Genotype distribution and evolutionary analysis of rotavirus associated with acute diarrhea outpatients in Hubei, China, 2013-2016.

Group A human rotaviruses (RVAs) annually cause the deaths of 215,000 infants and young children. To understand the epidemiological characteristics and genetic evolution of RVAs, we performed sentinel surveillance on RVA prevalence in a rotavirus-surveillance network in Hubei, China. From 2013 to 2016, a total of 2007 fecal samples from hospital outpatients with acute gastroenteritis were collected from four cities of Hubei Province. Of the 2007 samples, 153 (7.62%) were identified positive for RVA by real-time RT-PCR. RVA infection in Hubei mainly occurred in autumn and winter. The highest detection rate of RVA infection was in 1-2 years old of outpatients (16.97%). No significant difference of RVA positive rate was observed between females and males. We performed a phylogenetic analysis of the G/P genotypes based on the partial VP7/VP4 gene sequences of RVAs. G9P[8] was the most predominant strain in all four years but the prevalence of G2P[4] genotype increased rapidly since 2014. We reconstructed the evolutionary time scale of RVAs in Hubei, and found that the evolutionary rates of the G9, G2, P[8], and P[4] genotypes of RVA were 1.069 â€‹× â€‹10-3, 1.029 â€‹× â€‹10-3, 1.283 â€‹× â€‹10-3 and 1.172 â€‹× â€‹10-3 nucleotide substitutions/site/year, respectively. Importantly, using a molecular clock model, we showed that most G9, G2, P[8], and P[4] genotype strains dated from the recent ancestor in 2005, 2005, 1993, and 2013, respectively. The finding of the distribution of RVAs in infants and young children in Hubei Province will contribute to the understanding of the epidemiological characteristics and genetic evolution of RVAs in China.

Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an appropriate dose of the candidate vaccine for an efficacy study. METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389. FINDINGS: 603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2-749·2) and 571·0 (467·6-697·3), with seroconversion rates at 96% (95% CI 93-98) and 97% (92-99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8-22·7) and 18·3 (14·4-23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85-93) of 253 and 113 (88%, 81-92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented. INTERPRETATION: The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation. FUNDING: National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.

Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial.

BACKGROUND: A vaccine to protect against COVID-19 is urgently needed. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. METHODS: We did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 1010, 1 × 1011, and 1·5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays. This study is registered with ClinicalTrials.gov, NCT04313127. FINDINGS: Between March 16 and March 27, 2020, we screened 195 individuals for eligibility. Of them, 108 participants (51% male, 49% female; mean age 36·3 years) were recruited and received the low dose (n=36), middle dose (n=36), or high dose (n=36) of the vaccine. All enrolled participants were included in the analysis. At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 [46%]), fatigue (47 [44%]), headache (42 [39%]), and muscle pain (18 [17%]. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination. INTERPRETATION: The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation. FUNDING: National Key R&D Program of China, National Science and Technology Major Project, and CanSino Biologics.

Elevated Arsenic Exposure Is Associated with an Increased Risk of Chronic Hepatitis B Virus Infection: NHANES (2003-2014) in U.S. Adults.

Studies concerning the association between arsenic exposure and hepatitis B virus (HB V) infection have been lacking. The present study aimed to examine the association between total urinary arsenic (TUA) and infection of HBV. A total of 5186 participants from National Health and Nutrition Examination Survey (NHANES) 2003-2014 were included in the analysis. We used logistic regression to evaluate the association. We defined two measures of TUA. TUAI was the sum of arsenous acid, arsenicacid, monomethylarsonic acid and dimethylarsenic acid. TUA2 was defined as TUA minus arsenobetaine and arsenocholine. The results showed that the weighted overall prevalence of HBV infection was 6.08%. For NHANES 2003-2014, the medians (interquartile range) of TUAI and TUA2 were 5.60 µg/L (3.97-8.09 µg/L) and 4.91 µg/L (2.36-9.11 µg/L), respectively. Comparing the highest quartile to the lowest quartile after multivariable adjustment showed that the odds ratios (ORs) and 95% confidence intervals (CIs) for TUAI and TUA2 were 2.44 (1.40-4.27) and 2.84 (1.60-5.05), respectively. In conclusion, elevated urinary arsenic was associated with the risk of HBV infection. Further studies, especially prospective studies, are needed to confirm the causal relationship between arsenic exposure and HBV infection.

Risk factors for bunyavirus-associated severe Fever with thrombocytopenia syndrome, china.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging disease that is caused by a novel bunyavirus, referred to as SFTS virus. During January 2011 to December 2011 we conducted a case-control study in Henan, Hubei and Shandong Provinces of China to determine the risk factors for SFTS. METHODS: Case-patients were identified in hospitals and reported to provincial Centers for Disease Control and Prevention while being notified electronically to the National Surveillance System. Controls were randomly selected from a pool of patients admitted to the same hospital ward within one week of the inclusion of the cases. They were matched by age (+/-5 years) and gender. RESULTS: A total of 422 patients participated in the study including 134 cases and 288 matched controls. The median age of the cases was 58.8 years, ranging from 47.6 to 70.1 years; 54.5% were male. No differences in demographics were observed between cases and controls; however, farmers were frequent and more common among cases (88.8%) than controls (58.7%). In multivariate analysis, the odds for SFTS was 2.4∼4.5 fold higher with patients who reported tick bites or presence of tick in the living area. Other independent risk factors included cat or cattle ownership and reported presence of weeds and shrubs in the working environment. CONCLUSIONS: Our findings support the hypothesis that ticks are important vectors of SFTS virus. Further investigations are warranted to understand the detailed modes of transmission of SFTS virus while vector management, education on tick bites prevention and personal hygiene management should be implemented for high-risk groups in high incidence areas.

[Investigation on the risk factors for reported rising of measles incidence during November, 2011 to February, 2012, in some areas of Hubei province].

OBJECTIVE: To identify the risk factors for reported sudden rise of measles incidence in November, 2011, in some areas of Hubei province. METHODS: We analyzed all measles patients reported in the measles surveillance system from November 2011 to February 2012 in two prefectures with highest attack rates and their vaccination history by reviewing vaccination records. We interviewed patients' parents by telephone to obtain the history of visiting health care within 7 to 21 days before onset. We also used case-crossover study to estimate the relative risk (RR) of hospital acquired infection and to compare the exposure to health care between 7-21 days before onset to 37-51 days before onset among measles patients. RESULTS: Totally 140 patients were reported in the two prefectures. Reported measles incidence rates among the population aged <8 m(69/100 000) and 8 m to 17 m (72/100 000) were higher than other age groups (rang from 0 to 5.8 per 100 000). Among the population aged 8 m to 17 m, estimated vaccination coverage was lower than 75%, and it was lower than 90% among those aged 18 m to 3 yrs. During 7-21 days before onset, 58% (29/50) of the patients had an exposure to health care settings, compared to 14% (7/50) of patients during 37 to 51 days before onset (MH RR = 5.4, 95% confidence interval = 2.1-14.0). CONCLUSION: Under the condition of measles vaccination coverage lower than 95%, iatrogenic infection was a risk factor for measles in Hubei.

[Epidemiologic analysis on severe fever with thrombocytopenia syndrome in Hubei province, 2010].

OBJECTIVE: To identify the epidemic characteristics and risk factors of an emerging infectious disease-severe fever with thrombocytopenia syndrome (SFTS) in Hubei province. METHODS: Active surveillance program on SFTS was set up in monitoring sites-hospitals, at the township level or above, in Suizhou, Huanggang and Wuhan from January to December, 2010. Specific surveillance program on SFTS was launched across the province in hospitals above the county level. Cases that matched the definition of surveillance case were identified and reported to Centers for Disease Control and Prevention (CDCs). Cases were interviewed and their blood samples collected and detected using PCR and virus isolation. We also conducted serum antibody surveys among healthy population and livestock and surveillance on vector ticks in those high-epidemic areas. RESULTS: 188 cases that matched the definition of surveillance case and 21 deaths were reported in 11 cities, 32 countries and 100 towns in 2010, with an incidence rate of 0.33/10(6). The fatality rate was 11.2%. Data showed that the patients were from hilly areas at the altitude elevated between 28-940 meters. The epidemic period was between April and December with the peak from May to September. The youngest case was an 11-year old, while the eldest was 81 with median age as 56-year old. 95.3% of the patients were farmers. All Patients did not have the history of traveling, two weeks before the onset of SFTS. 93.6% of the patients engaged in different kind of work which was associated with agriculture. 52.8% of the patients had been exposed to ticks. 22.0% of the patients had been bitten by ticks. Skin injury was found in 64.2% of the patients. Samples from 129 cases (68.6%) were collected and detected, with 67.4% of them (87 cases) showed positive by Real time-PCR for SFTS virus. An elevation in antibody titer by a factor of four or evidence of sero-conversion was observed in 11 patients; SFTS virus was isolated from 2 patients. The total antibody positive rates were 3.8%, 55.0% (6/11), 36.7% (2/3) and 80.0% (4/5) respectively in healthy population, dogs, sheep and cows. Ticks from grass, cattle and sheep were detected positive by Real time-PCR. CONCLUSION: Most cases of SFTS in Hubei were infected by SFTS virus, and cases of livestock were infected by SFTS virus. Ticks might serve as an important vector. Skin injury, exposure to tick bites seemed to be the risk factors.

Fever with thrombocytopenia associated with a novel bunyavirus in China.

BACKGROUND: Heightened surveillance of acute febrile illness in China since 2009 has led to the identification of a severe fever with thrombocytopenia syndrome (SFTS) with an unknown cause. Infection with Anaplasma phagocytophilum has been suggested as a cause, but the pathogen has not been detected in most patients on laboratory testing. METHODS: We obtained blood samples from patients with the case definition of SFTS in six provinces in China. The blood samples were used to isolate the causal pathogen by inoculation of cell culture and for detection of viral RNA on polymerase-chain-reaction assay. The pathogen was characterized on electron microscopy and nucleic acid sequencing. We used enzyme-linked immunosorbent assay, indirect immunofluorescence assay, and neutralization testing to analyze the level of virus-specific antibody in patients' serum samples. RESULTS: We isolated a novel virus, designated SFTS bunyavirus, from patients who presented with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction. RNA sequence analysis revealed that the virus was a newly identified member of the genus phlebovirus in the Bunyaviridae family. Electron-microscopical examination revealed virions with the morphologic characteristics of a bunyavirus. The presence of the virus was confirmed in 171 patients with SFTS from six provinces by detection of viral RNA, specific antibodies to the virus in blood, or both. Serologic assays showed a virus-specific immune response in all 35 pairs of serum samples collected from patients during the acute and convalescent phases of the illness. CONCLUSIONS: A novel phlebovirus was identified in patients with a life-threatening illness associated with fever and thrombocytopenia in China. (Funded by the China Mega-Project for Infectious Diseases and others.).

[Clinical characteristics and treatment assessments of severe enterovirus 71 infected children].

OBJECTIVE: To facilitate early recognition of ominous clinical manifestations, to understand pathophysiology and assess treatment effects in patients with severe enterovirus 71 (EV71) associated hand, foot and mouth disease (HFMD). METHOD: A retrospective analysis was performed based on the clinical records, laboratory data and treatment effects which were collected from twelve severe EV71 infected cases from nine hospitals in 2008, in Hubei province, China. RESULT: Of the 12 severe cases, ten (83.3%) were male and two female. The median age was 1.96 yrs (8 m to 7 yrs). The mean hyperthermic duration was 6 days with the peak temperature over 38.5 degrees C, and mean rash duration was 7 days. Fever and rash emerged simultaneously in 4 of 5 cases with cardiopulmonary failure. The severe complications included encephalitis (10 cases), pulmonary edema or hemorrhage (5 cases). Eleven cases were checked with magnetic resonance imaging (MRI) and four cases showed characteristics of encephalitis or meningitis, two with images of naso sinusitis and ethmoid-mastoid inflammation. Chest X-ray examination showed with pulmonary edema on single or both sides (5 cases), bronchitis (4 cases), and normal image (3 cases). There was no specific finding in the cardiac ultrasound and electrocardiogram in any of the patients, as well as the white blood cell count, blood glucose, prothrombin time, partial thromboplastin time and D-dimer. Cerebrospinal fluid showed aseptic meningitis with the increase of cell count in 7 cases. All patients were treated with antibiotics and/or antivirals, such as cephalosporins, ribavirin etc. Eleven patients were treated with intravenous immunoglobulin (total dose 2 - 4.5 g/kg) for 2 - 5 days, and the highest blood concentration of immunoglobulin was detected increasing at 7 g/L. Seven cases were also treated with methylprednisolone 10 - 30 mg/(kg x d), four with dopamine, dobutamine, or digitalis. In addition, by using continuous positive airway pressure by nasal catheter and maintenance of circulation in the cases with cardiopulmonary failure could not relieve the symptoms of dyspnoea, and mechanical ventilation was required to maintain for a mean of 72 hrs (24 - 96 hrs). Except one case died of pulmonary edema in the early stage, others were cured without sequelae. CONCLUSION: Severe EV71 infection is more common in children younger than 3 years old, in which the profound complications include encephalitis and pulmonary edema. The mechanical ventilation should be critically urged for child with complicating cardiopulmonary failure as soon.