizations in Taiwan were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes abstracted from a national database; population data were provided from the Department of Household Registration Affairs. Population and hospitalizations were aggregated by month and year (July 2003-June 2013) and grouped by age: <5 years, 5-19 years, 20-64 years, and ≥65 years. Monthly counts of cause-unspecified AGE hospitalizations were modeled as a function of counts of known causes, and the residuals were then analyzed to estimate norovirus-associated hospitalizations. Results: Over the study period, an annual mean of 101400 gastroenteritis-associated hospitalizations occurred in Taiwan (44 per 10000 person-years), most of which (83%) had no specified cause. The overall estimated rate of norovirus-associated hospitalizations was 6.7 per 10000 person-years, with the highest rates in children aged <5 years (63.7/10000 person-years). Predicted norovirus peaked in 2006-2007 and 2012-2013. Conclusions: Our study is one of the first to generate a population-based estimate of severe norovirus disease incidence in Asia, and highlights the large burden of norovirus in Taiwan, particularly in children. Predicted peak norovirus seasons coincided with the emergence of new strains and resulting pandemics, supporting the validity of the estimates.

Global Impact of Rotavirus Vaccination on Childhood Hospitalizations and Mortality From Diarrhea.

In 2006, 2 rotavirus vaccines were licensed. We summarize the impact of rotavirus vaccination on hospitalizations and deaths from rotavirus and all-cause acute gastroenteritis (AGE) during the first 10 years since vaccine licensure, including recent evidence from countries with high child mortality. We used standardized guidelines (PRISMA) to identify observational evaluations of rotavirus vaccine impact among children <5 years of age that presented at least 12 months of pre- and post-vaccine introduction surveillance data. We identified 57 articles from 27 countries. Among children <5 years of age, the median percentage reduction in AGE hospitalizations was 38% overall and 41%, 30%, and 46% in countries with low, medium, and high child mortality, respectively. Hospitalizations and emergency department visits due to rotavirus AGE were reduced by a median of 67% overall and 71%, 59%, and 60% in countries with low, medium, and high child mortality, respectively. Implementation of rotavirus vaccines has substantially decreased hospitalizations from rotavirus and all-cause AGE.

Effectiveness of Rotavirus Vaccination: A Systematic Review of the First Decade of Global Postlicensure Data, 2006-2016.

Two rotavirus vaccines, Rotarix (RV1) and RotaTeq (RV5), were licensed for global use in 2006. A systematic review of 48 peer- reviewed articles with postlicensure data from 24 countries showed a median RV1 vaccine effectiveness (VE) of 84%, 75%, and 57% in countries with low, medium, and high child mortality, respectively, and RV5 VE of 90% and 45% in countries with low and high child mortality, respectively. A partial vaccine series provided considerable protection, but not to the same level as a full series. VE tended to decline in the second year of life, particularly in medium- and high-mortality settings, and tended to be greater against more severe rotavirus disease. Postlicensure data from countries across geographic regions and with different child mortality levels demonstrate that under routine use, both RV1 and RV5 are effective against rotavirus disease, supporting the World Health Organization recommendation that all countries introduce rotavirus vaccine into their national immunization program.

Use of Patients With Diarrhea Who Test Negative for Rotavirus as Controls to Estimate Rotavirus Vaccine Effectiveness Through Case-Control Studies.

BACKGROUND: Case-control studies are often performed to estimate postlicensure vaccine effectiveness (VE), but the enrollment of controls can be challenging, time-consuming, and costly. We evaluated whether children enrolled in the same hospital-based diarrheal surveillance used to identify rotavirus cases but who test negative for rotavirus (test-negative controls) can be considered a suitable alternative to nondiarrheal hospital or community-based control groups (traditional controls). METHODS: We compared calculated VE estimates as a function of varying values of true VE, attack rates of rotavirus and nonrotavirus diarrhea in the population, and sensitivity and specificity of the rotavirus enzyme immunoasssay. We also searched the literature to identify rotavirus VE studies that used traditional and test-negative control groups and compared VE estimates obtained using the different control groups. RESULTS: Assuming a 1% attack rate for severe rotavirus diarrhea, a 3% attack rate for severe nonrotavirus diarrhea in the population, a test sensitivity of 96%, and a specificity of 100%, the calculated VE estimates using both the traditional and test-negative control groups closely approximated the true VE for all values from 30% to 100%. As true VE decreased, the traditional case-control approach slightly overestimated the true VE and the test-negative case-control approach slightly underestimated this estimate, but the absolute difference was only ±0.2 percentage points. Field VE estimates from 10 evaluations that used both traditional and test-negative control groups were similar regardless of control group used. CONCLUSIONS: The use of rotavirus test-negative controls offers an efficient and cost-effective approach to estimating rotavirus VE through case-control studies.

Epidemiology and molecular characteristics of norovirus GII.4 Sydney outbreaks in Taiwan, January 2012-December 2013.

In 2012, a new norovirus GII.4 variant (GII.4 Sydney) emerged and caused the majority of the acute gastroenteritis outbreaks in Australia, Asia, Europe, and North America. We examined the epidemiologic and molecular virologic characteristics of reported acute gastroenteritis outbreaks determined to be caused by norovirus in Taiwan from January 2012 to December 2013. A total of 253 (45.7%) of 552 reported acute gastroenteritis outbreaks tested positive for norovirus, of which 165 (65.5%) were typed as GII.4 Sydney. GII.4 Sydney outbreaks were reported from all geographic areas of Taiwan and occurred most frequently in schools (35.8%) and long-term care facilities (24.2%). Person-to-person transmission was identified in 116 (70.3%) of the outbreaks. Phylogenetic analyses of full-length ORF2 of eight specimens indicated that GII.4 Sydney strains detected in Taiwan were closely related to strains detected globally. Continued outbreak surveillance and strain typing are needed to provide information on epidemiologic and virologic trends of novel norovirus strains.

WHO global rotavirus surveillance network: a strategic review of the first 5 years, 2008-2012.

Since 2008, the World Health Organization (WHO) has coordinated the Global Rotavirus Surveillance Network, a network of sentinel surveillance hospitals and laboratories that report to ministries of health (MoHs) and WHO clinical features and rotavirus testing data for children aged <5 years hospitalized with acute gastroenteritis. In 2013, WHO conducted a strategic review to assess surveillance network performance, provide recommendations for strengthening the network, and assess the network's utility as a platform for other vaccine-preventable disease surveillance. The strategic review team determined that during 2011 and 2012, a total of 79 sites in 37 countries met reporting and testing inclusion criteria for data analysis. Of the 37 countries with sites meeting inclusion criteria, 13 (35%) had introduced rotavirus vaccine nationwide. All 79 sites included in the analysis were meeting 2008 network objectives of documenting presence of disease and describing disease epidemiology, and all countries were using the rotavirus surveillance data for vaccine introduction decisions, disease burden estimates, and advocacy; countries were in the process of assessing the use of this surveillance platform for other vaccine-preventable diseases. However, the review also indicated that the network would benefit from enhanced management, standardized data formats, linkage of clinical data with laboratory data, and additional resources to support network functions. In November 2013, WHO's Strategic Advisory Group of Experts on Immunization (SAGE) endorsed the findings and recommendations made by the review team and noted potential opportunities for using the network as a platform for other vaccine-preventable disease surveillance. WHO will work to implement the recommendations to improve the network's functions and to provide higher quality surveillance data for use in decisions related to vaccine introduction and vaccination program sustainability.

Trends in intussusception hospitalizations among US infants before and after implementation of the rotavirus vaccination program, 2000-2009.

BACKGROUND: Although US data have not documented an intussusception risk with current rotavirus vaccines, international data indicate a possible low risk, primarily after the first dose. METHODS: Among infants in 26 US states comprising 75% of the birth cohort, we examined age-specific trends in population-level intussusception hospitalization rates before (2000-2005) and after (2007-2009) rotavirus vaccine introduction. RESULTS: Compared with 2000-2005 (35.3 per 100,000), the rate was greater in 2007 (39.0 per 100,000; rate ratio [RR], 1.10; 95% confidence interval [CI], 1.04-1.18), similar in 2008 (33.4 per 100,000; RR, 0.95; 95% CI, .89-1.01), and lower in 2009 (32.9 per 100,000; RR, 0.93; 95% CI, .87-.99). Among infants aged 8-11 weeks, compared with 2000-2005 (6.9 per 100,000), a small, significant increase was observed in each of 2007 (11.4 per 100,000; RR, 1.64; 95% CI, 1.08-2.50), 2008 (12.2 per 100,000; RR, 1.76; 95% CI, 1.17-2.65), and 2009 (11.0 per 100,000; RR, 1.59; 95% CI, 1.04-2.44). CONCLUSIONS: Following rotavirus vaccine introduction, a small increase in intussusception rates was seen among US infants aged 8-11 weeks, to whom most first doses of vaccine are given; no sustained population-level change in overall rates was observed.

Impact and effectiveness of Rotavin-M1 under conditions of routine use in two provinces in Vietnam, 2016-2021, an observational and case-control study.

Background: Half of diarrhea hospitalizations in children aged <5 years in Vietnam are due to rotavirus. Following introduction of a locally developed and licensed oral rotavirus vaccine, Rotavin-M1, into the routine immunization program in two Vietnamese provinces, Nam Dinh and TT Hue, we describe changes in rotavirus positivity among children hospitalized for diarrhea and calculate vaccine effectiveness against moderate-to-severe rotavirus hospitalizations. Methods: Active rotavirus surveillance among children <5 years began in December 2016 at sentinel hospitals in districts where rotavirus vaccine was introduced in December 2017. To estimate reductions in rotavirus detection, we calculated risk ratios comparing rotavirus positivity pre- and post-vaccine introduction. We used a test-negative case-control design to calculate vaccine effectiveness. Findings: From December 2016 to May 2021, 7228 children <5 years hospitalized for diarrhea were enrolled. Following introduction, Rotavin-M1 coverage was 77% (1066/1377) in Nam Dinh and 42% (203/489) in TT Hue. In Nam Dinh, rotavirus positivity among children <5 years significantly declined by 40.6% (95% CI: 34.8%-45.8%) during the three-year post-vaccine introduction period. In TT Hue, no change in rotavirus positivity was observed. Among children aged 6-23 months, a 2-dose series of Rotavin-M1 was 57% (95% CI: 39%-70%) effective against moderate-to-severe rotavirus hospitalizations. Interpretation: Higher vaccination coverage in Nam Dinh than TT Hue likely contributed to substantial declines in rotavirus positivity observed in Nam Dinh following rotavirus vaccine introduction. Robust vaccine effectiveness was observed through the second year of life. National rotavirus vaccine introduction with high coverage may have substantial impact on reducing rotavirus disease burden in Vietnam. Funding: Bill and Melinda Gates Foundation.

Efficacy of Messenger RNA-1273 Against Severe Acute Respiratory Syndrome Coronavirus 2 Acquisition in Young Adults From March to December 2021.

Background: The efficacy of messenger RNA (mRNA)-1273 against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well defined, particularly among young adults. Methods: Adults aged 18-29 years with no known history of SARS-CoV-2 infection or prior vaccination for coronavirus disease 2019 (COVID-19) were recruited from 44 US sites from 24 March to 13 September 2021 and randomized 1:1 to immediate vaccination (receipt of 2 doses of mRNA-1273 vaccine at months 0 and 1) or the standard of care (receipt of COVID-19 vaccine). Randomized participants were followed up for SARS-CoV-2 infection measured by nasal swab testing and symptomatic COVID-19 measured by nasal swab testing plus symptom assessment and assessed for the primary efficacy outcome. A vaccine-declined observational group was also recruited from 16 June to 8 November 2021 and followed up for SARS-CoV-2 infection as specified for the randomized participants. Results: The study enrolled 1149 in the randomized arms and 311 in the vaccine-declined group and collected >122 000 nasal swab samples. Based on randomized participants, the efficacy of 2 doses of mRNA-1273 vaccine against SARS-CoV-2 infection was 52.6% (95% confidence interval, -14.1% to 80.3%), with the majority of infections due to the Delta variant. Vaccine efficacy against symptomatic COVID-19 was 71.0% (95% confidence interval, -9.5% to 92.3%). Precision was limited owing to curtailed study enrollment and off-study vaccination censoring. The incidence of SARS-CoV-2 infection in the vaccine-declined group was 1.8 times higher than in the standard-of-care group. Conclusions: mRNA-1273 vaccination reduced the incidence of SARS-CoV-2 infection from March to September 2021, but vaccination was only one factor influencing risk. Clinical Trials Registration: NCT04811664.

Infant rotavirus vaccination may provide indirect protection to older children and adults in the United States.

Following the introduction of rotavirus vaccination in the United States, rotavirus and cause-unspecified gastroenteritis discharges significantly decreased in 2008 in the 0-4, 5-14, and 15-24-year age groups, with significant reductions observed in March, the historic peak rotavirus month, in all age groups. We estimate that 15% of the total 66 000 averted hospitalizations and 20% of the $204 million in averted direct medical costs attributable to the vaccination program were among unvaccinated 5-24 year-olds. This study demonstrates a previously unrecognized burden of severe rotavirus in the population >5 years and the primacy of very young children in the transmission of rotavirus.

Monovalent rotavirus vaccine provides protection against an emerging fully heterotypic G9P[4] rotavirus strain in Mexico.

After the introduction of monovalent rotavirus vaccine (RV1) in Mexico in 2006-2007, diarrhea mortality and morbidity declined substantially among Mexican children under 5 years of age. In January 2010, surveillance identified the emergence of a novel G9P[4] rotavirus strain nationwide. We conducted a case-control study to assess the field effectiveness of RV1 against severe rotavirus gastroenteritis caused by this unusual strain and to determine whether the G9P[4] emergence was related to vaccine failure or failure to vaccinate. RV1 was 94% effective (95% confidence interval, 16%-100%) against G9P[4] rotavirus-related hospitalization, indicating that its emergence was likely unrelated to vaccine pressure.

Impact of an emergent norovirus variant in 2009 on norovirus outbreak activity in the United States.

In October 2009, a new genogroup II, type 4 (GII.4) norovirus variant was identified in the United States. We collected norovirus outbreak data from 30 states to assess whether this new strain was associated with increased acute gastroenteritis activity. No increase in norovirus outbreaks was observed during the 2009-2010 winter.

Transmission of norovirus among NBA players and staff, winter 2010-2011.

In December 2010, 24 players and staff members from 13 National Basketball Association teams were affected with gastroenteritis symptoms. Four of 5 stool specimens from ill players and staff tested positive for norovirus genogroup II. We document evidence of transmission both within teams and, potentially, between teams in 2 instances.

Decline in diarrhea mortality and admissions after routine childhood rotavirus immunization in Brazil: a time-series analysis.

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.

A class I ligase ribozyme with reduced Mg2+ dependence: Selection, sequence analysis, and identification of functional tertiary interactions.

The class I ligase was among the first ribozymes to have been isolated from random sequences and represents the catalytic core of several RNA-directed RNA polymerase ribozymes. The ligase is also notable for its catalytic efficiency and structural complexity. Here, we report an improved version of this ribozyme, arising from selection that targeted the kinetics of the chemical step. Compared with the parent ribozyme, the improved ligase achieves a modest increase in rate enhancement under the selective conditions and shows a sharp reduction in [Mg(2+)] dependence. Analysis of the sequences and kinetics of successful clones suggests which mutations play the greatest part in these improvements. Moreover, backbone and nucleobase interference maps of the parent and improved ligase ribozymes complement the newly solved crystal structure of the improved ligase to identify the functionally significant interactions underlying the catalytic ability and structural complexity of the ligase ribozyme.

Rotavirus vaccines: update on global impact and future priorities.

Early rotavirus vaccine adopter countries in the Americas, Europe, and in Australia have documented substantial declines in rotavirus disease burden following the introduction of vaccination.  However, the full public health impact of rotavirus vaccines has not been realized as they have not been introduced into routine immunization programs in countries of Africa and Asia with the highest rotavirus disease morbidity and mortality burden.  In this article, we review the epidemiology of rotavirus disease, the development and current status of rotavirus vaccines including newly available vaccine impact data from early-introducer countries, and future priorities for implementation and monitoring of rotavirus vaccination programs in developing countries.