Changes in peripheral blood cytokines in patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is recognized as an emerging infectious disease. This study aimed to investigate the pathogenic mechanism of SFTS. A total of 100 subjects were randomly included in the study. Cytokine levels were detected by enzyme-linked immunosorbent assay and the viral load was detected by micro drop digital PCR. The results showed that levels of interleukin-6 (IL-6), IL-8, IL-10, IFN-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), transforming growth factor-ß1 (TGF-ß1), and regulated upon activation normal T cell expressed and secreted factor (RANTES) differed significantly among the SFTS patient group, healthy people group, and asymptomatic infection group (p < .05). Compared to the healthy people group, the patient group had increased cytokine levels (IL-6, IL-10, IP-10, MCP-1, and IFN-γ) but reduced levels of IL-8, TGF-ß1, and RANTES (p < .0167). IL-6, IL-8, IL-10, IP-10, MCP-1, MIP-1α, TGF-ß1, and the RANTES levels had different trends after the onset of the disease. IL-6, IL-10, IP-10, and MCP-1 levels in severe patients were higher than those in mild patients (p < .05). There was a positive correlation between viral load and IL-6 and IP-10 but a negative correlation between viral load and RANTES. SFTSV could cause a cytokine change: the cytokine levels of patients had different degrees of fluctuation after the onset of the disease. The levels of IL-6 and IL-8 in the asymptomatic infection group were found between the SFTS patients group and the healthy people group. The levels of IL-6, IL-10, IP-10, and MCP-1 in the serum could reflect the severity of the disease, and the levels of IL-6, IP-10, and RANTES were correlated with the viral load.

Severe fever with thrombocytopenia syndrome: a systematic review and meta-analysis of epidemiology, clinical signs, routine laboratory diagnosis, risk factors, and outcomes.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with the high case-fatality rate, and lack of vaccines. We aimed to systematically analysed the epidemiological characteristics, clinical signs, routine laboratory diagnosis, risk factors, and outcomes. METHODS: Documents on SFTS were collected by searching the Chinese National Knowledge Infrastructure, Wan Fang Data, PubMed, Embase, and Web of Science databases from 2011 to 2018. Meta-analysis was performed by using Review Manager and Stata software. RESULTS: Twenty-five articles involving 4143 cases were included. Diarrhea (odds ratio (OR) =1.60, 95% confidence interval (CI): 1.06 to 2.42, P = 0.02), and vomiting (OR = 1.56, 95% CI: 1.01 to 2.39, P = 0.04) on admission were associated with the fatal outcomes of SFTS. Compared to patients with mild symptoms, patients with severe symptoms had significantly elevated levels of lactic acid dehydrogenase (standard mean difference (SMD) =1.27, 95% CI: 0.59 to 1.94), alanine aminotransferase (SMD = 0.55, 95% CI: 0.24 to 0.85), aspirate aminotransferase (SMD = 1.01, 95% CI: 0.69 to 1.32), and creatine kinase (SMD = 1.04, 95% CI: 0.74 to 1.33) but had reduced platelet counts (SMD = -0.87, 95% CI: - 1.16 to - 0.58) and albumin levels (SMD = -1.00, 95% CI: - 1.32 to - 0.68). The risk factors for poor prognosis included age (mean difference (MD) =6.88, 95% CI: 5.41 to 8.35) and farming (OR = 2.01, 95% CI: 1.06 to 3.80). For the risk factors of contracting SFTS, the incidence of SFTS related to tick bites was 24% [95% CI: 0.18 to 0.31]. The pooled case-fatality rate of SFTS patients was 18% [95% CI: 0.16 to 0.21]. CONCLUSIONS: China is the country with the highest incidence of SFTS. May to July was the peak of the epidemic, and farmers were a high-risk group. The risk factor for SFTS included age (poor prognosis) and tick bites (contracting SFTS). Patients with severe diarrhea and vomiting symptoms on admission should be noted. Clinicians could use routine laboratory parameters and clinical symptoms as references for clinically suspected cases, classification of SFTS, and timely treatment, especially in basic hospitals.

Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials.

Importance: A vaccine against coronavirus disease 2019 (COVID-19) is urgently needed. Objective: To evaluate the safety and immunogenicity of an investigational inactivated whole-virus COVID-19 vaccine in China. Interventions: In the phase 1 trial, 96 participants were assigned to 1 of the 3 dose groups (2.5, 5, and 10 µg/dose) and an aluminum hydroxide (alum) adjuvant-only group (n = 24 in each group), and received 3 intramuscular injections at days 0, 28, and 56. In the phase 2 trial, 224 adults were randomized to 5 µg/dose in 2 schedule groups (injections on days 0 and 14 [n = 84] vs alum only [n = 28], and days 0 and 21 [n = 84] vs alum only [n = 28]). Design, Setting, and Participants: Interim analysis of ongoing randomized, double-blind, placebo-controlled, phase 1 and 2 clinical trials to assess an inactivated COVID-19 vaccine. The trials were conducted in Henan Province, China, among 96 (phase 1) and 224 (phase 2) healthy adults aged between 18 and 59 years. Study enrollment began on April 12, 2020. The interim analysis was conducted on June 16, 2020, and updated on July 27, 2020. Main Outcomes and Measures: The primary safety outcome was the combined adverse reactions 7 days after each injection, and the primary immunogenicity outcome was neutralizing antibody response 14 days after the whole-course vaccination, which was measured by a 50% plaque reduction neutralization test against live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: Among 320 patients who were randomized (mean age, 42.8 years; 200 women [62.5%]), all completed the trial up to 28 days after the whole-course vaccination. The 7-day adverse reactions occurred in 3 (12.5%), 5 (20.8%), 4 (16.7%), and 6 (25.0%) patients in the alum only, low-dose, medium-dose, and high-dose groups, respectively, in the phase 1 trial; and in 5 (6.0%) and 4 (14.3%) patients who received injections on days 0 and 14 for vaccine and alum only, and 16 (19.0%) and 5 (17.9%) patients who received injections on days 0 and 21 for vaccine and alum only, respectively, in the phase 2 trial. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting; no serious adverse reactions were noted. The geometric mean titers of neutralizing antibodies in the low-, medium-, and high-dose groups at day 14 after 3 injections were 316 (95% CI, 218-457), 206 (95% CI, 123-343), and 297 (95% CI, 208-424), respectively, in the phase 1 trial, and were 121 (95% CI, 95-154) and 247 (95% CI, 176-345) at day 14 after 2 injections in participants receiving vaccine on days 0 and 14 and on days 0 and 21, respectively, in the phase 2 trial. There were no detectable antibody responses in all alum-only groups. Conclusions and Relevance: In this interim report of the phase 1 and phase 2 trials of an inactivated COVID-19 vaccine, patients had a low rate of adverse reactions and demonstrated immunogenicity; the study is ongoing. Efficacy and longer-term adverse event assessment will require phase 3 trials. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000031809.

Clinical and Neuroimaging Features of Acute Ischemic Stroke in Cancer Patients.

BACKGROUND: The occurrence of acute ischemic stroke in cancer patients is not unusual. In clinical practice, acute ischemic stroke with cancer usually cannot be diagnosed promptly due to lack of specific markers. But for cancer patients, advanced prevention, accurate diagnosis and proper treatment of acute ischemic stroke are very important. The aim of the present study was to investigate the clinical and neuroimaging features of acute ischemic stroke in patients with cancer. METHODS: We conducted a retrospective review of all cancer-associated acute ischemic stroke patients (n = 46) admitted to the Affiliated Hospital of Academy of Military Medical Sciences between October 2011 and March 2015. A group of non-cancer acute ischemic stroke patients (n = 50) at the same period were selected randomly as control. The clinical and neuroimaging data were collected and compared between the 2 groups. RESULTS: Patients with cancer-associated stroke (CS) had a lower body mass index (23.26 ± 3.70 vs. 24.88 ± 2.83, p = 0.021) compared to non-cancer stroke (NC) patients. A lower proportion of CS patients suffered from hypertension (45.7 vs. 68.0%, p = 0.039) and hyperlipidemia (10.9 vs. 72.0%, p = 0.000) than the NC group. A higher proportion of CS patients had deep vein catheter (24.0 vs. 0%) before the onset of stoke than that of the NC group. Levels of hemoglobin, albumin and triglyceride were lower in CS groups compared with that of the NC group (p < 0.05). The prothrombin time, international normalized ratio, D-dimer and fibrinogen levels were significantly higher in the CS group than in the NC group (p < 0.05). As to the neuroimaging patterns, disperse lesions (OR 7.01; 95% CI 1.17-42.12; p < 0.05) was independently associated with CS. CONCLUSIONS: Cancer-associated ischemic stroke was different form conventional ischemic stroke in the aspect of clinical and neuroimaging manifestation. This phenomenon might be because of the embolic etiology of CS. These features together could become a clue to CS.

[Surveillance of adverse events following immunization in Henan Province, China between 2010-2011].

OBJECTIVE: To analyze the epidemiological features of adverse events following immunization (AEFI) in Henan Province, China and to evaluate the safety of vaccines currently used in Henan. METHODS: The AEFI cases reported in Henan from January 1, 2010 to December 31, 2011 were collected through the China Surveillance System of Information on National Immunization Program. The descriptive method was used for epidemiological analysis. RESULTS: A total of 2415 cases of AEFI were reported in Henan from January 1, 2010 to December 31, 2011, and 1238 (51.26%) of them were found in Zhengzhou, Luoyang, and Jiaozuo cities. The male-to-female ratio was 1.32:1. Seven hundred and ninety-nine (33.08%) of these cases were less than one year old. Measles vaccine and DPT vaccine (against diphtheria, pertussis, and tetanus) were the main causes of AEFI, contributing to 61.24% of cases; the incidence rates of AEFI among people receiving measles and DPT vaccines were 30.3/105 and 5.0/105, respectively. 1528 cases (63.27%) developed AEFI after the first dose of vaccination. Inflammation and allergic symptoms were the predominant adverse effects caused by the top 5 vaccines AEFI-causing vaccines, and the clinical manifestations were significantly different among AEFI cases caused by different vaccines (χ2=304.5, P<0.001). Among the 2415 AEFI cases, 1946 (80.58%) had common adverse reaction, 348 (14.41%) had rare adverse reaction, 98 (4.06%) had coupling disease, 13 (0.51%) had psychogenic reaction, and 10 (0.41%) had reaction for unknown reasons. The prognosis of most AEFI cases was good, with a cure rate as high as 90.64%. CONCLUSIONS: AEFI occurs mostly in young children and after the first dose of vaccination. This should be brought to the attention of vaccination service personnel and the children's parents.

Safety and Immunogenicity of an Inactivated COVID-19 Vaccine, WIBP-CorV, in Healthy Children: Interim Analysis of a Randomized, Double-Blind, Controlled, Phase 1/2 Trial.

Safe and effective vaccines against SARS-CoV-2 for children are urgently needed. Here we aimed to assess the safety and immunogenicity of an inactivated COVID-19 vaccine candidate, WIBP-CorV, in participants aged 3-17 years. A randomized, double-blind, placebo-controlled, phase 1/2 clinical trial was conducted in Henan Province, China, in healthy children aged 3-17 years. 240 participants in phase 1 trial and 576 participants in phase 2 trial were randomly assigned to vaccine or control with an age de-escalation in three cohorts (3-5, 6-12 and 13-17 years) and dose-escalation in three groups (2.5, 5.0 and 10.0µg/dose), and received 3 intramuscular injections at day 0, 28, and 56. WIBP-CorV showed a promising safety profile with approximately 17% adverse reactions within 30 days after injection and no grade 3 or worse adverse events. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting. The geometric mean titers of neutralizing antibody ranged from 102.2 to 1065.5 in vaccinated participants at 28 days after the third vaccination, and maintained at a range of 14.3 to 218.2 at day 180 after the third vaccination. WIBP-CorV elicited significantly higher titers of neutralizing antibody in the cohort aged 3-5 years than the other two cohorts. There were no detectable antibody responses in all alum-only groups. Taken together, our data demonstrate that WIBP-CorV is safe and well tolerated at all tested doses in participants aged 3-17 years, and elicited robust humoral responses against SARS-CoV-2 lasted for at least 6 months after the third vaccination. This study is ongoing and is registered with www.chictr.org.cn, ChiCTR2000031809.

Safety and immunogenicity of an inactivated COVID-19 vaccine, BBIBP-CorV, in people younger than 18 years: a randomised, double-blind, controlled, phase 1/2 trial.

BACKGROUND: Although SARS-CoV-2 infection often causes milder symptoms in children and adolescents, young people might still play a key part in SARS-CoV-2 transmission. An efficacious vaccine for children and adolescents could therefore assist pandemic control. For further evaluation of the inactivated COVID-19 vaccine candidate BBIBP-CorV, we assessed the safety and immunogenicity of BBIBP-CorV in participants aged 3-17 years. METHODS: A randomised, double-blind, controlled, phase 1/2 trial was done at Shangqiu City Liangyuan District Center for Disease Control and Prevention in Henan, China. In phases 1 and 2, healthy participants were stratified according to age (3-5 years, 6-12 years, or 13-17 years) and dose group. Individuals with a history of SARS-CoV-2 or SARS-CoV infection were excluded. All participants were randomly assigned, using stratified block randomisation (block size eight), to receive three doses of 2 µg, 4 µg, or 8 µg of vaccine or control (1:1:1:1) 28 days apart. The primary outcome, safety, was analysed in the safety set, which consisted of participants who had received at least one vaccination after being randomly assigned, and had any safety evaluation information. The secondary outcomes were geometric meant titre (GMT) of the neutralising antibody against infectious SARS-CoV-2 and were analysed based on the full analysis set. This study is registered with www.chictr.org.cn, ChiCTR2000032459, and is ongoing. FINDINGS: Between Aug 14, 2020, and Sept 24, 2020, 445 participants were screened, and 288 eligible participants were randomly assigned to vaccine (n=216, 24 for each dose level [2/4/8 µg] in each of three age cohorts [3-5, 6-12, and 13-17 years]) or control (n=72, 24 for each age cohort [3-5, 6-12, and 13-17 years]) in phase 1. In phase 2, 810 participants were screened and 720 eligible participants were randomly assigned and allocated to vaccine (n=540, 60 for each dose level [2/4/8 µg] in each of three age cohorts [3-5, 6-12, and 13-17 years]) or control (n=180, 60 for each age cohort [3-5, 6-12, and 13-17 years]). The most common injection site adverse reaction was pain (ten [4%] 251 participants in all vaccination groups of the 3-5 years cohort; 23 [9·1%] of 252 participants in all vaccination groups and one [1·2%] of 84 in the control group of the 6-12 years cohort; 20 [7·9%] of 252 participants in all vaccination groups of the 13-17 years cohort). The most common systematic adverse reaction was fever (32 [12·7%] of 251 participants in all vaccination groups and six [7·1%] of 84 participants in the control group of the 3-5 years cohort; 13 [5·2%] of 252 participants in the vaccination groups and one [1·2%] of 84 in the control group of the 6-12 years cohort; 26 [10·3%] of 252 participants in all vaccination groups and eight [9·5%] of 84 in the control group of the 13-17 years cohort). Adverse reactions were mostly mild to moderate in severity. The neutralising antibody GMT against the SARS-CoV-2 virus ranged from 105·3 to 180·2 in the 3-5 years cohort, 84·1 to 168·6 in the 6-12 years cohort, and 88·0 to 155·7 in the 13-17 years cohort on day 28 after the second vaccination; and ranged from 143·5 to 224·4 in the 3-5 years cohort, 127 to 184·8 in the 6-12 years cohort, and 150·7 to 199 in the 13-17 years cohort on day 28 after the third vaccination. INTERPRETATION: The inactivated COVID-19 vaccine BBIBP-CorV is safe and well tolerated at all tested dose levels in participants aged 3-17 years. BBIBP-CorV also elicited robust humoral responses against SARS-CoV-2 infection after two doses. Our findings support the use of a 4 µg dose and two-shot regimen BBIBP-CorV in phase 3 trials in the population younger than 18 years to further ascertain its safety and protection efficacy against COVID-19. FUNDING: National Program on Key Research Project of China, National Mega projects of China for Major Infectious Diseases, National Mega Projects of China for New Drug Creation, and Beijing Science and Technology Plan. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Application of a decision tree model in the early identification of severe patients with severe fever with thrombocytopenia syndrome.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a serious infectious disease with a fatality of up to 30%. To identify the severity of SFTS precisely and quickly is important in clinical practice. METHODS: From June to July 2020, 71 patients admitted to the Infectious Department of Joint Logistics Support Force No. 990 Hospital were enrolled in this study. The most frequently observed symptoms and laboratory parameters on admission were collected by investigating patients' electronic records. Decision trees were built to identify the severity of SFTS. Accuracy and Youden's index were calculated to evaluate the identification capacity of the models. RESULTS: Clinical characteristics, including body temperature (p = 0.011), the size of the lymphadenectasis (p = 0.021), and cough (p = 0.017), and neurologic symptoms, including lassitude (p<0.001), limb tremor (p<0.001), hypersomnia (p = 0.009), coma (p = 0.018) and dysphoria (p = 0.008), were significantly different between the mild and severe groups. As for laboratory parameters, PLT (p = 0.006), AST (p<0.001), LDH (p<0.001), and CK (p = 0.003) were significantly different between the mild and severe groups of SFTS patients. A decision tree based on laboratory parameters and one based on demographic and clinical characteristics were built. Comparing with the decision tree based on demographic and clinical characteristics, the decision tree based on laboratory parameters had a stronger prediction capacity because of its higher accuracy and Youden's index. CONCLUSION: Decision trees can be applied to predict the severity of SFTS.

Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18 years or older: A randomized, double-blind, placebo-controlled, phase 1/2 trial.

BACKGROUND: We aimed to assess the safety and immunogenicity of an inactivated vaccine against COVID-19 in Chinese adults aged ≥18 years. METHODS: This is an ongoing randomized, double-blind, placebo-controlled, phase 1/2 clinical trial among healthy adults aged ≥18 years in Henan Province, China. Participants (n = 336 in 18-59 age group and n = 336 in ≥60 age group) were enrolled between April 12 and May 17 2020, and were equally randomized to receive vaccine or placebo (aluminum hydroxide adjuvant) in a three-dose schedule of 2·5, 5, or 10 µg on days 0, 28, and 56. Another 448 adults aged 18-59 years were equally allocated to four groups (a one-dose schedule of 10 µg, and two-dose schedules of 5 µg on days 0 and 14/21/28) and received vaccine or placebo (ratio 3:1 within each group). The primary outcomes were 7-day post-injection adverse reactions and neutralizing antibody titres on days 28 and 90 after the whole-course vaccination. Trial registration: www.chictr.org.cn #ChiCTR2000031809. FINDINGS: The 7-day adverse reactions occurred in 4·8% to 32·1% of the participants in various groups, and most adverse reactions were mild, transient, and self-limiting. Twenty participants reported 68 serious adverse events which were judged to be unrelated to the vaccine. The 90-day post-injection geometric mean titres of neutralizing antibody ranged between 87 (95% CI: 61-125) and 129 (99-169) for three-dose schedule among younger and older adults; 20 (14-27), 53 (38-75), and 44 (32-61) in 5 µg days 0 and 14/21/28 groups, respectively, and 7 (6-9) in one-dose 10 µg group. There were no detectable antibody responses in all placebo groups. INTERPRETATION: The inactivated vaccine against COVID-19 was well tolerated and immunogenic in both younger and older adults. The two-dose schedule of 5 µg on days 0 and 21/28 and three-dose schedules on days 0, 28, and 56 could be further evaluated for long-term safety and efficacy in the phase 3 trials.

Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial.

BACKGROUND: The ongoing COVID-19 pandemic warrants accelerated efforts to test vaccine candidates. We aimed to assess the safety and immunogenicity of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidate, BBIBP-CorV, in humans. METHODS: We did a randomised, double-blind, placebo-controlled, phase 1/2 trial at Shangqiu City Liangyuan District Center for Disease Control and Prevention in Henan Province, China. In phase 1, healthy people aged 18-80 years, who were negative for serum-specific IgM/IgG antibodies against SARS-CoV-2 at the time of screening, were separated into two age groups (18-59 years and ≥60 years) and randomly assigned to receive vaccine or placebo in a two-dose schedule of 2 µg, 4 µg, or 8 µg on days 0 and 28. In phase 2, healthy adults (aged 18-59 years) were randomly assigned (1:1:1:1) to receive vaccine or placebo on a single-dose schedule of 8 µg on day 0 or on a two-dose schedule of 4 µg on days 0 and 14, 0 and 21, or 0 and 28. Participants within each cohort were randomly assigned by stratified block randomisation (block size eight) and allocated (3:1) to receive vaccine or placebo. Group allocation was concealed from participants, investigators, and outcome assessors. The primary outcomes were safety and tolerability. The secondary outcome was immunogenicity, assessed as the neutralising antibody responses against infectious SARS-CoV-2. This study is registered with www.chictr.org.cn, ChiCTR2000032459. FINDINGS: In phase 1, 192 participants were enrolled (mean age 53·7 years [SD 15·6]) and were randomly assigned to receive vaccine (2 µg [n=24], 4 µg [n=24], or 8 µg [n=24] for both age groups [18-59 years and ≥60 years]) or placebo (n=24). At least one adverse reaction was reported within the first 7 days of inoculation in 42 (29%) of 144 vaccine recipients. The most common systematic adverse reaction was fever (18-59 years, one [4%] in the 2 µg group, one [4%] in the 4 µg group, and two [8%] in the 8 µg group; ≥60 years, one [4%] in the 8 µg group). All adverse reactions were mild or moderate in severity. No serious adverse event was reported within 28 days post vaccination. Neutralising antibody geometric mean titres were higher at day 42 in the group aged 18-59 years (87·7 [95% CI 64·9-118·6], 2 µg group; 211·2 [158·9-280·6], 4 µg group; and 228·7 [186·1-281·1], 8 µg group) and the group aged 60 years and older (80·7 [65·4-99·6], 2 µg group; 131·5 [108·2-159·7], 4 µg group; and 170·87 [133·0-219·5], 8 µg group) compared with the placebo group (2·0 [2·0-2·0]). In phase 2, 448 participants were enrolled (mean age 41·7 years [SD 9·9]) and were randomly assigned to receive the vaccine (8 µg on day 0 [n=84] or 4 µg on days 0 and 14 [n=84], days 0 and 21 [n=84], or days 0 and 28 [n=84]) or placebo on the same schedules (n=112). At least one adverse reaction within the first 7 days was reported in 76 (23%) of 336 vaccine recipients (33 [39%], 8 µg day 0; 18 [21%], 4 µg days 0 and 14; 15 [18%], 4 µg days 0 and 21; and ten [12%], 4 µg days 0 and 28). One placebo recipient in the 4 µg days 0 and 21 group reported grade 3 fever, but was self-limited and recovered. All other adverse reactions were mild or moderate in severity. The most common systematic adverse reaction was fever (one [1%], 8 µg day 0; one [1%], 4 µg days 0 and 14; three [4%], 4 µg days 0 and 21; two [2%], 4 µg days 0 and 28). The vaccine-elicited neutralising antibody titres on day 28 were significantly greater in the 4 µg days 0 and 14 (169·5, 95% CI 132·2-217·1), days 0 and 21 (282·7, 221·2-361·4), and days 0 and 28 (218·0, 181·8-261·3) schedules than the 8 µg day 0 schedule (14·7, 11·6-18·8; all p<0·001). INTERPRETATION: The inactivated SARS-CoV-2 vaccine, BBIBP-CorV, is safe and well tolerated at all tested doses in two age groups. Humoral responses against SARS-CoV-2 were induced in all vaccine recipients on day 42. Two-dose immunisation with 4 µg vaccine on days 0 and 21 or days 0 and 28 achieved higher neutralising antibody titres than the single 8 µg dose or 4 µg dose on days 0 and 14. FUNDING: National Program on Key Research Project of China, National Mega projects of China for Major Infectious Diseases, National Mega Projects of China for New Drug Creation, and Beijing Science and Technology Plan.

The impact of universal live attenuated hepatitis A vaccines in Henan, China, 2005-2018.

OBJECTIVES: To analyze the effects of one dose of live attenuated hepatitis A vaccine in a developing country. METHODS: The reported cases of hepatitis A virus (HAV) infection from 2005 to 2018 in Henan province, China, were analyzed. Data of vaccinated children were assessed on the childhood immunization information management system. Questionnaire survey and blood sample collection were randomly conducted in six counties and districts of Henan province to analyze the prevalence of HAV lgG among the population aged 0-70 years. RESULTS: In 2008, Henan province began to expand its program on immunization, and children aged 18 months were given one dose of live attenuated hepatitis A vaccine (HepA-L). From 2005 to 2007, the HAV incidence remained steady at above 5000 cases per year and increased to 7489 in 2007. Since 2008, the HAV incidence decreased cumulatively from 4576 to 237 in 2018, indicating a 94.8% decrease, which was particularly pronounced among adolescents (98.2%). The proportion of hepatitis A cases in patients younger than 10 years continually decreased from 41.6% in 2012 to 3.8% in 2018. The reduction of reported cases older than 40 years was slower than that of children. In 2012, the proportion of hepatitis A cases older than 40 years was 27.6%, and continually increased to 69.2% (164/237) in 2018. The results of serological investigation showed that the 0-1.5-year age group had the lowest anti-HAV IgG prevalence (38.6%), which increased to 75.0% in the 4-6-year age group, covered by this immunization program. CONCLUSIONS: The data indicated a large decrease in HAV infections in Henan province from 2008 onward in response to the introduction of a planned immunization program of HepA-L.

The "1-3-7" Approach to Malaria Surveillance and Response - Henan Province, China, 2012-2018.

What is already known about this topic? The "1-3-7" approach to malaria surveillance and response was a key measure for malaria elimination in China and was first introduced into the World Health Organization (WHO) as an international guideline for malaria surveillance and response in 2018. What is added by this report? The "1-3-7" approach was well implemented in Henan Province from 2012-2018. Over this study period, a total of 1,294 malaria cases were detected and reported, and all cases were diagnosed and reported within 1 day with 99.23% (1,284/1,294) of cases were investigated within 3 days. In addition, 93.7% (1,212/1,294) of foci were investigated and vector control was implemented within 7 days at all residual non-active foci to prevent further spread. What are the implications for public health practice? The "1-3-7" controlling pattern would be an effective and approachable method for implementation especially in malaria-eliminating countries and regions, but the interval from symptom onset to diagnosis cannot be ignored. Thus, the roles and responsibilities that all actors involved in the health sector must be specified too.

Epidemiological and clinical characteristics of 671 COVID-19 patients in Henan Province, China.

BACKGROUND: Despite many reports on the characteristics of coronavirus disease 2019 (COVID-19) in Wuhan, China, relatively little is known about the transmission features of COVID-19 outside Wuhan, especially at the provincial level. METHODS: We collected epidemiological, demographic, clinical, laboratory, radiological and occupation information, along with contact history, of 671 patients with laboratory-confirmed COVID-19 reported from January 23 to February 5, 2020, in Henan province, China. We described characteristics of these cases, compared the diagnostic accuracy and features of blood testing, computed tomography (CT) scans and X-rays, and analysed SARS-CoV-2 transmission sources and patients' occupations in Henan province. RESULTS: The mean age of patients in this case series was 43 years, 56.2% were male and 22.4% had coexisting medical disorders. The death rate was 0.3%. Fourteen patients did not show any symptoms. Lymphocyte percentage was associated with disease severity (χ2 = 6.71, P = 0.035) but had a large variation in each sample group. The mean time from illness onset to diagnosis was 5.6 days. A total of 330 patients had ever lived in or visited Wuhan, 150 had contact with confirmed cases, 323 had been to a hospital and 119 had been to a wet market. There were 33 patients who did not have a traceable transmission source, with 21.2% of these being farmers and 15.2% being workmen. CONCLUSIONS: Lymphocyte percentage was a sign of severe COVID-19 in general but was not a good diagnostic index. Longer time from illness onset to diagnosis was associated with higher COVID-19 severity, older age, higher likelihood of having coexisting cardiovascular diseases including hypertension, and being male. Farming was found to be a high-risk occupation in Henan province, China.

Molecular characterization and antimicrobial susceptibility of Salmonella isolates from infections in humans in Henan Province, China.

We characterized 208 human Salmonella isolates from 2006 to 2007 and 27 human Salmonella enterica serovar Typhimurium isolates from 1987 to 1993 from Henan Province, China, by serotyping, by antimicrobial susceptibility testing, and, for the most common serovars, by pulsed-field gel electrophoresis (PFGE). The most common serovars among the 2006-2007 isolates were S. enterica serovar Typhimurium (27%), S. enterica serovar Enteritidis (17%), S. enterica serovar Derby (10%), S. enterica serovar Indiana (6%), and S. enterica serovar Litchfield (6%). A high percentage of the isolates were multiple-drug resistant, and 54% were resistant to both nalidixic acid and ciprofloxacin. Of these, 42% were resistant to a high level of ciprofloxacin (MIC > 4 microg/ml), whereas for the remaining isolates, the MICs ranged from 0.125 to 2 microg/ml. Five isolates (2%) were ceftiofur resistant and harbored bla(CTX-M14) or bla(CTX-M15). With the possible exception of the quinolones and cephalosporins, the 1987-1993 S. enterica serovar Typhimurium isolates were almost as resistant as the recent isolates. PFGE typing of S. enterica serovar Typhimurium showed that the most common cluster predominated over time. Two other clusters have emerged, and another cluster has disappeared.

[Epidemiology of pediatric HIV infection in six provinces of China].

OBJECTIVE: To investigate the epidemiology of pediatric human immunodeficiency virus (HIV) infection in six provinces of China. METHODS: A cross-sectional study was conducted in six provinces with the highest HIV prevalence. Surveys on demographics and HIV-related questions (transmission modes, time of diagnosis, clinical stage, laboratory test) were distributed to clinicians in these provinces. Descriptive and bivariate analyses were performed on the completed surveys. RESULTS: Survey results of 650 children [405 males and 245 females; average age: (7.9 +/- 3.2) years] were eligible for analysis. The interval between possible transmission and diagnosis was (7.1 +/- 3.2) years. The location distribution was as follows: 570 cases (87.7%) in Henan Province, 23 cases (3.5%) in Guangxi Province, 21 cases (3.2%) in Yunnan Province, 19 cases (2.9%) in Hubei Province, 10 cases (1.5%) in Anhui Province, and 7 cases (1.1%) in Shanxi Province. Transmission routes included mother-to-child transmission (75.1%), blood transfusion/ plasma donation (15.7 %), and injecting drug use (IDU, 0.5%). Former plasma donation (FPD) was the main transmission route in some provinces (Henan, Shanxi, Hubei, and Anhui), while IDU was the main transmission route in other provinces (Guangxi and Yunnan). The average age in the FPD provinces was significantly higher than that in IDU provinces [(8.1 +/- 3.2) vs. (5.4 +/- 2.2) years, P <0.001]. Among 178 patients in all six provinces who required treatment (on the basis of CD4 count or WHO staging), 133 (74.7%) did not receive treatment and 45 (25.3%) received antiretroviral therapy. CONCLUSION: Mother-to-child transmission is the main transmission mode in pediatric patients. Efforts should be made to strengthen the diagnosis and treatment of pediatric HIV/AIDS patients.

[Safety and immunogenicity of seasonal inactivated influenza vaccine (split virion) and cross-reactive antibody responses to the H7N9 avian influenza virus].

OBJECTIVE: To evaluate the safety and immunogenicity of seasonal inactivated influenza vaccine (split virion) and to analyze its cross-reactive antibody responses to H7N9 avian influenza virus. METHODS: An open-labeled clinical trial was carried out in infants aged 6-35 months, adults aged 18-60 years and the elderly aged >60 years. After vaccinations (one dose for adults and the elderly and two doses for infants), adverse events were observed. Serum samples were obtained before vaccination and 21 days after vaccination from adults and elderly subjects. Three types of antibody against seasonal influenza virus and antibody against H7N9 avian influenza virus were tested using microhemagglutination inhibition (HI) assay. Immunogenicity of the vaccine was evaluated based on the immunogenicity criteria for adults and the elderly, set by the Committee for Medicinal Products for Human Use (CHMP) for the European Medicines Agency. RESULTS: A total of 202 subjects (65 infants, 69 adults and 68 elderly) were enrolled and injected for at least one dose. The overall rate of adverse events was 12.4% (25/202) and most of them were under systemic reaction. No serious adverse event was reported. Pre- and post-vaccination serum samples were collected from 124 subjects (64 adults, 60 elderly). After 21 days of vaccination, the sero-conversion rate, sero-protection rate, and geometric mean titer (GMT) ratio (post-/pre-vaccination) of antibody against seasonal influenza virus were 78.1%-90.6%, 92.2%-100.0% and 7.9-41.0 among adults while 66.7%-83.3%, 86.7%-100.0% and 5.7-20.4 among the elderly, respectively. However, after vaccination, both sero-conversion rate and sero-protection rate of antibody against H7N9 avian influenza virus among adults and the elderly became zero, with GMT ratio between 1.2 and 1.4. CONCLUSION: This trial vaccine appeared to have good safety and immunogenicity but inducing no cross-reactive antibody response to H7N9 avian influenza virus.

[Sero-prevalence and associated risk factors on hepatitis C in Maqiao township, Henan province of China].

OBJECTIVE: To describe the prevalence and risk factors of hepatitis C virus (HCV) occurred in Henan province, at the end of 2011. METHODS: Five villages round Maqiao township, including 5187 residents, were selected for the study. Five-milliliter-blood was drawn from every one of the interviewee. Clinical data including age, gender and anti-HCV antibody was recorded. Patients with positive antibodies against HCV were tested for HCV RNA. RESULTS: A total number of 5187 people from five villages were studied, with age span from 1 to 97. The average age was 48 years and the sex ratio was 1:1.34. The anti-HCV result showed that the prevalence was 2.27%, with 1-9 age group the lowest (1.55%) and the ≥ 50 year-olds the highest (4.93%). Different villages seemed to have significant differences on the prevalence of HCV, with the highest as 8.68% and the lowest as 0.55%. Under risk factors analysis and distance-infection rates linear regression analysis, data showed that the prevalence might have correlated to the behavior of a certain family-run clinic. RESULTS: from multivariate analysis indicated that factors as intravenous dropping, intravenous injection and the use of surgery/endoscope were associated with the HCV infection in this village. CONCLUSION: Although the public health care system had been developed for more than ten years, iatrogenic infection was yet responsible for the infection of HCV patients in the rural areas of China that called for further attention paid to the system.

Emergence and transmission pathways of rapidly evolving evolutionary branch C4a strains of human enterovirus 71 in the Central Plain of China.

BACKGROUND: Large-scale outbreaks of hand, foot, and mouth disease (HFMD) occurred repeatedly in the Central Plain of China (Shandong, Anhui, and Henan provinces) from 2007 until now. These epidemics have increased in size and severity each year and are a major public health concern in mainland China. PRINCIPAL FINDINGS: Phylogenetic analysis was performed and a Bayesian Markov chain Monte Carlo tree was constructed based on the complete VP1 sequences of HEV71 isolates. These analyses showed that the HFMD epidemic in the Central Plain of China was caused by at least 5 chains of HEV71 transmission and that the virus continued to circulate and evolve over the winter seasons between outbreaks. Between 1998 and 2010, there were 2 stages of HEV71 circulation in mainland China, with a shift from evolutionary branch C4b to C4a in 2003-2004. The evolution rate of C4a HEV71 was 4.99×10(-3) substitutions per site per year, faster than the mean of all HEV71 genotypes. The most recent common ancestor estimates for the Chinese clusters dated to October 1994 and November 1993 for the C4a and C4b evolutionary branches, respectively. Compared with all C4a HEV71 strains, a nucleotide substitution in all C4b HEV71 genome (A to C reversion at nt2503 in the VP1 coding region, which caused amino acid substitution of VP1-10: Gln to His) had reverted. CONCLUSIONS: The data suggest that C4a HEV71 strains introduced into the Central Plain of China are responsible for the recent outbreaks. The relationships among HEV71 isolates determined from the combined sequence and epidemiological data reveal the underlying seasonal dynamics of HEV71 circulation. At least 5 HEV71 lineages circulated in the Central Plain of China from 2007 to 2009, and the Shandong and Anhui lineages were found to have passed through a genetic bottleneck during the low-transmission winter season.

[Surveillance and control of Japanese encephalitis in Henan province, 1950 - 2008].

OBJECTIVE: To analyze the characteristics and trend of Japanese encephalitis (JE) in Henan province. METHODS: Adopting descriptive epidemiological method to analyze the data on the epidemic situation of JE from 1950 to 2008, and on mosquitoes and host animals at disease surveillance points. The host serum JE IgG antibody was detected by ELISA. Data was analyzed using SPSS 12.0 and Excel 2003 software. RESULTS: The incidence of JE in Henan province had a fluctuant downward trend. Peak of the incidence fell in July to September, accounting for 88.09% of total cases. The scope of geographical distribution was increasing from northern to southern parts of the province. Cases mainly concentrated in the southern and south-eastern parts of the province. 0 - 14 year-old group had the highest incidence (81.95%). In Luoyang city, there was a significant increase in children at 15-years or older (58.93%). Most patients were farmers (42.33%). The positive-times for half of the antibodies of JE in piglets of the surveillance sentinels were different, which might be the reason for the different levels for the incidence rates. The proportion of different kinds of mosquitoes were also different in surveillance sentinel sites, and the time for the density peak of the mosquitoes was in accordance with the incidence peak of JE. CONCLUSION: To develop control strategies, evidence should be based on the characteristics of geographical variance, age, occupation differences, data related to monitoring on animal host and media mosquitoes of JE incidence in Henan province.

[Complete genome sequencing of enterovirus 71 (EV71) HENAN08 strain isolated in Henan province].

OBJECTIVE: To sequence the whole-genome of enterovirus 71 (EV71) srtain isolated from patient with hand, foot and mouth in Henan province in 2008. METHODS: Eight overlapping clones covering the whole viral genome were obtained by RT-PCR and the sequences were determined by Sanger dideoxg-mediated chain termination method. RESULTS: Data it showed that the full length of enterovirus 71 (EV71) HENAN08 genome (not including Poly A tail) is 7405 bp. No deletion or insertion was detected in the coding region. There were several deletions and insertions in 5'UTR and 3'UTR regions. In P1 region, HENAN08 strain shared high homology with AnhuiFY08 strain, Zhejiang08 strain and SHZH strains (SHZH98, SHZH03) but low homology with Cox. A16. In P2 and P3 regions, HENAN08 strain shared higher nucleotide homology with Cox. A16 (81.7% and 83.7%) than that with BrCr and TW2086 strains. The phylogenetic analysis based on P1 region demonstrates that HENAN08 strain had the nearest genetic relationship with AnhuiFY and Zhejiang strains (isolated in 2008). CONCLUSION: The HENAN08 strain might belong to the same genogroup with AnhuiFY08 and Zhejiang08 strains as C4 gene subtypes.