Safety and immunogenicity of a recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in Sierra Leone: a single-centre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: A recombinant adenovirus type-5 vector-based vaccine expressing the glycoprotein of Ebola Zaire Makona variant showed good safety and immunogenicity in a phase 1 trial of healthy Chinese adults. We aimed to assess the safety and immunogenicity of this vaccine in healthy adults in Sierra Leone and to determine the optimal dose. METHODS: We did a single-centre, randomised, double-blind, placebo-controlled, phase 2 clinical trial at Sierra Leone-China Friendship Hospital, Freetown, Sierra Leone. We recruited healthy adults aged 18-50 years who were HIV negative, had no history of Ebola virus infection, and had no previous immunisation with other Ebola vaccine candidates. Participants were sequentially enrolled and randomly assigned (2:1:1), by computer-generated block randomisation (block size of eight), to receive the high-dose vaccine (1·6 × 1011 viral particles), low-dose vaccine (8·0 × 1010 viral particles), or placebo (containing only vaccine excipients, with no viral particles). Participants, investigators, and study staff (except two study pharmacists) were masked from treatment allocation. The primary safety outcome was occurrence of solicited adverse reactions within 7 days of vaccination, analysed by intention to treat. The primary immunogenicity outcome was glycoprotein-specific antibody responses at days 14, 28, and 168 after vaccination, analysed in all vaccinated participants who had blood samples drawn for antibody tests. The trial is registered with the Pan African Clinical Trials Registry, number PACTR201509001259869, and is completed. FINDINGS: During Oct 10-28, 2015, 500 participants were enrolled and randomly assigned to receive the high-dose vaccine (n=250), low-dose vaccine (n=125), or placebo (n=125). 132 (53%) participants in the high-dose group, 60 (48%) in the low-dose group, and 54 (43%) in the placebo group reported at least one solicited adverse reaction within 7 days of vaccination. Most adverse reactions were mild and self-limiting. Solicited injection-site adverse reactions were significantly more frequent in vaccine recipients (65 [26%] in high-dose group and 31 [25%] in low-dose group) than in those receiving placebo (17 [14%]; p=0·0169). Glycoprotein-specific antibody responses were detected from day 14 onwards (geometric mean titre 1251·0 [95% CI 976·6-1602·5] in low-dose group and 1728·4 [1459·4-2047·0] in high-dose group) and peaked at day 28 (1471·8 [1151·0-1881·8] and 2043·1 [1762·4-2368·4]), but declined quickly in the following months (223·3 [148·2-336·4] and 254·2 [185·0-349·5] at day 168). Geometric mean titres in the placebo group remained around 6·0-6·8 throughout the study period. Three serious adverse events (malaria, gastroenteritis, and one fatal asthma episode) were reported in the high-dose vaccine group, but none was deemed related to the vaccine. INTERPRETATION: The recombinant adenovirus type-5 vector-based Ebola vaccine was safe and highly immunogenic in healthy Sierra Leonean adults, and 8·0 × 1010 viral particles was the optimal dose. FUNDING: Chinese Ministry of Science and Technology and the National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology.

Long-term efficacy of a hepatitis E vaccine.

BACKGROUND: Hepatitis E virus (HEV) is a leading cause of acute hepatitis. The long-term efficacy of a hepatitis E vaccine needs to be determined. METHODS: In an initial efficacy study, we randomly assigned healthy adults 16 to 65 years of age to receive three doses of either a hepatitis E vaccine (vaccine group; 56,302 participants) or a hepatitis B vaccine (control group; 56,302 participants). The vaccines were administered at 0, 1, and 6 months, and the participants were followed for 19 months. In this extended follow-up study, the treatment assignments of all participants remained double-blinded, and follow-up assessments of efficacy, immunogenicity, and safety were continued for up to 4.5 years. RESULTS: During the 4.5-year study period, 60 cases of hepatitis E were identified; 7 cases were confirmed in the vaccine group (0.3 cases per 10,000 person-years), and 53 cases in the control group (2.1 cases per 10,000 person-years), representing a vaccine efficacy of 86.8% (95% confidence interval, 71 to 94) in the modified intention-to-treat analysis, rather than (95% confidence interval, 71 to 84) [corrected]. Of the participants who were assessed for immunogenicity and were seronegative at baseline, 87% of those who received three doses of the hepatitis E vaccine maintained antibodies against HEV for at least 4.5 years; HEV antibody titers developed in 9% in the control group. The rate of adverse events was similar in the two groups. CONCLUSIONS: Immunization with this hepatitis E vaccine induced antibodies against HEV and provided protection against hepatitis E for up to 4.5 years. (Funded by the Chinese Ministry of Science and Technology and others; ClinicalTrials.gov number, NCT01014845.).

Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial.

BACKGROUND: Up to now, all tested Ebola virus vaccines have been based on the virus strain from the Zaire outbreak in 1976. We aimed to assess the safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine expressing the glycoprotein of the 2014 epidemic strain. METHODS: We did this randomised, double-blind, placebo-controlled, phase 1 clinical trial at one site in Taizhou County, Jiangsu Province, China. Healthy adults (aged 18-60 years) were sequentially enrolled and randomly assigned (2:1), by computer-generated block randomisation (block size of six), to receive placebo, low-dose adenovirus type-5 vector-based Ebola vaccine, or high-dose vaccine. Randomisation was pre-stratified by dose group. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was occurrence of solicited adverse reactions within 7 days of vaccination. The primary immunogenicity endpoints were glycoprotein-specific antibody titres and T-cell responses at day 28 after the vaccination. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT02326194. FINDINGS: Between Dec 28, 2014, and Jan 9, 2015, 120 participants were enrolled and randomly assigned to receive placebo (n=40), low-dose vaccine (n=40), or high-dose vaccine. Participants were followed up for 28 days. Overall, 82 (68%) participants reported at least one solicited adverse reaction within 7 days of vaccination (n=19 in the placebo group vs n=27 in the low-dose group vs n=36 in the high-dose group; p=0·0002). The most common reaction was mild pain at the injection site, which was reported in eight (20%) participants in the placebo group, 14 (35%) participants in the low-dose group, and 29 (73%) participants in the high-dose vaccine group (p<0·0001). We recorded no statistical differences in other adverse reactions and laboratory tests across groups. Glycoprotein-specific antibody titres were significantly increased in participants in the low-dose and high-dose vaccine groups at both day 14 (geometric mean titre 421·4 [95% CI 249·7-711·3] and 820·5 [598·9-1124·0], respectively; p<0·0001) and day 28 (682·7 [424·3-1098·5] and 1305·7 [970·1-1757·2], respectively; p<0·0001). T-cell responses peaked at day 14 at a median of 465·0 spot-forming cells (IQR 180·0-1202·5) in participants in the low-dose group and 765·0 cells (400·0-1460·0) in those in the high-dose group. 21 (18%) participants had mild fever (n=9 in the placebo group, n=6 in the low-dose group, and n=6 in the high-dose group). No serious adverse events were recorded. INTERPRETATION: Our findings show that the high-dose vaccine is safe and robustly immunogenic. One shot of the high-dose vaccine could mount glycoprotein-specific humoral and T-cell response against Ebola virus in 14 days. FUNDING: China National Science and Technology, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology.

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.

Immunogenicity and safety of an enterovirus 71 vaccine in healthy Chinese children and infants: a randomised, double-blind, placebo-controlled phase 2 clinical trial.

BACKGROUND: Enterovirus 71 (EV71) outbreaks are a socioeconomic burden, especially in the western Pacific region. Results of phase 1 clinical trials suggest an EV71 vaccine has a clinically acceptable safety profile and immunogenicity. We aimed to assess the best possible dose and formulation, immunogenicity, and safety profile of this EV71 vaccine in healthy Chinese children. METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial was undertaken at one site in Donghai County, Jiangsu Province, China. Eligible participants were healthy boys or girls aged 6­36 months. Participants were randomly assigned (1:1:1:1:1) to receive either 160 U, 320 U, or 640 U alum-adjuvant EV71 vaccine, 640 U adjuvant-free EV71 vaccine, or a placebo (containing alum adjuvant only), according to a blocked randomisation list generated by SAS 9.1. Participants and investigators were masked to the assignment. The primary endpoint was anti-EV71 neutralising antibody geometric mean titres (GMTs) at day 56, analysed according to protocol. The study is registered with ClinicalTrials.gov, number NCT01399853. FINDINGS: We randomly assigned 1200 participants, 240 (120 aged 6­11 months [infants] and 120 aged 12­36 months [children]) of whom were assigned to each dose. 1106 participants completed the study and were included in the according-to-protocol analysis. The main reasons for dropout were withdrawal of consent and refusal to donate a blood sample. Infants who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (742·2 [95% CI 577·3­954·3]), followed by those who received the 320 U formulation (497·9 [383·1­647·0]). For children, those who received the 320 U formulation had the highest GMTs on day 56 (1383·2 [1037·3­1844·5]). Participants who received the vaccine had significantly higher GMTs than did who received placebo (p<0·0001). For the subgroup of participants who were seronegative at baseline, both infants and children who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (522·8 [403·9­676·6] in infants and 708·4 [524·1­957·6] in children), followed by those who received the 320 U adjuvant vaccine (358·2 [280·5­457·5] in infants and 498·0 [383·4­646·9] in children). 549 (45·8%) of 1200 participants (95 CI 42·9­48·6%) reported at least one injection-site or systemic adverse reaction, but the incidence of adverse reactions did not differ significantly between groups (p=0·36). The 640 U alum-adjuvant vaccine group had a significantly higher incidence of induration than did the 640 U adjuvant-free group (p=0·001). INTERPRETATION: Taking immunogenicity, safety, and production capacity into account, the 320 U alum-adjuvant formulation of the EV71 vaccine is probably the best possible formulation for phase 3 trials. FUNDING: The National Science and Technology Major Project (2011ZX10004-902) of the Chinese Ministry of Science and Technology, China's 12­5 National Major Infectious Disease Program (2012ZX10002-001), and Beijing Vigoo Biological.

Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: A vaccine for enterovirus 71 (EV71) is needed to address the high burden of disease associated with infection. We assessed the efficacy, safety, immunogenicity, antibody persistence, and immunological correlates of an inactivated alum-adjuvant EV71 vaccine. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 trial. Healthy children aged 6-35 months from four centres in China were randomly assigned (1:1) to receive vaccine or alum-adjuvant placebo at day 0 and 28, according to a randomisation list (block size 30) generated by an independent statistician. Investigators and participants and their guardians were masked to the assignment. Primary endpoints were EV71-associated hand, foot, and mouth disease (HFMD) and EV71-associated disease during the surveillance period from day 56 to month 14, analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01508247. FINDINGS: 10,245 participants were enrolled and assigned: 5120 to vaccine versus 5125 to placebo. 4907 (with three cases of EV71-associated HFMD and eight cases of EV71-associated disease) versus 4939 (with 30 cases of EV71-associated HFMD and 41 cases of EV71-associated disease) were included in the primary efficacy analysis. Vaccine efficacy was 90·0% (95% CI 67·1-96·9) against EV71-associated HFMD (p=0·0001) and 80·4% (95% CI 58·2-90·8) against EV71-associated disease (p<0·0001). Serious adverse events were reported by 62 of 5117 (1·2%) participants in the vaccine group versus 75 of 5123 (1·5%) in the placebo group (p=0·27). Adverse events occurred in 3644 (71·2%) versus 3603 (70·3%; p=0·33). INTERPRETATION: EV71 vaccine provides high efficacy, satisfactory safety, and sustained immunogenicity. FUNDING: China's 12-5 National Major Infectious Disease Program, Beijing Vigoo Biological.

[Value of computer-assisted slide-screening system in ThinPrep cervical cytology].

OBJECTIVE: To investigate the value of computer-assisted slide-screening system (ThinPrep imaging system, TIS) in the diagnosis of cervical Thinprep smears. METHODS: A total of 19 600 ThinPrep smears were collected, including 9800 slides by TIS-assisted screening from September 2011 to March 2012 and 9800 slides by manual screening from September 2010 to April 2011 as control. The detection rates of abnormal cells and common microbial infection by the different screening methods were compared. With histopathological diagnosis of colposcopic biopsy as the gold standard, the screening efficiency and correlation of cytologic diagnosis among different screening methods were analyzed. RESULTS: Compared with manual screening, the detection rate of abnormal cells in 9800 cases by TIS-assisted screen was increased from 5.4% (525/9800) to 6.8% (665/9800), mainly in the categories of ASCUS and LSIL (P < 0.05). TIS had a higher accordance rate between cytologic diagnosis and histopathological diagnosis in the NILM and ASCUS than that by manual screening. False-negative rate of finding abnormal cells by TIS decreased from 8.5% (17/200) to 0.7% (2/289, P < 0.01) with an increased sensitivity compared to manual screening, although the specificity was similar. Both TIS and manual screening had advantages and disadvantages respectively in the detection of microbial organisms. TIS improved screening efficiency by 50%. CONCLUSION: TIS improves not only the screening efficiency but also the detection of abnormal cells with a reduced false negativity, and it therefore has a broad application prospect.

Safety and immunogenicity of an Escherichia coli-produced 9-valent human papillomavirus L1 virus-like particle vaccine (types 6/11/16/18/31/33/45/52/58) in healthy adults: an open-label, dose-escalation phase 1 clinical trial.

Background: A safe and highly efficacious Escherichia coli (E. coli)-produced HPV 16/18 bivalent vaccine has been prequalified by the World Health Organization. Here, we conducted a single-center, open-label, dose-escalation phase 1 clinical trial to evaluate the safety and immunogenicity of the second-generation nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine. Method: Twenty-four eligible volunteers aged 18-45 years were enrolled in January 2019 in Dongtai, China and received 0.5 mL (135 µg) or 1.0 mL (270 µg) of the candidate vaccine with a 0/1/6-month dose-escalation schedule. Local and systemic adverse events (AEs) occurring within 30 days after each vaccination and serious adverse events (SAEs) occurring within 7 months were recorded. Blood samples from each participant were collected before and 2 days after the first and third vaccinations to determine changes in laboratory parameters. Serum IgG and neutralizing antibody (nAb) levels against each HPV type at month 7 were analyzed (ClinicalTrials.gov: NCT03813940). Findings: The incidences of total AEs in the 135 µg and 270 µg groups were 66.7% and 83.3%, respectively. All AEs were mild or moderate, and no SAEs were reported. No clinically significant changes were found in paired blood indices before or after any of the vaccinations. All the participants in the per-protocol set except for two who failed to seroconvert for HPV 11 or 58 in the 135 µg group seroconverted at month 7 for both IgG and nAbs. Interpretation: The candidate E. coli-produced 9vHPV vaccine has been preliminarily proven to be well tolerated and immunogenic, which encourages further studies in large cohorts with a wider age range. Funding: This study was supported by the National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Fujian Province Health and Education Joint Research Program, Xiamen Science and Technology Plan Project, Fundamental Research Funds for the Central Universities, CAMS Innovation Fund for Medical Sciences of China, and Xiamen Innovax Biotechnology Co., Ltd.

Immunogenicity and safety of an Escherichia coli-produced human papillomavirus (types 6/11/16/18/31/33/45/52/58) L1 virus-like-particle vaccine: a phase 2 double-blind, randomized, controlled trial.

The Escherichia coli-produced human papillomavirus (HPV) 16/18 bivalent vaccine (Cecolin) has received prequalification by the World Health Organization based on its high efficacy and good safety profile. We aimed to evaluate the immunogenicity and safety of the second-generation nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine (Cecolin 9) through the randomized, blinded phase 2 clinical trial. Eligible healthy women aged 18-45 years were randomly (1:1) allocated to receive three doses of 1.0 mL (270 µg) of Cecolin 9 or placebo with a 0-1-6-month schedule. The primary endpoint was the seroconversion rate and geometric mean titer of neutralizing antibodies (nAbs) one month after the full vaccination course (month 7). The secondary endpoint was the safety profile including solicited adverse reactions occurring within 7 d, adverse events (AEs) occurring within 30 d after each dose, and serious adverse events (SAEs) occurring during the 7-month follow-up period. In total, 627 volunteers were enrolled and randomly assigned to Cecolin 9 (n = 313) or placebo (n = 314) group in Jiangsu Province, China. Almost all participants in the per-protocol set for immunogenicity (PPS-I) seroconverted for nAbs against all the nine HPV types at month 7, while two failed to seroconvert for HPV 11 and one did not seroconvert for HPV 52. The incidence rates of total AEs in the Cecolin 9 and placebo groups were 80.8% and 72.9%, respectively, with the majority of them being mild and recovering shortly. None of the SAEs were considered related to vaccination. In conclusion, the E. coli-produced 9-valent HPV (9vHPV) vaccine candidate was well tolerated and immunogenic, which warrants further efficacy studies in larger populations.

A novel influenza A (H1N1) vaccine in various age groups.

BACKGROUND: There is an urgent need for a vaccine that is effective against the 2009 pandemic influenza A (H1N1) virus. METHODS: A split-virus, inactivated candidate vaccine against the 2009 H1N1 virus was manufactured, and we evaluated its safety and immunogenicity in a randomized clinical trial. Subjects were between 3 and 77 years of age, stratified into four age groups. The immunization schedule consisted of two vaccinations, 21 days apart. Subjects were injected with placebo or with vaccine, with or without alum adjuvant, at doses of 7.5 microg, 15 microg, or 30 microg. Serologic analysis was performed at baseline and on days 21 and 35. RESULTS: A total of 2200 subjects received one dose, and 2103 (95.6%) received the second dose, of vaccine or placebo. No severe adverse side effects associated with the vaccine were noted. In the nonadjuvanted-vaccine groups, injection-site or systemic reactions, most mild in nature, were noted in 5.5 to 15.9% of subjects. Among the subjects receiving 15 microg of nonadjuvanted vaccine, a hemagglutination-inhibition titer of 1:40 or more was achieved by day 21 in 74.5% of subjects between 3 and 11 years of age, 97.1% of subjects between 12 and 17 years, 97.1% of subjects between 18 and 60 years, and 79.1% of subjects 61 years of age or older; by day 35, the titer had been achieved in 98.1%, 100%, 97.1%, and 93.3% of subjects, respectively. The proportion with a titer of 1:40 or more was generally highest among the subjects receiving 30 microg of vaccine, with or without adjuvant. Vaccine without adjuvant was associated with fewer local reactions and greater immune responses than was vaccine with adjuvant. CONCLUSIONS: These data suggest that a single dose of 15 microg of hemagglutinin antigen without alum adjuvant induces a typically protective immune response in the majority of subjects between 12 and 60 years of age. Lesser immune responses were seen after a single dose of vaccine in younger and older subjects. (ClinicalTrials.gov number, NCT00975572).

Evaluation of a recombinant five-antigen Staphylococcus aureus vaccine: The randomized, single-centre phase 1a/1b clinical trials.

BACKGROUND: Staphylococcus aureus is an important pathogen that causes hospital and community infections. To control Staphylococcus aureus infection and reduce the usage of antibiotics, we evaluated the safety and immunogenicity of a recombinant five-antigen Staphylococcus aureus vaccine (rFSAV) in healthy adults. METHODS: We conducted a randomized, double-blind, placebo-controlled phase 1a study and a randomized, open-label phase 1b study. In phase 1a, we randomly allocated 144 healthy participants in a ratio of 1:1:1:1 to receive the low-(60 µg), middle-(120 µg), and high-dose (240 µg) vaccine or placebo at day 0, 3, 7 and 14. In phase 1b, 144 healthy participants were randomly allocated at a ratio of 1:1:1:1 to receive 0-3-7, 0/0-7, 0/0-3-7, 0/0-7-14 regimens to estimate the optimal strategy. The primary study endpoint was the incidence of solicited adverse events post-vaccination. The immunogenicity endpoints included the level of specific antibodies to five antigens after vaccination, as well as the cellular immune responses and functional antibodies. RESULTS: There were 31 (86%), 30 (83%), and 32 (89%) of 36 participants in the low-, middle-, and high-dose group reported solicited adverse events, respectively, most of the adverse events were mild or moderate. In phase 1b, the dose-adjusted rFSAV (90 µg) showed a better safety profile in the four immune procedures, and no vaccine-related serious adverse events were reported. The antigen-specific binding antibodies started to increase at day 7 and reached the peak around day 14 to 21. The cellular immune responses and functional antibodies also were substantially above background levels. CONCLUSIONS: rFSAV is safe, well tolerated in healthy adults, elicits rapid and robust specific humoral and cellular immune responses with unconventional immunization procedure in phase 1a and 1b. It deserves to be noted and further explored. CLINICAL TRIALS REGISTRATION: NCT02804711 and NCT03966040.

Efficacy, safety, and immunogenicity of an Escherichia coli-produced Human Papillomavirus (16 and 18) L1 virus-like-particle vaccine: end-of-study analysis of a phase 3, double-blind, randomised, controlled trial.

BACKGROUND: This Escherichia coli-produced bivalent HPV 16 and 18 vaccine was well tolerated and effective against HPV 16 and 18 associated high-grade genital lesions and persistent infection in interim analysis of this phase 3 trial. We now report data on long-term efficacy and safety after 66 months of follow-up. METHODS: This phase 3, double-blind, randomised, controlled trial was done in five study sites in China. Eligible participants were women aged 18-45 years, with intact cervix and 1-4 lifetime sexual partners. Women who were pregnant or breastfeeding, had chronic disease or immunodeficiency, or had HPV vaccination history were excluded. Women were stratified by age (18-26 and 27-45 years) and randomly (1:1) allocated by software (block randomisation with 12 codes to a block) to receive three doses of the E coli-produced HPV 16 and 18 vaccine or hepatitis E vaccine (control) and followed-up for 66 months. The primary outcomes were high-grade genital lesions and persistent infection (longer than 6 months) associated with HPV 16 or 18 in the per-protocol susceptible population. This trial was registered with ClinicalTrials.gov, NCT01735006. FINDINGS: Between Nov 22, 2012, and April 1, 2013, 8827 women were assessed for eligibility. 1455 women were excluded, and 7372 women were enrolled and randomly assigned to receive the HPV vaccine (n=3689) or control (n=3683). Vaccine efficacy was 100·0% (95% CI 67·2-100·0) against high-grade genital lesions (0 [0%] of 3310 participants in the vaccine group and 13 [0·4%] of 3302 participants in the control group) and 97·3% (89·9-99·7) against persistent infection (2 [0·1%] of 3262 participants in the vaccine group and 73 [2·2%] of 3271 participants in the control group) in the per-protocol population. Serious adverse events occurred at a similar rate between vaccine (267 [7·2%] of 3691 participants) and control groups (290 [7·9%] of 3681); none were considered related to vaccination. INTERPRETATION: The E coli-produced HPV 16 and 18 vaccine was well tolerated and highly efficacious against HPV 16 and 18 associated high-grade genital lesions and persistent infection and would supplement the global HPV vaccine availability and accessibility for cervical cancer prevention. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Fujian Provincial Project, Fundamental Funds for the Central Universities, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Xiamen Innovax.

Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial.

BACKGROUND: Seroprevalence data suggest that a third of the world's population has been infected with the hepatitis E virus. Our aim was to assess efficacy and safety of a recombinant hepatitis E vaccine, HEV 239 (Hecolin; Xiamen Innovax Biotech, Xiamen, China) in a randomised, double-blind, placebo-controlled, phase 3 trial. METHODS: Healthy adults aged 16-65 years in, Jiangsu Province, China were randomly assigned in a 1:1 ratio to receive three doses of HEV 239 (30 microg of purified recombinant hepatitis E antigen adsorbed to 0.8 mg aluminium hydroxide suspended in 0.5 mL buffered saline) or placebo (hepatitis B vaccine) given intramuscularly at 0, 1, and 6 months. Randomisation was done by computer-generated permuted blocks and stratified by age and sex. Participants were followed up for 19 months. The primary endpoint was prevention of hepatitis E during 12 months from the 31st day after the third dose. Analysis was based on participants who received all three doses per protocol. Study participants, care givers, and investigators were all masked to group and vaccine assignments. This trial is registered with ClinicalTrials.gov, number NCT01014845. FINDINGS: 11,165 of the trial participants were tested for hepatitis E virus IgG, of which 5285 (47%) were seropositive for hepatitis E virus. Participants were randomly assigned to vaccine (n=56,302) or placebo (n=56,302). 48,693 (86%) participants in the vaccine group and 48,663 participants (86%) in the placebo group received three vaccine doses and were included in the primary efficacy analysis. During the 12 months after 30 days from receipt of the third dose 15 per-protocol participants in the placebo group developed hepatitis E compared with none in the vaccine group. Vaccine efficacy after three doses was 100.0% (95% CI 72.1-100.0). Adverse effects attributable to the vaccine were few and mild. No vaccination-related serious adverse event was noted. INTERPRETATION: HEV 239 is well tolerated and effective in the prevention of hepatitis E in the general population in China, including both men and women age 16-65 years. FUNDING: Chinese National High-tech R&D Programme (863 programme), Chinese National Key Technologies R&D Programme, Chinese National Science Fund for Distinguished Young Scholars, Fujian Provincial Department of Sciences and Technology, Xiamen Science and Technology Bureau, and Fujian Provincial Science Fund for Distinguished Young Scholars.

Safety and immunogenicity of meningococcal (Groups A and C) polysaccharide vaccine in children 2 to 6 y of age in China: a randomized, active-controlled, non-inferiority study.

Meningococcal serogroups A and C cause significant numbers of cases in China. The Sanofi Pasteur meningococcal polysaccharide A + C vaccine (Men-AC) was licensed in China in 1995. Immunogenicity and safety of a single dose of Men-AC against a similar marketed vaccine, the Lanzhou Institute serogroups A and C vaccine (Lanzhou-AC), were evaluated in children 2 to 6 y of age. Antibody titers were determined before and on Day 30 after vaccination using a serum bactericidal assay using baby rabbit complement (SBA-BR). Immunogenicity endpoints included rates of seroconversion (postvaccination antibody titers ≥4-fold higher) and seroprotection (postvaccination titers ≥1:8). Unsolicited systemic adverse events (AEs) within 30 minutes after vaccination, solicited injection site and systemic reactions between Days 0 and 7, unsolicited non-serious AEs within 30 d, and serious adverse events (SAEs) throughout were recorded. Seroconversion rates against serogroups A and C were 97.0% (95% confidence interval [CI], 94.5-98.6) and 94.7% (95% CI, 91.6-97.0), respectively, in the Men-AC group and 97.7% (95% CI, 95.4-99.1) and 94.8% (95% CI, 91.7-97.0), respectively, in the Lanzhou-AC group, while seroprotection rates were 98.0% (95% CI, 95.8-99.3) and 97.0% (95% CI, 94.5-98.6), respectively, in the Men-AC group and 99.0% (95% CI, 97.2-99.8) and 96.8% (95% CI, 94.1-98.4), respectively, in the Lanzhou-AC group. Non-inferiority of Men-AC with regard to immunogenicity was demonstrated since the lower bounds of the 95% CIs of the differences in rates between the two groups were > -5% for both serogroups. Both vaccines were well tolerated.

Quadrivalent influenza vaccine (Sinovac Biotech) for seasonal influenza prophylaxis.

INTRODUCTION: Quadrivalent Influenza Vaccine (Sinovac Biotech) is a quadrivalent split-virion-inactivated influenza vaccine approved in China in June 2020 for individuals ≥3 years of age. It contains 15 µg hemagglutinin per strain including A/H1N1, A/H3N2, B/Victoria, and B/Yamagata, which could potentially improve protection against influenza B viruses. AREAS COVERED: In this review, we summarize the development of quadrivalent influenza vaccines in China and foreign countries, and assess the immunogenicity and safety from the phase I and III clinical trials of Quadrivalent Influenza Vaccine in individuals ≥3 years of age. We also discuss the potential application of Quadrivalent Influenza Vaccine in young children 6-35 months of age according to the results of the phase III trial. EXPERT COMMENTARY: The immunogenicity and safety profiles of Quadrivalent Influenza Vaccine containing two A and two B strains were comparable to the trivalent vaccines for the shared strains. The addition of a second B strain to the trivalent vaccine could induce superior immune responses for the alternate B strain. Since the two B strains co-circulated worldwide, the introduction of quadrivalent influenza vaccines has been expected to be a cost-effective strategy.

TGF-ß1-regulated miR-3691-3p targets E2F3 and PRDM1 to inhibit prostate cancer progression.

Transforming growth factor-ß1 (TGF-ß1) acts as a tumor promoter in advanced prostate cancer (PCa). We speculated that microRNAs (miRNAs) that are inhibited by TGF-ß1 might exert anti-tumor effects. To assess this, we identified several miRNAs downregulated by TGF-ß1 in PCa cell lines and selected miR-3691-3p for detailed analysis as a candidate anti-oncogene miRNA. miR-3691-3p was expressed at significantly lower levels in human PCa tissue compared with paired benign prostatic hyperplasia tissue, and its expression level correlated inversely with aggressive clinical pathological features. Overexpression of miR-3691-3p in PCa cell lines inhibited proliferation, migration, and invasion, and promoted apoptosis. The miR-3691-3p target genes E2F transcription factor 3 (E2F3) and PR domain containing 1, with ZNF domain (PRDM1) were upregulated in miR-3691-3p-overexpressing PCa cells, and silencing of E2F3 or PRDM1 suppressed PCa cell proliferation, migration, and invasion. Treatment of mice bearing PCa xenografts with a miR-3691-3p agomir inhibited tumor growth and promoted tumor cell apoptosis. Consistent with the negative regulation of E2F3 and PRDM1 by miR-3691-3p, both proteins were overexpressed in clinical PCa specimens compared with noncancerous prostate tissue. Our results indicate that TGF-ß1-regulated miR-3691-3p acts as an anti-oncogene in PCa by downregulating E2F3 and PRDM1. These results provide novel insights into the mechanisms by which TGF-ß1 contributes to the progression of PCa.

Inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.

Concerns about vaccine safety are an important reason for vaccine hesitancy, however, limited information is available on whether common adverse reactions following vaccination affect the immune response. Data from three clinical trials of recombinant vaccines were used in this post hoc analysis to assess the correlation between inflammation-related solicited adverse reactions (ISARs, including local pain, redness, swelling or induration and systematic fever) and immune responses after vaccination. In the phase III trial of the bivalent HPV-16/18 vaccine (Cecolin®), the geometric mean concentrations (GMCs) for IgG anti-HPV-16 and -18 (P<0.001) were significantly higher in participants with any ISAR following vaccination than in those without an ISAR. Local pain, induration, swelling and systemic fever were significantly correlated with higher GMCs for IgG anti-HPV-16 and/or anti-HPV-18, respectively. Furthermore, the analyses of the immunogenicity bridging study of Cecolin® and the phase III trial of a hepatitis E vaccine yielded similar results. Based on these results, we built a scoring model to quantify the inflammation reactions and found that the high score of ISAR indicates the strong vaccine-induced antibody level. In conclusion, this study suggests inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.

Immunogenicity of an Escherichia coli-produced bivalent human papillomavirus vaccine under different vaccination intervals.

A new Escherichia coli-produced human papillomavirus (HPV)-16/18 vaccine has been shown to be safe and highly efficacious and was recently licensed in China. As a post hoc analysis of the phase III trial, this study aimed to assess the impact of vaccination time deviations on the specific antibody response and guide the better usage of this vaccine in the real world. A total of 3689 healthy women aged 18-45 years old were randomly assigned to receive the bivalent HPV-16/18 vaccine according to a 0-, 1- and 6-month schedule with a wide vaccination interval. The first vaccination interval between the 1st and 2nd doses (the 1st interval) was divided into three groups: 28-40 d, 41-50 d and 51-60 d. The second vaccination interval between the 2nd and 3rd doses (the 2nd interval) was divided into three groups: 103-139 d, 140-160 d and 161-198 d. The reverse cumulative curves for the IgG of the three groups with different 1st vaccination intervals or with different 2nd vaccination intervals at month 7 almost overlapped for both HPV-16 and HPV-18. Compared with the standard vaccination schedule (a 1st interval of 28-40 d and a 2nd interval of 140-160 d) subgroup, all the subgroups had GMC ratios greater than 0.83, with the lower limit of 95% CIs higher than 0.64. In conclusion, a slight deviation in the vaccination time of the 2nd and 3rd doses has only a minor, insignificant impact on the immune response induced by the Escherichia coli-produced HPV-16/18 vaccine.

Lot-to-lot consistency study of an Escherichia coli-produced bivalent human papillomavirus vaccine in adult women: a randomized trial.

An Escherichia. coli-produced HPV-16/18 bivalent vaccine has been proved to be well-tolerated and highly efficacious against diseases associated with vaccine HPV types. As a part of the multi-center, randomized, double-blind phase III clinical trial, this lot-to-lot consistency study aimed to assess the safety and immunogenicity consistency of this novel HPV vaccine, which is also one of the objectives of the phase III trial. A total of 3689 healthy women aged 18-45 years were enrolled and randomly assigned 1:1:1 to three lots of the HPV vaccine groups. The primary outcomes were the IgG antibody level at 1 month after the last dose (month 7). In the immunogenicity per-protocol set (PPS), almost all of the participants seroconverted at month 7 and remained seropositive at month 42. For each paired comparison of the three lot groups, the two-sides of 90% CIs of GMC ratios for both IgG and neutralizing antibodies for HPV-16 and HPV-18 at month 7 were within the equivalence interval [0.5, 2]. Lot consistency was also demonstrated at month 42. The majority of recorded solicited reactions were mild or moderate. The incidences of solicited reactions of Lot 2 and Lot 3 were slightly higher than Lot 1. However, the incidences of solicited reactions of ≥ grade 3 and solicited reactions by symptoms were all similar among the three lot groups. None of the SAEs was considered related to vaccination by the investigator. In conclusion, this study demonstrates lot-to-lot consistency of the 3 consecutive lots of the E. coli-produced HPV-16/18 bivalent vaccine.