Projected health impact and cost-effectiveness of rotavirus vaccination among children <5 years of age in China.

INTRODUCTION: Two rotavirus vaccines have been licensed globally since 2006. In China, only a lamb rotavirus vaccine is licensed and several new rotavirus vaccines are in development. Data regarding the projected health impact and cost-effectiveness of vaccination of children in China against rotavirus will assist policy makers in developing recommendations for vaccination. METHODS: Using a Microsoft Excel model, we compared the national health and economic burden of rotavirus disease in China with and without a vaccination program. Model inputs included 2007 data on burden and cost of rotavirus outcomes (deaths, hospitalizations, outpatient visits), projected vaccine efficacy, coverage, and cost. Cost-effectiveness was measured in US dollars per disability-adjusted life-year (DALY) and US dollars per life saved. RESULTS: A 2-dose rotavirus vaccination program could annually avert 3013 (62%) deaths, 194,794 (59%) hospitalizations and 1,333,356 (51%) outpatient visits associated with rotavirus disease in China. The medical break-even price of the vaccine is $1.19 per dose. From a societal perspective, a vaccination program would be highly cost-effective in China at the vaccine price of $2.50 to $5 per dose, and be cost-effective at the price of $10 to $20 per dose. CONCLUSIONS: A national rotavirus vaccination program could be a cost-effective measure to effectively reduce deaths, hospitalizations, and outpatient visits due to rotavirus disease in China.

Importance and challenges of accurately counting rotavirus deaths in China, 2002.

Rotavirus mortality is an important component of the total burden of rotavirus disease for children under 5 years old, but accurate estimation is difficult for many developing countries. Here we applied a more direct method to improve estimates of rotavirus mortality in China using 2002 Chinese-specific data. Results indicate that in 2002, approximately 13,400 children under 5 years old in China died from rotavirus and 70% of these deaths occur in rural areas. Thus, a national rotavirus immunization program targeting rural areas with high mortality from diarrhoea could dramatically reduce these deaths and urban areas could reduce childhood hospitalizations attributed to rotavirus by 43%.

Hospital-Based Surveillance of Rotavirus Diarrhea in the People's Republic of China, August 2003-July 2007.

Rotaviruses cause acute diarrhea worldwide. Previous studies of rotavirus diarrhea in China found that rotavirus infection is the most common cause of severe diarrhea in young children. In the present study, surveillance of rotavirus diarrhea was conducted involving 9549 children aged <5 years who were admitted for treatment of diarrhea at 11 sentinel hospitals in China from August 2003 through July 2007. Group A rotavirus was detected in 3749 (47.8%) of the 7846 fecal specimens by using enzyme-linked immunosorbent assay. Rotavirus isolates were characterized by reverse-transcriptase polymerase chain reaction to determine G and P genotypes. All the strains that are common worldwide were detected; G3P[8] was the most common. An unusual G5 strain was detected in 2 specimens. Of all episodes of rotavirus diarrhea, 94% occurred during the first 2 years of life, peaking at 6-23 months of age. Our findings indicate that globally common rotavirus strains continue to be a major cause of severe childhood diarrhea in China. Introduction of routine immunization with effective rotavirus vaccines would substantially reduce this burden.

Viral agents associated with acute gastroenteritis in children hospitalized with diarrhea in Lanzhou, China.

BACKGROUND: Gastroenteritis is a major cause of childhood morbidity and mortality worldwide. Rotavirus, human caliciviruses (HucV), adenovirus, and astrovirus are recognized as common etiologies of acute gastroenteritis. OBJECTIVES: To use antigen detection and molecular methods to determine the viral etiology of childhood diarrhea in Lanzhou, China, 2005-2007. STUDY DESIGN: 544 stool specimens were collected from children hospitalized with diarrhea. ELISA, RT-PCR, or PCR were used to detect viruses commonly causing diarrhea. RESULTS: Group A rotavirus, norovirus, sapovirus, astrovirus, and adenovirus, were detected in 54.0%, 9.2%, 1.1%, 3.3%, and 4.4%, respectively. No group B or group C rotaviruses were detected. The relative contribution of these viruses changed greatly over 2 years. The percentage of rotavirus and adenovirus dropped from 61.2% and 5.4% to 47.6% and 1.4%, whereas HucV increased from 5.0% to 15.0%. G1 and P[8] were the predominant rotavirus strains, and P[6] was detected for the first time in this area. The predominant norovirus strain changed from GII3 to GII4, and the subtypes of GII4 changed from the Hunter strain to the variant 2006b strain. CONCLUSIONS: The distribution of viruses and genotypes of individual viruses causing gastroenteritis in Lanzhou, China changed greatly during 2005-2007.

Molecular epidemic features and variation of rotavirus among children with diarrhea in Lanzhou, China, 2001-2006.

BACKGROUND: Human rotavirus (HRV) is the most common pathogen causing severe diarrhea among infants and young children worldwide. This study aims to understand rotavirus epidemiology and its variation in the period of 2001-2006 in Lanzhou, Gansu Province, China, and to provide an epidemiological basis for the development of rotavirus vaccine. METHODS: A total of 1019 stool specimens were collected from patients with acute diarrhea admitted to the First Hospital of Lanzhou University from 2001 to 2006, who were younger than 5 years old. Dako IDEIATM kits were used for detection of rotavirus, and RT-PCR was performed for determination of G serotype and P genotype of the rotavirus. RESULTS: Rotavirus was present in 51.6% (526) of the 1019 specimens. G serotype identified G3 at 40.9%, G2 14.6%, G1 22.2% and G9 1.9%. Mixed-G infection was observed in 4.4% and non-typeable infection 16.0%. P genotype was observed in 372 samples, of which P[8] accounted for 186 cases (50.0%), P[4] 72 cases (19.4%), mixed-P infection 2 cases (0.5%), and non-typeable cases 112 (30.1%). G3 was the most prevalent G serotype found in this study from 2001 to 2004, G2 was the most prevalent G serotype (34.4%) from 2004 to 2005, and G1 (61.5%) was the most prevalent strain from 2005 to 2006. G9 was detected in 10 cases (1.9%) and G4 was not detected during this 5-year period. P[8] was the most prevalent P genotype found over the 5 consecutive years of this study, although there was a significant transition of P genotype from 2004 to 2005 with P[4] (45%) identified as the predominant P genotype, followed by P[8] (22.1%). The predominant G-P combination was P[8]G1 (33.6%), followed by P[8]G3 (32.1%) and P[4]G2 (17.2%). Rotavirus diarrhea admissions peaked between October and December. Continuous surveillance showed that the incidence rate of rotavirus was the highest in infants aged 6-23 months, averaging 11.0-11.9 months. CONCLUSIONS: Five years of continuous surveillance showed that rotavirus remains the most significant viral agent causing diarrhea hospitalization among children under 5 years old in Lanzhou, China although the predominant strain of rotavirus varies between years. Mixed-G serotype infection also appears to occur at a relatively high rate in Lanzhou.

Emergence of the GII4/2006b variant and recombinant noroviruses in China.

Noroviruses are an important cause of acute gastroenteritis. Increasing data showed that the GII-4 strains are predominant worldwide and new GII-4 variants emerge every 1-2 years causing major epidemics. Surveillance of gastroenteritis in hospitalized children under 5 years of age in China is described. Among 1,110 specimens, 114 (10.3%) were positive for noroviruses, which was higher than adenoviruses (7.6%), astroviruses (3.5%), and sapoviruses (0.9%) and only lower than group A rotaviruses (40.6%). Thirty-eight of the 114 positive norovirus cases were co-infected with other enteric viruses. Five norovirus genotypes (GI-2, GI-4, GII-3, GII-4, and GII-14) were detected, with GII-4/2006b the most predominant type (64.9%). The reported recombinant of GII-3 capsid and GII-4 polymerase described previously was also detected frequently and a recombinant of GII-14 capsid and GII-6 polymerase was found for the first time. This study suggests that continual surveillance focusing on strain variation and dynamic change is important for understanding the epidemiology and development of a strategy for disease control and prevention.

[Characteristics analysis on major genes and the encoded proteins of human G9P[8] rotaviruses LL52696 and LL52727].

Two Rotavirus G9P[8] strains (LL52696 and LL52727) were recognized during a sentinel-based survey in Lulong, China. Phylogenetic analysis of the VP7 gene showed that both strains isolated constituted a divergent genetic cluster distinct from the other G9 strains isolated in China. Analysis of VP4, VP6, and NSP4 genes revealed that these strains were closely related to Lulong strains. We hold that two strains were reassortant between G9 and Lulong predominant strains.

Human bocavirus in children hospitalized for acute gastroenteritis: a case-control study.

BACKGROUND: Human bocavirus (HBoV) was recently discovered in children with respiratory tract disease and gastroenteritis. The causative role of HBoV in human gastroenteritis remains uncertain, and, to our knowledge, no previous case-control study has studied the relationship between HBoV and gastroenteritis. METHODS: We conducted a case-control study that examined stool samples from 397 children with diarrhea and from 115 asymptomatic control subjects. HBoV was detected using polymerase chain reaction. Real-time polymerase chain reaction was used to quantify the HBoV loads in case and control groups. Common enteric viruses were examined using enzyme-linked immunosorbent assays, polymerase chain reaction, and reverse-transcription polymerase chain reaction. RESULTS: At least 1 viral agent was discovered in 60.2% of cases. HBoV was detected in 14 samples, and 9 were coinfected with either rotavirus (7 of 14 samples) or human calicivirus (2 of 14). Many (8 [57.1%] of 14) of the HBoV infections occurred during September-December 2006. Most (12 [85.7%]) of the HBoV-infected children were 7-18 months of age. The percentage of children with HBoV infection did not differ significantly between case patients and control subjects (3.5% vs. 3.5%), and the statistical analysis did not support a correlation between HBoV infection and more-severe clinical symptoms. The viral load differences between the 2 groups were not statistically significant (P = .09, by log-normal Student's t test). In addition, the VP1/VP2 partial gene of HBoV from case patients and control subjects showed minimal sequence variation. CONCLUSIONS: A single genetic lineage of HBoV was revealed in persons in China. Despite its high prevalence in stool samples, our study does not support a causative role of HBoV in gastroenteritis.

[A research on rotaviral diarrhea outbreak in Guangxi Province].

OBJECTIVE: To analyze epidemiological characters of an outbreak of rotavirus diarrhea in Daxing County, Guangxi Province. METHODS: Rotavirus-positive specimens were identified by ELISA kit. G/P typing assays were confirmed with multiplex seminested RT-PCR. Full-length VP7 genes of 4 positive specimens were amplified and analyzed. RESULTS: 30 cases of Rotavirus-positive were identified from 64 specimens. The attack rate was 46.9%, and G/P typing was G1P[8]. A change of VP7 amino acid residue is at positions 68. CONCLUSION: G1P[8] rotavirus is the etiologic agents of this diarrhea outbreak. In addition, adults were included in this outbreak.

Human bocavirus infection in children hospitalized with acute gastroenteritis in China.

BACKGROUND: Human bocavirus (HBoV) was first identified in children with acute respiratory-tract infections, but recent studies have revealed that HBoV is also frequently detected in fecal specimens from children with gastroenteritis. OBJECTIVES: To investigate the prevalence of HBoV in children hospitalized with gastroenteritis in different areas of China. STUDY DESIGN: Employing ELISA, RT-PCR or PCR, we evaluated 1216 fecal samples for common diarrheal agents from children aged less than 5-year-old hospitalized with acute gastroenteritis. MEGA software was used to construct phylogenetic trees of the VP1/VP2 partial sequences of the HBoV genome. RESULTS: There were 67 HBoV-positive specimens, 52 (77.6%) were co-infected with rotavirus, norovirus, astrovirus, or enteric adenovirus. Statistical analysis of the clinical data indicated that children infected with both rotavirus and bocavirus did not have more severe clinical symptoms than children infected with rotavirus. The phylogenetic analysis of the VP1/VP2 partial sequences of the HBoV genome revealed a single genetic lineage. CONCLUSIONS: Despite its high infection rate, there was no statistically significant a causual relationship between HBoV and gastroenteritis in children.

[Genetic variation in VP7 gene of rotavirus serotype G3 predominated in Changchun, China].

Group A rotavirus (RV) is the most important etiologic agent of severe gastroenteritis among children and the development of an effective vaccine becomes the top public health priority. Since survey of RV serotypes circulating in local community is important for introduction or development of RV vaccine, RV serotype G3 had proved as the predominant strain in Changchun from 2001 to 2005. Stool specimens collected from children with acute diarrhea were tested for group A rotavirus by enzyme-linked immunosorbent assay (ELISA) and RV isolates were typed by reverse transcription-polymerase chain reaction (RT-PCR) using serotype-specific primers. The complete VP7 gene segments of 31 rotavirus strains selected in Changchun from 1999 to 2005 were amplified with RT-PCR. Amplicons were cloned and sequenced. Comparative analysis of the VP7 sequences showed that there were no obvious differences among 31 RV strains. There was similar genetic variation among VP7 genes during the same RV season. The nucleotide sequence of VP7 gene of six G3 RV strains had one base deletion at nt1038 in 2003 RV season. The nucleotide mutations in regions A, B and C of VP7 gene took place at the same position or position near-by. Increase of nucleotide mutation in non- high variation region may benefit maintenance of serotype G3 as pre dominant strain after 2002. Increase of non continuous variation in non-high variation regions was notable.

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.

[Epidemiological investigation of an outbreak of acute gastroenteritis caused by human calicivirus in Lulong County].

OBJECTIVE: To survey an outbreak of acute gastroenteritis in Lulong County and analyze the cause of the disease. METHODS: Epidemiological methods were applied to investigate an outbreak of acute gastroenteritis occurred in June 2000 in Lulong County. Stool specimens were collected from diarrhea patients and were tested for human calicivirus by ELISA and RT-PCR. The products of RT-PCR were cloned and sequenced, then phylogenetic analysis was carried out. RESULTS: In total, 736 farmers were surveyed, among them 134 had acute gastroenteritis, the attack rate was 18.20%, and one elderly patient died. The age of patients was from 1 to 77 years and the incidence of the disease among young people was higher with a peak in June 25 through 30. Six stool specimens were tested for caliciviruses by ELISA and 3 were positives, one of them was confirmed by RT-PCR and belonged to norovirus genotype GI/2. No other pathogens were detected. CONCLUSION: Human calicivirus was confirmed to be the cause of the outbreak of acute gastroenteritis.

[Rotavirus diarrhea among children in three hospitals under sentinel surveillance, from August 2001 to July 2004].

OBJECTIVE: To learn the epidemiologic characteristics of rotavirus diarrhea in three hospitals under sentinel surveillance from August 2001 to July 2004 and to provide background information for developing and implementing rotavirus vaccine. METHODS: Data from hospital-based rotavirus surveillance among children < 5 years old hospitalized with acute diarrhea was used. Patients' clinic information and feces specimens were collected. Specimens were tested and typed for rotavirus. RESULTS: Totally, 3121 specimens were tested and the detection rate of rotavirus was 51%. Among all the children with rotavirus diarrhea, 94% were < 2 years old. G3 (69.9%) was the most prevalent serotype followed by G1 (6.6%) and G2 (2.9%). P[8] was the most common genotype of rotavirus. The most common G-P combination identified in this study was P[8] G3 (64.0%). Seveal other combinations of minor frequency were also identified. CONCLUSION: Rotavirus infection was most commonly seen among children < 5 years old hospitalized with acute diarrhea in the three hospitals. It is important to develop and implement rotavirus vaccine to prevent and control severe rotavirus infection. Because of the diversity of rotavirus strains, it is necessary to perform rotavirus strain surveillance to understand the dynamic nature of viral transmission.

[Investigation of human calicivirus (HuCV) diarrhea among infantile and young children in China, 1999--2005].

Human calicivirus (HuCV) has been well known as an important pathogen of outbreak and sporadic acute nonbacterial gastroenteritis worldwide. To investigate epidemiological feature and genetic diversity of HuCV among children in China, fecal specimens were collected from children under 5 years of age with acute diarrhea at 13 hospitals in different provinces across China. The study was performed year-round from January 1999 to June 2005. Fecal specimens were tested for bacteria and rotavirus first and the negative specimens then were tested for HuCV using ELISA and RT-PCR. PCR amplicons were cloned and sequenced for strain characterization. A total of 4426 rotavirus- negative fecal samples were screened. From these, 840 (19%) were positive for HuCV by either or both ELISA (14%) and RT-PCR (9.6%). HuCV infection occurred year-round with an epidemic in each winter (October-January) and mainly in children at 6 -- 17 months of age. Of 151 HuCV strains characterized, 146 belong to norovirus (NV, 96.7%) and 5 were sapoviruses (SV). Among norovirus strains, genotype GG II/4 was most common (99/146), followed by GG II/3 (22/146), GG II/5 (8/146), and 2 strains of each of GG II/6, GG II/7, GG II/8, and GG I/2, the other 9 strains of NV GG II were unique, potentially belonging to new genotypes. These results plus the epidemiology data suggested that HuCVs are an important cause of severe diarrhea in Chinese children that were under reported due to a lack of a simple diagnostic assay. The finding of the potential new genotypes indicates that the current assays need to be improved for broader detection and besides, a continual surveillance for better understanding the epidemiology the disease burden and the searching for new strains of HuCVs is necessary.

[Sequence analysis of norovirus CHN02/LZ35666 from Lanzhou city of China based on RdRp and VP1 genes].

Sequence analysis of a new norovirus (NV) isolated from Lanzou city of China was performed based on partial sequence of RNA dependent RNA polymerase (RdRp) and complete capsid protein (VP1) gene. The isolated strain CHN02/LZ35666 shared high sequence homology with GII-4 NVs. Nucleotide homologies of RdRp region and encoded capsid protein region were 90.4% -- 98.6% and 89.8% -- 95.7% , respectively, while amino acid homology of capsid protein region was 94.4% -- 97.4%. The analysis of GDD motif in RdRp region indicated this GDD motif of Lanzhou strain differed from those of the GII-4 predominant epidemic strains. Lanzhou strain formed an independent branch in GII-4 cluster in the phylogenetic tree based on nucleotide sequence of RdRp region and amino acid sequence of capsid protein. Sequence alignment revealed a mutation at the fourth key site of the receptor-binding interface in the strains isolated after 2002 compared with those of previous strains suggesting a possible change of binding pattern to HBGAs receptors.

[Relationship between severity of rotavirus diarrhea and serotype G and genotype].

OBJECTIVE: To learn the relationship between severity of rotavirus diarrhea and serotype G and genotype P. METHOD: The clinical information and fecal specimens of hospitalized children less than 5 years of age with acute diarrhea in four sentinel hospitals were collected from Aug 2001 to July 2003. Specimens were tested and typed for rotavirus. Each child with rotavirus infection was assessed for severity of diarrhea according to the 20-points scoring system of Vesikari. RESULTS: When combined with P[8], the severity scores for rotavirus diarrhea of P[8]G1 and P[8]G3 were 13 and 12 points, respectively, and the durations of diarrhea were 6 days and 5 days, respectively. The percentage of fever in patients with diarrhea caused by P[8]G1 was higher than that in those with diarrheas caused by P[8]G3 (97 percent vs. 73 percent). And the highest temperature in the cases with diarrheas caused by G1 and G3 was 39 degrees C and 38.6 degrees C, respectively. When combined with G3, the difference of diarrhea severity scores between P[4]G3 and P[8]G3 was not significant. But duration of diarrhea caused by P[4] was longer than that of diarrheas caused by P[8] (6.5 days vs. 5 days) and the maximum times of vomiting in P[8] cases was higher than in p[4] cases (4 times vs. 3 times per day). There was no significant difference in other clinical features between P[8] and P[4] infected cases. CONCLUSION: When combined with P[8], RV diarrhea caused by G1 was associated with higher severity scores than diarrhea caused by G3. When combined with G3, there was no significant difference in severity scores between P[4] and P[8] infected cases.