Comparative genomic analyses provide insight into the pathogenicity of three Pseudomonas syringae pv. actinidiae strains from Anhui Province, China.

BACKGROUND: Pseudomonas syringae pv. actinidiae (Psa) is an important bacterial plant pathogen that causes severe damage to the kiwifruit industry worldwide. Three Psa strains were recently obtained from different kiwifruit orchards in Anhui Province, China. The present study mainly focused on the variations in virulence and genome characteristics of these strains based on the pathogenicity assays and comparative genomic analyses. RESULTS: Three strains were identified as biovar 3 (Psa3), along with strain QSY6 showing higher virulence than JZY2 and YXH1 in pathogenicity assays. The whole genome assembly revealed that each of the three strains had a circular chromosome and a complete plasmid. The chromosome sizes ranged from 6.5 to 6.6 Mb with a GC content of approximately 58.39 to 58.46%, and a predicted number of protein-coding sequences ranging from 5,884 to 6,019. The three strains clustered tightly with 8 Psa3 reference strains in terms of average nucleotide identity (ANI), whole-genome-based phylogenetic analysis, and pangenome analysis, while they were evolutionarily distinct from other biovars (Psa1 and Psa5). Variations were observed in the repertoire of effectors of the type III secretion system among all 15 strains. Moreover, synteny analysis of the three sequenced strains revealed eight genomic regions containing 308 genes exclusively present in the highly virulent strain QSY6. Further investigation of these genes showed that 16 virulence-related genes highlight several key factors, such as effector delivery systems (type III secretion systems) and adherence (type IV pilus), which might be crucial for the virulence of QSY6. CONCLUSION: Three Psa strains were identified and showed variant virulence in kiwifruit plant. Complete genome sequences and comparative genomic analyses further provided a theoretical basis for the potential pathogenic factors responsible for kiwifruit bacterial canker.

Rewiring cis-2-butene-1,4-dial mediated urinary metabolomics fingerprints of short-term exposure to furan.

Furan represents one of the dietary-sourced persistent organic pollutants and thermal processing contaminants. Given its widespread occurrence in food and various toxicological effects, accurately assessing furan exposure is essential for informing public health risks. Furan is metabolized to a reactive primary product, cis-2-butene-1,4-dial (BDA) upon absorption. Some of the resulting BDA-derived metabolites have been proposed as potential exposure biomarkers of furan. However, the lack of quantification for recognized and feasible furan biomarkers has hampered the development of internal exposure risk assessment of furan. In this study, we employed reliable non-targeted metabolomics techniques to uncover urinary furan metabolites and elucidate their chemical structures. We characterized 8 reported and 11 new furan metabolites derived from the binding of BDA with glutathione (GSH), biogenic amines, and/or amino acids in the urine of male rats subjected to varying doses of furan. Notably, a mono-GSH-BDA adduct named cyclic GSH-BDA emerged as a highly prospective specific biomarker of furan exposure, as determined by an ultrahigh-performance liquid chromatography-tandem mass spectrometry method. Cyclic GSH-BDA demonstrated a robust mass spectrometry ion response intensity and exhibited evident time- and dose response. Additionally, we conducted a comprehensive profiling of the kinetics of potential furan biomarkers over time to capture the metabolic dynamics of furan in vivo. Most urinary furan metabolites reached peak concentrations at either the first (3 h) or second (6 h) sampling time point and were largely eliminated within 36 h following furan treatment. The present study provides novel insights into furan metabolism and sheds light on the biomonitoring of furan exposure.

A comprehensive review of furan in foods: From dietary exposures and in vivo metabolism to mitigation measures.

Furan is a thermal food processing contaminant that is ubiquitous in various food products such as coffee, canned and jarred foods, and cereals. A comprehensive summary of research progress on furan is presented in this review, including discussion of (i) formation pathways, (ii) occurrence and dietary exposures, (iii) analytical techniques, (iv) toxicities, (v) metabolism and metabolites, (vi) risk assessment, (vii) potential biomarkers, and (viii) mitigation measures. Dietary exposure to furan varies among different countries and age groups. Furan acts through various toxicological pathways mediated by its primary metabolite, cis-2-butene-1,4-dial (BDA). BDA can readily react with glutathione, amino acids, biogenic amines, or nucleotides to form corresponding metabolites, some of which have been proposed as potential biomarkers of exposure to furan. Present risk assessment of furan mainly employed the margin of exposure approach. Given the widespread occurrence of furan in foods and its harmful health effects, mitigating furan levels in foods or exploring potential dietary supplements to protect against furan toxicity is necessary for the benefit of food safety and public health.

Machine learning prediction of exposure to acrylamide based on modelling of association between dietary exposure and internal biomarkers.

The ubiquitous occurrence of acrylamide in various thermal processing food products poses a potential health risk for the public. An accurate exposure assessment is crucial to the risk evaluation of acrylamide. Machine learning emerging as a powerful computational tool for prediction was employed to establish the association between internal exposure and dietary exposure to acrylamide among a Chinese cohort of middle-aged and elderly population (n = 1,272). Five machine learning regression models were constructed and compared to predict the daily dietary acrylamide exposure based on urinary biomarkers including N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), N-acetyl-S-(2-carbamoylethyl)-L-cysteine-sulfoxide (AAMA-sul), N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA), and N-acetyl-S-(1-carbamoyl-2-hydroxyethyl)-L-cysteine (iso-GAMA). Other important covariates such as age, gender, physical activities, and total energy intake were also considered as predictors in the models. Average dietary intake of acrylamide among Chinese elderly participants was 8.9 µg/day, while average urinary contents of AAMA, AAMA-sul, GAMA, and iso-GAMA were 52.2, 19.1, 4.4, and 1.7 nmol/g Ucr (urine creatinine), respectively. Support vector regression (SVR) model showed the best prediction performance with a R of 0.415, followed by light gradient boosting machine (LightGBM) model (R = 0.396), adjusted multiple linear regression (MLR) model (R = 0.378), neural networks (NN) model (R = 0.365), MLR model (R = 0.363), and extreme gradient boosting (XGBoost) model (R = 0.337). The present study firstly correlated dietary exposure with internal exposure to acrylamide among Chinese elderly population, providing an innovative perspective for the exposure assessment of acrylamide.

Comparative genomic analyses reveal genetic characteristics and pathogenic factors of Bacillus pumilus HM-7.

Bacillus pumilus plays an important role in industrial application and biocontrol activities, as well as causing humans and plants disease, leading to economic losses and biosafety concerns. However, until now, the pathogenesis and underlying mechanisms of B. pumilus strains remain unclear. In our previous study, one representative isolate of B. pumilus named HM-7 has been recovered and proved to be the causal agent of fruit rot on muskmelon (Cucumis melo). Herein, we present a complete and annotated genome sequence of HM-7 that contains 4,111 coding genes in a single 3,951,520 bp chromosome with 41.04% GC content. A total of 3,481 genes were functionally annotated with the GO, COG, and KEGG databases. Pan-core genome analysis of HM-7 and 20 representative B. pumilus strains, as well as six closely related Bacillus species, discovered 740 core genes and 15,205 genes in the pan-genome of 21 B. pumilus strains, in which 485 specific-genes were identified in HM-7 genome. The average nucleotide identity (ANI), and whole-genome-based phylogenetic analysis revealed that HM-7 was most closely related to the C4, GR8, MTCC-B6033, TUAT1 and SH-B11 strains, but evolutionarily distinct from other strains in B. pumilus. Collinearity analysis of the six similar B. pumilus strains showed high levels of synteny but also several divergent regions for each strains. In the HM-7 genome, we identified 484 genes in the carbohydrate-active enzymes (CAZyme) class, 650 genes encoding virulence factors, and 1,115 genes associated with pathogen-host interactions. Moreover, three HM-7-specific regions were determined, which contained 424 protein-coding genes. Further investigation of these genes showed that 19 pathogenesis-related genes were mainly associated with flagella formation and secretion of toxic products, which might be involved in the virulence of strain HM-7. Our results provided detailed genomic and taxonomic information for the HM-7 strain, and discovered its potential pathogenic mechanism, which lay a foundation for developing effective prevention and control strategies against this pathogen in the future.

Associations of 3-monochloropropane-1,2-diol and glycidol with prevalence of metabolic syndrome: Findings from Lanxi Nutrition and Safety Study.

In this study, we investigated the association of 2,3-dihydroxypropyl mercapturic acid (DHPMA), a urinary biomarker of environmental and dietary exposure to 3-monochloropropane-1,2-diol and glycidol, with prevalent MetS in a Chinese middle-aged and elderly population. The urinary DHPMA concentrations were determined by ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) analysis and further calibrated by the urinary creatinine content. MetS cases were defined by the Adult Treatment Panel III criteria for Asian-Americans of National Cholesterol Education Program (NCEP/ATPIII). Multivariate-adjusted modified Poisson regression models were used to analyze the associations between the urinary DHPMA concentrations and MetS prevalence. Of the 1613 participants aged 45-75 years, we documented 552 (34.2%) MetS cases. After adjustment for potential risk factors, the relative risks (95% confidence intervals) of MetS prevalence across the increasing quartiles of DHPMA concentrations were 1.14 (0.93-1.39), 1.29 (1.06-1.56), and 1.50 (1.25-1.80), respectively, compared with the lowest quartile. We also observed strong positive association between urinary DHPMA concentrations and hypertriglyceridemia prevalence (P < 0.001 for trend). These positive associations remained unchanged in the subgroups stratified by general demographic, dietary and behavioral risk factors. These results suggested that urinary DHPMA was associated with higher prevalence of MetS among Chinese elderly people.

Comprehensive profile of DNA adducts as both tissue and urinary biomarkers of exposure to acrylamide and chemo-preventive effect of catechins in rats.

Two representative DNA adducts from acrylamide exposure, N7-(2-carbamoyl-2-hydroxyethyl) guanine (N7-GA-Gua) and N3-(2-carbamoyl-2-hydroxyethyl) adenine (N3-GA-Ade), are important long-term exposure biomarkers for evaluating genotoxicity of acrylamide. Catechins as natural antioxidants present in tea possess multiple health benefits, and may also have the potential to protect against acrylamide-induced DNA damage. The current study developed an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous analysis of N7-GA-Gua and N3-GA-Ade in tissues and urine. The validated UHPLC-MS/MS method showed high sensitivity, with limit of detection and limit of quantification ranging 0.2-0.8 and 0.5-1.5 ng/mL, respectively, and achieved qualified precision (RSD<14.0%) and spiking recovery (87.2%-110.0%) with elution within 6 min, which was suitable for the analysis of the two DNA adducts in different matrices. The levels of N7-GA-Gua and N3-GA-Ade ranged 0.9-11.9 and 0.6-3.5 µg/g creatinine in human urine samples, respectively. To investigate the interventional effects of catechins on the two DNA adducts from acrylamide exposure, rats were supplemented with three types of catechins (tea polyphenols, epigallocatechin gallate, and epicatechin) 30 min before administration with acrylamide. Our results showed that catechins effectively inhibited the formation of DNA adducts from acrylamide exposure in both urine and tissues of rats. Among three catechins, epicatechin performed the best inhibitory effect. The current study provided evidence for the chemo-preventive effect of catechins, indicating that dietary supplement of catechins may contribute to health protection against exposure to acrylamide.

Egg and Dietary Cholesterol Consumption and Mortality Among Hypertensive Patients: Results From a Population-Based Nationwide Study.

Background: Hypertensive patients are sensitive to the amount of dietary cholesterol intake, especially cholesterol from the whole eggs. Whether whole egg and dietary cholesterol consumption are suitable for hypertensive patients is still controversial. Aim: The objective of the study was to examine the associations of intake of eggs as well as the dietary cholesterol with total mortality in a Chinese nationwide cohort. Methods: We utilized data from the China Health and Nutrition Survey (CHNS) from the year of 1991 to 2015. Cumulative averages of egg and cholesterol intake were calculated to represent the consumption of the long-term diet of the participants in each available round of the survey. Cox regression models were employed to estimate the effects of eggs and dietary cholesterol from the different sources on mortality among hypertensive patients. Results: A total of 8,095 participants were included in the final analysis and followed up for a mean of 11.4 years. Finally, 927 cases of death were detected. After adjustment for the multivariate factors, consuming more than seven eggs per week was related to 29% lower mortality among the hypertensive patients compared with the consumers with not more than two eggs per week [hazard ratio (HR): 0.71; 95% CI: 0.59-0.85; P < 0.001]. Similarly, the egg-sourced cholesterol intake was inversely associated with mortality (P = 0.002) whereas intake of the dietary cholesterol from the non-egg sources was significantly related to the higher mortality (P < 0.001). However, total cholesterol intake was not related to mortality among hypertensive patients. Substituting eggs for an equivalent amount of non-egg-sourced protein-abundant foods was also associated with lower mortality. Conclusion: Higher consumption of eggs and egg-sourced dietary cholesterol was associated with lower mortality among the enrolled Chinese hypertensive patients but non-egg-sourced cholesterol intake was related to higher mortality. Therefore, our findings do not support the view that hypertensive patients should avoid whole egg consumption for the purpose of restricting dietary cholesterol intake.

Cooking oil/fat consumption and deaths from cardiometabolic diseases and other causes: prospective analysis of 521,120 individuals.

BACKGROUND: Increasing evidence highlights healthy dietary patterns and links daily cooking oil intake with chronic diseases including cardiovascular disease (CVD) and diabetes. However, food-based evidence supporting the consumption of cooking oils in relation to total and cardiometabolic mortality remains largely absent. We aim to prospectively evaluate the relations of cooking oils with death from cardiometabolic (CVD and diabetes) and other causes. METHODS: We identified and prospectively followed 521,120 participants aged 50-71 years from the National Institutes of Health-American Association of Retired Persons Diet and Health Study. Individual cooking oil/fat consumption was assessed by a validated food frequency questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for mortality through the end of 2011. RESULTS: Overall, 129,328 deaths were documented during a median follow-up of 16 years. Intakes of butter and margarine were associated with higher total mortality while intakes of canola oil and olive oil were related to lower total mortality. After multivariate adjustment for major risk factors, the HRs of cardiometabolic mortality for each 1-tablespoon/day increment were 1.08 (95% CI 1.05-1.10) for butter, 1.06 (1.05-1.08) for margarine, 0.99 (0.95-1.03) for corn oil, 0.98 (0.94-1.02) for canola oil, and 0.96 (0.92-0.99) for olive oil. Besides, butter consumption was positively associated with cancer mortality. Substituting corn oil, canola oil, or olive oil for equal amounts of butter and margarine was related to lower all-cause mortality and mortality from certain causes, including CVD, diabetes, cancer, respiratory disease, and Alzheimer's disease. CONCLUSIONS: Consumption of butter and margarine was associated with higher total and cardiometabolic mortality. Replacing butter and margarine with canola oil, corn oil, or olive oil was related to lower total and cardiometabolic mortality. Our findings support shifting the intake from solid fats to non-hydrogenated vegetable oils for cardiometabolic health and longevity.

Egg and cholesterol consumption and mortality from cardiovascular and different causes in the United States: A population-based cohort study.

BACKGROUND: Whether consumption of egg and cholesterol is detrimental to cardiovascular health and longevity is highly debated. Data from large-scale cohort studies are scarce. This study aimed to examine the associations of egg and cholesterol intakes with mortality from all causes, cardiovascular disease (CVD), and other causes in a US population. METHODS AND FINDINGS: Overall, 521,120 participants (aged 50-71 years, mean age = 62.2 years, 41.2% women, and 91.8% non-Hispanic white) were recruited from 6 states and 2 additional cities in the US between 1995 and 1996 and prospectively followed up until the end of 2011. Intakes of whole eggs, egg whites/substitutes, and cholesterol were assessed by a validated food frequency questionnaire. Cause-specific hazard models considering competing risks were used, with the lowest quintile of energy-adjusted intake (per 2,000 kcal per day) as the reference. There were 129,328 deaths including 38,747 deaths from CVD during a median follow-up of 16 years. Whole egg and cholesterol intakes were both positively associated with all-cause, CVD, and cancer mortality. In multivariable-adjusted models, the hazard ratios (95% confidence intervals) associated with each intake of an additional half of a whole egg per day were 1.07 (1.06-1.08) for all-cause mortality, 1.07 (1.06-1.09) for CVD mortality, and 1.07 (1.06-1.09) for cancer mortality. Each intake of an additional 300 mg of dietary cholesterol per day was associated with 19%, 16%, and 24% higher all-cause, CVD, and cancer mortality, respectively. Mediation models estimated that cholesterol intake contributed to 63.2% (95% CI 49.6%-75.0%), 62.3% (95% CI 39.5%-80.7%), and 49.6% (95% CI 31.9%-67.4%) of all-cause, CVD, and cancer mortality associated with whole egg consumption, respectively. Egg white/substitute consumers had lower all-cause mortality and mortality from stroke, cancer, respiratory disease, and Alzheimer disease compared with non-consumers. Hypothetically, replacing half a whole egg with equivalent amounts of egg whites/substitutes, poultry, fish, dairy products, or nuts/legumes was related to lower all-cause, CVD, cancer, and respiratory disease mortality. Study limitations include its observational nature, reliance on participant self-report, and residual confounding despite extensive adjustment for acknowledged dietary and lifestyle risk factors. CONCLUSIONS: In this study, intakes of eggs and cholesterol were associated with higher all-cause, CVD, and cancer mortality. The increased mortality associated with egg consumption was largely influenced by cholesterol intake. Our findings suggest limiting cholesterol intake and replacing whole eggs with egg whites/substitutes or other alternative protein sources for facilitating cardiovascular health and long-term survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT00340015.

Analytical chemistry, formation, mitigation, and risk assessment of polycyclic aromatic hydrocarbons: From food processing to in vivo metabolic transformation.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the air, oils, water, and food products we encounter every day. Among these exposures, food consumption is a major route of PAH exposure for nonsmokers. The PAH dietary exposure levels vary among different countries; however, many studies have shown PAH exposure to be highly concerning to human health. The levels of PAH contamination in food are mainly influenced by processing procedures and cooking methods, and they could be attenuated by modifying cooking procedures and adding antioxidant-rich marinades. Several PAHs have toxic, mutagenic, and carcinogenic properties. The PAH benzo[a]pyrene (BaP) is particularly regarded as carcinogenic. There are three major metabolism pathways for PAHs, and the final products can bind to DNA, thus exerting mutagenic effects. Biological monitoring through the use of biomarkers is necessary for comprehensive and accurate risk assessments of human PAH exposure. It is important to reduce dietary PAH exposure and to implement reasonable and effective risk management strategies to reduce PAH levels in food to improve public health.

Current intake levels of potatoes and all-cause mortality in China: A population-based nationwide study.

OBJECTIVE: Current levels of potato consumption in relation to mortality in Chinese people remains unknown. The aim of this study was to investigate the intakes of total potatoes, fried potatoes, non-fried potatoes, and sweet potatoes as dietary carbohydrate sources in relation to all-cause mortality in the China Health and Nutrition Survey (CHNS). METHODS: Overall 14 117 participants ≥20 y of age were included, with a median follow-up of 14 y. The cumulative average consumption of potatoes and other foods were calculated and validated using weighing methods in combination with 3-d, 24-h dietary recalls at both household and individual levels. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models after multivariate adjustment. RESULTS: We documented 1007 deaths among the participants. The low and moderate intakes of total potatoes, fried potatoes, and non-fried potatoes were inversely associated with mortality. Compared with non-consumers, the intakes of total potatoes (HR, 0.48; 95% CI, 0.38-0.59), fried potatoes (HR, 0.44; 95% CI, 0.34-0.56), and non-fried potatoes (HR, 0.47; 95% CI, 0.37-0.61) at low consumption levels were most significantly related to lower mortality. Sweet potato consumption was inversely associated with mortality after full adjustment (HR, 0.82; 95% CI, 0.69-0.96) compared with non-consumers. Substituting grains and mixed beans for potatoes with equal amounts at high consumption levels strengthened the inverse associations. CONCLUSION: In the CHNS, current low and moderate, but not high levels of total potato and fried/non-fried potato consumption as well as sweet potato consumption were inversely associated with all-cause mortality among Chinese people.

Rapid Simultaneous Determination of Cascade Metabolites of Acrylamide in Urine for Toxicokinetics Profiles and Short-Term Dietary Internal Exposure.

The current study developed an ultrahigh-performance liquid chromatography tandem mass spectrometry method to simultaneously analyze cascade metabolites of acrylamide in urine of rats and humans, including acrylamide, glycidamide, N-acetyl-S-(2-carbamoylethyl)-l-cysteine (AAMA), N-acetyl-S-(2-carbamoylethyl)-l-cysteine-sulfoxide, N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine, and N-acetyl-S-(1-carbamoyl-2-hydroxyethyl)-l-cysteine. A tandem solid-phase extraction procedure was novelly used to purify all metabolites at once from human urine. The rapid analysis showed high sensitivity with LOD and LOQ ranges of 0.1-0.8 and 0.4-5.8 ng/mL, respectively, and achieved acceptable within-laboratory reproducibility (RSD < 12.0%) and spiking recovery (92.2%-117.3%) within 8 min per sample. Approximately 70.7 and 63.0% of ingested acrylamide were recovered during the toxicokinetics analysis from urine of male and female rats, respectively. For nonsmoking participants, the urinary levels of acrylamide and glycidamide were higher in men than women, whereas the urinary concentration of AAMA showed the opposite behavior. The current analysis provides methodological support of cascade metabolites of acrylamide for the dietary short-term internal exposure assessment of acrylamide.

Efficacy, immunogenicity and safety of the AS04-HPV-16/18 vaccine in Chinese women aged 18-25 years: End-of-study results from a phase II/III, randomised, controlled trial.

BACKGROUND: Cervical cancer is a major public health concern in China. We report the end-of-study results of a phase II/III trial to assess the efficacy, immunogenicity, and safety of the AS04-human papillomavirus (HPV)-16/18 vaccine in Chinese women aged 18-25 years followed for up to 72 months after first vaccination. Results of approximately 57 months following first vaccination have been previously reported. METHODS: Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of AS04-HPV-16/18 vaccine or Al(OH)3 (control) at Months 0-1-6. Vaccine efficacy against HPV-16/18 infection and cervical intraepithelial neoplasia (CIN), cross-protective vaccine efficacy against infections and lesions associated with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. Efficacy was assessed in the according-to-protocol efficacy (ATP-E) cohort (vaccine N = 2888; control N = 2892), total vaccinated cohort for efficacy (TVC-E; vaccine N = 2987; control N = 2985) and TVC-naïve (vaccine N = 1660; control N = 1587). RESULTS: In initially HPV-16/18 seronegative/DNA-negative women, vaccine efficacy against HPV-16/18-associated CIN grade 2 or worse was 87.3% (95% CI: 5.5, 99.7) in the ATP-E, 88.7% (95% CI: 18.5, 99.7) in the TVC-E, and 100% (95% CI: 17.9, 100) in the TVC-naïve. Cross-protective efficacy against incident infection with HPV-31, HPV-33 and HPV-45 was 59.6% (95% CI: 39.4, 73.5), 42.7% (95% CI: 15.6, 61.6), and 54.8% (95% CI: 19.3, 75.6), respectively (ATP-E). At Month 72, >95% of initially seronegative women who received HPV vaccine in the ATP cohort for immunogenicity (N = 664) remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and anti-HPV-18 geometric mean titers were 678.1 EU/mL (95% CI: 552.9, 831.5) and 343.7 EU/mL (95% CI: 291.9, 404.8), respectively. Serious adverse events were infrequent (1.9% vaccine group [N = 3026]; 2.7% control group [N = 3025]). Three and zero women died in the control group and the vaccine group respectively. New onset autoimmune disease was reported in two women in the vaccine group and two in the control group. CONCLUSIONS: This is the first large-scale randomized clinical trial of HPV vaccination in China. High and sustained vaccine efficacy against HPV-16/18-associated infection and cervical lesions was demonstrated up to Month 72. The vaccine had an acceptable safety profile. Combined with screening, prophylactic HPV vaccination could potentially reduce the high burden of HPV infection and cervical cancer in China. TRIAL REGISTRATION: NCT00779766.

Efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine in Chinese women aged 18-25 years: event-triggered analysis of a randomized controlled trial.

We previously reported the results of a phase II/III, double-blind, randomized controlled study in Chinese women (NCT00779766) showing a 94.2% (95% confidence interval: 62.7-99.9) HPV-16/18 AS04-adjuvanted vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or higher (CIN1+) and/or 6-month (M) persistent infection (PI) with a mean follow-up of <2 years, and immunogenicity until 7 months post-dose 1. Here, we report efficacy and safety results from an event-triggered analysis with ~3 years longer follow-up, and immunogenicity until M24. Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of HPV-16/18 vaccine or Al(OH)3 (control) at M0, 1, 6. VE against HPV-16/18-associated CIN2+, and cross-protective VE against infections with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. In the according-to-protocol efficacy cohort, in initially seronegative/DNA-negative women (vaccine group: N = 2524; control group: N = 2535), VE against HPV-16/18-associated CIN2+ was 87.3% (5.3-99.7); VE against incident infection or against 6-month persistent infection associated with HPV-31/33/45 was 50.1% (34.3-62.3) or 52.6% (24.5-70.9), respectively. At least, 99.6% of HPV-16/18-vaccines remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and -18 geometric mean titers were 1271.1 EU/mL (1135.8-1422.6) and 710.0 EU/ml (628.6-801.9), respectively. Serious adverse events were infrequent (1.7% vaccine group [N = 3026]; 2.5% control group [N = 3026]). Of the 1595 reported pregnancies, nine had congenital anomalies (five live infants, three elective terminations, one stillbirth) that were unlikely vaccination-related (blinded data). VE against HPV-16/18-associated CIN2+ was demonstrated and evidence of cross-protective VE against oncogenic HPV types was shown. The vaccine was immunogenic and had an acceptable safety profile.

Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Helicobacter pylori is one of the most common gastric pathogens, affecting at least half the world's population, and is strongly associated with gastritis, peptic ulcer, gastric adenocarcinoma, and lymphoma. We aimed to assess the efficacy, safety, and immunogenicity of a three-dose oral recombinant H pylori vaccine in children in China. METHODS: We did this randomised, double-blind, placebo-controlled, phase 3 trial at one centre in Ganyu County, Jiangsu Province, China. Healthy children aged 6-15 years without past or present H pylori infection were randomly assigned (1:1), via computer-generated randomisation codes in blocks of ten, to receive the H pylori vaccine or placebo. Participants, their guardians, and study investigators were masked to treatment allocation. The primary efficacy endpoint was the occurrence of H pylori infection within 1 year after vaccination. We did analysis in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT02302170. FINDINGS: Between Dec 2, 2004, and March 19, 2005, we randomly assigned 4464 participants to either the vaccine group (n=2232) or the placebo group (n=2232), of whom 4403 (99%) participants completed the three-dose vaccination schedule and were included in the per-protocol efficacy analysis. We extended follow-up to 3 years. We recorded 64 events of H pylori infection within the first year (14 events in 2074·3 person-years at risk in the vaccine group vs 50 events in 2089·6 person-years at risk in the placebo group), resulting in a vaccine efficacy of 71·8% (95% CI 48·2-85·6). 157 (7%) participants in the vaccine group and 161 (7%) participants in the placebo group reported at least one adverse reaction. Serious adverse events were reported in five (<1%) participants in the vaccine group and seven (<1%) participants in the placebo group, but none was considered to be vaccination related. INTERPRETATION: The oral recombinant H pylori vaccine was effective, safe, and immunogenic in H pylori-naive children. This vaccine could substantially reduce the incidence of H pylori infection; however, follow up over a longer period is needed to confirm the protection of the vaccine against H pylori-associated diseases. FUNDING: Chongqing Kangwei Biological Technology.

Baseline prevalence and type distribution of human papillomavirus in healthy Chinese women aged 18-25 years enrolled in a clinical trial.

Baseline human papillomavirus (HPV) prevalence and type distribution were evaluated in young Chinese women enrolled in a clinical trial of an HPV vaccine (ClinicalTrials.gov registration NCT00779766). Cervical specimens and blood samples were collected at baseline from women aged 18-25 years (n = 6,051) from four sites across Jiangsu province. Cervical specimens were tested for HPV DNA by SPF10 PCR-DEIA-LiPA25 version 1, and HPV-16/18 type-specific polymerase chain reaction. Anti-HPV-16 and anti-HPV-18 antibody titres were quantified by enzyme-linked immunosorbent assay. At baseline, 15.3% of women were DNA positive for any of 14 HPV high-risk (hr) types (HPV-16/18/31/33/35/39/45/51/52/56/58/59/66/68). The most commonly detected hrHPV types in cervical specimens were HPV-52 (4.0%) and HPV-16 (3.7%). High-risk HPV DNA-positivity increased with severity of cytological abnormalities: 39.3% in atypical squamous cells of undetermined significance, 85.0% in low-grade squamous intraepithelial lesions and 97.8% in high-grade squamous intraepithelial lesions (HSIL). The hrHPV types most frequently detected in HSIL were HPV-16 (63.0%), HPV-18 (17.4%), HPV-52 (17.4%), HPV-58 (15.2%) and HPV-33 (15.2%). The hrHPV types most frequently detected in cervical intraepithelial neoplasia 2+ were HPV-16 (66.1%), HPV-33 (16.1%), HPV-52 (16.1%), HPV-58 (14.5%) and HPV-51 (11.3%). Multiple hrHPV infections were reported for 24.4% of hrHPV DNA positive women. Regardless of baseline HPV DNA status, 30.5% and 16.0% of subjects were initially seropositive for anti-HPV-16 and anti-HPV-18, respectively. In conclusion, the high baseline seropositivity rate and intermediate prevalence of cervical hrHPV types in Chinese women aged 18-25 years underlines the importance of early HPV vaccination in this population.

Efficacy, immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese women aged 18-25 years: results from a randomized controlled trial.

This phase II/III, double-blind, randomized trial assessed the efficacy, immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in young Chinese women (ClinicalTrials.gov registration NCT00779766). Women aged 18-25 years from Jiangsu province were randomized (1:1) to receive HPV vaccine (n = 3,026) or Al(OH)3 control (n = 3,025) at months 0, 1 and 6. The primary objective was vaccine efficacy (VE) against HPV-16/18 associated 6-month persistent infection (PI) and/or cervical intraepithelial neoplasia (CIN) 1+. Secondary objectives were VE against virological and clinical endpoints associated with HPV-16/18 and with high-risk HPV types, immunogenicity and safety. Mean follow-up for the according-to-protocol cohort for efficacy (ATP-E) was ∼15 months after the third dose. In the ATP-E (vaccine = 2,889; control = 2,894), for initially HPV DNA negative and seronegative subjects, HPV-16/18 related VE (95% CI) was 94.2% (62.7, 99.9) against 6-month PI and/or CIN1+ and 93.8% (60.2, 99.9) against cytological abnormalities. VE against HPV-16/18 associated CIN1+ and CIN2+ was 100% (-50.4, 100) and 100% (-140.2, 100), respectively (no cases in the vaccine group and 4 CIN1+ and 3 CIN2+ cases in the control group). At Month 7, at least 99.7% of initially seronegative vaccine recipients had seroconverted for HPV-16/18; geometric mean antibody titres (95% CI) were 6,996 (6,212 to 7,880) EU/mL for anti-HPV-16 and 3,309 (2,942 to 3,723) EU/mL for anti-HPV-18. Safety outcomes between groups were generally similar. The HPV-16/18 AS04-adjuvanted vaccine is effective, immunogenic and has a clinically acceptable safety profile in young Chinese women. Prophylactic HPV vaccination has the potential to substantially reduce the burden of cervical cancer in China.

Immune response to hepatitis B vaccine with high antigen content in non-responders after standard primary vaccination in Chinese adults.

CONTEXT: Alternative schedules are needed to provide greater immunogenicity in adults who fail to respond to the standard hepatitis B (HB) vaccine regimen. OBJECTIVE: To evaluate the immunogenicity and safety of high antigen content HB vaccine formulations administered to non-responders after routine primary vaccination. DESIGN SETTING, AND PARTICIPANTS: This was a phase III, double-blind, controlled clinical trial in China. We enrolled healthy participants (16-60 years old) seronegative for HB surface (HBs) antigen after primary vaccination, who had HBs antibody (anti-HBs) titres <10 mIU/ml at 28 days following routine vaccination with licensed HB vaccine containing 10 µg of antigen. Participants were randomised (2:2:1) to receive three booster doses of HB vaccine formulations containing 60 µg, 30 µg or 10 µg of antigen per dose 28 days apart. Blood samples were obtained pre-vaccination and 28 days after each dose to assess immunogenicity. Reactogenicity and safety were evaluated up to 28 days after each vaccine dose. RESULTS: Seroconversion rates were ≥ 92.1% and ≥ 87.1% as from the second dose of the 60 µg and 30 µg HB vaccine formulations, respectively, with geometric mean concentrations (GMCs) of ≥ 286.0 mIU/ml and ≥ 164.0 mIU/ml. In the 10 µg HB vaccine group the seroconversion rates were ≥ 83.0% and the GMCs ≥ 110.1 mIU/ml as from the second vaccine dose. All HB vaccine formulations were well tolerated: 352/1091 (32.3%) participants reported at least one injection-site or systemic adverse reaction (145/434 [33.4%] from the 60µg group; 138/435 [31.7%] from the 30 µg group and 69/222 [31.1%] from the 10 µg group). Most reactions were mild or moderate and resolved within 24h. No serious adverse events were reported. CONCLUSION: Booster vaccination with a three-dose schedule of a high antigen content HB vaccine formulation was immunogenic and well tolerated in healthy adults. Clinicaltrialsgov Identifier: NCT01203319.

Retrospective study of the incidence of HFMD and seroepidemiology of antibodies against EV71 and CoxA16 in prenatal women and their infants.

BACKGROUND: Hand, foot, and mouth disease (HFMD) has been emerging as an important public problem over the past few decades, especially in Asian and Pacific regions. A national program on EV71 vaccine development against HFMD was initiated in China, in 2008, which called for a need for seroepidemiological study for the target population. METHODOLOGY/PRINCIPAL FINDINGS: This was a retrospective study conducted in Jiangsu Province, in October, 2010. We measured the neutralizing antibodies against EV71 and CoxA16 in a cohort of infants aged of 2, 7, 12, and 27-38 months and their mothers just before delivery. Series sera samples from 975 infants and 555 mothers were collected and analyzed. Questionnaires on the history of HFMD were completed in the survey. A total of 143 HFMD cases were collected, but only 11.2% were reported to the National Infectious Disease Information Management System. The level of maternal antibody titers decreased dramatically during the first 7 month and remained at a relatively low level thereafter. But it increased significantly from month 12 to months 27-38. The accumulate incidence density of HFMD demonstrated a significant increase after 14 months of age, resulting in a accumulate incidence density of 50.8/1000 person-years in survey period. Seropositivity of EV71 antibody in infants at the age of 2 months seems to demonstrate a protective effect against HFMD. CONCLUSIONS AND SIGNIFICANCE: High seropositive rate of EV71 and CoxA16 antibody was found in prenatal women in mainland China, and there is a need to enhance the HFMD case management and the current surveillance system. We suggest that infants aged between 6 to 14 months should have the first priority to receive EV71 vaccine.