Immune persistence after different polio sequential immunization schedules in Chinese infants.

Trivalent oral poliovirus vaccine (tOPV) has been withdrawn and instead an inactivated poliovirus vaccine (IPV) and bivalent type 1 and type 3 OPV (bOPV) sequential immunization schedule has been implemented since 2016, but no immune persistence data are available for this polio vaccination strategy. This study aimed to assess immune persistence following different polio sequential immunization schedules. Venous blood was collected at 24, 36, and 48 months of age from participants who had completed sequential schedules of combined IPV and OPV in phase III clinical trials. The serum neutralizing antibody titers against poliovirus were determined, and the poliovirus-specific antibody-positive rates were evaluated. A total of 1104 participants were enrolled in this study. The positive rates of poliovirus type 1- and type 3-specific antibodies among the sequential immunization groups showed no significant difference at 24, 36, or 48 months of age. The positive rates of poliovirus type 2-specific antibody in the IPV-IPV-tOPV group at all time points were nearly 100%, which was significantly higher than the corresponding rates in other immunization groups (IPV-bOPV-bOPV and IPV-IPV-bOPV). Immunization schedules involving one or two doses of IPV followed by bOPV failed to maintain a high positive rate for poliovirus type 2-specific antibody.

Safety and immunogenicity of a skin- and neuro-attenuated live vaccine for varicella: a randomized, double-blind, controlled, dose-escalation and age de-escalation phase 1 clinical trial.

Background: Despite the success in decreasing varicella-related disease burden, live-attenuated Oka vaccine strain of varicella-zoster virus (vOka) remains neuro-virulence and may establish latency and reactivate, raising safety concerns. Here we aimed to evaluate the safety and immunogenicity of a skin- and neuro-attenuated varicella vaccine candidate (v7D). Methods: This is a randomized, double-blind, placebo-controlled, dose-escalation and age de-escalation phase 1 clinical trial conducted in Liuzhou, China (ChiCTR1900022284). Eligible healthy participants aged 1-49 years, with no history of varicella vaccination and had no history of varicella or herpes zoster were sequentially enrolled and allocated to subcutaneously receive one of the three doses (3.3, 3.9, and 4.2 lg PFU) of v7D, vOka or placebo in a dose-escalation and age de-escalation manner. The primary outcome was safety, assessed by adverse events/reactions within 42 days after vaccination and serious adverse events (SAEs) throughout six months after vaccination. The secondary outcome was immunogenicity, assessed by the VZV IgG antibodies measured with fluorescent antibody to membrane antigen (FAMA) assay. Findings: Between April 2019 and March 2020, totally 224 participants were enrolled. Within 42 days post-vaccination, the incidences of adverse reactions were 37.5%-38.7% in the three doses of v7D groups which were similar to that of the vOka (37.5%) and placebo (34.4%) groups. No SAE has been judged as causally related to vaccination. At 42 days post-vaccination, 100% of children aged 1-12 years in the per-protocol set of immunogenicity cohort of the v7D groups became seropositive. Meanwhile, in the intent-to-treat set of immunogenicity cohort of subjects aged 1-49 years, the geometric mean increases of the three groups of v7D vaccine were 3.8, 5.8 and 3.2, respectively, which were similar to that of the vOka vaccine group (4.4) and significantly higher than that of the placebo group (1.3). Interpretation: The candidate v7D vaccine has been preliminarily shown to be well-tolerated and immunogenic in humans. The data warrant further evaluation of the safety advantage and efficacy of v7D as a varicella vaccine. Funding: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, and Beijing Wantai CO., LTD.

Safety and immunogenicity of a bivalent HPV16/18 vaccine in Chinese females.

As global supply is still inadequate to address the worldwide requirements for HPV vaccines, we assessed the safety and immunogenicity of a new bivalent HPV16/18 vaccine. In this randomized, double-blind, placebo-controlled, phase 2 trial, healthy 9-45-year-old Chinese females in three age cohorts (600 aged 9-17 years; 240 aged 18-26 years; 360 aged 27-45 years) were randomized 1:1 to receive three doses (0,2,6 months) of HPV16/18 vaccine or placebo. We measured neutralizing antibodies against HPV 16 and 18 at 7 months and monitored safety to 12 months in all age cohorts; 9-17-year-old girls were monitored for safety and immunogenicity to 48 months. In vaccinees, 99.8% seroconverted for HPV 16 and 18 types at 7 months; respective GMTs of 5827 (95% CI: 5249, 6468) and 4223 (3785, 4713) were significantly (p < .001) higher than controls for all comparisons. GMTs in the 9-17-year-olds, which were significantly higher than in older women at 7 months, gradually declined to 48 months but remained higher than placebo with seropositivity rates maintained at 98.5% and 97.6% against HPV 16 and 18, respectively. Adverse events occurred at similar rates after vaccine and placebo (69.8% vs. 72.5%, p = .308), including solicited local reactions and systemic adverse events which were mainly mild-to-moderate. The bivalent HPV16/18 vaccine was well tolerated and induced high levels of neutralizing antibodies in all age groups which persisted at high levels to 48 months in the 9-17-year-old age group which would be the target for HPV vaccination campaigns.

Safety and immunogenicity of an Escherichia coli-produced bivalent human papillomavirus type 6/11 vaccine: A dose-escalation, randomized, double-blind, placebo-controlled phase 1 trial.

A dose-escalation, randomized, double-blind, placebo-controlled phase 1 clinical trial enrolled 145 eligible participants aged 18-55 years in March 2015 in Liuzhou, China. Stratified by age and sex, the participants were randomly assigned to receive either 30, 60, or 90 µg of the HPV-6/11 vaccine (n = 41/40/40) or the parallel placebo vaccine (n = 8/8/8) with a 0/1/6-month dose-escalation schedule. Participants were actively followed-up to record local and systemic AEs occurring within 30 days after each vaccination, and SAEs occurred in 7 months. Blood and urine samples of each participant were collected before and 2 days after the first and third vaccination to determine changes in routine blood, serum biochemical, and urine indexes. Serum HPV-6/11-specific IgG and neutralizing antibody levels at month 7 were analyzed. A total of 79 adverse events were reported, and no SAEs occurred. The incidences of total adverse reactions in the 30 µg, 60 µg, and 90 µg HPV vaccine groups and the control group were 31.7%, 50.0%, 42.5%, and 62.5%, respectively. All but one of the adverse reactions was mild or moderate with grade 1 or 2. No vaccine-related changes with clinical significance were found in paired blood and urine indexes before and after vaccinations. All the participants in the per-protocol set seroconverted at month 7 for both IgG and neutralizing antibodies. The candidate novel Escherichia-coli-produced bivalent HPV-6/11 vaccine has been preliminarily proven to be well tolerated and with robust immunogenicity in a phase 1 clinical study, supporting further trials with larger sample size. The study has been registered at ClinicalTrials.gov (NCT02405520).

Burden and etiology of moderate and severe diarrhea in children less than 5 years of age living in north and south of China: Prospective, population-based surveillance.

BACKGROUND: Diarrhea remains the leading cause of childhood illness in China. Better understanding of burden and etiology of diarrheal diseases is important for development of effective prevention measures. METHODS: Population-based diarrhea surveillance was conducted in Sanjiang (southern China) year-round and Zhengding (northern China) in autumn/winter. Stool specimens were collected from children < 5 years of age experiencing diarrhea. The TaqMan Array Card (TAC), based on multiplex real-time PCR, was applied to detect multiple enteric microbial agents simultaneously. Results using these methods were compared to those derived from conventional PCR assays. RESULTS: During the study period, 6,380 children in Zhengding and 3,581 children in Sanjiang < 5 years of age participated. Three hundred and forty (31.2%) and 279 (22.9%) diarrhea episodes were identified as moderate-to-severe in the two counties, with incidence of 60.4 and 88.3 cases per 1,000 child-years in Zhengding and Sanjiang, respectively. The five most frequently detected bacterial and viral agents in Sanjiang were adenovirus, enterovirus, enteroaggregative Escherichia coli (EAEC), rotavirus, and sapovirus all the year round, while the most common viral agents in Zhengding were rotavirus, followed by astrovirus and adenovirus during the cool season. Compared to conventional PCR assay, the average incremental detection via the TAC method was twofold. CONCLUSION: Our study demonstrated high diversity and prevalence of multiple major bacterial and viral agents, including rotavirus and calicivirus, among children in China. Further studies are needed to define the public health significance of neglected but frequently detected pathogens such as EAEC, enterotoxigenic E. coli, Campylobacter, adenovirus, and enterovirus.

Burden of viral gastroenteritis in children living in rural China: Population-based surveillance.

BACKGROUND: Despite the considerable disease burden caused by the disease, rotavirus vaccine has not been introduced into routine national immunization schedule, and norovirus vaccines are being developed without a comprehensive understanding of gastroenteritis epidemiology. To bridge this knowledge gap, we investigated the disease burden of viral gastroenteritis in rural China. METHODS: Between October 2011 and December 2013, population-based surveillance was conducted in Zhengding and Sanjiang counties in China. Stool samples were collected from children <5 years of age with diarrhea. All specimens were tested for rotaviruses, noroviruses, sapoviruses, enteric adenoviruses, and astroviruses. RESULTS: The most common pathogen causing diarrhea was rotavirus (54.7 vs 45.6 cases/1,000 children/year in Zhengding and Sanjiang, respectively), followed by norovirus (28.4 vs 19.3 cases/1,000 children/year in Zhengding and Sanjiang, respectively). The highest incidence of these viruses was observed in children 6-18 months of age. Among the 5 viral pathogens, rotaviruses caused the most severe illness, followed by noroviruses. CONCLUSION: Rotavirus and norovirus are the 2 most important viral pathogens causing childhood diarrhea in both northern and southern China; they should be the major targets for viral gastroenteritis prevention strategies among children in China.

G2 rotavirus within an emergent VP7 evolutionary lineage circulating in children with acute diarrhea in Guangxi Province of China, 2014.

Routine surveillance revealed that the prevalence of P[4] rotaviruses circulating in children with acute diarrhea in Guangxi Province, China, increased in 2014. However, VP7 genotyping for these P[4] rotaviruses was unsuccessful. Exhaustive database searching and sequence analysis indicated that the G genotype of these P[4] rotaviruses was G2, and the VP7 genes clustered with recently emerging G2 strains in several countries within an emergent evolutionary lineage that was distinct from the previously designated lineages I-IV as well as lineage V including porcine rotaviruses. Further studies are essential to monitor the potential global spread of this emerging G2 rotavirus.

Reactogenicity and safety of a liquid human rotavirus vaccine (RIX4414) in healthy adults, children and infants in China: randomized, double-blind, placebo-controlled Phase I studies.

We report the findings of three randomized, double-blind, placebo-controlled Phase I studies undertaken to support licensure of the liquid formulation of the human G1P[8] rotavirus (RV) vaccine (RIX4414; GlaxoSmithKline Biologicals SA) in China. Healthy adults aged 18-45 y (n=48) and children aged 2-6 y (n=50) received a single dose of the human RV vaccine or placebo. Healthy infants (n=50) aged 6-16 weeks at the time of first vaccination received two oral doses of the human RV vaccine or placebo according to a 0, 1 mo schedule. In infants, blood samples were collected prior to vaccination and one month post-dose 2 to assess anti-RV IgA antibody concentrations using ELISA. Stool samples were collected from all infants on the day of each vaccination, at 7 and 15 d after each vaccination and one month post-dose 2. Stool samples were analyzed by ELISA for detection of RV antigen to assess RV antigen excretion. The reactogenicity profile of the human RV vaccine was found to be comparable to that of placebo in all age groups studied. The anti-RV IgA antibody seroconversion rate in infants after two vaccine doses was 86.7% (95% CI: 59.5-98.3). Vaccine take in infants who received the liquid human RV vaccine was 86.7% (95% CI: 59.5-98.3). A Phase III efficacy study of the human RV vaccine in the infant population in China has now been completed (ROTA-075/NCT01171963).

[Study on the status of infection and distribution of rabies virus in China].

OBJECTIVE: To investigate the status of infection and distribution of rabies virus (RV) in different epidemic areas in China. METHODS: Brain specimens from animals and suspected patients were collected at the districts of high-, medium- and low incidence rates of human rabies and detected by both direct Immunofluorescence assay (DFA) and RT-PCR. RESULTS: 254 of 3007 specimens of dog brains showed RV positive by DFA (positive rate of 8.4%). Among these 254 samples, 78 showed positive (positive rate of 30.7%) by RT-PCR. 93 specimens from dogs and cats that had attacked human beings, 63 of them showed positive by DFA (positive rate of 67.7%) and all of them were also positive by RT-PCR. In addition, RV could also be detected in Apodemus agrarius, ferret badger, and suspected patients specimens from the districts under survey. There was no statistical difference between the infection rates of RV in different provinces and regions with different incidence of rabies. CONCLUSION: There might be a relatively high infection rate of RV among the domestic dogs/cats in the endemic areas in China. Wild animals might have been infected with RV in the districts under survey.

[Analysis of human rabies high-occurrence factors in Guangxi from 2004 to 2008].

OBJECTIVE: Analysis the epidemiological characteristics on rabies cases occurred in Guangxi from 2004 to 2008 and summarize the result of healthy-dog infection rabies virus investigation from 2006 to 2008. Exploring the high-occurrence and correlated factors on rabies in Guangxi. METHODS: Data collected from the National Disease Surveillance System and the National Active Surveillance System for Rabies from 2004 to 2008 and Data of healthy-dog infection rabies virus investigation from 2006 to 2008 were analyzed. RESULTS: The total rabies cases were 2463 in Guangxi from 2004-2008 and average incidence rate was 0.98 per 100 thousand per year. There were 95 counties had rabies case reported, anyway more than 10 cases occurred county number was declined while less than 5 cases rose year by year. The rabies case incidence area was expanded and the cases in middle and west area of Guangxi rose significantly. Rabies cases were reported whole year and no seasonal peak. Human rabies cases mainly were farmers, students and children. Yanger than 20 years old and elder 40 years old were the highest age groups in the population of the investigation, 83.79% cases were attacked by dogs. 78.5% cases classification category III. 83.17% cases had exposed on the upper and lower limbs, 10.56% exposed to the head, face or neck. But 67.88% cases did not receive any PEP and only 18.31% cases vaccinated and 3.63% category III exposure cases combined administration of RIG. The incubation median was 60 days. The rabies virus infection rate among randomly collection healthy-dog brain samples from 2006 to 2008 was 1.92%, 0.93% and 0.89%. CONCLUSION: Unsuccessful and inadequate PEP of patients were the main factors leading to the high-occurrence of human rabies in Guangxi. And there are a lot of infection rabies virus healthy-dogs alive in Guangxi also as a high-occurrence factor.

Epidemiological investigations of human rabies in China.

BACKGROUND: The epidemic of rabies showed a rising trend in China in recent years. To identify the potential factors involved in the emergence, we investigated and analyzed the status and characteristics of human rabies between 1996 and 2008. Moreover, the status of rabies infection and vaccination in dogs, and prophylaxis of humans after rabies exposure were analyzed. METHODS: Human rabies data in China between 1996 and 2008 collected from the annual reports of Chinese Center for Disease Control and Prevention (China CDC) were analyzed. To investigate the status of dogs and postexposure prophylaxis (PEP) of humans, brain specimens of domestic dogs were collected and detected, and the demographic details, exposure status and PEP of rabies patients were obtained in 2005 and 2006 in Guangxi, Hunan and Guizhou provinces. RESULTS: The results showed 19,806 human rabies cases were reported in China from 1996 to 2008, with an average of 1,524 cases each year, and the incidence almost was rising rapidly, with the peak in 2007 (3,300 cases). It was notable that nearly 50% of the total rabies cases nationwide were reported in Guangxi, Hunan and Guizhou provinces. In these three provinces, the rabies infection rate in dogs was 2.3%, and 60% investigated cities had a dog vaccination rate of below 70%; among the 315 recorded human cases, 66.3% did not receive any PEP at all, 27.6% received inadequate PEP, and only 6.0% received a full regime of PEP. CONCLUSIONS: In recent years, rabies is reemerging and becoming a major public-health problem in China. Our analysis showed that unsuccessful control of dog rabies and inadequate PEP of patients were the main factors leading to the high incidence of human rabies in China, then there are following suggestions: (1) Strict control of free-ranging dogs and mandatory rabies vaccination should be enforced. (2)Establishing national animal rabies surveillance network is imperative. (3) PEP should be decided to initiate or withhold according to postmortem diagnosis of the biting animal. (4) The cost of PEP should be decreased or free, especially in rural areas. (5)Education of the public and health care staff should be enhanced.

Molecular epidemiology of rabies in Southern People's Republic of China.

In recent years, the number of human rabies cases in the People's Republic of China has increased during severe epidemics in 3 southern provinces (Guizhou, Guangxi, and Hunan). To analyze the causes of the high incidence of human rabies in this region, during 2005-2007, we collected 2,887 brain specimens from apparently healthy domestic dogs used for meat consumption in restaurants, 4 specimens from suspected rabid dogs, and 3 from humans with rabies in the 3 provinces. Partial nucleoprotein gene sequences were obtained from rabies-positive specimens. Phylogenetic relationships and distribution of viruses were determined. We infer that the spread of rabies viruses from high-incidence regions, particularly by long-distance movement or transprovincial translocation of dogs caused by human-related activities, may be 1 cause of the recent massive human rabies epidemics in southern China.

[Survey and anslysis of infection rate of dog rabies in the regions with high incidence of human rabies].

OBJECTIVE: To investigate the situation of dog rabies and analyze it's relationship with human rabies. METHODS: In Guizhou, Guangxi and Hunan provinces which suffered from rabies most heavily, one or two cities were selected respectively from regions with high-, middle-, low-incidence rate of human rabies as investigation spots where Dogs' brain specimens were collected and detected with both direct immunofluorescence assay (IFA) and RT-PCR. RESULTS: A total of 2887 specimens were collected and 66 of these were positive for IFA and RT-PCR. Therefore, the rate of positive specimens was 2.3%. However, there was not a close relationship in the incidence rate of dog rabies and human rabies. CONCLUSION: Dog's infection situation of rabies contributed to the severe epidemic of human rabies.

[Characterization of rabies virus phosphoprotein in high prevalence provinces of China].

OBJECTIVE: Characterization of rabies virus phosphoprotein through analyzation of genetic variations about rabies virus phosphoproteins in high-incidence regions in China. METHODS: The nucleotide sequence of the P gene of Guangxi, Guizhou and Hunan provinces positive sample's were sequenced, and the P region's similarity and phylogenetic analyses were completed by using softer wares. RESULTS: The similarity of P region's nucleotide sequence is 82.1%-100%, while, the similarity of amino acid sequence is 87.5%-100%. A little variation in phosphoprotein cannot influence its biological functions. CONCLUSION: All rabies viruses isolated from Guangxi, Guizhou and Hunan provinces belong to genotype 1 and share same phylogenesis and same genome characteristic; Virus distribution presents unique Characterization; Some virus isolates from Hunan province and Thailand may come from the same virus.

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

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

[Study on the variations of hepatitis B virus status among people having received hepatitis B vaccine].

OBJECTIVE: To study the epidemiological pattern and trends of hepatitis B virus (HBV) in the area where people had been immunized by HBV vaccine for long time. METHODS: Through cluster sampling and cross-sectional study, relative information and blood samples from people in Long-an county by families were collected. Signals of HBV infection were tested by solid-phase reverse immunosorbent test. RESULTS: (1) The average HBsAg positive rate was 7.5% with anti-HBs as 44.5 %, and anti-HBc as 47.8%. The positive rates of HBsAg and anti-HBc among 0-19 year-olds were lower than those of > or = 20 year-olds. (2) The positive rates of HBsAg, anti-HBc and HBV infection among HBV vaccine immunized group were 2.8%, 12.0% and 12.5% respectively, comparing with which among the un-immunized group as 10.2%, 69.8% and 71.2% respectively. (3) The HBsAg positive rate of male was higher than the female's but with no significant difference of anti-HBs and anti-HBc between different sexes. (4) The average HBsAg positive rate of 0-19 years old group was only 2.4%, while that of 20-30 years old group was 13.6%-17.7% and dropped from 60 years old group and on. The anti-HBs positive rate of 0-19 years old people started to drop significantly by age. The anti-HBs and anti-HBc positive rates of > or = 20 years people were showing a rising trend by ages. CONCLUSION: It seemed obviously that the HBV epidemiological patterns had changed after HBV vaccine had been universally used for long time in newborns. The age peak of infection had been pushed backward for nearly 20 years. It had been proved that the HBV vaccine immunization program had obtained excellent efficacy.

[Variations of hepatitis B virus infection epidemic pattern after long-term HBV vaccine immunization].

OBJECTIVE: To study the epidemic pattern and trend of HBV infection in the area where the people had been immunized by HBV vaccine for 20 years. METHODS: The whole sampling method was applied in combination with cross-sectional investigation. Blood samples were taken from every member of families. Markers of HBV infection were determined by using solid-phase radioimmunoassay (SPRIA). RESULTS: (1) The average HBsAg positive rate was 7.5%. The positive rate of markers for HBV infection of 0-19 years old subjects were lower than those of > or = 20 years old subjects. (2) The positive rate of HBsAg of 0-19 years old subjects in 1985 was higher than that in 2005. The anti-HBs positive rate in 1985 stemmed to be higher with age. It was 12.4% in 1- age group to 53.8% in >60 years age group. While the result of 2005 showed that the anti-HBs positive rate of 0-19 years old subjects dropped with age. The anti-HBc positive rate in 1985 also tended to be higher with age. But the result of 2005 showed that the rate of 0-19 years old subjects was just 1.4% to 16.8%. CONCLUSION: The epidemic patterns of HBV infection have had significant variations in the target population. HBV vaccine immunization has obtained excellent efficacy.

[Analysis on the factors related to rabies epidemic in China, in 2005].

OBJECTIVE: To analyse the related epidemic factors of rabies and to provide basic evidence for developing rabies control and prevention programs in China. METHODS: Possible factors that causing rabies epidemics in the southern part of China were obtained through collecting both epidemic and surveillance data of rabies in 2005, and to analyse every factor by software of Excel 2002. RESULTS: The number of rabies cases was 2548 in 2005. Among 885 cases being investigated, 60.56%, 49.04%, 96.16% had not had any chance to receive treatment, vaccine or immunoglobulin. Among the exposed persons, 89.95% received treatment on wounds and 94.93% were immunized, and 8.56% received immunoglobulin. 94.86% of them accomplished the full rabies post-exposure prophylaxis course, but 8.56% of them did not accomplish it. 88.50% of the cases and 92% of the persons under exposure were bitten by dogs. The density of dogs was 3.20-13.37 per 100 persons. The vaccination coverage rates among dogs were 5.31% -75.11% with a positive rate of 2.93 % -6.40%. CONCLUSION: Factors as: low rate of post-exposure prophylaxis and failed to have finished the necessary post-exposure treatment (PET) of the cases, nonstandard PET in hospital or local clinic, low rabies vaccination coverage and high infectivity of rabies virus in animal host (mainly for dog) might be responsible for rabies epidemics in China, in 2005.