[Show abstract][Hide abstract] ABSTRACT: ABSTRACT In recent years, noroviruses have become recognized as an important cause of both sporadic and epidemic acute gastroenteritis (AGE), largely due to the improved availability of broadly reactive real-time RT-PCR (TaqMan-based RT-PCR) assays. While there is substantial diversity among noroviruses, one specific genotype, GII.4, is the most common etiology in sporadic and epidemic AGE. Outbreaks of norovirus AGE most commonly occur in healthcare facilities and restaurants and result in significant morbidity and mortality and substantial healthcare costs. Norovirus vaccine development is progressing, and Phase I and II human trials have shown proof-of-principle that norovirus vaccines can reduce illness and infection.
[Show abstract][Hide abstract] ABSTRACT: Background
Pneumonia and diarrhea are leading causes of death for children under five (U5). It is challenging to estimate the total number of deaths and cause-specific mortality fractions. Two major efforts, one led by the Institute for Health Metrics and Evaluation (IHME) and the other led by the World Health Organization (WHO)/Child Health Epidemiology Reference Group (CHERG) created estimates for the burden of disease due to these two syndromes, yet their estimates differed greatly for 2010.Methods
This paper discusses three main drivers of the differences: data sources, data processing, and covariates used for modelling. The paper discusses differences in the model assumptions for etiology-specific estimates and presents recommendations for improving future models.ResultsIHME¿s Global Burden of Disease (GBD) 2010 study estimated 6.8 million U5 deaths compared to 7.6 million U5 deaths from CHERG. The proportional differences between the pneumonia and diarrhea burden estimates from the two groups are much larger; GBD 2010 estimated 0.847 million and CHERG estimated 1.396 million due to pneumonia. Compared to CHERG, GBD 2010 used broader inclusion criteria for verbal autopsy and vital registration data. GBD 2010 and CHERG used different data processing procedures and therefore attributed the causes of neonatal death differently. The major difference in pneumonia etiologies modeling approach was the inclusion of observational study data; GBD 2010 included observational studies. CHERG relied on vaccine efficacy studies.DiscussionGreater transparency in modeling methods and more timely access to data sources are needed. In October 2013, the Bill & Melinda Gates Foundation (BMGF) hosted an expert meeting to examine possible approaches for better estimation. The group recommended examining the impact of data by systematically excluding sources in their models. GBD 2.0 will use a counterfactual approach for estimating mortality from pathogens due to specific etiologies to overcome bias of the methods used in GBD 2010 going forward.
[Show abstract][Hide abstract] ABSTRACT: Background:
Although norovirus is the most common cause of gastroenteritis, there are few data on the community incidence of infection/disease or the patterns of acquired immunity or innate resistance to norovirus.
We followed a community-based birth cohort of 194 children in Ecuador with the aim to estimate (1) the incidence of norovirus gastroenteritis from birth to age 3 years, (2) the protective effect of norovirus infection against subsequent infection/disease, and (3) the association of infection and disease with FUT2 secretor status.
Over the 3-year period, we detected a mean of 2.26 diarrheal episodes per child (range, 0-12 episodes). Norovirus was detected in 260 samples (18%) but was not found more frequently in diarrheal samples (79 of 438 [18%]), compared with diarrhea-free samples (181 of 1016 [18%]; P = .919). A total of 66% of children had at least 1 norovirus infection during the first 3 years of life, and 40% of children had 2 infections. Previous norovirus infections were not associated with the risk of subsequent infection. All genogroup II, genotype 4 (GII.4) infections were among secretor-positive children (P < .001), but higher rates of non-GII.4 infections were found in secretor-negative children (relative risk, 0.56; P = .029).
GII.4 infections were uniquely detected in secretor-positive children, while non-GII.4 infections were more often found in secretor-negative children.
The Journal of Infectious Diseases 12/2014; 211(11). DOI:10.1093/infdis/jiu672 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We discuss recent advances in the understanding of acquired immunity and susceptibility to the two major pediatric enteric viral pathogens, norovirus and rotavirus.
The prominent decline in severe rotavirus gastroenteritis in areas with mature rotavirus vaccination programmes has correspondingly unmasked the significant burden of disease associated with norovirus gastroenteritis among children. As epidemiologists and vaccinologists set their sights on this next vaccine target, we provide an update on norovirus vaccine development.In addition to these developments regarding acquired immunity, refinements to our understanding of innate susceptibility to norovirus has advanced. Significant recent advances now describe similar immunologic mechanisms in understanding susceptibility for both norovirus and rotavirus, involving histo-blood group antigenic associations, which may also prove to be genotype specific.
This information can potentially be used to tailor both applied and developmental efforts to public health interventions against these important pediatric enteric viral pathogens.
Current Opinion in Pediatrics 12/2014; 27(1). DOI:10.1097/MOP.0000000000000166 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While a monovalent Rotarix® [RV1] and a pentavalent RotaTeq® [RV5] have been extensively tested and found generally safe and equally efficacious in clinical trials, the question still lingers about the evolving diversity of circulating rotavirus strains over time and their relationship with protective immunity induced by rotavirus vaccines. We reviewed data from clinical trials and observational studies that assessed the efficacy or field effectiveness of rotavirus vaccines against different rotavirus strains worldwide. RV1 provided broad clinical efficacy and field effectiveness against severe diarrhea due to all major circulating strains, including the homotypic G1P and the fully heterotypic G2P strains. Similarly, RV5 provided broad efficacy and effectiveness against RV5 and non-RV5 strains throughout different locations. Rotavirus vaccination provides broad heterotypic protection; however continuing surveillance is needed to track the change of circulating strains and monitor the effectiveness and safety of vaccines.
Infection Genetics and Evolution 10/2014; DOI:10.1016/j.meegid.2014.10.008 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An estimated 179 million acute gastroenteritis (AGE) illnesses occur annually in the United States. The role of noroviruses in hospital-related AGE has not been well-documented in the U. S. We estimated the population incidence of community- acquired outpatient and inpatient norovirus AGE encounters, as well as hospital-acquired inpatient norovirus AGE among inpatients at four Veterans Affairs (VA) Medical Centers (VAMCs). Fifty (4%) of 1,160 stool specimens collected ≤7 days from symptom onset tested positive for norovirus. During a one year period, the estimated incidence of outpatient, community- and hospital-acquired inpatient norovirus AGE was 188 cases, 11 cases, and 54 cases/ 100,000 patients, respectively. This study demonstrates the incidence of outpatient and community- and hospital-acquired inpatient norovirus AGE among the VA population seeking care at these four VAMCs.
PLoS ONE 10/2014; 10(5). DOI:10.1371/journal.pone.0126733 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Concerns exist whether monovalent (RV1) and pentavalent (RV5) rotavirus vaccines provide adequate protection against diverse strains and whether vaccine introduction will lead to selective pressure.
We systematically reviewed vaccine effectiveness (VE) studies and classified strains as (1) homotypic: both G- and P-type antigen of the circulating strain were in the vaccine; (2) partially heterotypic: either the G- or P-type antigen of the circulating strain was in the vaccine; and (3) fully heterotypic: neither G- or P-type antigen of the circulating strain was in the vaccine. Some RV5 studies reported VE against the G- and the P-type component separately and could not be discreetly classified into the three categories. To make complete use of the data, we included these strains in our analysis, classifying them either as (1) single antigen (SA) vaccine-type; or (2) SA nonvaccine-type. We estimated pooled odds ratios using random effect regression models, and tested for differences in strain-specific VE. Strain distribution trends were assessed from surveillance reports.
In high income countries, RV1 pooled VE (95% CI) was 94% (80-98), 71% (39-86), and 87% (76-93) against homotypic, partially heterotypic, and fully heterotypic strains, respectively. RV5 VE was 83% (78-87), 82% (70-89), 82% (70-89) and 75% (47-88) against homotypic, SA vaccine-type, partially heterotypic, and SA nonvaccine-type strains, respectively.
In middle income countries, RV1 pooled VE was 59% (36-73), 72% (58-81), and 47% (28-61) against homotypic, partially, and fully heterotypic strains, respectively. RV5 VE was 70% (58-78) against SA vaccine-type, 37% (10-56) against partially heterotypic strains and 87% (38-97) against SA nonvaccine-type. We found no evidence of a difference in VE for either vaccine in any setting (all p<0.05)
Prevalent strains in RV1 countries were G2P (50%) and G1P (22%), compared with G1P (33%) and G2P (30%) in RV5 countries . Sustained predominance of a single strain was not observed.
RV1 and RV5 exert similar effectiveness against homotypic and heterotypic strains. We found no evidence for persistence of specific strains indicating vaccine-induced selective pressure.
IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
[Show abstract][Hide abstract] ABSTRACT: Background
The effectiveness of the rotavirus vaccine under conditions of routine use in an African setting with a high prevalence of HIV infection needs to be established. We assessed the vaccine effectiveness of monovalent human rotavirus vaccine in preventing admission to hospital for acute rotavirus diarrhoea, after its introduction at age 6 and 14 weeks into South Africa's national immunisation programme.
This case-control study was done at seven hospitals in South Africa between April 19, 2010, and Oct 31, 2012. The hospitals were located in a range of urban, peri-urban, and rural settings, with varying rates of population HIV infection. Cases were children aged from 18 weeks to 23 months who were age-eligible to have received at least one dose of the human rotavirus vaccine (ie, those born after June 14, 2009) admitted to hospital with laboratory-confirmed acute rotavirus diarrhoea, and the primary control group was children admitted to hospital with diarrhoea testing negative for rotavirus. A second control group comprised children admitted to a subset of three of the seven hospitals with respiratory illness. The primary endpoint was adjusted vaccine effectiveness (1 – adjusted odds ratio × 100%) in children aged from 18 weeks to 23 months and was calculated by unconditional logistic regression. This study is registered on the South African National Clinical Trial Register, number DOH-27-0512-3247.
Of 540 rotavirus-positive cases, 278 children (52%) received two doses, 126 (23%) one dose, and 136 (25%) no doses of human rotavirus vaccine, compared with 1434 rotavirus-negative controls of whom 856 (60%) received two doses, 334 (23%) one dose, and 244 (17%) no doses. Adjusted vaccine effectiveness using rotavirus-negative controls was 57% (95% CI 40–68) for two doses and 40% (16–57) for one dose; estimates were similar when respiratory controls were used as the control group. Adjusted vaccine effectiveness for two doses was similar between age groups 18 weeks–11 months (54%, 95% CI 32–68) and 12–23 months (61%, 35–77), and was similar in HIV-exposed-uninfected (64%, 95% CI 34–80) and HIV-unexposed-uninfected children (54%, 31–69).
Human rotavirus vaccine provided sustained protection against admission to hospital for acute rotavirus diarrhoea during the first and second years of life. This finding is encouraging and establishes the public health value of rotavirus vaccine in an African setting, especially as rotavirus vaccines are introduced into an increasing number of African countries.
GAVI Alliance (with support from PATH).
[Show abstract][Hide abstract] ABSTRACT: Group A Rotaviruses (RVA) are double stranded RNA viruses that are a significant cause of acute pediatric gastroenteritis. Beginning in 2006 and 2008, respectively, two vaccines, Rotarix™ and RotaTeq®, have been approved for use in the USA for prevention of RVA disease. The effects of possible vaccine pressure on currently circulating strains in the USA and their genome constellations are still under investigation. In this study we report 33 complete RVA genomes (ORF regions) collected in multiple cities across USA during 2006 – 2009, including 8 collected from children with verified receipt of 3 doses of rotavirus vaccine. The strains included 16 G1P, 10 G3P, and 7 G9P. All 33 strains had a Wa like backbone with the consensus genotype constellation of G(1/3/9)-P-I1-R1-C1-M1-A1-N1-T1-E1-H1. From maximum likelihood based phylogenetic analyses, we identified 3 to7 allelic constellations grouped mostly by respective G types, suggesting a possible allelic segregation based on the VP7 gene of RVA primarily for the G3 and G9 strains. The vaccine failure strains showed similar grouping for all genes in G9 strains and most genes of G3 strains suggesting that these constellations were necessary to evade vaccine-derived immune protection. Substitutions in the antigenic region of VP7 and VP4 genes were also observed for the vaccine failure strains which could possibly explain how these strains escape vaccine induced immune response. This study helps elucidate how RVA strains are currently evolving in the population post vaccine introduction and supports the need for continued RVA surveillance.
[Show abstract][Hide abstract] ABSTRACT: We used Truven Health Marketscan claims database (2008–2011) to compare gastroenteritis rates during January–June among households
whose child had received rotavirus vaccine with those whose child did not receive vaccine. Statistically significantly lower
rates of hospitalization with a rotavirus gastroenteritis or unspecified-gastroenteritis discharge code occurred in vaccinated
households among persons 20–29 years and females 20–29 years (2008/2009), and males 30–39 years (2009/2010). Lower emergency
department gastroenteritis rates occurred in vaccinated households among females 20–29 years (2009/2010) and individuals 5–19
years (2010/2011). These data suggest rotavirus vaccination of infants provides indirect protection against moderate-to-severe
rotavirus disease in young parents and older siblings.
The Journal of Infectious Diseases 09/2014; 211(4). DOI:10.1093/infdis/jiu503 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Comprehensive reviews of pre licensure rotavirus strain prevalence data indicated the global importance of six rotavirus genotypes, G1P, G2P, G3P, G4P, G9P and G12P. Since 2006, two vaccines, the monovalent Rotarix (RV1) and the pentavalent RotaTeq (RV5) have been available in over 100 countries worldwide. Of these, 60 countries have already introduced either RV1 or RV5 in their national immunization programs. Post licensure vaccine effectiveness is closely monitored worldwide. This review aimed at describing the global changes in rotavirus strain prevalence over time. The genotype distribution of the nearly 47,000 strains that were characterized during 2007-2012 showed similar picture to that seen in the preceding period. An intriguing finding was the transient predominance of heterotypic strains, mainly in countries using RV1. Unusual and novel antigen combinations continue to emerge, including some causing local outbreaks, even in vaccinated populations. In addition, vaccine strains have been found in both vaccinated infants and their contacts and there is evidence for genetic interaction between vaccine and wild-type strains. In conclusion, the post-vaccine introduction strain prevalence data do not show any consistent pattern indicative of selection pressure resulting from vaccine use, although the increased detection rate of heterotypic G2P strains in some countries following RV1 vaccination is unusual and this issue requires further monitoring.
Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 09/2014; 28. DOI:10.1016/j.meegid.2014.08.017 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: India is poised to introduce rotavirus vaccines into its routine childhood immunization programme. Substantial data ara available on disease and economic burden of rotavirus gastroenteritis and on circulating strains in India, which highlight the public health need for a rotavirus vaccine. A locally manufactured oral rotavirus vaccine has been licensed in India and it has been shown to be effective against severe rotavirus gastroenteritis in Indian children. The Government of India has announced that the vaccine will be included in the universal immunization n programme. Careful planning and preparation for post-licensure impact and safety evaluations will ensure that additional high quality benefit-risk data will be available for India.
The National medical journal of India 09/2014; 27(5):245-8. · 0.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Concerns exist about whether monovalent (RV1) and pentavalent (RV5) rotavirus vaccines provide adequate protection against diverse strains and whether vaccine introduction will lead to selective pressure. We aimed to investigate the distribution of rotavirus strains and strain-specific rotavirus vaccine effectiveness after vaccine introduction.
We did a systematic review of published work to assess the strain-specific effectiveness of RV1 and RV5 rotavirus vaccines. We classified strains as homotypic, partly heterotypic, and fully heterotypic based on the amount of antigen-matching between strain and vaccine. When studies reported vaccine effectiveness against single antigens (G-type or P-type), we categorised them as either single-antigen vaccine type or single-antigen non-vaccine type. Our primary outcome was strain-specific vaccine effectiveness, comparing effectiveness of homotypic strains with fully or partly heterotypic strains. A secondary outcome was the prevalence of rotavirus strains after vaccine introduction. We estimated pooled odds ratios using random-effect regression models, stratified by country income level and vaccine type, and tested for differences in strain-specific vaccine effectiveness. We assessed strain distribution trends from surveillance reports.
In high-income countries, RV1 pooled vaccine effectiveness was 94% (95% CI 80–98) against homotypic strains, 71% (39–86) against partly heterotypic strains, and 87% (76–93) against fully heterotypic strains. In middle-income settings, respective pooled data were 59% (36–73), 72% (58–81), and 47% (28–61). In high-income countries, RV5 vaccine effectiveness was 83% (78–87) against homotypic strains, 82% (70–89) against single-antigen vaccine type strains, 82% (70–89) against partly heterotypic strains, and 75% (47–88) against single-antigen non-vaccine type strains. In middle-income settings, RV5 vaccine effectiveness was 70% (58–78) against single-antigen vaccine type strains, 37% (10–56) against partly heterotypic strains, and 87% (38–97) against single-antigen non-vaccine type strains. No difference was noted in vaccine effectiveness for either RV1 or RV5 in any setting (all p>0·05). Prevalent strains in countries using RV1 were G2P (2198 of 4428, 50%) and G1P (953, 22%), and those in countries using RV5 were G1P (1280 of 3875, 33%) and G2P (1169, 30%). Sustained predominance of a single strain was not recorded.
RV1 and RV5 exert similar effectiveness against homotypic and heterotypic rotavirus strains. Persistence of specific strains was not recorded, suggesting vaccine-induced selective pressure did not occur. Expansion of rotavirus surveillance efforts to low-income countries and ongoing surveillance are crucial to identify emergence of new strains and to assess strain-specific vaccine effectiveness in various settings.
The Lancet Infectious Diseases 09/2014; DOI:10.1016/S1473-3099(14)70832-1 · 22.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Estimates of population-based incidence for rotavirus inpatient and outpatient visits, as well as their associated medical costs, can provide valuable information to assess the potential benefits of rotavirus vaccination.
We conducted active surveillance for rotavirus gastroenteritis at 6 medical institutions for children younger than 5 years from July 2012 to June 2013 in Beijing Municipality and Gansu Province. We collected stool samples of diarrhea patients for testing rotavirus, and epidemiological, clinical and cost data.
The proportion of rotavirus-positive for inpatient and outpatient visits from Beijing was 28.7% (138/481) and 19.4% (133/687); a statistically lower proportion than observed in Gansu among inpatient visits (45.2%, 245/542, P < 0.001) and among outpatient visits (28.8%, 66/229, P = 0.003), respectively. The G9P genotype was most prevalent in Beijing (60.6%) and in Gansu (77.6%). The median Vesikari scale value was 16 for rotavirus inpatients and 15 for nonrotavirus inpatients. Population-based estimated rates of rotavirus-related hospitalizations were 14.4 (95% CI, 13-16) per 10,000 children, and the rate of rotavirus gastroenteritis in the outpatient setting was 149 (95% CI, 145-153) per 10,000 children younger than 5 years. The estimated total number of rotavirus-related inpatient visits were 3790 (95% CI, 2488-3827) cases and 29,101 (95% CI: 27,748-29,279) outpatient visits. The total cost of rotavirus infection was $1.4 million (95% CI, $0.9-1.4 million) for hospitalizations and $4.2 million (95% CI, $4.0-4.2 million) for outpatient visits per year in Beijing and Gansu.
Rotavirus gastroenteritis is associated with a large disease burden in Chinese children younger than 5 years in Beijing and Gansu.Rotavirus is the most common cause of severe acute gastroenteritis (AGE) in children younger than 5 years worldwide, accounting for an estimated 25 million clinic visits, 2 million hospitalizations and 453,000 deaths each year., In China, the world's most populous nation, surveillance at sentinel hospitals showed that approximately 48% of AGE hospitalizations among children younger than 5 years were attributed to rotavirus from 2003 to 2007, and 13,387 rotavirus deaths were estimated in China in 2002 alone., The Lanzhou lamb rotavirus vaccine, consisting of serotype G10P, was licensed in 2000 but is not included in the National Expanded Program of Immunization vaccine recommendations for Chinese children. License applications for new rotavirus vaccines (Rotarix, produced by GlaxoSmithKline Biologicals, and RotaTeq, produced by Merck and Company) have been submitted for administering these vaccines to Chinese infants.